Clinical trial NCT03714022
Conditions: Rheumatoid Arthritis
Sponsor: Bristol-Myers Squibb
Start date: 2018-11-09; Completion date: 2019-04-02
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to compare the pharmacokinetics (PK) of the abatacept drug product converted from drug substance by a new drug substance process (Treatment A) relative to the current drug substance process (Treatment B) following a single dose (750 mg) intravenous (IV) infusion in healthy participants.

Detailed description:
Participants will be admitted to the clinical facility the day prior to dosing (Day -1) and will be confined until at least 24 hours post-dose. On Day 1, eligible participants will be randomized in a 1:1 ratio to either Treatment A or Treatment B. The randomization will be stratified by weight categories: \>= 60 to \< 70 kg, \>= 70 to \< 80 kg, \>= 80 to \< 90 kg, and \>= 90 to \<= 100 kg.

Arms: arm 1: Participants will receive abatacept at a single dose of 750 mg as IV infusion on Day 1 converted from drug substance by a new process. arm 2: Participants will receive abatacept at a single dose 750 mg as IV infusion on Day 1 converted from drug substance by converted from drug substance by the current process.
Interventions: intervention 1: Abatacept
Intervention descriptions: intervention 1: Participants will receive abatacept at a single dose 750 mg as IV infusion.

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
IM101682
IND Number:
BB-IND 9,391
EUDRACT Number:
NA
Date:
07-Sep-2018
Revised Date:
15-Nov-2018
CLINICAL PROTOCOL IM101682
A Randomized, Open-Label, Parallel-Group, Single-dose, Biocomparability Study of the 
Pharmacokinetics of the Abatacept (BMS-188667) Drug Product Converted from Drug 
Substance of a New Abatacept Drug Substance Process Relative to the Current Abatacept Drug
Process in Healthy Participants
Short Title:
A Study to Evaluate the Pharmacokinetics of Abatacept Converted From Drug Substance by Two 
Different Processes
Revised Protocol Number: 01
Incorporates Administrative Letters 01 and 02
Study Director
Medical Monitor
Uma Arumugam, MD
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 
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abatacept
Revised Protocol No: 01
Date: 15-Nov-2018
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organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No: 01
Date: 15-Nov-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
01
15-Nov-2018
Exclusion criterion modified, adverse event appendix updated, and 
incorporation of changes described in protocol administrative letters dated 
26-Sep-2018 and 22-Oct-2018.
Administrative 
Letter 02
22-Oct-2018

Updated the address and phone number for the Study Director

To align the start of the collection period of nonserious adverse events 
in Section 2 with Section 9.2.1

Aligned terminology describing study participants
Administrative 
Letter 01
26-Sep-2018

Updated the address and phone number for the Study Director

Aligned the start of the collection period of nonserious adverse events 
in Section 2 with Section 9.2.1

Aligned terminology describing study participants
Original Protocol
07-Sep-2018
Not applicable.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Title page
Address and phone number 
for Study Director updated.
 
Section 2, Schedule of Activities
Modified time of the start of 
the collection of nonserious 
AEs on Day 1. 
 
Section 6.2, Exclusion Criteria
Exclusion criterion 3a 
modified.
 
 
Section 7.7.2.1, Precautions, 
Infectious Complications
Subject was replaced with 
participant.
 
Appendix 3, Adverse Events and 
Serious Adverse Events. 
Definitions and Procedures for 
Recording, Evaluating, Follow 
Up and Reporting
Appendix 3 replaced with 
current version.  
 
All
Minor formatting and 
typographical corrections
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 01: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
3.3 Benefit/Risk/Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
 
 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.3.1 Meals and Dietary Restrictions ............................................................... 
6.3.2 Alcohol and Tobacco ............................................................................... 
6.3.3 Activity ..................................................................................................... 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
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7.5.2 Retained Samples for Biocomparability .................................................. 
7.6 Treatment Compliance ...................................................................................... 
 
 
 
 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.1.1 Medical Photography...................................................................... 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Suicidal Risk Monitoring ......................................................................... 
9.4.6 Imaging Safety Assessment ...................................................................... 
9.4.7 Chest X-ray .............................................................................................. 
9.5 Pharmacokinetics .............................................................................................. 
9.5.1 Pharmacokinetics: Blood Collection and Processing ............................. 
 
 
 
 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
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10.3.1 Pharmacokinetic Analyses ..................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.3.1 Immunogenicity ............................................................................. 
 
10.3.4 Interim Analyses ..................................................................................... 
 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE .. 
APPENDIX 6 REPRESENTATIVE LIGHT BREAKFAST ....................................... 
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1
SYNOPSIS
Not applicable.
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2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented in Table 2-1 and Table 2-2.
Table 2-1:
Screening Procedural Outline (IM101682)
Procedure
Screening
Visit
Day -1
Visit
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed consent 
is signed.
Inclusion/Exclusion Criteria
X
X
Medical History
X
Include any toxicities or allergy related to previous treatments.
Admission to the Clinical Facility
X
Safety Assessments
Physical Examination (PE)
X
X
If the screening PE is performed within 24 hours prior to dosing on Day 1 then a 
single exam may count as both the screening and predose evaluation. In addition to 
the PE, a skin exam will be conducted on Day -1. See Section 9.4.1.1. 
Physical Measurements
X
X
Includes height, weight, and BMI. Body weight only on Day -1.
Vital Signs
X
X
Includes body temperature, respiratory rate, and seated blood pressure and heart rate. 
Blood pressure and heart rate should be measured after the participant has been 
resting quietly in the seated position for at least 5 minutes. 
Concomitant Medication Use
X
X
12-Lead Electrocardiogram (ECGs)
X
X
ECGs should be recorded after the participant has been supine for at least 5 minutes. 
Laboratory Tests
Includes blood and urine samples. Participants are required to fast for at least 
10 hours prior to the collection of specimens for clinical laboratory tests. See 
Section 9.4.4.
Serology
X
Includes hepatitis C antibody, hepatitis B surface antigen (HBsAg), hepatitis B core 
antigen antibody (anti-HBc), and HIV-1 and -2 antibodies. Results must be available 
and reviewed prior to admission on Day -1.
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Table 2-1:
Screening Procedural Outline (IM101682)
Procedure
Screening
Visit
Day -1
Visit
Notes
Urine Drug Test (Including Cotinine) 
X
X
Screening results must be available and reviewed prior to admission on Day -1. 
Day -1 results must be available and reviewed prior to dosing on Day 1.
Alcohol Urine or Breath Test
X
X
Screening results must be available and reviewed prior to admission on Day -1. 
Day -1 results must be available and reviewed prior to dosing on Day 1.
Pregnancy Test (quantitative results)
X
X
For WOCBP only. Serum only. Screening results must be available and reviewed 
prior to admission on Day -1. Day -1 results must be available and reviewed prior to 
dosing on Day 1.
Follicle Stimulating Hormone (FSH)
X
Women only. Refer to Appendix 4. Results must be available and reviewed prior to 
admission on Day -1.
Tuberculosis (TB) Screening
X
QuantiFERON®TB Gold test. A QuantiFERON-TB Gold test performed within 
4 weeks of dosing on Day 1 is acceptable as long as there is documentation of a 
negative result.
Hematology and Serum Chemistry
X
X
Screening results must be available and reviewed prior to admission on Day -1. 
Day -1 results must be available and reviewed prior to dosing on Day 1. See 
Section 9.4.4.
Thyroid Function Test 
X
Thyroid-stimulating hormone (TSH) with reflex to free thyroxine (free T4), free 
triiodothyronine (free T3). Results must be available and reviewed prior to admission 
on Day -1.
Urinalysis
X
X
Screening results must be available and reviewed prior to admission on Day -1. 
Day -1 results must be available and reviewed prior to dosing on Day 1. See 
Section 9.4.4
Chest X-ray
X
A posterior-anterior and lateral chest x-ray will be performed. Results must be 
available and reviewed prior to admission on Day -1. See Section 9.4.7
Adverse Event Reporting
Monitor for Serious Adverse Events
X
X
All SAEs must be collected from the date of participant’s written consent until 
101 days post dose. If a participant prematurely discontinues, all SAEs must be 
collected 30 days post last visit. 
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Table 2-2:
On Treatment Procedural Outline(IM101682)
Procedure
Day 
1
Day
2 
Day
4
Day
8
Day
15
Day
22
Day 29 
± 2 Days
Day 43
± 2 Days
Day 57 
± 2 Days
Day 71
± 2 Days
Study 
Dischargea
Notes
Safety Assessments
Physical 
Examination (PE)
X
X
X
Targeted PE
X
Day 1 predose. Targeted 
examination of skin. 
Photographs may be taken of 
any areas affected by rash that 
develop after the start of the 
infusion (including evolving 
changes). See Section 9.4.1.1. 
Continued monitoring of rashes 
will occur as needed. Targeted 
examination of other systems 
based on clinical symptoms. 
Inspection of IV 
injection site
X
Predose and 1 hour post end of 
the infusion. Additional 
inspections (including 
photography of any changes) 
may be conducted as 
warranted. See Section 9.4.1.1.
Physical 
Measurements 
X
Weight only.
Vital Signs
Xb
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
Electrocardiogram 
(ECGs) 
Xc
X
See note in screening 
procedures. 
 
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Table 2-2:
On Treatment Procedural Outline(IM101682)
Procedure
Day 
1
Day
2 
Day
4
Day
8
Day
15
Day
22
Day 29 
± 2 Days
Day 43
± 2 Days
Day 57 
± 2 Days
Day 71
± 2 Days
Study 
Dischargea
Notes
Laboratory Tests
Hematology and 
Serum Chemistry
X
X
X
X
X
See note in screening 
procedures and Section 9.4.4.
Pregnancy Test
X
X
X
X
Serum quantitative results.
Adverse Event 
Reporting
Monitor for 
Nonserious Adverse 
Events
X
X
X
X
X
X
X
X
X
X
All nonserious AEs must be 
collected at the start of study 
treatment on Day 1 through 
Day 71.
Monitor for Serious 
Adverse Events
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
Pharmacokinetic 
(PK) Assessments
Blood PK Sampling
X
X
X
X
X
X
X
X
X
X
On Day 1, the blood sample 
should be drawn at predose. 
See Section 9.5.1.
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Table 2-2:
On Treatment Procedural Outline(IM101682)
Procedure
Day 
1
Day
2 
Day
4
Day
8
Day
15
Day
22
Day 29 
± 2 Days
Day 43
± 2 Days
Day 57 
± 2 Days
Day 71
± 2 Days
Study 
Dischargea
Notes
Blood Sampling for 
Immunogenicity 
Assessment
X
X
X
X
X
On Day 1, the immunogenicity 
sample should be drawn at 
predose. See Section 9.8.2.
Participants who seroconvert 
and continue to have a high 
titer at study discharge that is 
considered to be significantly 
increased versus baseline will 
be asked to return for follow-up 
assessment(s) for anti-abatacept 
antibodies approximately every 
4 months until their titers 
and/or sero-status are judged to 
be stable by the investigator.
 
 
.
Clinical Drug 
Supplies
Randomize
X
Participants will be randomized 
prior to dosing.
Study Treatment
Administrationd
X
Supplied by BMS.
a Evaluations performed prior to study discharge, or for participants who are prematurely discontinued. 
b Measurements at predose, 30 minutes (end of infusion), and 60 minutes after the start of the infusion
c Prior to dosing and 3 hours after the start of the infusion
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d Participants will be randomized to receive a 30-minute IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by a new 
process (Treatment A), or a 30-minute IV infusion (750 mg) abatacept drug product converted from drug substance by the current process (Treatment B).
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In the event that multiple procedures are required at a single time point, the ECG may be obtained 
up to 15 minutes earlier, vital signs may be obtained up to 10 minutes earlier or later, and clinical 
laboratory sample may be obtained up to 5 minutes earlier than the nominal time point, ensuring 
the pharmacokinetic (PK) samples can be collected on time.
For the predose assessments on Day 1 PK, immunogenicity, and PD samples, ECG, vital signs, 
and examinations may be obtained up to 60 minutes prior to study treatment administration.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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27,28
3.3
Benefit/Risk/Assessment
Abatacept is a fully human fusion protein representing a new class of therapeutic agent known as 
a selective costimulation modulator with potential for immunomodulatory activity. This expected 
activity should be taken into consideration in caring for human participants participating in clinical 
trials with abatacept. Investigators should be alert to signs of infection in participants, and 
participants should be cautioned to report any signs of infection, such as fever, sore throat, cough 
or unusual appearances of skin lesions (swelling, warmth, tenderness, or exudate) to their 
physician without delay. The risks of infection occurring in the currently proposed single dose
study, however, are expected to be very low. 
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This study is in healthy participants, a population that would not receive any health benefit from 
participating in this study. Although this single dose study for normal healthy participants should 
not pose an unacceptable health risk to participants based on the established safety profile of 
abatacept, in order to minimize the overall risk to participants, this protocol has inclusion and 
exclusion criteria appropriate to the population and proposed dosing, exclusionary screening tests 
(tuberculosis testing, chest x-ray, medical history, physical examination), and specific follow-up 
safety assessments. Adverse events and SAEs will be reviewed on an ongoing basis by the BMS 
Medical Monitor and by the BMS Pharmacovigilance Department to look for trends and any safety 
issues.
Risks from the PK, immunogenicity, and clinical safety phlebotomy procedures are standard and 
include infection, bleeding, bruising, blood clot formation, discomfort at the injection site, and
(rarely) fainting.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of abatacept may be found in the Investigator’s Brochure4, an addendum to the 
Investigator’s Brochure33, and the prescribing information.1
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the PK of the abatacept drug product converted from drug 
substance by a new drug substance process (Treatment A) relative to the 
current drug substance process (Treatment B) following a single dose (750 
mg) IV infusion in healthy participants.
Cmax and AUC(INF) of abatacept
Secondary
To assess the safety of a single dose (750-mg) IV infusion of the abatacept 
drug product converted from drug substance by a new drug substance 
process (Treatment A) versus drug substance by the current drug 
substance process (Treatment B).
Safety assessments will be based on 
medical review of AE reports, vital 
sign measurements, ECGs, physical 
examinations, and clinical 
laboratory tests.
To assess the immunogenicity of abatacept drug product converted from 
drug substance by a new drug substance process (Treatment A) versus 
drug substance by the current drug substance process (Treatment B).
Immunogenicity determination will 
be based on the incidence of 
laboratory-reported positive 
responses and titers of anti-
abatacept antibodies specific for 
“CTLA4 and possibly Ig” and “Ig 
and/or Junction Region.”
To characterize the PK of abatacept drug product converted from drug 
substance by a new drug substance process (Treatment A) versus drug 
substance by the current drug substance process (Treatment B).
Tmax, AUC(0-T), AUC(0-28 day), 
CLT, Vss, and T-HALF of 
abatacept
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
 
Abbreviations: AUC(0-28 day) = area under the serum concentration-time curve from time zero to 28 days after 
dosing; AUC(0-T) = area under the serum concentration-time curve from zero to the last time of the last quantifiable 
concentration; AUC(INF) = area under the serum concentration-time curve from time zero extrapolated to infinity; 
CD86 = cluster of differentiation 86; CLT = total body clearance; Cmax = maximum observed serum concentration; 
CTLA-4-T = cytotoxic T lymphocyte (T cell)-associated antigen 4; ECG = electrocardiogram; IV = intravenous; 
PD = pharmacodynamic; PK = pharmacokinetic; T-HALF = terminal phase elimination half-life in serum; 
Tmax = time of maximum observed serum concentration; Vss = volume of distribution at steady-state.
5
STUDY DESIGN
5.1
Overall Design
This is an open-label, randomized, parallel group, single-dose study in healthy participants 
following IV administration of abatacept. 
Participants will undergo screening evaluations to determine eligibility within 28 days prior to 
drug administration on Day 1. All participants are required to weigh between 60 and 100 kg, 
inclusive, and should be weighed using the same scale at each site. 
Participants will be admitted to the clinical facility the day prior to dosing (Day -1) and will be 
confined until at least 24 hours post-dose. 
On Day 1, eligible participants will be randomized in a 1:1 ratio. The randomization will be 
stratified by weight categories: 60 to < 70 kg, 70 to < 80 kg, 80 to < 90 kg, and 
90 to ≤100 kg. Within each weight category, participants will be randomly assigned to abatacept 
drug product converted from drug substance by a new drug substance process (Treatment A) or 
abatacept drug product converted from drug substance by the current drug substance process
(Treatment B) in a 1:1 ratio. A minimum of 10 participants per treatment per weight category are 
planned to be randomized.
In order to decrease variability, the goal of the treatment group assignment is to match each 
participant 1:1 by weight category to a participant with the opposite treatment assignment. 
Randomization numbers will be sequential within each weight category, starting with 1001, 2001, 
3001, and 4001 for 60 to < 70 kg, 70 to < 80 kg, 80 to < 90 kg, and 90 to ≤100 kg weight 
categories, respectively.
On Day 1, participants will receive a single IV infusion of either Treatment A or Treatment B at a 
dose of 750 mg over approximately 30 minutes using a calibrated, constant-rate infusion pump.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
*Treatment A: IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by a new 
process
**Treatment B: IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by the 
current 
process
Abbreviations: IV = intravenous; PD = pharmacodynamic; PK = pharmacokinetic
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for adverse events throughout the study. Blood samples for 
PK analysis, immunogenicity, 
will be collected for up to 1680 hours (70 days) 
after study treatment administration. Approximately 260 mL of blood will be drawn from each 
participant during the study.
Participants will be closely monitored for AEs throughout the duration of the study. Participants 
will be discharged from the study following completion of evaluations on Day 71.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
5.2
Number of Participants
A sufficient number of participants will be screened to randomize approximately 140 participants 
into the study. 
Approximately 70 participants will be assigned to each of the 2 treatment groups and will receive 
a single IV infusion of either Treatment A or Treatment B. Sample size determination is discussed 
in Section 10.1.
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5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or last health status follow-up contact made to a participant discharged 
from the study. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same.
The approximate duration of the study for each participant will be 99 days which includes the 
28-day screening period and the 71 day on-treatment period.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Signed written informed consent must be obtained from the participants in accordance with 
requirements of the clinical facility’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) prior to the initiation of any protocol-required procedures.
2) Type of Participant and Target Disease Characteristics
a) Healthy participants as determined by no clinically significant deviation from normal in 
medical history, physical examination, vital signs, ECGs, and clinical laboratory 
determinations. 
b) Body weight will be between 60 and 100 kg, inclusive.
3)
Age and Reproductive Status
a) Males and Females, ages 18 or age of majority to 55 years, inclusive
b) Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with abatacept plus 5 half-lives of abatacept (85 days) plus 30 days (duration 
of ovulatory cycle) for a total of 115 days post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with abatacept plus 
5 half-lives of abatacept (85 days) plus the duration of spermatogenesis (90 days) for a total 
of 175 days after the last dose of study treatment. In addition, male participants must be 
willing to refrain from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4) 
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants who have a present malignancy or previous malignancy within the last 5 years 
prior to screening (except documented history of cured non-metastatic squamous or basal 
cell skin carcinoma or cervical carcinoma in situ). Participants who had a screening 
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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.
b) Participants at risk for tuberculosis (TB) defined as follows: 
i)
Current clinical, radiographic, or laboratory evidence of active TB, even if currently 
being treated. Chest x-rays (posterior/anterior and lateral) obtained within the 6 months 
prior to screening and TB testing (IFN-release assay or QuantiFERON_TB Gold) 
performed in the past month prior to screening will be accepted; however, a copy of 
the reports must be placed in the participant binder.
ii) A history of active TB unless there is documentation that the participant had received 
prior anti-TB treatment that was appropriate in duration and type according to local 
health authority guidelines.
c) Participants with a history of herpes zoster
d) Any acute or chronic bacterial infection in the previous 12 weeks of dosing
e) Any recent infection requiring antibiotic treatment within 4 weeks of dosing
f)
Known or suspected infection, including infection with human immunodeficiency virus 
(HIV), hepatitis B or C viruses
g) Presence of any factors that would predispose the participant to develop infection 
(eg, rectal fissures, poor dentition, open skin lesions)
h) Known or suspected autoimmune disorder
i)
Any history of known or suspected congenital or acquired immunodeficiency state or 
condition that would compromise the participant’s immune status
j)
Any significant acute or chronic medical illness
k) Any major surgery within 4 weeks of study treatment administration
l)
Donation of blood to a blood bank or in a clinical study (except a screening visit or 
follow-up visit) within 4 weeks of study treatment administration (within 2 weeks of study 
treatment administration for plasma only)
m) Blood transfusion within 4 weeks of study treatment administration
n) Inability to be venipunctured and/or tolerate venous access
o) Recent (within 6 months of study treatment administration) history of smoking or current 
smokers. This includes participants using electronic cigarettes or nicotine-containing 
products such as tobacco for chewing, nicotine patches, nicotine lozenges, or nicotine gum.
p) Recent (within 6 months of study treatment administration) drug or alcohol abuse as 
defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 5)
q) Any other sound medical, psychiatric and/or social reason as determined by the investigator
2) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7.
3) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG, or clinical laboratory determinations beyond what 
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is consistent with the target population. Estimated glomerular filtration rate (based on the 
MDRD equation) < 70 mL/min/1.73 m2
b) Any of the following on 12-lead ECG prior to study treatment administration, confirmed 
by repeat
i)
PR 210 msec
ii) QRS 120 msec
iii) QT 500 msec
iv) QTcF 450 msec for males, 470 msec for females
c) Any of the following clinical laboratory evaluation, at screening or Day -1, confirmed by 
repeat:
i)
Alanine aminotransferase (ALT) > ULN
ii) Aspartate aminotransferase (AST) > ULN
iii) Direct bilirubin > ULN
iv) Total bilirubin > ULN
v) LDH > ULN
vi) Serum creatinine > ULN
vii)Creatine kinase (CK) > 4 ULN
viii)
Electrolytes (sodium, potassium, chloride, calcium, or phosphorus) outside of the 
reference range deemed to be clinically significant by the investigator
ix) Complete blood count (including platelets) outside the reference range deemed to be 
clinically significant by the investigator
d) Positive urine screen for drugs of abuse including cotinine
e) Positive alcohol urine or breath test
f)
Positive blood screen for hepatitis C antibody, hepatitis B surface antigen (HBsAg), 
hepatitis B core antigen antibody (anti-HBc), or HIV-1 and -2 antibody 
g) Clinically significant abnormal thyroid-stimulating hormone (TSH) at screening. A reflex 
test for free triiodothyronine (T3)/free thyroxine (T4) will be completed for TSH values 
out of the reference range to assist in the determination of clinical significance.
4) Allergies and Adverse Drug Reaction
a) History of allergy to abatacept or related compounds
b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Inability to comply with restrictions as listed in Section 6.3 Lifestyle Restrictions
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions

Participants are required to fast (nothing to eat or drink except water) for 1 hour prior to study 
treatment administration. Participants are required to continue to fast (nothing to eat or drink 
except water) for at least 1 hour after study treatment administration. Water may be consumed 
ad libitum at other times.

Participants are required to fast (nothing to eat or drink except water) for 10 hours before blood 
laboratory evaluations.

On Day 1:

A light breakfast (see Appendix 6) will be served approximately 1 hour post the end of the 
study treatment administration. 

A standard lunch will be served approximately 4 hours post the end of study treatment 
administration. 

A standard dinner will be served approximately 8 hours after post the end of study 
treatment administration. 

A standard light snack will be served approximately 12 hours after post the end of study 
treatment administration. 
6.3.2
Alcohol and Tobacco

Participants are not permitted to consume alcohol-containing beverages from 3 days prior to 
dosing until release from the clinical facility on Day 2, and for 48 hours prior to study visits 
during which clinical laboratory assessments are scheduled.

Participants are not permitted to smoke or use electronic cigarettes or any nicotine-containing 
products within 6 months prior to dosing on Day 1 until study discharge.
6.3.3
Activity

Participants are to refrain from strenuous exercise, contact sports, and sunbathing from 
screening to end of the study.

Participants are required to remain in the clinical facility for at least 24 hours after dosing.

Participants should remain in a seated or reclined position during IV infusion of abatacept and 
for a minimum of 1 hour after the end of the infusion. Participants must be under direct 
observation for 1 hour after the end of the infusion.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized/has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.

Investigational products: abatacept (new drug substance process), abatacept (current drug 
substance process)
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication

Other drugs administered as part of the study that are critical to claims of efficacy (eg, 
background therapy, rescue medications)

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
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Table 7-1:
Study treatments for IM101682
Product Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Abatacept for IV infusion,
250 mg/vial
250 mg/vial
IP
Open Label
Vial
Refer to the label on 
the container
Abbreviation: IP = investigational product
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study 
Treatment
Unit dose 
strength(s)/Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
A
750 mg
Single 30-minute infusion on 
Day 1
IV
B
750 mg
Single 30-minute infusion on 
Day 1
IV
Abbreviations: A = IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by a 
new process; B = IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by the 
current process; IV = intravenous
In the morning on Day 1, after fasting for at least 1 hour, each participant will receive a single IV 
dose of abatacept.
The start time of the IV dose administration will be called “0” hour.
Restrictions related to food and fluid intake are described in Section 6.3.
7.2
Method of Treatment Assignment
Participants will be randomized on Day 1 in a 1:1 ratio to either Treatment A or Treatment B
groups. The randomization will be stratified by weight categories: 60 to < 70 kg, 70 to < 80 kg, 
80 to < 90 kg, and 90 to ≤100 kg according to a computer generated randomization scheme 
prepared by ICON.
Within each weight category, participants will be randomly assigned to abatacept drug product 
converted from drug substance by a new drug substance process (Treatment A) or abatacept drug 
product converted from drug substance by the current drug substance process (Treatment B).
In order to decrease variability, the goal of the treatment group assignment is to match each 
participant 1:1 by weight category to a participant with the opposite treatment assignment. A 
minimum of 10 participants per treatment per weight category are planned to be randomized.
Randomization numbers will be sequential within each weight category, starting with 1001, 2001, 
3001, and 4001 for 60 to < 70 kg, 70 to < 80 kg, 80 to < 90 kg, and 90 to ≤100 kg weight 
categories, respectively. A copy of the randomization listing will be provided to the pharmacist 
prior to study initiation.
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001 (eg, 00001, 00002, 00003.... 00010). Sequential numbering may restart at 
00001 for each participating site as the distinct patient identification number (PID) will ultimately 
be comprised of the site number and participant number, (eg, 0002-00001). Those enrolled 
participants meeting inclusion and exclusion criteria will be eligible to be randomized. 
Randomization numbers will be assigned prior to dosing. 
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Participants will not be replaced if they are discontinued from the study secondary to an adverse 
event unless the adverse event can be determined to be unrelated to treatment. If a participant is 
replaced after dosing, the replacement participant will be identified from the same site and from 
the same weight category to the discontinued participant. The replacement participant will receive 
the same treatment as the participant that was discontinued but a new randomization number will 
be assigned to him or her. The new randomization number will be the original randomization 
number plus 4000. For example, Participant 1004 would be replaced by Participant 5004.
7.3
Blinding
Not applicable.
7.4
Dosage Modification
Not applicable.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For study drugs not provided by BMS and obtained commercially by the site, storage should in 
accordance with the product label.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 as specified by the study team.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.5.2
Retained Samples for Biocomparability
At the time of receipt of the investigational product by the investigator or designee, BMS will 
specify the appropriate number of containers or units to select for retention, the conditions of 
sample storage, required duration of sample retention, and provisions for returning or disposing of 
the investigational product. When samples are selected, containers or units should be placed in 
packaging with a tamper evident seal either provided by BMS, or sourced by the site. Package 
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labeling should clearly identify the contents as biocomparability samples and state that the 
investigational product should be stored in the restricted area with limited access. 
7.6
Treatment Compliance
Study treatment will be administered in the clinical facility.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)

Pregnancy

Inability to comply with the protocol

Discretion of the investigator

The infusion of study medication should be immediately discontinued if there is any sign of 
anaphylaxis
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets 1 of the conditions outlined in Section 9.2.7 or if the 
investigator believes that it is in best interest of the participant.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately notify within 24 hours of awareness 
of the pregnancy, the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy. 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including posttreatment study followup or loses the 
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ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by participant to 
1 registered mail letter. All attempts should be documented in the participant’s medical 
records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
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If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities. 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Not applicable.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of SAEs for expedited reporting.
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 101 days of discontinuation of dosing.
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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 treatment or protocol-specified procedure (eg, a follow-up skin biopsy).
All nonserious AEs must be collected at the start of study treatment until the timepoints specified 
in the Schedule of Activities (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
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
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
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 Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant /sponsor 
/IRB/EC, as applicable.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
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Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
For this study, any dose of abatacept greater than the protocol-required amount will be considered 
an overdose.
All occurrences of overdose must be reported as an SAE (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Schedule of Activities.
9.4.1.1
Medical Photography
Initial and subsequent photographs may be taken of any areas of rash and/or of the IV injection 
site (for any local reaction such as redness, swelling, or rash) that may develop after the start of
the infusion.
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9.4.2
Vital signs
Refer to Schedule of Activities.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
A local laboratory will perform the analyses and will provide reference ranges for these tests.
Results of clinical laboratory tests performed on Day -1 must be available and reviewed prior to 
dosing.
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Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Fasting glucose
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase (screening only)
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antigen 
antibody (anti-HBc), HIV-1 and -2 antibodies will be conducted (screening only)
Other Analyses
Urine test for drugs of abuse including cotinine (screening and Day -1)
Urine or breath alcohol test (screening and Day -1)
Thyroid-stimulating hormone (TSH) with reflex to free triiodothyronine (T3) and free
thyroxine (T4) as applicable (screening only)
QuantiFERON-TB Gold test (screening only)
Pregnancy test (quantitative results) (WOCBP only): screening, on Day -1, Day 15, Day 29, 
Day 57, and Day 71 (study discharge).
Follicle stimulating hormone (FSH) (screening only for women only) 
9.4.5
Suicidal Risk Monitoring
Not applicable. 
9.4.6
Imaging Safety Assessment
Not applicable.
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9.4.7
Chest X-ray
A posterior-anterior and lateral chest x-ray, performed during screening, is required for all 
participants. All participants must have a chest x-ray negative for TB to be entered in this study. 
The chest x-ray result will be recorded on the appropriate page of the CRF.
9.5
Pharmacokinetics
Pharmacokinetics of abatacept will be derived from serum concentration versus time data. The PK 
parameters to be assessed include:
Cmax
Maximum observed serum concentration
Tmax
Time of maximum observed serum concentration
AUC(0-28 day)
Area under the serum concentration-time curve from time zero to 28 days 
after dosing
AUC(0-T)
Area under the serum concentration-time curve from time zero to time of 
last quantifiable concentration
AUC(INF)
Area under the serum concentration-time curve from time zero 
extrapolated to infinite time
T-HALF
Terminal phase elimination half-life in serum
CLT
Clearance
Vss
Volume of distribution at steady-state
Individual participant PK parameter values will be derived by non-compartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses.
9.5.1
Pharmacokinetics: Blood Collection and Processing
Table 9.5.1-1 lists the sampling schedule to be followed for the assessment of PK. The capture of 
precise PK sampling times relative to the actual dosing time is integral to the PK analysis and must 
be accurately recorded on the eCRF. The date and time of sample collection must be recorded so 
that compliance with the sampling schedule can be confirmed.
Table 9.5.1-1:
Pharmacokinetic Sampling Schedule for Abatacept
Study Day of 
Sample Collection
Event
Time
(Relative To Start 
of Infusion of 
Abatacept)
Hour: Min
Blood Sample for Serum 
Abatacept
1
predose
00:00
X
1
00:15
X
1
EOIa
00:30
X
1
01:00
X
1
02:00
X
1
06:00
X
1
12:00
X
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Table 9.5.1-1:
Pharmacokinetic Sampling Schedule for Abatacept
Study Day of 
Sample Collection
Event
Time
(Relative To Start 
of Infusion of 
Abatacept)
Hour: Min
Blood Sample for Serum 
Abatacept
2
24:00
X
4
72:00
X
8
168:00
X
15
336:00
X
22
504:00
X
29
672:00
X
43
1008:00
X
57
1344:00
X
71
1680:00
X
a EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, 
the collection of this sample should also be delayed accordingly.
The serum samples will be analyzed for abatacept by a validated enzyme-linked immunosorbent 
assay (ELISA).
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will 
be provided to the site in the procedure manual.
 
 
 
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9.8.2
Immunogenicity Assessments 
Table 9.8.2-1 lists the sampling schedule to be followed for immunogenicity assessments. Blood 
samples for determination of antibodies to abatacept and time-matched PK samples will be 
collected on Days 1, 15, 29, 57, and 71. Participants who seroconvert and continue to have a high 
titer at study discharge that is considered to be significantly increased versus baseline will be asked 
to return for follow-up assessment(s) for anti-abatacept antibodies approximately every 4 months
until their titers and/or sero-status are judged to be stable by the investigator.
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Table 9.8.2-1:
Immunogenicity Sample Schedule
Study Day of 
Sample Collection
Event
Time
(Relative To Start of 
Infusion of Abatacept 
Hour: Min
Blood Sample for 
Immunogenicity
1
predose
00:00
X
15
336:00
X
29
672:00
X
57
1344:00
X
71
1680:00
X
A validated, sensitive, electrochemiluminescence assay (ECL) method will be used to detect anti-
abatacept-antibodies with specificities to “CTLA4 and possibly Ig” and “Ig and/or Junction 
Region”.34
Samples that are confirmed positive with specificity to “CTLA4 and possibly Ig” antibodies with 
the ECL immunogenicity assay will be further analyzed with a validated, in vitro, cell-based 
bioassay to determine whether the anti-abatacept-antibodies have neutralizing activity.
Record the date and time of sample collection so that compliance with the sampling schedule can 
be confirmed. Detailed instructions for the immunogenicity blood collection, labeling, processing, 
storage, and shipping will be provided to the site in the procedure manual.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Biocomparability of Treatment A to Treatment B will be concluded if the 90% CIs for the ratios 
of geometric means for abatacept Cmax and AUC(INF) are contained within 80% to 125%. 
Seventy participants per treatment group (Treatment A or Treatment B) will provide 88% power 
to conclude that Treatment A is biocomparable to Treatment B if Treatment A increases abatacept 
exposure by 10% compared to Treatment B; if Treatment A decreases abatacept exposure by 10%, 
70 participants per treatment group will provide 83% power to conclude that Treatment A is 
biocomparable to Treatment B. 
Participants who drop out will be replaced to ensure that there will be at least 65 evaluable 
participants per treatment group. Sixty-five participants per treatment group will provide 86% 
power to conclude that Treatment A is biocomparable to Treatment B if Treatment A increases 
abatacept exposure by 10% compared to Treatment B and 80% power if Treatment A decreases 
abatacept exposure by 10%. 
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These calculations assume that AUC(INF), and Cmax are log-normally distributed with 
between-participant standard deviation of 0.21 for Cmax and 0.27 for AUC(INF), 
 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Enrolled Participants
All participants who sign informed consent
All Treated Participants
All participants who receive study treatment
Pharmacokinetic 
Population
All participants who receive abatacept and have any available 
concentration-time data.
Evaluable 
Pharmacokinetic 
Population
All participants in the PK Population with adequate PK profiles 
for accurate estimation of PK parameters. All available derived PK 
parameter values will be included in the PK data set and reported, 
but only participants with evaluable PK will be included in the 
summary statistics and statistical analysis.
All participants who receive study treatment will be included in the safety data set.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. 
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender, and race.
No efficacy analyses will be performed.
Below is a summary of planned statistical analyses of the primary and secondary endpoints.
10.3.1
Pharmacokinetic Analyses
Pharmacokinetic results will be listed for the PK population; descriptive summary statistics will 
use the evaluable PK population.
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Endpoint
Statistical Analysis Methods
Primary
Cmax and AUC(INF)
Summary statistics by treatment will be tabulated for serum concentrations and PK 
parameters of abatacept. Geometric means and coefficients of variation (CV%) will be 
presented for Cmax and AUC(INF). 
To assess comparability of Treatment A to Treatment B, point estimates and the two-
sided 90% confidence intervals (CIs) will be constructed for the ratios of geometric 
means of abatacept AUC(INF) and Cmax based on analyses of covariance on 
log(AUC(INF)) and log(Cmax) adjusted for baseline body weight. Biocomparability of 
Treatment A to Treatment B will be concluded if the 90% CIs for the ratios of 
geometric means for abatacept Cmax and AUC(INF) are contained within 80% to 
125%.
Secondary
Tmax, AUC(0-T), 
AUC(0-28 day), CLT,
Vss, and T-HALF
Summary statistics by treatment will be tabulated for PK parameters of abatacept. 
Geometric means and coefficients of variation (CV%) will be presented for AUC(0-T),
AUC(0-28 day), CLT, and Vss. Medians and ranges will be presented for Tmax. Means 
and standard deviations (SDs) will be presented for T-HALF.
10.3.2
Safety Analyses
All safety analyses will be performed on the All Treated Participants Population.
Endpoint
Statistical Analysis Methods
The occurrence of nonserious 
AEs, SAEs, AEs leading to 
study discontinuation or 
death; results of clinical 
laboratory tests, vital sign 
measurements, ECGs, and 
physical examinations; and 
marked abnormalities in 
clinical laboratory test results
All AEs will be listed and summarized by system organ class and preferred term 
for all treated participants.
Vital signs, ECGs, and laboratory test results will be listed and summarized by 
time point.
Any significant physical examination findings and marked abnormal clinical 
laboratory test results will be listed. Electrocardiogram recordings will be 
evaluated by the investigator and abnormalities, if present, will be listed.
Acute peri-infusional and postinfusional AEs will be tabulated for the 30-minute
infusion period and the 24-hour postinfusion period, respectively, after the start 
of the abatacept infusion.
10.3.3
Other Analyses 
10.3.3.1
Immunogenicity
Endpoint
Statistical Analysis Methods
anti-abatacept antibodies antibodies 
specific for “CTLA4 and possibly 
Ig” and “Ig and/or Junction Region”
The incidence of laboratory-reported positive responses and the 
corresponding titer values will be listed by participant and by study day.
The frequency and percentage of positive abatacept-induced 
immunogenicity response will be summarized by treatment.
Lack of immunogenicity is defined as the absence of a positive antibody response generated 
against abatacept. 
A participant is considered to have a positive abatacept-induced immunogenicity for ‘CTLA4 and 
possibly Ig’or ‘Ig and/or Junction Region’ if 1 of the following criteria are met:
A missing baseline immunogenicity measurement and
a positive laboratory-reported 
immunogenicity response after baseline.
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
A negative laboratory-reported baseline immunogenicity response and a positive 
laboratory-reported immunogenicity response after baseline.

A positive laboratory-reported baseline immunogenicity response and a positive 
laboratory-reported immunogenicity response after baseline that has a titer value strictly 
greater than the baseline titer value.
This definition will be applied for each antibody-reactivity separately. All other ECL 
immunogenicity measurements will be classified as negative.
 
 
10.3.4
Interim Analyses 
Not applicable.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
anti-HBc
hepatitis B core antigen antibody
APC
antigen presenting cell
AUC
area under the serum concentration-time curve
AUC(0-28 days)
area under the serum concentration-time curve from time zero to 
28 days after dosing
AUC(INF)
area under the serum concentration-time curve from time zero 
extrapolated to infinity
AUC(0-T)
area under the serum concentration-time curve from time zero to the 
time of the last quantifiable concentration
BCG
Bacillus Calmette-Guerin
BMI
body mass index
BMS
Bristol-Myers Squibb
CD
cluster of differentiation
CFR
Code of Federal Regulations 
CI
confidence interval
CK
creatine kinase
CLR
renal clearance
CLT
total body clearance
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form, paper or electronic
CRO
Contract Research Organization
CTLA-4
cytotoxic T-lymphocyte (T-cell)-associated antigen 4
CV%
coefficient of variation
DILI
drug-induced liver injury
ECG
electrocardiogram
eCRF
electronic case report form
EU
European Union
FDA
Food and Drug Administration
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Term
Definition
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IgG1
immunoglobulin G1
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
JIA
juvenile idiopathic arthritis
MS
multiple sclerosis
MTX
methotrexate
PD
pharmacodynamics
PE
physical examination
PK
pharmacokinetic
PPK
population PK
PK
pharmacokinetic(s)
RA
rheumatoid arthritis
SAE
serious adverse event
SC
subcutaneous
TB
tuberculosis
T-HALF
terminal plasma half-life
Tmax
time of maximum observed concentration
TNF
tumor necrosis factor
Treatment A
abatacept drug product converted from drug substance by a new drug 
substance process
Treatment B
abatacept drug product converted from drug substance by the current
drug substance process
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Term
Definition
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
USA
United States (of America)
Vss
volume of distribution at steady-state
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical GuidelinesGood Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A breach of 
the conditions and principles of Good Clinical Practice (GCP) (occurring in any country) in 
connection with that trial or the protocol related to the trial which is likely to affect to a significant 
degree the safety or physical or mental integrity of 1 or more subjects of the trial or the scientific 
value of the trial.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. 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, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects 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 participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects 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 participant 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.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
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 
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original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant 
identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (e.g., 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.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
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CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
MONITORING
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
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RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
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It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT 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:
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the eCRF.

The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
When paper forms are used, the original paper forms are to remain on site

Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Any one of the approved methods of contraception (highly effective and/or less than highly 
effective) listed below is required during study duration and for 115 days after treatment has been 
discontinued. 
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Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 85 days after the end of treatment plus an additional 90 days for 
a total of 175 days.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure defined as 85 days after the end of 
treatment in the male participant.
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
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 175 days after the end of treatment. 

Refrain from donating sperm for the duration of the study treatment and for 85 days after the 
end of treatment for a total of 175 days.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE
The following is taken from DSM-IV:
Diagnostic Criteria for Psychoactive Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment or distress as 
manifested by 3 (or more) of the following, occurring at any time in the same 12-month period:
1. Tolerance, as defined by either of the following:
a) A need for markedly increased amounts of the substance to achieve intoxication or desired 
effect,
b) Markedly diminished effect with continued use of the same amount of the substance.
2. Withdrawal, as manifested by either of the following:
a) The characteristic withdrawal syndrome for the substance,
b) The same (or closely related) substance is taken to relieve or avoid withdrawal symptoms.
3. The substance is often taken in larger amounts or over a longer period than was intended.
4. There is a persistent desire or unsuccessful efforts to cut down or control substance use.
5. A great deal of time is spent in activities necessary to obtain the substance (eg, visiting multiple 
doctors or driving long distances), use the substance (eg, chain-smoking) or recover from its 
effects.
6. Important social, occupational or recreational activities are given up or reduced because of 
substance use.
7. The substance use is continued despite knowledge of having a persistent or recurring physical 
or psychological problem that is likely to have been caused or exacerbated by the substance 
(eg, current cocaine use despite recognition of cocaine-induced depression, or continued 
drinking despite recognition that an ulcer was made worse by alcohol consumption.)
Criteria for Severity of Psychoactive Substance Dependence:
Mild:  Few, if any, symptoms in excess of those required to make the diagnosis, and the symptoms 
result in no more than mild impairment in occupational functioning or in usual social activities or 
relationships with others.
Moderate:  Symptoms or functional impairment between “mild” and “severe”.
Severe:  Many symptoms in excess of those required to make the diagnosis, and the symptoms 
markedly interfere with occupational functioning or with usual social activities or relationships
with others.
In Partial Remission:  During the past six months, some use of the substance and some symptoms 
of dependence.
In Full Remission:  During the past six months, either no use of the substance, or use of the 
substance and no symptoms of dependence.
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Diagnostic Criteria for Psychoactive Substance Abuse
A. A maladaptive pattern of psychoactive substance use, leading to clinically significant 
impairment or distress as manifested by one (or more) of the following, occurring at any time 
in the same 12-month period:
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, 
school, or home (eg, repeated absences or poor work performance related to substance use; 
substance-related absences, suspensions, or expulsions from school, neglect of children or 
household).
2. Recurrent substance use in situations in which it is physically hazardous (eg, driving an 
automobile or operating a machine when impaired by substance use).
3. Recurrent substance-related legal problems (eg, arrests for substance-related disorderly 
conduct).
4. Continued substance use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the substance (eg, arguments with spouse 
about consequences of intoxication, physical fights).
B. The symptoms have never met the criteria for substance dependence for this class of substance.
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APPENDIX 6
REPRESENTATIVE LIGHT BREAKFAST
Food Item
Calories (kcal)
Fat (g)
Carbohydrates (g)
Protein (g)
2 slices of white 
bread
128
1.8
24.0
4.0
1 teaspoonful low 
fat margarine
26
2.9
Trace
Trace
1 tablespoon jam
56
Trace
13.8
Trace
5 oz apple juice
71
0.2
17.5
0.2
5 oz skim (nonfat) 
milk
54
0.3
7.5
53
Total grams (g)
-
5.2
62.8
9.5
Total calories 
(kcal)
335
47
251
38
% of total calories
100
14
75
11
 
 
Revised Protocol No: 01
Date: 15-Nov-2018
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SAP_001.pdf: 
Official Title of Study: 
A Randomized, Open-Label, Parallel-Group, Single-dose, Biocomparability Study of the 
Pharmacokinetics of the Abatacept (BMS-188667) Drug Product Converted from Drug 
Substance of a New Abatacept Drug Substance Process Relative to the Current Abatacept 
Drug 
Process in Healthy Participants 
 
NCT Number: NCT03714022 
 
Document Date (Date in which document was last revised): Aug 28, 2019 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
FOR 
 
 
 
A Randomized, Open-Label, Parallel-Group, Single-dose, Biocomparability Study of the 
Pharmacokinetics of the Abatacept (BMS-188667) Drug Product Converted from Drug 
Substance of a New Abatacept Drug Substance Process Relative to the Current Abatacept Drug 
Process in Healthy Participants 
 
 
 
FINAL VERSION # 2.0 
Revision History 
Revision 
Date 
Revised By 
Changes Made -- Reasons for the Change 
1.0 
11Feb2019 
 
Original issue 
2.0 
28Aug2019 
 
Added neutralizing antibody analysis and PK 
analysis excluding subjects with positive abatacept-
induced ADA 


Statistical Analysis Plan 
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2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
 
 
2 
STUDY DESCRIPTION ..............................................................................................4 
2.1 
Study Design .................................................................................................................4 
2.2 
Treatment Assignment ..................................................................................................5 
2.3 
Blinding and Unblinding ..............................................................................................6 
2.4 
Protocol Amendments ..................................................................................................6 
 
 
3 
OBJECTIVES AND ENDPOINTS ..............................................................................8 
4 
SAMPLE SIZE AND POWER ....................................................................................8 
5 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES .........................................................................................................9 
5.1 
Study Periods ................................................................................................................9 
5.2 
Treatment Regimens .....................................................................................................9 
5.3 
Populations for Analyses ..............................................................................................9 
6 
STATISTICAL ANALYSES .....................................................................................10 
6.1 
General Methods .........................................................................................................10 
6.2 
Study Conduct ............................................................................................................10 
6.3 
Study Population .........................................................................................................10 
6.3.1 
Participant Disposition ...............................................................................................10 
6.3.2 
Demographic Characteristics .....................................................................................10 
6.3.3 
Physical Measurements ..............................................................................................11 
6.3.4 
Medical History and Previous Medications ...............................................................11 
6.4 
Extent of Exposure .....................................................................................................11 
6.5 
Efficacy .......................................................................................................................11 
6.6 
Safety ..........................................................................................................................11 
6.6.1 
Deaths .........................................................................................................................11 
6.6.2 
Serious Adverse Events ...............................................................................................11 
6.6.3 
Adverse Events ............................................................................................................11 
6.6.4 
Injection Site Reaction ................................................................................................12 
6.6.5 
Clinical Laboratory Evaluations ................................................................................12 
6.6.6 
Electrocardiograms ....................................................................................................13 


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6.6.7 
Vital Signs ...................................................................................................................13 
6.6.8 
Physical Examination Findings ..................................................................................14 
6.7 
Pharmacokinetics ........................................................................................................14 
 
 
6.8.1 
Immunogenicity ...........................................................................................................15 
 
 
6.9 
Conventions ................................................................................................................16 
6.9.1 
Decimal Places ...........................................................................................................16 
6.9.2 
Pharmacokinetic Summaries ......................................................................................16 
7 
CONTENT OF REPORTS .........................................................................................17 
 
 
 


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2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is an open-label, randomized, parallel group, single-dose study in healthy participants 
following IV administration of abatacept. 
Participants will undergo screening evaluations to determine eligibility within 28 days prior to 
drug administration on Day 1. All participants are required to weigh between 60 and 100 kg, 
inclusive, and should be weighed using the same scale at each site. 
Participants will be admitted to the clinical facility the day prior to dosing (Day -1) and will be 
confined until at least 24 hours post-dose. 
On Day 1, participants will receive a single IV infusion of either Treatment A or Treatment B at a 
dose of 750 mg over approximately 30 minutes using a calibrated, constant-rate infusion pump. 


Statistical Analysis Plan 
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5 
The study design schematic is presented in Figure 2.1-1. 
Figure 2.1-1: 
Study Design Schematic 
 
*Treatment A: IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by a new 
process 
**Treatment B: IV infusion of single dose (750 mg) abatacept drug product converted from drug substance by the 
current process 
Abbreviations: IV = intravenous; PD = pharmacodynamic; PK = pharmacokinetic 
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for adverse events (AEs) throughout the study. Blood 
samples for PK analysis, immunogenicity, and PD assessments will be collected for up to 
1680 hours (70 days) after study treatment administration. Approximately 260 mL of blood will 
be drawn from each participant during the study. 
Participants will be closely monitored for AEs throughout the duration of the study. Participants 
will be discharged from the study following completion of evaluations on Day 71. 
2.2 
Treatment Assignment 
Participants will be randomized on Day 1 in a 1:1 ratio to either Treatment A or Treatment B 
groups. The randomization will be stratified by weight categories: ≥ 60 to < 70 kg, ≥ 70 to < 80 kg, 
≥ 80 to < 90 kg, and ≥ 90 to ≤ 100 kg according to a computer generated randomization scheme 
prepared by ICON. 


Statistical Analysis Plan 
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Within each weight category, participants will be randomly assigned to abatacept drug product 
converted from drug substance by a new drug substance process (Treatment A) or abatacept drug 
product converted from drug substance by the current drug substance process (Treatment B). 
In order to decrease variability, the goal of the treatment group assignment is to match each 
participant 1:1 by weight category to a participant with the opposite treatment assignment. A 
minimum of 10 participants per treatment per weight category are planned to be randomized. 
Randomization numbers will be sequential within each weight category, starting with 1001, 2001, 
3001, and 4001 for ≥ 60 to < 70 kg, ≥ 70 to < 80 kg, ≥ 80 to < 90 kg, and ≥ 90 to ≤ 100 kg weight 
categories, respectively. A copy of the randomization listing will be provided to the pharmacist 
prior to study initiation. 
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001 (eg, 00001, 00002, 00003.... 00010). Sequential numbering may restart at 
00001 for each participating site as the distinct patient identification number (PID) will ultimately 
be comprised of the site number and participant number, (eg, 0002-00001). Those enrolled 
participants meeting inclusion and exclusion criteria will be eligible to be randomized. 
Randomization numbers will be assigned prior to dosing. 
Participants will not be replaced if they are discontinued from the study secondary to an AE unless 
the AE can be determined to be unrelated to treatment. If a participant is replaced after dosing, the 
replacement participant will be identified from the same site and from the same weight category 
to the discontinued participant. The replacement participant will receive the same treatment as the 
participant that was discontinued but a new randomization number will be assigned to him or her. 
The new randomization number will be the original randomization number plus 4000. For 
example, Participant 1004 would be replaced by Participant 5004. 
2.3 
Blinding and Unblinding 
This is an open-label study. 
2.4 
Protocol Amendments 
There has been one protocol amendment for this study. The first protocol amendment was issued 
on November 15, 2018 and includes the following updates: 
• Exclusion criterion 3a was updated 
 
 
• Appendix 3 (Adverse Events and Serious Adverse Events, Definitions and Procedures for 
Recording, Evaluation, Follow Up and Reporting) was replaced with the most current 
version. 
• In the schedule of activities, the collection of nonserious AEs on Day 1 was specified to 
begin at the start of study treatment.  
• Terminology describing study patients was aligned (“subject” was replaced with 
“participant”). 


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• The Study Director’s contact information was updated. 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
OBJECTIVES AND ENDPOINTS 
Table 3-1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To compare the PK of the abatacept drug product converted from 
drug substance by a new drug substance process (Treatment A) 
relative to the current drug substance process (Treatment B) 
following a single dose (750 mg) IV infusion in healthy 
participants. 
• 
Cmax and AUC(INF) of abatacept 
Secondary 
 
• 
To assess the safety of a single dose (750-mg) IV infusion of the 
abatacept drug product converted from drug substance by a new 
drug substance process (Treatment A) versus drug substance by the 
current drug substance process (Treatment B). 
• 
Safety assessments will be based on 
medical review of AE reports, vital sign 
measurements, 
ECGs, 
physical 
examinations, and clinical laboratory 
tests. 
• 
To assess the immunogenicity of abatacept drug product converted 
from drug substance by a new drug substance process (Treatment 
A) versus drug substance by the current drug substance process 
(Treatment B). 
• 
Immunogenicity determination will be 
based on the incidence of laboratory-
reported positive responses and titers of 
anti-abatacept antibodies specific for 
“CTLA4 and possibly Immunoglobulin 
(Ig)” and “Ig and/or Junction Region.” 
• 
To characterize the PK of abatacept drug product converted from 
drug substance by a new drug substance process (Treatment A) 
versus drug substance by the current drug substance process 
(Treatment B). 
• 
Time of maximum observed 
concentration (Tmax), area under the 
serum concentration-time curve from 
time zero to time of the last 
quantifiable concentration (AUC(0-
T)), AUC(0-28 day), CLT, Vss, and T-
HALF of abatacept 
 
 
 
 
 
 
 
 
 
 
4 
SAMPLE SIZE AND POWER 
Biocomparability of Treatment A to Treatment B will be concluded if the 90% confidence intervals 
(CIs) for the ratios of geometric means for abatacept Cmax and AUC(INF) are contained within 
80% to 125%. Seventy participants per treatment group (Treatment A or Treatment B) will provide 
88% power to conclude that Treatment A is biocomparable to Treatment B if Treatment A 
increases abatacept exposure by 10% compared to Treatment B; if Treatment A decreases 
abatacept exposure by 10%, 70 participants per treatment group will provide 83% power to 
conclude that Treatment A is biocomparable to Treatment B. 
Participants who drop out will be replaced to ensure that there will be at least 65 evaluable 
participants per treatment group. Sixty-five participants per treatment group will provide 86% 


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9 
power to conclude that Treatment A is biocomparable to Treatment B if Treatment A increases 
abatacept exposure by 10% compared to Treatment B and 80% power if Treatment A decreases 
abatacept exposure by 10%. 
These calculations assume that AUC(INF), and Cmax are log-normally distributed with between-
participant standard deviation (SD) of 0.21 for Cmax and 0.27 for AUC(INF), as reported in the 
single dose IV study in healthy participants (IM101292) for manufacturing site transfer.3 
5 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
5.1 
Study Periods 
• The pre-treatment period will be from the time the Informed Consent form is signed 
until dosing on Study Day 1 for all participants. The pretreatment period should be 
no longer than 28 days and will include all screening, enrollment, and Day -1 
procedures. 
• Study Period will be from the day of dosing on Study Day 1 until discharge visit 
on Study Day 71. 
5.2 
Treatment Regimens 
In the morning on Day 1, after fasting for at least 1 hour, each participant will receive a 30-minute 
IV infusion of a single dose (750 mg) abatacept drug product converted from drug substance by a 
new process or a 30-minute IV infusion of a single dose (750 mg) abatacept drug product converted 
from drug substance by the current process.  
The start time of the IV dose administration will be called “0” hour. 
5.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
All Enrolled Participants 
All participants who sign informed consent 
All Treated Participants 
All participants who receive study treatment  
Pharmacokinetic 
Population 
All participants who receive abatacept and have any available 
concentration-time data. 
Evaluable 
Pharmacokinetic 
Population 
All participants in the PK Population with adequate PK profiles 
for accurate estimation of PK parameters. All available derived PK 
parameter values will be included in the PK data set and reported, 
but only participants with evaluable PK will be included in the 
summary statistics and statistical analysis. 
All participants who receive study treatment will be included in the safety data set. 
Pharmacokinetic listings and PK parameter calculations will be based on the PK population. All 
available derived PK parameter values will be included in the PK data set and reported, but only 


Statistical Analysis Plan 
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10 
participants in the Evaluable PK Population will be included in the summary statistics and 
statistical analysis. 
 
6 
STATISTICAL ANALYSES 
SAS, version 9.3 or higher, will be used for statistical analyses, tabulations, and graphical 
presentations.  
6.1 
General Methods 
All data recorded on case report forms will be listed by participant. Descriptive summaries will be 
presented for continuous variables using number of subjects (N), mean, SD, median, minimum, 
and maximum. Geometric mean and coefficient of variation (%CV) will also be presented for PK 
parameters as applicable. Descriptive summaries for categorical variables will utilize counts and 
percentages.  
Where appropriate, baseline is defined as the last nonmissing result with a collection date-time 
less than the date-time of the first dose of study treatment. 
Adverse events and medical history will be coded according to the most recent Medical Dictionary 
for Regulatory Activities (MedDRA) version. Previous and concomitant medications will be coded 
using the World Health Organization (WHO) Drug Dictionary.  
6.2 
Study Conduct 
Deviations from the study protocol, and administrative changes will be documented. In general, 
relevant protocol deviations are a subset of the significant protocol deviations that could potentially 
affect the interpretability of study results. In this healthy volunteer study there are no relevant 
protocol deviation criteria specified.  
6.3 
Study Population 
6.3.1 
Participant Disposition 
Participant disposition will be listed. Summary tables reflecting the number of subjects who are 
enrolled, who are randomized, who are not randomized, who are treated, and reasons for not being 
randomized and not entering treatment period will be presented as overall.  
The number of participants who complete the study, who do not complete the study, and reasons 
for not completing the study, will be summarized for all treated participants, overall and by 
treatment. 
6.3.2 
Demographic Characteristics 
Demographic characteristics such as gender, age, race, and ethnicity will be listed for all treated 
participants. Demographic characteristics will also be summarized for all treated participants, as 
overall and by treatment. 


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6.3.3 
Physical Measurements 
Physical measurements such as body weight, height, and body mass index (BMI) will be listed for 
all treated participants. Measurements will also be summarized by nominal visit for all treated 
participants, as overall and by treatment.  
6.3.4 
Medical History and Previous Medications 
Medical history and previous/concomitant medications taken prior to dosing or during the course 
of the trial will be listed for all treated participants.  
6.4 
Extent of Exposure 
No analysis regarding extent of exposure is planned. Study drug administration and the 
randomization schedule will be documented as per participant listings. Any non-study medications 
taken by participants, any conducted non-study medical treatment procedures, and any utilized 
non-study diagnostic procedures will also be listed. 
6.5 
Efficacy 
There are no efficacy assessments in the study. 
6.6 
Safety 
Analysis of all safety data will follow the BMS guideline of analysis of safety data. The evaluation 
of safety is based on clinical AEs, vital signs, ECG results, and clinical laboratory results reported 
during the study.  
All data collected from the sampling outside the scheduled visits will only be included in the listing 
and will be excluded from the summary tables. 
6.6.1 
Deaths 
All reported deaths after a participant is enrolled (ie, has signed the informed consent) will be 
listed by participant.  
6.6.2 
Serious Adverse Events 
All reported serious adverse events (SAEs) will be listed for all enrolled participants.  
6.6.3 
Adverse Events 
Adverse events that occur on or after the administration of study treatment will be tabulated.   
Events occurring after discharge will be assigned to the study treatment received for up to 56 days 
after the termination of study drug. The proportion of participants having an AE will be calculated 
as the number of participants having the event in the specific treatment interval, divided by the 
total number of participants receiving study treatment during that treatment interval. 
All AE listings will indicate the unique subject identifier, age, gender, current treatment, the date 
of onset, the date of resolution, day of onset relative to the start of treatment, action taken, 
investigator’s assessment of severity, and relationship to study drug. The AE listing of all AEs will 
also include those AEs that occurred beyond 56 days after the termination of study drug. Additional 
listings will be provided for AEs leading to discontinuation and AEs without recorded resolution.  


Statistical Analysis Plan 
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12 
All AEs will be summarized by system organ class, preferred term, treatment and overall for all 
treated participants. Summaries of AEs will include AEs, AEs by intensity and AEs related to 
study drug. 
Additional summaries will be provided for acute peri-infusional and postinfusional AEs that 
occurred during the 30-minute infusion period and the 24-hour post-infusion period, respectively, 
after the start of the abatacept infusion. 
AE Counting Rules: 
Where a participant has the same AE, based on preferred terminology, reported multiple times in 
a single analysis period, the subject will only be counted once at the preferred terminology level 
in AE frequency tables. 
Where a participant has multiple AEs within the same system organ class in a single analysis 
period, the participant will only be counted once at the system organ class level in AE frequency 
tables. 
When a participant has the same AE, based on preferred terminology, reported multiple times in a 
single analysis period, the following criteria, in order of precedence, will be used to select the 
event to be included in summary tables: 
• Relationship to study medication 
• Intensity of event 
• Onset date and time 
When reporting AEs by intensity, in addition to providing a summary table based on the event 
selection criteria detailed above, summary tables will also be provided based on the most intense 
event  during the analysis period - independent of relationship to study medication. For these 
tables, the following criteria, in order of precedence, will be used to select the event to be included 
in summary tables: 
• Intensity of event 
• Onset date and time 
Participants will only be counted once in the ‘Total’ at their maximum intensity, regardless of SOC 
or PT. 
6.6.4 
Injection Site Reaction 
Injection site reaction data will be listed per participant and time point. 
6.6.5 
Clinical Laboratory Evaluations 
The results of all protocol-specified clinical laboratory tests and corresponding change from 
baseline values will be listed by subject for all treated participants. Laboratory measurements and 
corresponding change from baseline values will be summarized by treatment and scheduled 
nominal visit for each laboratory test. 
The criteria used for classifying laboratory test results as markedly abnormal will be listed.  
Laboratory results will be classified as markedly abnormal based on sponsor defined criteria. 


Statistical Analysis Plan 
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13 
Laboratory results for participants with any marked laboratory abnormality (scheduled and 
unscheduled) will be listed. This listing will include all observations for the specific laboratory 
test and participant, not only the marked laboratory abnormality measurements. The frequency of 
participants with any marked laboratory abnormality, based on pre-specified criteria, will be 
presented.  
6.6.6 
Electrocardiograms 
All recorded electrocardiograms (ECGs) will be listed for all treated participants. 
QTcF will be made available in the database. If QTcF is not available in the database, QTcF will 
be calculated using the reported uncorrected QT interval and heart rate (HR), and the following 
formula:  
(
)
3
/
1
60
RATE
HEART
QT
QTcF =
 
If QTcB is not available in the database, QTcB will not be calculated.  
Summaries of ECG parameters (HR, QT (QT, QTcB, QTcF), PR, and QRS intervals) will be 
tabulated by study day and treatment. Summaries of ECG parameters will include change from 
baseline at Day 1, 3 hours after the start of infusion, and Day 71 (at discharge).  Baseline will be 
considered as Day 1 pre-dose measurement.  
Participants with ECG intervals outside of a pre-specified range and investigator identified ECG 
abnormalities will also be listed. 
The following criteria will be used to determine ECG results that are outside of a pre-specified 
range: 
PR (msec): 
Value > 200 
QRS (msec): 
Value > 120 
QT (msec): 
Value > 500 or change from baseline > 30 
QTcB (msec): 
Value > 450 or change from baseline > 30 
QTcF (msec): 
Value > 450 or change from baseline > 30 
 
6.6.7 
Vital Signs 
Vital signs parameters (systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate, and body temperature) will be listed. Summaries of vital sign parameters will be provided for 
each vital sign parameter at corresponding visits by treatment and respective changes from 
baseline. 
Participants with vital signs outside of a pre-specified range will also be listed. 


Statistical Analysis Plan 
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14 
The following criteria will be used to determine vital sign results that are outside of a pre-specified 
range, where changes from baseline are calculated as parameter value - baseline parameter value: 
Heart Rate (bpm) 
Value > 100 and change from baseline > 30, or 
Value < 55 and change from baseline < -15 
Systolic BP (mmHg) 
Value > 140 and change from baseline > 20, or 
Value < 90 and change from baseline < -20 
Diastolic BP (mmHg)  
Value > 90 and change from baseline > 10, or 
Value < 55 and change from baseline < -10 
Respiration (breaths/min) 
Value > 16 or change from baseline > 10 
Temperature (°C) 
Value > 38.3°C or change from baseline > 1.6°C 
 
6.6.8 
Physical Examination Findings 
All physical examination abnormal findings will be listed per participant and visit.  
6.7 
Pharmacokinetics 
The Pharmacokinetic (PK) population will be used for all listings. Evaluable PK population will 
be used for summary statistics and statistical analyses. Statistical analyses will be repeated 
excluding subjects with positive abatacept induced ADA responses. Analysis will include all valid 
analyte data for BMS-188667.  
Subject serum concentration-time profiles will be listed and summarized by treatment and nominal 
collection time. Plot of individual serum concentration profiles over time will be provided. Overlay 
of individual serum concentration profiles over time will be provided by treatment. Plots of mean 
(+SD) serum concentration profiles versus time will be presented, for the first 24 hours and 
separately for the entire study duration on both linear and log-linear scale and both treatments will 
be superimposed on the same plot. Scatter plots of PK parameters for Cmax, T-HALF, CLT, Vss, 
AUC(0-28 day), AUC(0-T), and AUC(INF) will be produced for each treatment.  
All individual PK parameters will be listed including any exclusions and reasons for exclusion. 
Summary statistics will be tabulated for each PK parameter by treatment. Geometric means and 
coefficients of variation will be presented for Cmax, AUC(INF), AUC(0-T), AUC(0-28 day), CLT 
and Vss. Medians and ranges will be presented for Tmax. Means and standard deviations will be 
presented for other PK parameters (i.e., T-HALF). Decimal place specifications for summary 
statistics are described in Section 6.9. 
To assess comparability of Treatment A (new drug substance process) to Treatment B (current 
drug substance process), an ANCOVA model will be fitted with treatment as a fixed effect and 
adjusted for baseline body weight. Point estimates and 90% CIs for treatment differences on the 
log scale for AUC(INF) and Cmax will be exponentiated to express the results as ratios of 
geometric means and the corresponding 90% CIs on the original scale.  Biocomparability of 
Treatment A to Treatment B will be concluded if the 90% CIs for the ratios of geometric means 
for abatacept Cmax and AUC(INF) are contained within 80% to 125%. 


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15 
  
  
 
 
 
 
 
 
 
In addition, the adjusted geometric mean ratios (GMRs) and corresponding 90% CIs for 
AUC(INF) and Cmax will be summarized in forest plots overall and by baseline weight class. 
These estimates will be obtained from a model with treatment and baseline body weight class as 
fixed effects.  
 
 
  
 
 
 
 
 
 
 
 
A listing of subjects excluded from the Evaluable PK Population along with reasons for exclusion 
will be provided. 
 
 
6.8.1 
Immunogenicity 
On Day 1, the immunogenicity sample should be drawn at predose.  
Participants who seroconvert and continue to have a high titer at study discharge that is considered 
to be significantly increased versus baseline will be asked to return for follow-up assessment(s) 
for anti-abatacept antibodies approximately every 4 months until their titers and/or sero-status are 
judged to be stable by the investigator. 
Lack of immunogenicity is defined as the absence of a positive antibody response generated 
against abatacept. A participant is considered to have a positive abatacept-induced 
immunogenicity for “CTLA4 and possibly immunoglobulin (Ig)” and “Ig and/or Junction Region” 
if one of the following criteria are met: 
1. A missing baseline immunogenicity measurement and a positive laboratory-reported 
immunogenicity response after baseline. 


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2. A negative laboratory-reported baseline immunogenicity response and a positive 
laboratory-reported immunogenicity response after baseline. 
3. A positive laboratory-reported baseline immunogenicity response and a positive 
laboratory-reported immunogenicity response after baseline that has a titer value strictly 
greater than the baseline titer value. 
This definition will be applied for each antibody-reactivity separately. All other 
electrochemiluminescence (ECL) immunogenicity measurements will be classified as negative. 
The incidence of laboratory-reported positive responses and the corresponding titer values will be 
listed by participant and by study day. The frequency and percentage of positive, abatacept-
induced immunogenicity response will be summarized by treatment.  
Titer will be listed. 
The number and percentage of subjects with a positive neutralizing antibody response will be 
summarized by treatment group and study day. The summary will include all subjects with a 
positive abatacept-induced immunogenicity response.  
Neutralizing antibody data will be listed. 
 
 
 
 
  
 
6.9 
Conventions 
EmBARC (Enhanced Biometric Analysis & Reporting Capability) standard time windowing, 
imputation rules, and counting rules will be applied.   
6.9.1 
Decimal Places 
The number of decimal places displayed in all listings will be determined by the number of decimal 
places in the raw data.   
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, one more decimal place for the mean and median, and two more decimal places for the 
standard deviation.  The adjusted geometric mean, geometric mean ratio, and the lower and upper 
limits of the CI will be displayed to three decimal places. 
One decimal place for percent change from baseline data and 3 decimal places for ratio will be 
used for data presentation.  
6.9.2 
Pharmacokinetic Summaries 
In-text Tables 
For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. For 
other statistics except for standard deviations, values of 100 or higher will be presented as integers, 


Statistical Analysis Plan 
IM101682 
BMS-188667 
abatacept 
 
17 
values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will be displayed 
to two decimal places. Values less than 1 will be displayed to three decimal places.  Ratios will 
also be displayed to three decimal places. Standard deviations will be reported to a precision of 1 
decimal place more than the mean. 
Handling of Non-Quantifiable Concentrations 
For the summaries of serum concentration-time data, concentrations that are less than the lower 
limit of quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as 
missing in summary tables and plots.  For the purpose of calculating PK parameters pre-dose 
concentrations that are less than LLOQ and concentrations prior to the first quantifiable 
concentration that are less than LLOQ will be set to zero, and all other concentrations less than 
LLOQ will be set to missing. 
All available serum concentration-time data and derived pharmacokinetic parameter values will 
be included in the PK data set and listed accordingly. 
Treatment of Outliers 
Individual serum concentrations, if deemed to be anomalous, may be excluded from the analysis 
following a review of available documentation (e.g., bioanalytical report, clinical data). Any such 
exclusion will be clearly listed in the study report along with justification for exclusion. 
Entire serum concentration-time profiles for a subject may be excluded following review of 
available documentation (e.g., bioanalytical report, clinical data). However, results of analysis with 
and without the excluded profiles may be presented in the study report. Any such exclusion will 
be clearly listed in the study report along with justification for exclusion. 
PK Exclusions 
PK Analysis, Reporting, and Exclusion criteria should following the BMS PK Harmonization 
document Version 2.0. Specific guideline for exclusionary criteria for half-life and how other PK 
parameters are affected for exclusion is under section 9.2 of the BMS PK Harmonization 
document. 
Exclusion of one or more parameters or the entire dataset may be considered due to incomplete 
profile such as AUC(INF) or when T-HALF cannot be reliably calculated, or there is no sample 
around the suspected Cmax. In addition, subjects may be excluded from the analysis if they missed 
dosing.  
7 
CONTENT OF REPORTS 
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Details of the tables, listings, and figures to be prepared for the final CSR 
will be included in a study-specific Data Presentation Plan (DPP). 


Statistical Analysis Plan 
IM101682 
BMS-188667 
abatacept 
 
18