Clinical trial NCT02557100
Conditions: Rheumatoid Arthritis
Sponsor: Bristol-Myers Squibb
Start date: 2015-11-19; Completion date: 2019-03-28
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine changes in immune cells and proteins in response to treatment with two approved therapies for Rheumatoid arthritis (RA), abatacept versus adalimumab, both given in combination with methotrexate.

Detailed description:

Arms: arm 1: Abatacept Single Blind Treatment Period arm 2: Adalimumab Single Blind Treatment Period arm 3: Abatacept Cumulative Treatment Period
Interventions: intervention 1: Abatacept intervention 2: Adalimumab intervention 3: Methotrexate
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
IM101567
IND Number:
BB-IND 9391
Ex-US
Non-IND
EUDRACT Number
N/A
Date:
27-Jul-2015
Clinical Protocol IM101567
A Randomized, Head-to-Head, Single-Blinded Study to Assess Changes in the Immune Profile 
in Response to Treatment with Subcutaneous Abatacept in Combination with Methotrexate 
versus Subcutaneous Adalimumab in Combination with Methotrexate in Adults with Early 
Rheumatoid Arthritis who are Naive to Biologic Disease-Modifying Antirheumatic Drugs
Medical Monitor/Study Director
Alyssa Johnsen, MD, PhD
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 
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who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Original 
Protocol
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Not applicable
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SYNOPSIS
Clinical Protocol IM101567
Protocol Title: A Randomized, Head-to-Head, Single-Blinded Study to Assess Changes in the Immune Profile in 
Response to Treatment with Subcutaneous Abatacept in Combination with Methotrexate versus Subcutaneous 
Adalimumab in Combination with Methotrexate in Adults with Early Rheumatoid Arthritis who are Naive to 
Biologic Disease-Modifying Antirheumatic Drugs
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
Subjects will receive investigational products for a period of 24 weeks. In this protocol, investigational products are:

abatacept subcutaneous (SC) injection, 125mg/pre-filled syringe (125 mg/mL)

adalimumab (Humira®) SC injection, 40 mg/prefilled syringe (40 mg/0.8 mL) 
Study Phase: IV
 
 
 
 
Objectives:
Primary Objective:
Not Applicable
Secondary Objective:
Not Applicable
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Design: See schematic below for study design.
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 informed consent. Subjects that experience an 
acute infection or initiate treatment for latent TB may extend the screening period to 42 days
Treatment Period (Day 1 - Week 24):
On Day 1, subjects will be randomized to one of two parallel treatment arms in a 1:1 ratio: 
1.
Abatacept SC (125 mg) weekly 
2.
Adalimumab SC (40 mg) once every two weeks
The Treatment Period duration is 24 weeks.
Abatacept and adalimumab administration:
On Day 1, subjects and/or personal caregivers will be trained in self administration of SC injections using pre-filled 
syringes. 
Methotrexate:
Subjects must have been treated with oral methotrexate for at least 12 weeks prior to randomization with a stable 
dose for at least 28 days prior to randomization. The stable dose of oral methotrexate should be a minimum targeted 
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dose of at least 20 mg weekly. A dose of methotrexate < 20 mg/week but 7.5 mg/week is permitted if intolerance to 
higher doses has been recorded in the source documents.
The dose of methotrexate must remain stable throughout the study, and may only be lowered due to intolerance or 
adverse event. Should intolerance occur and the dose of methotrexate requires reduction, subjects must stay on the 
lower methotrexate dose for the remainder of the study.
Parenteral administration of methotrexate is not permitted at any time during the study. All subjects must receive 
folic acid, folinic acid, or leucovorin according to the manufacturer’s recommendations.
Post-Treatment Follow-up Period:
Subjects who discontinue treatment of study drug or complete the study will have one follow-up visit 85 days after 
the last dose of investigational product to perform safety assessments.. 
Study Population: Men or women (not nursing or pregnant) years old who have early RA, defined as 
diagnosed with RA by ACR/EULAR 2010 classification (Appendix 1) and have had symptoms of RA for no more 
than 9 months prior to signing the informed consent. Symptoms of RA are defined as pain, stiffness or swelling in 
joints which are typically inflamed in RA. Subjects who had a single isolated episode of palindromic symptoms that 
occurred less than 2 years prior to enrollment are still eligible. Subjects must have a second generation anti-cyclic 
citrullinated peptide (anti-CCP2) test result that is greater than 3-times the upper limit of normal and be rheumatoid 
factor (RF) positive at screening according to central laboratory testing. Subjects must have a DAS28CRP 
(Appendix 2) at screening and have at least 3 tender and at least 3 swollen joints (excluding distal 
interphalangeals) at screening and at randomization.
Eligible subjects must have been treated with oral methotrexate for at least 12 weeks prior to randomization with a 
stable dose for at least 28 days prior to randomization. The stable dose of oral methotrexate should be a minimum 
targeted dose of at least 20 mg weekly, unless the dose of methotrexate was limited by intolerance, in which case 7.5 
mg is the minimum required dose.
Investigational [Medicinal] Products (IP/IMP) are as listed:
IP/IMP 
Potency 
Abatacept SC injection
125mg/pre-filled syringe (125 mg/mL)
Adalimumab SC injection
40 mg/prefilled syringe (40 mg/0.8 mL)
Study Assessments: See Section 5 of the protocol for detailed information regarding study assessments.
Statistical Considerations:
Sample Size: In this study 25 subjects will be randomized per treatment arm.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening Period ...................................................................................... 
3.1.2 Treatment Period (Day 1 to Week 24) ..................................................... 
3.1.3 Post-Treatment Follow-up Period ........................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
 
 
 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
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4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Abatacept Treatment Arm ........................................................................ 
4.5.1.1 Self-Administration of Subcutaneous Injection ............................... 
4.5.1.2 Administration Window .................................................................. 
4.5.1.3 Dose Modifications ......................................................................... 
4.5.2 Adalimumab Treatment Arm .................................................................... 
4.5.2.1 Self-Administration of Subcutaneous Injection ............................... 
4.5.2.2 Administration Window .................................................................. 
4.5.2.3 Dose Modifications ......................................................................... 
4.5.3 Guidelines for Methotrexate .................................................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening, Extended Screening, or Rescreening ......... 
5.1.2 Order of Study Assessments ..................................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Physical Examination .............................................................................. 
5.3.2 Chest X-ray .............................................................................................. 
5.3.3 Physical Measurements ........................................................................... 
5.3.4 Vital Signs ................................................................................................ 
5.3.5 TB Screening ............................................................................................ 
5.3.6 Laboratory Assessments........................................................................... 
5.3.6.1 Hematology ..................................................................................... 
5.3.6.2 Blood Chemistry.............................................................................. 
5.3.6.3 Urinalysis ........................................................................................ 
5.3.6.4 Hepatitis Screen .............................................................................. 
5.3.6.5 Pregnancy Tests .............................................................................. 
5.3.6.6 HIV Testing ..................................................................................... 
 
 
 
 
 
 
 
 
 
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6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
 
 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
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9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
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).
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2.2
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, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. 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 and any updates. 
The investigator or BMS 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.
2.3
Informed Consent
Investigators must ensure that subjects 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 to subjects, 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 subject volunteers to participate. 
BMS 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:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) 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, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
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subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an exploratory, randomized, single-blinded assessment study in subjects who have 
recently been diagnosed with rheumatoid arthritis according to ACR/EULAR 2010 classification
(Appendix 1), and having symptoms of RA for 9 months or less prior to screening, and have 
been on MTX for at least 12 weeks with a stable dose of MTX for at least 28 days prior to 
randomization and are naive to biologic DMARD. It consists of a screening period of up to 28 
days, followed by a 24 week Treatment Period, followed by 85 day follow-up period.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
3.1.1
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 
informed consent. Subjects that experience an acute infection or initiate treatment for latent TB 
may extend the screening period to 42 days.
Eligible subjects will have been diagnosed with rheumatoid arthritis by ACR/EULAR 2010 
classification (Appendix 1) and have had symptoms of RA for no more than 9 months prior to 
signing the informed consent. Symptoms of RA are defined as pain, stiffness or swelling in joints 
which are typically inflamed in RA. Subjects who had a single isolated episode of palindromic 
symptoms that occurred less than 2 years prior to enrollment are still eligible. In order to recruit a 
cohort of subjects with similar biomarker profiles, subjects must have an anti-CCP2 test result 
that is greater than 3-times the upper limit of normal19 and be RF positive at screening according 
to central laboratory testing. Subjects must have a DAS28CRP (Appendix 2) at screening 
and have at least 3 tender and at least 3 swollen joints (excluding distal interphalangeals [DIPs]) 
at screening and at randomization.
Subjects must have been treated with oral methotrexate for at least 12 weeks prior to 
randomization with a stable dose for at least 28 days prior to randomization. The stable dose of 
oral methotrexate should be a minimum targeted dose of at least 20 mg weekly. A dose of 
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methotrexate < 20 mg/week but 7.5 mg/week is permitted if intolerance to higher doses has 
been recorded in the source documents.
To minimize potential methotrexate toxicity, all subjects must receive folic acid, folinic acid, or 
leucovorin according to the manufacturer recommendations, methotrexate label instructions, and 
the local medical standard of care guidelines. 
Subjects 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. Subjects may not have received an 
IM, IV or IA administration of a corticosteroid within 4 weeks prior to randomization.
3.1.2
Treatment Period (Day 1 to Week 24)
On Day 1, subjects will be randomized to one of two parallel treatment arms in a 1:1 ratio:
1) Abatacept SC (125 mg) weekly 
2) Adalimumab SC (40 mg) once every two weeks 
The Treatment Period duration is 24 weeks.
Abatacept and adalimumab administration:
On Day 1, subjects and/or personal caregivers will be trained in self administration of SC 
injections using pre-filled syringes. 
Methotrexate:
Subjects must have been treated with oral methotrexate for at least 12 weeks prior to 
randomization with a stable dose for at least 28 days prior to randomization. The stable dose of 
oral methotrexate should be a minimum targeted dose of at least 20 mg weekly. A dose of 
methotrexate < 20 mg/week but 7.5 mg/week is permitted if intolerance to higher doses has 
been documented in the source documents.
The dose of methotrexate must remain stable throughout the study, and may only be lowered due 
to intolerance or adverse event. Should intolerance occur and the dose of methotrexate requires 
reduction, subjects should stay on the lower methotrexate dose for the remainder of the study.
Parenteral administration of methotrexate is not permitted at any time during the study. All 
subjects must receive folic acid, folinic acid, or leucovorin according to the manufacturer’s 
recommendations.
3.1.3
Post-Treatment Follow-up Period
Subjects who discontinue treatment of study drug or complete the study will have one follow-up
visit 85 days after the last dose of investigational product to perform safety assessments.
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3.2
Post Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
Treatment codes will not be provided to the investigators after completion of the study as the 
study drug is provided in an open-labeled fashion to sites during the study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subject is willing to participate in the study and has signed the informed consent.
2. Target Population
a) Subjects have early RA, defined as symptoms of RA that started 9 months prior to 
screening and a diagnosis made by the ACR/EULAR 2010 criteria for the classification 
of RA (Appendix 1)
b) Subjects must be naive to biologic DMARDs
c) Subjects must be naive to conventional synthetic DMARDs other than methotrexate
d) Subjects must be naive to targeted synthetic DMARDs25 such as tofacitinib, baricitinib, 
and investigational therapies for RA.
e) Subjects must have been treated with oral methotrexate for at least 12 weeks prior to 
randomization with a minimum targeted dose of 20 mg/week methotrexate and at least 
the last 28 days being a stable dose. Subjects can be randomized if the minimum stable 
targeted dose of methotrexate is < 20 mg/week but 7.5 mg/week if intolerance to higher 
doses has been documented in the source documents.
f)
Subjects have an anti-CCP2 test that is > 3x ULN and are positive for RF according to 
central lab testing during screening.
g) Subjects must have at least a DAS28 C-reactive protein (CRP) 3.2 (Appendix 2) at 
screening.
h) Subjects must have currently at least 3 tender and at least 3 swollen joints (excluding 
DIPs) at screening and at randomization
i)
Subjects receiving oral corticosteroids must be on a stable dose and at the equivalent of 
10 mg prednisone daily for at least 4 weeks. Subjects may not receive an IM, IV or IA 
administration of a corticosteroid within 4 weeks prior to randomization.
j)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated), still meets all inclusion/exclusion criteria, and no more than 
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9 months have elapsed since the onset of symptoms of RA prior to re-enrollment. If re-
enrolled, the subject must be re-consented.
3. Age and Reproductive Status
a) Men and women, ages 18 years (or age of majority)
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding and must agree not to breastfeed during the study and 
for 100 days thereafter
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug plus 5 half-lives of study drug (70 days) plus 30 days 
(duration of ovulatory cycle) for a total of 100 days post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug, plus 5 half-lives 
of the study drug (70 days) plus 90 days (duration of sperm turnover) for a total of 
160 days post-treatment completion.
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating in 
the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug

Nonhormonal IUDs, such as ParaGard

Tubal ligation 
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abatacept

Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male Condom without spermicide 

Progestin only pills by WOCBP subject or male subject’s WOCBP partner 

Female Condom*
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects 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.
b) Prior history of or current inflammatory joint disease other than RA (such as psoriatic 
arthritis, gout, reactive arthritis, Lyme disease).
2. Medical History and Concurrent Diseases
a) Subjects at risk for tuberculosis (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 randomization 
will be permitted but the images must be available and reviewed by the investigator. 
TB testing (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 
subject binder.
ii) A history of active TB 
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iii) Subjects with a positive TB screening test 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) They 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, subjects 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. 
b) Subjects 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.
c) Subjects with history of chronic or recurrent bacterial infection (such as chronic 
pyelonephritis, osteomyelitis, and bronchiectasis etc.).
d) Subjects with any history of infection of a joint prosthesis or artificial joint.
e) Subjects who have a history of systemic fungal infections (such as histoplasmosis, 
blastomycosis, or coccidiomycosis).
f)
Subjects 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.
g) Subjects with history of Human Immunodeficiency Virus (HIV) infection or who test 
positive for HIV at screening.
h) Subjects with history of primary immunodeficiency 
i)
Subjects who have present or previous malignancies, except documented history of cured 
non-metastatic squamous or basal skin cell carcinoma, or cervical carcinoma in situ, with 
no recurrence in the 5 years prior to screening. Subjects who had 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.
j)
Current clinical findings or a history of a demyelinating disorder
k) New York Heart Association (NYHA) Class III or IV heart failure
l)
Any previous or current medical conditions that are warnings against the use of TNF 
inhibitor agents.
m) Current clinical findings of severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, pulmonary, psychiatric, cardiac, endocrine, neurological, 
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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 subject at unacceptable risk for participation in this study.
n) Subjects 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 subjects 
should not be administered a live virus vaccine for a minimum of 3 months following the 
last dose of study medication. Subjects who are in close contact with others who have 
received a live vaccine may be enrolled at the investigator’s discretion.
o) Subjects who have undergone a major surgical procedure within the 60 days prior to 
randomization.
p) Subjects for whom 5 or more joints cannot be assessed for tenderness or swelling (ie due 
to surgery, fusion, amputation, etc).
q) Subjects with a history of (within 12 months of signing informed consent), or known 
current problems with drug or alcohol abuse history or known cirrhosis including 
alcoholic cirrhosis 
r)
Subjects who are impaired, incapacitated, or incapable of completing study related 
assessments
3. Physical and Laboratory Test Findings
a) Hepatitis B surface antigen (HBsAg)-positive, or Hepatitis B core antibody 
(HBcAb)-positive subjects with detectable hepatitis B viral DNA
b) Hepatitis C antibody (HcAb)-positive subjects with detectable hepatitis C viral RNA
c) Hemoglobin (Hgb) < 8.5 g/dl
d) White Blood Count (WBC) < 3,000/mm3 (3 x 109/L)
e) Platelets < 100,000/mm3 (100 x 109/L)
f)
Serum creatinine > 2 times upper limit of normal.
g) Serum ALT or AST > 2 times upper limit of normal.
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 subject at 
unacceptable risk for participation in this study
4. Allergies and Adverse Drug Reaction
a) Hypersensitivity to one of the investigational products and/or its excipients.
5. Prohibited Treatments and/or Therapies
a) Subjects who have had previous exposure to abatacept or adalimumab
b) Subjects who have had previous exposure to any DMARD other than methotrexate
c) Subjects who have been exposed to any treatment with an approved or investigational 
biologic DMARD including but not limited to infliximab, etanercept, anakinra, 
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rituximab, tocilizumab, golimumab, and certolizumab, or an investigational or approved 
targeted non-biologic DMARD, such as tofacitinib or baricitinib
d) Subjects who have received an IM, IV or IA administration of a corticosteroid within 4
weeks prior to randomization (Day 1)
e) Subjects currently taking NSAIDs must have been on a stable dose, as assessed by the 
Investigator, for at least 14 days prior to randomization.
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects 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 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause 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 > 40mIU/mL to confirm menopause.
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. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:

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.
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
 
 
 
 
 
 
 
 
 
 
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Use of prohibited medication

Pregnancy

Missed Doses:

Missed greater than 6 doses of abatacept OR greater than 3 doses of adalimumab for any 
reason during the study

Missed greater than 4 consecutive doses of abatacept OR greater than 2 consecutive 
doses of adalimumab for any reason during the study

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject.

Subject’s request to stop study treatment or withdrawal of informed consent

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
Subjects who discontinue study drug may continue to be followed. Subjects who withdraw 
consent (according to Section 3.6.1) or are lost to follow-up (according to Section 3.6.2) will not 
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be followed in this study; all other subjects will continue to be followed for collection of 
follow up data as required and in line with Section 5, Study Procedures and Assessments.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects 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 drug 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 subject 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.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the 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 subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP).
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is defined a pharmaceutical form of an 
active substance or placebo being tested or used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) differently than the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is the responsibility of the investigator 
to ensure that investigational product is only dispensed to study subjects. The investigational product must be dispensed only from 
official study sites by authorized personnel according to local regulations.
In this protocol, investigational products are:
Table 4.1-1:
Investigation Product for IM101-567
Product Description / 
Class and Dosage Form
Potency
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
Abatacept SC injection
125 mg/prefilled syringe 
(125 mg/mL)
Open label
Clear to slightly opalescent, 
colorless to pale yellow 
solution, essentially free of 
particulate matter on visual 
inspection
Store refrigerated, 2-8° C (36-46 
° F); protect from light; protect 
from freezing
Adalimumab SC injection
40 mg/prefilled syringe 
(40mg/0.8 mL)
Open Label
Clear; colorless solution;
essentially free of visible
particulate
Store refrigerated, 2-8° C (36-46 
° F). Do not freeze. Do not use if 
frozen even if it has been thawed. 
Store in original carton until time 
of administration to protect from 
light
BMS will supply the investigational products described above.
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4.2
Non-investigational Product
In this protocol, non-investigational product(s) include include methotrexate, corticosteroids, 
NSAIDs, (including aspirin), folic acid, and/or folinic acid (leucovorin). BMS will not provide 
non-investigational products.
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
4.4
Method of Assigning Subject Identification
At the time of enrollment, immediately after written informed consent is obtained and before any 
study-related procedures are performed, each subject will be assigned a unique, sequential 
five-digit number beginning with 00001, 00002, 00003, and so on, for identification throughout 
the study. This subject number must not be reused for any other subject. The study physician or 
research coordinator must contact the Central Randomization System to enroll each subject into 
a centralized database at the time consent is obtained. 
After completion of all screening evaluations and concomitant adjustment or stabilization, all 
eligible subjects will be randomized into the Treatment Phase of the study. Randomization 
schedules will be generated and kept by the Randomization Group within Drug Supply 
Management of Bristol-Myers Squibb. Each subject who qualifies for treatment will be assigned 
a unique randomization number. Randomization numbers will be assigned using a Central 
Randomization System in the order in which subjects qualify for treatment, not in the order of 
study enrollment. Subjects will be randomized on a 1:1 basis to either the abatacept treatment 
arm or the adalimumab treatment arm. 
4.5
Selection and Timing of Dose for Each Subject
On “Office Visit” days, study medication should be administered AFTER all assessments have 
been completed, including blood draws for assessment of immunogenicity and possible drug 
concentrations.
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4.5.1
Abatacept Treatment Arm
On Day 1, subjects will self-administer abatacept 125 mg SC from a pre-filled syringe. On 
Day 8,
subjects will self-administer abatacept 125
mg SC.
Thereafter, subjects will 
self-administer abatacept 125 mg SC once every 7 days, up to and including Week 23 (Day 162).
Treatment duration is 167 days for all randomized subjects (who have not discontinued study 
therapy).
4.5.1.1
Self-Administration of Subcutaneous Injection
Each pre-filled syringe contains one weekly dose of abatacept, 125 mg/mL. Subjects will be 
trained to self-administer their weekly SC injection. Training should be performed by 
investigational personnel who are considered qualified trainers by the principal investigator. A 
procedure guide will be provided by BMS. The subject 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 subject to office visits.
4.5.1.2
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 a SC injection is not given within the administration window, the next SC injection 
should be given on the next scheduled target administration day.
4.5.1.3
Dose Modifications
Dose Modifications in the Absence of Adverse Events
Subjects should complete their scheduled SC injections as described above. Subjects who miss 
the dose window should skip the SC injection and wait until the next targeted administration day.
Dose Modifications Due to Adverse Events
If abnormal laboratory test results or clinical adverse events indicate toxicity that, in the 
judgment of the investigator, could place the subject at risk, study drug administration should be 
interrupted and the investigator should notify the BMS medical monitor. Subjects may receive 
further study medication treatment only if full resolution of the adverse event or abnormal 
laboratory finding is documented. Under no circumstances should the dose of study drug be 
altered due to an adverse event.
4.5.2
Adalimumab Treatment Arm
Subjects randomized to adalimumab will self-administer an initial dose of adalimumab 40 mg 
SC from a pre-filled syringe on Day 1. On Day 15, subjects will self-administer adalimumab 
40 mg SC. Thereafter, subjects will self-administer adalimumab 40 mg SC once every 14 days, 
up to and including Week 22 (Day 152). 
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Treatment duration is 167 days for all randomized subjects (who have not discontinued study 
therapy).
4.5.2.1
Self-Administration of Subcutaneous Injection
Each pre-filled syringe contains one bi-weekly dose of adalimumab, 40 mg/mL. Subjects will be 
trained to self-administer their bi-weekly SC injection. Training should be performed by 
investigational personnel who are considered qualified trainers by the principal investigator. A 
procedure guide will be provided by BMS. The subject 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 subject to office visits.
4.5.2.2
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 a SC injection is not given within the administration window, the next SC injection 
should be given on the next scheduled target administration day.
4.5.2.3
Dose Modifications
Dose Modifications in the Absence of Adverse Events
Subjects should complete their scheduled SC injections as described above. In exceptional cases, 
the administration window may be extended to 7 days. Beyond that, the subject should skip the 
SC injection and wait until the next targeted administration day.
Dose Modifications Due to Adverse Events 
If abnormal laboratory test results or clinical adverse events indicate toxicity that, in the 
judgment of the investigator, could place the subject at risk, study drug administration should be 
interrupted and the investigator should notify the BMS medical monitor. Subjects may receive 
further study medication treatment only if full resolution of the adverse event or abnormal 
laboratory finding is documented. Under no circumstances should the dose of study drug be
altered due to an adverse event.
4.5.3
Guidelines for Methotrexate
Subjects must enroll on a stable minimum targeted dose of 20 mg/week. Subjects may enroll 
with MTX doses < 20 mg/week but 7.5 mg/week if intolerance to higher doses has been 
recorded in the source documents. All subjects must be maintained on the enrollment MTX dose, 
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 adverse events. 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.
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4.6
Blinding/Unblinding
Double blinding of study drug, adalimumab vis-à-vis abatacept, is not feasible due to logistical 
barriers around re-packaging 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 end-points 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/subinvestigator to complete/approve the 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, AE causality assessment) and routine clinical care (laboratory result review, 
medication adjustment). To preserve blinding, they must be shielded from treatment allocation. 
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 
subject 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 drug by name

not discuss the color or use of the pre-filled syringe

not discuss how often injections are performed

only discuss injection site reactions of significant concern.
To comply with requirements for Case Report Form Completion (CRF), a qualified physician 
who is an investigator or subinvestigator who is unblinded to study drug assignment will be 
needed to promptly review, sign, and date the CRF.
The site should maintain two distinct sets of source documents, one set accessible to the 
unblinded site staff and one set for the blinded Clinical Assessor.
Care should be taken by the Study/Research Coordinator to retrieve any study drug and sharps 
container returned by the subject at the beginning of each visit to shield the assessor from 
inadvertent exposure to subject allocation. Similarly, study drug dispensing should be done after 
blinded assessments. Both retrieval and dispensing of study drug should be done in an area 
shielded from the blinded assessor(s). 
The joint count assessment should be performed after completion of the patient report outcomes 
(PRO), 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 
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evaluator(s) will complete the assessment for each subject. If the usual evaluator is not available, 
another trained evaluator blinded to study drug allocation for the subject 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 physician global 
assessment of disease activity) should not be reported.
The Sponsor will be unblinded to the treatment assignments of the subject in the trial as it is not 
possible to restrict access to the dosing CRF pages. However, the Sponsor’s medical monitor, 
protocol manager, biomarker representative, and statistician will make every effort to review 
data in an unbiased fashion. However, the impact on the study is believed to be minimal based 
on the primary objective.
The BMS Bioanalytical Science Department or its designee will be unblinded to the randomized 
treatment assignments in order to accurately perform sample analysis for the PK and 
immunogenicity samples.
Unblinding of study drug allocation for safety purposes is not necessary because all study drug 
provided to the site is open-labeled.
4.7
Treatment Compliance
All subjects are expected to receive study therapy as outlined in the protocol. Subjects will use 
diary cards to document self-injection of study drug between clinic visits. Permitted dose 
modifications are described in Section 4.5. Conditions under which therapy must be discontinued 
due to non-compliance are outlined in Section 3.5.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site.
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are 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.
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If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Flow Chart for Protocol IM101-567 - Screening Period
Procedure
Screening
Visita
Extended Screening 
Visitb
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
X
Enroll Subject
X
Contact IVRS for subject number. If subject does not meet eligibility 
criteria, contact IVRS to screen fail subject.
Safety Assessments
Physical Examination
X
X
Height and Weight
X
Vital Signs
X
X
Body temperature, seated blood pressure, and heart rate.
Adverse Events Assessment
X
X
Prior and Concomitant Medication
X
X
TB Screening Test
X
TB testing (IFN-γ release assay or PPD) performed locally within the 
month prior to Screening will be accepted. A copy of the report must 
be filed in the subject binder. See Section 5.3.5 for important details.
Chest X-ray (CXR)
X
Required only if the results of a CXR performed within the 3 months 
prior to enrollment are not available.
Laboratory Tests
Hematology (CBC) 
X
X
Chemistry
X
X
Urinalysis
X
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Table 5.1-1:
Flow Chart for Protocol IM101-567 - Screening Period
Procedure
Screening
Visita
Extended Screening 
Visitb
Notes
HBsAg
X
If positive, obtain HBV DNA (see Section 5.3.6.4)
Hepatitis C Antibody
X
If positive, reflex to HCV confirmation such as PCR
HIV
X
Quantitative Immunoglobulins (IgG,
IgA, IgM)
X
Urine Pregnancy Test
X
X
WOCBP only; see Section 5.3.6.5. Performed locally.
ESR
X
X
Performed locally, kits provided centrally.
 
Disease Assessments
Tender (68)/swollen (66) Joint Count
X
X
Subject Global Assessment of Disease 
Activity
X
X
See Appendix 5
a The duration of the screening period should not exceed 28 days.
b Subjects that experience an acute infection or initiate treatment for latent TB may extend the screening period to 42 days. Under these circumstances, all 
screening procedures except subject consenting, IVRS enrollment, height/weight, immunoglobulins, urinalysis, anti-CCP2, RF, chest x-ray, TB testing,
HepB/C and HIV should be repeated prior to randomization.
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Table 5.1-2:
Flow Chart for Protocol IM101567 - Treatment Perioda
Procedure
Day 1
(Rand)
Week 
4
Week 
8
Week 12 
(Phone 
Visit)
Week 
16
Week 20
(Phone 
Visit)
Week24/
Early 
Termina
tion
Notes
Randomize Subject Using IVRS
X
Eligibility Assessments
Inclusion/Exclusion Criteria
X
Review of I/E criteria that are relative 
to the Randomization day
Safety Assessments
Physical Examination
X
Vital Signs
X
X
X
X
X
Body temperature, seated blood 
pressure, and heart rate.
Weight
X
X
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
X
Causality determined by a blinded 
Clinical Assessor
Laboratory Assessments
Hematology (CBC)
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
Urine Pregnancy Test
X
X
X
X
X
X
X
WOCBP only; see Section 5.3.6.5.
Performed locally. Pregnancy testing 
also performed prior to dosing at 
Weeks 12 and 20.
MTX polyglutamate
X
X
X
X
X
ANA and reflex ENA panels
X
X
X
X
X
Anti-dsDNA
X
X
X
X
X
Anti-cardiolipin antibodies
X
X
X
X
X
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Table 5.1-2:
Flow Chart for Protocol IM101567 - Treatment Perioda
Procedure
Day 1
(Rand)
Week 
4
Week 
8
Week 12 
(Phone 
Visit)
Week 
16
Week 20
(Phone 
Visit)
Week24/
Early 
Termina
tion
Notes
 
 
 
 
 
 
 
 
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Table 5.1-2:
Flow Chart for Protocol IM101567 - Treatment Perioda
Procedure
Day 1
(Rand)
Week 
4
Week 
8
Week 12 
(Phone 
Visit)
Week 
16
Week 20
(Phone 
Visit)
Week24/
Early 
Termina
tion
Notes
Efficacy Assessment
Tender (68)/swollen (66) Joint 
Count
X
X
X
X
X
Performed by a blinded Clinical 
Assessor
Subject Assessment of Pain
X
X
X
X
X
See Appendix 4
Subject Global Assessment of 
Disease Activity
X
X
X
X
X
See Appendix 5
Physician Global Assessment of 
Disease Activity
X
X
X
X
X
Performed by a blinded Clinical 
Assessor; See Appendix 6
Physical Function (HAQ-DI)
X
X
X
X
X
See Appendix 7
Study Drug Administration
Contact IVRS
X
X
X
X
X
Contact is required to randomize the 
subject on Day 1 and to dispense 
medication at each office visit.
Train subjects and/or caregiver on 
how to self-inject and how to fill out 
the diary cards
X
Dispense diary cards
X
X
X
X
Collect and review diary cards
X
X
X
X
Dispense urine pregnancy kits for 
WOCBP for home use every 
4 weeks
X
X
Not applicable if serum pregnancy 
testing is required per local 
regulations.
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Table 5.1-2:
Flow Chart for Protocol IM101567 - Treatment Perioda
Procedure
Day 1
(Rand)
Week 
4
Week 
8
Week 12 
(Phone 
Visit)
Week 
16
Week 20
(Phone 
Visit)
Week24/
Early 
Termina
tion
Notes
Dispense urine pregnancy kits for 
possible use during Follow-up 
Period
X
See Table 5.1-3
Dosing of weekly 
abatacept/biweekly adalimumab
X
X
X
X
X
X
Must be administered weekly 
(abatacept) or biweekly (adalimumab) 
between visits. See Section 4.5
Dispense monthly abatacept or 
adalimumab monthly kits
X
X
X
X
Two monthly kits are dispensed at 
Week 8 and Week 16.
Reconciliation of abatacept or 
adalimumab monthly kits
X
X
X
X
a All visits and procedures during the Treatment Period must occur within 3 days of the expected visit.
b These samples will only be evaluated to determine serum abatacept or adalimumab concentration in the event there is a corresponding positive 
immunogenicity result.
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Table 5.1-3:
Flow Chart for Protocol IM101567 - Follow-Up Period
Procedure
Day 85 after last dosea
Notes
Safety Assessments
Vital Signs
X
Body temperature, seated blood pressure, and heart rate.
Adverse Events Assessment
X
Concomitant Medication Review
X
Laboratory Assessments
Urine Pregnancy Test 
X
WOCBP only; see Section 5.3.6.5. Performed locally. 
a Visit must occur within 10 days of the expected day of the visit. 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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5.1.1
Retesting During Screening, Extended Screening, or Rescreening
All screening procedures are to be performed within 4 weeks of the randomization visit except as 
described below.
Retesting:
A single retest of the anti-CCP2, RF and hsCRP within the Screening period will be permitted 
(in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Period,
may be repeated in an effort to find all possible well-qualified subjects. Consultation with the 
Medical Monitor may be needed to identify whether repeat testing of any particular parameter is 
clinically relevant.
Extended Screening:
Subjects that experience an acute infection or initiate treatment for latent TB may extend the 
screening period to 42 days, as long as the infection did not require hospitalization or 
administration of parenteral antibiotics agents. Under these circumstances, all screening 
procedures except IVRS enrollment, height/weight, immunoglobulins, urinalysis, anti-CCP2, RF, 
chest x-ray, TB testing, HepB/C and HIV should be repeated prior to randomization.
Rescreening:
This study permits the rescreening of a subject that has discontinued the study as a pre-treatment 
failure (ie, subject has not been randomized / has not been treated), still meets all 
inclusion/exclusion criteria, and no more than 9 months have elapsed prior to enrollment since 
the onset of symptoms of RA. If rescreened, the subject must be re-consented. A subject may be 
rescreened only once. Medical Monitor approval is required and rescreens are not permitted less 
than 28 days after signing the first informed consent. The subject will need to sign a new 
informed consent and be reenrolled with a new subject number via the IVRS. Some tests such as 
chest x-ray, may not need to be repeated if they were performed within the protocol defined 
window.
5.1.2
Order of Study Assessments
Study assessments should be performed in the following order:
1) Patient reported outcomes (PROs) questionnaires
2) AE collection
3) Vital signs
4) Joint assessments
5) Investigator assessments
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6) Blood draws
7) Study drug administration
5.2
Study Materials
The following materials will be provided for use during the trial:

Diary cards to record SC dosing administration and the monthly pregnancy test results for 
WOCBPs (mandatory)

Written instructions on how to use the SC syringes

eCRF instructions

Pregnancy Surveillance Forms

Subject and Investigator-rated questionnaires/scales (paper)

Drug Inventory binder (optional)

Interactive Voice Response System (IVRS) worksheets

Laboratory test kits for all required laboratory testing

Cooler bags and gel packs will be provided to assist subjects in transporting study drug

Sharps containers will be provided to assist subjects in disposing of used SC syringes

Tote bags to transport cooler bags, sharp containers and study drug

For WOCBP urine pregnancy kits/instructions will be provided to be used between office 
visits.
5.3
Safety Assessments
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 subject’s randomization 
assignment.
Subjects who terminate treatment early should complete the appropriate Early Termination Visit 
and the Post Drug Follow-up Visits. The Early Termination 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 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the subject’s medical 
record and should not be provided to BMS, unless specifically requested from BMS.
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5.3.1
Physical Examination
Physical examinations may be performed by a Doctor of Medicine (MD), Doctor of Osteopathy 
(DO), Physician Assistant (PA), or Nurse Practitioner (NP).
The physical examination should include examination of the heart, lungs, abdomen, the lymph 
nodes, liver, spleen and skin. A physical examination may note any changes in the subject’s 
condition (body systems) since the last assessment and does not preclude examination of any 
other body systems as clinically indicated.
5.3.2
Chest X-ray
A posterior-anterior and lateral chest x-ray, performed during screening, is required for all 
subjects 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 eCRF.
5.3.3
Physical Measurements
Weight and height is to be recorded at screening. Weight will also be recorded at Day 1 and 
Week 24/Early Termination.
5.3.4
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 subject has been seated quietly for at least 5 minutes.
5.3.5
TB Screening
Chest x-ray, history, and physical examination are considered part of the process to assess a 
subject’s eligibility. In addition to a chest x-ray that does not show any evidence or suspicion of 
latent TB, a tuberculin skin test will be performed and interpreted according to local country 
Health Authorities and/or Medical Society guidelines. Some guidelines have specific 
recommendations for subjects who are to receive biologics or immunosuppressant therapies 
(eg, RA experience with biologic agents),27,28,29 or who are immunocompromised and who have 
had prior BCG vaccination(s).30,31 Tuberculin skin testing is not contraindicated for persons who 
have been vaccinated with BCG. An interferon gamma release assay (eg, QuantiFERONGold 
or Tspot/ELISpot) is an acceptable alternative when skin testing for tuberculosis (ie, PPD) is not 
appropriate.
5.3.6
Laboratory Assessments
All laboratory assessments will be analyzed centrally except if noted otherwise.
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Blood samples will be obtained at all visits noted in Time and Events Schedule. Any laboratory 
test result that the investigator considers clinically relevant should be recorded on the appropriate 
Adverse Event page of the CRF (see Appendix 8).
5.3.6.1
Hematology

Hemoglobin

Hematocrit

Total WBC count, including differential

Platelet count
5.3.6.2
Blood Chemistry
Sodium 
Creatinine
Potassium 
Blood urea nitrogen (BUN)
Chloride 
Total bilirubin
Total Protein 
Alanine aminotransferase (ALT)
Albumin 
Aspartate aminotransferase (AST)
Calcium 
Gamma-glutamyltransferase (GGT)
Phosphorus 
Alkaline phosphatase
Glucose
hsCRP
Rheumatoid Factor
ANA and reflex ENA panels
MTX polyglutamate
ESR*
Quantitative Immunoglubulins (IgG, IgA, IgM)
*Performed locally, kits provided centrally.
5.3.6.3
Urinalysis 

pH

Protein

Glucose

Blood
5.3.6.4
Hepatitis Screen 
The Laboratory results must be available on Day 1 prior to dosing.

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
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5.3.6.5
Pregnancy Tests
Urine/serum pregnancy tests (minimum sensitivity 25 IU/L of -HCG) must be performed for all 
WOCBP within 24 hours prior to dosing for visits specified in Section 5.1. 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 subject between office visits, if permitted by local 
regulations. If any female subject becomes pregnant, she will stop receiving study treatment 
immediately and enter the Post Treatment Follow-up Period. A pregnancy surveillance form will 
be completed and submitted to Bristol-Myers Squibb. Serum pregnancy tests will be processed 
centrally.
5.3.6.6
HIV Testing
HIV testing will be performed for all subjects.
5.4
Efficacy Assessments
Questionnaires and investigator/subject assessments will be completed prior to study drug 
administration. 
Physicians Global Assessment
The Physicians Global Assessment of Disease Activity (PGA) can be performed by the
investigator or sub-investigator. The sub-investigator may be a Doctor of Medicine (MD) or 
Doctor of Osteopathy (DO).
Joint Count Assessments
The Joint Count Assessor may perform the PGA for the same subject. For both assessments 
every effort should be made to ensure the same assessor is used for a given subject throughout 
the study. 
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 the centralized BMS training. 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 BMS 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 BMS 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 BMS site manager, and their eligibility as joint assessor must be confirmed by 
the BMS medical monitor before the individual’s participation in the study as joint assessor.
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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 subject with the initial assessor to ensure 
consistency between subject evaluations.
Patient Reported Outcomes
Subjects will complete the Global Assessment of Disease Activity (VAS), HAQ-DI, and 
Assessment of Pain (VAS). 
5.4.1
Imaging Assessment for the Study
Not Applicable.
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
The following assessments will be performed: 
a) Subject Assessment of Pain: Pain reported by patients, measured on 10 cm VAS. See 
Appendix 4.
b) Subject Assessment of Physical Functioning: The Health Assessment Questionnaire 
(HAQ), published in 1980, is one of the most widely used, comprehensive, validated, 
patient-oriented outcome assessment instruments available. HAQ disability index takes 
into account the subject’s use of aids, devices, or assistance in the scoring algorithm for a 
disability category. See Appendix 8.
c) Subject Assessment of Disease Activity: Global disease assessment of disease activity by 
patients measured on 10 cm VAS. See Appendix 5.
 
 
 
 
 
 
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.)
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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 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs.
(See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
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)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.5.1 in the Investigator Brochure (IB) represent the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting. Following the 
subject’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected that occur during the screening period and within
85 days of discontinuation of the Treatment Period. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
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The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the eCRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
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 drug 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
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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.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5
half lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1.
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.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. 
Standard medical practice in identifying and monitoring hepatic issues should be followed.
6.7
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. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
In this study 25 subjects will be randomized per treatment arm.
This is an exploratory study with only exploratory objectives. No formal sample size and power 
calculation will be provided. It should be noted that with 25 subjects per arm the half width of 
the 95% CI for differences in proportion (eg, proportion of seroconversion for anti-CCP2, 
ACPA) will range from 25 to 30%. This means that only if the treatment difference in proportion 
is larger than 25-30% the difference will be declared statistically significant at 5% significance 
level. For changes from baseline in continuous variables the minimal detectable effect size 
(treatment difference in changes divided by common standard deviation) to declare statistical 
significance (with 5 % significance level) is 0.57. 
The population will be enriched to allow for assessment of important changes in the immune 
phenotype by including only subjects who are anti-CPP2 positive.
8.2
Populations for Analyses
The as-treated analysis population will contain all subjects who received at least 1 dose of study 
medication. The treatment that is received will be used in the analysis. This population will be 
used for all analyses, including demography, biomarker, efficacy and safety analyses.
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
No primary endpoints are defined for this protocol.
8.3.2
Secondary Endpoint(s)
No secondary endpoints are defined for this protocol.
 
 
 
 
 
 
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Summary statistics of all demographics and baseline characteristics will be provided by 
treatment group using the as-treated analysis population.
 
 
 
 
 
 
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8.4.3
Safety Analyses
The evaluation of drug safety is primarily based on clinical adverse events and laboratory 
abnormalities reported during the study.
Frequency distributions and listings of all adverse events, deaths, serious adverse events, events 
leading to discontinuation and adverse events of special interest will be generated. Adverse 
events of special interest are infections, malignancies, autoimmune disorders and injection site 
reactions.
Laboratory marked abnormalities, using pre-defined abnormality criteria, will also be 
descriptively summarized.
8.4.4
Pharmacokinetic Analyses
Not Applicable.
 
 
 
 
 
 
8.4.6
Outcomes Research Analyses
Not applicable
8.4.7
Other Analyses 
Not applicable
8.5
Interim Analyses
Not applicable
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (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 
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 prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
In addition, the study may be evaluated by BMS 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 BMS.
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9.1.2.1
Source Documentation
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 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.
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product.
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 subject, including unique subject identifiers
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
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, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
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 BMS 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 paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects 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, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

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

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined as complete 
avoidance of heterosexual intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined as complete 
avoidance of heterosexual intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are not required to use a second 
method of contraception, but female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete avoidance of 
heterosexual intercourse is an acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle of the patient. This does 
not mean periodic abstinence (eg, calendar, ovulation, symptothermal, profession of 
abstinence for entry into a clinical trial, post-ovulation methods) and withdrawal, which 
are not acceptable methods of contraception. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence.
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LIST OF ABBREVIATIONS
Term
Definition
ABA
abatacept
ACPA
anti-citrullinated protein antibody
ACR
American College of Rheumatology
ADA
adalimumab
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody
ANC
absolute neutrophil count
anti-CCP
anti-cyclic citrullinated peptide
anti-CCP2
commercially available test for ACPA
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the time-concentration curve
-HCG
beta-human chorionic gonadotrophin
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
cm
centimeter
CRF
Case Report Form, paper or electronic
CRP
C-reactive protein
DIP
distal interphalangeal
dL
deciliter
DMARD
disease-modifying anti-rheumatic drug
dsDNA
double-stranded DNA
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
ECG
electrocardiogram
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Term
Definition
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ENA
extractable nuclear antigen
ESR
Erythrocyte Sedimentation Rate
ET
early termination
EU
European Union
EULAR
European League Against Rheumatism
F
Fahrenheit
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
h
hour
HBcAb
Hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
Hgb
hemoglobin
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IM
intramuscular
IMP
investigational medicinal products
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Term
Definition
IND
Investigational New Drug
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
kg
kilogram
L
liter
LDH
lactate dehydrogenase
mg
milligram
MHC
major histocompatibility complex
min
minute
mL
milliliter
mmHg
millimeters of mercury
MRHD
maximum recommended human dose
MTD
maximum tolerated dose
MTX
methotrexate
g
microgram
N
number of subjects or observations
N/A
not applicable
NIMP
non-investigational medicinal products 
NP
nurse practitioner
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
PA
physician assistant
PBMC
Peripheral blood mononuclear cell
PGA
Physicians Global Assessment of Disease Activity
PO
per os (by mouth route of administration)
PT
prothrombin time
QC
quality control
QD, qd
quaque die, once daily
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Term
Definition
RA
rheumatoid arthritis
RBC
red blood cell
RF
Rheumatoid factor
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SLE
systemic lupus erythematosus
SOP
Standard Operating Procedures
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TB
tuberculosis
TNF
tumor necrosis factor 
WBC
white blood cell
US
United States
WHO
World Health Organization
WOCBP
women of childbearing potential
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
A RANDOMIZED, HEAD-TO-HEAD, SINGLE-BLINDED STUDY TO ASSESS 
CHANGES IN THE IMMUNE PROFILE IN RESPONSE TO TREATMENT WITH 
SUBCUTANEOUS ABATACEPT VERSUS SUBCUTANEOUS ADALIMUMAB, IN 
COMBINATION WITH METHOTREXATE IN ADULTS WITH EARLY RHEUMATOID 
ARTHRITIS 
 
NCT02557100 
 
11-July-2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A RANDOMIZED, HEAD-TO-HEAD, SINGLE-BLINDED STUDY TO ASSESS 
CHANGES IN THE IMMUNE PROFILE IN RESPONSE TO TREATMENT WITH 
SUBCUTANEOUS ABATACEPT VERSUS SUBCUTANEOUS ADALIMUMAB, IN 
COMBINATION WITH METHOTREXATE IN ADULTS WITH EARLY RHEUMATOID 
ARTHRITIS
PROTOCOL(S) IM101-567
VERSION # 3.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
5
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................7
2.3
Blinding and Unblinding...........................................................................................7
2.4
Protocol Amendments...............................................................................................7
3
OBJECTIVES ..........................................................................................................8
3.1
Primary.....................................................................................................................8
3.2
Secondary.................................................................................................................8
8
4
ENDPOINTS............................................................................................................8
5
SAMPLE SIZE AND POWER.................................................................................9
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ....................................................................................................9
6.1
Study Periods............................................................................................................9
6.2
Treatment Regimens...............................................................................................10
6.3
Populations for Analyses ........................................................................................10
7
STATISTICAL ANALYSES..................................................................................10
7.1
General Methods ....................................................................................................10
7.2
Study Conduct........................................................................................................11
7.3
Study Population ....................................................................................................11
7.3.1
Subject Disposition.................................................................................................11
7.3.2
Demography and Baseline Characteristics .............................................................11
7.3.3
Medical History and Prior Medication ...................................................................12
7.4
Extent of Exposure .................................................................................................12
7.4.1
Study Therapy.........................................................................................................12
7.4.2
Discontinuation of Study Therapy...........................................................................13
7.4.3
Treatment Compliance............................................................................................14
14
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21
7.7
Safety.....................................................................................................................24
7.7.1
Adverse Events .......................................................................................................24
7.7.2
Adverse Events of Interest.......................................................................................25
7.7.2.1
Infections................................................................................................................25
7.7.2.2
Malignancy.............................................................................................................25
7.7.2.3
Autoimmune Disorders ...........................................................................................25
7.7.2.4
Injection Adverse Events.........................................................................................26
7.7.3
Deaths ....................................................................................................................26
7.7.4
Other Serious Adverse Events.................................................................................26
7.7.5
Adverse Events Leading to Discontinuation of Study Therapy.................................26
7.7.6
Multiple Adverse Events .........................................................................................26
7.7.7
Summaries of Laboratory Data...............................................................................27
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28
7.7.7.2
Vital Signs ..............................................................................................................29
8.2
Baseline Measures..................................................................................................31
8.3
Missing Measurements ...........................................................................................31
8.4
Missing, Unknown or Partial Dates.........................................................................31
8.5
Day Ranges for Analysis of Time Points.................................................................31
 
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Statistical Analysis Plan
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6
 
 
 
2
STUDY DESCRIPTION
2.1
Study Design
This is an exploratory, randomized, single-blinded assessment study in subjects with early RA 
defined as symptoms of RA for no more than 12 months prior to screening and satisfying the 
criteria for RA according to the ACR/EULAR 2010 classification at some point during the 
12-month period. Eligible subjects must have been on methotrexate (MTX) for at least 12 weeks 
with a stable dose of MTX for at least 28 days prior to randomization and are naive to biologic 
DMARD. The study consists of a screening period of up to 28 days, followed by a 24-week single-
blind treatment period with abatacept or adalimumab, followed by a 24-week open-label treatment 
period with abatacept, followed by an 85-day follow-up 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 informed 
consent. 
On Day 1, subjects will be randomized to one of two parallel treatment arms in a 1:1 ratio:

abatacept SC (125mg) weekly

adalimumab SC (40mg) once every two weeks
All subjects continuing in the open-label treatment period will receive abatacept 125mg SC, 
weekly. Those subjects randomized to adalimumab will switch to abatacept at Week 28 following 
a six week washout period. The dose of methotrexate must remain stable throughout the study and 
may only be lowered due to intolerance or adverse event. Subjects not wishing to continue on 
open-label abatacept have the option of discontinuing treatment at the end of the single-blind 
period and proceeding to the post-treatment follow-up period.
Subjects who discontinue treatment of study drug or complete the study will have one follow-up 
visit 85 days after the last dose of investigational product to perform safety assessments.
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2.2
Treatment Assignment
At the time of enrollment, immediately after written informed consent is obtained and before any 
study-related procedures are performed, each subject will be assigned a unique, sequential 
five-digit number beginning with 00001, 00002, 00003 and so on, for identification throughout the 
study. This study number must not be reused for any other subject. The study physician or research 
coordinator must contact the Central Randomization System to enroll each subject into a 
centralized database at the time consent is obtained.
After completion of all screening evaluations and concomitant medication adjustment or 
stabilization, all eligible subjects will be randomized into the single-blind treatment phase of the 
study. Randomization schedules will be generated and kept by the Randomization Group within 
Drug Supply Management of Bristol-Myers Squibb. Each subject who qualifies for treatment will 
be assigned a unique randomization number. Randomization numbers will be assigned using a
Central Randomization System in the order in which subjects qualify for treatment, not in the order 
of study enrollment. Subjects will be randomized on a 1:1 basis to either the abatacept treatment 
arm or the adalimumab treatment arm.
2.3
Blinding and Unblinding
Double blinding of study drug, adalimumab vis-à-vis abatacept, is not feasible due to logistical 
barriers around re-packaging 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 makes 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/subinvestigator to complete/approve the CRF.
2.4
Protocol Amendments
The purpose of Amendment 1 (March 14, 2016) is to extend the treatment period of the study an 
additional 24 weeks. Subjects receiving abatacept will continue to receive abatacept for the 
additional 24 weeks. Subjects receiving adalimumab will switch to abatacept at Week 28 following 
a six week washout period and continue treatment with abatacept for the additional 24 weeks.
The purpose of Amendment 2 (June 8, 2016) is to modify some of the inclusion criteria to better 
align the characteristics of the targeted study population with patients with early Rheumatoid 
Arthritis seen in clinical practice.
The purpose of Amendment 6 (February 22, 2017) is to include the addition of blood sample 
collection for PBMC.
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3
OBJECTIVES
3.1
Primary
Not applicable
3.2
Secondary
Not applicable
 
 
 
 
 
 
 
 
 
 
 
 
 
4
ENDPOINTS
No primary or secondary endpoints are defined for this protocol.
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5
SAMPLE SIZE AND POWER
In this study, 25 subjects will be randomized per treatment arm.
This is an exploratory study with only exploratory objectives. No formal sample size and power 
calculation was provided. It should be noted that with 25 subjects per arm the half width of the 
95% CI for differences in proportion (e.g., proportion of seroconversion for anti-CCP2, ACPA) 
will range from 25 to 30%. This means that only if the treatment difference in proportion is larger 
than 25-30% the difference will be declared statistically significant at 5% significance level. For 
changes from baseline in continuous variables the minimum detectable effect size (treatment 
difference in changes divided by common standard deviation) to declare statistical significance 
(with 5% significance level) is 0.57.
During the study, the sample size was increased to get at least 30 subjects with additional collection 
of blood for With 40 (instead of 25) subjects per arm the half width of the 95% CI for differences 
in proportion (e.g., proportion of seroconversion for anti-CCP2, ACPA) will range from 17% to 
21%. This means that only if the treatment difference in proportion is larger than 17-21% the 
difference will be declared statistically significant at 5% significance level. For changes from 
baseline in continuous variables the minimum detectable effect size (treatment difference in 
changes divided by common standard deviation) to declare statistical significance (with 5% 
significance level) is 0.44.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
The following periods are defined for this statistical analysis plan: 

The pre-treatment period covers the time period prior to or on the first dose time of single-
blind study medication. 

The single-blind treatment period starts at the time of the first dose of single-blind study 
medication and lasts until : 

the time of the last dose of single-blind study medication for concomitant medication 
summaries

56 days post last dose of single-blind study medication for subjects who do not enter OL. 
For those subjects who do enter OL, the single-blind treatment period lasts until first day 
of open-label for abatacept randomized subjects or until 10 days post last dose of single-
blind treatment for adalimumab randomized subjects for safety analyses (AE and labs).

21 days post last dose of single-blind study medication for subjects who do not enter OL
For those subject who do enter OL, the single-blind treatment period lasts until first day 
of open-label for abatacept randomized subjects or until 10 days post last dose of single-
blind treatment for adalimumab randomized subjects for immunogenicity analyses
Note: To align the cut-off of the single-blind treatment period for abatacept and adalimumab 
and taking into account that for adalimumab there is a wash-out period of 6 weeks, 10 days is 
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used to cut the single-blind treatment period for adalimumab. Ten (10) is equal to the expected 
maximum number of days after last single-blind abatacept dose and prior to first open-label 
abatacept dose (7 days +/- 3 days).

The open-label abatacept treatment period starts at the time of the first dose of open-label 
abatacept treatment and lasts until 56 days post last open-label abatacept dose (AE and labs), 
except for immunogenicity analyses for which the open-label period goes up to 21 days post 
last open-label abatacept dose.

The cumulative abatacept period starts at the time of the first  dose of abatacept (single-blind 
or open-label) and lasts until 56 days post last abatacept dose (single-blind or open-label), 
except for immunogenicity analyses for which the cumulative abatacept period goes up to 21 
days post last abatacept dose.
6.2
Treatment Regimens
There are 2 single -blind treatment groups: abatacept 125mg SC weekly or adalimumab 40mg SC 
biweekly, both with concomitant MTX therapy.
There is one open-label treatment group defined: abatacept 125mg SC weekly with concomitant 
MTX therapy.
6.3
Populations for Analyses
The as-treated analysis population will contain all randomized subjects who received at least one 
dose of single-blind study medication, and subjects will be grouped on an as-randomized basis 
unless the subject received the incorrect medication for the entire period of single-blind treatment. 
In that case, the subject will be analyzed in the treatment group associated with the incorrect 
medication they received. This population will be used for all analyses of the single blind period, 
including demography, baseline disease characteristics, biomarker, efficacy safety and 
immunogenicity analyses and for the Week 48 efficacy and biomarker analyses.
The open-label abatacept population will contain all subjects treated with open-label abatacept.
The cumulative abatacept population will contain all subjects treated with single-blind and/or 
open-label abatacept.
7
STATISTICAL ANALYSES
7.1
General Methods
All the analyses, with the exception of the analysis for efficacy responder rate, will be ‘as-
observed’, ie. the available data will be used and there will be no impuation for missing values.
For the efficacy responder rate analysis a non-responder imputation will be applied for missing 
data.
In APPENDIX 1 the list of biomarkers is shown. The different biomarkers are classified into 
different biomarker categories (category 1 up to 12). The biomarker results (tables and plots) will 
be provided for each of these biomarker categories separately.
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The focus of the exploration will be on Day 169 analysis. However, mean or median changes from 
baseline (with 95 % CI) over time from day 1 to day 169 of the single-blind period will be displayed 
for all biomarkers. These plots will be grouped by biomarker category (see APPENDIX 1).
All Day 337 analyses and analyses over time from day 1 to day 337 (efficacy and biomarkers) will 
be provided by original randomized treatment and grouped by biomarker category if applicable
(see APPENDIX 1).
7.2
Study Conduct
As this study includes only exploratory objectives, relevant protocol deviations will not be 
assessed.
7.3
Study Population
Frequency distributions or summary statistics of data pertaining to subject disposition, 
demographics, baseline characteristics, and medical history will be tabulated and displayed by 
treatment group. No statistical test will be carried out for comparison of any baseline measures 
among treatment groups
7.3.1
Subject Disposition
The number of subjects enrolled into the study at screening, the number of subjects randomized, 
the number of subjects who received at least 1 dose of single-blind study medication (abatacept or 
adalimumab), and the number of subjects who discontinued during the single-blind treatment 
period, together with reasons for discontinuation taken from the eCRF status page, will be 
summarized. The summary will also present the number of subjects treated in the OL period.
In addition, the number of subjects treated in open-label abatacept period, and the number of 
subjects who discontinued during the OL abatacept treatment period, together with reasons for 
discontinuation taken from the eCRF status page will be summarized.
7.3.2
Demography and Baseline Characteristics
Demographic, baseline disease characteristics and biomarkers at baseline of all randomized 
subjects who received at least one dose of study medication will be summarized. For continuous 
variables, they will be summarized using means, standard deviations, median, quartiles and ranges. 
The distribution of categorical variables will be summarized by treatment group using frequencies 
and percentages.
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Baseline demographic characteristics include the following:

age in years

weight in kg

gender

race

geographic region
Baseline disease characteristics include:

duration of disease in months

number of tender joints (28)

number of swollen joints (28)

number of tender joints (68)

number of swollen joints (66)

pain

HAQ-DI

subject assessment of disease activity

physician assessment of disease activity

CRP

Rheumatoid factor status

DAS28-CRP

SDAI

CDAI
In addition, all the biomarkers will be summarized at baseline.
7.3.3
Medical History and Prior Medication
Medical history and prior anti-rheumatic medication information will be summarized by treatment 
group using frequencies for all subjects in the as-treated analysis population. 
7.4
Extent of Exposure
7.4.1
Study Therapy
Extent of exposure to single-blind study drug (abatacept and adalimumab) in the as-treated analysis 
population will be summarized in two ways; first, by the number of study drug doses, summarizing 
frequency distribution of number of study drug doses by treatment group, and second, by the 
number of days the subject is known to be on study drug, ignoring any dosing interruptions. 
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For subjects who are not treated in the open-label period, exposure to single-blind study drug in 
days is calculated as:

exposure = (date of last single-blind study medication - date of first single-blind study 
medication +1) + 56.
The offset of 56 days represents approximately four times the half-life of abatacept in humans.
For subjects who receive single-blind abatacept study drug and enter the open-label period within 
56 days of the last dose of single-blind study medication, exposure to single-blind study drug in 
days is calculated as:

exposure = (date of first open-label study medication - date of first single-blind study 
medication).
For subjects who receive single-blind adalimumab study drug, exposure to single-blind study drug 
in days is calculated as:

exposure = (date of last single-blind study medication +10 - date of first single-blind study 
medication).
To align the exposure of adalimumab with the exposure of abatacept and taking into account that 
for adalimumab there is a wash-out period of 6 weeks, 10 days is used to adjust the exposure for 
adalimumab.  Ten (10) is equal to the expected maximum number of days after last single-blind 
abatacept dose and prior to the first open-label abatacept dose (7 days +/- 3 days).
Extent of exposure to abatacept (single blind and open-label) during the cumulative abatacept 
period will be summarized in two ways; first, by the number of abatacept injections, and second, 
by the number of days the subject is known to be on abatacept, ignoring any dosing interruptions. 
exposure = (date of last abatacept dose - date of first abatacept dose +1) + 56.
The offset of 56 days represents approximately four times the half-life of abatacept in humans.
Abatacept includes single-blind abatacept and open-label abatacept. Exposure will be summarized 
for  cumulative abatacept population and presented for all subjects in this population combined
Extent of exposure to abatacept  during the open-label abatacept period will be summarized in two 
ways; first, by the number of abatacept injections, and second, by the number of days the subject 
is known to be on abatacept, ignoring any dosing interruptions. 

exposure = (date of last OL abatacept dose - date of first OL abatacept dose +1) + 56.
The offset of 56 days represents approximately four times the half-life of abatacept in humans.
Exposure will be summarized for the open-label population by the original randomized treatment 
groups and for all OL treated subjects combined.
7.4.2
Discontinuation of Study Therapy
See Section 7.3.1.
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7.4.3
Treatment Compliance
The number of subjects who missed study doses during the single-blind (excluding missed study 
doses due to premature discontinuation from the study) will be summarized by treatment and 
number of study doses missed. A corresponding listing of subjects with missed doses during the 
single-blind period will be provided.
In addition, the number of subjects who missed study doses during the cumulative abatacept period 
(excluding missed study doses due to premature discontinuation from the study) will be 
summarized for the cumulative abatacept population. A corresponding listing of subjects with 
missed doses during cumulative abatacept period will be provided.
 
 
 
 
 
 
 
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7.7
Safety
Analysis of all safety data will follow the BMS standard safety data conventions2,3 and 
supplements to the standard conventions for the abatacept programs4.
The evaluation of drug safety is based primarily on clinical AEs, vital signs and laboratory 
abnormalities reported during the single-blind treatment period. All safety presentations for the 
Week 24 analyses will be based on the as-treated analysis population by treatment group. 
All safety presentations for the cumulative abatacept period will be based on the cumulative 
abatacept population and the presentation will be for all abatacept treated subjects (single-blind 
and/or open-label) combined into one group.
Frequency distribution and individual listings of all AEs will be generated. Changes in clinical 
laboratory test results from baseline will be summarized. Laboratory marked abnormalities using 
pre-defined abnormality criteria will also be descriptively summarized. There will be no statistical 
testing of group difference with respect to frequencies of AEs or laboratory marked abnormalities.
7.7.1
Adverse Events
All AEs are coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), using 
the latest approved version of the Medical Dictionary for Regulatory Activities (MedDRA) at the 
time of database lock. Listings and summaries will be based on the resulting SOCs and PTs.
All reported AEs during the single-blind treatment period and all reported AEs reported during the 
cumulative abatacept period will be listed, indicating the subjects id, age, gender, the date of onset, 
the day of onset relative to the start of treatment, investigator’s assessment of severity and 
relationship to study drug.
In addition, all reported AEs during the washout-out period (beyond 20 days past last single blind 
dose of adalimumab up to first dose of open-label abatacept) will be in a separate listing. This 
listing will only include adalimumab patients who are treated with OL abatacept. The threshold of 
20 days is chosen for this listing, because AEs up to 20 days past last single-blind dose of 
adalimumab are included in the AE summaries of the single-blind period.  It should be noted that 
for the single-blind analysis a threshold of 20 days (post-hoc) was used instead of 10 days defined 
in version 1.0 of SAP.
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AEs will be summarized for the single-blind treatment period and the cumulative abatacept period. 
This period is defined in Section 6.1. These AE summaries will be based on proportions, which 
represent the number of subjects experiencing the AEs divided by the number of subjects who 
received at least 1 dose of single-blind study medication for the Week 24 analysis and by the 
number of subjects treated with abatacept for the cumulative abatacept period analysis.
Any AEs irrespectively of when they occur, but will appear on the above mentioned 
comprehensive listing. 
Summary information (the number and percent of subjects by treatment) will be tabulated for the 
following AEs:

all AEs including clinical and laboratory AEs

most common AEs (reported in 10% of subjects or more in any treatment group)

categorized by severity

related events

most common (reported in 5% of subjects or more in any treatment group)

categorized by severity

serious adverse events (SAEs)

discontinuations due to SAEs/AEs
7.7.2
Adverse Events of Interest
7.7.2.1
Infections
All reported infections and infestations within the SOC: Infections and infestations occurring 
during the single-blind treatment period will be summarized by preferred term and treatment group 
and also provided in a separate listing. The events will also be summarized by severity.
Similar summaries and listings will be done for the cumulative abatacept period .
7.7.2.2
Malignancy
All events in the MedDRA Maintenance and Support Services Organization (MSSO) malignancies 
Structured MedDRA Query (SMQ) list occurring during the single-blind treatment period will be 
captured and reported. These events will be summarized by preferred term and treatment group 
and will also be listed.
Similar summaries and listings will be done for the cumulative abatacept period .
7.7.2.3
Autoimmune Disorders
The frequency of pre-specified autoimmune disorders, defined using a BMS customized SMQ, 
occurring during the single-blind treatment period will be provided. Autoimmune disorders 
occurring during the single-blind treatment period will be summarized by severity. All reported 
autoimmune disorders occurring during the single-blind treatment period will be listed.
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Similar summaries and listings will be done for the cumulative abatacept period.
7.7.2.4
Injection Adverse Events
A. Systemic Injection Reactions (pre-specified, defined using a BMS customized SMQ) are defined 
as systemic AEs (such as hypersensitivity reactions) occurring during the first 24 hours after 
abatacept/adalimumab SC administration.
B. Local Injection Site Reactions (pre-specified, defined using a BMS customized SMQ) are 
defined as those AEs that occur at the site of SC injection.
The pre-specified systemic injection reactions and local injection site reactions occurring during 
the single-blind treatment period will be summarized by severity. These AEs will also be listed.
In addition, a pre-specified local injection site reaction event of interest, defined as the AEs with 
the following PT that occur at the site of SC injection: Erythema, Pain, Pruritus, Haematoma, and 
Swelling will be summarized by severity.
Similar summaries and listings will be done for the cumulative abatacept period.
7.7.3
Deaths
All AEs with the outcome of death reported during the single-blind treatment period will be listed 
by treatment group, together with a clinical narrative relating to the death of the subjects.
A similar listing will be done for the cumulative abatacept period.
7.7.4
Other Serious Adverse Events
SAEs are captured on a CRF page. All SAEs occurring during the single-blind treatment period 
will be summarized by treatment group and listed.
Similar summaries and listings will be done for the cumulative abatacept period.
7.7.5
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation of study drug are identified as those AEs with an action code of 5 
on the eCRF page (5 = discontinued study drug). All such AEs occurring during the single-blind 
treatment period will be listed and summarized by SOC, PT and treatment group. In addition, a 
listing of subjects with SAEs leading to discontinuation will be provided.
Similar summaries and listings will be done for the cumulative abatacept period.
7.7.6
Multiple Adverse Events
Several descriptive summaries of adverse events that takes into account the number of occurrences 
that an AE was reported by individual patients will be provided. In order to prepare these 
summaries, the CRF data will be processed according to standard BMS algorithms to categorize 
each line of patient data as a new occurrence or a continuation of an existing event. This 
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determination will be based upon onset and resolution dates. Each line of patient data will represent 
the maximum severity observed as well as the last known assessed relationship to study medication 
by the investigator. 
This data will be presented as the rate per 100 years of patient exposure. Exposure to study 
medication will be calculated according to approved standard BMS algorithms as well. 
As an example, if 5 patients report 7 unique episodes of headache and had a combined cumulative 
exposure of 20 
years to study 
medication, the 
incidence rate is reported as 
7 / 20 * (100) or 35 cases per 100 patient years of exposure. 
The following summary tables will be provided:

A table showing the total number and rate (exposure adjusted) of occurrences for all AEs 
occurring in at least 10% of the subjects treated will be presented for the single-blind period.

Listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated 
and overlapping and contiguous occurrences of the same event have been collapses.
Similar summaries and listings will be done for the cumulative abatacept period.
7.7.7
Summaries of Laboratory Data
Safety summaries based on laboratory test results include evaluation of laboratory abnormalities 
and change in laboratory test values from baseline. The baseline value on a per analyte basis is the 
last non-missing value prior to the start of single-blind study drug
Laboratory abnormalities are identified using a pre-defined set of marked abnormality criteria. The 
criteria will be listed in the CSR. The frequencies of laboratory abnormalities will be presented by 
laboratory test and treatment group during the single-blind treatment period and by laboratory test 
and all abatacept subject combined into one group for the cumulative abatacept period. The single-
blind treatment period and the cumulative abatacept period for the laboratory analyses are defined 
in Section 6.1.
Evaluation of change from baseline during the single-blind treatment period and during the 
cumulative abatacept period will be carried out for all laboratory parameters whose regular 
collection is indicated in the protocol. Summary statistics will be presented for baseline, post-
baseline laboratory values and the change from baseline. Subject who have laboratory measures at 
baseline and corresponding measure on at least 1 scheduled visit during the single-blind treatment 
period or on at least 1 scheduled visit during the cumulative abatacept period will be included in 
the laboratory analyte assessment. Note that not all subjects have laboratory determinations for all 
analytes at all visits, and therefore the sample size may vary from analyte to analyte. Some 
laboratory samples may be inadvertently analyzed multiple times for the same test, producing 
multiple laboratory results for the same collection date and time for the same subjects. The average 
of a subject’s multiple laboratory results will be taken as the final lab result on that date and time 
for this subject if assessments are tested at the same laboratory center.
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7.7.7.2
Vital Signs
On each visit day, vital signs are monitored. Body temperature, seated blood pressure and heart 
rate will be summarized using mean, standard deviation, median and range at each visit measured 
during the single-blind treatment period.
Similar summaries will be done for the cumulative abatacept period.
8
CONVENTIONS
8.1
Calculations of Key Measures
8.1.1
Evaluation of Joint Counts
Joints may have been surgically replaced/fused due to worsening RA during the study. Joint status 
is adjusted for surgical replacement and intra-articular injections according to the following rules:

If a joint is replaced/fused on or before the start of single-blind study drug, then for this joint 
both tenderness and swelling will be imputed as ‘not done’ for all visits.

If a joint is replaced/fused due to RA involvement and occurs after the start of study drug, then 
for this joint both tenderness and swelling will be considered as ‘present’ for all visits on or 
after the replacement procedure date.

If a joint is replaced for reason other than RA involvement and occurs after the start of study 
drug, then for this joint both tenderness and swelling will be considered as ‘not done’ for all 
visits on or after the replacement procedure date.

If an intra-articular injection occurs, then for that joint both tenderness and swelling will be 
considered as ‘present’ at that particular visit and all subsequent visits.
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The ACR20, 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 50%, or 70% 
improvement, respectively in 3 of the 5 remaining core data set measures (components #3 to #7).
8.1.6
Evaluation of CDAI 
CDAI is a simple linear sum of the following four components:

Tender joint counts out of 28 joints

Swollen joint counts out of 28 joints

Subject global assessment of disease activity (0-10cm)

Physicians global assessment of disease activity (0-10cm)
8.2
Baseline Measures
For all outcome measures, the baseline value is the last assessment taken prior to first dose of 
single-blind study medication. In general, this is the assessment taken on study Day 1 before the 
administration of study medication. For some variables that are also measured during screening, if 
Day 1 assessments are unavailable then the last assessment prior to Day 1 from screening 
assessments will be used as baseline value. When there is a missing baseline assessment in joint 
counts, it will not be imputed. Thus, subjects are excluded from any change from baseline analysis 
for which they have a missing baseline value.
8.3
Missing Measurements
For listings of efficacy measures or biomarkers, missing values will be represented as missing. For 
analyses involving efficacy or biomarkers, missing values will not be imputed.
8.4
Missing, Unknown or Partial Dates
The BMS safety guidelines2,3,4 for conventions relating to the handling of missing or partial dates 
and the determination of appropriate default values in such cases (in particular, for concomitant 
medication dose start dates and end dates and AE onset dates) will be utilized.
8.5
Day Ranges for Analysis of Time Points
Single -blind period
Subjects do not always adhere strictly to the visit schedule timing in the protocol. Therefore, the 
designation of visits during the single-blind period of the study will be based on the day of 
evaluation relative to the trial (day of first single-blind study medication = study Day 1) rather than 
the nominal visit recorded in the CRF. Mutually exclusive relative day windows are defined below 
to provide derived visits that correspond to the post-baseline time points. If a visit falls outside the 
pre-specified visit windows, then the data collected at that visit will not be assigned a derived visit 
but will remain in the derived data sets. Determination of baseline values is addressed in 
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Section 8.2. The day ranges for assessments during the single-blind treatment period are presented 
in Table 8.5-1.
Table 8.5-1:
Day Ranges for Assessments during Single-Blind Treatment Period
Visit
Target Day
Assessments
Screening
< 1
< 1
Day 1 (Baseline)
1
1*
Week 4
29
8 - 43
Week 8
57
44 - 85
Week 16
113
86 - 141
Week 24
169
142 - 211
* Note: See Section 8.3 for baseline measures. 
For subjects who receive single-blind abatacept and continue into the open-label treatment period, the upper limit of 
Week 24 window is first dose day of the open-label period. For subjects who receive single-blind adalimumab and 
continue into the open-label treatment period, the upper limit of this window is the last dose of single-blind study 
medication + 10 days.
 
 
 
Open-label period
The day ranges for assessments during the open-label period are presented in Table 8.5-2.
Table 8.5-2:
Day Ranges for Assessments during Open-label Period
Visit
Target Day
Assessments
Week 28
197
Day 2 OL - 211
Week 32
225
212 - 253
Week 40
281
254 - 309
Week 48
337
310 - 365
Efficacy and biomarker assessments performed beyond 42 days after the last dose are excluded.
Lab assessment performed beyond 56 days after the last dose are excluded.
If a subject has more than 1 visit where a measurement is recorded within a window, the 
measurement closest to the target day will be used. In case of 2 visits being equidistant from the 
target, the later measurement will be used in analyses.
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9
CONTENT OF REPORTS
At the time of the first lock when the last randomized subject completes the 24 week single-blind 
treatment period, the analyses described in this SAP, with the exceptions of the analyses for the 
biomarker categories 2, 3 and 5 in APPENDIX 1, will be performed. The results of these analyses 
will be presented in a standard BMS Clinical Study Report (CSR). 
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