Clinical trial NCT03652961
Conditions: Rheumatoid Arthritis
Sponsor: NYU Langone Health
Start date: 2019-06-02; Completion date: 2021-09-27
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single-Open Label Study to Assess Changes in the Immune Profile in Response to Treatment with Intravenous Abatacept Adults with Rheumatoid Arthritis who are Naive to Biologic Disease-Modifying Antirheumatic Drugs

Detailed description:
The immune system of patients with Rheumatoid Arthritis (RA) is different from that of people who do not have RA. The purpose of this study is to examine participants' immune cells and proteins before initiation of study medication and after initiation of treatment with an approved therapy for RA, abatacept that will be given in combination with Methotrexate and/or anti-rheumatic drugs (DMARDS) that are approved for the treatment of RA. This study will assess whether participants have clinically responded to these medications. This assessment will also include a study of whether characteristics of participants' immune systems were changed by therapy with the study drug, abatacept.

Arms: arm 1: Abatacept will be used concomitantly with standard of care disease-modifying anti-rheumatic drugs (DMARDs), other than tumor necrosis factor (TNF) antagonists or Janus kinase (JAK) inhibitors.

Intravenous (IV) Abatacept will be administered as a 30-minute IV infusion utilizing weight range-based dosing:

1. Less than 60 kg: 500 mg
2. 60 to 100 kg: 750 mg
3. More than 100 kg: 1000 mg

Following the initial IV Abatacept administration, an IV infusion will be given at Weeks 2 and 4 after the first infusion and every 4 weeks thereafter for a total of 7 Abatacept doses.

Abatacept will be discontinued after 6 months in all patients. Patients who have flared or failed to achieve low disease activity at 6 months will exit the trial except for one post-study visit for lab work at 9 months. In patients who have achieved low disease activity, Abatacept will be held for 6 months or until a flare results while DMARD use is continued.
Interventions: intervention 1: Abatacept intervention 2: DMARDs
Intervention descriptions: intervention 1: Abatacept for reconstitution and dilution prior to intravenous (IV) administration. Each single-use vial of Abatacept for injection provides 250-mg Abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. intervention 2: Patients will receive methotrexate or remain on pre-existing conventional synthetic disease-modifying anti-rheumatic drug (DMARD) if already prescribed.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
Rheumatoid Arthritis Memory B cells and Abatacept 
(RAMBA) 
Single-Open Label Study to Assess Changes in the Immune Profile in Response to Treatment 
with Intravenous Abatacept Adults with Rheumatoid Arthritis who are Naive to Biologic 
Disease-Modifying Antirheumatic Drugs 
 
Regulatory Sponsor: 
William Rigby, MD  
Rheumatology 
Dartmouth-Hitchcock Medical Center 
One Medical Center Drive, Lebanon, NH 03756 
(603) 650-4735 
Gregg J. Silverman, MD 
Professor of Medicine and Pathology 
NYU School of Medicine 
Alexandria Center for Life Science 
450 E. 29th St. 
NY, NY 10016 
Tel: 212 263 9440 
 
Funding Support: 
Bristol-Myers Squibb Research and Development 
Route 206 & Province Line Road 
Lawrenceville, NJ 08543 
Study Product: 
Abatacept 
Protocol Number: 
Insert Protocol Number Used by Sponsor 
BMS Protocol Number:  
IM101-768 
IND Number: 
BB-IND 9391 
 
 
 
 
 
 
 
 
NCT03652961 


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Initial version: 24 JUL 18 
Amended: 
[date] 
Amended: 
[date] 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND .............................................................................. ERROR! BOOKMARK NOT DEFINED. 
1.2 
INVESTIGATIONAL AGENT ............................................................. ERROR! BOOKMARK NOT DEFINED. 
1.3 
PRECLINICAL DATA ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.4 
CLINICAL DATA TO DATE .............................................................. ERROR! BOOKMARK NOT DEFINED. 
1.5 
DOSE RATIONALE AND RISK/BENEFITS .......................................... ERROR! BOOKMARK NOT DEFINED. 
2 
STUDY OBJECTIVES ............................................................. ERROR! BOOKMARK NOT DEFINED. 
3 
STUDY DESIGN .................................................................................................................................. 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 9 
3.4 
PRIMARY SAFETY ENDPOINTS ........................................................................................................ 9 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 10 
4.1 
INCLUSION CRITERIA .................................................................................................................... 10 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 14 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .............................................................................................. 14 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 14 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 14 
5 
STUDY DRUG .................................................................................................................................... 15 
5.1 
DESCRIPTION............................................................................................................................... 15 
5.2 
TREATMENT REGIMEN ......................................................................................................................  
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 16 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 16 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................ 16 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................ 16 
5.7 
PACKAGING ................................................................................................................................. 17 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 17 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ......................................................................... 17 
5.9.1 
Receipt of Drug Supplies ...................................................................................................... 17 
5.9.2 
Storage .................................................................................................................................. 17 
5.9.3 
Dispensing of Study Drug ..................................................................................................... 17 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 18 
6 
STUDY PROCEDURES ..................................................................................................................... 18 
6.1 
VISIT 1 ........................................................................................................................................ 18 
6.2 
VISIT 2 ........................................................................................................................................ 18 
6.3 
ETC. ............................................................................................................................................ 18 
7 
STATISTICAL PLAN ......................................................................................................................... 18 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 18 
7.2 
STATISTICAL METHODS ................................................................................................................ 18 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ...................................................................................... 19 
8 
SAFETY AND ADVERSE EVENTS .................................................................................................. 19 
8.1 
DEFINITIONS ................................................................................................................................ 19 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 24 


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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 25 
8.3.1 
Investigator reporting: notifying the study sponsor ............................................................... 25 
8.3.2 
Investigator reporting: notifying the Dartmouth IRB .............................................................. 28 
8.3.3 
Investigator reporting: Notifying a non-Dartmouth IRB ......................................................... 30 
8.3.4 
Sponsor reporting: Notifying the FDA .......................................................................................  
8.3.5 
Sponsor reporting: Notifying participating investigators ........................................................ 30 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 29 
8.5 
STOPPING RULES ........................................................................................................................ 30 
8.6 
MEDICAL MONITORING ................................................................................................................. 30 
8.6.1 
Internal Data and Safety Monitoring Board ...............................................................................  
8.6.2 
Independent Data and Safety Monitoring Board ................................................................... 30 
9 
DATA HANDLING AND RECORD KEEPING................................................................................... 31 
9.1 
CONFIDENTIALITY ......................................................................................................................... 31 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 31 
9.3 
CASE REPORT FORMS ................................................................................................................. 31 
9.4 
RECORDS RETENTION .................................................................................................................. 32 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 32 
10.1 
STUDY MONITORING PLAN ........................................................................................................... 32 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 32 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 32 
12 
STUDY FINANCES ............................................................................................................................ 33 
12.1 
FUNDING SOURCE........................................................................................................................ 33 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 33 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 33 
13 
PUBLICATION PLAN ........................................................................................................................ 33 
14 
REFERENCES ................................................................................................................................... 34 
15 
ATTACHMENTS ................................................................................................................................ 35 
 


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List of Abbreviations 
 
Term 
 Definition 
ACPA  
 anti-citrullinated protein antibody 
ACR  
American College of Rheumatology 
AE  
adverse event 
ALT  
alanine aminotransferase 
ANA  
anti-nuclear antibody 
ANC  
absolute neutrophil count 
anti-CCP  
anti-cyclic citrullinated peptide 
anti-CCP2 
 commercially available test for ACPA 
AST  
aspartate aminotransferase 
BMS 
 Bristol-Myers Squibb 
BP 
 blood pressure 
C  
Celsius 
CBC 
complete blood count 
CRP  
C-reactive protein 
DIP  
distal interphalangeal 
DMARD  
disease-modifying anti-rheumatic drug 
dsDNA  
double-stranded DNA 
EDC  
Electronic Data Capture 
eg  
exempli gratia (for example) 
ET  
early termination 
F  
Fahrenheit 
FSH 
 follicle stimulating hormone 
GCP  
Good Clinical Practice 
HR  
heart rate 
F  
Fahrenheit 
hsCRP  
high-sensitivity C-reactive protein 
INOVA 
Inova Diagnostics 
IP  
investigational product 
IRB  
Institutional Review Board 
kg 
 Kilogram 
mg  
Milligram 
mL  
Milliliter 
MTX  
Methotrexate 
N  
number of subjects or observations 
N/A  
not applicable 
NIMP  
non-investigational medicinal products 
NSAID  
nonsteroidal anti-inflammatory drug 
NYU 
New York University 


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Term 
 Definition 
PBMC  
Peripheral blood mononuclear cell 
PGA  
Physicians Global Assessment of Disease 
Activity 
PO  
per so (by mouth route of administration) 
QD 
qd quaque die, once daily 
RA  
rheumatoid arthritis 
RBC  
red blood cell 
RF  
Rheumatoid factor 
SAE  
serious adverse event 
SC  
Subcutaneous 
SOP  
Standard Operating Procedures 
Subj  
Subject 
TB  
Tuberculosis 
TNF  
tumor necrosis factor 
WOCBP  
women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
page 1 
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Study Summary 
Title 
Rheumatoid arthritis memory B cells and Abatacept 
Short Title 
RAMBA 
Protocol Number 
IM101-768 
BMS 
Protocol 
Number 
IM101-768 
Phase 
Phase 4 
Methodology 
Open label 
Study Duration 
12 months 
Study Center(s) 
Single-center  
Objectives 
We will test the hypothesis that ABATACEPT treatment 
influences 
the 
levels 
of 
circulating 
autoimmune 
anti-
citrullinated protein antigen (ACPA) memory B cells are central 
drivers of pathogenesis. 
Number of Subjects 
25 
Diagnosis and Main 
Inclusion Criteria 
Adults with Seropositive (CCP or ACPA) Rheumatoid Arthritis 
who are Naive to Biologic Disease-Modifying Antirheumatic 
Drugs 
Study Product, Dose, 
Route, Regimen 
Abatacept Time 0, Week 2, Month 1, 2, 3, 4, & 5 IV 
administration on Abatacept (7 infusions) 
Duration 
of 
administration 
6 months with active therapy followed by holding Abatacept 
for 6 months or until flare occurs while concurrent MTX or 
csDMARDs are continued. 
Reference therapy 
 
Statistical 
Methodology 
We will assess whether ABATACEPT challenge that induces 
clinical benefits are paralleled by reductions (i.e.,normalization) 
in the in vivo representation of disease-associated anti-
citrullinated protein antigen (ACPA) memory B cells, and 
circulating autoantibody levels after 6 months of treatment. 
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be 
conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and 
procedures.  
1.1 
Background 
 
 
Rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis, 
affecting approximately 1% of the population worldwide. 1   Women are 2 to 3 times 
more likely to develop the disease compared to men, with a peak incidence between 
the fourth and sixth decades of life. 2,3,4,5  The natural history of RA is characterized by 
joint destruction, impaired physical function, and poor health-related quality of life. 6 
Joint erosions can be seen within 6 months of disease onset in the majority of patients, 
and occur more rapidly in the first year compared with later disease. 
 
Activated T-cells are believed to play an important role in the pathogenesis of RA, 
especially early in the disease process, by participating in the autoimmune cascade 
that leads to joint inflammation and destruction. It is hypothesized that autoreactive 
T cells may be central to this process by producing pro-inflammatory cytokines and 
providing help to B cells leading to the production of autoantibodies, which in turn 
contribute to downstream inflammatory events, including the recruitment of 
neutrophils, elaboration of cytokines, such as tumor-necrosis factor (TNF)-alpha, 
synovitis and ultimately joint destruction. 7 
 
1.2 
Investigational Agent 
Abatacept is a selective costimulation modulator that blocks the interaction between 
CD80/CD86 on antigen presenting cells and CD28 on T cells.8   This interaction 
provides a key signal necessary for full activation of T cells. By inhibiting CD28-
mediated immune activation, Abatacept blocks antigen recognition and modulates 
the immune response to decrease T cell activation and antibody production. 
Therefore, Abatacept interferes with a step hypothesized to be early in the 
pathogenesis of RA. 
 
Intravenously (IV) administered Abatacept was first approved in the United States 
(US) for the treatment of moderate to severe RA in adults in December 2005. Since 
then, IV Abatacept has received marketing approval for the treatment of adult RA in 
many other countries, including the European Union (EU), Japan, Latin America and 
other countries.8  The subcutaneous (SC) formulation was first approved in the US for 
the treatment of moderate to severe RA in adults in July 2011. Abatacept SC has 


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subsequently received marketing approval or the treatment of adult RA in the EU 
and other regions of the world.8 
 
1.3 
Preclinical Data 
Not applicable 
1.4 
Clinical Data to Date 
Abatacept has been shown to be effective therapy in patients who have had 
inadequate responses to Methotrexate (MTX-IR) and TNF inhibitors.9  In the AMPLE 
trial Abatacept showed equivalent efficacy and safety to the TNF-inhibitor, 
Adalimumab.   
While it is clearly resolved that continued therapy with MTX alone induces remission 
in ~30% of patients, the addition of Abatacept increased that to 60% in the AVERT 
trial.  Moreover, MTX +Abatacept induced drug-free remission in up to 10% of 
patients for up to 6 months later.10 
In this challenging landscape of RA therapeutics it is unresolved whether Abatacept 
in addition to MTX in new onset RA can induce a remission that can be maintained 
with MTX alone.   Drug-free remission appears unlikely with Abatacept + 
methotrexate, so the next step to a cure would naturally examine this question. A 
corollary to this question is whether this effect of Abatacept is transduced in concert 
with a decline in memory B cells. 
The time has come to address this question for Abatacept because autoimmune 
memory B cells have been shown to persist at high levels during therapy with TNF-
inhibitors in RA, typically given with MTX as concurrent therapy.11  The rate of 
remission on methotrexate alone was even more powerful given the fact that patients 
enrolled in this latter trial had previously failed methotrexate.  The premise being 
tested (that Abatacept decreases circulating arthritogenic B cells) is a very real 
possibility, given the effect of Abatacept to reduce B cell infiltration in the synovium 
and circulating memory B cell levels.  12,13 
1.5 
Dose Rationale and Risk/Benefits 
Abatacept intravenous should be administered as a 30-minute intravenous infusion 
utilizing the weight range-based dosing specified below. Following the initial 
intravenous administration, an intravenous infusion should be given at 2 and 4 
weeks after the first infusion and every 4 weeks thereafter for a total of 7 doses.  
 
 
2 Study Objectives 
 


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As a step toward a cure, we will directly assess the impact of a treatment on the 
underlying autoimmune disease process. Because Abatacept has unique mechanisms 
of action we believe that ABATACEPT treatment ameliorates RA clinical disease 
activity through beneficial effects on the pathologic breaches in adaptive immunity 
that are causal for disease. We will therefore conduct a prospective open therapeutic 
trial with adult seropositive (i.e., ACPA-positive) RA patients and perform intensive 
quantitative surveys of pathologic autoantigen-specific B cell memory. 
 
We will test whether the clinical benefit induced by ABATACEPT treatment are 
paralleled by reductions (i.e., normalization) in the in vivo representation of disease-
associated anticitrullinated protein antigen (ACPA) memory B cells after 6 months of 
treatment. The corollary is to determine whether reductions of disease-associated 
memory B cells are the most meaningful marker of therapeutic response? ii) 
Hypothesis 2: The cessation of ABATACEPT treatment (i.e., dechallenge) with 
continued methotrexate therapy results in clinical flare, is then paralleled by 
reaccumulation in the bloodstream of disease-associated ACPA memory B cells. 
 
 
Primary Objective 
To assess the efficacy of Abatacept + csDMARD to induce low disease activity that 
can be maintained on csDMARD (primarily MTX) alone.  A necessary co-primary 
objective is the relationship between clinical response and changes in B cell and 
antibody parameters that are unaffected by TNF-inhibition. 
 
To directly determine whether ABATACEPT treatment normalizes immune (i.e., B 
cell and antibody) abnormalities associated with seropositive RA over time and 
assess for correlations with clinical response measures. The investigations will 
include: i). Direct quantitation of the frequency of circulating ACPA-bearing memory 
B cells (2); ii Flow cytometric determinations of effects on B-cell subsets, to determine 
whether ABATACEPT normalizes disease-associated increases in activated memory 
B cells, and the plasmablast expansions that are associated with active RA disease. iii) 
The effects of ABATACEPT on circulating IgM-, IgG- and IgG-ACPA antibody levels, 
in assays using a panel of matched citrulline- and arginine-containing peptides/self-
proteins. iv) Serum will be collected for cytokine/chemokine profiling, which will be 
highly informative due to the challenge/dechallenge design. 
 
Secondary Objective 
We will correlate the relationships between co-primary endpoints over time and then 
confirm this relationship by dechallenge of Abatacept after induction of low disease 
activity at 24 weeks. 
 
We will assess whether ABATACEPT therapy that induces clinical benefits, are 
paralleled by reductions (i.e., normalization) in the in vivo representation of disease-
associated anti-citrullinated protein antigen (ACPA) memory B cells after 6 months of 


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treatment.  This can be confirmed by dechallenge experiments in the approximately 
70-80% we expect to be in low-disease activity at this time point.  While MTX therapy 
will be maintained, little or no effect of MTX on memory B cell formation is expected 
as seen in Juvenile Idiopathic Arthritis.14 
3 Study Design 
3.1 
General Design 
 
A phase IV open-label clinical trial in which each CCP/ACPA+ patient will be their 
own longitudinal control for the immunomodulatory activity of Abatacept.  All 
patients will have blood collection, including for peripheral blood mononuclear cells 
(PBMC), PBMC RNA and plasma, at screening and at day 0 after which Abatacept 
will be initiated in concert with methotrexate or pre-existing csDMARD. Each patient 
will then be reevaluated at 3 months and 6 months. In all patients, Abatacept will be 
discontinued after 6 months. Patients who have flared or failed to achieve low disease 
activity at 6 months, will exit the trial except for one post study visit for lab work at 9 
months.    
 
In patients who have achieved low disease activity by DAS28-CRP (<3.2) or CDAI 
(<10), Abatacept will be held for 6 months or until a flare results.  A flare is defined by 
an examination demonstrating a DAS28-CRP that is greater than an absolute value of 
4.0) or a CDAI >15, both defining the mid-range of a moderate flare.  Alternatively, a 
30% increase in the absolute level of the DAS28-CRP or CDAI that result in measures 
of 3.2 and 10 respectively, will be considered evidence of a flare.   If patients do not 
experience a flare after 6 months off Abatacept (by week 52) they will also exit the 
study after a final visit with an exit blood draw.    
 
 
Overall, in this pilot study, patient screening will continue until 25 suitable patients 
are enrolled and started on therapy in the trial. We predict enrollment of 2-3 
patients/month, and hence the study should be fully enrolled by month 14 with the 
expectation that 70-80% will achieve low disease activity at week 24 enabling 17-20 


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patients to be followed for flare following Abatacept dechallenge.  This estimate is 
based on the observation that treat provides nearly 60% ACR 50 responses, despite 
the fact that patients were selected for evidence of erosive disease.15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NON-RESPONDERS TABLE OF EVENTS 


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REMISSION OR LOW DISEASE ACTIVITY TABLE OF EVENTS WITH FLARE 
Procedure 
 
Screening 
Period 
 
DAY 1 
 
WEEK 2 
 
MONTH 
1, 2, 3,4,5 
 
MONTH 
6/ET  
 
MONTH 
9 
 
FOLLOW-UP  
(WEEK 48-52) 
Medication review 
X 
X 
X 
 
 
X 
X 
Review of side effects 
X 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
Height (screening only) & 
weight 
X 
X 
X 
X 
X 
 
 
Blood sample(s) (Approx.166-
176 - ml, or - 12tablespoons per 
visit ) 
X 
X 
X 
X 
X 
X 
 
Urine sample 
X 
X 
X 
X 
X 
 
 
Pregnancy test for women who 
can become pregnant 
X 
X 
X 
X 
 
 
 
Vital signs (temperature, blood 
pressure, heart rate (pulse)) 
X 
X 
X 
X 
X 
 
 
 
Assessments of your tender and 
swollen joints 
X 
X 
X 
X 
X 
X 
 
Assessments of disease activity 
X 
X 
X 
X 
X 
X 
 
Your Assessment of pain 
X 
X 
X 
X 
X 
X 
 
Rapid 3 patient questionnaire 
X 
X 
X 
X 
X 
 
 
Abatacept infusion 
 
X 
X 
X 
 
 
 
Adverse events 
 
X 
 
X 
X 
X 
X 


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REMISSION OR LOW DISEASE ACTIVITY TABLE OF EVENTS 
Procedure 
 
Screening 
Period 
DAY 1 
 
 
WEEK 2 
 
MONTH 
1,2,3,4,5 
MONTH 
6/ET 
 
FLARE 
 
EVERY 4 
WEEKS 
FOLLOW-
UP 
(WEEK 
48-52) 
Medication review 
X 
X 
X 
X 
 
X 
X 
X 
Review of side effects 
X 
X 
 
 
 
X 
 
 
Physical examination 
X 
X 
 
 
X 
X 
 
 
Height (screening only) & 
weight 
X 
X 
 
X 
X 
X 
X 
 
Blood 
sample(s) 
(Approx.166-176 - ml, or – 
12 tablespoons per visit ) 
X 
X 
 
X 
X 
X 
X 
 
Urine sample 
X 
X 
 
X 
X 
X 
X 
 
Pregnancy test for women 
who can become pregnant 
X 
X 
 
X 
X 
X 
X 
 
Vital signs (temperature, 
blood pressure, heart rate 
(pulse)) 
X 
X 
 
X 
X 
 
X 
X 
 
Assessments of your tender 
and swollen joints 
X 
X 
 
X 
X 
X 
X 
 
Assessments 
of 
disease 
activity 
X 
X 
 
X 
X 
X 
X 
 
Your Assessment of pain 
X 
X 
 
X 
X 
X 
X 
 
Rapid 
3 
patient 
questionnaire 
X 
X 
 
X 
X 
X 
X 
 
Abatacept infusion 
 
X 
X 
X 
 
X 
X 
 
Adverse events 
 
X 
 
X 
X 
X 
X 
X 


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3.2 
Primary Study Endpoints 
To assess the efficacy of Abatacept + csDMARD to induce low disease activity 
[DAS28-CRP (<3.2) or CDAI (<10) that can be maintained on csDMARD alone.  A 
necessary co-primary objective is the relationship between clinical response and 
changes in B cell and antibody parameters that are unaffected by TNF-inhibition. 
3.3 
Secondary Study Endpoints 
We will correlate the relationships between co-primary endpoints over time and then 
confirm this relationship by dechallenge of Abatacept after induction of low disease 
activity at 24 weeks. 
3.4 
Primary Safety Endpoints 
 
This is a Phase 4 study using an agent with demonstrated efficacy and safety in all 
stages of RA.9  Most relevant to this study, the efficacy and safety of Abatacept in 
combination with MTX in early RA has already been demonstrated.10 
 
Procedure 
 
Screening 
Period 
 
DAY 1 
 
WEEK 2 
 
MONTH 
1, 2, 3,4,5 
 
MONTH 
6/ET  
 
MONTH 
9 
 
FOLLOW-UP  
(WEEK 48-52) 
Medication review 
X 
X 
X 
 
 
X 
X 
Review of side effects 
X 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
Height (screening only) & weight 
X 
X 
X 
X 
X 
 
 
Blood sample(s) (Approx.166-176 - 
ml, or - 12tablespoons per visit) 
X 
X 
X 
X 
X 
X 
 
Urine sample 
X 
X 
X 
X 
X 
 
 
Pregnancy test for women who 
can become pregnant 
X 
X 
X 
X 
 
 
 
Vital signs (temperature, blood 
pressure, heart rate (pulse)) 
X 
X 
X 
X 
X 
 
 
 
Assessments of your tender and 
swollen joints 
X 
X 
X 
X 
X 
X 
 
Assessments of disease activity 
X 
X 
X 
X 
X 
X 
 
Your Assessment of pain 
X 
X 
X 
X 
X 
X 
 
Rapid 3 patient questionnaire 
X 
X 
X 
X 
X 
 
 
Abatacept infusion 
 
X 
X 
X 
 
 
 
Adverse events 
 
X 
 
X 
X 
X 
X 


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4 Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
1. Signed Written Informed Consent 
a) Subject is willing to participate in the study and has signed the informed 
consent. 
2. Target Population 
a) Men or women (not nursing or pregnant) over 18 years old who have active 
RA, defined as symptoms of RA prior to screening and have satisfied the 
ACR/EULAR 2010 criteria for the classification of RA prior to signing the 
informed consent.   
b) Subjects must have a DAS28CRP or CDAI assessment at screening and 
have at least 3 tender and at least 3 swollen joints (excluding distal 
interphalangeal joints) at screening and at Day 1.  Patients must have at least 
moderate disease activity {CDAI>16); DAS28CRP (>4.0 )]. 
c) Subjects must be naive to biologic DMARDs 
d) Subjects must be naive to targeted synthetic DMARDs such as tofacitinib, 
baricitinib, and investigational therapies for RA. 
e) Subjects receiving oral corticosteroids must be on a stable dose and at the 
equivalent of 10 mg prednisone daily for at least 4 weeks. Subjects may not 
receive an IM, IV or IA administration of a corticosteroid within 4 weeks prior 
to screening visit or initiation of therapy 
f) Patients with prior (including discontinued) therapy with Methotrexate 
and/or Hydroxychloroquine are permitted as long as they meet other 
inclusionary criteria. 
g) Subjects must have a DAS28CRP or CDAI  at screening and have at least 3 
tender and at least 3 swollen joints (excluding distal interphalangeal joints) at 
screening and at Day 1. 
 
Age and Reproductive Status 
a) Men and women, age’s  18 years (or age of majority) 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug. 
c) Women must not be breastfeeding and must agree not to breastfeed during the 
study and for 100 days thereafter 
d) WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study drug plus 5 half-lives of study drug (70 days) plus 
30 days (duration of ovulatory cycle) for a total of 100 days post-treatment 
completion. 
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method(s) of contraception for the duration of treatment with study drug, plus 5 half-
lives of the study drug (70 days) plus 90 days (duration of sperm turnover) for a total 
of 160 days post-treatment completion. 
f) Azoospermic males and WOCBP who are continuously not heterosexually active 
are exempt from contraceptive requirements. However they must still undergo 
pregnancy testing as described in this section. Investigators shall counsel WOCBP 
and male subjects who are sexually active with WOCBP on the importance of 
pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with 
WOCBP on the use of highly effective methods of contraception. Highly effective 
methods of contraception have a failure rate of < 1% when used consistently and 
correctly. 
At a minimum, subjects must agree to use one highly effective method of 
contraception as listed below. 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Highly effective methods of contraception have a failure rate of < 1% when used 
consistently and correctly. WOCBP and female partners of male subjects, who are 
WOCBP, are expected to use one of the highly effective methods of contraception 
listed below. Male subjects must inform their female partners who are WOCBP of the 
contraceptive requirements of the protocol and are expected to adhere to using 
contraception with their partner. 
1) Progestogen only hormonal contraception associated with inhibition of ovulation. 
2) Hormonal methods of contraception including oral contraceptive pills containing 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices 
(IUDs) such as Mirena®. 
3) Nonhormonal IUDs, such as ParaGard® 
4) Bilateral Tubal occlusion 
5) Vasectomized partner with documented azoospermia 90 days after procedure 
Vasectomized partner is a highly effective birth control method provided that partner 
is the sole sexual partner of the WOCBP trial participant and that the vasectomized 
partner has received medical assessment of the surgical success. 
6) Intrauterine hormone-releasing system (IUS) 
7) Complete abstinence- Complete abstinence is defined as the complete avoidance of 
heterosexual intercourse  
a) Complete abstinence is an acceptable form of contraception for all study 
drugs and must be used throughout the duration of the study treatment (plus 
5 half-lives of the investigational drug plus 30 days). 
 
b) It is not necessary to use any other method of contraception when complete 
abstinence is elected. 
c) Subjects who choose complete abstinence must continue to have pregnancy 
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d)  Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
e) The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
 
 
UNACCEPTABLE METHODS OF CONTRACEPTION 
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
2) Withdrawal (coitus interruptus) 
3) Spermicide only 
4) Lactation amenorrhea method (LAM) 
 
4.2 
Exclusion Criteria 
1. Target Disease Exceptions 
a) Subjects with autoimmune disease other than RA [e.g., psoriasis, systemic 
lupus erythematosus (SLE), vasculitis, seronegative spondyloarthritis, 
Inflammatory Bowel Disease, Sjogren’s syndrome] or currently active 
fibromyalgia. 
b) Prior history of or current inflammatory joint disease other than RA (such 
as psoriatic arthritis, gout, reactive arthritis, Lyme disease). 
2. Medical History and Concurrent Diseases 
a) Subjects at risk for tuberculosis (TB) defined as follows:  
Current clinical, radiographic or laboratory evidence of active TB. Chest x-
rays (posterior anterior and lateral) obtained within the 3 months prior to 
obtaining written informed consent will be permitted but the images must be 
available and reviewed by the investigator. TB testing (IFN-gamma release 
assay or PPD) performed in the past month prior to Screening will be 
accepted; however, a copy of the report must be placed in the subject binder. 
b) A history of active TB 
c) Subjects with a positive TB screening test indicative of latent TB will not be 
eligible for the study unless they: 
1) Have no evidence of current TB based on chest x-ray performed  
And they are actively being treated for TB or the site has 
documentation of successful prior treatment of latent TB. Treatment 
regimens should be dictated by local guidelines as long as the 
treatment dose and duration meet or exceed local health authority 
guidelines.  
b) Subjects with recent acute infection defined as: 
1) Any acute infection within 60 days prior to randomization that 
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2) Any acute infection within 30 days prior to randomization that 
required oral antimicrobial or antiviral therapy. 
c) Subjects with history of chronic or recurrent bacterial infection (such 
as chronic pyelonephritis, osteomyelitis, and bronchiectasis etc.). 
d) Subjects with any history of infection of a joint prosthesis or 
artificial joint. 
e) Subjects who have a history of systemic fungal infections (such as 
histoplasmosis, blastomycosis, or coccidiomycosis). 
f) Subjects with history of recurrent herpes zoster (more than 1 
episode) or disseminated (more than 1 dermatome) herpes zoster or 
disseminated herpes simplex, or ophthalmic zoster will be excluded. 
Symptoms of herpes zoster or herpes simplex must have resolved 
more than 60 days prior to screening. 
g) Subjects with history of Human Immunodeficiency Virus (HIV) 
infection or who tested positive for HIV  
h) Subjects with history of primary immunodeficiency 
i) Subjects 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). Subjects who had a screening procedure 
that is suspicious for malignancy, and in whom the possibility of 
malignancy cannot be reasonably excluded following additional 
clinical, laboratory or other diagnostic evaluations. 
j) Current clinical findings or a history of a demyelinating disorder 
k) New York Heart Association (NYHA) Class III or IV heart failure 
l) Any previous or current medical conditions that are warnings 
against the use of TNF inhibitor agents. 
m) Current clinical findings of severe, progressive, or uncontrolled 
renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, 
cardiac, endocrine, neurological, or cerebral disease including severe 
and uncontrolled infections, such as sepsis and opportunistic 
infections. Concomitant medical conditions that, in the opinion of the 
investigator, might place the subject at unacceptable risk for 
participation in this study. 
n) Subjects who have received any live vaccines within 3 months of the 
study drug administration or are scheduled to receive live vaccines 
during the study. Study subjects should not be administered a live 
virus vaccine for a minimum of 3 months following the last dose of 
study medication. Subjects who are in close contact with others who 
have received a live vaccine may be enrolled at the investigator’s 
discretion. 
o) Subjects who have undergone a major surgical procedure within the 
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p) Subjects for whom 5 or more joints cannot be assessed for 
tenderness or swelling (i.e. due to surgery, fusion, amputation, etc.). 
3. Subjects who are prisoners, or compulsory detained. 
4.3 
Subject Recruitment and Screening 
 Eligibility will be based on specified inclusion and exclusion criteria, medical history, 
disease activity and safety assessments. Day 1 must occur within 28 days of signing 
the informed consent. Subjects that experience an acute infection or initiate treatment 
for latent TB may extend the screening period to 42 days. 
 
Eligible subjects will have had symptoms and diagnosis of RA prior to signing the 
informed consent. Symptoms of RA are defined as pain, stiffness or swelling in joints 
which are typically inflamed in RA.  Subjects must also have fulfilled criteria for 
rheumatoid arthritis by ACR/EULAR 2010 classification prior to signing informed 
consent.  
 
Subjects treated with MTX must remain on a stable dose of oral methotrexate for at 
least 4 weeks prior to Day 1. The stable dose of oral MTX should be the maximum 
tolerated dose (minimum of 15 mg and maximum of 25 mg per week). A dose of 
methotrexate 7.5-12.5mg/week is permitted if intolerance to 15 mg or higher doses 
has been recorded in the source documents and the dose of oral methotrexate is 
stable for 4 weeks prior to randomization. 
 
To minimize potential methotrexate toxicity, all subjects must receive folic acid, 
folinic acid, or leucovorin according to the manufacturer recommendations, 
methotrexate label instructions, and the local medical standard of care guidelines. 
Subjects receiving oral corticosteroids must be on a stable dose and at the equivalent 
of 10 mg prednisone daily for at least 4 weeks prior to randomization. Subjects may 
not have received an IM, IV or IA administration of a corticosteroid within 4 weeks 
prior to randomization. 
 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
All subjects who have received at least one dose of study drug and exit the study 
early will complete an early termination (ET) visit at the time of study 
discontinuation.  Subjects will continue standard of care appointments with their 
primary rheumatologist after ET visit. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status. This includes follow-up with persons authorized by the subject. Lost 


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to follow-up is defined by the inability to reach the subject after a minimum of 3 
documented phone calls, faxes or emails (not performed on the same day), as well as 
a lack of response by the subject to 1 registered mail letter. All attempts should be 
documented in the subject’s medical records. If it is determined that the subject has 
died, the site will use permissible local methods to obtain the date and cause of death 
and as much other information as can be obtained, including post-mortem reports. 
Data to be collected at subsequent visits will be considered missing. 
 
4.2.1 End of Study 
 
 At the end of the study period, Bristol-Myers Squibb Company will not continue to 
supply study drug to subjects/investigators unless the Sponsor-Investigator chooses 
to extend their study. The investigator is responsible to ensure that the subject 
receives appropriate standard of care or other appropriate treatment in the 
independent medical judgement of the Investigator to treat the condition under 
study. 
 
5 Study Drug  
5.1 
Description and Treatment Regimen   
Abatacept for adult patients with RA, ABATACEPT will be administered as an 
intravenous infusion. Abatacept will be used concomitantly with DMARDs other 
than TNF antagonists or JAK inhibitors. Intravenous Dosing Regimen Abatacept 
lyophilized powder should be reconstituted and administered after dilution [see 
Dosage and Administration below] as a 30-minute intravenous infusion utilizing the 
weight range-based dosing specified. Following the initial intravenous 
administration, an intravenous infusion should be given at 2 and 4 weeks after the 
first infusion and every 4 weeks thereafter.  
 
 Dose of ABATACEPT for Intravenous Infusion in Adult RA Patients  
Body Weight of Patient Dose Number of Vials 
 
 Each vial provides 250 mg of Abatacept for administration. 
 
1. 
Less than 60 kg:  
500 mg 2 vials 
2.  
60 to 100 kg: 
 
750 mg 3 vials 
3. 
More than 100 kg  
1000 mg 4 vials 
 
Dose Modifications in the Absence of Adverse Events 
Subjects should complete their scheduled infusions as described above.  
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If abnormal laboratory test results or clinical adverse events indicate toxicity that, in 
the judgment of the investigator, could place the subject at risk, study drug 
administration should be interrupted.  Subjects may receive further study medication 
treatment only if full resolution of the adverse event or abnormal laboratory finding 
is documented. Under no circumstances should the dose of study drug be altered 
due to an adverse event. 
 
5.2 
Method for Assigning Subjects to Treatment Groups 
N/A. 
5.3 
Preparation and Administration of Study Drug 
Abatacept for reconstitution and dilution prior to intravenous administration. 
Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for 
Injection, USP, the solution of Abatacept is clear, colorless to pale yellow, with a pH 
range of 7.2 to 7.8. Each single-use vial of Abatacept for Injection provides 250 mg 
Abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium 
chloride (14.6 mg) for administration. 
 
Reconstitute using only the silicone-free disposable syringe provided with each vial 
and an 18- to21-guage needle. If the Abatacept powder is accidentally reconstituted 
using a siliconized syringe, the solution may develop a few translucent particles. 
Discard any solutions prepared using siliconized syringes. Administer the entire, 
fully diluted Abatacept solution over a period of 30 minutes with an infusion set and 
a sterile, nonpyrogenic, low-protein–binding filter (pore size of 0.2 μm to 1.2 μm). 
 
The Dartmouth-Hitchcock Medical Center Investigational Pharmacy will ensure that 
the study drug is stored in accordance with the environmental conditions 
(temperature, light, and humidity). If concerns regarding the quality or appearance of 
the study drug arise, the study drug should not be dispensed.  Investigational 
product documentation will 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). 
5.4 
Subject Compliance Monitoring 
 
All subjects are expected to receive study therapy as outlined in the protocol. Subjects 
will use diary cards to document self-injection of study drug between clinic visits.  
 
5.5 
Prior and Concomitant Therapy 
Patients with newly diagnosed or established seropositive active RA will be allowed 
to enter this clinical trial that meet the above inclusion and exclusion criteria.  The 


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ideal candidate for this trial is newly diagnosed RA about to be initiated on weekly 
methotrexate therapy (20 mg/week or the maximally tolerated dose).    Prior or 
concurrent therapy with methotrexate or hydroxychloroquine (< 400 mg/d).  
Established treatment (>4 weeks) with daily Prednisone (<10 mg/d) is permitted. 
5.6 
Packaging 
N/A 
5.7 
Blinding of Study Drug   
N/A 
5.8 
Receiving, Storage, Dispensing and Return 
 
5.8.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed 
and a drug receipt log filled out and signed by the person accepting the shipment.  It 
is important that the designated study staff counts and verifies that the shipment 
contains all the items noted in the shipment inventory.  Any damaged or unusable 
study drug in a given shipment (active drug or comparator) will be documented in 
the study files.  The investigator must notify study sponsor of any damaged or 
unusable study treatments that were supplied to the investigator’s site. 
5.8.2 Storage 
The fully diluted Abatacept solution may be stored at room temperature or 
refrigerated at 36°F to 46°F (2°C to 8°C) before use.  The infusion of the fully diluted 
Abatacept solution must be completed within 24 hours of reconstitution of the 
Abatacept vials. Discard the fully diluted solution if not administered within 24 
hours. 
 
The infusion of the fully diluted Abatacept solution must be completed within 24 
hours of reconstitution of the Abatacept vials. Discard the fully diluted solution if not 
administered within 24 hours. 
 
5.8.3 Dispensing of Study Drug 
The investigator is responsible for ensuring adequate accountability of all used and 
unused study drugs. This includes acknowledgement of receipt of each shipment of 
study drugs (quantity and condition). All used and unused study drugs dispensed to 
subjects must be returned to the site. 
Abatacept accountability records will be provided by Dartmouth-Hitchcock 
Investigational Pharmacy: 
 
Record the date received and quantity of study drugs 


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 
Record the date, subject number, subject initials, the study drug number 
dispensed 
 
Record the date, quantity of used and unused study drugs returned, along 
with the initials of the person recording the information. 
 
Dispensing records will include the initials of the person dispensing the study 
drug  
5.8.4 Supplies, Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. 
 
For this study, study drugs (those supplied by BMS or sourced by the investigator) 
such as partially used study drug containers, vials and syringes may be destroyed on 
site. Any unused study drugs can only be destroyed,  
 
5.9 
Vi sit 1  
See above 
5.10 
Visit 2 
5.11 
etc. 
6 Statistical Plan 
6.1 
Sample Size Determination 
Not applicable, this is a pilot study 
6.2 
Statistical Methods 
These studies are considered exploratory and will enable power analyses for 
subsequent larger studies.  We anticipate that clinical responders will concurrently 
have more than 25% decreases in IgG anti-CCP3 levels (INOVA).  The mean change 
in IgG anti-CCP levels in responders versus non-responders will be analyzed by t-
test. A proportional decrease in the estimated level of IgG anti-CCP3 secreting 
recirculating memory B cells is predicted as well. Clinical non-responders are 
predicted to not have a significant change. No significant effects on total IgG, IgA or 
IgM are anticipated. In a recent report with cross-sectional analyses we documented 
highly significant correlations r=0.57 p=0.0033) between ACPA and memory B cell 
levels in studies of 24 RA patients (11).  With longitudinal analyses we anticipate that 
relationships should require fewer subjects to document correlations between shifts 
in clinical activity and ACPA IgG and ACPA-memory B cell levels overtime. We will 


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assess non-parametric paired-sample comparisons by Spearman correlations, and 
longitudinal measurements using paired t test, with Prism v6.0e (GraphPad, La Jolla, 
CA). P<0.05 will be considered significant.  
6.3 
Subject Population(s) for Analysis 
All treated subjects in study. 
7 Safety and Adverse Events 
7.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-
related documents such as the IRB-approved protocol or consent form, the 
investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome 
may have been caused by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation participant 
administered study drug and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(such as an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the 
investigational product. 
The causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). The casual relationship can be one of the 
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Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, subjects should not be questioned regarding the specific occurrence of one or 
more AEs.) 
 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
 fatal 
 
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 or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 
an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE.  
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance.   They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
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Although pregnancy, overdose, potential drug-induced liver injury (DILI), and 
cancer are not always serious by regulatory definition, these events must be handled 
as SAEs. 
Any component of a study endpoint that is considered related to study therapy 
should be reported as an SAE (e.g., death is an endpoint, if death occurred due to 
anaphylaxis, anaphylaxis must be reported). 
 
All adverse events that do not meet any of the criteria for serious should be regarded 
as non-serious adverse events.  
NONSERIOUS ADVERSE EVENT 
 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via 
interim or final study reports as specified in the agreement or, if a regulatory 
requirement [e.g., IND US trial] as part of an annual reporting requirement.  
 
Non-serious AE information should also be collected from the start of a 
placebo lead-in period or other observational period intended to establish a 
baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of study drug. 
All non-serious adverse events (not only those deemed to be treatment-related) 
should be collected continuously during the treatment period and for a minimum of 
30 days following the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the end 
of study treatment as appropriate.  
 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined 
as the period from the initiation of any study procedures to the end of the study 
treatment follow-up.  For this study, the study treatment follow-up is defined as 30 
days following the last administration of study treatment.  
 
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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time 
after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor should also be notified if the 
investigator should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a subject that has participated in 
this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, 
further diagnostic investigation, etc. 
any laboratory test result that is clinically significant or meets the definition of an 
SAE 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported to BMS as such. It is expected that wherever possible, the clinical rather than 
laboratory term would be used by the reporting investigator (eg, anemia versus low 
hemoglobin value). 


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Potential Drug Induced Liver Injury (DILI)  
Specific criteria for identifying potential DILI have not been identified for this 
protocol. Standard medical practice in identifying and monitoring hepatic issues 
should be followed. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should 
be documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for and adverse 
event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
 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) 
 Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 
 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). 
 


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Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered 
that a study participant is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 5 half-lives after product 
administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event 
via either the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in 
accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant. 
Follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome and, where applicable, offspring information must be reported 
on the CIOMS, MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE 
form.  A BMS Pregnancy Surveillance Form may be provided upon request. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 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.  
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of 
a product that is considered both excessive and medically important. All occurrences 
of overdose must be reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or 
not these procedures are required by the protocol, should also be recorded as a non-
serious or serious AE, as appropriate, and reported accordingly.  
7.1 
 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on 
all adverse events should be recorded immediately in the source document, and also 
in the appropriate adverse event module of the case report form (CRF).  All clearly 


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related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the study period must be followed 
up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
7.2 
Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting 
timelines, formats and requirements of the various entities to which they are 
responsible, but at a minimum those events that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be 
provided at the time of the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the 
event 
 
Date of onset 
 
Current status 
 
Whether study treatment was 
discontinued 
 
The reason why the event is classified 
as serious 
 
Investigator assessment of the 
association between the event and 
study treatment 
 
7.2.1 
Investigator reporting: notifying the study sponsor 
. 
Any study-related unanticipated problem posing risk of harm to subjects or others, 
and any type of serious adverse event, must be reported to the study sponsor by 
telephone within 24 hours of the event.  To report such events, a Serious Adverse 
Event (SAE) form must be completed by the investigator and faxed to the study 
sponsor within 24 hours.  The investigator will keep a copy of this SAE form on file at 
the study site.  Report serious adverse events by phone and facsimile to: 
 
24-hr Emergency Telephone Number 
 
(603) 650-5000  


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Within the following 48 hours, the investigator must provide further information on 
the serious adverse event or the unanticipated problem in the form of a written 
narrative.  This should include a copy of the completed Serious Adverse Event form, 
and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing serious adverse events should be provided 
promptly to the study sponsor 
 
Investigator Reporting to BMS 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 30 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety, whether related or not related to 
study drug. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (e.g., a follow-up skin biopsy). 
 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those 
thought to be associated with protocol-specified procedures. The investigator 
should report any SAE occurring after these aforementioned time periods, 
which is believed to be related to study drug or protocol-specified procedure. 
 
An SAE report should be completed for any event where doubt exists regarding 
its seriousness;  
 
If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of 
previous therapy or a complication of a study procedure), the relationship 
should be specified in the narrative section of the SAE Report Form. 
 
If the BMS safety address is not included in the protocol document (eg, 
multicenter studies where events are reported centrally), the procedure for 
safety reporting must be reviewed/approved by the BMS Protocol Manager. 
Procedures for such reporting must be reviewed and approved by BMS prior to 
study activation. 
An appropriate SAE form (e.g.  ex-US = CIOMS form or USA = Medwatch form) 
should be used to report SAEs to BMS.  If you prefer to use your own Institutional 
form, it must be reviewed by BMS prior to study initiation.  Note:  Please include the 
BMS Protocol number on the SAE form or on the cover sheet with the SAE form 
transmission.   
o 
The CIOMS form is available at: 
http://www.cioms.ch/index.php/cioms-form-i  
o The MedWatch form is available at: MedWatch 3500 Form  


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 
 
 
Worldwide.Safety@bms.comaepbusinessprocess@bms.com 
 
In accordance with local regulations, BMS will notify investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (ie, not previously described in the IB). An event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of a SUSAR Report.  
o Other important findings which may be reported by BMS as an Expedited 
Safety Report (ESR) include: increased frequency of a clinically significant 
expected SAE, an SAE considered associated with study procedures that 
could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding 
from a nonclinical (eg, animal) study, important safety recommendations 
from a study data monitoring committee, or sponsor decision to end or 
temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain 
the ESR with the IB. Where required by local regulations or when there is a 
central IRB/IEC for the study, the sponsor will submit the ESR to the 
appropriate IRB/IEC. The investigator and IRB/IEC will determine if the 
informed consent requires revision. The investigator should also comply 
with the IRB/IEC procedures for reporting any other safety information.  
o In addition to the Sponsor Investigator’s responsibility to report events to 
their local HA, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health 
authorities in all concerned countries according to local regulations (either 
as expedited and/or in aggregate reports). 
SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS within 24 hours \ 1 Business Day of becoming aware of the event. 
SAEs must be recorded on either CIOMS, MedWatch, or approved site SAEform.   
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or,  
3. Approved site SAE form  
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 


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If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially 
reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours \ 1 Business Day to BMS using the same procedure used for transmitting the 
initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
7.2.2 
Investigator reporting: notifying the Dartmouth IRB 
 
This section describes the requirements for safety reporting by investigators who are 
Dartmouth faculty, affiliated with a Dartmouth research site, or otherwise 
responsible for safety reporting to the Dartmouth IRB. The Dartmouth College IRB 
(CPHS) requires expedited reporting of those events related to study participation 
that are unforeseen and indicate that participants or others are at increased risk of 
harm.  The Dartmouth IRB will not acknowledge safety reports or bulk adverse event 
submissions that do not meet the criteria outlined below.  The Dartmouth IRB 
requires researchers to submit reports of the following problems within 10 working 
days from the time the investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, 
on-site or off-site) that occurs any time during or after the research study, 
which in the opinion of the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document and other relevant sources 
of information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research 
procedures” if in the opinion of the principal investigator or sponsor, the event 
was more likely than not to be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be 
reported to the Dartmouth IRB using the form: “Unanticipated Problems Posing 
Risks to Subjects or Others Including Reportable Adverse Events” or as a written 
report of the event (including a description of the event with information regarding 


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its fulfillment of the above criteria, follow-up/resolution and need for revision to 
consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept 
in the Clinical Investigator’s study file. 
 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following 
describes the more rapid reporting requirement of the Dartmouth IRB for specific 
situations: 
 Report the event within 24 hours when the death is unforeseen (unexpected) 
and indicates participants or others are at increased risk of harm. 
 Report the event within 72 hours, for all other deaths, regardless of whether 
the death is related to study participation. 
 
For reportable deaths, the initial submission to the Dartmouth IRB may be made by 
contacting the IRB Director or Associate Director. The AE/Unanticipated Problem 
Form is required as a follow up to the initial submission. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Dartmouth IRB: 
 Any adverse experience that, even without detailed analysis, represents a 
serious unexpected adverse event that is rare in the absence of drug exposure 
(such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
 Any adverse event that would cause the sponsor to modify the investigators 
brochure, protocol or informed consent form, or would prompt other action by 
the IRB to assure protection of human subjects. 
 Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of 
response to treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or 
more frequent than initially expected. 
– A paper is published from another study that shows that an arm of your 
research study is of no therapeutic value. 
 Change in FDA safety labeling or withdrawal from marketing of a drug, 
device, or biologic used in a research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 


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 Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
 Complaint of a participant when the complaint indicates unexpected risks or 
the complaint cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the 
IRB approved protocol) that in the opinion of the investigator placed one or 
more participants at increased risk, or affects the rights or welfare of subjects. 
7.2.3 
Investigator reporting: Notifying another IRB 
Investigators who are not Dartmouth faculty or affiliated with a Dartmouth research 
site are responsible for safety reporting to their local IRB.  Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must 
submit the required reports to their IRB no later than 10 working days.  Copies of 
each report and documentation of IRB notification and receipt will be kept in the 
investigator’s study file. 
7.2.4 
Sponsor reporting: Notifying participating investigators 
 
It is the responsibility of the study sponsor to notify all participating investigators, in 
a written IND safety report, of any adverse event associated with the use of the drug 
that is both serious and unexpected, as well as any finding from tests in laboratory 
animals that suggest a significant risk for human subjects.  Additionally, sponsors are 
also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the 
previous reports. 
7.3 
Stopping Rules  
7.4 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study 
at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the construction 
and implementation of a site data and safety-monitoring plan (see section 9 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
7.4.1 Independent Data and Safety Monitoring Board 
There is no DSMB. 


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8 Data Handling and Record Keeping 
8.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the 
subject of the following:  
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their 
PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to 
the revocation of subject authorization.  For subjects that have revoked authorization 
to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
8.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
8.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If 
any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes 
must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, 
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8.4 
Records Retention 
The clinical research records are the property of the clinical subcontractor awardee 
institution. These records include clinical research records, IRB records, and records 
related to investigations or proceedings of research misconduct.  
 Storage  
Clinical research records are stored in a manner that ensures privacy, confidentiality, 
security, and accessibility when the clinical research is being conducted and after the 
research is completed. Records can be kept in hardcopy, electronic or other media 
form. It is permissible to transfer these documents from paper records to electronic 
formats and to archive this information on available media.  
Record Keeping  
The research team will maintain adequate documentation of all IRB/EC records and 
clinical research records. Records must be retained for at least three 2 years after the 
completion of research. Records must be accessible for inspection and copying by 
authorized representatives of the department or agency at reasonable times and in a 
reasonable manner 
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
N/A 
9.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, the sponsor, government regulatory bodies, and Dartmouth compliance and 
quality assurance groups of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable Dartmouth 
compliance and quality assurance offices. 
10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or Institutional Review Board (IRB), in 


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agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the EC/IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study.  The investigator should provide a list of EC/IRB 
members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about 
their participation in this study.  See Attachment 1 for a copy of the Subject Informed 
Consent Form.  This consent form will be submitted with the protocol for review and 
approval by the EC/IRB for the study.  The formal consent of a subject, using the 
EC/IRB-approved consent form, must be obtained before that subject undergoes any 
study procedure.  The consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  
11 Study Finances 
11.1 
Funding Source 
From BMS 
11.2 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by a properly constituted Conflict of Interest 
Committee with a Committee-sanctioned conflict management plan that has been 
reviewed and approved by the study sponsor prior to participation in this study.  All 
Dartmouth investigators will follow the Dartmouth conflict of interest policy. 
11.3 
Subject Stipends or Payments 
N/A 
12 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor.  Any investigator involved with this study is obligated 
to provide the sponsor with complete test results and all data derived from the study. 
 
 


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13 References   
1. Wolfe F. The epidemiology of drug treatment failure in rheumatoid arthritis. 
Baillieres Clin Rheumatol 1995;9(4):619-932. 
 
2. Hochberg MC and Spector TD. Epidemiology of rheumatoid arthritis: Update. 
Epidemiol Rev 1990;12:247-252 
 
3. Markenson JA. Worldwide trends in the socioeconomic impact and long-term 
prognosis of rheumatoid arthritis. Semin Arthritis Rheum 1991;21(2 Suppl 1):4-12 
 
4. Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am 1990;16(3):513-537 
 
5. Zvaifler NJ. Etiology and pathogenesis of rheumatoid arthritis. In: Arthritis and 
Allied Conditions. Philadelphia, PA: Lea & Febiger;1993:723-736. 
 
6. Lindqvist E, Jonsson K, Saxne T, et al. Course of radiographic damage over 10 years 
in a cohort with early rheumatoid arthritis. Ann Rheum Dis 2003;62:611-616 
 
7. Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac'h N, Falgarone G. 
Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. J 
Autoimmun. 2012 39(3):222-8 
 
8. Bristol-Myers Squibb Abatacept Investigator Brochure, version 18, version date 13-
Nov-2014 
 
9. Schiff M. Co-stimulation Therapy in Rheumatoid Arthritis: Today and Tomorrow. 
Curr Treatm Opt Rheumatol. 2015;1(4):334-349).   
 
10.  Emery P, Burmester GR, Bykerk VP, Combe BG, Furst DE, Barré E, Karyeka CS, 
Wong DA, Huizinga TW. valuating drug-free remission with Abatacept in early 
rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-
controlled AVERT study of 24 months, with a 12-month, double-blind treatment 
period.Ann Rheum Dis. 2015 74(1):19-26. 
 
11. Pelzek AJ, Grönwall C, Rosenthal P, Greenberg JD, McGeachy M, Moreland L, Rigby 
WFC, Silverman GJ. Persistence of Disease-Associated Anti-Citrullinated Protein Antibody-
Expressing Memory B Cells in Rheumatoid Arthritis in Clinical Remission. Arthritis  
Rheumatol. 2017 69(6):1176-1186.   
 
12.  Kanbe K, Chiba J, Nakamura A.  Immunohistological analysis 
of synovium treated with Abatacept in rheumatoid arthritis.  Rheumatol Int. 2013  
33(7):1883-7. 
 


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13.   Gazeau P, Alegria GC, Devauchelle-Pensec V, Jamin C, Lemerle J, Bendaoud B, 
Brooks WH, Saraux A, Cornec D, Renaudineau Y.  Memory B Cells and Response to 
Abatacept in Rheumatoid Arthritis Clin Rev Allergy Immunol. 2017 Oct;53(2):166-
176. 
 
14.  Marasco E, Aquilani A, Cascioli S, Moneta GM, Caiello I, Farroni C, Giorda E, 
D'Oria V, Marafon DP, Magni-Manzoni S, Carsetti R, De Benedetti F. Arthritis 
Rheumatol. Switched Memory B Cells Are Increased in Oligoarticular and 
Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to 
Response to Tumor Necrosis Factor Inhibitors.  2018 70(4):606-615).   
 
15.  Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, 
Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, 
Becker JC, Covucci A, Helfrick R, Bathon J.Ann Rheum Dis. 2009 68(12):1870-7. doi: 
10.1136/ard.2008.101121) 
 
 
 
 
 
 
 
 
 
 
14 Attachments Insert what is needed 
1. Informed consent 
2. Patient Rapid 3 questionnaire