A Randomized, Head-to-head, Single-blind Study to Compare the Response to Treatment With Subcutaneous Abatacept vs Adalimumab, on Background Methotrexate, in Adults With Early, Seropositive Rheumatoid Arthritis Who Have "Shared Epitope" HLA Class II Risk Alleles and Have an Inadequate Response to Methotrexate
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Randomized, Head-to-head, Single-blind Study to Compare the Response to Treatment With 
Subcutaneous Abatacept vs Adalimumab, on Background Methotrexate, in Adults With Early, 
Seropositive Rheumatoid Arthritis Who Have "Shared Epitope" HLA Class II Risk Alleles and Have an 
Inadequate Response to Methotrexate 
 
 
NCT Number: NCT04909801 
  
 
Document Date (Date in which document was last revised): February 26, 2021 

Page:
1
Protocol Number:
IM101863
Date:
29-Jan-2021
Revised Date:
26-Feb-2021
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: BB-IND-9391
EudraCT: 2020-000350-96
CLINICAL PROTOCOL IM101863
A Randomized, Head-to-head, Single-blind Study to Compare the Response to Treatment with 
Subcutaneous Abatacept vs Adalimumab, on Background Methotrexate, in Adults with Early, 
Seropositive Rheumatoid Arthritis Who Have "Shared Epitope" HLA Class II Risk Alleles and 
Have an Inadequate Response to Methotrexate
Short Title: Abatacept vs Adalimumab in Early, Seropositive, and SE-positive RA
Protocol Amendment Number: 01
Medical Monitor
3401 Princeton Pike
Lawrenceville NJ, USA
Telephone (office): 
86 Morris Avenue
Summit, NJ 07901
Telephone: 
24-hr Emergency Telephone Number
USA: 
International: 
Japan: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1327, Japan
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Clinical Protocol
IM101863
BMS-188667
abatacept
Protocol Amendment No.: 01
Date: 26-Feb-2021
2
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 
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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Clinical Protocol
IM101863
BMS-188667
abatacept
Protocol Amendment No.: 01
Date: 26-Feb-2021
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 01
26-Feb-2021
Removed pharmacokinetics and immunogenicity 
assessments, removed Krebs von den Lungen-6 testing, and 
clarified country-specific requirements.
Original Protocol
29-Jan-2021
Not applicable
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IM101863
BMS-188667
abatacept
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01:
The primary reasons for these changes are to remove pharmacokinetics (PK) and 
immunogenicity (IMG) assessments, remove Krebs von den Lungen-6 (KL-6) testing, and clarify 
country-specific requirements.
This protocol amendment applies to all participants.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & Title
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities; Section 7.1: 
Treatments Administered; 
Section 9.5: Pharmacokinetics 
and Immunogenicity (and all 
subsections); Section 9.8.3: 
Additional Research Collection; 
Section 10.2: Populations for 
Analyses; Section 10.3.2: Safety 
Analyses; Section 10.3.3.1: PK 
Analyses
Removed all language related to
PK and IMG assessments.
Given that the PK and IMG of abatacept 
have been studied extensively in this 
rheumatoid arthritis (RA) population (ie, 
methotrexate-inadequate responders) in 
addition to the broader RA population, 
PK and IMG assessments can be omitted 
from the study.
Section 2: Schedule of 
Activities; Section 9.4.7: 
Clinical Safety Laboratory 
Assessments
The following updates were 
made:
Removed KL-6 testing.
Removed (1 to 3) β-D glucan 
testing.
These changes were made for the 
following reasons:
KL-6 testing is no longer applicable.
Country-specific (1 to 3) β-D glucan 
testing is now included in Appendix 16.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & Title
Description of Change
Brief Rationale
Appendix 16: Country-specific 
Requirements/Differences
The following updates were 
made:
Removed country-specific 
differences related to human 
immunodeficiency virus and 
hepatitis.
Removed Norway from list of 
countries.
For Japan:
‒ Updated differences for 
(1 to 3) β-D glucan testing.
‒ Added differences related to 
hepatitis B testing.
‒ Added differences related to 
self-administration training.
‒ Removed differences for 
contraceptive guidance.
Clarified country-specific 
requirements/differences.
All
Minor formatting and 
typographical corrections.
Changes are minor, and therefore have 
not been summarized.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: ............................ 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 ................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.2 Background ....................................................................................................... 
3.2.1 Abatacept Mechanism of Action .............................................................. 
3.2.2 Efficacy .................................................................................................... 
3.2.3 Safety ........................................................................................................ 
3.2.4 Abatacept and COVID-19 ........................................................................ 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Screening Period ...................................................................................... 
5.1.2 Treatment Period ..................................................................................... 
5.1.2.1 Single-blind Treatment Period: Day 1 - Week 24 ........................... 
5.1.2.2 Open-label Treatment Period: Week 24 - Week 104 ...................... 
5.1.3 Post-treatment Follow-up Period ............................................................ 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
5.1.4.1 Data Monitoring Committee ........................................................... 
5.1.4.2 Study Steering Committee ............................................................... 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Population Profile ............................................................. 
5.4.2 Rationale for Choice of Endpoints ........................................................... 
5.4.3 Rationale for Timing of Endpoints ........................................................... 
5.4.4 Rationale for Choice of Comparator Arm ............................................... 
5.4.5 Rationale for Switching............................................................................ 
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 or Lead-in Period ....................................... 
6.4.1.1 Retesting .......................................................................................... 
6.4.1.2 Extended Screening ......................................................................... 
6.4.1.3 Rescreening ..................................................................................... 
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7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Abatacept Treatment ................................................................................ 
7.1.1.1 Abatacept Self-administration of Subcutaneous Injection .............. 
7.1.1.2 Abatacept Administration Window ................................................. 
7.1.2 Adalimumab Treatment ............................................................................ 
7.1.2.1 Adalimumab Self-administration of Subcutaneous Injection .......... 
7.1.2.2 Adalimumab Administration Window ............................................. 
7.1.3 Guidelines for Methotrexate .................................................................... 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Modifications for Abatacept ........................................................... 
7.4.1.1 Dose Modifications for Abatacept in the Absence of Adverse Events
............................................................................................................... 
7.4.1.2 Dose Modifications for Abatacept Due to Adverse Events ............. 
7.4.2 Dose Modifications for Adalimumab ....................................................... 
7.4.2.1 Dose Modifications for Adalimumab in the Absence of Adverse 
Events .................................................................................................... 
7.4.2.2 Dose Modifications for Adalimumab Due to Adverse Events ......... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability/Bioequivalence/Biocomparability 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.1.1 Prohibited Treatment During the Treatment Period ...................... 
7.7.1.2 Restricted Treatments During the Treatment Period ...................... 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Immunizations ................................................................................. 
7.7.2.2 Infectious Complications ................................................................ 
7.7.2.3 Management of Possible Acute Hypersensitivity Reactions ........... 
7.8 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 Physician’s Global Assessment................................................................ 
9.1.2 Joint Count Assessments .......................................................................... 
9.1.3 Patient-reported Outcomes ...................................................................... 
9.1.3.1 36-item Short Form Survey ............................................................. 
9.1.3.2 Work Productivity and Activity ....................................................... 
9.1.3.3 Fatigue ............................................................................................ 
9.1.3.4 Morning Stiffness ............................................................................ 
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9.1.4 Imaging Assessment for the Study ........................................................... 
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 ..................................................... 
9.2.7 Potential Drug-induced Liver Injury (DILI) ............................................ 
9.2.8 COVID-19-related AEs/SAEs .................................................................. 
9.2.9 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examination .............................................................................. 
9.4.2 Chest X-ray .............................................................................................. 
9.4.3 Physical Measurements ........................................................................... 
9.4.4 Vital Signs ................................................................................................ 
9.4.5 TB Screening ............................................................................................ 
9.4.6 Viral Hepatitis Screening and Monitoring .............................................. 
9.4.7 Clinical Safety Laboratory Assessments .................................................. 
9.4.8 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics and Immunogenicity ............................................................ 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.8.1 HLA-DRB1 Shared Epitope Alleles ......................................................... 
 
9.8.2.1 Autoantibodies ................................................................................ 
 
 
 
 
9.8.3 Additional Research Collection ............................................................... 
9.8.4 Other Assessments ................................................................................... 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
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....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.3.2 Patient-reported Outcomes Analyses ............................................ 
10.3.4 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
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12 APPENDICES ......................................................................................................... 
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 AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF DISEASE ACTIVITY VISUAL ASSESSMENT SCALE .... 
APPENDIX 6 AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF PAIN VISUAL ASSESSMENT SCALE ............................... 
APPENDIX 7 AMERICAN COLLEGE OF RHEUMATOLOGY PHYSICIAN 
GLOBAL ASSESSMENT OF DISEASE ACTIVITY VISUAL ASSESSMENT 
SCALE .................................................................................................................... 
APPENDIX 8 AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF PHYSICAL FUNCTION SCALE: HEALTH ASSESSMENT 
QUESTIONNAIRE (HAQ) .................................................................................... 
APPENDIX 9 SF-36 V2.0 ............................................................................................ 
APPENDIX 10 WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE-RHEUMATOID ARTHRITIS, V2.0 (WPAI-RA) ................ 
APPENDIX 11 FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS 
THERAPY (FACIT) - FATIGUE .......................................................................... 
APPENDIX 12 MORNING STIFFNESS DURATION .............................................. 
APPENDIX 13 2010 ACR-EULAR CLASSIFICATION CRITERIA FOR 
RHEUMATOID ARTHRITIS ................................................................................ 
APPENDIX 14 RA DISEASE ACTIVITY DEFINITIONS ........................................ 
APPENDIX 15 JOINT COUNT ASSESSMENT COMPONENTS FOR DAS28 
(RIGHT AND LEFT SIDE) .................................................................................... 
APPENDIX 16 COUNTRY-SPECIFIC REQUIREMENTS/DIFFERENCES............ 
APPENDIX 17 LABORATORY GUIDELINES: PATIENT STUDIES (REVISED 
AUGUST 13, 1999) ................................................................................................ 
 
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930165131
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Clinical Protocol
IM101863
BMS-188667
abatacept
1
SYNOPSIS
Protocol Title: A Randomized, Head-to-head, Single-blind Study to Compare the Response to 
Treatment with Subcutaneous Abatacept vs Adalimumab, on Background Methotrexate, in Adults 
with Early, Seropositive Rheumatoid Arthritis Who Have "Shared Epitope" HLA Class II Risk 
Alleles and Have an Inadequate Response to Methotrexate
Short Title: Abatacept vs Adalimumab in Early, Seropositive, and SE-positive RA
Study Phase: 3
Rationale:
Available data sources describing the use of abatacept for the treatment of rheumatoid 
arthritis (RA) show that a subset of RA patients have characteristics that may predict a better 
response to abatacept than to treatment with tumor necrosis factor (TNF) inhibitor. These 
characteristics are: 1) early disease duration; 2) high titers of anti-citrullinated protein 
antibodies (ACPA) and rheumatoid factor (RF; dual seropositivity); 3) inadequate response to 
initial treatment with methotrexate (MTX; methotrexate inadequate responders [MTX-IR]); and 
4) presence of the “shared epitope” (SE). Together, these characteristics appear to comprise a 
predictive response profile for enhanced clinical response with abatacept therapy. This study will 
test whether this predictive response profile will lead to better clinical outcomes for treatment with 
abatacept in this patient population compared with treatment with adalimumab.
Analyses of several prior Bristol-Myers Squibb (BMS) randomized, controlled trials (RCTs) of 
abatacept for the treatment of RA and external real-world clinical data suggested that RA patients 
early in their disease course who had high titers of ACPA demonstrated higher, differential benefit 
from abatacept therapy. In the Abatacept vs adaliMumab comParison in bioLogic-naivE RA 
participants with background methotrexate (AMPLE) study (IM101235; ClinicalTrials.gov: 
NCT00929864), baseline anti-cyclic citrullinated peptide (anti-CCP-2) positivity was associated 
with a better response to both abatacept and adalimumab; however, participants with the highest 
anti-CCP-2 antibody concentrations (1060-4894 IU/mL) had better clinical response with 
abatacept but not with adalimumab. Similarly, in the Assessing Very Early Rheumatoid Arthritis 
Treatment (AVERT; IM101226; ClinicalTrials.gov: NCT01142726) study, a higher proportion of 
anti-CCP-2-positive (anti-CCP-2+) vs anti-CCP-2-negative (anti-CCP-2-) participants achieved 
remission after 1 year of treatment with abatacept with background MTX. In a United 
States (US)-based clinical practice setting, greater efficacy was seen with abatacept, but not TNF 
inhibitors, in anti-CCP-2+ vs anti-CCP-2- patients with RA. In a meta-analysis of 19 studies, 
anti-CCP-2 positivity was associated with better European League Against Rheumatism (EULAR)
responses in patients with RA receiving abatacept but not in those receiving a TNF inhibitor.
To further explore this early seropositive population and identify any novel characteristics that 
could confirm or further refine an RA subpopulation with differential benefit from treatment with 
abatacept over adalimumab, BMS
executed the IM101567 study (Early AMPLE; 
ClinicalTrials.gov: NCT02557100). This was a mechanistic, head-to-head study between 
abatacept and adalimumab, designed to study a population of RA participants enriched for 
Protocol Amendment No.: 01
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IM101863
BMS-188667
abatacept
abatacept differential responders. These adult RA participants
were characterized by: 
a) 12 months of disease symptoms; b) seropositivity for both RF and ACPA (3upper limit of 
normal [ULN]);
and c) moderate-to-severe RA (American College of Rheumatology 
[ACR]/EULAR 2010 criteria, and Disease Activity Score 28-joint count calculated using 
C-reactive protein [DAS28-CRP] ≥ 3.2) in spite of at least 3 months of therapy with 
methotrexate (MTX-IR). Eighty participants were randomized 1:1 to subcutaneous (SC) abatacept 
125 mg weekly or SC adalimumab 40 mg every 2 weeks (both with stable, background oral MTX 
weekly) for 24 weeks. Higher ACR responses were seen with abatacept vs adalimumab after 
24 weeks of treatment, supporting prior findings that early seropositive RA patients should 
respond better to abatacept (see Figure 1-1). To further refine the abatacept-response group, BMS
prospectively explored the relationship between clinical efficacy to abatacept or adalimumab and 
the presence of a genetic marker known as the SE. The SE is encoded by a group of human
leukocyte antigen Class II histocompatibility antigen, DRB2 beta chain (HLA-DRB1) alleles with 
shared homology in the beta chain (HLA-DRB1) at positions 70-74. The SE is a genetic marker 
of risk associated with earlier-onset, ACPA-positive (ACPA+), destructive RA and is present in 
70-80% of ACPA+ RA patients. Seventy-five percent of Early AMPLE randomized participants
were SE-positive (SE+) and showed even higher differential ACR response to abatacept compared 
with adalimumab (see Figure 1-2), suggesting that the differential benefit to therapy with abatacept 
in this population is driven by the SE+ participant subgroup. The current study, IM101863, aims 
to confirm the findings from Early AMPLE and other studies by demonstrating the superiority in 
efficacy of abatacept compared with adalimumab in a population of RA patients characterized by 
early disease, MTX-IR, and seropositivity (RF-positive [RF+] and ACPA+) and expressing SE 
HLA Class II risk alleles (ie, SE+). 
Figure 1-1:
Proportion of Patients with ACR Responses Over Time During the 
Single-blind Treatment Period (as-treated analysis IM101567)
Abbreviations: ABA, abatacept; ACR, American College of Rheumatology; ACR20/50/70, 20%/50%/70% 
improvement in American College of Rheumatology criteria; ADA, adalimumab; CI, confidence interval.
Note: Missing values were imputed as nonresponders. Error bars represent 95% CI. 
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IM101863
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abatacept
Figure 1-2:
Proportion of SE+ Patients with (A) ACR Responses Over Time and 
(B) Week 24 ACR Responses and DAS28-CRP Remission by 
Treatment Group (as-treated analysis IM101567)
Abbreviations: ABA, abatacept; ACR20/50/70, 20%/50%/70% improvement in American College of Rheumatology 
criteria; ADA, adalimumab; CI, confidence interval; DAS28-CRP, Disease Activity Score 28 joint count calculated 
using C-reactive protein; SE, shared epitope.
Note: ABA, n = 30; ADA, n = 31. DAS28-CRP remission was defined as DAS28-CRP < 2.6. Patients with missing 
data for efficacy parameters at Week 24 were imputed as nonresponders. Values above bars show estimate of 
difference (95% CI) for ABA vs ADA. 
Study Population:
Adults (18 years old) who have early RA, defined as symptoms of RA (pain, stiffness, or joint 
swelling) for no more than 12 months prior to screening and satisfy the ACR/EULAR 2010 criteria 
for the classification of RA at some point during the 12-month period prior to signing the informed 
consent form (ICF). Participants who have had a single isolated episode of palindromic symptoms 
that occurred less than 2 years prior to enrollment are still eligible. Participants must have a 
second-generation anti-CCP-2 test result that is greater than 3ULN and be RF+ at screening 
according to central laboratory testing. The anti-CCP-2 test is commonly used in the clinic to 
measure ACPA, and the 3ULN cutoff in the anti-CCP-2 central laboratory test ensures a stable 
positive ACPA profile. Participants must have a DAS28-CRP of at least 3.2 at screening and have 
at least 3 tender and at least 3 swollen joints (excluding distal interphalangeals) at screening and 
at randomization.
 
 
Eligible participants must have been treated with MTX for at least 12 weeks prior to randomization 
with a stable dose of oral or parenteral MTX
for at least 4 weeks prior to 
randomization (ie, MTX-IR). The stable dose of oral or parenteral MTX should be the maximum 
tolerated oral or parenteral dose (15 mg to 25 mg per week). Participants may enroll with MTX 
doses < 15 mg/week but ≥7.5 mg/week if intolerance to higher doses has been documented and 
the dose of oral or parenteral MTX is stable for 4 weeks prior to randomization. Participants in 
Japan may also enroll at doses between 7.5 and 15 mg per week at the discretion of the investigator.
Participants must be naive to prior therapy with other disease-modifying antirheumatic 
drugs (DMARDs), except brief exposure to either sulfasalazine or hydroxychloroquine.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 1-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To demonstrate the superiority in efficacy of abatacept 
compared with adalimumab, both on background MTX, in 
achieving clinical response (ACR50) at Week 24, in early, 
seropositive (RF+ and ACPA+) RA patients with the SE
HLA Class II risk alleles (ie, SE+).
Proportion of SE+ participants meeting 
ACR50 response at Week 24
Key Secondary
To compare the efficacy of abatacept with adalimumab, both 
on background MTX, in achieving clinical remission criteria 
(DAS28-CRP remission) at Week 24 in early, seropositive 
RA patients with the SE HLA Class II risk alleles (ie, SE+).
Proportion of SE+ participants achieving 
DAS28-CRP remission (DAS28-CRP < 2.6) 
at Week 24
To compare the efficacy of abatacept with adalimumab, both 
on background MTX, in achieving clinical response 
(ACR50) at Week 24 in the whole study population of early, 
seropositive RA patients.
Proportion of whole study population 
participants meeting ACR50 response at 
Week 24
To compare the efficacy of abatacept with adalimumab, both 
on background MTX, in achieving clinical remission 
criteria (CDAI remission) at Week 24 in early, seropositive 
RA patients with the SE HLA Class II risk alleles (ie, SE+).
Proportion of SE+ participants achieving 
CDAI remission (CDAI 2.8) at Week 24
To compare the efficacy of abatacept with adalimumab, both 
on background MTX, in achieving improvement in pain at 
Week 24 in early, seropositive RA patients with the SE HLA 
Class II risk alleles (ie, SE+).
Mean change from baseline in SE+ 
participant-reported pain (VAS) at Week 24
Other Secondary
To determine the efficacy over time by treatment in early, 
seropositive RA patients (SE+ subset and whole 
population).
Proportion of SE+ subset and whole 
population
achieving 
ACR20/50/70 
responses, DAS remission, CDAI remission, 
SDAI remission over the SBTP and OLTP; 
Mean changes from baseline in DAS28-CRP, 
CDAI, SDAI over the SBTP and OLTP; 
Mean changes from baseline in the 7 ACR 
core components over the SBTP and OLTP
To determine the improvement in health-related quality of 
life over time by treatment in early, seropositive RA 
patients (SE+ subset and whole population).
Mean change from baseline in SF-36 in SE+ 
subset and whole population at Week 24 and 
Week 104 (4 physical and 4 mental subscales 
and the physical component and mental 
component summary)
Abbreviations: +, positive; ACPA, anti-citrullinated protein antibodies; ACR20/50/70, 20%/50%/70% improvement 
in American College of Rheumatology criteria; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease 
Activity Score 28-joint count calculated using C-reactive protein; MTX, methotrexate; OLTP, Open-label Treatment 
Period; RA, rheumatoid arthritis; RF, rheumatoid factor; SBTP, Single-blind Treatment Period; SDAI, Simple Disease 
Activity Index; SE, shared epitope; SF-36, 36-item Short Form Survey; VAS, visual analog scale.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
Overall Design:
See schematic below for study design (Figure 1-3).
Figure 1-3:
Study Design Schematic
Abbreviations: ACPA+,
anti-citrullinated protein antibody-positive; D,
Day; MTX,
methotrexate;
MTX-IR, methotrexate inadequate responders;
OLTP, Open-label Treatment Period; R, randomize; RA, rheumatoid arthritis; RF+, rheumatoid factor-positive; SBTP, Single-blind Treatment Period; 
SC, subcutaneous.
a In reference to Day 729 for participants who complete the OLTP or the day of last study treatment for participants who discontinue study treatment during the
SBTP or OLTP.
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IM101863
BMS-188667
abatacept
Screening Period:
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity, and safety assessments. Randomization must occur within 28 days of signing the ICF. 
Participants that experience delays may extend the screening period to 42 days.
Single-blind Treatment Period: Day 1 - Week 24:
On Day 1, participants will begin the Single-blind Treatment Period (SBTP) and be randomized 
according to a computer-generated fixed-block randomization schedule. The site must complete 
the Tender (68)/Swollen (66) Joint Count to verify the final inclusion criteria (at least 3 tender and 
at least 3 swollen joints, excluding distal interphalangeals) prior to contacting Interactive Response 
Technology (IRT) for randomization. The site must also have the results of the genotyping for the 
SE from the central lab prior to randomization because participants will be stratified by SE 
status (positive/negative). Participants will be randomized to 1 of 2 parallel treatment arms in a 
1:1 ratio:
1) Abatacept SC (125 mg) weekly with background stable MTX therapy
2) Adalimumab SC (40 mg) once every 2 weeks with background stable MTX therapy
Abatacept and adalimumab administration: On Day 1, participants and/or personal caregivers will 
be trained in self administration of SC injections using prefilled syringes.
Methotrexate: Participants must have been treated with MTX for at least 12 weeks prior to 
randomization with a stable dose of oral or parenteral MTX for at least 4 weeks prior to 
randomization. The stable dose of oral or parenteral MTX should be the maximum tolerated dose 
(minimum of 15 mg and maximum of 25 mg per week). A dose of MTX < 15 mg/week but 
7.5 mg/week is permitted if intolerance to higher doses has been recorded in the source 
documents and the dose of oral or parenteral MTX is stable for 4 weeks prior to randomization.
Participants in Japan may also enroll at doses between 7.5 and 15 mg per week at the discretion of 
the investigator.
Switching between routes of administration of MTX or dose adjustment for any reason other than 
toxicity is not permitted during the SBTP. 
All participants must receive folic acid, folinic acid, or leucovorin according to the manufacturer’s 
recommendations.
Open-label Treatment Period: Week 24 - Week 104:
At Week 24, all participants ongoing in the Open-label Treatment Period (OLTP) will receive 
abatacept 125 mg SC weekly for the duration of the treatment period:
1) Participants receiving abatacept SC (125 mg) weekly will continue to receive abatacept.
2) Participants receiving adalimumab SC (40 mg) will switch to abatacept SC (125 mg) weekly 
at Week 24.
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Clinical Protocol
IM101863
BMS-188667
abatacept
3) Participants will continue to be treated with oral or parenteral MTX as described above.
Adjustments in MTX dosing and route of administration is allowed at the investigator’s 
discretion in the OLTP.
4) Participants not wishing to continue on open-label abatacept have the option of discontinuing 
treatment at the end of the SBTP and continuing to the Post-treatment Follow-up 
Period (PTFUP).
Post-treatment Follow-up Period:
There will be a PTFUP for safety assessments. This period will be required only for some 
participants based on how they will be treated after study completion or Early Termination. 
Participants who complete the treatment periods (ie, OLTP) or discontinue prior to completing the 
OLTP AND are not treated with post-study abatacept, regardless of the source, will need to 
complete the PTFUP. This will consist of 2 follow-up visits on Day 85 and Day 169 post cessation 
of investigational product. The PTFUP will begin on Day 729 for participants who complete the 
OLTP. The PTFUP will begin on the day of last study treatment for participants who discontinue 
study treatment during the SBTP or OLTP. Participants who complete the OLTP or discontinue at 
any time prior to completing the OLTP AND are treated with post-study abatacept, regardless of 
the source, will not need to complete the PTFUP.
Number of Participants: 300
It is anticipated that approximately 400 participants will be screened to treat 300 eligible 
participants with abatacept (n = 150) or adalimumab (n = 150) with background stable MTX 
therapy. 
Treatment Arms and Duration:
The study treatments for IM101863 are provided in Table 1-2.
Table 1-2:
Study Treatment for IM101863
Medication 
Potency
IP/Non-IMP
Abatacept SC injection
125 mg/prefilled syringe (125 mg/mL)
IP
Adalimumab SC injection
40 mg/prefilled syringe (40 mg/0.4 mL)
IP
Abbreviations: IMP, investigational medicinal product; IP, investigational product.
Data Monitoring Committee: Not applicable.
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Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (IM101863)
Procedure
Screening
Visita
Extended 
Screening Visitb
Notes
Eligibility Assessments
Informed Consent
X
Enroll Participant
X
Contact IRT for participant number. If participant does not meet 
eligibility criteria, contact IRT to screen fail participant.
Inclusion/Exclusion Criteria
X
X
Medical History
X
X
Safety Assessments
Complete Physical Examination
X
Includes height and weight.
Targeted Physical Examination
X
See Section 9.4.1.
Vital Signs
X
X
Includes body temperature, and seated blood pressure and heart rate.
Prior and Concomitant Medication Use
X
X
Serious Adverse Events Assessment
X
X
Causality assessments must be performed by a blinded Clinical Assessor.
Smoking History and Current Status
X
TB Screening Test
X
See Section 9.4.5. TB testing (IFN-release assay or PPD) performed 
locally within 1 month prior to Screening will be accepted. A copy of the 
report must be filed in the participant binder. 
Chest X-ray
X
Required only if the results of a chest x-ray performed within the 
3 months prior to (re)enrollment are not available (see Section 9.4.2).
Laboratory Tests
Perform as noted 
below and any
safety laboratory 
tests deemed 
necessary.
Hematology (CBC)
X
X
See Table 9.4.7-1.
Blood Chemistry
X
X
See Table 9.4.7-1.
hsCRP
X
X
hsCRP falls under blood chemistry but will be tracked separately.
Urinalysis
X
See Table 9.4.7-1.
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-1:
Screening Procedural Outline (IM101863)
Procedure
Screening
Visita
Extended 
Screening Visitb
Notes
Hepatitis Screening
X
See Section 9.4.6 and Section 9.4.7 for details of testing for positive 
results and other guidance.
HIV
X
Performed only where required or local standard of care (see 
Section 9.4.7).
Urine Pregnancy Test
X
X
WOCBP only; serum test if needed (see Section 9.4.7). Performed 
locally.
FSH
X
As needed (see Section 9.4.7 and Appendix 4).
Anti-CCP-2
X
See Section 9.8.
RF
X
See Section 9.8.
HLA-DRB1 Shared Epitope Alleles 
Testing
X
Result required for randomization. See Section 9.8.
Disease Assessments
Tender (68)/Swollen (66) Joint Count
X
X
Must be performed by a blinded Clinical Assessor (see Section 9.1.2).
Participant Global Assessment of Disease 
Activity
X
X
See Appendix 5.
Abbreviations: anti-CCP-2, anti-cyclic citrullinated peptide-2; CBC, complete blood count; FSH, follicle-stimulating hormone; HIV, human immunodeficiency 
virus; HLA-DRB1, human leukocyte antigen Class II histocompatibility antigen, DRB1 beta chain; hsCRP, high-sensitivity C-reactive protein; IFN-γ, interferon 
gamma; IRT, Interactive Response Technology; PPD, purified protein derivative; RF, rheumatoid factor; TB, tuberculosis; WOCBP, women of childbearing 
potential.
a Randomization must occur within 28 days of signing the informed consent form. Participants who experience delays may extend the screening period to 
42 days (see Section 6.4.1.2). Rescreening is allowed (see Section 6.4.1.3).
b Please see Section 6.4.1.2 (Extended Screening) for further information.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-2:
On-treatment Procedural Outline (IM101863): Single-blind Treatment Period (SBTP)
Procedure
Day 1 
(Rand.)
Visit 1
Week 4
Visit 2
(± 3 days)
Week 8
Visit 3
(± 3 days)
Week 12
Visit 4
(± 3 days)
Week 16
Visit 5
(± 3 days)
Week 20
Visit 6
(± 3 days)
Week 24a/
ET
Visit 7a
(± 3 days)
Notes
Day 29
Day 57
Day 85
Day 113
Day 141
Day 169 or 
ET
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Review of inclusion/exclusion 
criteria that are relative to the 
Randomization day.
Tender (68)/Swollen (66) Joint 
Count
X
Must be performed by a blinded 
Clinical Assessor; to be 
performed prior to randomization
(see Section 9.1.2).
Randomize Participant Using IRT
X
Contact of IRT is required to 
randomize the participant on 
Day 1 (see Section 7.2).
Safety Assessments
Targeted Physical Examination
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Body temperature, seated blood 
pressure, and heart rate.
Adverse Events Assessment
X
X
X
X
X
X
X
Causality assessments must be 
performed by a blinded Clinical 
Assessor.
Concomitant Medication Use
X
X
X
X
X
X
X
Laboratory Tests
Urine Pregnancy Test 
X
X
X
X
X
X
X
WOCBP only; serum test if 
needed (see Section 9.4.7). 
Performed locally.
Hematology (CBC)
X
X
X
X
X
See Table 9.4.7-1.
Blood Chemistry
X
X
X
X
X
X
X
See Table 9.4.7-1.
hsCRP
X
X
X
X
X
X
X
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-2:
On-treatment Procedural Outline (IM101863): Single-blind Treatment Period (SBTP)
Procedure
Day 1 
(Rand.)
Visit 1
Week 4
Visit 2
(± 3 days)
Week 8
Visit 3
(± 3 days)
Week 12
Visit 4
(± 3 days)
Week 16
Visit 5
(± 3 days)
Week 20
Visit 6
(± 3 days)
Week 24a/
ET
Visit 7a
(± 3 days)
Notes
Day 29
Day 57
Day 85
Day 113
Day 141
Day 169 or 
ET
RF
X
X
X
See Section 9.8.
Anti-CCP-2
X
X
X
See Section 9.8.
Efficacy Assessments
Tender (68)/Swollen (66) Joint 
Count
X
X
X
X
X
X
Must be performed by a blinded 
Clinical Assessor (see 
Section 9.1.2).
Participant Assessment of Pain
X
X
X
X
X
X
X
See Appendix 6.
Participant Global Assessment of 
Disease Activity
X
X
X
X
X
X
X
See Appendix 5.
Physician Global Assessment of 
Disease Activity
X
X
X
X
X
X
X
Must be performed by a blinded 
Clinical Assessor (see
Section 9.1.1 and Appendix 7).
Physical Function (HAQ-DI)
X
X
X
X
X
X
X
See Appendix 8.
Quality of Life Scale (SF-36)
X
X
See Appendix 9.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-2:
On-treatment Procedural Outline (IM101863): Single-blind Treatment Period (SBTP)
Procedure
Day 1 
(Rand.)
Visit 1
Week 4
Visit 2
(± 3 days)
Week 8
Visit 3
(± 3 days)
Week 12
Visit 4
(± 3 days)
Week 16
Visit 5
(± 3 days)
Week 20
Visit 6
(± 3 days)
Week 24a/
ET
Visit 7a
(± 3 days)
Notes
Day 29
Day 57
Day 85
Day 113
Day 141
Day 169 or 
ET
Work Productivity and 
Activity (WPAI-RA v2)
X
X
See Appendix 10.
Fatigue (FACIT-F v4)
X
X
X
See Appendix 11.
Duration of Morning Stiffness
X
X
X
See Appendix 12.
Study Treatment
Contact IRT
X
X
X
X
X
X
Contact of IRT is required to 
dispense medication at each 
office visit.
Dispense Study Treatment
X
X
X
X
X
X
Self-injection and Diary Card 
Training
X
Dispense Diary Cards
X
X
X
X
X
X
Collect and Review Diary Cards
X
X
X
X
X
X
Dosing of Weekly 
Abatacept/Every-2-weeks 
Adalimumab
X
X
X
X
X
X
Must be self-administered weekly 
(abatacept) or every 2 weeks 
(adalimumab) between visits (see 
Section 7.1).
Reconciliation of Abatacept or 
Adalimumab Monthly Kits
X
X
X
X
X
X
Abbreviations: anti-CCP-2, anti-cyclic citrullinated peptide-2; CBC, complete blood count; 
 ET, early termination; 
FACIT-F, Functional Assessment of Chronic Illness Therapy - Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; hsCRP, high-sensitivity 
C-reactive protein; IRT, Interactive Response Technology; OLTP, Open-label Treatment Period; 
 Rand., randomization; 
RF, rheumatoid factor; 
 SF-36, 36-item Short Form Survey; WOCBP, women of childbearing 
potential; WPAI-RA, Work Productivity and Activity Impairment Questionnaire - Rheumatoid Arthritis.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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2.0
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Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-3:
On-treatment Procedural Outline (IM101863): Open-label Treatment Period (OLTP)
Procedure
Wk 
24b
V7b
(± 3 
Days)
Wk 
28
V8
(± 7
Days)
Wk 
32
V9
(± 7
Days)
Wk 
36
V10
(± 7
Days)
Wk 
40
V11
(± 7
Days)
Wk 
44
V12
(± 7
Days)
Wk 
48
V13
(± 7
Days)
Wk 
52
V14
(± 7
Days)
Wk 
60
V15
(± 7
Days)
Wk 
68
V16
(± 7
Days)
Wk 
76
V17
(± 7
Days)
Wk 
84
V18
(± 7
Days)
Wk 
92
V19
(± 7
Days)
Wk 
104/ET
V20
(± 7
Days)
Notes
Day 
169
Day 
197
Day 
225
Day 
253
Day 
281
Day 
309
Day 
337
Day 
365
Day 
421
Day 
477
Day 
533
Day 
589
Day 
645
Day 
729
Safety Assessments
Targeted Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Body temperature, 
seated blood 
pressure, and heart 
rate.
Concomitant Medication Use
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Causality 
assessments must 
be performed by a 
blinded Clinical 
Assessor.
Laboratory Tests
Urine Pregnancy Test 
X
X
X
X
X
X
X
X
X
X
X
X
X
WOCBP only; 
serum test if 
needed (see 
Section 9.4.7). 
Performed locally.
Hematology (CBC)
X
X
X
X
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol Amendment No.: 01
Date: 26-Feb-2021
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v

Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-3:
On-treatment Procedural Outline (IM101863): Open-label Treatment Period (OLTP)
Procedure
Wk 
24b
V7b
(± 3 
Days)
Wk 
28
V8
(± 7
Days)
Wk 
32
V9
(± 7
Days)
Wk 
36
V10
(± 7
Days)
Wk 
40
V11
(± 7
Days)
Wk 
44
V12
(± 7
Days)
Wk 
48
V13
(± 7
Days)
Wk 
52
V14
(± 7
Days)
Wk 
60
V15
(± 7
Days)
Wk 
68
V16
(± 7
Days)
Wk 
76
V17
(± 7
Days)
Wk 
84
V18
(± 7
Days)
Wk 
92
V19
(± 7
Days)
Wk 
104/ET
V20
(± 7
Days)
Notes
Day 
169
Day 
197
Day 
225
Day 
253
Day 
281
Day 
309
Day 
337
Day 
365
Day 
421
Day 
477
Day 
533
Day 
589
Day 
645
Day 
729
RF
X
X
X
See Section 9.8.
Anti-CCP-2
X
X
X
See Section 9.8.
Efficacy Assessments
Tender (68)/Swollen (66) Joint 
Count
X
X
X
X
X
X
X
X
X
X
X
X
X
Must be performed 
by a blinded 
Clinical Assessor 
(see Section 9.1.2).
Participant Assessment of Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
See Appendix 6.
Participant Global Assessment 
of Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
See Appendix 5.
Protocol Amendment No.: 01
Date: 26-Feb-2021
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930165131
2.0
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Approved
1.0
v

Clinical Protocol
IM101863
BMS-188667
abatacept
Table 2-3:
On-treatment Procedural Outline (IM101863): Open-label Treatment Period (OLTP)
Procedure
Wk 
24b
V7b
(± 3 
Days)
Wk 
28
V8
(± 7
Days)
Wk 
32
V9
(± 7
Days)
Wk 
36
V10
(± 7
Days)
Wk 
40
V11
(± 7
Days)
Wk 
44
V12
(± 7
Days)
Wk 
48
V13
(± 7
Days)
Wk 
52
V14
(± 7
Days)
Wk 
60
V15
(± 7
Days)
Wk 
68
V16
(± 7
Days)
Wk 
76
V17
(± 7
Days)
Wk 
84
V18
(± 7
Days)
Wk 
92
V19
(± 7
Days)
Wk 
104/ET
V20
(± 7
Days)
Notes
Day 
169
Day 
197
Day 
225
Day 
253
Day 
281
Day 
309
Day 
337
Day 
365
Day 
421
Day 
477
Day 
533
Day 
589
Day 
645
Day 
729
Physician Global Assessment 
of Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
Must be performed 
by a blinded 
Clinical 
Assessor (see 
Section 9.1.1 and 
to Appendix 7).
Physical Function (HAQ-DI)
X
X
X
X
X
X
X
X
X
X
X
X
X
See Appendix 8.
Quality of Life Scale (SF-36)
X
X
See Appendix 9.
Work Productivity and 
Activity (WPAI-RA v2)
X
X
See Appendix 10.
Fatigue (FACIT-F v4)
X
X
See Appendix 11.
Duration of Morning Stiffness
X
X
See Appendix 12.
Study Treatment Administration
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact of IRT is 
required to 
dispense 
medication at each 
office visit.
Dispense Diary Cards
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect and Review Diary 
Cards
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2-3:
On-treatment Procedural Outline (IM101863): Open-label Treatment Period (OLTP)
Procedure
Wk 
24b
V7b
(± 3 
Days)
Wk 
28
V8
(± 7
Days)
Wk 
32
V9
(± 7
Days)
Wk 
36
V10
(± 7
Days)
Wk 
40
V11
(± 7
Days)
Wk 
44
V12
(± 7
Days)
Wk 
48
V13
(± 7
Days)
Wk 
52
V14
(± 7
Days)
Wk 
60
V15
(± 7
Days)
Wk 
68
V16
(± 7
Days)
Wk 
76
V17
(± 7
Days)
Wk 
84
V18
(± 7
Days)
Wk 
92
V19
(± 7
Days)
Wk 
104/ET
V20
(± 7
Days)
Notes
Day 
169
Day 
197
Day 
225
Day 
253
Day 
281
Day 
309
Day 
337
Day 
365
Day 
421
Day 
477
Day 
533
Day 
589
Day 
645
Day 
729
Dispense Urine Pregnancy Kits 
for WOCBP for Home Use 
Every 4 Weeks
X
X
X
X
X
X
Not applicable if 
serum pregnancy 
testing is required 
per local 
regulations.
Dosing of Weekly Abatacept
X
X
X
X
X
X
X
X
X
X
X
X
X
Abatacept must be 
self-administered 
weekly between 
visits. See 
Section 7.1.
Dispense Abatacept Kits
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 7.2.
Reconciliation of Abatacept 
Kits
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: anti-CCP-2, anti-cyclic citrullinated peptide-2; CBC, complete blood count; ET, early termination; FACIT-F, Functional Assessment of Chronic 
Illness Therapy - Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; hsCRP, high-sensitivity C-reactive protein; IRT, Interactive Response 
Technology; 
 RF, rheumatoid factor; 
 SF-36, 36-item 
Short Form Survey; V, Visit; Wk, Week; WOCBP, women of childbearing potential; WPAI-RA, Work Productivity and Activity Impairment Questionnaire -
Rheumatoid Arthritis.
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Table 2-4:
Post-treatment Follow-up Period (PTFUP; IM101863)
Procedure
Week 12
FU V1 (± 10 days)a
Week 24
FU V2 (± 10 days)a
Notes
Day 85
Day 169
Safety Assessments
Vital Signs
X
X
Body temperature, seated blood pressure, and heart rate.
Adverse Events Assessment
X
X
Concomitant Medication Report
X
X
Laboratory Assessments
Urine Pregnancy Test
X
X
WOCBP only; serum test if needed (see Section 9.4.7). 
Performed locally.
Abbreviations: FU, Follow-up; OLTP, Open-label Treatment Period; PTFUP, Post-treatment Follow-up Period; SBTP, Single-blind Treatment Period; V, Visit; 
WOCBP, women of childbearing potential.
a Visits only apply to participants who complete the study at Day 729 or discontinue study treatment during the SBTP or OLTP AND are not treated with abatacept 
as a post-study drug. The first day of the PTFUP is Day 729 for participants who complete the OLTP or the day of last study treatment for participants who 
discontinue study treatment during the SBTP or OLTP. Participants who complete the OLTP or discontinue at any time prior to completing the OLTP AND are 
treated with post-study abatacept, regardless of the source, will not need to complete the PTFUP. The follow-up visit should ideally be an in-person visit. If this 
is not possible, a telephone follow-up visit will be performed to confirm the results of the urine pregnancy test as well as adverse event and concomitant 
medication review. Vital signs will not be collected as part of a telephone follow-up phone visit.
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3
INTRODUCTION
Rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis, affecting 
approximately 1% of the population worldwide.1 It is a complex and progressive disease with 
several heterogeneous aspects, including clinical presentation, detectable serological biomarkers, 
genetic risk factors, and speed of disease progression.2,3,4,5 Women are 2 to 3 times more likely to 
develop the disease as compared with men, with a peak incidence between the fourth and sixth 
decades of life.6,7,8,9 The etiology of RA involves genetic and epigenetic components, as well as
environmental stimuli, such as cigarette smoking, dust exposure, and the microbiome, which 
represents an “internal” environment.10 The natural history of RA is characterized by joint 
destruction, impaired physical function, and poor health-related quality of life. Joint erosions can 
be seen within 6 months of disease onset in the majority of patients and occur more rapidly in the 
first year compared with later disease.11 Radiographic evidence of joint damage can be difficult to 
detect in early RA but has been shown to progress in a linear manner after the first year, and there 
is little evidence that current therapies can reverse the structural damage once it occurs.12
The underlying pathophysiology of RA involves an interplay between the adaptive and innate 
immune systems. Several environmental and genetic factors are prominent risks for the 
development and clinical course of RA.4 The role of genetics in RA was first identified by 
researchers who noted that lymphocytes from RA patients were less likely to stimulate
lymphocytes from other unrelated RA patients in mixed lymphocyte cultures.13 The genetic basis 
of this was later identified as being due to the high frequency of related human leukocyte antigen 
Class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1) locus alleles among RA 
patients, a major histocompatibility complex Class II protein receptor. These HLA-DRB1 alleles 
encode for a common amino acid motif in codon positions 70-74. Together these alleles are 
referred to as the shared epitope (SE), and they increase the risk of developing, and the severity 
of, RA.14 While the specific HLA-DRB1 risk allele present shows regional variability, they all 
share the same amino acid motif of the SE, indicating the SE is a genetic risk shared across human 
populations.15
Abnormalities in the cellular and humoral immune response in RA drive the production of 
autoantibodies (such as rheumatoid factor [RF] and anti-citrullinated protein antibodies [ACPA])
that define “seropositive” RA. Of all RA patients, approximately 70-90% are ACPA-positive 
(ACPA+), 60-80% are RF-positive (RF+), and ~70% are seropositive for both ACPA and RF.3,16
Seropositivity drives a severe disease subtype of RA because autoantibodies such as ACPA and 
RF are directly involved in the inflammatory response that is a key driver of disease 
pathophysiology.17 The presence of autoantibodies in RA is associated with increased disease 
activity, systemic manifestations, and joint damage.17,18,19,20 One of the most significant genetic 
risk factors for ACPA+ RA is the SE, and 70-80% of ACPA+ RA patients are SE-positive (SE+; 
see Section 9.8.1 for definition of SE positivity).4,21,22,23 At diagnosis, ACPA+ and 
ACPA-negative (ACPA-) RA patients have similar clinical presentations, but as they progress, 
ACPA+ patients experience more extensive radiological destruction.24 As compared with ACPA 
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seropositivity, RF serostatus has a similar but less severe impact on progressive bone erosion.5
Based on real-world data analysis of the Brigham and Women's Rheumatoid Arthritis Sequential 
Study (BRASS) registry, ACPA seropositivity is associated with reduced likelihood of disease 
remission.25 In addition to articular disease, seropositivity is also associated with higher rates of 
developing various systemic manifestations, including lung involvement and cardiovascular 
disease, that contribute to increased morbidity and mortality of RA patients.18,19,20,26,27,28,29,30,31,32
Consequently, seropositive RA is associated with a greater economic burden, as evidenced by a 
46% higher RA-related cost as compared with seronegative RA, based on a retrospective analysis 
of United States (US) claims data.33
In general, treatment options for RA patients range from agents that provide symptomatic 
relief (eg, analgesics, nonsteroidal anti-inflammatory drugs [NSAIDs]), to corticosteroids and 
disease-modifying antirheumatic drugs [DMARDs] that affect long-term structural damage. The 
approach to RA treatment involves early intervention and progressive changes in therapy to 
improve signs and symptoms and to prevent long-term structural damage. Traditionally, patients 
who are early in the disease course initiate treatment with 1 or more conventional synthetic 
DMARDs (eg, methotrexate [MTX]). Early intervention appears to offer the best opportunity for 
achieving favorable outcomes, such as induction of clinical remission, prevention of long-term 
joint damage, and restoration of normal physical function in patients with early RA.34,35,36,37,38,39
If there is an inadequate response to conventional synthetic DMARDs, these patients may be 
candidates for biologic therapy. The treatment paradigm for treating RA patients has been shifting 
to the early use of combination therapy with both conventional and biologic DMARDs, which has 
been shown to result in more favorable outcomes.40
Commercially available biologic agents for RA have been shown to improve the signs and 
symptoms of RA and decrease the progression of structural damage in patients who have had an 
inadequate response to at least 1 DMARD, and in patients with severe, active, and progressive 
disease not previously treated with DMARDs. Consistent with the principle of early treatment with 
combination therapy, use of these biologic agents is becoming increasingly frequent in patients 
with factors predictive of rapidly progressive disease, such as early radiographic erosion and
positive autoantibodies, such as RF and ACPA, which have been shown to be predictive of severe 
erosive disease. Guidelines from organizations such as the French Society of Rheumatologists 
Working Group for Therapeutic Strategies for Rheumatoid Arthritis (Strategies Therapeutiques de 
la Polyarthrite Rhumatoıde [STPR]) and others, specifically recommend the very early use of 
biologic therapy in patients with poor prognostic factors, taking into account the benefit-risk 
profile of the different therapeutic options.
Tumor necrosis factor (TNF) antagonists, which are the most commonly prescribed biologics for 
RA, have demonstrated consistent and favorable benefit-risk profiles; however, many patients do 
not achieve an adequate response or complete control of inflammation. In those who do achieve a 
response, prolonged maintenance of response is difficult. In addition, there are important safety 
concerns associated with TNF antagonists and other biologic agents. As clinical practice shifts to 
the earlier use of biologics, it is anticipated that patients will be treated with biologic therapies for 
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a longer duration over the course of their disease. As such, the availability of a treatment option 
with prolonged maintenance of efficacy and a favorable long-term safety profile, such as abatacept, 
would be highly desirable for these patients.
Abatacept is a selective costimulation modulator that blocks the interaction between cluster of 
differentiation (CD) 80/CD86 on antigen-presenting cells and CD28 on T cells.41 This interaction 
provides a key signal necessary for full activation of T cells. Activated T cells play an important 
role in the pathogenesis of RA, especially early in the disease process, by participating in the 
autoimmune cascade that leads to joint inflammation and destruction. It is hypothesized that 
autoreactive T cells may be central to this process by producing proinflammatory cytokines and 
providing help to B cells, leading to the production of autoantibodies, which in turn contribute to 
downstream inflammatory events, including the recruitment of neutrophils, elaboration of 
cytokines such as TNF-alpha, synovitis, and ultimately joint destruction.42 By inhibiting 
CD28-mediated immune activation, abatacept blocks antigen recognition and modulates the 
immune response to decrease T-cell activation and antibody production. Therefore, abatacept 
interferes with a step hypothesized to be early in the pathogenesis of RA.
Intravenously (IV) administered abatacept was first approved in the US for the treatment of 
moderate-to-severe RA in adults in Dec-2005. Since then, IV abatacept has received marketing 
approval for the treatment of adult RA in many other countries, including the European Union 
(EU), Japan, Latin America, and other countries.41
The subcutaneous (SC) formulation of abatacept was first approved in the US for the treatment of 
moderate-to-severe RA in adults in Jul-2011. Abatacept SC has subsequently received marketing 
approval for the treatment of adult RA in the EU and other regions of the world.41
The IM101235 (Abatacept vs adaliMumab comParison in bioLogic-naivE RA participants with 
background methotrexate [AMPLE]; ClinicalTrials.gov: NCT00929864)43 study compared the 
efficacy of abatacept (125 mg weekly) and TNF-alpha blockade (adalimumab, 40 mg biweekly), 
both in combination with MTX, in adult participants with RA for 5 or fewer years who had an 
inadequate response to MTX (methotrexate inadequate responders [MTX-IR]) but who were naive 
to a biologic DMARDs. The primary endpoint was met, demonstrating that abatacept was 
noninferior to adalimumab based on the proportion of participants who achieved a 20% 
improvement in American College of Rheumatology criteria (ACR20) at 1 year. In addition, 
ACR20 response rates in both treatment groups increased comparably over the 12-month treatment 
period.
The IM101567 (Early AMPLE; ClinicalTrials.gov: NCT02557100)44 trial was a mechanistic
head-to-head study assessing changes in the immune profile with abatacept (125 mg weekly) and 
TNF-alpha blockade (adalimumab, 40 mg biweekly), both in combination with MTX, in 80 adult 
participants with early RA (symptoms for ≤ 12 months) who had an inadequate response to MTX.
Although this exploratory study did not have any primary or secondary endpoints, numerically 
higher American College of Rheumatology (ACR) responses were seen with abatacept vs 
adalimumab after 24 weeks of treatment. The study also prospectively explored the relationship 
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between clinical efficacy and the presence of HLA-DRB1 risk alleles (ie, SE). The vast majority 
of participants randomized in the Early AMPLE study were SE+ and showed higher differential 
efficacy (ACR responses and Disease Activity Score 28-joint count calculated using C-reactive 
protein [DAS28-CRP] remission) to abatacept vs adalimumab compared with the overall 
population, indicating that the differential benefit to therapy with abatacept in this population is 
driven by the SE+ patient subgroup.
In order to confirm the exploratory observations in Early AMPLE relating to abatacept efficacy in 
SE+ participants, IM101863 aims to demonstrate the superiority in efficacy of abatacept compared 
with adalimumab in a population of RA participants characterized by early disease, MTX-IR, and 
seropositivity (RF+ and ACPA+) and expressing SE HLA Class II risk alleles (ie, SE+). 
3.1
Study Rationale
Available data sources describing the use of abatacept for the treatment of RA show that a subset 
of RA patients have characteristics that may predict a better response to abatacept than to treatment 
with TNF inhibitor.44,45,46,47 These characteristics are: 1) early disease duration; 2) high titers of 
ACPA and RF (dual seropositivity); 3) inadequate response to initial treatment with 
MTX (MTX-IR); and 4) presence of the SE. Together, these characteristics appear to comprise a 
predictive response profile for enhanced clinical response with abatacept therapy. This study will 
test whether this predictive response profile will lead to better clinical outcomes for treatment with 
abatacept in this patient population compared with treatment with adalimumab.
Analyses of several prior Bristol-Myers Squibb (BMS) randomized, controlled trials (RCTs) of 
abatacept for the treatment of RA and external real-world clinical data suggested that RA patients 
early in their disease course who had high titers of ACPA demonstrated higher, differential benefit 
from abatacept therapy.45,46,47,48
In the AMPLE
study (IM101235; ClinicalTrials.gov: 
NCT00929864), baseline anti-cyclic citrullinated peptide-2 (anti-CCP-2) positivity was associated 
with a better response to both abatacept and adalimumab; however, participants with the highest 
anti-CCP-2 antibody concentrations (1060-4894 IU/mL) had better clinical response with 
abatacept but not with adalimumab.45 Similarly, in the Assessing Very Early Rheumatoid Arthritis 
Treatment (AVERT; IM101226; ClinicalTrials.gov: NCT01142726) study, a higher proportion of 
anti-CCP-2-positive (anti-CCP-2+) vs anti-CCP-2-negative (anti-CCP-2-) participants achieved 
remission after 1 year of treatment with abatacept with background MTX.48 In a US-based clinical 
practice setting, greater efficacy was seen with abatacept, but not TNF inhibitors, in anti-CCP-2+ 
vs anti-CCP-2- patients with RA.46 In a meta-analysis of 19 studies, anti-CCP-2 positivity was 
associated with better European League Against Rheumatism (EULAR) responses in patients with 
RA receiving abatacept but not in those receiving a TNF inhibitor.47
To further explore this early seropositive population and identify any novel characteristics that 
could confirm or further refine an RA subpopulation with differential benefit from treatment with 
abatacept over adalimumab, BMS
executed the IM101567 study (Early AMPLE; 
ClinicalTrials.gov: NCT02557100).44 This was a mechanistic, head-to-head study between 
abatacept and adalimumab, designed to study a population of RA participants enriched for 
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abatacept differential responders. These adult RA participants were characterized by: 
a) 12 months of disease symptoms; b) seropositivity for both RF and ACPA (3upper limit of 
normal [ULN]); and c) moderate-to-severe RA (ACR/EULAR 2010 criteria and DAS28-CRP 
≥3.2) in spite of at least 3 months of therapy with MTX (MTX-IR). Eighty participants were 
randomized 1:1 to SC abatacept 125 mg weekly or SC adalimumab 40 mg every 2 weeks (both 
with stable, background oral MTX weekly) for 24 weeks. Higher ACR responses were seen with 
abatacept vs adalimumab after 24 weeks of treatment, supporting prior findings that early 
seropositive RA patients should respond better to abatacept (see Figure 3.1-1). To further refine 
the abatacept-response group, BMS prospectively explored the relationship between clinical 
efficacy to abatacept or adalimumab and the presence of a genetic marker known as the SE. The 
SE is encoded by a group of HLA-DRB1 alleles with shared homology in the beta chain at positions 
70-74. The SE is a genetic marker of risk, associated with earlier-onset, ACPA+, destructive RA, 
and is present in 70-80% of ACPA+ RA patients. Seventy-five percent of Early AMPLE 
randomized participants were SE+ and showed even higher differential ACR response to abatacept 
compared with adalimumab (see Figure 3.1-2), suggesting that the differential benefit to therapy 
with abatacept in this population is driven by the SE+ patient subgroup. The current study, 
IM101863, aims to confirm the findings from the Early AMPLE and other studies by 
demonstrating the superiority in efficacy of abatacept compared with adalimumab in a population 
of RA patients characterized by early disease, MTX-IR, and seropositivity (RF+ and ACPA+) and 
expressing SE HLA Class II risk alleles (ie, SE+). 
Figure 3.1-1:
Proportion of Patients with ACR Responses Over Time During the 
Single-blind Treatment Period (as-treated analysis IM101567)
Abbreviations: ABA, abatacept; ACR, American College of Rheumatology; ACR20/50/70, 20%/50%/70% 
improvement in American College of Rheumatology criteria; ADA, adalimumab; CI, confidence interval.
Note: Missing values were imputed as nonresponders. Error bars represent 95% CI. 
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Figure 3.1-2:
Proportion of SE+ Patients with (A) ACR Responses Over Time and 
(B) Week 24 ACR Responses and DAS28-CRP Remission by 
Treatment Group (as-treated analysis IM101567)
Abbreviations: ABA, abatacept; ACR20/50/70, 20%/50%/70% improvement in American College of Rheumatology 
criteria; ADA, adalimumab; CI, confidence interval; DAS28-CRP, Disease Activity Score 28-joint count calculated 
using C-reactive protein; SE, shared epitope.
Note: ABA, n = 30; ADA, n = 31. DAS28-CRP remission was defined as DAS28-CRP < 2.6. Patients with missing 
data for efficacy parameters at Week 24 were imputed as nonresponders. Values above bars show estimate of 
difference (95% CI) for ABA vs ADA. 
3.2
Background
3.2.1
Abatacept Mechanism of Action
Abatacept is a recombinant fusion protein consisting of the extracellular domain of human 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and a fragment of the Fc domain of human 
immunoglobulin (Ig) G1. Abatacept is the only member of a class of agents termed “selective 
costimulation modulators.”
Effective T-cell activation involves a combination of 2 signals.49 Starting with antigen presentation 
by an HLA Class II molecule, the first signal is the recognition by the T-cell receptor of an antigen 
presented by an antigen-presenting cell (APC) on its surface HLA molecule. The second 
costimulatory signal is from the interaction of CD28 on the T cell with CD80 or CD86 on the APC 
surface. A costimulatory signal is required for the full activation of naive T cells and may be 
required for the survival of autoimmune effector T cells. The SE, which is one of the strongest 
genetic risk factors for earlier-onset, ACPA+, erosive RA, is encoded by a group of HLA-DRB1
alleles and comprises a small portion of the antigen-binding groove of the HLA molecule. 
HLA-DRB1 molecules with the SE have a higher affinity for citrullinated peptides, and thus may 
have increased binding and presentation of these citrullinated peptides. This SE-driven increase in 
the presentation of citrullinated self-peptides could lead to increase activation of autoreactive 
T cells.21,49 Activated autoreactive T cells subsequently lead to increased autoreactive B-cell 
activation and ACPA production.50 Indeed, RA patients who have the SE HLA risk alleles have
higher levels of serum anti-CCP-2 (common laboratory assay used to measure ACPA).
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Abatacept is a selective costimulation modulator that blocks the interaction between the 
costimulatory molecules CD80/CD86 and their receptor (CD28) that provides a key signal 
necessary for full activation of immune cells such as T cells. By inhibiting CD28-mediated 
immune activation upstream of inflammatory cytokines, such as TNF, abatacept blocks antigen 
recognition and modulates the immune response to decrease T-cell activation and antibody 
production. Activated T cells play an important role in the pathogenesis of RA, especially early in 
the disease process, by amplifying the inflammatory cascade that leads to joint inflammation and 
destruction. By inhibiting CD28-mediated T-cell activation upstream of inflammatory 
cytokines (eg, TNF), abatacept utilizes a unique mechanism of action that offers significant 
therapeutic benefit to patients with inflammatory arthritis by specifically modifying key 
underlying disease pathophysiology early in the cascade through autoantigen recognition
blockade.
Adalimumab is a recombinant human IgG1 monoclonal antibody specific for the human TNF. 
Adalimumab binds specifically to TNF-alpha and blocks its interaction with the cell-surface TNF 
receptor p55 and p75. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence 
of complement.51
IV-administered abatacept was first approved in the US for the treatment of moderate-to-severe 
RA in adults in Dec-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 Apr-2008. 
In addition, IV abatacept has received marketing approval for the treatment of JIA in several other 
countries, including the EU, Canada, and Australia.
The SC formulation of abatacept was first approved in the US for the treatment of 
moderate-to-severe RA in adults in Jul-2011. Abatacept SC has subsequently received marketing 
approval for the treatment of adult RA in the EU, Japan, and other regions of the world.
A detailed description of the chemistry, pharmacology, efficacy, and safety of abatacept is 
provided in the Investigator’s Brochure (IB).41
3.2.2
Efficacy
Abatacept has an established benefit of improving signs and symptoms and halting progression of 
radiographic damage in patients with RA. This includes both seronegative and seropositive 
patients; patients with the full range of prior therapy, from naive to biologic DMARD failure; and 
disease duration from early to late disease. However, based on the mechanism of action of 
abatacept, which includes modulating the activation of autoreactive immune cells, participants 
with early RA would be expected to have a greater likelihood of achieving clinical remission. This 
was demonstrated in several studies in early RA that serve as a proof of concept that early 
intervention with abatacept may induce clinical remission in a substantial number of patients.
In the IM101023 study (Abatacept study to Gauge Remission and joint damage progression in 
MTX-naive patients with Early Erosive rheumatoid arthritis [AGREE]; ClinicalTrials.gov: 
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NCT00122382),52 treatment with IV abatacept in participants with moderate-to-severe early RA 
(diagnosis within prior 2 years) who were MTX-naive, were seropositive for anti-CCP-2 
antibodies or RF, and had erosions on imaging resulted in sustained rates of low disease activity. 
During the first year of the study, 41.4% of participants on abatacept plus MTX achieved Disease 
Activity Score (DAS)-defined remission (DAS28 < 2.6) compared with 23.3% on MTX alone. Of 
the participants who completed Year 2 of the study, 55.2% of participants treated with abatacept 
plus MTX achieved DAS28 < 2.6 compared with 26.9% on MTX alone. Of those participants who 
switched from MTX treatment alone to abatacept plus MTX at 1 year, 44.5% achieved 
DAS28 < 2.6 at 2 years.
In the IM101046 study (ADJUST; ClinicalTrials.gov: NCT00124449),53 a population with earlier 
disease was targeted. In participants with a diagnosis of undifferentiated arthritis who satisfied 
1 but no more than 3 classification criteria for RA (1987 classification) and who had less than 
18 months of symptoms, had current active synovitis, and were positive for anti-CCP-2 antibodies, 
abatacept monotherapy demonstrated a therapeutic response over 6 months, which continued after 
drug discontinuation for another 6 months. Treatment with abatacept delayed progression to 
diagnosis of RA compared with the placebo control arm, which was left untreated. The placebo 
arm also developed more joint damage, as evidenced by radiographic evaluation and magnetic 
resonance imaging (MRI). 
In the IM101235 study (AMPLE; ClinicalTrials.gov: NCT00929864),43 RA patients treated with 
abatacept or adalimumab, on background of MTX therapy, demonstrated similar improvement 
across all efficacy outcomes over 2 years of treatment.54 In a post-hoc analysis, the subset of 
participants enrolled in AMPLE with early, rapidly progressive disease (defined as ≤ 6 months’ 
disease duration; seropositive for RF and/or ACPAs and had ≥ 1 radiographic erosion) were 
compared for efficacy outcomes.55 When comparing abatacept with adalimumab, over 2 years of 
treatment, the adjusted mean change in DAS28-CRP from baseline at Day 365 
was -2.58 (95% confidence interval [CI] -2.99 to -2.17) vs -1.68 (95% CI -2.10 to -1.25) and in 
Health Assessment Questionnaire Disability Index (HAQ-DI) from baseline at Day 365 
was -0.70 (95% CI -0.90 to -0.51) vs -0.50 (95% CI -0.71 to -0.30), respectively. In this subset of 
RA patients with early, seropositive disease, abatacept appears to be more efficacious than 
adalimumab.
In another post-hoc analysis of the AMPLE study, study participants were tested for baseline 
anti-CCP-2 levels.45 CCP-2 is a routine clinical assay for assessing ACPAs. Participants were 
divided according to CCP-2 concentrations in quartiles. Patients in the higher quartiles, especially
Q4, had a better clinical response to abatacept than to adalimumab, independent of any other 
clinical characteristics. Here also, seropositivity and magnitude of this auto-antibody response was
associated with better response to abatacept therapy.
The IM101567 trial (Early AMPLE; ClinicalTrials.gov: NCT02557100) was a mechanistic 
head-to-head study assessing changes in the immune profile with abatacept (125 mg weekly) and 
TNF-alpha blockade (adalimumab, 40 mg biweekly), both in combination with MTX, in 80 adult 
participants with early RA (symptoms for ≤ 12 months) who had an inadequate response to 
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MTX.44 Numerically higher ACR responses were seen with abatacept vs adalimumab after 
24 weeks of treatment; 50% improvement in ACR (ACR50) estimate of difference % was 
25 (95% CI 2 to 46; see Figure 3.1-1). The vast majority (76%) of participants randomized in the 
Early AMPLE study were SE+ and showed higher differential efficacy to abatacept vs adalimumab 
compared with the overall population
(estimate of difference %
for ACR50 was 
32 [95% CI 7 to 55] and for DAS28-CRP was 27 [95% CI 1 to 50]; see Figure 3.1-2).
Taken together, these previous studies provide evidence for the concept that abatacept may have 
differential benefits in patients who are MTX-IR with early seropositive RA, including inhibition 
of radiographic progression, and may enable higher rates of remission. The presence of the genetics 
encoding for the SE may further predict robust abatacept response.
Abatacept has been studied in RA patients with a variety of prior DMARD exposure. The 
understanding of the possible role that a novel therapeutic agent may have in the RA treatment 
paradigm has evolved to include its utility in populations based on prior DMARD experience. As a 
general concept,
this can be organized into 3 categories: 1) before any DMARD 
use (ie, DMARD-naive); 2) after conventional synthetic DMARD use (usually MTX); and 3) after 
biologic DMARD (usually TNF inhibitors). This concept has been one of the core concepts in 
treatment guidelines since the emergence of novel targeted therapies.56,57 The underlying rationale 
is to understand DMARD treatment choice by taking into account both acceptable safety and 
likelihood of response. What has not been well understood is what determines why some patients 
will respond well to one DMARD and not another. Clearly, stochastic effects could be at play, but 
evidence suggests underlying disease heterogeneity (including genetic variation) may be mostly 
responsible. Having a suboptimal response to initial therapy with MTX may therefore be 
understood as much a marker of the underlying pathomechanism. Work by Stuhlmüller et al.
suggests that such an effect underlies an inadequate response to MTX.58 RA patients naive to 
DMARD therapy, in whom analysis of whole blood transcriptomic showed a preponderance of 
transcripts 
for 
T-
and 
B-lymphocytes, 
were 
less 
likely 
to 
respond 
to 
MTX. 
HLA-DRB4-positive (ie, SE+) patients with a prominent adaptive immune response profile were 
also more likely to be MTX-IR. This suggests that an MTX-IR designation is not random but may 
be a core marker of underlying disease pathogenesis, with impact on responsiveness to DMARD 
treatment.58 The active comparator for the current study is adalimumab, which also has proven 
efficacy for improving the signs and symptoms of RA and is approved for the treatment of RA.51
3.2.3
Safety
Abatacept treatment in RA has an acceptable safety profile regarding serious infections, 
malignancies, and autoimmune reactions. The Phase 2/3 clinical program included participants 
from 5 core studies that, combined with 3 other studies, comprise more than 10,000 patient-years 
of exposure. The main identified risks of abatacept therapy are infections (primarily bacterial) and 
slightly increased risk of infusion reactions (for the IV formulation) compared with placebo. 
Autoimmune events (primarily psoriasis) have been noted. Malignancies are not increased in 
abatacept-treated participants compared with placebo-treated participants. The IB provides
additional details on the information discussed in this section.41
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The potential safety concerns associated with the use of adalimumab have been well described in 
the prescribing information.51 Specifically, some of the safety events that have been noted include 
cases of serious and opportunistic infections, including invasive fungal infections; hepatitis B 
reactivation; anaphylaxis or serious allergic reactions; exacerbation or new onset of demyelinating 
disease; worsening or new onset of heart failure; and malignancies. These events are well 
recognized and managed by treating physicians through a combination of patient 
selection (eg, exclusion of high-risk patients), preventive screening (eg, chest x-ray, purified 
protein derivative [PPD] testing), and close observation during therapy. This study will aim to 
utilize investigators with prior experience using biologic DMARDs in the care of patients with 
RA.
3.2.4
Abatacept and COVID-19
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped 
ribonucleic acid (RNA) beta-coronavirus that is the etiological agent of coronavirus disease 
2019 (COVID-19). COVID-19 produced a high incidence of mortality and morbidity and has been 
declared a pandemic by the World Health Organization (WHO). 
Abatacept has been studied in human clinical trials for over 15 years. Based on the review of safety 
data relevant to viral infections from clinical studies and post-marketing experience, there is no 
current evidence suggesting increased risk of viral respiratory illnesses, severe or otherwise, 
associated with abatacept use that would warrant avoiding use of abatacept. Currently available 
information from published literature, active clinical studies, or post-marketing surveillance about 
acute infection with SARS-CoV-2 in patients receiving abatacept is limited. While poor outcomes 
have been reported, most reports suggest that good outcomes are likely.
Of note, abatacept is being proposed as a therapy that can modulate an 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 
activation (eg, CD4+ T cells, B cells, macrophages) and production of cytokines and interrupting 
the feedforward pathological process. Two studies evaluating abatacept in the treatment of 
hospitalized COVID-19 patients are ongoing (ClinicalTrials.gov Identifier: NCT04472494 and 
NCT04593940).
Due to ongoing community transmission of SARS-CoV-2, study execution will be carefully 
managed through participant and site selection, infection control recommendations, appropriate 
SARS-CoV-2 vaccination upon availability, close observation of COVID-19-related adverse 
events (AEs)/serious adverse events (SAEs)
 
. 
3.3
Benefit/Risk Assessment
RA is an autoimmune disorder that can lead to progressive joint destruction, deformity, significant 
physical disability, and poor quality of life. The standard of care is to use DMARDs; however, 
which, when, and how has evolved significantly with the emergence of modern targeted therapies. 
Treatment guidelines consider both efficacy and safety in their recommendation.56,57 Both
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abatacept and adalimumab have well-established benefit-risk profiles in the treatment of RA 
patients and are included in current treatment guidelines. This benefit-risk is in part dependent on 
following established screening and ongoing safety monitoring. This protocol will follow these 
established processes. 
In order to minimize the overall risk to participants, this protocol has inclusion and exclusion 
criteria appropriate to the population and proposed treatments (see Section 6 [Study Population]). 
Exclusionary screening tests will be used to identify latent tuberculosis (TB), viral hepatitis, risk 
factors/age-specific screening, medical history, and specific follow-up safety assessments will be 
performed. Women of childbearing potential (WOCBP) will be required to use highly effective 
contraception and to comply with pregnancy testing throughout this study. In addition, AEs and 
SAEs will be reviewed on an ongoing basis by the Clinical Trial Physician/Medical Monitor and 
pharmacovigilance group to look for trends and any safety issues.
There is no current evidence suggesting increased risk of viral respiratory illnesses, severe or 
otherwise, associated with abatacept. The potential benefit of abatacept in the treatment of 
COVID-19, and therefore its potential utility, is being studied in 2 ongoing studies. No concerns 
for adalimumab has been reported. The impact of COVID-19-associated risk will still be carefully 
monitored during the trial. Country and site selection will include assessment of specific barriers 
to safe recruitment. The current understanding of the risk associated with COVID-19 and the use 
of abatacept or adalimumab does not appear to alter the benefit-risk assessment.
Currently, clinicians do not have an evidence-based method of choosing the most efficacious 
targeted therapies for any given RA patient. This trial will test whether a set of clinical and 
laboratory parameters can identify patients who are more likely to respond to abatacept therapy, 
both in frequency and magnitude, than adalimumab. To achieve an earlier and more profound 
clinical outcome will prevent joint damage that cannot be reversed and minimize impact on quality 
of life and work productivity for these patients. This will further improve the benefit-risk 
assessment by minimizing suboptimal therapy that nonetheless has risk.
Potential benefits: Abatacept has demonstrated consistent and statistically robust effects on all 
primary and secondary endpoints in RA efficacy trials. Based on the data from IM101023,52
IM101046,53 and IM101226,59 the use of abatacept (in combination with MTX) in early RA has 
the potential to induce remission in a large proportion of patients. Finally, very early use of 
effective therapy may curtail or even halt radiographic progression of disease, which could lead to 
long-term joint protection. 
Potential risks: The clinical safety profile of abatacept in RA is well established. The Phase 2/3 
clinical program includes patients from 5 core studies that, combined with other studies, have 
24,000 patient-years of abatacept exposure. Clinical studies of abatacept provide extensive 
experience characterizing the safety and efficacy/effectiveness of abatacept. Abatacept was first 
approved in 2005. Since that time, there have been an estimated 763,109 patient-years of exposure 
to abatacept in the marketplace. Post-marketing reports have not altered the favorable benefit-risk 
profile for abatacept, and its safety profile remains generally similar to that established during the 
clinical trials.
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Abatacept treatment in RA has an acceptable safety profile regarding serious infections, 
malignancies, and autoimmune reactions that are usually a concern with agents acting on the 
immune system. The main identified risks of abatacept therapy are infections (primarily bacterial) 
and slightly increased risk of infusion reactions vs placebo. The overall frequency of infections 
was slightly increased in the abatacept-treated population, but the severity, treatment, and outcome 
of these infections was similar to those treated with placebo. Serious viral, fungal, or mycobacterial 
infections were uncommon. The risks of autoimmune disorders and malignancies are not increased 
in abatacept-treated participants vs placebo-treated participants. 
In the IM10102352 and IM10122659 studies, the combination of abatacept and MTX administered 
IV or SC was generally safe and well tolerated in MTX-naive participants with early RA and was 
similar to MTX alone. The overall proportion of AEs was similar in both groups. Infections, mainly 
upper respiratory tract infections, were among the most frequent AEs and were generally mild. 
There were no reports of opportunistic infections. There was 1 case of pancreatic cancer in the 
active group. Autoimmune diseases were infrequent in both treatment groups, and the infusions 
were well tolerated. Similar to IM101023, in the IM101046 study, the safety of abatacept 
monotherapy was unremarkable. The latest IB provides details on the information discussed in this 
section.41
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of abatacept and adalimumab may be found in their respective Prescribing 
Information.51,60
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To demonstrate the superiority in efficacy of 
abatacept compared with adalimumab, both on 
background MTX, in achieving clinical response 
(ACR50) at Week 24, in early, seropositive (RF+ and 
ACPA+) RA patients with the SE HLA Class II risk 
alleles (ie, SE+).
Proportion of SE+ participants meeting ACR50 
response at Week 24
Key Secondary
To compare the efficacy of abatacept with
adalimumab, both on background MTX, in achieving 
clinical remission criteria (DAS28-CRP remission) 
at Week 24 in early, seropositive RA patients with 
the SE HLA Class II risk alleles (ie, SE+).
Proportion 
of 
SE+ 
participants 
achieving 
DAS28-CRP remission (DAS28-CRP < 2.6) at Week 
24
To compare the efficacy of abatacept with
adalimumab, both on background MTX, in achieving 
clinical response (ACR50) at Week 24 in the whole 
study population of early, seropositive RA patients.
Proportion of whole study population participants 
meeting ACR50 response at Week 24
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
To compare the efficacy of abatacept with
adalimumab, both on background MTX, in achieving 
clinical remission 
criteria (CDAI remission) at 
Week 24 in early, seropositive RA patients with the 
SE HLA Class II risk alleles (ie, SE+).
Proportion of SE+ participants achieving CDAI 
remission (CDAI 2.8) at Week 24
To compare the efficacy of abatacept with
adalimumab, both on background MTX, in achieving 
improvement in pain at Week 24 in early, 
seropositive RA patients with the SE HLA Class II 
risk alleles (ie, SE+).
Mean 
change
from 
baseline 
in 
SE+ 
participant-reported pain (VAS) at Week 24
Other Secondary
To determine the efficacy over time by treatment in 
early, seropositive RA patients (SE+ subset and 
whole population).
Proportion of SE+ subset and whole population
achieving ACR20/50/70 responses, DAS remission, 
CDAI remission, SDAI remission over the SBTP and 
OLTP; mean changes from baseline in DAS28-CRP, 
CDAI, 
SDAI 
over 
the 
SBTP 
and 
OLTP; 
mean changes from baseline in the 7 ACR core 
components over the SBTP and OLTP
To determine the improvement in health-related 
quality of life over time by treatment in early, 
seropositive RA patients (SE+ subset and whole 
population).
Mean change from baseline in SF-36 in SE+ subset 
and whole population at Week 24 and Week 104
(4 physical and 4 mental subscales and the physical 
component and mental component summary)
Exploratory

To assess improvement in work and productivity
over time.
Mean change from baseline in WPAI-RA score at 
Week 24 and Week 104
To assess improvement of fatigue over time.
Mean change from baseline in FACIT-F score at 
Week 24 and Week 104

To assess improvement in duration of morning 
stiffness over time.
Mean change from baseline in duration of morning 
stiffness at Week 24 and Week 104
To assess/explore biomarkers, including:
‒
Serum proteins 
‒
Genetic risk alleles

 autoantibodies
Target gene (eg, HLA-DRB1, 
)
Abbreviations: +, positive; ACPA, anti-citrullinated protein antibodies; ACR20/50/70, 20%/50%/70% improvement 
in American College of Rheumatology criteria; CDAI, Clinical Disease Activity Index; 
 
 DAS, disease activity score; DAS28-CRP,
Disease Activity Score 28-joint count calculated using C-reactive protein; FACIT-F, Functional Assessment of 
Chronic Illness Therapy - Fatigue; HLA-DRB1, human leukocyte antigen Class II histocompatibility antigen; 
MTX, methotrexate; OLTP, Open-label Treatment Period; 
 
 RA, rheumatoid arthritis; RF, rheumatoid factor; 
 
SBTP, Single-blind Treatment Period; SDAI, Simple Disease Activity Index; SE, shared epitope; SE+, shared 
epitope-positive; SF-36, 36-item Short Form Survey; VAS, visual analog scale; WPAI-RA, Work Productivity and 
Activity Impairment Questionnaire - Rheumatoid Arthritis.
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5
STUDY DESIGN
5.1
Overall Design
This is a randomized, single-blind, multicenter, global Phase 3 study. The head-to-head study is 
designed to evaluate the superiority in efficacy of abatacept compared with adalimumab in a 
population of RA patients who have early disease and are MTX-IR, seropositive (RF+ and 
ACPA+), and expressing SE HLA Class II risk alleles (ie, SE+). 
Eligible participants will include adults (18 years old) who have early RA, defined as symptoms 
of RA (pain, stiffness, or joint swelling) for no more than 12 months prior to screening, and satisfy 
the ACR/EULAR 2010 criteria for the classification of RA at some point during the 12-month 
period prior to signing the informed consent form (ICF). Participants who had a single isolated 
episode of palindromic symptoms that occurred less than 2 years prior to enrollment are still 
eligible. Participants must have a second-generation anti-CCP-2 test result that is greater than 
3ULN and be RF+ at screening according to central laboratory testing. The anti-CCP-2 test is 
commonly used in the clinic to measure ACPA, and the 3ULN cutoff in the anti-CCP-2 central 
laboratory test ensures a stable positive ACPA profile. Participants must have a DAS28-CRP of at 
least 3.2 at screening and have at least 3 tender and at least 3 swollen joints (excluding distal 
interphalangeals) at screening and at randomization.
 
 
Eligible participants must have been treated with MTX for at least 12 weeks prior to randomization 
with a stable dose of oral or parenteral MTX for at least 4 weeks prior to 
randomization (ie, MTX-IR). The stable dose of oral or parenteral MTX should be the maximum 
tolerated oral or parenteral dose (expected doses from 15 mg to 25 mg per week; see Section 7.1.3). 
Participants may enroll with MTX doses < 15 mg/week but ≥ 7.5 mg/week if intolerance to higher 
doses has been documented and the dose of oral or parenteral MTX is stable for 4 weeks prior to 
randomization. Participants in Japan may also enroll at doses between 7.5 and 15 mg per week at 
the discretion of the investigator. Participants must be naive to prior therapy with other DMARDs, 
except brief exposure to either sulfasalazine or hydroxychloroquine. See Section 6 (Study 
Population, Inclusion/Exclusion Criteria) for additional details.
The study is divided into 4 periods: Screening Period, Single-blind Treatment Period (SBTP) from 
Day 1 to Week 24, Open-label Treatment Period (OLTP) from Week 24 to Week 104, and 
Post-treatment Follow-up Period (PTFUP).
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Abbreviations: ACPA+,
anti-citrullinated protein antibody-positive; D,
Day; MTX,
methotrexate;
MTX-IR, methotrexate inadequate responders;
OLTP, Open-label Treatment Period; R, randomize; RA, rheumatoid arthritis; RF+, rheumatoid factor-positive; SBTP, Single-blind Treatment Period;
SC, subcutaneous.
a In reference to Day 729 for participants who complete the OLTP or the day of last study treatment for participants who discontinue study treatment during the 
SBTP or OLTP.
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5.1.1
Screening Period
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity, and safety assessments. Randomization must occur within 28 days of signing the ICF. 
Participants that experience delays may extend the screening period to 42 days (see 
Section 6.4.1.2). Rescreening is allowed (see Section 6.4.1.3).
5.1.2
Treatment Period
5.1.2.1
Single-blind Treatment Period: Day 1 - Week 24
On Day 1, participants will begin the SBTP and be randomized according to a computer-generated 
fixed-block randomization schedule. The site must complete the Tender (68)/Swollen (66) Joint 
Count to verify the final inclusion criteria (at least 3 tender and at least 3 swollen joints, excluding 
distal interphalangeals) prior to contacting Interactive Response Technology (IRT) for 
randomization. The site must also have the results of the genotyping for the SE from the central 
lab prior to randomization because participants will be stratified by SE status (positive or negative).
Participants will be randomized to 1 of 2 parallel treatment arms in a 1:1 ratio:
1) Abatacept SC (125 mg) weekly with background stable MTX therapy
2) Adalimumab SC (40 mg) once every 2 weeks with background stable MTX therapy
Abatacept and adalimumab administration: On Day 1, participants and/or personal caregivers will 
be trained in self-administration of SC injections using prefilled syringes.
Methotrexate: Participants must have been treated with MTX for at least 12 weeks prior to 
randomization with a stable dose of oral or parenteral MTX for at least 4 weeks prior to 
randomization. The stable dose of oral or parenteral MTX should be the maximum tolerated dose 
(minimum of 15 mg and maximum of 25 mg per week). A dose of MTX < 15 mg/week but 
7.5 mg/week is permitted if intolerance to higher doses has been recorded in the source 
documents and the dose of oral or parenteral MTX is stable for 4 weeks prior to randomization.
Participants in Japan may also enroll at doses between 7.5 and 15 mg per week at the discretion of 
the investigator. For complete details of MTX use, see Section 7.1.3.
5.1.2.2
Open-label Treatment Period: Week 24 - Week 104
At Week 24, all participants ongoing in the OLTP will receive abatacept 125 mg SC weekly for 
the duration of the treatment period:
1) Participants receiving abatacept SC (125 mg) weekly will continue to receive abatacept.
2) Participants receiving adalimumab SC (40 mg) will switch to abatacept SC (125 mg) weekly 
at Week 24.
3) Participants will continue to be treated with oral or parenteral MTX as described above.
4) Participants not wishing to continue on open-label abatacept have the option of discontinuing 
treatment at the end of the SBTP and continuing to the PTFUP.
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5.1.3
Post-treatment Follow-up Period
There will be a PTFUP for safety assessments. This period will be required only for some 
participants based on how they will be treated after study completion or Early Termination (ET). 
Participants who complete the treatment periods (ie, OLTP) or discontinue prior to completing the 
OLTP AND are not treated with post-study abatacept, regardless of the source, will need to 
complete the PTFUP. This will consist of 2 follow-up visits on Day 85 and Day 169 post cessation 
of investigational product (IP; see Table 2-4). The PTFUP will begin on Day 729 for participants 
who complete the OLTP. The PTFUP will begin on the day of last study treatment for participants 
who discontinue study treatment during the SBTP or OLTP. Participants who complete the OLTP 
or discontinue at any time prior to completing the OLTP AND are treated with post-study 
abatacept, regardless of the source, will not need to complete the PTFUP.
5.1.4
Data Monitoring Committee and Other External Committees
5.1.4.1
Data Monitoring Committee
Not applicable.
5.1.4.2
Study Steering Committee
A Study Steering Committee (SSC) will be established to obtain scientific guidance and advice on 
the protocol and conduct of the study. Detailed information can be found in the SSC Charter.
5.2
Number of Participants
It is anticipated that approximately 400 participants will be screened to treat 300 eligible 
participants with abatacept (n = 150) or adalimumab (n = 150) with background stable MTX 
therapy.
 
 See Section 10.1 (Sample Size Determination) for 
additional details.
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial 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 were or are
expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for Population Profile
Taking together the prior study results described in Section 3 (Introduction) as well as the 
association of the SE with ACPA61 and the immunopathogenesis of RA, it is reasonable to 
hypothesize that seropositive, SE+ patients with early RA may respond better to a T-cell 
costimulatory modulator, such as abatacept, than to a TNF-alpha inhibitor, such as adalimumab, 
due to their different mechanisms of action. Abatacept is a selective costimulation modulator that 
blocks the interaction between CD80/CD86 on APCs and CD28 on T cells. Relative to 
adalimumab, abatacept interferes more directly with T-cell activation and the continued breaking 
of immune tolerance in SE+ patients, as evidenced by the increased production of ACPAs.61
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Consistent with this hypothesis, in a retrospective Japanese observational study, clinical efficacy 
of abatacept was significantly higher in SE+ vs SE- patients.62 Moreover, SE positivity was 
predictive of response to treatment with abatacept, but not tocilizumab, which inhibits the 
interleukin (IL)-6 pathway.63
Because this study aims to demonstrate more definitively the higher abatacept vs adalimumab 
efficacy observed in IM101567, the study population will be aligned with the RA population
enrolled in IM101567. Further, the primary endpoint and several key secondary endpoint analyses 
will be focused on the SE+ subgroup because this appears to define a more refined patient profile
that is enriched for abatacept responders.
Participants in this study should have had symptoms of RA for 12 months or less prior to screening. 
Symptoms of RA are defined as signs and symptoms of synovitis (pain, swelling, tenderness) of 
joints commonly affected by RA. All participants must be seropositive for both RF and 
ACPA (measured with an anti-CCP-2 test that is > 3× ULN, which is considered high-level 
positive according to the 2010 ACR/EULAR RA classification criteria). Participants must have a 
DAS28-CRP ≥3.2 at screening in order to align with the population studied in the IM101235 and 
IM101567 trials comparing abatacept plus MTX with adalimumab plus MTX.
 
 
 
5.4.2
Rationale for Choice of Endpoints
The primary endpoint of this study will be ACR50 at Week 24 in the SE+ subgroup. In IM101567,
within the overall population, ACR50 estimate of difference between the abatacept and 
adalimumab showed the largest differential benefit (25), and the 95% CIs did not cross zero.44
Moreover, the driver of this differential efficacy was the SE+ subgroup, because within the SE+ 
subgroup, the ACR50 estimate of difference between the abatacept and adalimumab was even 
larger (32), and the 95% CIs again did not cross zero. Because this study is aimed at replicating 
this observation of differential abatacept efficacy, the primary endpoint will be ACR50 at Week 24 
in the SE+ population.
The list of key secondary efficacy endpoints and their hierarchical ordering is based on the 
magnitude of treatment differences observed in the IM101567 study.
5.4.3
Rationale for Timing of Endpoints
Because this study aims to recapitulate the abatacept vs adalimumab efficacy observed in 
IM10156744 at Week 24, the duration of the SBTP, and therefore the timing of the primary analysis 
for this study, will also be performed at Week 24.
With the trend for clinical practice shifting to the earlier use of biologics, it is anticipated that 
patients will be treated with biologic therapies for a longer duration over the course of their disease. 
As such, the availability of a treatment option with prolonged maintenance of efficacy and a 
favorable long-term safety profile, such as abatacept, would be highly desirable for these patients. 
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Therefore,
the OLTP
will have a longer duration (80 weeks) as compared with
IM101567 (24 weeks).
5.4.4
Rationale for Choice of Comparator Arm
The active comparator in this study is adalimumab, a recombinant human IgG1 monoclonal 
antibody specific for the human TNF. Adalimumab is approved for use in the treatment of RA. 
Because this study aims to confirm the higher efficacy of abatacept vs adalimumab observed in 
IM101567,44 the dose of adalimumab will remain the same as that in IM101567; however, instead 
of the 40 mg/0.8 mL formulation of adalimumab, the choice of comparator for this study will be 
the citrate-free formulation of adalimumab (40 mg/0.4 mL [smaller volume]) in the prefilled 
syringe presentation that has a smaller-gauge needle than the 40 mg/0.8 mL forumlation.51 In a 
randomized crossover comparison study of participants withRA, the citrate-free 40 mg/0.4 mL 
adalimumab formulation was associated with less injection site-related pain than the 40 mg/0.8 mL 
adalimumab formulation, with a tolerability and safety profile consistent with 40 mg/0.8 mL 
adalimumab.64
Participants will receive background MTX in both study arms. MTX is a cornerstone in the 
treatment of RA. Based on the IM101023 study,52 the addition of abatacept to MTX is superior to 
MTX alone in inducing DAS-defined remission after a year of treatment in participants who have 
serologically positive early RA and are MTX-naive. In the control arm (initially treated with MTX
alone), joint damage was more notable after the second year of open-label treatment (during which 
abatacept was added to MTX) than in the cohort that received combination therapy from the 
beginning of the study. In addition, the safety profile of the combination was similar to MTX alone.
5.4.5
Rationale for Switching
In IM101567,44 participants in the adalimumab arm were required to undergo a 6-week washout
period prior to receiving the first dose of open-label abatacept. The primary reason for this washout 
was to enable comparative immune biomarker analysis of these 2 biologic DMARDs with distinct 
mechanisms of action. Notably, based on the ARRIVE study, there is no safety-related concern 
with administering abatacept following treatment with a TNF inhibitor agent, including
adalimumab, without a washout period.65 Therefore, in IM101863, where the objective is focused 
on demonstrating differential efficacy, there is no requirement for an adalimumab washout before 
starting open-label abatacept.
5.5
Justification for Dose
The doses of abatacept and adalimumab will be the same as those used in IM101567.44 The 
selected SC doses of both abatacept and adalimumab are the globally approved doses for the 
treatment of RA in patients receiving MTX.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
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6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participant is willing to participate in the study and has signed the ICF.
2) Type of Participant and Target Disease Characteristics
a) Participants have early RA, defined as symptoms of RA that started 12 months prior to 
screening and satisfied the ACR/EULAR 2010 criteria for the classification of 
RA (Appendix 13) at some point during the 12-month period. Participants who had a single 
isolated episode of palindromic symptoms that occurred less than 2 years prior to 
enrollment are still eligible.
b) Participants will have the HLA-DRB1 alleles genotyped during screening and will be 
identified as carrying at least 1 copy of the SE alleles or not. The list of alleles comprising 
the SE are listed in Section 9.8.1. 
 
c) Participants must be naive to any targeted (biologic or nonbiologic) DMARDs.
d) Participants must be naive to conventional synthetic DMARDs other than MTX.
e) Participants must be naive to investigational therapies for RA. 
f)
Participants must have been treated with MTX for at least 12 weeks, with a stable dose of 
oral or parenteral MTX for at least 4 weeks prior to randomization. Participants must 
randomize on the maximum tolerated dose of oral or parenteral MTX (minimum of 15 mg 
and maximum of 25 mg per week). Participants may enroll with MTX doses < 15 mg/week 
but 7.5 mg/week if intolerance to higher doses has been documented and the dose of oral 
or parenteral MTX is stable for 4 weeks prior to randomization. Participants in Japan may 
also enroll at doses between 7.5 and 15 mg per week at the discretion of the investigator.
 
h) Participants must have at least a DAS28-CRP 3.2 (Appendix 14, Appendix 15) at 
screening.
i)
Participants must have currently at least 3 tender and at least 3 swollen joints (excluding 
distal interphalangeals) at screening and at randomization.
j)
Participants receiving oral corticosteroids must be on a stable dose and at the equivalent of 
10 mg prednisone daily for at least 4 weeks prior to randomization. Participants may not 
receive an intramuscular (IM), IV, or intra-articular administration of a corticosteroid 
within 4 weeks prior to randomization.
k) Participant Rescreening: This study permits the rescreening of a participant who has 
discontinued the study as a pretreatment failure (ie, participant
has not been 
randomized/has not been treated)and still meets all inclusion/exclusion criteria. 
If rescreened, the participant must be re-consented. Participants can only be rescreened 
once.
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3) Age and Reproductive Status
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 serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 24 hours 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) Women must not be breastfeeding and must agree not to breastfeed during the study 
and for 100 days thereafter.
vi) Additional requirements for pregnancy testing during and after study intervention are 
located in Section 2, Schedule of Activities.
vii)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.
viii)
WOCBP must agree to follow instructions for method(s) of contraception defined 
in Appendix 4 and as described below and included in the ICF.
ix) WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4).
x) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 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 (5 half-lives 
of the study treatment), 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 not exempt from contraceptive requirements and 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 participant has undergone a 
successful vasectomy or if the partner is pregnant.
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iv) 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. Males should continue to use a condom during the 
intervention period and for at least 70 days (5 half-lives of the study treatment) after 
the last dose of study intervention. 
v) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least
70 days (5 half-lives of the study treatment) after the last dose of study intervention in 
the male participant.
vi) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual
activity or use a male condom during any sexual 
activity (eg, vaginal, anal, oral), even if the participants have undergone a successful 
vasectomy, during the intervention period and for at least 70 days (5 half-lives of the 
study treatment) after the last dose of study intervention.
vii)Male participants must refrain from donating sperm during the intervention period and 
for at least 70 days (5 half-lives of the study treatment) after the last dose of study 
intervention.
viii)
Breastfeeding partners should be advised to consult their health care providers 
about using appropriate highly effective contraception during the time the participant 
is required to use condoms.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the 
potential of fetal toxicity occurring due to transmission of treatment, present in seminal fluid, to a 
developing fetus, even if the participant has undergone a successful vasectomy or if the partner is 
pregnant.

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.
6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are breastfeeding.
b) Participants with autoimmune disease other than RA (eg, psoriasis, systemic lupus 
erythematosus [SLE], vasculitis, seronegative spondyloarthritis, inflammatory bowel 
disease, Sjogren’s syndrome) or currently active fibromyalgia.
c) Prior history of or current inflammatory joint disease other than RA (eg, psoriatic arthritis, 
gout, reactive arthritis, Lyme disease).
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d) Participants at risk for TB defined as follows:
i)
Current clinical, radiographic,
or laboratory
evidence of active TB. Chest 
x-rays (posterioranterior and lateral) obtained within the 3 months prior to obtaining 
written informed consent will be permitted, but the images must be available and 
reviewed by the investigator. TB testing (interferon gamma [IFN-release assay or 
PPD) performed in the past month prior to Screening will be accepted; however, a copy 
of the report must be placed in the participant binder.
ii) A history of active TB: within the last 3 years, even if it was treated; > 3 years unless 
there is documentation that the prior anti-TB treatment was appropriate in duration and 
type.
iii) Participants with a positive TB screening test (PPD or IFN-release assay) indicative 
of latent TB will not be eligible for the study unless they:
(1) Have no evidence of current TB based on chest x-ray performed during the 
screening period and by history and physical exam; and 
(2) Are actively being treated for TB or the site has documentation of successful prior 
treatment of latent TB. Treatment regimens should be dictated by local guidelines,
as long as the treatment dose and duration meet or exceed local Health Authority 
guidelines. If permitted by local guidelines regarding treatment with biologic 
medications, participants may be randomized prior to completion of treatment as 
long as they have completed at least 4 weeks of treatment and they have no evidence 
of current TB on chest x-ray at screening. 
e) Participants with recent acute infection, defined as:
i)
Any acute infection within 60 days prior to randomization that required hospitalization 
or treatment with parenteral antibiotics.
ii) Any acute infection within 30 days prior to randomization that required oral 
antimicrobial or antiviral therapy.
iii) In the case of prior SARS-CoV-2 infection within 30 days prior to enrollment, 
symptoms must have completely resolved with no clinically significant sequelae that 
would indicate a higher risk of participation in the study. Investigators should consult 
with the Clinical Trial Physician the decision to randomize these participants.
f)
Participants with history of chronic or recurrent bacterial infection (eg, chronic 
pyelonephritis, osteomyelitis, bronchiectasis).
g) Participants with any history of infection of a joint prosthesis or artificial joint.
h) Participants who have a history of systemic fungal infections (such as histoplasmosis, 
blastomycosis, or coccidiomycosis).
i)
Participants with history of recurrent herpes zoster (more than 1 episode) or 
disseminated (more than 1 dermatome) herpes zoster or disseminated herpes simplex or 
ophthalmic zoster will be excluded. Symptoms of herpes zoster or herpes simplex must 
have resolved more than 60 days prior to screening. Participants with history of human 
immunodeficiency virus (HIV) infection or who test positive for HIV at screening.
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j)
Participants with history of primary immunodeficiency.
k) Participants who have a present malignancy or previous malignancy within the last 5 years 
prior to screening (except documented history of cured nonmetastatic squamous or basal 
cell skin carcinoma or cervical carcinoma in situ). Participants who had a screening 
procedure that is suspicious for malignancy and in whom the possibility of malignancy 
cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic 
evaluations.
l)
Current clinical findings or a history of a demyelinating disorder.
m) New York Heart Association (NYHA) Class III or IV heart failure.
n) Any previous or current medical conditions that are warnings against the use of TNF 
inhibitor agents.
o) 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. Concomitant medical conditions that, in the opinion of the 
investigator, might place the participant at unacceptable risk for participation in this study.
p) 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. Study participants 
should not be administered a live virus vaccine for a minimum of 3 months following the 
last dose of study medication. Participants who are in close contact with others who have 
received a live vaccine may be enrolled at the investigator’s discretion.
q) Participants who have received live attenuated or replication-competent vector
SARS-CoV-2 vaccines within 3 months of study enrollment.
r)
Participants who have undergone a major surgical procedure within the 60 days prior to 
randomization.
s) Participants for whom 5 or more joints cannot be assessed for tenderness or 
swelling (ie, due to surgery, fusion, amputation, etc).
t)
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.
u) Participants who are impaired, incapacitated, or incapable of completing study-related 
assessments.
2) Prior/Concomitant Therapy
a) Participants who have had previous exposure to abatacept or adalimumab.
b) Participants who have had previous exposure to conventional synthetic DMARD other than 
MTX. Prior exposure to sulfasalazine or hydroxychloroquine for less than 6 weeks prior to 
randomization will be allowed.
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c) Participants who have been exposed to any treatment with an approved or investigational 
biologic DMARD, including, but not limited to, infliximab, etanercept, anakinra, 
rituximab, tocilizumab, golimumab, and certolizumab, or an investigational or approved 
targeted synthetic DMARD, including, but not limited to, tofacitinib, baricitinib, 
upadacitinib, or filgotinib.
d) Participants who have received an IM, IV, or intra-articular administration of a 
corticosteroid within 4 weeks prior to randomization (Day 1).
e) Participants currently taking NSAIDs must have been on a stable dose, as assessed by the 
investigator, for at least 14 days prior to randomization.
3) Physical and Laboratory Test Findings
a) Hepatitis B surface antigen (HBsAg)-positive, or hepatitis B core antibody (HBcAb)
positive participants with detectable hepatitis B viral deoxyribonucleic acid (DNA).
b) Hepatitis C antibody (HcAb)-positive participants with detectable hepatitis C viral RNA.
c) Hemoglobin (Hgb) < 8.5 g/dL.
d) White blood count (WBC) < 3,000/mm3 (3× 109/L).
e) Platelets < 100,000/mm3 (100× 109/L).
f)
Serum creatinine > 2× ULN.
g) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2× ULN.
h) Evidence of active cardiac or pulmonary disease on chest x-rays.
i)
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 1 of the IPs 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 BMS 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. No restrictions are required.
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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 SAEs.
6.4.1
Retesting During Screening or Lead-in Period
Participant Re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented. If the initial screen failure was 
due to a medical concern (eg, TB assessment), the site must notify the Clinical Trial 
Physician/Medical Monitor of the intent to rescreen, describe the cause of the initial screen failure 
and the resolution of the medical consent, and receive approval prior to proceeding. This 
communication must be documented in the study record.
All screening procedures are to be performed within 4 weeks of the randomization visit except as 
described below.
6.4.1.1
Retesting
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value)
for laboratory errors.
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.
Laboratory parameters and/or assessments that are included in Table 2-1 may be repeated in an 
effort to find all possible well-qualified participants. Consultation with the Clinical Trial 
Physician/Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
6.4.1.2
Extended Screening
Participants who experience a delay in completing screening may extend the screening period to 
42 days, as long as this delay was not due to an intercurrent significant medical illness such as an 
infection requiring hospitalization or administration of parenteral antibiotic agents. This extension 
is intended to address nonmedical issues or extended medical assessments (eg, acute infection or 
assessment of latent TB). For medical events, like initiation of treatment for latent TB, 
consideration should be given to screen failure with the expectation of rescreening after resolution 
and approval from the Clinical Trial Physician/Medical Monitor.
If screening is extended beyond 28 days, all screening procedures except IRT enrollment, 
height/weight, urinalysis, anti-CCP-2, RF, HLA-DRB1 SE alleles, chest x-ray, TB, hepatitis B 
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virus (HBV)/hepatitis C virus (HCV), and HIV testing, should be repeated prior to randomization, 
as noted in Table 2-1.
6.4.1.3
Rescreening
This study permits the rescreening of a participant who has discontinued the study as a 
pretreatment failure (ie, participant has not been randomized/has not been treated) and still meets 
all inclusion/exclusion criteria. If rescreened, the participant must be re-consented. A participant
may be rescreened only once. Clinical Trial Physician/Medical Monitor approval is required for 
screen failures due to medical concerns, and rescreens are not permitted less than 28 days after 
signing the first ICF. The participant will need to sign a new ICF and be re-enrolled with a new 
participant number via the IRT. Chest x-ray and TB screening will not be repeated if they were 
performed within the last 3 months, and prior results must be added to the study record. SE
genotyping will not be repeated, and results from prior testing should be added to the study record.
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.
Study treatment includes both IP/investigational medicinal product (IMP) and non-IP/non-IMP, 
and can consist of the following (see Table 7-1):
IPs to be supplied by the Sponsor:

Abatacept (BMS-188667)

Adalimumab (citrate-free formulation in prefilled syringe)
Non-IPs (the Sponsor will not provide non-IPs):

MTX

Corticosteroids

NSAIDs (including aspirin)

Folic acid and/or folinic acid (leucovorin)
An IP, also known as IMP in some regions, is defined as 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-IP.
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Table 7-1:
Study Treatments for IM101863
Product Description/
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open-label
Packaging/ 
Appearance
Storage Conditions
(per label)
Abatacept Injection
125 mg/mL
IP
Open-label
Prefilled syringe
Refer to the label on the container.
Adalimumab Injection
40 mg/0.4 mL
IP
Open-label
Prefilled syringe
Refer to the label on the container.
Abbreviations: IMP, investigational medicinal product; IP, investigational product.
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7.1
Treatments Administered
The selection and timing of dose for each participant is provided in Table 7.1-1.
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
125 mg
Weekly
SC injection
Adalimumab
40 mg
Once every 2 weeks
SC injection
Abbreviations: mg, milligram; SC, subcutaneous.
On “office visit” days, study medication should be administered AFTER all assessments have been 
completed.
7.1.1
Abatacept Treatment
On Day 1, participants will self-administer abatacept 125 mg SC from a prefilled syringe. 
On Day 8, participants will self-administer abatacept 125 mg SC. Thereafter, participants will 
self-administer abatacept 125 mg SC once every 7 days, up to and including Week 103 (Day 722).
Participants randomized to adalimumab will switch to abatacept 125 mg SC weekly at 
Week 24 (Day 169).
7.1.1.1
Abatacept Self-administration of Subcutaneous Injection
Each prefilled syringe contains 1 weekly dose of abatacept, 125 mg/mL. Participants will be 
trained to self-administer their weekly SC injection. Training should be performed by 
investigational personnel who are considered qualified trainers by the site principal investigator. 
A procedure guide will be provided by the Sponsor. The participant should be able to 
self-administer the SC injection between office visits or have an office-trained caregiver do so.
On office visit days, SC injections should be given AFTER all assessments are completed, 
including blood draws. If a caregiver is responsible for giving the injections, he or she should 
accompany the participant to office visits.
7.1.1.2
Abatacept Administration Window
SC injections of study medication may be administered 3 days around the target day. The last 
dose before each office visit should be administered at least 4 days before the scheduled visit date. 
If an SC injection is not given within the administration window, the next SC injection should be 
given on the next scheduled target administration day.
7.1.2
Adalimumab Treatment
Participants randomized to adalimumab will self-administer an initial dose of adalimumab 40 mg 
SC from a prefilled syringe on Day 1. On Day 15, participants will self-administer adalimumab 
40 mg SC. Thereafter, participants will self-administer adalimumab 40 mg SC once every 14 days, 
up to and including Week 22 (Day 155). 
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Participants randomized to adalimumab will switch to abatacept 125 mg SC weekly at Week 24
and continue with the self-administration of abatacept 125 mg SC once every 7 days, up to and 
including Week 103. 
Participants not wishing to continue on open-label abatacept have the option of discontinuing 
treatment at the end of the SBTP and proceeding to the PTFUP.
7.1.2.1
Adalimumab Self-administration of Subcutaneous Injection
Each prefilled syringe contains 1 biweekly dose of adalimumab, 40 mg/0.4 mL. Participants will 
be trained to self-administer their biweekly SC injection. Training should be performed by 
investigational personnel who are considered qualified trainers by the site principal investigator. 
A procedure guide will be provided by the Sponsor. The participant should be able to 
self-administer the SC injection between office visits or have an office-trained caregiver do so.
On office visit days, SC injections should be given AFTER all assessments are completed, 
including blood draws. If a caregiver is responsible for giving the injections, he or she should 
accompany the participant to office visits.
7.1.2.2
Adalimumab Administration Window
SC injections of study medication may be administered 7 days around the target day. The last 
dose before each office visit should be administered at least 7 days before the scheduled visit date. 
If an SC injection is not given within the administration window, the next SC injection should be 
given on the next scheduled target administration day.
7.1.3
Guidelines for Methotrexate
Participants must enroll on a stable dose of maximum tolerated oral or parenteral MTX (minimum 
of 15 mg and maximum of 25 mg per week) for at least 4 weeks prior to randomization.
Participants may enroll with MTX doses < 15 mg/week but 7.5 mg/week if intolerance to higher 
doses has been recorded in the source documents and the dose of oral or parenteral MTX is stable 
for 4 weeks prior to randomization. Participants in Japan may also enroll at doses between 7.5 and 
15 mg per week at the discretion of the investigator.
All participants must be maintained on the enrollment MTX dose during the SBTP, unless toxicity 
or intolerability occurs during the course of the study. In that event, the dose may be reduced or 
held as medically necessary for AEs. However, MTX should be returned to the baseline dose as 
soon as possible, or to the maximally tolerated dose below the baseline dose, but not less than 
7.5 mg/week for the duration of the study. MTX should be given orally or parenterally.
Switching between routes of administration of MTX or dose adjustment for any reason other than 
toxicity is not permitted during the SBTP. Adjustments in MTX dosing and route of administration 
are allowed at the investigator’s discretion in the OLTP. 
All participants must receive folic acid, folinic acid, or leucovorin according to the manufacturer’s 
recommendations.
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7.2
Method of Treatment Assignment
All participants will be centrally randomized using an IRT. Before the study is initiated, each user 
will receive log-in information and directions on how to access the IRT. Each participant will be 
assigned a unique participant number after signing the ICF. Participant numbers will be used on 
all participants’ study information. Participant numbers will not be reassigned. The investigator or 
designee will register the participant for enrollment by following the enrollment procedures 
established by the Sponsor.
The following information is required for enrollment:

Date that informed consent was obtained

Year of birth

Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for participant randomization:

Participant number

Year of birth

Gender at birth (female or male)

SE status (positive or negative)
The exact procedures for using the IRT will be detailed in the IRT manual.
Study treatment will be dispensed at the study visits as listed in Section 2 (Schedule of Activities).
Sufficient drug will be dispensed at each visit to cover treatment until the next scheduled visit. 
These will be in intervals of 4, 8, or 12 weeks according to the visit schedule.
7.3
Blinding
Double blinding of study drug, adalimumab vis-à-vis abatacept, is not feasible due to logistical 
barriers around repackaging adalimumab as well as the expected differences in injection-site 
reactions. Both of these together make effective blinding of the patients to the randomized drug 
assignment impractical and unsustainable. The nature and frequency of adalimumab-associated 
injection-site reactions make blinding investigators responsible for clinical care unsustainable 
under usual practices. It is possible, however, to preserve the objectivity of clinical assessments 
with the following strategy that has been designed to establish and maintain a single-blinded 
assessor for clinical endpoints throughout the study. This will require a minimum of 3 individuals: 
a blinded Clinical Assessor, an unblinded Study Research Coordinator, and an unblinded physician 
investigator/sub-investigator to complete/approve the case report form (CRF).
Clinical Assessors will be blinded to treatment allocation so as to preserve the objectivity of 
study-related assessments (tender and swollen joint count, Physician’s Global Assessment of 
Disease Activity [PGA], AE causality assessment) and routine clinical care (laboratory result 
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review, medication adjustment). To preserve blinding, they must be shielded from treatment 
allocation throughout the entire study. This will be the responsibility of the Study/Research 
Coordinators who need not be blinded to treatment allocation. At the beginning of each study visit 
throughout the study duration, the participant should be reminded that the Clinical Assessor is 
blinded to treatment allocation and that care must be taken to prevent revealing treatment 
allocation. They should be instructed to:

Not discuss study treatment by name

Not discuss the color or use of the prefilled syringe

Not discuss how often injections are performed

Only discuss injection-site reactions of significant concern
To comply with requirements for CRF completion, a qualified physician who is an investigator or 
sub-investigator who is unblinded to study treatment assignment will be needed to promptly 
review, sign, and date the CRF.
The site should maintain 2 distinct sets of source documents: 1 set accessible to the unblinded site 
staff and 1 set for the blinded Clinical Assessor.
Care should be taken by the Study/Research Coordinator to retrieve any study treatment and sharps 
containers returned by the participant at the beginning of each visit to shield the assessor from 
inadvertent exposure to participant allocation. Similarly, study treatment dispensing should be 
done after blinded assessments. Both retrieval and dispensing of study treatment should be done 
in an area shielded from the blinded Clinical Assessor(s). 
The joint count assessment should be performed after completion of the patient-reported
outcomes (PROs), vital sign assessment, and AE assessment. The Clinical Assessor will similarly 
be reminded at the beginning of each study visit throughout the study duration that they are 
performing a blinded-assessment for the study and to not ask question or elicit comments that may 
reveal treatment allocation as outlined above. Every effort must be made to ensure the same 
evaluator(s) will complete the assessment for each participant. If the usual evaluator is not 
available, another trained evaluator blinded to study treatment allocation for the participant may 
perform the clinical assessment. In the event that no blinded evaluator is available during the study 
visit, blinded clinical assessment measures (tender and swollen joint counts and PGA) should not 
be reported.
In cases of accidental unblinding of blinded staff, contact the Clinical Trial Physician/Medical 
Monitor and ensure every attempt is made to preserve the blind. The purpose of this is to review 
options to continue blinded assessments and review site processes to prevent additional unblinding.
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7.4
Dosage Modification
7.4.1
Dose Modifications for Abatacept
7.4.1.1
Dose Modifications for Abatacept in the Absence of Adverse Events
Participants should complete their scheduled SC injections as described above. Participants who 
miss the dose window (± 3 days) should skip the SC injection and wait until the next targeted 
administration day.
7.4.1.2
Dose Modifications for Abatacept Due to Adverse Events
If abnormal laboratory test results or clinical AEs indicate toxicity that, in the judgment of the 
investigator, could place the participant at risk, study drug administration should be interrupted. 
If drug interruption exceeds 14 days, the investigator should notify the Sponsor’s Clinical Trial 
Physician/Medical Monitor. Participants may receive further study medication treatment only if 
full resolution of the AE or abnormal laboratory finding is documented. Under no circumstances 
should the dose of study drug be altered due to an AE.
7.4.2
Dose Modifications for Adalimumab
7.4.2.1
Dose Modifications for Adalimumab in the Absence of Adverse Events
Participants should complete their scheduled SC injections as described above. Participants who 
miss the dose window (± 7 days) should skip the SC injection and wait until the next targeted 
administration day.
7.4.2.2
Dose Modifications for Adalimumab Due to Adverse Events 
If abnormal laboratory test results or clinical AEs indicate toxicity that, in the judgment of the 
investigator, could place the participant at risk, study drug administration should be interrupted.
If drug interruption exceeds 14 days, the investigator should notify the Sponsor’s Clinical Trial 
Physician/Medical Monitor. Participants may receive further study medication treatment only if 
full resolution of the AE or abnormal laboratory finding is documented. Under no circumstances 
should the dose of study drug be altered due to an AE.
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study participants. The IP 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.
IP 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, 
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administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable.
7.6
Treatment Compliance
All participants are expected to receive study therapy as outlined in the protocol. Participants will 
use diary cards to document self-injection of study drug between office visits. Permitted dose 
modifications are described in Section 7.4. Conditions under which therapy must be discontinued 
due to noncompliance are outlined in Section 8.1.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
7.7.1.1
Prohibited Treatment During the Treatment Period

Conventional synthetic DMARDs other than methotrexate (including, but not limited to,
sulfasalazine, leflunomide, hydroxychloroquine, chloroquine)

Targeted synthetic DMARDs (including, but not limited to, tofacitinib, baricitinib, 
upadacitinib, or filgotinib)

Adrenal corticotropic hormone (ACTH)

Oral or parenteral gold

Quinacrine or other related antimalarials

D-penicillamine

Azathioprine

Oral cyclosporine

Nimesulide

Minocycline

Sirolimus

Everolimus

Tacrolimus

Mycophenolate mofetil (MPA)

6-mercaptopurine

All investigational or approved targeted (biologic or nonbiologic) RA therapies other than 
abatacept and adalimumab (including, but not limited to, tocilizumab, etanercept, anakinra, 
infliximab, rituximab, etc.)

Use of any investigational drug other than study medication

Any prohibited concomitant medication listed in the current Humira® (adalimumab) or 
Orencia® (abatacept) prescribing information51,60

Intra-articular injections of hyaluronic acid

Immunoabsorption (ie, Prosorba) column or cholestyramine
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
Administration of a live vaccine (FluMist; measles, mumps, rubella [MMR]; yellow fever;
etc.)
7.7.1.2
Restricted Treatments During the Treatment Period
Methotrexate:
For complete details on MTX use, see Section 7.1.3, Guidelines for Methotrexate.
Corticosteroids for Treatment of RA Symptoms:
All participants who are receiving oral corticosteroids must continue to receive the dose being 
administered at the time of signing the ICF throughout the 24-week controlled SBTP (this dose 
may not exceed the equivalent of 10 mg of prednisone), except if a decrease in dose is necessitated 
by toxicity. IV and IM corticosteroid injections are not permitted during the study except to treat 
AEs. Use of parenteral corticosteroids to treat AEs should be limited to the lowest dose possible 
and not exceed 14 days. If treatment is to exceed 14 days during the 24-week controlled SBTP, 
contact the Clinical Trial Physician/Medical Monitor to discuss. After Week 24, corticosteroid 
taper is allowed if deemed appropriate. Tapers exceeding the equivalent rate of 1 mg of 
prednisone (or prednisone equivalent) a week is not recommended.
One instance of intra-articular glucocorticoids (no greater than 40 mg methylprednisolone or 
40 mg of triamcinolone [or methylprednisolone or triamcinolone equivalent]) may be administered 
into 1 joint or divided into 2 joints. No intra-articular injections will be permitted within 42 days 
of the Week 24 visit. A joint that receives an intra-articular injection will be counted as “active” 
for the remainder of the study.
Inhaled corticosteroids for the treatment of asthma, chronic obstructive pulmonary
disease (COPD), etc, are permitted, but the dose should remain stable throughout the study. Other 
nonparenteral corticosteroid formulations, such as topical corticosteroid use, are permitted.
Analgesics and NSAIDs:

NSAIDs and analgesics (including topical NSAIDs) are not permitted within 12 hours before 
a joint assessment.

NSAIDs doses should remain stable, as assessed by the investigator, with the exception of 
decreases being permitted due to related AEs, such as gastric toxicity, during the initial 
24-week study period. After the initial 24-week study period, adjustment in NSAID use can be 
made at the discretion of the investigator.

Analgesics

Acetaminophen (paracetamol)
Average dose of 3 g/day
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No single dose exceeding 1 g
NOTE: combination products,
including acetaminophen and narcotic analgesics 
(eg, acetaminophen with codeine phosphate, acetaminophen with propoxyphene napsylate, 
acetaminophen with oxycodone HCl, acetaminophen with hydrocodone bitartrate), are 
allowed provided the acetaminophen component dosage is accounted for in the maximum 
of 3 g/day.

Narcotic analgesics must not exceed 30 mg/day of morphine or its equivalent.

Tramadol, gabapentin, and pregabalin are allowed, but doses must be stable throughout 
Treatment Period.

Acetylsalicylic acid is allowed in low doses (eg, 100 mg/day) for cardiovascular 
prophylaxis.

Analgesics are not permitted within 12 hours before joint assessments.

Short courses of NSAIDs and analgesics may be used to treat episodes of pain that are unrelated 
to arthritis, such as headache. Care should be taken to avoid taking these within 12 hours before 
a joint assessment.
7.7.2
Other Restrictions and Precautions
The prescribing label of all concomitant medications used as participant’s background therapy 
should be evaluated by the investigator for continued administration during the participant’s 
participation in this study (eg, known toxicities, drug-drug interactions). Participant eligibility and 
the decision to continue a participant in the study must take into consideration all precautions 
outlined in the locally approved labels for MTX, abatacept, and adalimumab.
7.7.2.1
Immunizations
Limited data are available on the effect of therapeutic vaccinations in participants receiving 
abatacept or adalimumab. All routine vaccinations should be administered prior to the study. 
SARS-CoV-2 vaccination, when available, is recommended prior to enrollment. If vaccination is 
performed near the expected enrollment date, delay enrollment until the vaccination series is 
completed and symptoms related to vaccination have resolved. If vaccination becomes available 
only after enrollment, vaccination can proceed at discretion of the investigator. These include 
genetic, protein-based, replication incompetent, or inactivated vaccine as approved by local 
authorities. All appropriate vaccination with non-live vaccines should be performed when 
appropriate based on local guidelines (eg, SARS-CoV-2 vaccine, seasonal influenza vaccine).
Please contact the Clinical Trial Physician/Medical Monitor with any questions related to 
COVID-19 vaccines.
Due to the risk of infection, vaccination of participants with any live vaccine is absolutely 
contraindicated during the study drug treatment period of the study, as is the administration of live
oral polio vaccine to household contacts. The Centers for Disease Control and Prevention (CDC) 
Advisory Committee on Immunization Practices (ACIP) recommends that participants should not 
be administered a live virus vaccination for at least 3 months after discontinuing high-dose 
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corticosteroid therapy (defined as more than 20 mg of prednisone per day for more than 2 weeks). 
In view of the long half-life of abatacept and adalimumab, study participants should not be 
administered a live virus vaccine for a minimum of 3 months following the last dose of study 
medication.
7.7.2.2
Infectious Complications
Participants who develop significant infectious complications during the study should be treated 
appropriately, have study medication withheld, and be restarted only when clinically resolved and 
the investigator considers it appropriate
7.7.2.3
Management of Possible Acute Hypersensitivity Reactions
Hypersensitivity resulting in severe, acute allergic reactions may occur as a result of the protein 
nature of abatacept and adalimumab. As defined in a recent consensus statement,66 anaphylaxis is 
highly likely if 2 or more of the following occur rapidly after administration of the study 
drug (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, generalized hives; itching or flushing; swollen 
lips, tongue, or uvula)

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)

Reduced blood pressure
or associated symptoms (eg, hypotonia/collapse, syncope, 
incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
Sites must be appropriately prepared to handle medical emergencies such as severe 
hypersensitivity, including anaphylaxis. Participants must be rapidly assessed and stabilized at the 
site and transferred to an emergency facility as required. If participants experience symptoms of 
severe allergic reactions at home, he/she should be advised to seek immediate medical attention, 
including a visit to the local emergency facility, as needed. The site will provide emergency contact 
information to the participant. A blood sample for analysis of anti-abatacept antibodies should be 
obtained in case of a hypersensitivity reaction.
The decision whether to continue treatment with the study drug will be left to the medical judgment 
of the investigator. Care should be taken to treat any acute toxicity expeditiously should they occur. 
Adequate equipment and trained health care personnel should be available to handle medical 
emergencies when they occur at the site.
7.8
Treatment After the End of the Study
At the end of the OLTP, 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
8.1
Discontinuation From Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:

Use of prohibited medication. Hold IP and contact Clinical Trial Physician/Medical Monitor 
to discuss ongoing participation.

Pregnancy

Missed doses. If the participant meets any of the following criteria, the Clinical Trial 
Physician/Medical Monitor should be contacted to discuss ongoing participation:

Missed greater than 6 doses of abatacept OR greater than 3 doses of adalimumab for any 
reason during the initial 24-week study period.

Missed greater than 4 consecutive doses of abatacept OR greater than 2 consecutive doses 
of adalimumab for any reason between Week 8 and Week 24 of the study period.

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 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 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.)
Refer to Section 2 (Schedule of Activities) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy. 
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).
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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 CRF page.
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment may continue to be followed. Participants who 
withdraw consent (according to Section 8.2) or are lost to follow-up (according to Section 8.3) will 
not be followed in this study; all other participants will continue to be followed for collection of 
follow-up data as required and in line with Section 2 (Schedule of Activities).
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 
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.
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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 Section 2 (Schedule of Activities) and are 
recommended to be performed in the following order:
1) PRO questionnaires
2) AE collection
3) Vital signs
4) Joint assessments
5) Investigator assessments
6) Blood draws
7) Study drug administration
Additionally, please note the following:

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.

Adherence to the study design requirements, including those specified in Section 2 (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 Section 2 (Schedule of Activities).
9.1
Efficacy Assessments
Questionnaires and investigator/participant assessments will be completed prior to study drug 
administration. 
9.1.1
Physician’s Global Assessment
The PGA (Appendix 7) can be performed by the principal investigator or sub-investigator. The 
sub-investigator preferably should be a qualified physician or Doctor of Medicine (MD). Where 
permitted by local practice and guidelines, a qualified Doctor of Osteopathy (DO), Physician 
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Assistant (PA), or Nurse Practitioner (NP) may perform the PGA. The staff member performing 
the PGA needs to meet the definition of blinded Clinical Assessor (see Section 7.3).
9.1.2
Joint Count Assessments
The Joint Count Assessor may perform the PGA for the same participant. For both assessments,
every effort should be made to ensure the same assessor is used for a given participant throughout 
the study. The staff member performing the joint count assessment needs to meet the definition of 
blinded Clinical Assessor (see Section 7.3).
Training and instruction on joint count assessments will be discussed at the Investigator’s Meeting 
or at other trainings and workshops. Any assessors at a site who were not trained by a centralized 
BMS trainer should receive instruction by their site primary assessor who has undergone a 
standardized joint assessment training by BMS or by another Sponsor (if the training by another 
Sponsor is approved by the Clinical Trial Physician/Medical Monitor). The secondary assessor 
may conduct joint counts for the trial only after having performed satisfactorily at least 3 patient 
assessments under the supervision of the primary assessor. Additional information related to joint 
assessor training will be provided by the Sponsor or a delegate.
Joint Count Assessors should have appropriate medical credentials and/or should be individuals 
with appropriate scientific/medical background who are experienced in performing joint 
assessments for the Sponsor’s Phase 3 RA studies. If the individual does not have medical 
credentials, documentation of their experience (preferably on a curriculum vitae) must be provided 
to the Sponsor’s Trial Manager, and their eligibility as Joint Count Assessor must be confirmed 
by the Sponsor’s Clinical Trial Physician/Medical Monitor before the individual’s participation in 
the study as Joint Count Assessor.
Visits should be scheduled with the availability of the assessor taken into account. If the assessor 
is unable to complete the evaluation, then another qualified individual can take the place of the 
initial evaluator, as long as the restrictions described above are still met. The substitute evaluator 
will have also examined and reviewed the participant with the initial assessor to ensure consistency 
between participant evaluations.
9.1.3
Patient-reported Outcomes
Participants will complete the Global Assessment of Disease Activity (visual analog scale [VAS]; 
Appendix 5), Assessment of Pain (VAS; Appendix 6), and HAQ-DI (Appendix 8). Participants 
will also complete the 36-item Short Form Survey (SF-36; Appendix 9) measure of health-related 
quality of life, the Work Productivity and Activity Impairment Questionnaire - Rheumatoid 
Arthritis (WPAI-RA; Appendix 10), the Functional Assessment of Chronic Illness Therapy -
Fatigue 
(FACIT-F;
Appendix 
11), 
and 
morning 
stiffness 
(MS) 
duration 
questionnaire (Appendix 12). 
Questionnaires should be completed by the participant prior to any procedures being performed at 
the visit, if possible. The forms should then be checked by site staff for completeness. If 
exceptional circumstances preclude the continued administration of measures using planned 
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modalities, then alternate administration methods may be required, including telephone 
administration by site staff.
The full scope of analysis will be outlined in the Statistical Analysis Plan (SAP).
9.1.3.1
36-item Short Form Survey
The SF-36 v2.0 (Appendix 9), which covers 8 health dimensions within 2 components, will be 
used to measure health-related quality of life.67 This tool has been validated for use in RA 
patients.68 It has been recommended by the Food and Drug Administration (FDA) for measuring 
broader effects of treatment on health-related quality of life in RA clinical studies.69
The physical component summary (PCS) of the SF-36 consists of these 4 subscales:

Physical functioning

Role-physical

Bodily pain

General health
The mental component summary (MCS) of the SF-36 consists of these 4 subscales:

Vitality

Social functioning

Role-emotional

Mental health
The 8 subscales will be scored using norm-based methods that have standardized the scores to a 
mean of 50 and a standard deviation of 10 in the general population. The scores range from 
0 to 100, with a higher score indicating better quality of life. The 2 summary scores (PCS and 
MCS) will be calculated by taking a weighted linear combination of the 8 individual subscales.
9.1.3.2
Work Productivity and Activity
The WPAI-RA v2 (Appendix 10) completed by the participant will be used in this study to measure 
aspects of productivity and activity impairment over the previous 7 days. The WPAI-RA is a 
6-item questionnaire that includes 2 visual analog scales: 1 for impact of disease on work and 1 for 
impact of disease on other daily activities.70,71
The WPAI-RA provides 4 types of scores:
1) Absenteeism (work time missed)
2) Presenteeism (impairment at work/reduced on-the-job effectiveness)
3) Work Productivity Loss (overall work impairment/absenteeism plus presenteeism)
4) Activity Impairment
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9.1.3.3
Fatigue 
Participant assessment of fatigue will be conducted using the FACIT-F Scale v4 (Appendix 11), a 
validated tool that measures the severity of fatigue over the past 7 days.72
This 
participant-completed questionnaire consists of 13 items, with response options rated on a scale 
of 0 to 4. Instrument scoring yields a range from 0 to 52, with higher scores representing better 
participant status (less fatigue). A total score is calculated by summing the responses.
9.1.3.4
Morning Stiffness
Prolonged MS is a common symptom for inflammatory arthritis like RA.73,74 In the past, it was 
used as part of the RA classification criteria.75 While assessment of MS has been recommended 
as part of the PROs in RA because it is associated with functional disability and pain, there has 
never been a validated assessment tool. The recommended assessment is to measure MS duration 
from time of waking to time of maximal improvement, as reported by the participant. We will 
ascertain duration of MS duration (in minutes) in a PRO questionnaire (Appendix 12) from the 
time of waking up to the time to maximal improvement in the stiffness that was experienced over 
the last week.73 For statistical analyses, MS duration will be analyzed as mean change from 
baseline in duration of MS and proportion of participants with change from baseline defined as 
none, mild (1-30 minutes), moderate (31-60 minutes), and severe (> 60 minutes) will be 
summarized.
9.1.4
Imaging Assessment for the Study
Not applicable.
9.2
Adverse Events
The definitions of an AE or 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. 
Casualty assessments for AEs or SAEs must be performed by a blinded Clinical Assessor (see 
Section 7.3). 
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 56 days of discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study treatment or protocol-specified procedure (eg, a follow-up skin biopsy).
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
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AE and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
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 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.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (malignancy, 
autoimmune diseases, injection-site reactions, and opportunistic infections) 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 toward the safety of participants and the safety of a 
product under clinical investigation are met.
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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 IB
and will notify the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), if appropriate, according to local requirements.
Sponsor or designee will be reporting AEs 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 suspected, unexpected serious adverse 
reaction (SUSAR) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
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 for
70 days (5 half-lives of the study treatment) 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 the 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. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
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 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF 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 (5 half-lives of the 
study treatment) 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 the Sponsor or designee to collect any pregnancy surveillance information from the 
female partner, the female partner(s) must sign an ICF for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
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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 vs low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs meeting the defined criteria must be reported as SAEs (see Section 9.2 and 
Appendix 3 for reporting details).
Potential DILI is defined as: 
1) Aminotransaminase (AT; ALT or AST) elevation > 3× ULN
AND
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
COVID-19-related AEs/SAEs
During the study, special attention will be taken on COVID-19-related AEs/SAEs. In cases where 
SARS-CoV-2 infection occurs, study treatment should be held and care should be provided as 
guided by local practice. This protocol does not further offer guidance nor restrictions on the 
management of SARS-CoV-2 infections. Please consult with the study Medical Monitor regarding 
the decision to resume treatment with study drug. 
COVID-19-related impact to the study will be captured in the general CRF pages and additional 
details for COVID-19 suspected or confirmed AEs/SAEs will be captured in specific clinical safety 
program (CSP) CRF pages.
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9.2.9
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
For this study, any dose of study treatment greater than the protocol-defined dose will be 
considered an overdose.
In the event of an overdose, the investigator should:
1) Closely monitor the participant for AEs/SAEs and laboratory abnormalities.
2) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
3) Notify the Clinical Trial Physician/Medical Monitor with a description of the event.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Clinical Trial Physician/Medical Monitor based on the clinical evaluation of 
the participant.
9.4
Safety
Planned time points for all safety assessments are listed in Section 2 (Schedule of Activities).
On Day 1, the results of all assessments must be reviewed to assure that eligibility requirements 
are met before contacting the Central Randomization System for the participant’s randomization 
assignment.
Participants who terminate treatment early should complete the appropriate ET Visit and the 
PTFUP Visits. The ET Visit should be as soon as possible after the last dose of study medication.
All assessments should be performed or administered prior to study drug administration unless 
otherwise indicated.
Only data for the procedures and assessments specified in this protocol should be submitted to the 
Sponsor on a CRF. Additional procedures and assessments may be performed as part of standard 
of care; however, data for these assessments should remain in the participant’s medical record and 
should not be provided to the Sponsor, unless specifically requested by the Sponsor.
9.4.1
Physical Examination
Physical examinations preferably should be performed by a qualified physician or MD. Where 
permitted by local practice and guidelines, a qualified DO, PA, or NP may perform the physical 
examination. 
The complete physical examination should include examination of the general appearance, 
HEEN (head, eyes, ears, nose), throat, neck, heart, lungs, abdomen, lymph nodes, liver, spleen, 
extremities, skin, and neurologic, psychiatric, and musculoskeletal examination. Height and 
weight will be part of the complete physical examination and recorded at screening.
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While the targeted physical examination may not be as comprehensive as the initial complete 
examination, key aspects of the targeted examination should evaluate important body systems 
clinically indicated. The targeted physical examination should include examination of the heart, 
lungs, and abdomen and may include other relevant body systems, such as the lymph nodes, liver, 
spleen, and breasts, at the discretion of the examiner. 
A physical examination may note any changes in the participant’s condition (body systems) since 
the last assessment and does not preclude examination of any other body systems as clinically 
indicated.
9.4.2
Chest X-ray
A posterior-anterior and lateral chest x-ray, performed during screening, is required for all 
participants unless performed within 3 months prior to obtaining written informed consent and 
documentation of the earlier x-ray is on file. Investigators must ensure that the results of the chest 
x-ray satisfy criteria for eligibility. The chest x-ray result will be recorded on the appropriate page 
of the CRF.
9.4.3
Physical Measurements
Weight and height are to be recorded at screening.
9.4.4
Vital Signs
Vital signs (seated blood pressure, heart rate, and temperature) will be recorded during every office 
visit and prior to dose administration, when applicable. Blood pressure and heart rate should be 
measured after the participant has been seated for at least 5 minutes.
9.4.5
TB Screening
A chest x-ray and physical examination are considered part of the process to assess a participant’s 
eligibility. In addition to a chest x-ray that does not show any evidence or suspicion of active or 
latent TB, a tuberculin test will be performed and interpreted according to local country Health 
Authorities and/or Medical Society guidelines. Some guidelines have specific recommendations 
for participants who are to receive biologics or immunosuppressant therapies (eg, RA experience 
with biologic agents)76,77 or who are immunocompromised and who have had prior Bacillus 
Calmette-Guérin (BCG) vaccination(s).78,79 (For ex-US sites, local guidelines endorsed by 
medical societies on PPD testing in participants with RA being treated with biologics may also 
apply.) Tuberculin skin testing is not contraindicated for persons who have been vaccinated with 
BCG. An IFN-γ release assay (eg, QuantiFERONGold or Tspot/ELISpot) is an acceptable 
alternative when skin testing for TB (ie, PPD) is not appropriate, feasible, or based on preference. 
TB screening test may be performed by qualified personnel and/or by a qualified local laboratory. 
If a TB test has been performed within 4 weeks prior to informed consent and clear documentation 
is available, the test result may be used to screen for eligibility.
9.4.6
Viral Hepatitis Screening and Monitoring
Screening participants with serologic evidence of HBV infection (HBsAg-positive or 
anti-HBcAb-positive) are at risk for HBV reactivation if they receive immunosuppressive therapy,
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such as adalimumab or abatacept. The risk increases with use of concomitant immunosuppressive 
drugs (eg, MTX). Risk is highest in participants who are HBsAg-positive. Reactivation in 
participants who are HBsAg-negative but anti-HBcAb-positive receiving immunosuppressive 
therapy (eg, MTX) is rare.80 The American Association for the Study of Liver Diseases (AASLD)
recommendations consider these patients to be at very low risk of HBV reactivation. HBV 
reactivation can be asymptomatic and have normal liver chemistries.81
Participants in this study will be screened for chronic or occult HBV infection with testing for 
HBsAg and anti-HBcAb-positive.82 Participants positive for HBsAg will be excluded from this 
study. Participants positive for anti-HBcAb will have reflex testing for HBV DNA. Participants
positive for anti-HBcAb and HBV DNA will be excluded from this study. Participants positive for 
anti-HBcAb but negative for HBV DNA (as defined by the lower limit of testing sensitivity) will 
be allowed to be randomized. These participants will be closely monitored for clinical and 
laboratory signs of HBV reactivation. HBV DNA testing should be performed on a monthly basis 
after initiation of treatment, for 6 months, along with review of liver chemistries. After 6 months, 
the interval and duration of surveillance should be decided at the investigator’s discretion and in 
accordance with local guidelines. In the event of HBV reactivation, study treatment should be 
discontinued and local guidelines followed for management (eg, treatment with entecavir or 
tenofovir).
There is much less concern for worsening of untreated HCV infection with immunosuppressive 
treatment but participants with evidence of active HCV infection will be excluded from this trial. 
Participants will be tested for HCV antibody, and those positive will reflex to HCV RNA testing. 
Participants with detectable levels of HCV RNA will be excluded.
9.4.7
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
A list of the clinical laboratory assessments to be tested is provided below in Table 9.4.7-1. 
Assessments will be carried out as outlined in Section 2 (Schedule of Activities) by a central and/or 
local laboratory. Additional information on specific local requirements and laboratory guidelines 
is provided in Appendix 16 and Appendix 17.
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Table 9.4.7-1:
Clinical Safety Laboratory Assessments
(Performed Centrally Unless Otherwise Stated)
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Blood Chemistry
Sodium
Potassium
Chloride
Total protein
Albumin
Calcium
Phosphorus
Glucose
Creatinine
BUN
Total bilirubin
ALT
AST
GGT
Alkaline phosphatase
hsCRP
Urinalysis
pH, protein, glucose, blood
Microscopic examination of the urine sediment if blood, protein, or glucose is positive on the dipstick.
Serology (screening only)
Hepatitis B surface antigen, hepatitis B core antibody. If positive, reflex HBV DNA testing must be performed.
Hepatitis C antibody. If positive, reflex HCV RNA testing must be performed.
HIV testing performed only where required or local standard of care (may be analyzed locally).
Other Analyses
TB screening: PPD or IFN-γ release assay (at screening only, may be analyzed locally); see Section 9.4.5.
Pregnancy test for WOCBP only: urine pregnancy test, serum pregnancy test as needed.a (Performed locally.)
FSH (as needed; refer to Appendix 4).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
DNA, deoxyribonucleic acid; FSH, follicle-stimulating hormone; GGT, gamma-glutamyltransferase; HBV, hepatitis 
B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN-γ, interferon gamma; 
hsCRP, high-sensitivity 
C-reactive 
protein; 
PPD, 
purified 
protein 
derivative; 
RNA, ribonucleic 
acid; 
WOCBP, women of childbearing potential.
a A serum test must be performed for confirmation of any positive urine test result. Urine tests can be processed 
locally and can be self-administered by the participant between office visits, if permitted by local regulations. If any 
female participant becomes pregnant, she will stop receiving study treatment immediately and enter the 
Post-treatment Follow-up Period (PTFUP). A pregnancy surveillance form will be completed and submitted to the 
Sponsor. 
9.4.8
Imaging Safety Assessment
Not applicable.
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9.5
Pharmacokinetics and Immunogenicity
Not applicable.
9.6
Pharmacodynamics
Not applicable.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
9.8.1
HLA-DRB1 Shared Epitope Alleles
In this study, whole blood will be collected to assess SE alleles. The alleles considered to be part 
of the SE will include those with the following amino acid sequence in positions 70-74 and the 
respective alleles (see Table 9.8.1-1). Results of SE genotyping must be received prior to 
randomization.
Table 9.8.1-1:
Shared Epitope-positive HLA-DRB1 Alleles
AA 70-74 Sequence
HLA-DRB1 Alleles
QKRAA
*04:01, *04:09, *04:13, *04:16, *04:21, *04:35, *04:66, *14:19, *14:21
QRRAA
*01:01, *01:02, *01:05, *04:04, *04:05, 04:08, *04:10, *04:19, *14:02, *14:06, 
*14:09, *14:13, *14:17, *14:20
RRRAA
*10:01
Abbreviations: AA, amino acid; HLA-DRB1, human leukocyte antigen Class II histocompatibility antigen, DRB1 
beta chain.
 
 
 
 
 
 
 
 
 
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Table 9.8.2-1:
Biomarker Sampling Schedule (All Participants)
Study Day of Sample Collectiona
anti-CCP-2 
and RF
HLA-DRB1 
Shared 
Epitope Allele
Screening
X
X
Day 1 Visit 1 (Randomization)
X
Week 4 Visit 2 (Day 29)c
Week 12 Visit 4 (Day 85)c
X
Week 24/ET Visit 7a (Day 169)c
X
Week 36 Visit 10 (Day 253)d
X
Week 52 Visit 14 (Day 365)d
X
Week 104/ET Visit 20 (Day 729)d
X
Abbreviations: anti-CCP-2, anti-cyclic citrullinated peptide-2; 
 ET, early termination; HLA-DRB1, human leukocyte antigen Class II 
histocompatibility antigen, DRB1 beta chain; 
 Rand., randomization; RF, rheumatoid factor; 
 
a All biomarker sampling must take place prior to study drug administration.
c Samples can be collected ± 3 days from scheduled time point.
d Samples can be collected ± 7 days from scheduled time point.
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9.8.2.1
Autoantibodies
Levels of autoantibodies (eg, anti-CCP-2 and RF) associated with RA will be collected and 
analyzed at the visits outlined in Table 9.8.2-1. The levels of other autoantibodies will be measured 
using serum biomarker samples collected at the visits outlined in Table 9.8.2-1. Additional 
exploratory autoantibody analyses,
including but not limited to,
anti-modified protein 
antibodies (AMPAs), ACPA isotypes, ACPA fine-specificities, and/or ACPA-glycosylation may 
be performed, if deemed relevant. Details for collection, processing, storing, and shipment of these 
samples will be provided in a separate Laboratory Manual.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8.3
Additional Research Collection
 
 
For All US Sites:
AR is required for all study participants, except where prohibited by IRBs/ethics committees, or 
academic/institutional requirements. Where 1 or more of these exceptions occurs, participation in 
the AR should be encouraged but will not be a condition of overall study participation.

If the IRB/ethics committees and site agree to the mandatory AR retention and/or collection, 
then the study participant must agree to the mandatory AR as a requirement for inclusion in 
the study.

If optional participation is permitted and approved, then the study participants may opt out of 
the AR retention and/or collection.
For Non-US Sites
AR is optional for all study participants, except where retention and/or collection is prohibited by 
local laws or regulations, ethics committees, or institutional requirements. 
This collection for AR is intended to expand the translational research and development (R&D)
capability at BMS, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support Health Authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment, etc. 
Sample Collection and Storage
All requests for access to samples or data for AR will be vetted through a diverse committee of the 
study Sponsor’s senior leaders in R&D (or designee) to ensure the research supports appropriate 
and well-defined scientific research activities.
 
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
 
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Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
9.8.4
Other Assessments
Not applicable.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
specifically captured and evaluated as a primary part of this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The planned sample size is approximately 150 participants per treatment group. Assuming that 
about 3/4 of the participants would be SE+, this would lead to approximately 112 SE+ participants 
per treatment group. 
 
 
 
 
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To preserve an overall type I error rate of 5%, the primary endpoint and secondary efficacy 
endpoints will be assessed using a hierarchical testing approach. The hierarchy in secondary 
endpoints is determined by the order they are listed in Table 4-1 and is as follows:
1) Proportion of participants meeting ACR50 response at Week 24 in the SE+ subpopulation.
2) Proportion of participants achieving DAS28-CRP remission (< 2.6) at Week 24 in the SE+ 
subpopulation.
3) Proportion of participants meeting ACR50 response at Week 24 in the full study population.
4) Proportion of participants achieving Clinical Disease Activity Index (CDAI) remission (≤2.8) 
at Week 24 in the SE+ subpopulation.
5) Mean change from baseline in participant-reported pain at Week 24 in the SE+ subpopulation.
Each endpoint will be tested with a 2-sided alpha level of 5% if the endpoints at a higher level in 
the hierarchy are statistically significant. The testing will stop as soon as an endpoint is not 
statistically significant.
Assuming that the difference between treatment groups in the primary endpoint will be statistically 
significant, the samples size of 112 per arm will have 
 power to detect a difference in 
DAS28-CRP remission in SE+ population at Week 24 (Day 169) under the assumption of a 
response rate of 
as observed in the SE+ subgroup in IM101567. 
Assuming that both ACR50 and DAS28-CRP remission are statistically significantly different 
between the treatment groups in the SE+ population, there will be 
 power to detect a difference 
in ACR50 between the treatment groups in the entire population (SE+ and SE-) with a sample size 
of 150 per group and assuming response rates of 
 as in IM101567. 
Assuming all endpoints higher in the hierarchy are statistically significantly different between the 
treatment groups, the sample size of 112 per arm will have 
 power to detect a difference in 
CDAI remission (≤ 2.8) at Week 24 if the underlying remission rate is 
 per 
treatment group as observed in the SE+ subgroup of IM101567. 
Assuming all endpoints higher in the hierarchy are statistically significantly different between the 
treatment groups, a sample size of 112 per group will have 
 power to detect a difference 
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between the groups in mean change from baseline in participant-reported pain at Week 24. This 
assumes that the underlying mean change from baseline is 
 as observed in the SE+ 
subgroup of IM101567, with a common standard deviation of 
, using a 2-group t-test with 
0.05 2-sided significance level.
10.2
Populations for Analyses
The populations for the purpose of analyses are defined in Table 10.2-1.
Table 10.2-1:
Populations for Analyses
Population
Description
Enrolled 
All participants who sign informed consent form.
Modified 
Intent-to-treat 
Analysis 
Population
All randomized participants who receive at least 1 dose of study medication. This population 
will exclude participants who are randomized, but not treated. Analyses using the mITT 
analysis population will group the participants according to the treatment group to which 
they are randomized. All efficacy analyses will use the mITT population.
Intent-to-treat 
Population
All randomized participants, also those who are never treated. Participants who were 
randomized and never treated
and did not return for any assessments after 
discontinuation (ie, lost to follow-up or withdrew consent) will be excluded from the ITT 
analysis population. This population may be used for a sensitivity analysis of the primary
endpoint. Analyses using the ITT analysis population will group the participants according
to the treatment group to which they are randomized.
Per-protocol 
Analysis 
Population
All randomized participants who receive at least 1 dose of study medication, excluding the 
participants with relevant protocol deviations. Relevant protocol deviations are those that 
potentially may impact the primary efficacy outcome. The criteria for relevant protocol 
deviations will be defined in the SAP. Analyses using the PP analysis population will 
group the participants according to the treatment group to which they are randomized.
As-treated Analysis 
Population
All participants who receive at least 1 dose of studymedication. Analyses using the as-treated 
analysis population will group the participants on an as-randomized basis unless a participant
received the incorrect medication for the entire period of treatment. In that case, the 
participant will be analyzed in the treatment group associated with the incorrect medication
they received (“as-treated”). The as-treated analysis population will be used for safety 
analyses of the SBTP.
Cumulative 
Abatacept 
Population
All randomized participants who receive at least 1 dose of abatacept during the SBTP and/or 
the OLTP. All participants of the as-treated population will be included, except for 
participants treated with adalimumab in the SBTP who never entered the OLTP.
Subgroup of SE+ 
Participants
The subgroup of participants that are SE+ at baseline.
Abbreviations: ITT, intent-to-treat; mITT, modified intent-to-treat; OLTP, Open-label Treatment Period; 
PP, per-protocol; SBTP, Single-blind Treatment Period; SC, subcutaneous; SE+, shared epitope-positive.
10.3
Statistical Analyses
A description of the participant population will be included in a 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 intent-to-treat (ITT) population. 
Continuous variables such as age and weight will be summarized using means, standard deviations, 
median, and ranges. Categorical variables such as gender, race, and region, will be summarized 
using frequencies.
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10.3.1
Efficacy Analyses
Hierarchical testing of the primary and key secondary endpoints, as described in Section 10.1, will 
be applied. P-values will be presented for the treatment comparisons of the primary and key 
secondary endpoints. Statistical analysis methods for efficacy analyses are provided in Table 
10.3.1-1.
Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
Proportions
The binary efficacy endpoints (eg, the proportion of participants meeting ACR50 response at 
Week 24) will be analyzed with a logistic regression including treatment in the model. The OR 
along with its 95% CI will be provided. A missing responder value at Day 169 due to 
discontinuation or for other reasons will be imputed as a nonresponder. For analysis of 
variables in the overall population (SE+ and SE-), the stratification variable SE +/- will also be 
included as a factor in logistic regression model. For analysis of proportions that are based on 
a cutoff value of continuous variable (eg, remission defined as DAS28-CRP < 2.6) for which a 
corresponding value is measured at baseline (baseline DAS28-CRP measurement), the analysis 
model will also include the continuous baseline covariate.
Mean Change 
From Baseline
Mean changes from baseline in continuous variables will be analyzed using a longitudinal 
repeated measures analysis. The model will include the fixed categorical effects of treatment, 
day (is a windowed time point), stratification variable SE +/- (as appropriate), treatment-by-day 
interaction, and covariate of corresponding baseline and baseline-by-day interaction. 
An unstructured covariance matrix will be used to represent the correlation of the repeated
measures within each participant. The parameter estimations will be based on the assumption 
of data being MAR and using the method of REML. The difference in adjusted LSMEANS 
between abatacept and adalimumab at the primary time point, Week 24, and corresponding 
95% CI will be provided. For the key secondary variable of mean change from baseline at 
Week 24, the P-value will be based on the longitudinal model.
Abbreviations: ACR50, 50% improvement in American College of Rheumatology criteria; CI, confidence interval; 
LSMEANS, least-squared means; DAS28-CRP, Disease Activity Score 28-joint count calculated using C-reactive 
protein; MAR, missing at random; OR, odds ratio; REML, restricted maximum likelihood; SAP, Statistical Analysis 
Plan; SE-, shared epitope; SE+, shared epitope-positive.
Details of the efficacy analysis during the OLTP will be provided in the SAP.
10.3.2
Safety Analyses
The proportion (%) of participants with AEs, deaths, SAEs, AEs of special interest, and AEs 
leading to discontinuation and of participants with laboratory marked abnormalities will be 
provided by treatment group. Summaries for the SBTP will include events from the start of study 
treatment up to start of the OLTP for participants continuing in the OLTP or up to last dosing 
date +56 days for participants discontinuing during the SBTP using the as-treated analysis 
population. AEs of special interest are infections, malignancies, autoimmune disorders, and 
injection-site reactions. Summaries for the cumulative abatacept period will include safety events 
with onset on or after the first day of abatacept treatment in the study up to 56 days after the last 
abatacept treatment in the study using the cumulative abatacept population. 
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10.3.3
Other Analyses 
10.3.3.2
Patient-reported Outcomes Analyses
For the individual components of the SF-36, WPAI-RA, and FACIT-F and duration of MS, 
changes from baseline will be summarized by treatment, and 95% CI for the treatment differences 
in changes from baseline will be constructed. 
10.3.4
Interim Analyses
Not applicable.
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11
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on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the 
iceberg? Hepatology 2015;61(2):703-11.
82 Bréchot C, Thiers V, Kremsdorf D, et al. Persistent hepatitis B virus infection in subjects 
without hepatitis B surface antigen: clinically significant or purely "occult"? Hepatology 
2001;34(1):194-203. 
 
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
+
positive
AA
amino acid
AASLD
American Association for the Study of Liver Diseases
ABA
abatacept
ADA
adalimumab
AE
adverse event
ACIP
Advisory Committee on Immunization Practices
ACPA
anti-citrullinated protein antibodies
ACPA-
anti-citrullinated protein antibodies-negative
ACPA+
anti-citrullinated protein antibody-positive
ACR
American College of Rheumatology
ACR20
20% improvement in American College of Rheumatology criteria
ACR50
50% improvement in American College of Rheumatology criteria
ACR70
70% improvement in American College of Rheumatology criteria
ACTH
adrenal corticotropic hormone
AGREE
Abatacept study to Gauge Remission and joint damage progression in 
MTX-naive patients with Early Erosive rheumatoid arthritis
ALT
alanine aminotransferase
AMPLE
Abatacept vs adaliMumab comParison in bioLogic-naivE RA 
participants with background methotrexate
anti-CCP-2
anti-cyclic citrullinated peptide-2
anti-CCP-2-
anti-cyclic citrullinated peptide-2-negative
anti-CCP-2+
anti-cyclic citrullinated peptide-2-positive
APC
antigen-presenting cell
AR
additional research
AST
aspartate aminotransferase
AT
aminotransaminase
AVERT
Assessing Very Early Rheumatoid Arthritis Treatment study
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Term
Definition
BCG
Bacillus Calmette-Guérin
BMS
Bristol-Myers Squibb
BRASS
Brigham and Women's Rheumatoid Arthritis Sequential Study
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation
CDAI
Clinical Disease Activity Index
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations 
CI
confidence interval
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
CRP
C-reactive protein
CSP
clinical safety program
CTAg
Clinical Trial Agreement
CTLA4
cytotoxic T-lymphocyte-associated protein 4
DAS
Disease Activity Score
DAS28-CRP
Disease Activity Score 28-joint count calculated using C-reactive protein
D
Day
DILI
drug-induced liver injury
DMARD
disease-modifying antirheumatic drug
DNA
deoxyribonucleic acid
DO
Doctor of Osteopathy
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Term
Definition
EDC
Electronic Data Capture
ET
early termination
EULAR
European League Against Rheumatism
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FACIT-F
Functional Assessment of Chronic Illness Therapy - Fatigue
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HAQ-DI
Health Assessment Questionnaire Disability Index
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HcAb
hepatitis antibody
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HEEN
head, eyes, ears, nose
Hgb
hemoglobin
HIV
human immunodeficiency virus
HLA-DRB1
human leukocyte antigen Class II histocompatibility antigen, DRB1 beta 
chain
hr
hours
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
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Term
Definition
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
Ig
immunoglobulin
IL
interleukin
IM
intramuscular
IMG
immunogenicity
IMP
investigational medicinal product
IND
Investigational New Drug Exemption
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IV
intravenous(ly)
JIA
juvenile idiopathic arthritis
LSMEANS
least-squared means
MAR
missing at random
MCID
minimal clinically important difference
MCS
mental component summary
MD
Doctor of Medicine
min
minutes
mITT
modified intent-to-treat
MMR
measles, mumps, rubella
MPA
mycophenolate mofetil
MRI
magnetic resonance imaging
MS
morning stiffness
MTX
methotrexate
MTX-IR
methotrexate inadequate responders
NCT
national clinical trial number
NP
Nurse Practitioner
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Term
Definition
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
OLTP
Open-label Treatment Period
OR
odds ratio
PA
Physician Assistant
PCS
physical component summary
PEF
peak expiratory flow
PGA
Physician’s Global Assessment of Disease Activity
PK
pharmacokinetics
PP
per-protocol
PPD
purified protein derivative
PRO
patient-reported outcome
PTFUP
Post-treatment Follow-up Period
R
randomize
R&D
research and development
RA
rheumatoid arthritis
Rand.
randomization
RCT
randomized, controlled trial
REML
restrictive maximum likelihood
RF
rheumatoid factor
RF+
rheumatoid factor-positive
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBTP
Single-blind Treatment Period
SC
subcutaneous
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Term
Definition
SDAI
Simple Disease Activity Index
SE
shared epitope
SE-
shared epitope-negative
SE+
shared epitope-positive
SF-36
36-item Short Form Survey
SLE
systemic lupus erythematosus
SOP
Standard Operating Procedures
STPR
Strategies Therapeutiques de la Polyarthrite Rhumatoıde
SSC
Study Steering Committee
SUSAR
suspected, unexpected serious adverse reaction
TB
tuberculosis
TNF
tumor necrosis factor
ULN
upper limit of normal
US
United States
V
Visit
VAS
visual analog scale
WBC
white blood cell
WHO
World Health Organization
Wk
Week
WNOCBP
women not of childbearing potential
WOCBP
women of childbearing potential
WPAI-RA
Work Productivity and Activity Impairment Questionnaire - Rheumatoid 
Arthritis
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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), and

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.
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If
Then
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment 
integrity in accordance with requirements applicable 
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. 
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 sub-investigator and who is delegated this task on the 
Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF approval 
task. 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.
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. 
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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).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
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If
Then
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:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design
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
Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
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/participants 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 
pre-existing 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 (eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study; appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
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 [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) 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 (eg, 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.
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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 
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 

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy

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 

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
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

Vasectomized partner 

For WOCPB: 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.
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
For male participants: A vasectomy is a highly effective contraception method provided 
that the participant 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.
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Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of > 1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (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
AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF DISEASE ACTIVITY VISUAL ASSESSMENT 
SCALE
Measure with a metric ruler. Line on Case Report Form is exactly 10 cm long. Scores should be recorded in millimeter 
format.  DO NOT USE THIS APPENDIX AS SOURCE DOCUMENT OR CASE REPORT FORM. 
Considering all the ways in which illness and health conditions may affect you at this time, please make a mark below 
to show how you are doing.
Very
Well
Very
Poorly
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APPENDIX 6
AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF PAIN VISUAL ASSESSMENT SCALE
Measure with a metric ruler. Line on Case Report Form is exactly 10 cm long.  Scores should be recorded in millimeter 
format.  DO NOT USE THIS APPENDIX AS SOURCE DOCUMENT OR CASE REPORT FORM. 
How much pain have you had because of your condition over the past week?  Place a mark on the line below to 
indicate how severely your pain has been:
No Pain
Pain as 
Bad as it 
Could be
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APPENDIX 7
AMERICAN COLLEGE OF RHEUMATOLOGY PHYSICIAN 
GLOBAL ASSESSMENT OF DISEASE ACTIVITY VISUAL 
ASSESSMENT SCALE
Measure with a metric ruler. Line on Case Report Form is exactly 10 cm long.  Scores should be recorded in millimeter 
format. DO NOT USE THIS APPENDIX AS SOURCE DOCUMENT OR CASE REPORT FORM. 
What is the disease activity independent of the participant’s self-assessment?
Very
Good
Very
Bad
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APPENDIX 8
AMERICAN COLLEGE OF RHEUMATOLOGY SUBJECT 
ASSESSMENT OF PHYSICAL FUNCTION SCALE: HEALTH 
ASSESSMENT QUESTIONNAIRE (HAQ)
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APPENDIX 9
SF-36 V2.0
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APPENDIX 10
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE-RHEUMATOID ARTHRITIS, V2.0 (WPAI-RA)
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APPENDIX 11
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS
THERAPY (FACIT) - FATIGUE
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APPENDIX 12
MORNING STIFFNESS DURATION
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APPENDIX 13
2010 ACR-EULAR CLASSIFICATION CRITERIA FOR 
RHEUMATOID ARTHRITIS
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APPENDIX 14
RA DISEASE ACTIVITY DEFINITIONS
American College of Rheumatology Core Data Set
ACR core data set component
Validated Measurement Tool
Tender joint count
Standardized 68 joint count
Swollen joint count
Standardized 66 joint count
Subject global assessment of pain
A 0-100mm visual analog scale
Subject global assessment of disease activity
A 0-100mm visual analog scale
Physician global assessment of disease activity
A 0-100mm visual analog scale
Subject assessment of physical function
Health Assessment Questionnaire (HAQ)
Acute phase reactant value
ESR (Westergren) and C-reactive protein
The ACR 20, ACR 50, or ACR 70 definition of improvement is a 20%, 50%, or 70% improvement, 
respectively, over baseline in tender and swollen joint counts (#1 and #2) and a 20%, 50%, or 70% 
improvement, respectively, in 3 of the 5 remaining core data set measures (components #3 to #7). 
Disease Activity Index (DAS)28-CRP is calculated using the following formula:
DAS28-CRP(4) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96
where t28 = number of painful joints from 28 joints, sw28 = number of swollen joints from 28 
joints, CRP = c-reactive protein in mg/L, and GH = general health or patient's global assessment 
of disease activity on a 100 mm VAS
Simple Disease Activity Index (SDAI) is calculated using the following formula:
TJC + SJC + PGA + MDGA + CRP
Clinical Disease Activity Index (CDAI) is calculated using the following formula:
TJC + SJC + PGA + MDGA
(TJC = number of painful joints from 28 joints, SJC = number of swollen joints from 28 joints, 
PGA = patient global assessment on a visual analog scale 0-10 cm, MDGA = physician global 
assessment on a visual analog scale 0-10 cm, and CRP = c-reactive protein in mg/dL)
Boolean Remission is defined as:
Tender joint count 1, Swollen joint count 1, CRP 1 mg/dL, patient global assessment 1 (on 
0 to 10 VAS scale).
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APPENDIX 15
JOINT COUNT ASSESSMENT COMPONENTS FOR DAS28 
(RIGHT AND LEFT SIDE)
Shoulder
Elbow
Wrist
MCP1
MCP2
MCP3
MCP4
MCP5
PIP1
PIP2
PIP3
PIP4
PIP5
Knee
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APPENDIX 16
COUNTRY-SPECIFIC REQUIREMENTS/DIFFERENCES
Country/Location 
Requirement
Original Language/
Section Number
Country-specific Language or Differences
France, Germany, 
Czech Republic, UK
Section 8.1: 
Discontinuation from 
Study Treatment
Second paragraph following bulleted text modified to read:
“In the case of pregnancy, the investigator must immediately 
notify the BMS Medical Monitor/designee of this event. In most 
cases, the study treatment will be permanently discontinued in 
an appropriate manner (eg, dose tapering if necessary for 
participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.”
France/Italy
Add to discontinuation criteria bullets an item for 
discontinuation due to product inefficacy.
France
Add to discontinuation criteria bullets an item for 
discontinuation due to severe infection.
Sweden
Section 9: Study 
Assessments and 
Procedures
All assessments must be performed by a qualified physician.
Japan
Table 2-1: Screening 
Procedural Outline 
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Add the following test at Screening: (1 to 3) β-D glucan.
Section 6.2: 
Exclusion Criteria
Add the following text as criterion 3) j): “Participants who are 
(1 to 3) β-D glucan positive.”
Section 9.4: Safety 
Add subsection for Fungal Testing, with the following text: 
“The (1 to 3) β-D glucan test will be performed at the 
Screening visit.”
Table 9.4.7-1:
Clinical Safety 
Laboratory 
Assessments
Add (1 to 3) β-D glucan.
Table 2-1: Screening 
Procedural Outline 
(IM101863)
Add the following test at Screening: hepatitis B surface 
antibody (HBsAb).
Section 6.2: 
Exclusion Criteria
Replace current text for criterion 3) a) with the following text: 
“Hepatitis B surface antigen (HBsAg)-positive participants are 
excluded from the study. 
Participants who are HBsAg negative but positive for hepatitis B 
surface antibody (HBsAb) or hepatitis B core antibody (HBcAb) 
must also be tested for quantitative hepatitis B virus (HBV)
DNA. Participants with detectable levels as specified by local 
guidance are excluded from the study.”
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Country/Location 
Requirement
Original Language/
Section Number
Country-specific Language or Differences
Japan (continued)
Section 9.4.6: Viral 
Hepatitis Screening 
and Monitoring
Add the following text: “Participants who are positive for 
anti-HBsAb but negative for HBV DNA (as defined by the 
lower limit of testing sensitivity) will be allowed to be 
randomized. These participants will be closely monitored for 
clinical and laboratory signs of HBV reactivation. HBV DNA 
testing should be performed on a monthly basis after initiation of 
treatment, for 6 months, along with review of liver chemistries. 
After 6 months, the interval and duration of surveillance should 
be decided at the investigator’s discretion and in accordance 
with local guidelines.”
Table 9.4.7-1:
Clinical Safety 
Laboratory 
Assessments
Add HBsAb.
Section 7.1.1.1: 
Abatacept 
Self-administration 
of Subcutaneous 
Injection
Add the following text: “Additional self-administration training 
for participants is allowed to be extended until Week 4. Training 
should be performed by unblinded study site personnel qualified 
in teaching patients about administration of medication in 
prefilled syringes. The site needs to ensure that any additional 
training visits do not imperil maintenance of the blind at the 
site (ie, shielding treatment allocation from blinded site study 
personnel).”
Section 7.1.2.1: 
Adalimumab 
Self-administration 
of Subcutaneous 
Injection
Add the following text: “Additional self-administration training 
for participants is allowed to be extended until Week 4. Training 
should be performed by unblinded study site personnel qualified 
in teaching patients about administration of medication in 
prefilled syringes. The site needs to ensure that any additional 
training visits do not imperil maintenance of the blind at the 
site (ie, shielding treatment allocation from blinded site study 
personnel).”
Section 9.2.9: Other 
Safety Considerations
Add the following text: “Malfunction of the prefilled syringes 
containing study treatment should be reported to the Sponsor via 
designated CRF. SAEs or events that could lead to an SAE that 
occurred as a result of the malfunction should be reported to the 
Sponsor within 24 hours of awareness of the event.”
Abbreviations: BMS, Bristol-Myers Squibb Company; CRF, case report form; DNA, deoxyribonucleic acid; HBcAb, 
hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis 
B virus; SAE, serious adverse event; UK, United Kingdom.
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APPENDIX 17
LABORATORY GUIDELINES: PATIENT STUDIES (REVISED 
AUGUST 13, 1999)
Laboratory test results, which meet these criteria, and the investigator feels is clinically relevant 
should be described on the Adverse Event Form. Those which are judged to be SERIOUS events 
require the completion of a Serious Adverse Event Form (see Section 9.2).
[NOTE:  LLN = lower limit of normal; ULN = upper limit of normal.]
albumin - <0.9xLLN or if pretreatment value is <LLN, <0.75x pretreatment
alkaline phosphatase - >2 x ULN; or if pretreatment >ULN, 3x pretreatment value
basophils (%) - >3% if 0-1% pretreatment, >3x pretreatment value if pretreatment >1%
bilirubin
a) direct - >1.5x ULN, or if pretreatment above ULN, >2x pretreatment
b) total - >2x upper limit of normal, or if pretreatment above ULN, >4 x pretreatment value
blasts - >0
blood urea nitrogen (BUN) - >2x pretreatment
calcium - <0.8x LLN or >1.2x ULN; <0.75x pretreatment if pretreatment below LLN, or >1.25x 
pretreatment if pretreatment above ULN; >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
chloride - <0.9x LLN or >1.1x ULN; or <0.9x pretreatment if pretreatment below LLN, or >1.1x 
pretreatment if pretreatment above ULN; >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
creatinine - >1.5x pretreatment value
eosinophils (%) - >3x pretreatment and > 8% if pretreatment normal; if pretreatment >ULN, >3 
x pretreatment
erythrocytes - <0.75x pretreatment value
glucose - <0.8x LLN or >1.5x ULN; if pretreatment <LLN then <0.8x pretreatment; if 
pretreatment >ULN then >2x pretreatment; <LLN if >ULN pretreatment, or >ULN if <LLN 
pretreatment
hematocrit - <0.75x pretreatment
hemoglobin - >3 g/dL decrease from pretreatment value
lactic dehydrogenase (LDH) - >1.5x ULN; if pretreatment value is above ULN, >3x pretreatment 
value
leukocyte (WBC) count - <0.75 x LLN or >1.25x ULN; <0.8x pretreatment if pretreatment <LLN 
or >1.2x pretreatment if pretreatment >ULN; >ULN if pretreatment <LLN or <LLN if >ULN 
pretreatment
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lymphocytes (%) - <0.5x LLN or >2.0 x ULN, or <0.5x pretreatment if below LLN pretreatment; 
>2.0x pretreatment if above ULN pretreatment.  >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
monocytes (%) - >2x ULN; >2x pretreatment if pretreatment above ULN
neutrophil count (neutrophils+bands) - <0.67x pretreatment if pretreatment <1000/mm3; 
otherwise, <1000/mm3.
phosphate - <0.75 x LLN or >1.25x ULN; <0.67x pretreatment value if below LLN pretreatment, 
or >1.33x pretreatment if above ULN pretreatment; >ULN if <LLN pretreatment, or <LLN if 
>ULN pretreatment
platelet count - <0.67x LLN or >1.5 x ULN; if below normal pretreatment, <0.5x pretreatment 
value and <100,000/mm3
potassium - <0.9x LLN or >1.1x ULN; <0.9x pretreatment if pretreatment below LLN, or >1.1x 
pretreatment if pretreatment above ULN; >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
protein, total - <0.9x LLN or >1.1x ULN; <0.9 x pretreatment if below LLN pretreatment, or 
>1.1x ULN if above ULN pretreatment; >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
SGOT and SGPT (ASAT and ALAT) - >3 x upper limit of normal; if pretreatment above ULN, 
>4x pretreatment value
sodium - <0.95x LLN or >1.05x ULN; <0.95x pretreatment if below LLN pretreatment, >1.05x 
pretreatment if above ULN pretreatment; >ULN if <LLN pretreatment, or <LLN if >ULN 
pretreatment
uric acid - >1.5x ULN; if pretreatment above ULN, >2x pretreatment value
urinalysis
a) urinary protein - >1 gram/24 hours and 2x pretreatment value
b) urinary RBC - >5/HPF or, >4x pretreatment if pretreatment value 5/HPF
c) urinary WBC - >5/HPF or, >4x pretreatment if 5/HPF pretreatment
d) creatinine clearance (glomerular filtration rate) - <0.67x pretreatment value
e) urine dipstick measurements:  Protein, blood, sugar, and acetone- 2+, or if 1+pretreatment, 
2x pretreatment. Do not evaluate protein if quantitative protein determination done
stool hemoccult - positive if negative pretreatment
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Date: 26-Feb-2021
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