Phase IV Open-Label Study to Evaluate Biomarkers to Predict the Efficacy of Abatacept in Subjects With Rheumatoid Arthritis
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Sponsor: University of Washington

 
1 
 
Title 
Phase IV Open-Label Study To Evaluate Biomarkers to Predict the Efficacy of 
Abatacept in Subjects with Rheumatoid Arthritis 
 
 
BMS Protocol # IM101-753 
University of Washington Protocol # STUDY00004744 
Version 1.0 
07/09/2018 
 
Investigator name  
Kwanghoon Han 
Natalia Giltiay 
Keith Elkon 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
Protocol Synopsis 
 
Study Title 
 
 
Phase IV Open-Label Study To Evaluate Biomarkers to 
Predict the Efficacy of Abatacept in Subjects with 
Rheumatoid Arthritis 
 
 
Sponsor 
 
 
Bristol-Myers Squibb (BMS) 
 
Indication 
 
 
Rheumatoid arthritis (RA) 
 
Objectives  
 
 
The primary objective of this study is:  
 
• To evaluate if baseline levels of T cell-associated 
biomarkers predict efficacy of abatacept during 24 
weeks of treatment in patients with moderate to 
severe active RA who have had an inadequate 
response to conventional disease modifying anti-
rheumatic drugs (cDMARDs) 
 
The secondary objectives of this study are: 
 
• To evaluate if baseline levels of B cell-associated or 
other biomarkers predict efficacy of abatacept in 
patients with moderate to severe active RA 
 
• To evaluate the effects of abatacept on the phenotypic 
distribution of circulating T cell and B cell subsets and 
levels of T or B cell-associated or other biomarkers in 
patients with moderate to severe RA 
 
 
 
Study design  
 
 
This is a phase 4, single-center study in patients with 
moderate to severe active RA who have had an inadequate 
response to cDMARDs. Subjects are to be recruited over 16 
months.  
 
All subjects receive abatacept 125mg subcutaneous 
injections every week for 24 weeks along with cDMARDs. 
Visits are scheduled at baseline, 6 weeks, 14 weeks and 24 
weeks. Evaluation of primary endpoint occurs at week 14. All 

 
3 
 
subjects receive a phone call from study personnel 4 weeks 
and 15 weeks after the last visit for post-study follow-up. 
 
 
Number of subjects 
 
 
25  
 
Target population 
 
 
Men and women ≥ 18 years of age, with moderate to severe 
RA who are currently experiencing an inadequate clinical 
response to cDMARDs therapy 
 
 
 
Length of study 
 
 
24-week treatment with a follow-up 15 weeks after the end of 
the treatment period 
 
 
Investigational 
Medicinal Product 
 
 
Abatacept 125mg subcutaneous injection every week 
 
Assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary endpoint 
 
• Baseline levels of T cell-associated biomarkers or other 
biomarkers predict ACR20 response with subcutaneous 
abatacept at week 14  
 
Secondary endpoints 
 
• Baseline levels of T cell-associated biomarkers or other 
biomarkers predict ACR20 response with subcutaneous 
abatacept at week 24  
• Baseline levels of T cell-associated biomarkers or other 
biomarkers predict ACR50 & 70 response, EULAR good or 
moderate response, low disease activity (DAS28 <3.2 or 
CDAI≤10) or remission (DAS28 < 2.6 or CDAI≤2.8) with 
subcutaneous abatacept at week 14 and 24 
• Change in phenotypic distribution of circulating T cell and B 
cell subsets, T cell-associated biomarkers and other 
biomarkers with subcutaneous abatacept at week 14 and 24  
• Adverse event monitoring 
 
Statistical analysis  
 
 
The primary endpoint will be the AUC of the receiver operator 
characteristic (ROC) curves for the biomarkers predicting 
AC20 response at week 14. We assume that 60% of the 

 
4 
 
patients will respond to abatacept therapy based on the data 
from the AMPLE trial. Thus, a total sample size of 25 patients 
will yield approximately 15 responders and 10 non-
responders. With this sample, the expected margin of error 
for 95% confidence intervals for the AUC will be 19% or 22% 
if the AUC is 0.8, or 0.7, respectively. 
 
The area under the ROC curve (AUC) will be the primary 
measure of the predictive value of the biomarker. Estimates 
of the AUC’s and 95% confidence intervals will be computed 
for each biomarker.  We will also evaluate the predictive 
value of combinations of any or all baseline biomarker 
information used in linear risk scores derived using logistic 
regression models (outcome = response to abatacept 
therapy).  We will evaluate each possible risk-score 
combination of biomarkers as a predictor by estimating the 
prediction error using leave-one-out cross-validation (at the 
80% specificity cutoff).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
5 
 
Table of Contents 
 
1. Background and rationale 
 
2. Objectives 
 
3. Ethical considerations 
 
3.1. 
Good clinical practice 
3.2. 
Institutional review board 
3.3. 
Informed consent 
 
4. Study Design 
 
4.1. 
Overview of study design  
4.2. 
Eligibility  
4.3. 
Concomitant medication and treatment 
4.4. 
Premature withdrawal 
 
5. Study Drug/Treatment 
 
5.1. 
Investigational Product (IP) 
5.2. 
Storage, Administration, and Destruction of Investigational Product 
 
6. Study procedures 
 
7. Safety and Reporting 
 
7.1. 
Adverse events 
7.2. 
Serious Adverse Events and Reportable Medical Events 
 
8. Statistical analysis 
 
8.1. 
Study end points 
8.2. 
Statistical and analytical methods 
 
9. Reference list  
 
 
 
 
 
 

 
6 
 
1. Background and rationale 
 
Rheumatoid arthritis (RA) is a heterogeneous disease with multiple cells and 
cytokines contributing to its pathogenesis. Even if several new advanced 
therapies targeting a specific pathway in the pathogenesis of RA are available, 
the response to those treatments is highly variable and unpredictable. Currently, 
there are no reliable biomarkers to predict therapeutic response to targeted 
therapies. Many patients with moderate to severe RA have to undergo “trial and 
error” treatment plans until they find what agent is the most effective for their 
condition. Therefore, there is an urgent need for effective biomarkers that are 
predictive of treatment response in RA. 
 
Abatacept is a fusion protein consisting of the extracellular domain of human 
CTLA-4 and a fragment of the Fc domain IgG1 and works by blocking an 
interaction between CD80/CD86 on antigen presenting cells and CD28 on T 
cells. Unlike other targeted therapies for RA such as TNFα or IL-6 inhibitors, 
abatacept inhibits a pathway which is only involved in T cell activation. Abatacept 
is reported to be more effective in RA patients who are positive for anti-CCP and 
patients with the highest baseline anti-CCP concentrations have a better 
response (1). These results support the notion that abatacept is involved in 
modulation of adaptive immunity.      
 
CD4 T cells play an important role in RA pathogenesis by stimulating effector 
cells including macrophages and B cells. In an “alternative” pathway, 
macrophages are activated and secrete pro-inflammatory cytokines including 
TNFα and IL-6 likely through Toll-like receptor engagement with lesser 
involvement of T cells. It has been shown that there are several synovial 
phenotypes in RA including myeloid, lymphoid, low inflammatory and fibroid with 
distinct gene expression signature (2). A recent study has demonstrated higher 
levels of T cells and B cells in synovium from anti-CCP positive RA patients 
compared to anti-CCP negative patients (3). These findings suggest there may 
be subsets of RA in which inflammation is primarily driven by T cells, 
macrophages, or both.  
 
Soluble CD27 (sCD27) is released from activated T cells (4,5) and the levels of 
sCD27 in cerebrospinal fluid is studied as a diagnostic marker for multiple 
sclerosis (5). We have shown that serum sCD27 levels are elevated in RA 
patients compared to healthy controls and significantly higher in seropositive RA 
patients than in seronegative RA (unpublished data). It’s been reported soluble 
CD28 (sCD28) and soluble CTLA4 (sCTLA4) are elevated in RA (6,7) and 
baseline numbers of circulating CD28-negative helper T cells (Th) and cytotoxic 
T cells (Tc)  predict the response to abatacept although the number of CD28-
negative T cells decreases progressively during therapy (8). The relationship 

 
7 
 
between the number of CD28-negative T cells and levels of sCD28, sCTLA4 or 
sCD27 remains to be investigated. Soluble CD40 ligand (sCD40L), a molecule 
from T cells, is elevated in RA and other autoimmune diseases (9) although it is 
also released from platelets. Soluble CD137 (sCD137) is released from activated 
T cells and is elevated in RA (10,11). ICOS plays an important role in 
development of T follicular helper cells (Tfh) and upregulation of ICOS on T cells 
is suppressed by abatacept (12). The significance of soluble ICOS (sICOS) in RA 
is not known although it is shown to be elevated in systemic sclerosis (13). Taken 
together, these markers could be potentially used to assess T cell activation in 
RA.  
 
There are markers from other immune cells including macrophages, neutrophils 
and B cells that could be used to assess inflammation in RA along with T cell 
markers. Macrophage-associated biomarkers include soluble CD14 (sCD14), 
soluble CD 163 (sCD163) and calprotectin (S100A8/A9). Both sCD14 and 
sCD163 are primarily released from macrophages and correlate with disease 
activity in RA (14, 15). It has been shown sCD14 stimulates pro-inflammatory 
cytokine production in a manner that is dependent on the TLR4/CD14 membrane 
complex, NF-κB and inflammasome (16). Although calprotectin is released from 
macrophages, the main source is neutrophils, whose cytoplasmic content 
consists of up to 60% calprotectin. Calprotectin is an endogeneous ligand for 
Toll-like receptor 4 (17) and serum calprotectin levels correlate with synovitis 
measured by ultrasound (18). It has been reported calprotectin is a predictor of 
the response to treatments in RA (19). MPO-DNA complexes, a marker of 
NETosis, a special form of neutrophil death, in which citrullination of RA 
autoantigens occurs (20), correlate with RA disease activity as demonstrated by 
us (unpublished data). Other markers are derived from several cell types. Soluble 
CD25 (sCD25) is a marker for macrophage and T cell activation and the levels of 
sCD25 decrease in response to abatacept in RA (21). Soluble CD23 (sCD23) is 
released from activated B cells, monocytes and many other cells and may reflect 
B cell activity in RA (22,23).    
 
Subsets of CD4 T cells are generated in RA and serum chemokine levels have 
been used to assess T cell subsets. T helper cell 1 (Th1) pathway is promoted by 
IL-12 and type I interferon (IFN) and associated with chemokines including 
CXCL10. It has been shown that type I IFN gene expression signature observed 
in a subset of RA patients is associated with the response to treatments in RA 
(24). Therefore, CXCL10, which is shown to correlate with disease activity in 
early RA (25), could be used as surrogate serum markers for both Th1 cells and 
type I IFN activities in RA patients.  
 
Recently, PD-1hi CXCR5−T peripheral helper cell (Tph) pathway has been 
described in synovium of seropositive RA patients (26) as opposed to CXCR5+ T 

 
8 
 
follicular helper cells (Tfh) which primarily function in lymph nodes. One of the 
primary functions of Tfh and Tph cells is to stimulate differentiation of B cells into 
antibody-secreting plasma cells. Both Tfh and Tph pathways are associated with 
IL-21 and CXCL13, cytokines known to support GC formation and plasma cell 
differentiation. Serum CXCL13 levels are higher in seropositive RA (27) and may 
predict the therapeutic response in RA (28).  
 
It has been reported that abatacept is more effective in anti-CCP-positive RA 
patients (1) and suppresses Tfh cell maturation and proliferation in murine 
models of RA (12). Abatacept treatment in patients with primary Sjogren’s 
syndrome was recently reported to reduce circulating Tfh cells and lower the 
expression of the activation marker ICOS on T cells (29). Regarding B cell 
activation, abatacept has been shown to reduce serum ACPA and RF and lower 
the frequencies of post-switched memory B cells in RA (30). These results 
suggest that, inhibition of activated Tfh (and Tph) cells, leading to attenuated T 
cell-dependent B cell activation may underlie the efficacy of abatacept.  
 
The intent of this study is to demonstrate whether baseline levels of the above 
biomarkers are helpful in predicting the response to abatacept in RA patients 
who have an inadequate response to methotrexate and other conventional 
disease modifying anti-rheumatic drugs (cDMARDs). Further evaluation of the 
effects of abatacept on the phenotypic distribution of circulating T cell and B cell 
subsets will provide additional information regarding action mechanisms of 
abatacept. 
 
 
2. Objectives  
 
The primary objective of this study is 
 
• To evaluate if baseline levels of T cell-associated biomarkers and other 
biomarkers predict efficacy of abatacept during 24 weeks of treatment in patients 
with moderate to severe active RA who have had an inadequate response to 
cDMARDs  
 
The secondary objectives of this study are  
 
• To evaluate change in phenotypic distribution of circulating T cell and B cell 
subsets, T cell-associated biomarkers and other biomarkers with subcutaneous 
abatacept in moderate to severe RA patients 
 
 
3. Ethical Considerations 

 
9 
 
 
3.1. 
Good Clinical Practice 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH), World Health 
Organization (WHO) and local directives.  
 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and subject informed consent will receive Institutional Review 
Board (IRB) approval/favorable opinion before initiation of the study.  
 
Personnel involved in conducting this study will be qualified by education, training 
and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there 
has been scientific misconduct or fraud. 
 
3.2  
Institutional Review Board 
 
Before study initiation, the investigator must have written and dated approval 
from the IRB for the protocol, consent form, subject recruitment material, and any 
other written information to be provided to subjects. The investigator or designee 
should provide the IRB with reports, updates, and other information according to 
regulatory requirements or institutional procedures. 
 
3.3 Informed Consent 
 
Investigators will ensure that subjects are clearly and fully informed about the 
purpose, potential risk, and other critical issues regarding clinical studies in which 
they volunteer to participate. The consent form must adhere to the ethical 
principles that have their origin in the Declaration of Helsinki. The informed 
consent will include relevant safety information regarding dose and schedule of 
investigational product, and detailed information regarding other medications and 
study procedures. The informed consent will include investigator contact 
information, and information regarding the role of sponsor BMS to provide 
funding and investigational product for this study.  
 
Study participants will be provided with information regarding the use and access 
of their personal information and study records by the study team, the institution, 
the sponsor BMS, and health authorities. The investigator must ensure that a 
signed and dated informed consent form is obtained prior to any study 
procedures. 
 
 

 
10 
 
4. Study Design 
 
4.1. 
Overview of study design  
This is a phase 4, single-center study in patients with moderate to severe active 
RA who have had an inadequate response to DMARDs. A total of 25 patients are 
to be recruited over a planned recruitment period of 16 months.  
All subjects receive abatacept 125mg subcutaneous injections every week for 24 
weeks. The following DMARDs are permitted in this study: methotrexate, 
hydroxychloroquine, sulfasalazine and leflunomide. These DMARDs can be used 
alone or in combination, except for the combination of methotrexate and 
leflunomide which is not allowed. Permitted DMARDs are continued at the stable 
pre-entry dose. 
Visits are scheduled at baseline, 6 weeks, 14 weeks and 24 weeks. Evaluation of 
primary endpoint occurs at week 14. All subjects receive a phone call from study 
personnel 4 weeks and 15 weeks after the last visit for post-study follow-up. 
 
4.2. 
Eligibility 
 
Inclusion Criteria 
 
1. Male or non-pregnant, non-nursing female 
2. Age ≥18 years  
3. Body weight ≤120kg 
4. Classification of RA according to the 1987 ACR criteria or 2010 ACR/EULAR 
criteria  
5. Symptoms of RA present for at least 3 months and less than 10 years prior to 
screening  
6. Clinical Disease Activity Index (CDAI) ≥16 corresponding to moderate to 
severe disease activity 
7. Patients taking oral DMARDs must be on stable doses of DMARDs for at least 
4 weeks prior to abatacept initiation 
8. Treatment within the past year with either methotrexate (MTX), leflunomide 
(LEF), hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ) for ≥ 8 weeks 
9. Patient who have received one prior anti-TNF must have discontinued 
etanercept, infliximab, adalimumab, certolizumab, or golimumab for at least 6 
months prior to screening 
10. Patients taking oral corticosteroid, the dose must be ≤ 5 mg/day prednisone 
or equivalent 
11. Females of childbearing potential and males with female partners of 
childbearing potential may participate in this study only if using a reliable means 
of contraception 

 
11 
 
 
 
Exclusion Criteria 
 
 
1. Previous treatment with abatacept 
2. Previous treatment with rituximab, tocilizumab, tofacitinib, sarilumab or 
anakinra 
3. Previous treatment with IV immunoglobulin, plasmapheresis, alkylating agents 
such as cyclophosphamide 
4. Intraarticular or parenteral corticosteroids within 4 weeks of screening 
5. Rheumatic autoimmune disease other than RA including systemic lupus 
erythematosus, primary Sjogren syndrome, spondyloarthritis, systemic sclerosis, 
dermatomyositis, mixed connective tissue disease, vasculitis 
6. Non-rheumatic autoimmune disease including inflammatory bowel disease, 
psoriasis, multiple sclerosis 
7. Recurrent or chronic bacterial, viral, fungal, mycobacterial or other infections 
including HIV, Hepatitis B or C, latent TB (TB not adequately treated according to 
guidelines) 
8. Primary or secondary immunodeficiency   
9. Current uncontrolled renal, gastrointestinal, endocrine, pulmonary, cardiac, or 
neurologic disease  
10. History of malignancy within 10 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix and non-melanoma skin 
carcinoma 
11. History of alcohol, drug or chemical abuse within 1 year prior to screening 
12. Laboratory exclusion criteria at screening including 
-eGFR <30 ml/min 
-ALT or AST >1.5 times upper limit of normal 
13. Major surgery (including joint surgery) within 8 weeks prior to screening or 
planned major surgery during the study 
14. Immunization with a live/attenuated vaccine within 4 weeks prior to screening 
15. Pregnant or nursing women, or women of child bearing potential who plan to 
become pregnant prior to 14 weeks after the last dose of abatacept treatment. 
16. Patients of reproductive potential not willing to use an effective method of 
contraception 
17. Prisoners, or subjects who are compulsory detained 
 
4.3. 
Concomitant medication and treatment 
 
In addition to abatacept, patients receive permitted conventional DMARDs at a 
stable pre-entry dose. The dose of DMARDs at entry into the study should be 
continued without change during the study. Oral corticosteroid (5mg/day 
prednisone or equivalent) and NSAIDs are permitted during the study if the dose 
has been stable.  

 
12 
 
 
4.4. 
Premature withdrawal 
Patients have the right to withdraw from the study at any time for any reason. All 
patients who withdraw from the study must return to the clinic for a complete final 
evaluation 1 week following the last dose of study drug.  
 
 
5. Study Drug/Treatment 
 
5.1. 
 Investigational Product  
 
The investigational medicinal product (IP) for this study is subcutaneous 
abatacept 125mg once weekly for 24 weeks. All study participants will take 
abatacept in combination with standard of care anti-rheumatic background 
therapy, including DMARDs. 
 
5.2.   Storage, Administration, and Destruction of Investigational Product 
 
The sponsor, BMS, will provide the IP, abatacept, to the study site for use as 
specified in this study. Background therapy, including DMARDS, and anti-
rheumatic therapies will not be provided by the study. IP will be stored in 
accordance with the package insert at Investigational Drug Services (IDS), a 
secure pharmacy. IDS will maintain a record of all IP received, including 
inventory and dispensation records. Study participants will be instructed to 
dispose of used IP in accordance with community standards or to return used IP 
to the site for destruction. If study participants return used IP to the study site, 
IDS will ensure destruction of used IP in accordance with established institutional 
policies.  
 
IP will be dispensed only to study subjects who have met all the required 
eligibility criteria and are enrolled in the study. Participants will take their first and 
last dose of IP in the clinic. Participants are expected to take their study 
medication in the clinic at Day 0, Week 6, Week 14, and Week 24. All other study 
medication may be taken at home. 
 
 
6. Study procedures 
 
 
Table 6.1-1 Schedule of Assessments 

 
13 
 
Procedure 
Baseline/Day 
0 Visit 
Week 6 
Visit 
Week 
14 Visit 
Week 
24 Visit 
Post 
Treatment 4 
Week Follow 
Up 
(Telephone) 
Post 
Treatment 
15 Week 
Follow Up 
(Telephone) 
Visit Window 
 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 days 
+2 weeks 
Informed Consent 
x 
 
 
 
 
 
Eligibility Review 
x 
 
 
 
 
 
Patient Self-
Assessments 
 
 
 
 
 
 
MDHAQ 
x 
x 
x 
x 
 
 
Patient Global 
Assessment 
x 
x 
x 
x 
 
 
FACIT-F 
x 
x 
x 
x 
 
 
SF-12 
x 
x 
x 
x 
 
 
Physician 
Assessments 
 
 
 
 
 
 
Physician Global 
Assessment 
x 
x 
x 
x 
 
 
Symptom Targeted 
Physical Exam 
x 
x 
x 
x 
 
 
Complete Physical 
Exam 
x 
 
 
 
 
 
Joint Exam 
x 
x 
x 
x 
 
 
Study Procedures 
 
 
 
 
 
 
Biomarker Blood 
Draw  
x 
x 
x 
x 
 
 
Laboratory Tests: 
CBC, CMP, ESR, CRP, 
Immunoglobulins A, 
G, M 
x 
x 
x 
x 
 
 
Vital Signs 
x 
x 
x 
x 
 
 
Height 
x 
 
 
 
 
 
Ultrasound Exam 
x 
 
x 
x 
 
 
Adverse Event 
Review 
x 
x 
x 
x 
x 
x 
Medication Review 
x 
x 
x 
x 
x 
 
Investigational 
Product Dispensation 
x 
x 
x 
 
 
 
In clinic IP 
administration 
x 
x 
x 
X (Last 
Study 
Dose) 
 
 
Urine Pregnancy Test 
(WOCBP only) 
x 
 
 
 
 
 
 

 
14 
 
 
 
Baseline visit (Day 0) 
 
The following procedures and assessments are to be completed during the 
baseline visit. 
 
• Informed consent 
• Review patient eligibility and ensure that all inclusion and exclusion criteria 
are met 
• Patient self-assessment measures: MDHAQ, patient’s global assessment, 
FACIT-F, SF-12  
• Blood samples for laboratory tests: Complete Blood Count (CBC), 
Comprehensive Metabolic Panel (CMP), Erythrocyte Sedimentation Rate 
(ESR), C Reactive Protein (CRP), IgG, IgM and IgA rheumatoid factor, IgG 
and IgA anti-CCP, Immunoglobulins G, M, A 
• Biomarker blood draw (serum, PBMC) 
• Joint exam 
• Complete physical exam 
• Vitals signs: blood pressure, pulse, temperature, weight, height 
• Physician’s global assessment  
• Physician safety assessment 
• Ultrasound exam 
• Adverse event review 
• Medication review 
• For women of childbearing potential, a urine pregnancy test should be 
completed prior to dispensing study medication 
• Study drug (abatacept) dispensation and in clinic injection 
 
Treatment visit (Weeks 6, 14, 24)  
 
Patients must return to the clinic for assessments at weeks 6, 14 and 24. The 
following procedures and assessments are to be completed during the treatment 
visits. 
 
• Patient self-assessment measures: MDHAQ, PGA, FACIT-F, SF-12 
• Blood samples for laboratory tests: Complete Blood Count (CBC), 
Comprehensive Metabolic Panel (CMP), Erythrocyte Sedimentation Rate 
(ESR), C Reactive Protein (CRP), IgG, IgM and IgA rheumatoid factor, IgG 
and IgA anti-CCP, Immunoglobulins G, M, A 
• Biomarker blood draw (serum, PBMC) 
• Joint exam 

 
15 
 
• Symptom targeted physical exam 
• Vital signs including blood pressure, pulse, temperature, and weight 
• Physician’s global assessment  
• Physician safety assessment 
• Ultrasound exam (weeks 14 and 24) 
• Adverse event review 
• Medication review 
• Study drug (abatacept) dispensation and in clinic injection 
 
Follow-up telephone contact (4 & 15 weeks after the final treatment visit) 
 
Patients receive a follow-up phone call from study personnel 4 weeks and 15 
weeks after the week 24 visit. Patients who discontinue from the study early will 
have telephone visits at 4 weeks and 15 weeks after their end of treatment visit, if 
continued follow up is acceptable. The following procedures and assessments 
are to be completed at the follow-up telephone contact. 
 
• Follow-up on transition to standard of care (PT Week 4 only) 
• Follow-up on any adverse events  
 
 
7. Safety and Reporting 
 
7.1. 
Adverse events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation participant 
administered study drug and that does not necessarily have a causal relationship 
with this treatment.  
The causal relationship to study drug will be determined by a physician and will 
be used to assess all AE’s. the causal relationship will be one of the following: 
o Related: There is a reasonable causal relationship between study 
drug administration and the AE. 
o Not Related: there is not a reasonable causal relationship between 
study drug administration and the AE.  
All AE’s will be documented from the point the informed consent is signed 
through 100 days post treatment.  
7.2. 
Serious Adverse Events and Reportable Medical Events 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• Results in death 

 
16 
 
• 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 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or 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 
judgement, may jeopardize the subject or may require intervention 
[eg, medical, surgical] to prevent one of the other serious outcomes 
listed in the definition above.)  
• Suspected transmission of an infectious agent via the study drug is 
an SAE 
Following the subject’s written consent to participate in the study and through 
100 days post study treatment, all SAE’s, whether or not related to the IP or 
study procedures must be collected. All SAE’s will be reported to BMS within 24 
hours of the study site becoming aware of the event. All SAE’s will be reported by 
fax transmission or reported via email.  
SAE Email Address: Worldwide.Safety@bms.com 
SAE Fax Number: +1-609-818-3804 
7.3. 
Pregnancy  
If it is discovered a patient is pregnancy or may have been pregnant at the time 
of exposure to IP associated with this study, the pregnancy, AE’s associated with 
maternal exposure and pregnancy will be reported to BMS within 24 hours of the 
site becoming aware. Every effort should be made to obtain follow up and 
pregnancy outcomes date for one year following the birth of the offspring.  
Any pregnancy that occurs in a female partner of a male study participant should 
be reported to BMS within 24 hours of the study site becoming aware.  
Study participants who become pregnant during the study will have study 
treatment discontinued. The treating physician or study investigator will council 
the study participant on potential risks and treatment options available.  
Pregnancy Email Address: Worldwide.Safety@bms.com 
Pregnancy Fax Number: +1-609-818-3804 
 

 
17 
 
8. Statistical Analysis 
 
8.1. 
Study end points 
 
8.1.1. Primary end point 
 
• Baseline levels of T cell-associated biomarkers or other biomarkers predict 
ACR20 response with subcutaneous abatacept at week 14 [Time Frame: 14 
weeks] 
 
8.1.2. Secondary end points 
 
• Baseline levels of T cell-associated biomarkers or other biomarkers predict 
ACR20 response predict ACR20 response with subcutaneous abatacept at 
week 24 [Time Frame: 24 weeks] 
• Baseline levels of T cell-associated biomarkers or other biomarkers  predict 
ACR50/70 response, EULAR good or moderate response, low disease 
activity (DAS28 <3.2 or CDAI≤10) or remission (DAS28 < 2.6 or CDAI≤2.8) 
with subcutaneous abatacept at week 14 and 24 [Time Frame: 14 and 24 
weeks] 
• Change from baseline in T cell-associated biomarkers or other biomarkers 
with subcutaneous abatacept at week 14 and 24 [Time Frame: 14 and 24 
weeks] 
• Adverse event monitoring 
 
8.2. 
Statistical and analytical methods 
 
The primary endpoint will be the AUC of the receiver operator characteristic 
(ROC) curves for the biomarkers predicting AC20 response at week 14. We 
assume that 60% of the patients will respond to abatacept therapy based on the 
data from the AMPLE trial (31). Thus, a total sample size of 25 patients will yield 
approximately 15 responders and 10 non-responders. With this sample, the 
expected margin of error for 95% confidence intervals for the AUC will be 19% or 
22% if the AUC is 0.8, or 0.7, respectively (32). This is a pilot study and the 
results from this study would be assessed in other cohorts with bigger subject 
numbers.  
 
For each candidate biomarker, we will compute receiver operating characteristic 
(ROC) curves related to response rate to abatacept therapy.  We will consider a 
patient to have responded positively to abatacept if they achieve ACR 20 
response at week 14. 
 

 
18 
 
The area under the ROC curve (AUC) will be the primary measure of the 
predictive value of the biomarker. Estimates of the AUC’s and 95% confidence 
intervals will be computed for each biomarker.  We will also evaluate the 
predictive value of combinations of any or all baseline biomarker information 
used in linear risk scores derived using logistic regression models (outcome = 
response to abatacept therapy).  We will evaluate each possible risk-score 
combination of biomarkers as a predictor by estimating the prediction error using 
leave-one-out cross-validation (at the 80% specificity cutoff).  Similar analyses 
will be run evaluating the predictive power of the secondary-objective baseline 
patient characteristics 
 
 
9. Reference List 
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