Clinical trial NCT01921218
Conditions: Failing Renal Allograft
Keywords: Kidney transplant
Sponsor: Andrew B Adams
Start date: 2013-08-01; Completion date: 2019-12-12
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the safety and effectiveness of belatacept (Nulojix®) in preventing antibody formation in patients with chronic failing kidney transplants. This study is a randomized study of first-time kidney transplant patients who have worsening kidney function and biopsy proven grade 2 or 3 interstitial fibrosis/tubular atrophy (IF/TA). Patients must be eligible to get a second transplant. They must have completed or be actively undergoing evaluation for re-listing for a second transplant. Patients will be randomized to either convert to belatacept or continue on calcineurin inhibitor-based therapy.

Detailed description:
The purpose of this study is to test the safety and effectiveness of the medicine belatacept (Nulojix®) in preventing antibodies from forming in people with a failing kidney transplant. Kidney transplant patients take immunosuppression medicines to prevent kidney rejection. When a kidney transplant begins to fail, the immunosuppression medicines are slowly weaned. Once dialysis is started, the immunosuppressant medicines are usually stopped. After immunosuppression is stopped, some people form antibodies. Antibodies are proteins that the immune system makes to protect against harmful foreign substances like bacteria, viruses, or foreign tissues, like a transplant. High levels of antibodies can make it harder to find a kidney donor for that person.

Participants will be randomized into one of the two treatment groups. One group will continue taking their current immunosuppression medicines. The people in the treatment group will be switched to belatacept (Nulojix®). Belatacept (Nulojix®) is an immunosuppression medicine that is approved by the U.S. Food and Drug Administration (the FDA) to prevent rejection in kidney transplant. Participants will stop taking calcineurin inhibitors (either cyclosporine or tacrolimus) or sirolimus but will keep taking other immunosuppression medicines like Cellcept (MMF) or azathioprine (Imuran) and prednisone. These medicines will be slowly weaned and will be stopped if the participant has to start dialysis. Participants will continue taking belatacept (Nulojix®), even while on dialysis.

The study team will test both groups to see how many people in each group develop antibodies.

Arms: arm 1: Belatacept (Nulojix) IV arm 2: Calcineurin inhibitor based therapy (cyclosporine or tacrolimus)
Interventions: intervention 1: Belatacept intervention 2: Calcineurin inhibitor therapy intervention 3: Mycophenolate mofetil intervention 4: prednisone
Intervention descriptions: intervention 1: Belatacept, dosing 10mg/kg- day 0, 2 weeks, 1 month, 2 months, 3 months; subsequent doses 5mg/kg monthly through duration of trial or until retransplantation, whichever is first. intervention 2: Upon enrollment, wean calcineurin inhibitor (CNI) to target tacrolimus trough of 3-5 nanogram/milliliter (ng/ml)or equivalent cyclosporine trough. Upon initiation of hemodialysis, discontinue CNI therapy over 5 days. intervention 3: Continue current dose at enrollment. Upon initiation of dialysis, decrease dose by half, then discontinue 2 weeks later intervention 4: Begin steroid withdrawal one month after initiation of dialysis, with monthly reduction in dose by half, with plans to discontinue prednisone by 3 months after initiation of dialysis

Protocol documents:
Prot_SAP_000.pdf: 
 
Belatacept IM 103-133 Version 10.0 Date: 02Aug2020 
 
1 
 
Belatacept Therapy for the Failing Renal Allograft 
 
 
 
[BMS PROTOCOL NUMBER: IM103-133] 
 
 
Idelberto R. Badell MD  
Assistant Professor, Department of Surgery 
Emory Transplant Center 
   
 
 
[Protocol Version/Date: Version 10.0., last modified 02Aug2020] 
 
NCT Number: NCT01921218 
 
 
 


 
Belatacept IM 103-133 Version 10.0 Date: 02Aug2020 
 
2 
TABLE OF CONTENTS 
TITLE PAGE ................................................................................................. I 
TABLE OF CONTENTS ............................................................................. II 
PROTOCOL SYNOPSIS .............................................................................. 6 
1 
INTRODUCTION ....................................................................... 11 
1.1 
Research Hypothesis ................................................................... 11 
1.2 
Summary of Results of Investigational Program ..................... 11 
1.2.1 
Pharmacology of Belatacept ........................................................................11 
1.2.2 
Preclinical Toxicology of Belatacept ...........................................................12 
1.2.3 
Other Toxicity Studies ..................................................................................13 
1.2.3.1 
Immunogenicity ............................................................................................13 
1.2.4 
Human Pharmacokinetics of Belatacept ....................................................14 
1.2.5 
Clinical Safety with Belatacept ....................................................................16 
1.2.5.1 
Healthy Subjects ...........................................................................................16 
1.2.5.2 
Post Transplant .............................................................................................16 
1.2.5.3 
Rheumatoid Arthritis ...................................................................................31 
1.2.6 
Clinical Efficacy of Belatacept .....................................................................31 
1.2.6.1 
Acute Rejection .............................................................................................31 
1.2.6.2 
Chronic Allograft Nephropathy ..................................................................33 
1.2.6.3 
Subject and Graft Survival ..........................................................................34 
1.2.6.4 
Renal Function ..............................................................................................35 
1.2.6.5 
IM103100 Long Term Extension .................................................................35 
1.3 
Overall Risk/Benefit Assessment ............................................... 36 
1.3.1 
Potential Benefits ..........................................................................................36 
1.3.2 
Potential Risks ...............................................................................................37 
1.3.3 
Summary of Risk/Benefit Assessment ........................................................39 
1.4 
Study Rationale ........................................................................... 40 
 


 
Belatacept IM 103-133 Version 10.0 Date: 02Aug2020 
 
3 
2 
STUDY OBJECTIVES ............................................................... 41 
2.1 
Primary Objective ....................................................................... 41 
2.2 
Secondary Objectives .................................................................. 41 
 
3 
ETHICAL CONSIDERATIONS ............................................... 42 
3.1 
Good Clinical Practice ................................................................ 42 
3.2 
Institutional Review Board/Independent Ethics 
Committee .................................................................................... 42 
3.3 
Informed Consent........................................................................ 43 
 
4 
INVESTIGATIONAL PLAN..................................................... 43 
4.1 
Study Design and Duration ........................................................ 43 
4.2 
Study Population ......................................................................... 45 
4.2.1 
Inclusion Criteria ..........................................................................................45 
4.2.2 
Exclusion Criteria .........................................................................................46 
4.2.3 
Discontinuation of Subjects from Treatment .............................................47 
4.3 
Data Safety Monitoring Plan ..................................................... 48 
 
5 
TREATMENTS ........................................................................... 48 
5.1 
Study Treatment: Belatacept ..................................................... 48 
5.1.1 
Identification, Packaging and Labeling ......................................................49 
5.1.2 
Storage, and Handling ..................................................................................49 
5.1.3 
Preparation ....................................................................................................49 
5.2 
Drug Ordering and Accountability ........................................... 49 
5.2.1 
Initial Orders .................................................................................................49 
5.2.2 
Re-Supply ......................................................................................................49 
5.3 
Method of Assigning Subjects to a Treatment ......................... 50 
5.4 
Selection and Timing of Dose for Each Subject ....................... 50 
5.4.1 
Dose Modifications ........................................................................................51 


 
Belatacept IM 103-133 Version 10.0 Date: 02Aug2020 
 
4 
5.5 
Blinding/Unblinding .................................................................... 52 
5.6 
Concomitant Treatments ............................................................ 52 
5.6.1 
Prohibited and/or Restricted Treatments ..................................................52 
5.6.2 
Other Restrictions and Precautions ............................................................52 
5.7 
Treatment Compliance ............................................................... 53 
 
6 
STUDY ASSESSMENTS AND PROCEDURES ..................... 53 
6.1 
Time and Events Schedule ......................................................... 53 
6.2 
      Screening  Evaluation…………………………………………60 
6.3 
      Post enrollment/Randomization…………………….………...61 
6.4 
Study Material………………………………………………….62 
6.5 
Safety Assessments ...................................................................... 62 
6.6 
Efficacy Assessments ................................................................... 64 
6.6.1 
Primary Efficacy Assessment ......................................................................64 
6.6.2 
Secondary Efficacy Assessments .................................................................64 
 
7 
ADVERSE EVENT REPORTING ........................................... 65 
7.1 
Adverse Events ............................................................................ 65 
7.1.1 
Serious Adverse Events ................................................................................65 
7.1.2 
Nonserious Adverse Events ..........................................................................66 
7.2 
Assignment of Adverse Event Intensity and Relationship 
to Investigational Product .......................................................... 66 
7.3 
Collection and Reporting ............................................................ 67 
7.3.1 
Serious Adverse Events ................................................................................67 
7.3.2 
Handling of Expedited Safety Reports .......................................................69 
7.3.3 
Nonserious Adverse Events ..........................................................................70 
7.4 
Laboratory Test Abnormalities ................................................. 70 
7.5 
Overdose ....................................................................................... 70 
7.6 
Pregnancy ..................................................................................... 71 


 
Belatacept IM 103-133 Version 10.0 Date: 02Aug2020 
 
5 
7.6.1 
Requirements for Pregnancy Testing .........................................................71 
7.6.2 
Reporting of Pregnancy ...............................................................................71 
7.7 
Other Safety Considerations ...................................................... 72 
7.8               Influenza Guidelines………………………………………………………72                         
 
8 
STATISTICAL CONSIDERATIONS ...................................... 72 
8.1 
Sample Size Determination ........................................................ 72 
8.2 
Endpoint Definitions ................................................................... 73 
8.3 
Analyses ........................................................................................ 73 
8.3.1 
Demographics and Baseline Characteristics ..............................................73 
8.3.2 
Safety Analyses ..............................................................................................73 
8.3.3 
Efficacy Analyses ..........................................................................................74 
 
9 
ADMINISTRATIVE SECTION ................................................ 75 
9.1 
Compliance with the Protocol .................................................... 75 
9.2 
Records Retention ....................................................................... 75 
9.3 
Destruction of Investigational Product ..................................... 76 
 
10 
GLOSSARY OF TERMS ........................................................... 77 
11 
LIST OF ABBREVIATIONS .................................................... 78 
12 
REFERENCES ............................................................................ 80 
APPENDIX 1: DSMB Membership………………………………………………..83 
APPENDIX 2: 
APPENDIX 3: 
 


 
Belatacept IM 103-133 version 10.0  date: 02Aug2020 
 
PROTOCOL SYNOPSIS 
Protocol Title: 
Belatacept Therapy for the Failing Renal Allograft 
Site Numbers & 
Names: 
Protocol IM103-133, Emory University 
Research Hypothesis: 
Belatacept will effectively inhibit sensitization (ie donor-
specific allo-antibody production) in patients with a failing or 
failed renal allograft and as a result will facilitate re-
transplantation.  In addition treatment with belatacept will 
more favorably impact residual allograft function (ie 
preservation of GFR) in patients with IF/TA as compared to 
treatment with conventional immunosuppression thereby 
prolonging time to dialysis or need for re-transplant.  


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Belatacept IM 103-133 Version10.0 02Aug2020 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
-Standard of care arm- 
Upon enrollment into the study- wean tacrolimus, or sirolimus 
dose to target level of 3-5 (or equivalent CNI or mTOR 
inhibitor level), and if applicable continue mycophenolate 
mofetil (MMF) or mycophenolic acid (MPA) (equivalent of at 
least 1g daily) or azathioprine, and/or prednisone (at least 5 
mg daily) 
 
Upon initiation of dialysis or in subjects already requiring 
dialysis at time of enrollment- discontinue CNI or mTOR 
inhibitor over 5 days, if applicable MMF/MPA  or 
azathioprine dose decreased by half then discontinued 2 
weeks later, steroid withdrawal beginning 1 month after the 
initiation of dialysis with monthly reduction by half with 
plans to discontinue at 3 months after initiation of dialysis.    
  
-Belatacept arm- 
 
Upon enrollment into the study- initiate Belatacept, dosing 
10mg/kg- day 0, 2 weeks, 4 weeks, 8 weeks, and 12 
weeks; subsequent doses 5mg/kg qmonth through duration of 
trial or until re-transplantation, whichever is first. Dose of 
CNI or mTOR inhibitor will be reduced by 50% at time of 
first dose of belatacept. CNI or mTOR inhibitor will be 
discontinued at week 2 dose of belatacept. If applicable 
continue MMF or MPA (equivalent of at least 1g daily) or 
azathioprine, and/or prednisone 
 
Upon initiation of dialysis or in subjects already requiring 
dialysis at time of enrollment - wean 
remaining immunosuppression as above in standard of care 
arm except for belatacept which they will remain on for the 
duration of the study or until re-transplant.  
Study Objectives: 
• Primary: 
• Secondary: 
Primary:  To prevent the formation of donor-specific 
alloantibody in patients with chronic allograft injury (grade II 
or III IF/TA), thereby facilitating re-transplantation by 
avoiding sensitization 
Secondary:  To determine if treatment with belatacept better 
preserves GFR in those patients with marginal renal function 
as compared to those patients who continue calcineurin 
inhibitor therapy or mTOR inhibitor therapy and as a result 
delays time to initiation of dialysis. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Study Design: 
Open-label, prospective, randomized, controlled trial 
Accrual Goal: 
(Total number of subjects) 
72 patients, randomized 1:1 to either treatment arm-
Belatacept or control arm- (remaining on CNI or mTOR 
inhibitor as detailed above). 
This study will be performed in two phases: Phase I a total of 
36 patients will be enrolled (18 in each arm). Phase II will 
contingent on preliminary safety review and study progress 
from phase I and funding availability and will enroll an equal 
number of patients (36)  
Accrual Rate: 
(Number of subjects 
expected per month) 
36 patients enrolled over 24 months (Phase I) 
36 patients enrolled over 24 months (Phase II) 
FPFV: 
LPFV: 
Follow Up: 
(dd-mm-yy) 
Phase I  
 
Start: August 1, 2013 
 
FPFV: November 1, 2013 
 
LPLV: November 1, 2018 
 
Enrollment period: November 1, 2013 – November 1, 2015 
 
Follow-up: 36 months 
 
  Phase II: timing TBD 
Correlative Studies: 
(PK/PD, etc.) 
Scheduled sample collection for measurement of  allo-
antibody using HLA-specific microparticles; serum chemistry 
including calculated GFR (creatinine measurement); complete 
blood count, viral titer monitoring 
Inclusion Criteria: 
Adult recipients (age > 18yrs currently) of either living donor 
or deceased donor, non-HLA identical renal transplants who 
have a GFR< 35 ml/min with a decline in GFR of > 10% in 
the 12 months prior to enrollment with biopsy proven grade 2 
or 3 IF/TA, OR eGFR <20 ml/min over the 6 month period 
prior to enrollment absent other causes for graft dysfunction, 
and deemed to have a failing allograft by the patient’s 
transplant nephrologist, and who are being treated with a 
calcineurin-inhibitor or mTOR inhibitor, with or without 
MMF/MPA or azathioprine and/or prednisone as maintenance 
immunosuppression.  Patients must be > 1 year post-
transplant and a re-transplant candidate. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Exclusion Criteria: 
EBV(-) patients or history of PTLD 
Presence of donor-specific antibody at the time of enrollment 
Age>70 years 
Extra-renal organ transplant 
Biopsy proven acute rejection > Banff grade Ia within the last 
year prior to enrollment 
Positive BK serum PCR > 20,000 copies at the time of 
enrollment OR history of biopsy proven BK nephropathy 
within the last year prior to enrollment 
Patients who have a living donor identified and approved for 
transplant within 3 months 
Patients currently receiving belatacept as part of maintenance 
immunosuppression 
Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
A Data Monitoring Committee (DMC) will monitor emerging 
efficacy and overall safety data regularly to ensure that the 
benefits and risks of study participation remain acceptable.  
During its regular reviews, the DMC will also assess the rate 
progression to dialysis, development of allo-antibody, and 
serious adverse events (SAEs), including serious infections 
and malignancies.  Based on the regular reviews of emerging 
data, the DMC may recommend to the sponsor alteration 
and/or termination of the trial or cessation of further 
enrollment into a treatment group. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Statistics: 
There will be two main methods of analyzing the primary 
outcome at the end of the study.  One will be a chi-squared 
test comparing the proportion of patients who developed 
donor-specific antibody in each study group.  The second 
analysis will be a log-rank test comparing the survival curves 
(survival being defined as the time until development of donor 
specific antibody) between the two study groups.   A separate 
set of similar analyses will evaluate both the need and time to 
initiating dialysis. Subjects requiring dialysis at the time of 
enrollment will be excluded from this analysis. In both 
calculations there are similar assumptions made; we will use a 
two-sided test with a significance level of 0.05 and the sample 
size for each arm will be 30 patients. Other measures that will 
be evaluated with standard statistical methods include the 
change in PRA, the level of allo-antibody intensity, GFR and 
change in GFR. 
 
 


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Belatacept IM 103-133 Version10.0 02Aug2020 
1 
INTRODUCTION 
1.1 
Research Hypothesis 
Treatment with belatacept will effectively inhibit sensitization (ie donor-specific antibody 
production) in patients with a failing or failed renal allograft and as a result will facilitate 
re-transplantation.  In addition treatment with belatacept will more favorably impact 
residual allograft function (ie preservation of GFR) in patients with IF/TA as compared to 
treatment with conventional immunosuppression thereby prolonging time to dialysis or 
need for re-transplant. 
1.2 
Summary of Results of Investigational Program 
Belatacept represents a new class of immunosuppressive therapy. As a soluble chimeric 
protein, belatacept was designed to selectively inhibit the co-stimulation of T-cells by 
targeting the blockade of key co-stimulatory signals required for T-cell activation. 
Belatacept was derived from the novel fusion protein CTLA4Ig (abatacept, 
BMS-188667) and differs from its parent molecule at 2 point mutations. Comprised of a 
modified extracellular domain of human CTLA4 fused to a fragment of the Fc domain of 
a human immunoglobulin (Ig) G1 antibody, belatacept contains 2 amino acid 
modifications. Like its predecessor, belatacept differs from existing immunosuppressants 
in the selective distribution of its molecular target and the specificity of its effect. 
Additionally, it has demonstrated a higher avidity for the blockade of specific humoral 
responses.  
1.2.1  
Pharmacology of Belatacept 
T-cell activation requires 2 signals: T-cell receptor antigen binding and a subsequent 
co-stimulatory signal. The first signal, which is antigen specific, is delivered by 
engagement of the T-cell receptor with antigen presented in context with major 
histocompatibility complex molecules on the antigen presenting cell (APC). The second, 
or co-stimulatory signal, is delivered by engagement of a co-stimulatory ligand on the 
APC with a receptor on the T-cell. A key co-stimulatory signal is provided by the 
interaction of B7-1 (CD80) and B7-2 (CD86) on APCs with CD28 expressed on T-cells. 
In the absence of this second signal, the T-cell becomes anergic (unresponsive) or 
undergoes apoptosis. Engagement of this second signal allows for full T-cell activation 


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Belatacept IM 103-133 Version10.0 02Aug2020 
and initiation of the inflammatory cascade. When the T-cell becomes fully activated, 
CTLA4 (CD152) becomes expressed on the cell surface. CTLA4 has a substantially 
higher avidity (approximately 500- to 2,500-fold) than CD28 for CD80 and CD86. 
CD28/CTLA4 engagement blocks further activation of T-cells. The increased avidity of 
endogenous CTLA4, in comparison with CD28, affords a homeostatic mechanism to 
down-regulate T-cell activity. By binding avidly to CD80/86, the fusion protein 
CTLA4Ig (abatacept) blocks the interaction of the T-cell’s CD28 with the APC’s 
CD80/CD86, thus preventing T-cells from receiving the required second co-stimulatory 
signal. Belatacept has the same mechanism of action, but demonstrates a higher avidity 
for the CD86. 
Belatacept’s parent molecule, CTLA4Ig (abatacept), has been shown to be effective in a 
wide variety of preclinical models and in subjects with psoriasis and rheumatoid arthritis 
(RA). With respect to transplantation, CTLA4Ig (abatacept) demonstrated efficacy in 
rodent models of transplantation, but did not demonstrate substantial efficacy in a 
non-human primate renal transplant model (cynomolgus monkey). Therefore, belatacept, 
a 2 amino acid variant of CTLA4Ig, was developed. This alteration resulted in markedly 
increased binding avidity for B7 molecules, in particular B7-2 (CD86). Belatacept was 
subsequently shown to prevent allograft rejection in a non human primate renal transplant 
model in which CTLA4Ig was not effective (see Investigator Brochure for additional 
details). 
1.2.2  
Preclinical Toxicology of Belatacept 
In a single-dose IV toxicity study, cynomolgus monkeys were treated with 0 (control), 9, 
30, or 90 mg/kg of belatacept.1 No drug-related toxicity was observed in monkeys given 
belatacept at doses of up to 90 mg/kg. At doses of 9 and 30 mg/kg, antibodies to 
belatacept developed 5 and 6 weeks after drug administration, respectively. In the 
presence of these antibodies, the rate of drug elimination from serum was increased. 
In repeat-dose toxicity studies2,3 conducted in cynologus monkeys, IV belatacept was 
well tolerated at doses up to 50 mg/kg every other day for 1 month (15 doses), and once 
weekly for 6 months (26 doses). Major nonclinical findings were reversible, related to the 
pharmacology of the drug, and consisted of minimal decreases in serum IgG levels. 
Minimal to moderate lymphoid depletion of germinal centers in the spleen and/or lymph 
nodes at all dose levels was noted. Functional activity of the immune system was 
demonstrated at all doses by a robust antibody response to the immunogenic KLH 


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Belatacept IM 103-133 Version10.0 02Aug2020 
following immunization after an 8-week dose-free recovery-period. Immunogenicity 
when observed followed the treatment period. 
Although belatacept has demonstrated an increase in binding affinity in human and 
non-human primates for CD80 and CD86, the binding affinity for murine CD80 and 
CD86 is lower with belatacept as compared to abatacept.4 In studies evaluating the 
in vivo activity of belatacept in various species, belatacept was found to be either 
as active as, or less active than, abatacept in rodents and rabbits. Thus, belatacept’s 
increase in bioactivity seen in monkeys and humans do not directly translate to other 
species. As a result, the nonclinical safety assessment for belatacept was conducted in the 
cynomolgous monkey. To support this data, abatacept nonclinical safety assessments, 
including 6-month rodent toxicity, genetic toxicity, carcinogenicity, and reproductive 
toxicity studies were provided (see Investigator’s Brochure for further details). 
Currently, a complete battery of reproductive and developmental toxicity studies with 
belatacept is being conducted in rats and rabbits. Early results show that there were no 
effects of belatacept on reproductive function in either male or female rats, and no effect 
on early embryonic development at doses up to 200 mg/kg/day (human exposure multiple 
of 38-fold.5 Please refer to the Investigator’s Brochure for the most current information. 
1.2.3  
Other Toxicity Studies 
1.2.3.1 
Immunogenicity 
Belatacept, a human protein, is immunogenic in mice, rats, rabbits, and monkeys based 
on the ability of each species to induce belatacept-specific antibodies.1,2,3,6,7,8,9,10,11,12,13 
However, as expected, belatacept-specific antibodies were generally detected only during 
the recovery period, suggesting that belatacept-specific antibodies were not formed until 
after belatacept serum levels had dropped below immunosuppressive levels. Thus, in 
each species tested, belatacept suppressed the antibody response against itself. Once 
belatacept specific antibodies were present, clearance of drug from the blood vascular 
compartment was often accelerated. However, exposure was maintained during the 
treatment period of each pivotal study. The appearance of belatacept-specific antibodies 
was not associated with any acute or target-organ toxicity. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
1.2.4 Human Pharmacokinetics of Belatacept 
In a Phase 1 study14 assessing the pharmacokinetic (PK) of escalating single IV doses of 
belatacept in healthy volunteers, the Cmax appeared to increase proportionally to dose, 
and AUC(INF) appeared to increase in a more than dose-proportional manner. The 
observed T-HALF ranged between 86-222 hours at the dose levels tested. Following a 
single IV infusion of 1-20 mg/kg, CLT values ranged from 0.45-0.49 mL/h/kg. The VSS 
values were small, indicating that the drug (with high molecular weight) was confined 
mainly in the blood and in the extracellular space. Both CLT and VSS appeared to be 
dose independent between the 1 and 20 mg/kg dose levels. The PK of belatacept appears 
to be linear following IV administration in healthy subjects at dose levels of 1-20 mg/kg. 
The mean PK parameters in healthy patients are summarized in the table below. 
 
Table 1.2.4A: 
Summary of Belatacept Pharmacokinetic Parameters in 
Healthy Subjects (6/group) (Study IM103001) 
 
Pharmacokinetic Results 
Treatment 
Cmaxa 
µg/mL 
(% CV) 
Tmaxb 
h 
(Min, Max) 
AUC(INF)a  
µg.h/mL 
(% CV) 
T-HALFa 
h 
(SD) 
CLTc 
mL/h/kg 
(SD) 
VSSc 
mL/kg 
(SD) 
0.1 mg/kg 
i.v. infusion 
2.32 
(13.6) 
1.0 
(1.0, 1.0) 
143 
(14.4) 
86.4 
(14.7) 
0.71 
(0.12) 
80.2 
(14.8) 
1 mg/kg 
i.v. infusion 
28.2 
(20.2) 
1.0 
(1.0, 2.0) 
2232 
(16.0) 
137 
(24.3) 
0.45 
(0.07) 
79.6 
(19.1) 
5 mg/kg 
i.v. infusion 
126 
(14.9) 
1.0 
(1.0, 1.0) 
10341 
(21.8) 
176 
(25.8) 
0.49 
(0.11) 
102.0 
(15.4) 
10 mg/kg 
i.v. infusion 
260 
(9.9) 
1.0 
(1.0, 1.0) 
22049 
(15.1) 
197 
(36.6) 
0.46 
(0.07) 
98.8 
(10.1) 
20 mg/kg 
i.v. infusion 
466 
(10.3) 
1.5 
(1.0, 2.0) 
41380 
(4.1) 
222 
(37.1) 
0.49 
(0.02) 
117 
(12.6) 
a  Geometric mean. 
b  Median. 
c  Arithmetic mean. 
AUC(INF) = area under the concentration-time curve from time zero extrapolated to infinity, CLT = total 
body clearance, Cmax = maximum plasma concentration, i.v. = intravenous, T-HALF= half-life, 
Tmax = time of maximum observed concentration, and VSS = steady-state volume of distribution. 
 


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Belatacept IM 103-133 Version10.0 02Aug2020 
In a Phase 1 study15 assessing the single subcutaneous doses of belatacept in healthy 
volunteers, belatacept was dose dependent. From 50 to 100 mg, the Cmax increased 
slightly greater than the dose increment, whereas the AUC(INF) increased in a 
dose-related manner. From 100 to 150 mg, both Cmax and AUC increased in a 
proportion greater than the dose increment. 
The Cmax and AUC(0-6h) values of belatacept following IV infusion to renal transplant 
subjects were dose proportional at 5 and 10 mg/kg. Accumulation index values < 1.5 
indicated minimal belatacept accumulation after multiple dosing at the dosing intervals of 
2-8 weeks. The steady state was reached after approximately 3 doses for every 4-week 
dosing or after 1-2 doses for every 8-week dosing. The steady-state Cmin levels at 5 
mg/kg were 2-4 μg/mL for every 4-week dosing and 0.2-0.4 μg/mL for every 8-week 
dosing. 
During the long term extension phase (LTE), belatacept exposure [area under the 
concentration-time curve in 1 dosing interval, AUC(TAU)] for subjects on the 4-week 
schedule was slightly higher (1.3-fold) than those [AUC(0-T)] on the 8-week schedule, 
indicating minimal accumulation upon 4-week multiple dosing. The mean steady-state 
VSS was 0.12 L/kg, indicating that this high molecular weight drug was confined mainly 
in the blood in the extracellular space. Mean T-HALF of belatacept in renal transplant 
subjects was 197 hours (~8 days). Belatacept geometric mean steady-state Cmin for 
subjects on the 4-week schedule was 5.7 μg/mL. In contrast, geometric mean belatacept 
trough level for subjects on the 8-week schedule was 0.25 μg/mL. Overall, belatacept PK 
in renal transplant recipients was comparable to that in healthy subjects. 
In a multiple-dose Phase 2 study,16 the PK profile was evaluated in subjects with RA. 
Both Cmax and AUC(TAU) values appeared to increase in ratio comparable to the dose 
increment ratio after first and last dose administration. Accumulation of belatacept was 
found to be minimal in the applied dosing schedule. The mean PK parameters are 
summarized in the table below. 
 
 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Table 1.2.4B: 
Summary of Belatacept Pharmacokinetic Parameters in 
Subjects with Rheumatoid Arthritis (3/group) 
(Study IM103002) 
 
Pharmacokinetic Results 
 
First Dose (Day 1) 
Last Dose (Day 57) 
Treatment 
Cmaxa 
µg/mL 
(% CV) 
AUC(TAU)a 
µg.h/mL 
(% CV) 
T-HALFb 
h 
(SD) 
Cmaxa 
µg/mL 
(% CV) 
AUC(TAU)a 
µg.h/mL 
(% CV) 
T1/2b 
h 
(SD) 
0.5 mg/kg 
i.v. infusion 
10.4 
(9) 
683c 
(ND) 
51.5 
(37.1) 
11.2 
(6) 
816d 
(NR) 
64.3 
(38.8) 
2 mg/kg 
i.v. infusion 
39.3 
(17) 
4021 
(49) 
105.8d 
(NR) 
42.6d 
(NR) 
5114d 
(NR) 
178.8d 
(NR) 
10 mg/kg 
i.v. infusion 
305.8 
(NR) 
16379 
(NR) 
87.7 
(NR) 
268.4c 
(ND) 
13972c 
(ND) 
285.3c 
(ND) 
 
1.2.5  
Clinical Safety with Belatacept 
1.2.5.1 
Healthy Subjects 
No deaths or discontinuations due to AE’s were reported in healthy subjects treated with 
belatacept.14,15,17 Medical events including skin infection (n=1) and pharyngitis (n=1) 
was reported in subjects treated with 50 and 75 mg of belatacept, respectively. Common 
AEs included headache and nasopharyngitis. 
1.2.5.2 
Post Transplant 
Study IM103100 
In a Phase 2 Study (IM103100) 18 the safety of belatacept vs. cyclosporine (CsA) was 
assessed as part of a quadruple therapy with mycophenolate mofetil, corticosteroids, and 
basiliximab in de novo renal transplant recipients.  


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Subjects treated with belatacept were randomized to 2 dosing groups: more intensive 
(MI) and less intensive (LI). For the MI regimen, subjects were dosed at 10 mg/kg on 
Days 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, and 169, and then at 5 mg/kg every 4 or 8 
weeks starting on Day 197. For the LI regimen, subjects were dosed at 10 mg/kg on Days 
1, 15, 29, 57, and 85. Staring on Day 113, these subjects received 5 mg/kg belatacept 
every 4 or 8 weeks. PK parameters, such as AUC(0-6h), Cmax, and Cmin, were assessed, 
and the data are presented in Tables 5.2.5.1A, 5.2.5.1B, and 5.2.5.1C. 
Overall, almost all subjects in each treatment group experienced at least 1 AE.18 
 
Table 1.2.5.2A: 
Overall Incidence of Adverse Events During 12 Months 
Post-Transplant (As-Treated Population) - Study IM103100 
 
No. (%) of Subjects 
 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Discontinued Due to Adverse Events 
13 (17.6) 
15 (21.1) 
14 (19.7) 
Related Adverse Events 
43 (58.1) 
40 (56.3) 
50 (70.4) 
Serious Adverse Events 
50 (67.6) 
52 (73.2) 
42 (59.2) 
Related Serious Adverse Events 
21 (28.4) 
23 (32.4) 
21 (29.6) 
CsA = cyclosporine, LI = less intensive, and MI = more intensive. 
 
The most frequently reported AEs among patients who recieved belatacept post renal 
transplant are reported in the table below. Renal transplant rejection was reported more 
commonly with belatacept at high and low dose regimens when compared to CsA. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Table 1.2.5.2B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
During 12 Months Post-Transplant (As-Treated Population) - 
Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Subjects with Any Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Blood & Lymphatic System Disorders 
29 (39.2) 
28 (39.4) 
40 (56.3) 
 
Leukopenia 
14 (18.9) 
12 (16.9) 
21 (29.6) 
 
Anemia 
13 (17.6) 
12 (16.9) 
21 (29.6) 
Cardiac Disorders 
10 (13.5) 
10 (14.1) 
10 (14.1) 
Endocrine Disorders 
4 (5.4) 
8 (11.3) 
9 (12.7) 
Gastrointestinal Disorders 
45 (60.8) 
45 (63.4) 
42 (59.2) 
 
Nausea 
19 (25.7) 
18 (25.4) 
16 (22.5) 
 
Diarrhea 
17 (23.0) 
18 (25.4) 
17 (23.9) 
 
Constipation 
16 (21.6) 
22 (31.0) 
20 (28.2) 
 
Vomiting 
11 (14.9) 
14 (19.7) 
11 (15.5) 
General Disorders & Administration Site  
Conditions 
 
43 (58.1) 
 
40 (56.3) 
 
42 (59.2) 
 
Edema Peripheral 
23 (31.1) 
20 (28.2) 
21 (29.6) 
 
Pyrexia 
15 (20.3) 
19 (26.8) 
15 (21.1) 
 
Pain 
7 (9.5) 
6 (8.5) 
9 (12.7) 
 
Fatigue 
6 (8.1) 
6 (8.5) 
9 (12.7) 
 
Edema 
6 (8.1) 
7 (9.9) 
11 (15.5) 
Immune System Disorders 
22 (28.7) 
29 (40.8) 
16 (22.5) 
 
Transplant Rejection 
19 (25.7) 
23 (32.4) 
11 (15.5) 
Infections & Infestations 
54 (73.0) 
52 (73.2) 
53 (74.6) 
 
Urinary Tract Infection 
17 (23.0) 
17 (23.9) 
22 (31.0) 
 
Cytomegalovirus Infection 
11 (14.9) 
10 (14.1) 
13 (18.3) 
 
Nasopharyngitis 
9 (12.2) 
10 (14.1) 
11 (15.5) 
Injury, Poisoning & Procedural Complications 
44 (59.5) 
45 (63.4) 
45 (63.4) 
 
Incision Site Complication 
17 (23.0) 
16 (22.5) 
13 (18.3) 
 
Post Procedural Pain 
14 (18.9) 
17 (23.9) 
15 (21.1) 
 
Graft Dysfunction 
9 (12.2) 
10 (14.1) 
10 (14.1) 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Table 1.2.5.2B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
During 12 Months Post-Transplant (As-Treated Population) - 
Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Investigations 
26 (35.1) 
22 (31.0) 
29 (40.8) 
 
Blood Creatinine Increased 
13 (17.6) 
10 (14.1) 
13 (18.3) 
Metabolism & Nutrition Disorders 
36 (48.6) 
35 (49.3) 
42 (59.2) 
 
Hypophosphatemia 
14 (18.9) 
24 (33.8) 
15 (21.1) 
 
Hyperlipidemia 
9 (12.2) 
8 (11.3) 
6 (8.5) 
 
Hypercholesterolemia 
6 (8.1) 
4 (5.6) 
9 (12.7) 
 
Hypokalemia 
5 (6.8) 
5 (7.0) 
9 (12.7) 
Musculoskeletal & Connective Tissue Disorders 
26 (35.1) 
20 (28.2) 
20 (28.2) 
 
Arthralgia 
8 (10.8) 
6 (8.5) 
4 (5.6) 
 
Back Pain 
8 (10.8) 
3 (4.2) 
6 (8.5) 
Nervous System Disorders 
26 (35.1) 
20 (28.2) 
26 (36.6) 
 
Headache 
13 (17.6) 
10 (14.1) 
8 (11.3) 
 
Tremor 
8 (10.8) 
10 (14.1) 
14 (19.7) 
Psychiatric Disorders 
18 (24.3) 
27 (38.0) 
20 (28.2) 
 
Insomnia 
12 (16.2) 
19 (26.8) 
17 (23.9) 
Renal & Urinary Disorders 
28 (37.8) 
27 (38.0) 
25 (35.2) 
Reproductive System & Breast Disorders 
7 (9.5) 
12 (16.9) 
7 (9.9) 
Respiratory, Thoracic & Mediastinal Disorders 
23 (31.1) 
24 (33.8) 
29 (40.8) 
 
Cough 
7 (9.5) 
8 (11.3) 
11 (15.5) 
 
Dyspnea 
5 (6.8) 
6 (8.5) 
9 (12.7) 
Skin & Subcutaneous Tissue Disorders 
26 (35.1) 
18 (25.4) 
18 (25.4) 
Vascular Disorders 
27 (36.5) 
29 (40.8) 
29 (40.8) 
 
Hypertension 
16 (21.6) 
17 (23.9) 
22 (31.0) 
CsA = cyclosporine, LI = less intensive, MI = more intensive, and MedDRA = Medical Dictionary of 
Regulatory Activities 
 
 


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SAEs were more frequently reported among belatacept-treated subjects; however, SAEs 
considered to be drug related by the investigators were similarly distributed across all 
3 treatment groups. 
 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Subjects with Any Serious Adverse Events 
50 (67.6) 
52 (73.2) 
42 (59.2) 
Blood & Lymphatic System Disorders 
2 (2.7) 
3 (4.2) 
4 (5.6) 
Gastrointestinal Disorders 
7 (9.5) 
7 (9.9) 
5 (7.0) 
General Disorders & Administration Site  
Conditions 
 
5 (6.8) 
 
8 (11.3) 
 
7 (9.9) 
 
Pyrexia 
4 (5.4) 
8 (11.3) 
6 (8.5) 
Immune System Disorders 
20 (27.0) 
23 (32.4) 
13 (18.3) 
 
Transplant Rejection 
18 (24.3) 
20 (28.2) 
9 (12.7) 
Infections & Infestations 
17 (23.0) 
12 (16.9) 
18 (25.4) 
 
Cytomegalovirus Infection 
5 (6.8) 
4 (5.6) 
7 (9.9) 
 
Pyelonephritis 
4 (5.4) 
1 (1.4) 
2 (2.8) 
 
Urinary Tract Infection 
2 (2.7) 
0 
4 (5.6) 
Injury, Poisoning & Procedural Complications 
8 (10.8) 
6 (8.5) 
9 (12.7) 
Investigations 
8 (10.8) 
2 (2.8) 
4 (5.6) 
 
Blood Creatinine Increased 
8 (10.8) 
2 (2.8) 
4 (5.6) 
Metabolism & Nutrition Disorders 
1 (1.4) 
2 (2.8) 
4 (5.6) 
Renal & Urinary Disorders 
9 (12.2) 
11 (15.5) 
9 (12.7) 
Respiratory, Thoracic & Mediastinal Disorders 
6 (8.1) 
3 (4.2) 
4 (5.6) 
Vascular Disorders 
3 (4.1) 
5 (7.0) 
8 (11.3) 
CsA = cyclosporine, LI = less intensive, MI = more intensive, and MedDRA = Medical Dictionary of Drug 
Regulatory Activities 
 
Approximately 20% of subjects discontinued the study medication as a result of an AE, 
and the reported rates were comparable across all treatment groups. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Table 1.2.5.2C: 
Most Frequent (At Least 2% in Any Group) Adverse Events 
Leading to Discontinuation During 12 Months 
Post-Transplant (As-Treated Population) - Study IM103100 
 
No. (%) of Subjects 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Subjects Who Discontinued Due to Adverse Events 
13 (17.6) 
15 (21.1) 
14 (19.7) 
Immune System Disorders 
10 (13.5) 
11 (15.5) 
7 (9.9) 
 
Transplant Rejection 
9 (12.2) 
9 (12.7) 
3 (4.2) 
 
Kidney Transplant Rejection 
1 (1.4) 
2 (2.8) 
2 (2.8) 
 
Graft Loss 
0 
0 
2 (2.8) 
Injury, Poisoning & Procedural Complications 
0 
0 
4 (5.6) 
Investigations 
0 
0 
2 (2.8) 
 
Blood Creatinine Increased 
0 
0 
2 (2.8) 
Renal & Urinary Disorders 
0 
3 (4.2) 
2 (2.8) 
 
Proteinuria 
0 
2 (2.8) 
0 
CsA = cyclosporine, LI = less intensive, MI = more intensive, and MedDRA = Medical Dictionary of 
Regulatory Activities 
 
One death was reported in the belatacept MI group. No deaths were reported in the 
belatacept LI group.  
Study IM103100 Long Term Extension 
Among the 164 patients who completed the 12-month phase, 128 patients continued in a 
long term extension (LTE) phase of the study; 102 and 26 patients were entered into the 
pooled (MI+LI) belatacept and CsA groups, respectively. As of 12-OCT-07, a LTE safety 
analysis determined that overall rates of AEs, SAEs and discontinuations were similar 
between belatacept and CsA treated subjects. The safety summary of patients entered in 
the LTE phase is summarized in Table 1.2.5.2D below. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Table 1.2.5.2D: 
Summary of Safety in Long-term Extension Phase (Intent-to-
Treat Population)- IM103100 
 
No. (%) of Subjects 
 
Belatacept (MI+ LI) 
(N=102) 
CsA 
(N=26) 
Death 
3 (2.9) 
2 (7.7) 
SAEs 
47 (46.1) 
14 (53.8) 
Related SAEs 
27 (26.5) 
7 (26.9) 
Discontinued due to SAEs 
6 (5.9) 
1 (3.8) 
AEs 
92 (90.2) 
24 (92.3) 
Related AEs 
60 (50.8) 
16 (61.5) 
Discontinued due to AEs 
9 (8.8) 
1 (3.8) 
The most commonly reported AEs (≥ 10% in each arm) reported among the pooled 
belatacept patients (MI + LI) in the LTE were psychiatric disorders (22%), cough (17%), 
pyrexia (16%), bronchitis (14%), reproductive system and breast disorders (22%), cough 
(17%), influenza (12%) and hyperlipidemia (11%).  
The most frequently reported SAEs (≥ 2/5% subjects) among pooled belatacept patients 
included neoplasms and malignancies (12%), infections and infestations (16%), and 
immune disorders (11%). The belatacept group reported congenital, familial and genetic 
disorders (4 subjects, 4%) more frequently than the CsA group. 
During the LTE phase (as of 12-OCT-2007), 9 subjects discontinued belatacept (MI or 
LI). The most frequently reported AE leading to discontinuation among belatacept treated 
subjects was transplant rejection in 2 subjects (2%). 
During the IM103100 LTE, 3 deaths (2 belatacept MI and 1 belatacept LI) were reported 
in the belatcept group. Of these, 2 deaths were considered unrelated to study drug (severe 
cardio-respiratory arrest and cardiac infarction). One death attributed to P. carinii 
pneumonia, was considered possibly related to the study drug. 
Please refer to the most current Investigator’s Brochure for further details. 
Phase III Studies: IM103008 and IM103027 
Two phase III, randomized, controlled studies were performed to assess the efficacy and 
safety of Belatacept in de novo kidney transplant patients.  Study IM103008 (Study 1) 


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Belatacept IM 103-133 Version10.0 02Aug2020 
evaluated its use in recipients receiving standard criteria donor kidneys and study 
IM103027 (Study 2) evaluated its performance in recipients who were transplanted with 
kidneys from extended criteria donors.  Belatacept was studied at the currently 
recommended dose and frequency in a total of 401 patients compared to a cyclosporine 
control regimen in a total of 405 patients. These two trials also included a total of 403 
patients treated with a belatacept regimen of higher cumulative dose and more frequent 
dosing than currently recommended. All patients also received basiliximab induction, 
mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 
years. 
CNS PTLD, PML, and other CNS infections were more frequently observed in 
association with a belatacept regimen of higher cumulative dose and more frequent 
dosing compared to the current recommended regimen; therefore, administration of 
higher than the recommended doses and/or more frequent dosing of belatacept will not be 
used in this trial.  The average age of patients in these studies was 49 years, ranging from 
18 to 79 years.  Approximately 70% of patients were male; 67% were white, 11% were 
black, and 22% other races. About 25% of patients were from the United States and 75% 
from other countries. 
The most commonly reported adverse reactions occurring in ≥20% of patients treated 
with the recommended dose and frequency of belatacept were anemia, diarrhea, urinary 
tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, 
cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.  The 
proportion of patients who discontinued treatment due to adverse reactions was 13% for 
the recommended belatacept regimen and 19% for the cyclosporine control arm through 
three years of treatment. The most common adverse reactions leading to discontinuation 
in belatacept-treated patients were cytomegalovirus infection (1.5%) and complications 
of transplanted kidney (1.5%).  Information on selected significant adverse reactions 
observed during clinical trials is summarized below. 
 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Post-Transplant Lymphoproliferative Disorder 
Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months 
post transplant were obtained for belatacept by pooling both dosage regimens of 
belatacept in both studies (804 patients) with data from a third study in kidney 
transplantation (145 patients) which evaluated two belatacept dosage regimens similar, 
but slightly different, from those of Studies 1 and 2 (see table below). The total number 
of belatacept patients from these three studies (949) was compared to the pooled 
cyclosporine control groups from all three studies (476 patients). 
Among 401 patients in Studies 1 and 2 treated with the recommended regimen of 
belatacept and the 71 patients in Study 3 treated with a very similar (but non-identical) 
belatacept regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in 
EBV seronegative patients. Two of the 5 cases presented with CNS involvement.  Among 
the 477 patients in Studies 1, 2, and 3 treated with the belatacept regimen of higher 
cumulative dose and more frequent dosing than recommended, there were 8 cases of 
PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown 
patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of 
higher than the recommended doses or more frequent dosing of belatacept is not 
recommended.  
One of the 476 patients treated with cyclosporine developed PTLD, without CNS 
involvement.  All cases of PTLD reported up to 36 months post transplant in belatacept- 
or cyclosporine-treated patients presented within 18 months of transplantation.  Overall, 
the rate of PTLD in 949 patients treated with any of the belatacept regimens was 9-fold 
higher in those who were EBV seronegative or EBV serostatus unknown (8/139) 
compared to those who were EBV seropositive (5/810 patients). Therefore belatacept is 
recommended for use only in patients who are EBV seropositive. 


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Belatacept IM 103-133 Version10.0 02Aug2020 
Summary of PTLD Reported in Studies 1, 2, 3 Through Three Years of Treatment 
EBV Seropositive Subpopulation 
Other Malignancies 
Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 
and Study 2 in 3.5% (14/401) of patients treated with the recommended belatacept 
regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen.  
Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the 
recommended belatacept regimen and in 3.7% (15/405) of patients treated with 
cyclosporine. 
Progressive Multifocal Leukoencephalopathy 
Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been 
reported among 1096 patients treated with a belatacept-containing regimen: one patient in 


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clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in 
a trial of liver transplant (trial of 250 patients). No cases of PML were reported in 
patients treated with the recommended belatacept regimen or the control regimen in these 
trials. 
The kidney transplant recipient was treated with the belatacept regimen of higher 
cumulative dose and more frequent dosing than currently recommended, mycophenolate 
mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated 
with 6 months of a belatacept dosage regimen that was more intensive than that studied in 
kidney transplant recipients, MMF at doses higher than the recommended dose, and 
corticosteroids. 
Bacterial, Mycobacterial, Viral, and Fungal Infections 
Adverse reactions of infectious etiology were reported based on clinical assessment by 
physicians. The causative organisms for these reactions are identified when provided by 
the physician. The overall number of infections, serious infections, and select infections 
with identified etiology reported in patients treated with the belatacept recommended 
regimen or the cyclosporine control in Studies 1 and 2 are shown below. Fungal 
infections were reported in 18% of patients receiving belatacept compared to 22% 
receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. 
Tuberculosis and herpes infections were reported more frequently in patients receiving 
belatacept than cyclosporine. Of the patients who developed tuberculosis through 3 years, 
all but one belatacept patient lived in countries with a high prevalence of tuberculosis 
Overall Infections and Select infections with Identifies Etiology by Treatment 
Group following One and Three Years of Treatment 


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. 
 
 
 
 
 
 
 
 
 
 
 
 
Infections Reported in the CNS 
Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was 
reported in one patient out of 401 patients treated with the belatacept recommended 
regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control 
(0.2%).  Six patients out of the 403 who were treated with the belatacept regimen of 
higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 
(1.5%) were reported to have developed CNS infections, including 2 cases of 
cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, 
one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of 
PML (discussed above). 


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Infusion Reactions 
There were no reports of anaphylaxis or drug hypersensitivity in patients treated with 
belatacept in Studies 1 and 2 through three years.  Infusion-related reactions within one 
hour of infusion were reported in 5% of patients treated with the recommended dose of 
belatacept, similar to the placebo rate. No serious events were reported through Year 3. 
The most frequent reactions were hypotension and hypertension. 
Proteinuria 
At month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on 
urine dipstick in patients treated with the belatacept recommended regimen was 33% 
(130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. 
The frequency of 2+ proteinuria was similar between the two treatment groups between 
one and three years after transplantation (<10% in both studies).  There were no 
differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, 
and no patients experienced 4+ proteinuria. The clinical significance of this increase in 
early proteinuria is unknown. 
New-Onset Diabetes After Transplantation 
The incidence of new-onset diabetes after transplantation (NODAT) was defined in 
Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose 
values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the 
belatacept recommended regimen, 5% (14/304) developed NODAT by the end of one 
year compared to 10% (27/280) of patients on the cyclosporine control regimen. 
However, by the end of the third year, the cumulative incidence of NODAT was 8% 
(24/304) in patients treated with the belatacept recommended regimen and 10% (29/280) 
in patients treated with the cyclosporine regimen. 
Hypertension 
Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. 
By Year 3, one or more antihypertensive medications were used in 85% of belatacept-


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Belatacept IM 103-133 Version10.0 02Aug2020 
treated patients and 92% of cyclosporine-treated patients. At one year after 
transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood 
pressures were 3 mmHg lower in patients treated with the belatacept recommended 
regimen compared to the cyclosporine control regimen. At three years after 
transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood 
pressures were 3 mmHg lower in belatacept-treated patients compared to cyclosporine-
treated patients. Hypertension was reported as an adverse reaction in 32% of belatacept-
treated patients and 37% of cyclosporine-treated patients. 
Dyslipidemia 
Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 
and 2.  At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 
mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the belatacept 
recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, 
respectively, in 405 patients treated with the cyclosporine control regimen. At three years 
after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 
49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in belatacept-treated patients 
compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated 
patients.  The clinical significance of the lower mean triglyceride values in NULOJIX-
treated patients at one and three years is unknown. 
Other Adverse Reactions 
Adverse reactions that occurred at a frequency of ≥10% in patients treated with the 
belatacept recommended regimen or cyclosporine control regimen in Studies 1 and 2 
through three years are summarized by preferred term in decreasing order of frequency 
within the table below. 
 
 
 


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Adverse Reactions Reported by ≥10% of Patients Treated with Either 
the Belatacept Recommended Regimen or Control in Studies 1 and 2 
Through Three Years*,† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.5.3 
Rheumatoid Arthritis 
Twelve subjects reported SAEs, and none was considered drug related by the 
investigators. Sixteen subjects reported SAEs, and only 1 was considered possibly drug 
related by the investigators (elbow infection in an abatacept subject in the 2 mg/kg 
group). No deaths were reported during the treatment period or the follow-up period 
(through Day 169). All AEs and SAEs reported in belatacept-treated subjects that were 
not also reported in the renal transplant patients are listed in the updated Investigator’s 
Brochure. Please refer to that document for further details. 
1.2.6  
Clinical Efficacy of Belatacept 
In study IM103100 the efficacy of belatacept in post transplant patients was assessed. 
The trial evaluated the incidence of clinically-suspected and biopsy-proven acute 
rejection (CSBPAR) in patients at 6 months post-transplantation. Secondary variables 
including biopsy-proven acute rejections (BPARs), CSBPAR, death, and/or graft loss 
were assessed at 1 year. 
1.2.6.1 
Acute Rejection 
CSBPAR at 6 months, occurred infrequently across all treatment groups (Table 1.2.6). 
The incidence rate of CSBPAR was slightly lower in the belatacept groups than in the 
CsA group. The distribution of events by severity (as indicated by histological grade) was 
similar across the 3 treatment groups. Identical results were observed at 12 months. The 
criteria for non-inferiority to CsA were easily satisfied for both belatacept groups; 
however, the number of events was too small to support any further conclusions 
regarding the relative efficacy of the 3 regimens. 
The secondary endpoint of BPAR occurred 2 to 4 times more frequently than the primary 
endpoint of CSBPAR, indicating that most BPAR episodes were subclinical (ie, not 
associated with an increase in serum creatinine of ≥ 0.5 mg/dL). These episodes of 
subclinical rejection were observed on biopsies taken to satisfy the protocol requirements, 
according to local practice, or for other reasons than an increase in serum creatinine of 
≥ 0.5 mg/dL. 
BPAR occurred most frequently in the belatacept LI group. As the rate of CSBPAR was 
comparable across treatment groups, the difference in the rate of BPAR was due to an 
increase in the number of subclinical rejection episodes in the belatacept LI treatment 


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arm. Reallocation to 8-week treatment was associated with an increased frequency of 
subclinical rejection. Overall, the histologic severity grade of acute rejection episodes 
appeared to be similar across the 3 treatment groups.  
Table 1.2.6: 
Acute Rejection - Study IM103100 
Banff Grade for Acute Rejections 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=73) 
CSBPAR (ITT Analysis) at Month 6 (Primary Endpoint) 1 
Mild Acute (IA) 
2 (2.7%) 
0 
1 (1.4%) 
Mild Acute (IB) 
0 
0 
1 (1.4%) 
Moderate Acute (IIA) 
2 (2.7%) 
3 (4.2%) 
2 (2.7%) 
Moderate Acute (IIB) 
1 (1.4%) 
1 (1.4%) 
2 (2.7%) 
Total 
5 (6.8%) 
4 (5.6%) 
6 (8.2%) 
Difference in Event Rates (Belatacept - CsA) 
with Asymptotic 95% CI (%) 
-1.5 
(-10.0, 7.0) 
-2.6 
(-10.9, 5.7) 
--- 
BPAR (ITT Analysis) at Month 6 
Mild Acute (IA) 
2 (2.7%) 
3 (4.2%) 
3 (4.1%) 
Mild Acute (IB) 
0 
1 (1.4%) 
1 (1.4%) 
Moderate Acute (IIA) 
6 (8.1%) 
8 (11.3%) 
7 (9.6%) 
Moderate Acute (IIB) 
3 (4.1%) 
5 (7.0%) 
2 (2.7%) 
Total 
11 (14.9%) 
17 (23.9%) 
13 (17.8%) 
Difference in Event Rates (Belatacept - CsA) 
with Asymptotic 95% CI (%) 
-2.9 
(-14.9, 9.0) 
6.1 
(-7.1, 19.4) 
--- 
BPAR (ITT Analysis) at Month 12 
Mild Acute (IA) 
3 (4.1%) 
4 (5.6%) 
3 (4.1%) 
Mild Acute (IB) 
1 (1.4%) 
4 (5.6%) 
1 (1.4%) 
Moderate Acute (IIA) 
5 (6.8%) 
8 (11.3%) 
7 (9.6%) 
Moderate Acute (IIB) 
5 (6.8%) 
5 (7.0%) 
2 (2.7%) 
Total 
14 (18.9%) 
21 (29.6%) 
13 (17.8%) 
Difference in Event Rates (Belatacept - CsA) 
with Asymptotic 95% CI (%) 
1.1 
(-11.4, 13.6) 
11.8 
(-2.0, 25.5) 
--- 
1  The results for CSBPAR were the same at Month 12. 
BPAR = biopsy-proven acute rejection, CI = confidence interval, CsA = cyclosporine, CSBPAR = clinically-suspected 
and biopsy-proven acute rejection, ITT = intent to treat, LI = less intensive, and MI = more intensive. 
 


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1.2.6.2 
Chronic Allograft Nephropathy 
Biopsy specimens were also examined for chronic allograft nephropathy (CAN) 
including arteriolar hyalinosis, interstitial fibrosis, glomerulosclerosis and tubular 
atrophy. By Month 12, CAN was approximately 30% to 50%, in relative terms, less 
common with belatacept than with CsA. 
 
Table 1.2.6.2: 
Biopsy-proven Chronic Allograft Nephropathy - 
Study IM103100 
 
Biopsy-proven Chronic Allograft Nephropathy 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=73) 
Month 3 
3 (4.1%) 
2 (2.8%) 
9 (12.3%) 
Difference in Event Rates (Belatacept - CsA) with 
Asymptotic 95% CI (%) 
-8.3 
(-17.1, 0.5) 
-9.5 
(-18.0, -1.0) 
--- 
Month 6 
6 (8.1%) 
3 (4.2%) 
11 (15.1%) 
Difference in Event Rates (Belatacept - CsA) with 
Asymptotic 95% CI (%) 
-7.0 
(-17.3, 3.3) 
-10.8 
(-20.3, -1.4) 
--- 
Month 12 
15 (20.3%) 
11 (15.5%) 
22 (30.1%) 
Difference in Event Rates (Belatacept - CsA) with 
Asymptotic 95% CI (%) 
-9.9 
(-23.8, 4.1) 
-14.6 
(-28.1, -1.2) 
--- 
Note: 
Biopsy-proven chronic allograft nephropathy was assessed by the central pathologist; Day 1  
 
baseline biopsies were included. In an analysis restricted to subjects with at least 1 post-baseline  
 
biopsy, the rates of biopsy-proven chronic allograft nephropathy at 12 months were 29%, 20%,  
 
and 44% for the belatacept MI, belatacept LI, and CsA groups, respectively. 
CI = confidence interval, CsA = cyclosporine, LI = less intensive, and MI = more intensive. 
 


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1.2.6.3 
Subject and Graft Survival 
Death and/or graft loss occurred infrequently in all treatment groups, and was least 
frequently reported in the belatacept LI group. Most graft losses occurred for technical, 
rather than immunological, reasons. 
 
Table 1.2.6.3: 
Subject and Graft Survival - Study IM103100 
 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=73) 
Deaths at Month 12 (ITT Analysis) 
Total No. of Deaths 
1 (1.4%) 
0 
4 (5.5%) 
Reasons: 
 
 
 
 
Cardiac 
0 
0 
2 (2.7%) 
 
Infection / Sepsis 
1 (1.4%) 
0 
0 
 
Pulmonary Embolism 
0 
0 
1 (1.4%) 
 
Other – Unknown 
0 
0 
1 (1.4%) 
Graft Loss at Month 12 (ITT Analysis) 
Total No. of Graft Losses 
3 (4.1%) 
1 (1.4%) 
3 (4.1%) 
Reasons: 
 
 
 
 
Renal Vein or Renal Artery Thrombosis 
1 (1.4%) 
1 (1.4%) 
2 (2.7%) 
 
Other - Infarction (Etiology Unknown,  
 
Possibly Ongoing Rejection) 
 
1 (1.4%) 
 
0 
 
0 
 
Other - PTLD as Treatment of PTLD 
1 (1.4%) 
0 
0 
 
Other - Combination - Persistent DGF; 
 
Acute Rejection; Infection 
 
0 
 
0 
 
1 (1.4%) 
Note: 
After the cutoff date for the 12-month analysis, 1 additional death was reported 
 
(Subject IM103100-13-16 in the belatacept MI group died due to multiple organ failure). 
CsA = cyclosporine, DGF = delayed graft function, ITT = intent to treat, LI = less intensive, MI = more intensive, and 
PTLD = post-transplant lymphoproliferative disorder. 


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1.2.6.4 
Renal Function 
Renal function was assessed by measurement of iohexol clearance. Iohexol clearance was 
greater in the belatacept groups than in the CsA group at all time points. Serum creatinine 
and creatinine-based estimates of renal function were also assessed. These measures are 
known to be less sensitive and more variable than true measures of GFR. However, 
assessments of renal function by these measures generally favored belatacept. 
Mean systolic blood pressure (SBP) was slightly higher with CsA (133 mm Hg) than with 
belatacept by Month 12 (SBP: 130 and 129 mm Hg in the MI and LI groups, 
respectively). Antihypertensive medication use was also somewhat more common with 
CsA use than with belatacept use.  
At Month 12, mean total cholesterol was slightly lower with both the belatacept MI and 
LI groups, respectively, than with CsA (198 and 201 mg/dL vs. 212 mg/dL), as were both 
the mean non-high density lipoprotein (non-HDL) fraction (145 and 144 mg/dL vs. 151 
mg/dL) and the mean HDL fraction (53 and 56 mg/dL vs. 59 mg/dL). Lipid-lowering 
medications were used more frequently with CsA (53%) than with belatacept 
(32%-36%). 
At Month 12, mean HbA1c was slightly lower with belatacept (5.8% in both groups) than 
with CsA (6.2%). The incidence of new-onset PTDM was slightly lower with belatacept 
than with CsA (2 and 0 subjects in the MI and LI groups, respectively vs. 3 subjects). 
1.2.6.5 
IM103100 Long Term Extension 
Of the 164 subjects who completed the 12-month phase, 128 subjects (102/113 subjects 
from the MI + LI belatacept group and 26/51 subjects in the CsA group) consented to 
continue in the long term extension (LTE) phase of the study. 
During the LTE phase, a low rate of acute rejection, death, or graft loss was reported in 
belatacept subjects. Two cases of acute rejection (CSBPAR) were reported in the 
belatacept group (1 each in the MI/8-week and LI/8-week groups). Six cases of BPAR, 
including 2 cases of CSPAR, were reported in the combined belatacept group. All of 
these cases were mild or moderate in severity. The incidence of CAN was reported in 25 
cases in the combined belatacept group and 9 cases in the CsA group. 


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In the LTE phase, mean calculated GFR (MDRD formula) was reportedly higher in the 
belatacept group. At Months 12 and 60, GFR was reported as 75.8 and 
77.2 mL/min/1.73 m2, respectively in the combined belatacept group and 74.4 and 
59.3 mL/min/1.73 m2, respectively, in the CsA group. 
Five deaths were reported: 3 in the combined belatacept group (2 died with a functioning 
graft) and 2 in the CsA group (both died with a functioning graft). The causes of death 
reported among the belatacept subjects were myocardial infarction (LI), cardiopulmonary 
arrest (MI) and pneunomia (MI). 
1.3 
Overall Risk/Benefit Assessment 
1.3.1 Potential Benefits 
The field of transplantation is moving towards optimizing immunosuppression to avoid 
the toxicities of the current immunosuppressive regimens while at the same time 
achieving acceptable efficacy. Belatacept is being developed as an immunosuppressive 
agent for kidney transplant to provide comparable efficacy to the current standard 
immunosuppressive class, CNIs, with an improved safety profile. At present, CNI-based 
regimens are suboptimal for several reasons. First, CNIs are frequently not initiated until 
after there is sufficient clinical evidence of allograft function. This potential for delayed 
administration in a critical immunologic window may lead to increased acute rejection 
rates. Polyclonal antilymphocyte preparations may be used as an immunosuppressive 
bridge until a CNI may be safely administered; however, these preparations have 
short-term adverse effects (infection) as well as long-term sequelae (PTLD). These 
adverse effects must be factored into the risk burden of a CNI-based regimen. 
Second, the adverse cardiovascular and metabolic effects of CNI-based regimens further 
weigh on the benefit-risk ratio of these agents. Since CNIs are well known to cause or 
exacerbate conditions such as hypertension, hypercholesterolemia, or diabetes mellitus, 
renal transplant recipients are vulnerable to these adverse effects of CNIs. Unfortunately, 
while alternative CNI-free regimens have been previously tested, none have been proven 
to offer a favorable benefit-risk relationship. Therefore, CNIs remain the cornerstone for 
immunosuppression in these subjects despite their known liabilities. 
An alternative strategy to promote improvement in kidney transplant function has been 
the use of mTOR inhibitors, sirolimus or everolimus, instead of  CNI or in combination 


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with low dose CNI.  While conceptually this strategy had promise, in practice this has not 
borne true.  Attempts to wean patients from CNI and convert to mTOR-based therapy 
have been hampered by an increase in acute rejection upon removing CNI.  In addition to 
the detrimental effects of acute rejection, including a higher incidence of new donor 
specific antibody formation, patients required higher doses of mTOR inhibitor leading to 
an increased incidence of adverse events/side effects including hyperlipidemia, mouth 
ulcers, edema, anemia, proteinuria resulting in intolerability of the regimen and a high 
rate of discontinuation.  Belatacept, an immunosuppressive agent with a novel 
mechanism of action, is a promising non-nephrotoxic candidate for use in renal transplant 
recipients. Unlike CNIs or mTOR inhibitors, belatacept acts selectively rather than 
through ubiquitous pathways to afford immunosuppression. This targeted mechanistic 
approach may provide immunosuppressive efficacy while circumventing the intrinsic 
toxicities of CNIs. Consistent with this notion, existing data show comparable rates of 
acute rejection, with favorable trends in subject and graft survival, GFR, CAN, and 
cardiovascular adverse effect profile. 
Two dose regimens of belatacept are being studied in Phase 3. Both regimens are based 
on the regimens successfully studied in Phase 2, with minor modifications to increase the 
likelihood of a favorable outcome. 
1.3.2 Potential Risks 
Post-Transplant Lymphoproliferative Disorder 
Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months 
post transplant were obtained for belatacept by pooling both dosage regimens of 
belatacept in both studies (804 patients) with data from a third study in kidney 
transplantation (145 patients) which evaluated two belatacept dosage regimens similar, 
but slightly different, from those of Studies 1 and 2 (see table below). The total number 
of belatacept patients from these three studies (949) was compared to the pooled 
cyclosporine control groups from all three studies (476 patients). 
Among 401 patients in Studies 1 and 2 treated with the recommended regimen of 
belatacept and the 71 patients in Study 3 treated with a very similar (but non-identical) 
belatacept regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in 


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EBV seronegative patients. Two of the 5 cases presented with CNS involvement.  Among 
the 477 patients in Studies 1, 2, and 3 treated with the belatacept regimen of higher 
cumulative dose and more frequent dosing than recommended, there were 8 cases of 
PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown 
patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of 
higher than the recommended doses or more frequent dosing of belatacept is not 
recommended.  
One of the 476 patients treated with cyclosporine developed PTLD, without CNS 
involvement.  All cases of PTLD reported up to 36 months post transplant in belatacept- 
or cyclosporine-treated patients presented within 18 months of transplantation.  Overall, 
the rate of PTLD in 949 patients treated with any of the belatacept regimens was 9-fold 
higher in those who were EBV seronegative or EBV serostatus unknown (8/139) 
compared to those who were EBV seropositive (5/810 patients). Therefore belatacept is 
recommended for use only in patients who are EBV seropositive. 
Malignancy 
Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 
and Study 2 in 3.5% (14/401) of patients treated with the recommended belatacept 
regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen.  
Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the 
recommended belatacept regimen and in 3.7% (15/405) of patients treated with 
cyclosporine. 
Infection 
Adverse reactions of infectious etiology were reported based on clinical assessment by 
physicians. The causative organisms for these reactions are identified when provided by 
the physician. The overall number of infections, serious infections, and select infections 
with identified etiology reported in patients treated with the belatacept recommended 
regimen or the cyclosporine control in Studies 1 and 2 are shown above. Fungal 


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infections were reported in 18% of patients receiving belatacept compared to 22% 
receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. 
Tuberculosis and herpes infections were reported more frequently in patients receiving 
belatacept than cyclosporine. Of the patients who developed tuberculosis through 3 years, 
all but one belatacept patient lived in countries with a high prevalence of tuberculosis 
Other Potential Risks 
Other potential risks include those events that may theoretically be associated with 
belatacept, or that have been observed more frequently in belatacept-treated subjects in a 
single clinical trial. These events include graft thrombosis, infusional reactions, 
proteinuria, pulmonary edema, and autoimmune disorders. None of these events have 
been consistently associated with belatacept treatment. These events are undergoing 
augmented surveillance in the clinical trials. 
1.3.3 Summary of Risk/Benefit Assessment 
Belatacept, an immunosuppressive agent with a novel mechanism of action, is a 
promising non-nephrotoxic candidate for use in renal transplant recipients. Clinical data 
from approximately 1000 belatacept-treated patients in 3 trials in de novo renal 
transplantation indicate that belatacept results in similar rates of adverse events, serious 
adverse events, infections and malignancies to a CNI-based regimen. Overall rates of 
infection and malignancy were similar in belatacept and CNI-treated subjects. 
  
Appropriate screening for TB, per local guidelines, is required before treatment with 
belatacept. 
Although rare, PTLD and CNS PTLD have been observed more frequently in belatacept-
treated subjects. A thorough analysis indicates that the elevated risk of PTLD, an 
expected event in transplant patients, appears to be restricted to EBV-negative recipients, 
with no increase in risk in EBV-positive recipients treated with belatacept. 
Therefore, the current study offers a favorable benefit/risk relationship to study subjects, 
and the potential to provide important data for the development of new 
immunosuppressive regimens that have improved safety and tolerability when compared 
to existing therapies. 


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End stage renal disease is a major health problem affecting over 350,000 people in the 
US alone. Kidney transplantation is now the ideal treatment for renal failure, with nearly 
17,000 transplants performed annually.  While early outcomes have improved 
dramatically over the past 30 years, long-term results continue to be disappointing.  Ten 
years after transplant nearly all renal allografts have histologic evidence of chronic injury 
with accompanying impaired renal function.  Many patients with failing allografts 
ultimately return to dialysis.  Fortunately, a significant proportion of these patients are re-
transplant candidates.  Indeed 10-15% of all renal transplants are performed in recipients 
of prior renal allografts.  There is an ongoing debate regarding the management of 
patients with a failed kidney transplant.  Those patients who require dialysis and are 
maintained on immunosuppression continue to be subjected to increased risks of 
infection, cardiovascular disease, malignancies, etc.  In fact several studies have shown a 
significantly increased risk of infection and death for those who continue 
immunosuppression 
after 
graft 
failure. 
Thus 
most 
centers 
favor 
tapering 
immunosuppressive therapy off once a patient requires dialysis.  Unfortunately, this puts 
the patient at risk for developing allo-antibody which may limit options for re-transplant.  
The development of an immunosuppressive strategy to minimize the complications of 
persistent therapy while preventing sensitization could greatly enhance the likelihood of 
re-transplantation.   
1.4 
Study Rationale 
Kidney transplantation is an accepted form of treatment for end stage renal disease.  
Indeed transplant recipients not only live longer than those patients who remain on 
dialysis, their quality of life is superior and the therapy is cost effective.  Unfortunately, 
ten years after transplant nearly all renal allografts have histologic evidence of chronic 
injury and over 60% have evidence of severe chronic allograft nephropathy, grade III 
interstitial fibrosis/tubular atrophy (IF/TA).  Many of these patients ultimately return to 
dialysis. Given the increased risks of infection, cardiovascular disease and malignancy 
most patients have their immunosuppression discontinued when they start dialysis.  
Unfortunately this puts the patient at increased risk for developing allo-antibody which 
limits options for re-transplant.  Indeed a significant proportion of these patients will be 
re-listed for a subsequent transplant.  Belatacept has a unique mechanism of action as an 
immunosuppressive agent.  Given its favorable side-effect profile, lack of nephrotoxicity 
and effectiveness in preventing T-cell dependent antibody production including allo-
antibody, belatacept represents an ideal agent to test in this patient population.   


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Belatacept IM 103-133 Version10.0 02Aug2020 
The current study proposes a randomized clinical trial of first-time renal transplant 
recipients who now have impaired renal function (eGFR<35 with a decline in GFR of > 
10 % in the year prior to enrollment with biopsy proven grade II or III IF/TA OR a GFR 
< 20 in the 6 month period prior to enrollment absent other causes for graft dysfunction 
and deemed to have a failing allograft by the patient’s transplant nephrologist.  Patients 
must be re-transplant candidates and have completed or be actively undergoing the 
evaluation process for re-listing.  Patients will be randomized to a belatacept-based 
immunosuppressive regimen or standard of care with a calcineurin inhibitor-based or 
sirolimus therapy.  Endpoints include rate of donor-specific antibody production as well 
as renal function and rate/time to dialysis.  We hypothesize that belatacept will 
effectively inhibit sensitization (ie donor-specific antibody production) in patients with a 
failing or failed renal allograft and as a result will facilitate re-transplantation.  In 
addition treatment with belatacept will more favorably impact residual allograft function 
(ie preservation of GFR) in patients with IF/TA as compared to treatment with 
conventional immunosuppression thereby prolonging time to dialysis or need for re-
transplant. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To prevent the formation of donor-specific alloantibody in patients with chronic allograft 
injury, thereby facilitating re-transplantation by avoiding sensitization 
Primary Endpoint: The rate of donor-specific antibody formation 36 months following 
randomization. 
2.2 
Secondary Objectives 
To determine if treatment with belatacept better preserves GFR in those patients with 
marginal renal function as compared to those patients who continue calcineurin inhibitor 
therapy and as a result delays time to initiation of dialysis. Subjects already requiring 
dialysis at the time of enrollment will be excluded from this analysis. 
Secondary Endpoints:  
-Rate of change in GFR compared to participants maintained on CNI-based or mTOR-
based regimen. Subjects already requiring dialysis will be excluded from this endpoint 
analysis. 
-Time to dialysis measured from the time of randomization to initiation of dialysis 
compared to participants maintained on CNI-based or mTOR-based regimen.  


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Subjects already requiring dialysis at the time of enrollment will be excluded from this 
endpoint analysis.   
- Overall level of alloantibody as indicated by PRA.   
- Incidence of infectious complications.   
 
3 
ETHICAL CONSIDERATIONS 
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) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (eg, loss of medical licensure; debarment). Systems with 
procedures that ensure the quality of every aspect of the study will be implemented. 
3.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (eg, advertisements), and any other written information to be provided 


43 
Belatacept IM 103-133 Version10.0 02Aug2020 
to subjects. The investigator should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling, information to be provided to subjects, and any 
updates. The investigator should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
3.3 
Informed Consent 
Investigators must ensure that subjects (or, in those situations where consent cannot be 
given by subjects, the legally acceptable representative) are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject (or, in those situations where consent cannot be given by 
subjects, the legally acceptable representative) before clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
This is an open-label, prospective, randomized, controlled clinical trial.  First-time renal 
transplant recipients who now have impaired renal function (estimated GFR <35 with a 
decline in renal function of > 10% in the year prior to enrollment with biopsy proven 
grade II or III IF/TA) OR a GFR of < 20 over the 6 month period prior to enrollment 
absent other causes for graft dysfunction and deemed to have a failing allograft by the 
patient’s transplant nephrologist will be identified for randomization to either treatment 
(belatacept-based) or to continue standard of care (CNI-based or mTOR-based) regimen.  
There will be a total of 72 subjects, randomized in equal numbers, 36 patients in each 
arm.  Patients must be candidates for re-transplantation.  Those subjects who are EBV 
seronegative or have a history of PTLD will be excluded.  Follow up will be planned for 
36 months after randomization.  The study will proceed in two sequential phases with 
distinct funding periods.  Phase I will enroll 18 patients in each arm, 36 total patients.  
After discussions with BMS we will proceed with phase II, contingent on funding 


44 
Belatacept IM 103-133 Version10.0 02Aug2020 
availability and preliminary results from phase I.  Phase II will enroll an additional 36 
patients for a total of 72 patients, 36 in each arm. 
 
Study Design  
 
-Standard of care arm- 
 
GFR<35 - wean tacrolimus or sirolimus dose to target level of 3-5 (or equivalent CNI or 
mTOR inhibitor  level), and if applicable continue MMF or MPA (equivalent of at least 
1g daily) or azathioprine, and/or prednisone 
 
Upon initiation of dialysis or in subjects already requiring dialysis at time of enrollment -
 discontinue CNI or mTOR inhibitor over 5 days, if applicable  MMF, MPA or 
azathioprine dose decreased by half then discontinued 2 weeks later, steroid withdrawal 
beginning 1 month after the initiation of dialysis with monthly reduction by half with 
plans to discontinue at 3 months after initiation of dialysis.    
  
-Belatacept arm- 
 
GFR <35- initiate Belatacept; dose of CNI or mTOR inhibitor will be decreased by half 
at time of first dose. CNI or mTOR inhibitor will be discontinued at time of second dose 
of belatacept (week 2). Belatacept dosing 10mg/kg- day 0, 2 weeks, 4 weeks, 8 weeks, 
and 12weeks; subsequent doses 5mg/kg q month through duration of trial or until 
retransplantation, whichever is first.  If applicable continue MMF or MPA (equivalent of 
at least 1g daily) or azathioprine and/or prednisone 
 
Upon initiation of dialysis or in subjects already requiring dialysis at time of enrollment- 
wean remaining immunosuppression (if applicable) as above in standard of care arm 
except for belatacept which they will remain on for the duration of the study or until re-
transplant. If a subject progresses to dialysis dependence while still receiving belatacept 
at the 10 mg/kg dosing, the subject will continue to receive 10 mg/kg dose as scheduled 
through week 12 (5 total doses) and then decrease to 5 mg/kg IV q month for the duration 
of study participation. 
 
At the time of anticipated enrollment study patients will be greater than one (1) year post-
transplant and likely have already had their immunosuppression reduced.  Indeed, they 
probably do not require the same level of immunosuppression as they did in the 
immediate post-transplant period.  Thus the protocol is written to accept patients 
receiving CNI or mTOR monotherapy, or a CNI or mTOR based regimen with the 
equivalent of at least 1g daily of  MMF or comparable dose of MPA or azathioprine, 
and/or corticosteroid. (i.e. Total immunosuppression may be less intense than currently 
recommended in the prescribing instructions for Belatacept.  We would allow participants 
receiving reduced dose MMF (500mg BID) or equivalent and/or weaned off 
corticosteroids for any reason, or patients weaned off MMF or equivalent being 


45 
Belatacept IM 103-133 Version10.0 02Aug2020 
maintained on prednisone. This allows for inclusion of additional patients without 
subjecting them to increased immunosuppression. 
 
4.2 
Study Population 
The study population includes kidney transplant recipients who now have impaired renal 
allograft function or failed allograft requiring initiation of dialysis. 
For entry into the study, the following criteria MUST be met. 
4.2.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Before any study procedures are performed, subjects will have the details of the 
study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. 
2) Target Population 
a) The subject is a kidney transplant recipient (non-HLA identical donor) who now 
has impaired renal allograft function with at least one of the following: 
i) Estimated GFR < 35 with a decline in GFR of > 10% in the 12 months prior to 
enrollment and must have biopsy proven grade II or III interstitial 
fibrosis/tubular atrophy (IF/TA) 
 
ii) Estimated GFR persistently < 20 ml/min over the 6 month period prior to 
enrollment absent other causes for graft dysfunction, and deemed to have a 
failing allograft by the patient’s transplant nephrologist 
b) > 1 year post-transplant 
c) The subject must be a re-transplant candidate 
d) The subject must be on an immunosuppression regimen meeting one of the 
following criteria: 
i) A CNI (tacrolimus or cyclosporine) or mTOR inhibitor (sirolimus or 
everolimus) and at least one of the following: 
(1) MMF at a dose of at least 1 gm/day or comparable dose of MPA or 
azathioprine 
(2) Prednisone at a dose of at least 5 mg/day 
 
ii) A CNI (tacrolimus or cyclosporine) or mTOR inhibitor (sirolimus or 
everolimus) alone for 3 months or more, with no clinically significant changes 
in PRA during that time, as determined by the Emory HLA lab. 


46 
Belatacept IM 103-133 Version10.0 02Aug2020 
 
3) Age and Sex 
a) Men and women, ages 18 to 70, inclusive. 
4.2.2 
Exclusion Criteria 
1) Sex and Reproductive Status 
a) WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for up to 8 weeks after the last dose of 
study drug. 
b) Women who are pregnant or breastfeeding. 
c) Women with a positive pregnancy test. 
d) Sexually active fertile men not using effective birth control if their partners are 
WOCBP. 
2) Target Disease Exceptions  
a) Subjects who are EBV seronegative. 
b) Subjects with any prior solid organ (e.g., heart, liver, pancreas) or cell (e.g., islet, 
bone marrow) transplant other than a renal allograft. Exception may be made for 
recipient of a simultaneous kidney-pancreas transplant who had previously 
experienced graft loss of the pancreas allograft due to thrombosis or rejection. 
c) Subjects with presence of donor specific antibody at the time of enrollment 
d) Subjects who have a recent history (within 1 yr) of biopsy proven acute rejection 
> Banff grade Ia 
e) Subjects who have a living donor identified for re-transplant within 3 months 
3) Medical History and Concurrent Diseases 
a) Subjects with a history of PTLD 
b) Subjects at risk for tuberculosis (TB) 
c) Subjects with a history of cancer within the past 3 years, other than non-
melanoma skin cancer(s) 
4) Physical and Laboratory Test Findings 
a) Subjects with a positive BK serum PCR > 20,000 copies at the time of enrollment 
OR history of biopsy-proven BK nephropathy within the year prior to enrollment. 
b) Subjects with a mammogram that is suspicious for malignancy and in whom the 
possibility of malignancy cannot be reasonably excluded following additional 
clinical, laboratory, or other diagnostic evaluations. All women 50 years or older 
must have a screening mammogram, or provide results of a screening 
mammogram performed within 1 year of enrollment. If the screening 
mammogram was not performed within 1 year of enrollment, but the subject is 
deemed a suitable study candidate, the baseline mammogram may be obtained 
within 8 weeks after enrollment. Women of any age who have first degree 
relatives with a history of breast carcinoma or who have other risk factors of 


47 
Belatacept IM 103-133 Version10.0 02Aug2020 
breast carcinoma must undergo increased surveillance for breast cancer according 
to local practice. 
c) Subjects who have difficult intravenous access or other reasons that would likely 
preclude the ability to receive long-term intravenous infusions 
5) Allergies and Adverse Drug Reactions 
a) Hypersensitivity to any medications that will be used in the protocol 
6) Prohibited Treatments and/or Therapies 
a) Subjects who have used any investigational drug within the 30 days prior to 
anticipated enrollment 
b) Subjects currently receiving belatacept as part of their maintenance 
immunosuppressive regimen 
7) Other Exclusion Criteria 
a) Prisoners, or subjects who are involuntarily incarcerated. 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria. 
4.2.3 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue study treatment and withdraw from the study for any of the 
following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness 
which, in the opinion of the investigator, indicates that continued participation in 
the study is not in the best interest of the subject 
• Pregnancy 
− Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any 
time during study participation. Institutional policy and local regulations 
should determine the frequency of on-study pregnancy tests for WOCBP 
enrolled in the study. 
− The investigator must immediately notify BMS if a study subject becomes 
pregnant. The mechanism for reporting pregnancy is described in Section 7.6. 
• Termination of the study by BMS. 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious 
disease) illness. 


48 
Belatacept IM 103-133 Version10.0 02Aug2020 
Subjects who discontinue from the study for any reason other than withdrawal of 
consent will be asked to continue in the study under a reduced follow-up plan. 
4.3 
Data Safety Monitoring Plan 
An Independent Data Monitoring Committee (DMC) will monitor emerging efficacy and 
overall safety data regularly to ensure that the benefits and risks of study participation 
remain acceptable.  The DMC will assess the incidence of acute rejection, development 
of donor-specific antibody, graft loss, infectious complications, death, PTLD, and other 
serious adverse events (SAEs) in this study. In addition, other safety and efficacy 
variables (to be defined in the DMC charter) will be monitored by the DMC in order to 
minimize potential risks to study participants.   
 
The first review of data by the DMC will occur either after 10 subjects have been 
enrolled and randomized or approximately 6 months after the first subject is enrolled, 
whichever comes first.   The second review of the data by the DMC will occur either after 
30 subjects have been enrolled or 6 months after the first patient is enrolled, whichever 
comes first.  Subsequent reviews of data by the DMC will occur every 3 months during 
the remainder of the first year and approximately every 6 months thereafter.   
 
Based on regular reviews of the emerging data, the DMC may recommend alteration 
and/or termination of the trial or cessation of further enrollment.  Meeting structure, 
schedule, procedures, and communication between the Sponsor and the DMC, the content 
and format of DMC reports, and other relevant details will be determined in consultation 
with the DMC members and will be detailed in a separate charter. 
 
5 
TREATMENTS 
5.1 
Study Treatment: Belatacept 
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way 
different from the authorized form, or used for an unauthorized indication, or when used 
to gain further information about the authorized form. In this protocol, the investigational 
product is Belatacept. 
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons as components of a given standard of care are 
considered noninvestigational products. 


49 
Belatacept IM 103-133 Version10.0 02Aug2020 
5.1.1 
Identification, Packaging and Labeling 
Study Treatments 
Table 5.1: 
Product Description  
Product Description 
and Dosage Form 
Potency 
Primary Packaging 
(Volume)/ Label 
Type 
Secondary 
Packaging 
(Qty) /Label Type 
Appearance 
Storage Conditions 
(per label) 
 
 
 
 
 
 
Belatacept for 
Injection 250mg/vial 
250 mg 
Vial/Commercial 
presentation 
Commercial carton 
White to off white, 
whole or fragmented 
cake in a vial 
Store refrigerated, 2-
8 degrees Celsius. 
Protect from light. 
 
 
 
 
 
 
 
5.1.2 
Storage, and Handling 
The investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to study 
subjects and only from official study sites by authorized personnel, as dictated by local 
regulations. 
The investigator is responsible for ensuring that the investigational product is stored 
under the appropriate environmental conditions (temperature, light, and humidity).  
5.1.3  
Preparation 
Belatacept (Nulojix) will be prepared as per package insert. 
5.2 
 Drug Ordering and Accountability 
5.2.1 
Initial Orders 
The BMS project manager should be contacted for study drug requirements. Study drug 
requests need 10 business days of processing time. 
5.2.2 Re-Supply 
The BMS project manager should be contacted for re-supply of study drugs. The re-
supply requests need 10 business days of processing time. 


50 
Belatacept IM 103-133 Version10.0 02Aug2020 
5.3 
Method of Assigning Subjects to a Treatment 
Subjects will be randomized in equal numbers to the following treatment groups: 
1) CNI (tacrolimus or cyclosporine) or mTOR inhibitor (sirolimus or everolimus) 
based regimen (with or without MMF/MPA/azathioprine and/or steroids) 
2) Belatacept based regimen (with or without MMF/MPA/azathioprine and/or 
steroids) 
At the time of enrollment, immediately after written informed consent is obtained and 
before performing any study-related procedures, each subject will be assigned a unique 
sequential subject number for identification throughout the study.  This subject number 
will not be reused for any other participant during the study.  Once the subject has met all 
the entry criteria (inclusion and exclusion), the subject will be randomized to one of the 
two described treatment regimens.  Adverse event reporting for all subjects will begin at 
the time of randomization.   
5.4 
Selection and Timing of Dose for Each Subject 
Patients will be randomized as described above.  In the standard of care arm patients will 
remain on CNI or mTOR inhibitor therapy.  The tacrolimus or sirolimus dose will be 
weaned to achieve trough levels of 3-5 (if on equivalent medication, dose will be adjusted 
to achieve similar potency levels).  If on MMF they will continue on MMF, equivalent of 
at least 1 gram daily, or if on MPA or azathioprine, a comparable dose.  If on steroids 
they will continue on corticosteroids. If on both MMF/MPA/azathioprine and steroids 
they will continue on both.  Upon initiation of dialysis or in subjects already requiring 
dialysis at the time of enrollment, the CNI (tacrolimus or cyclosporine) or mTOR 
inhibitor (sirolimus or everolimus) will be discontinued over a 5 day period.  The MMF, 
MPA or azathioprine dose will be decreased by 50% and then discontinued 2 weeks later.  
Steroid dose will be weaned by 50% at one month after returning to dialysis, with a 
subsequent 50% reduction at 2 months and discontinuation at 3 months. 
In those patients randomized to receive belatacept, the CNI (tacrolimus or cyclosporine) 
or mTOR inhibitor (sirolimus or everolimus) will be weaned in the following fashion: 
dose of CNI or mTOR inhibitor will be reduced by 50% at time of first dose of 
belatacept. CNI or  mTOR inhibitor will be discontinued at week 2 dose of belatacept. 
Subjects will receive Belatacept 10mg/kg IV on the first study day, at 2 weeks,1 month, 2 


51 
Belatacept IM 103-133 Version10.0 02Aug2020 
months, and 3 months.  Subsequent belatacept doses will be 5mg/kg IV every month 
through the duration of the trial or until re-transplantation occurs, whichever is first.  A 
month will be defined as one true calendar month.  There will be a ±2 days window for 
the 2nd (2 week) belatacept infusion, and a ±5 days window for subsequent infusions.  If 
on MMF subjects will continue their MMF (equivalent of at least 1g daily) or if on MPA 
or azathioprine, a comparable dose.  If on steroids they will continue on corticosteroids. 
If on MMF/MPA/azathioprine and steroids they will continue on both.  Upon initiation of 
dialysis or in subjects already requiring dialysis at the time of enrollment, the MMF or 
azathioprine dose will be decreased by 50% and then discontinued 2 weeks later.  Steroid 
dose will be weaned by 50% at one month after returning to dialysis, with a subsequent 
50% reduction at 2 months and discontinuation at 3 months. Belatacept will be continued 
at 5mg/kg IV monthly (± 5 days) for the duration of the study or retransplantation 
whichever occurs first.  If a subject progresses to dialysis dependence while still 
receiving belatacept at the 10 mg/kg dosing, the subject will continue to receive 10 mg/kg 
dose as scheduled through month 3 (5 total doses) and then decrease to 5 mg/kg IV q 
month for the duration of study participation. 
Infusion doses will be based on the subject’s actual body weight at enrollment, and will 
not be modified during the course of the study, unless there is a change of body weight 
greater than ±10%. Study drug should be administered to the subject at a relatively 
constant rate over approximately 30 minutes. Once subjects have initiated hemodialysis, 
study infusion visits will be scheduled on non-dialysis days.  If patients perform 
peritoneal dialysis, study infusion visits will be scheduled without regard to dialysis 
schedule. 
5.4.1 Dose Modifications 
In the absence of AEs deemed at least possibly related to study drug treatment, subjects 
will complete their scheduled infusions as prescribed by the protocol. In the event of new, 
serious, and unexpected toxicity potentially related to belatacept, study drug 
administration should be interrupted. The investigator must immediately notify the 
medical monitor. The subject will be considered eligible to receive further study drug 
treatment only after discussion with the medical monitor. Under no circumstances should 
the dose of belatacept be modified. Subjects in whom belatacept dosing is discontinued 
should be placed on the standard of care regimen. 


52 
Belatacept IM 103-133 Version10.0 02Aug2020 
5.5 Blinding/Unblinding 
Not Applicable 
5.6 
Concomitant Treatments 
5.6.1 
Prohibited and/or Restricted Treatments 
Use of immunosuppressive agents and corticosteroids must be limited to those specified 
in the protocol. For full prescribing information, see the package inserts. 
5.6.2 
Other Restrictions and Precautions 
Vaccination 
There is limited information available regarding the effectiveness of immunizations in 
non-human primates and humans that have been treated with belatacept. No data are 
available on the effect of therapeutic vaccinations in subjects receiving belatacept. Due to 
the risk of infection, vaccination of subjects with any live vaccine is absolutely 
contraindicated during the course of the study, as is the administration of LIVE oral polio 
or varicella vaccine to household contacts. The Centers for Disease Control recommend 
that subjects should not be administered a live virus vaccination for at least 3 months 
after discontinuing high-dose corticosteroid therapy (defined as > 20 mg/day of 
prednisone for > 2 weeks). In view of the long half-life of belatacept, study subjects 
should not be administered a live virus vaccine for a minimum of 3 months following the 
last dose of study medication. 
Peri-infusional Reactions 
The infusion of protein biologic agents can be associated with hypersensitivity or acute 
allergic reactions. Subjects should be monitored frequently during and following study 
drug administration. Appropriate emergency equipment should be present at the 
treatment facility in the event of a serious anaphylactic reaction. 


53 
Belatacept IM 103-133 Version10.0 02Aug2020 
Other Potential Risks 
Proteinuria and pulmonary edema was reported more frequently as an AE among 
belatacept-treated subjects in clinical trials. Proteinuria, pulmonary edema, and 
congestive heart failure have been identified as events of special interest future trials. 
5.7 
Treatment Compliance 
All medications specified in this protocol must be administered as described within the 
protocol.  Belatacept will be exclusively administered at the study site.  Compliance for 
the other medications will be discussed with the subjects at each study visit and will be 
documented by the study coordinator.  Patients in the standard of care arm will have 
periodic CNI (tacrolimus or cyclosporine) or mTOR inhibitor (sirolimus or everolimus) 
levels evaluated to document compliance.   
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 
Baseline and study evaluations are summarized in table 6.1 
All assessments will be performed or administered prior to study drug administration 
unless otherwise indicated. 
If a subject needs to withdraw from the study, the next scheduled set of assessments will 
be performed early.  The reason for study discontinuation will be documented. 


 
Belatacept IM 103-133 version 10.0  date: 02Aug2020 
 
54 
 
6.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belatacept-Treatment Group Pre-Dialysis 
Visit # 
Screen 2 
3 
4 
5 
6 
7-8 
9 
10-
11 
12 13-14 15 16-20 21 
22-26 
27 
28-32 33 
34-38 39 
time points 
 
0 2 
wks 
1 
mo 
2 
mo 
3 
mo 
4-5 
mo 
6 
mo 
7-8 
mo 
9 
mo 
10-11 
mo 
12 
mo 
13-17 
mo 
18 
mo 
19-23 
mo 
24 
mo 
25-29 
mo 
30 
mo 
31-35 
mo 
36 
mo 
  
 ± 2 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
Eligibility Assessments  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician Visit 
X 
 
 X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Physical Examination 
X 
 
 X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Vital Signs 
X 
X 
X 
X 
X 
X 
XX 
X 
XX 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
  
X 
Assessment of Signs 
and Symptoms 
 
X 
X 
X 
X 
X 
XX 
X 
XX 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Adverse Events 
Assessments 
 
X 
X 
X 
X 
X 
XX 
X 
XX 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Laboratory Tests 
X 
X 
 X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
EBV/CMV titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurologic Evaluation X 
 
 X 
X 
X 
 X 
 
 
 X 
 X 
 X 
 X 
 X 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSA/PRA 
X 
X 
 X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
 X 
Mechanistic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample storage 
X 
X 
X 
X 
X 
X 
XX 
X 
XX 
X 
XX 
X 
X15 
X 
X15 
X 
XXXXX X 
XXXXX X 
Clinical Drug Supplies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belatacept Infusion3 
 
X1 
X 
X 
X 
X 
X2X X 
XX 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Tac/CsA dosing 
 
X4 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
immunosuppression6 
 
X 
X 
X 
X 
X 
XX 
X 
XX 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 


55 
Belatacept IM 103-133 Version10.0 02Aug2020 
6.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belatacept-Treatment Group Post-Dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit # 
Screening Initiation 
of Dialysis 
1 
2 
3 
4 
5 
6 
7 
8-9 10 
11-
12 
13 
14-18 19 
20-24 25 
26-30 
31 32-36 
37 
time points 
 
 
 2 
wks 
1 mo 2mo 3mo 4mo 5mo 6mo 7-
8mo 
9mo 10-
11 
mo 
12 
mo 
13-17 
mo 
18 
mo 
19-23 
mo 
24 
mo 
25-29 
mo 
30 
mo 
31-35 
mo 
36 
mo 
  
 ± 2 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
Eligibility Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician Visit 
X 
X 
 
 X 
X 
X 
X 
X 
 X 
   
 X 
   
 X 
 X 
Physical Examination 
X 
X 
 X 
X 
X 
X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
Vital Signs 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Assessment of Signs 
and Symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Adverse Events 
Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Laboratory Tests 
X 
X 
 X 
X 
X 
X 
X 
X 
 X 
 X 
 X 
 X 
 X 
 X 
EBV/CMV titer 
X 
X 
 X 
 X 
 
 X 
 
 
 X 
 X 
 X 
 X 
 X 
Neurologic Evaluation X 
X 
 
 
 X 
 
 
 
 X 
 X 
 X 
 X 
 X 
 X 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
DSA/PRA 
X 
X 
 
 X 
X 
X 
X 
X 
 
 
 X 
 
 
 X 
 X 
 X 
Mechanistic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
Sample storage 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
X15 
 XXXXX X 
XXXXX X 
XXXXX X 
Clinical Drug Supplies  
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMF weaning7 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


56 
Belatacept IM 103-133 Version10.0 02Aug2020 
Prednisone weaning8 
 
 
 X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belatacept Infusion9 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XXXXX X 
XXXXX X 
XXXXX X 
XXXXX X 
Tac/CsA dosing 
 
 X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
immunosuppression6 
 
 X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


57 
Belatacept IM 103-133 Version10.0 02Aug2020 
6.1 
 
 
 
 
 
 
 
 
 
 
 
 
Standard of Care Pre-Dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
Visit # 
Screen 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
time points 
 
0 1mo 
2mo 
3mo 
6mo 
9mo 
12mo 
18mo 
24mo 
30 mo 
36 mo 
  
 ± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
Eligibility Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Physician Visit 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Physical Examination 
X 
 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Signs and 
Symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EBV/CMV titer 
X 
 
 
 
 
 
 
 
 
 
 
 
Neurologic Evaluation 
X 
 X 
 X 
X 
 X 
 X 
 X 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
DSA/PRA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mechanistic 
 
 
 
 
 
 
 
 
 
 
 
 
Sample storage 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Drug Supplies 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
 
X 
 
 
 
 
 
 
 
 
 
 
Tac/CsA level10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitatnt 
immunosuppression11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


58 
Belatacept IM 103-133 Version10.0 02Aug2020 
6.1 
Standard of Care Post-
Dialysis 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Visit # 
Screen 
Initiation 
of 
Dialysis 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
time points 
1mo 
2mo 
3mo 
4mo 
5mo 
6mo 
9mo 
12mo 
15mo 
18mo 
21mo 
24mo 
30mo 
36mo 
  
  
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
± 5 
days 
Eligibility Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Safety Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physician Visit 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Signs and 
Symptoms 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessments 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EBV/CMV titer 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Neurologic Evaluation 
X 
  
  
  
X 
  
  
X 
  
X 
  
X 
  
X 
X 
X 
Efficacy Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DSA/PRA 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mechanistic 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Sample Storage 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Drug Supplies 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tac/CsA weaning12 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MMF weaning13 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Prednisone weaning14 
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  


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SOE footnotes
1 Belatacept dose 10 mg/kg IV  administered at study day 0, week 2, month 1, 2, 3
2 Belatacept dose 5 mg/kg IV  q month administered  beginning study month 4 and continuing through end of study treatment period
3 Infusion dose based on subject’s actual body weight at enrollment and will not be modified during the course of the study unless 
there is a change of body weight greater than + 10%
4 at first dose of belatacept, reduce CNI or mTOR inhibitor dose by 50%
5 at second dose of belatacept (week 2) discontinue CNI or mTOR inhibitor
6 Continue concomitant immunosuppression (MMF/MPA/AZA and/or prednisone) at current dose until initiation of dialysis
7 Decrease MMF/MPA/AZA dose by 50% at initiation of dialysis. Discontinue MMF/MPA/AZA 2 weeks after initiation of dialysis
8 Reduce prednisone dose by 50% one month after initiation of dialysis, by half again at 2 months after initiation of  dialysis. 
Discontinue prednisone at 3 months after initiation of dialysis
9 After initiation of hemodialysis, infusion visits will be scheduled on non-dialysis days
10Maintain target tacrolimus trough of 3-5 ng/ml (or equivalent CNI or mTOR inhibitor trough) until initiation of dialysis
11Continue concomitant immunosuppression (MMF/MPA/AZA and/or prednisone) at current dose until initiation of dialysis
12 Discontinue CNI or mTOR inhibitor over 5 days after initiation of dialysis
13 Decrease MMF/MPA/AZA dose by 50% at initiation of dialysis. Discontinue MMF/MPA/AZA  2 weeks after initiation of dialysis
14 Reduce prednisone dose by 50% one month after initiation of dialysis, by 50% again at 2 months after initiation of  dialysis.
Discontinue prednisone at 3 months after initiation of dialysis
Table 6.1 


 
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6.2 
Screening  Evaluation 
Obtain written consent and enroll the subject.  Consent will be obtained prior to 
any change in medical therapy or any procedure performed solely for the purpose 
of this study. 
Review inclusion and exclusion criteria with patient; determine if they remain a 
candidate for the trial 
Obtain a serum or urine pregnancy test 
EBV serology done at any previous time point will be accepted for eligibility 
criteria and will be documented.  If serology results are not available then serum 
will be sent for EBV antibody quantification.  Both EBV and CMV viral titers 
will be checked prior to randomization.  If the EBV viral load is positive in an 
EBV seropositive individual, the subject will have the EBV viral load repeated 
and the subject may be considered for enrollment when the result is undectable.   
If CMV titer is positive, the subject will be appropriately treated and reconsidered 
for enrollment once the viral load is undetectable for >1 month period. 
Obtain blood sample for donor specific antibody evaluation and overall allo-
antibody levels.  Donor specific antibody/anti-HLA antibody will be evaluated 
using the FlowPRA assay in the Emory University Hospital Clinical HLA 
Laboratory. The Emory Medical laboratory is a CLIA certified facility. If allo-
antibody is detected then antigen specificity will be assessed using single-antigen 
HLA beads.  Results from donor HLA typing will be used to determine if new 
anti-HLA antibody is donor specific constituting a new DSA.   
Obtain a complete medical history and physical examination including a 
neurologic exam. 
Obtain body weight (clothes on, shoes off) and height, measure vital signs (BP, 
HR, temp, respiration) 


 
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All women 50 years or older must have a screening mammogram, or provide 
results of a screening mammogram performed within the last year.  Women of 
any age who have first degree relatives with a history of breast carcinoma or who 
have other risk factors of breast carcinoma must undergo increased surveillance 
for breast cancer according to local practice 
Check and record all medications 
Obtain baseline laboratory tests including serum Cr and related estimated GFR 
6.3           Post-Enrollment/Randomization 
Prior to the first treatment time point, confirm all inclusion/exclusion criteria.  
Randomize when all entry criteria are satisfied.  Randomization may take place 
prior to the first post-screening visit if required due to scheduling constraints. 
Obtain vital signs, monitor for any adverse events, check and record any changes 
in medications immediately prior to first treatment session 
For subsequent study assessments see respective charts for either belatacept-
treated arm or standard of care group. 
If during the course of immunosuppressive withdrawal, the kidney allograft 
becomes a source of symptoms (swelling, fever, local pain, and/or hematuria) or 
infection then trial participants will be treated according to standard of care as 
deemed appropriate by the treating physician including, if appropriate, a limited 
course of oral or intravenous corticosteroids or if required allograft nephrectomy.  
Study participants will remain on their treatment protocol (i.e. continue to receive 
belatacept or wean quickly off the corticosteroid treatment back to no 
immunosuppression in the standard of care arm).  For the purposes of statistical 
analyses participants will be treated in an intent to treat fashion. 
Study participants will have the option to consent for storage of a banked blood 
sample for future mechanistic assays. If the subject consents to blood for storage, 
an additional 10 ml sample of blood will be collected at enrollment and every 3 
months during pre-dialysis period, upon initiation of dialysis, and every 3 months 
during post-initiation of dialysis period as noted on the schedule of events. 


 
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Banked samples will be stored in the PI’s research lab. Samples may remain 
stored indefinitely. Subjects will have the ability request destruction of samples at 
any time. 
6.4 Study Materials 
Bristol-Myers Squibb (BMS) will provide belatacept for this study. 
6.5 Safety Assessments 
All subjects who are randomized and remain in the study will be evaluated for safety.  
Safety assessments include monitoring of adverse events, clinically significant changes in 
vital signs, physical examination, neurologic assessment, or laboratory test abnormalities.  
The investigator will determine the severity of each adverse event as mild, moderate, 
severe, or very severe.  All adverse events will be documented.  In addition the 
investigator will determine the relationship of the adverse event to the administration of 
belatacept.   
All serious adverse events (SAEs) must be reported as described in Section 7.3.1. All 
nonserious adverse events must be collected as well and documented according to the 
procedures of the investigational site. They do not need to be sent to BMS. 
If the patient is a WOCBP, pregnancy tests (blood or urine; minimum sensitivity 25 IU/L 
of HCG) must be performed within 72 hours before the first infusion.  If the patient 
becomes pregnant at any point during the study, she will exit the study and belatacept 
treatment will be discontinued. 
Laboratory tests may be performed as part of routine standard of care as directed by the 
investigator. Laboratory specimens should be obtained before belatacept infusions. 
Additional tests may be ordered if deemed necessary for monitoring the patient’s safety. 
PTLD Safety Surveillance 
Specific surveillance for PTLD will be conducted for all subjects in this study. The PTLD 
safety surveillance should be implemented as soon as IRB/IEC approvals and subject 
consent are obtained. 
 


 
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Neurologic Examinations 
To assess for PTLD, neurologic examinations will be conducted periodically for the 
duration of the subject’s participation in the study. The neurologic history will include the 
subject’s description of any new neurologic symptoms, such as: 
• changes in personality 
• changes in memory 
• headaches 
• pain 
• seizures 
• impairment of consciousness 
• difficulty swallowing 
• changes in vision, hearing, or language function 
• changes in coordination or gait 
• weakness 
• sensory alterations 
• sphincter disturbance, or 
• involuntary movements. 
In addition, the following will be recorded:  
• time course of any new symptoms (onset and duration) 
• corroboration of any complaints with other individuals 
• medical illnesses, and 
• medication use. 
 
The neurologic examination will include assessment of: 
• mental status 
• gait 
• speech 
• cranial nerves 
• cerebellar function 
• sensory function 
• motor function. 


 
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Any new or worsening findings should be reported as adverse events and evaluated with 
a follow up neurologic examination, additional modalities, and/or neurologic consultation 
as appropriate. 
EBV Titers 
Subjects receiving belatacept who are on dialysis will have samples sent for EBV viral 
titers periodically for the duration of the study.  Positive titers will be confirmed and 
subjects will exit the study and belatacept treatment will be discontinued if they have 
persistent positive titers.  Again only patients who are seropositive for EBV will be 
enrolled in the study. 
Subjects with Suspected PTLD 
CNS imaging and/or neurologic consultation should be considered for any subject with a 
new or worsening neurologic finding. For subjects who undergo biopsy for suspicion of 
PTLD, the biopsy specimen will be evaluated for CD3, CD20, CD79 and EBER. 
Management of belatacept and other immunosuppressants in subjects with suspected 
PTLD should be discussed with the BMS Medical Monitor. BMS should be informed of 
all confirmed cases of PTLD. 
6.6 Efficacy Assessments 
6.6.1 Primary Efficacy Assessment 
The primary endpoint is the incidence of donor-specific allo-antibody formation in 
patients treated with belatacept vs standard of care arm.  Serum samples from study 
subjects will be evaluated periodically (see table 6.1) for the presence of donor-specific 
alloantibody using standard flow cytometric techniques.   
6.6.2 Secondary Efficacy Assessments 
Secondary endpoints will include assessment of renal function including estimated GFR 
and rate of change in GFR, the need for and time to initiation of dialysis, the overall level 
of alloantibody as indicated by PRA and the incidence of infectious complications.  GFR 
will be calculated based upon serum creatinine using the Diet in Renal Disease (study) 
formula as suggested by Levey et al. Subjects already requiring initiation of dialysis at 


 
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the time of enrollment will be excluded from the need for and time to initiation of dialysis 
analysis. 
GFR=170 x (SCr/0.95)(-0.999) x (Age)(-0.176) x (0.762 if the patient is female) x 
(1.180 if the patient is black) x (BUN)(-0.170) x (Alb)(0.318) 
GFR-glomerular filtration rate (ml/min), SCr-serum creatinine (mg/dL), Age in years, 
BUN- blood urea nitrogen (mg/dL), Alb-serum albumin (g/dL) 
Laboratory efficacy parameters will be evaluated utilizing the main laboratory results 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
7.1.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (eg, medical, surgical) to prevent one of the other serious 


 
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outcomes listed above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. 
All pregnancies, regardless of outcome, must be reported to BMS, including 
pregnancies that occur in the female partner of a male study subject. All 
pregnancies must be followed to outcome. See Section 7.6 for instructions on reporting 
pregnancies. 
Although overdose and cancer are not always serious by regulatory definition, these 
events should also be reported to BMS. 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that 
was planned before study entry. Appropriate documentation is required in these 
cases. 
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative). 
7.1.2 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
7.2 
Assignment of Adverse Event Intensity and Relationship to 
Investigational Product 
All adverse events, including those that are serious, will be graded by the physician 
investigator as follows: 
• Mild (Grade 1): awareness of event but easily tolerated 


 
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• Moderate (Grade 2): discomfort enough to cause some interference with usual 
activity 
• Severe (Grade 3): inability to carry out usual activity 
• Very Severe (Grade 4): debilitating; significantly incapacitates subject despite 
symptomatic therapy. 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used: 
• Related: There is a reasonable causal relationship to investigational product 
administration and the adverse event. 
• Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
7.3 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action 
taken, and treatment required. If treatment for the event was administered, it should be 
recorded in the medical record. The investigator must supply BMS and the IRB/IEC with 
any additional information requested, notably for reported deaths of subjects. 
7.3.1 
Serious Adverse Events 
Following the randomization of the subject, all SAEs must be collected, including those 
thought to be associated with protocol-specified procedures. Collection of all SAEs must 
continue for 8 weeks after the last administration of the investigational product. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy). The investigator should notify BMS of any SAE occurring 


 
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after this time period that is believed to be related to the investigational product or 
protocol-specified procedure. 
All SAEs, whether considered related or unrelated to belatacept, must be reported to 
BMS (by the investigator or designee) within 24 hours of study personnel becoming 
aware of the event. If only limited information is initially available, follow-up reports are 
required. The original SAE form must be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com  
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for 
all other SAEs) after the investigator’s or institution’s initial receipt of the 
information. BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on MedWatch Form 3500A, which can be 
accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/   
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com    


 
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If the investigator believes that an SAE is not related to the investigational product but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy, 
or a complication of a study procedure), the potential relationship should be specified in 
the narrative section of the SAE report. 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a 
follow-up SAE report should be sent immediately to BMS. As follow-up information 
becomes available it should be sent immediately using the same procedure used for 
transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. 
7.3.2 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union, an event meeting these 
criteria is termed a Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will 
send investigators an expedited safety report (ESR) to notify them of such an event. 
Other important findings that BMS may report as ESRs 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 findings from a nonclinical (eg, animal) 
study, important safety recommendations from a study data monitoring committee, or the 
decision by BMS to end or temporarily halt a clinical study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, BMS 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. 
In addition, BMS will report suspected serious adverse reactions (whether expected or 
unexpected) to the relevant health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 


 
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7.3.3 
Nonserious Adverse Events 
The collection of nonserious adverse event (NSAE) information will begin at 
randomization. This NSAE information will 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. 
All identified NSAEs will be recorded and described in the medical record. If an ongoing 
NSAE worsens in its intensity, or if its relationship to the investigational product 
changes, a new NSAE entry for the event should be completed. NSAEs should be 
followed to resolution or stabilization, or reported as SAEs if they become serious. 
Follow-up is also required for NSAEs that cause interruption or discontinuation of 
investigational product, or those that are present at the end of study participation. 
Subjects with NSAEs at study completion should receive post-treatment follow-up as 
appropriate. 
7.4 
Laboratory Test Abnormalities 
All laboratory test values captured during treatment must be documented appropriately, 
including the following: 
• any laboratory test result that is clinically significant or meets the definition of an 
SAE 
• any laboratory abnormality that required the patient to have belatacept discontinued 
or interrupted 
• any laboratory abnormality that required the patient to receive specific corrective 
therapy. 
When reporting laboratory abnormalities, the clinical term rather than the laboratory term 
should be used by the reporter (eg, document “anemia,” not “low hemoglobin value”). 
7.5 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose 
of a product that is considered both excessive and medically important. All occurrences 
of overdose must be reported as an SAE. 


 
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7.6 
Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in such a manner that the risk of failure is minimized. (See Section 4.2.1 for 
the definition of WOCBP.) Before study enrollment, WOCBP must be advised of the 
importance of avoiding pregnancy during study participation and of the potential risk 
factors for an unintentional pregnancy. 
7.6.1 
Requirements for Pregnancy Testing 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving 
belatacept. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG. If the pregnancy test is positive, the subject must not receive Belatacept 
and must not continue in the study. 
In addition, all WOCBP must be instructed to contact the investigator and/or other study 
personnel immediately if they suspect they might be pregnant (eg, missed or late 
menstrual period) at any time during study participation. 
7.6.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during 8 weeks after administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety). The investigator must immediately notify BMS of this event and record 
the pregnancy on the Pregnancy Surveillance Form (not on an SAE form). Initial 
information on a pregnancy must be reported immediately to BMS, and information on 
the outcome provided once it is available. Completed Pregnancy Surveillance Forms 
must be forwarded to BMS according to SAE reporting procedures. 
Note: Any pregnancy that occurs in a female partner of a male study subject must be 
reported. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
for the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 


 
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pregnancy follow-up procedures should be considered if indicated. Information regarding 
the course of the pregnancy, including perinatal and neonatal outcome, must be reported. 
7.7 
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 in the medical 
record. 
Subjects who prematurely withdraw or are terminated from study participation, for 
reasons other than withdrawal if consent, will be asked to continue in a reduced safety 
follow-up schedule. The study team will contact the patient every 3 months for the 
duration of the trial to assess patient survival, dialysis status, and serious adverse event 
occurrences. 
7.8               Influenza Guidelines 
Per current CDC influenza recommendations for persons with immunosuppression, 
including those caused by medications, subjects should be counseled to obtain influenza 
vaccination in accordance with CDC guidelines 
(http://www.cdc.gov/flu/professionals/vaccination/index.htm).  
In addition, they will be advised to promptly contact a healthcare provider upon onset of 
any fevers or flu like symptoms in order to  determine whether early or empirical 
antiviral therapy is indicated in accordance with CDC guidelines 
(http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm). 
 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Determination 
This is a single-center, randomized, controlled trial to evaluate the efficacy of belatacept 
to prevent the formation of donor-specific antibody in patients with a failing renal 
allograft thereby preventing sensitization and facilitating re-transplantation.  Based on 
clinical and statistical judgment, it is anticipated that a sample size of 36 patients per 
group will provide valuable preliminary data to assess the impact of belatacept on this 
growing population of patients. 


 
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The sample size for each arm will be 36 patients (Phase I 18 patients in each arm, Phase 
II 18 patients in each arm, total for each phase 36 patients).  From previous work it is 
assumed that the control arm will have about 60% of patients developing antibodies 
within a 3 year period. (unpublished results, analysis of patients at Emory Hospital) It is 
proposed that the group treated with belatacept will have a dramatic decrease in allo-
antibody production.  Assuming a rate of 20% in the treatment group, the power would 
be calculated at 90%.   
8.2 
Endpoint Definitions 
Primary Endpoint: The rate of donor-specific antibody formation 36 months following 
randomization. 
Secondary Endpoints:  
-Rate of change in GFR  
-Time to dialysis measured from the time of randomization to initiation of dialysis   
- Overall level of alloantibody as indicated by PRA.   
- Incidence of infectious complications.   
8.3 
Analyses 
8.3.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics of subjects will be summarized descriptively by 
means and standard deviations for continuous variables and frequency distribution for 
categorical variables.  Summaries will be performed based on all randomized subjects. 
8.3.2 
Safety Analyses 
All adverse events and serious adverse events will be summarized by treatment group.  
Serious adverse events will be collected and summarized following the subject’s written 
consent to participate in the study.  Non-serious adverse events will be collected and 
summarized beginning at the time of randomization.  Laboratory abnormalities will be 
descriptively summarized. 


 
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8.3.3 
Efficacy Analyses 
There will be two main methods of analyzing the primary outcome at the study end.  One 
will be a chi-squared test comparing the proportion of patients who developed donor 
specific antibodies in each study group.  The second analysis will be a log-rank test 
comparing the Kaplan-Meier time to event curves between the two study groups.  In both 
cases we will use a two-sided test with a significance level of 0.05.   
The sample size for each arm will be 36 patients.  This sample size calculation is based 
on several assumptions.  We assume that the incidence of developing donor-specific 
antibody among the control group is 60% and among the belatacept-treated group it is 
20% or less.  We also assume an alpha level of 0.05 and corresponding Z-alpha = 1.96 
and a one-to-one ration of exposed to unexposed subjects.  Calculations with these 
estimates yield a power of 90% to detect a three-fold difference in risk of developing 
donor specific antibodies between the control and belatacept-treated group.   
In addition to the aforementioned assumptions, additional assumptions required for the 
log-rank test include no loss to follow-up in 36 months and that the distribution of the 
incidence of the primary endpoint follows an exponential distribution.  Assuming an 
incidence of development of anti-donor antibody in the control group is 60% at 36 
months then the hazard rate can be calculated as 0.02545.  In the treatment arm, if the 
incidence of the primary endpoint is 30% then the hazard ratio becomes 0.0099 and if the 
incidence is 20% then the hazard rate is 0.00619. 
Analysis of secondary endpoints will be performed at the end of the study period. 
Differences in the mean level of allo-antibody (ie PRA) by control and belatacept-treated 
groups will be compared using a t-test statistic. The rate of decline of GFR among the 
belatacept group will be compared to the rate of decline of the control group using a Rate 
Ratio and corresponding 95% Confidence Intervals using the Mantel-Haenszel chi-square 
test statistic for significance. The time from randomization to initiation of dialysis will be 
compared between groups using Kaplan-Meier analysis and the log-rank test for 
significance. The small subset of subjects already requiring dialysis at the time of 
enrollment will be excluded from this analysis. The incidence of overall infectious 
episodes will be compared among the belatacept vs. control group by calculating a Risk 
Ratio and corresponding 95% Confidence Intervals and using the Mantel-Haenszel chi-


 
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square test statistic for significance. For all secondary endpoint analyses, two-tailed p 
<0.05 will be considered statistically significant.   
Interim analyses will be performed at 18 months to compare the primary endpoint 
between the belatacept-treated and control groups, using the log-rank test for 
significance.  A two-sided test with a more stringent significance level of 0.001 will be 
used to preserve the overall significance level of the trial. 
9 
ADMINISTRATIVE SECTION 
9.1 
Compliance with the Protocol 
The study must be conducted as described in the final IRB/IEC-approved protocol. 
Documentation of approval, signed by the IRB/IEC chairperson or designee, will be sent 
to the BMS protocol manager. 
All protocol amendments and revisions to the informed consent will be submitted to the 
BMS protocol manager and to the IRB/IEC. No protocol amendments will be 
implemented until written approval has been given by the IRB/IEC, except when 
necessary to eliminate an immediate hazard to study subjects. Administrative letters 
should also be sent to the BMS protocol manager and IRB/IEC; however, they do not 
require approval.  
If a protocol amendment mandates a revision to the informed consent, the revised consent 
must be used to obtain consent from subjects currently enrolled in the study if it affects 
them (eg, if it contains new information regarding safety), and the revised consent must 
be used to obtain consent from new subjects before enrollment.  
9.2 
Records Retention 
The investigator will retain, in a confidential manner, all data pertinent to the study for all 
treated subjects as well as those entered as control subjects. The investigator will retain 
source documents and accurate case histories that record all observations and other data 
pertinent to the investigation (eg, the medical record) for the maximum period required 
by applicable regulations and guidelines or following institutional procedures. If the 
investigator withdraws from the study (eg, relocation or retirement), the records will be 
transferred to a mutually agreed upon designee, such as another investigator or an IRB. 
Written documentation of such transfer will be provided to BMS.  


 
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The investigator will ensure that a current record of disposition of investigational product 
is maintained at each study site where the investigational product is inventoried and 
disposed. Records or logs must comply with applicable regulations and guidelines and 
should include:  
• amount received and placed in storage area 
• amount currently in storage area 
• label identification number or batch number and use date or expiry date 
• dates and initials of person responsible for each inventory entry/movement 
• amount dispensed to and returned by each subject, including unique subject 
identifiers 
• amount transferred to another area/site for dispensing or storage 
• non-study disposition (eg, lost, wasted, broken), and 
• amount destroyed at study site. 
9.3 
Destruction of Investigational Product 
If the investigational product is to be destroyed on site, it is the investigator’s 
responsibility to ensure that arrangements have been made for disposal, and that 
procedures for proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. Appropriate records of the disposal must be 
maintained. 


 
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10 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 
 


 
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11 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
APC 
Antigen Presenting Cell 
AUC 
Area Under the Concentration-Time Curve 
AUD(0-T) 
Area Under the Concentration-Time Curve from time zero to 
the time of the last quantifiable concentration 
AUC(INF) 
Area Under the Concentration-Time Curve from time zero 
extrapolated to infinity 
AUC(TAU) 
Area Under the Concentration-Time Curve in 1 dosing 
interval 
AZA 
Azathioprine (Imuran) 
BMS 
Bristol-Myers Squibb 
BPAR 
Biopsy-Proven Acute Rejections 
CLT 
Total Body Clearance 
Cmax 
Maximum Plasma Concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CsA 
Cyclosporine 
CSBPAR 
Clinically-Suspected and Biopsy-Proven Acute Rejection 
D5W 
5% Dextrose for Injection 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
LI 
Less Intensive 
LTE 
Long Term Extension 
MI 
More Intensive 
MMF 
Mycophenolate Mofetil (Cellcept) 
MPA 
Mycophenolic Acid (Myfortic) 
NCI 
National Cancer Institute 
NS 
Normal Saline 


 
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NSAE 
Non-Serious Adverse Event 
PK 
Pharmacokinetics 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SWFI 
Sterile Water for Injection 
T-HALF 
Half-Life 
VNS 
Vial, Needle, Syringe 
VSS 
Steady-State Volume of Distribution 
WOCBP 
Women of Child-Bearing Potential 
 


 
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12 
REFERENCES 
 
1    Study No. 98642: BMS-224818: Single-dose intravenous toxicity and toxicokinetics 
study in monkeys. Bristol Myers Squibb Pharmaceutical Research Institute; 1998. 
Document Control No. 910069252. 
2    Study No. 98699: BMS-224818: One-month intermittent-dose intravenous toxicity 
and toxicokinetics study in monkeys. Bristol Myers Squibb Pharmaceutical Research 
Institute; 1999. Document Control No. 910056595. 
3    Study No. 99655 Amended Report: BMS-224818: Six month intermittent-dose 
intravenous toxicity and toxicokinetics study in monkeys. Bristol Myers Squibb 
Pharmaceutical Research Institute; 2004. Document Control No. 920007203. 
4    Dodge R and Abraham R. Review of historical in vitro potency and binding data for 
BMS-224818 (LEA29Y) in murine cells and to murine B7 molecules. Bristol-Myers 
Squibb Pharmaceutical Research Institute; 2004. Document Control No. 930023829. 
5   Study No. DS02008: BMS-188667: One-year intermittent-dose intravenous toxicity 
and toxicokinetic study in monkeys, Bristol Myers Squibb Pharmaceutical Research 
Institute; 2004. Document Control No. 930002781. 
6    Study Nos. 092804klh, 102704klh, and 020805klh: Efficacy comparison of abatacept 
and belatacept in murine primary immune response model. Bristol-Myers Squibb 
Pharmaceutical Research Institute; Document Control No. 930019020. 
7    Study No. DS04256: Belatacept and abatacept: Two-week intermittent-dose 
intravenous exploratory study in rats. Bristol Myers Squibb Pharmaceutical Research 
Institute; 2005. Document Control No. 930009642. 
8    Study DS04284: Belatacept (BMS-224818) and abatacept (BMS 188667): Two week 
intermittent-dose intravenous exploratory bioactivity and pharmacokinetics study in 
rats. Bristol-Myers Squibb Pharmaceutical Research Institute; 2005. Document 
Control No. 930013223. 
 


 
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9    Study No. DS05055: Belatacept (BMS-224818) and BMS 188667 (abatacept): Two-
week intermittent dose intravenous exploratory bioactivity and pharmacokinetics 
study in rats. Bristol-Myers Squibb Pharmaceutical Research Institute; 2006. 
Document Control No. 930015077. 
10    
Study No. DS04252: BMS-224818 and abatacept: Two week intermittent-dose 
intravenous 
exploratory 
study 
in 
female 
rabbits. 
Bristol-Myers 
Squibb 
Pharmaceutical Research Institute; 2005. Document Control No. 930009600. 
11    
Study No. DS04287: Belatacept and abatacept: Two week intermittent-dose 
intravenous exploratory bioactivity and pharmacokinetics study in female rabbits. 
Bristol-Myers Squibb Pharmaceutical Research Institute; 2006. Document Control 
No. 930013910. 
12    
Study No. 96633 Amended Report: BMS-188667: Six month intermittent-dose 
(qw x 26) subcutaneous toxicity study in mice. Bristol Myers Squibb Pharmaceutical 
Research Institute; 2004. Document Control No. 910066124. 
13   Study No. DS02008: BMS-188667: One-year intermittent-dose intravenous toxicity 
and toxicokinetic study in monkeys, Bristol Myers Squibb Pharmaceutical Research 
Institute; 2004. Document Control No. 930002781. 
14   Study IM103001: A phase I, randomized, double blind, placebo controlled study to 
assess the safety, pharmacokinetics, and immunogenicity of escalating doses of BMS 
224818 given as a single intravenous infusion to healthy subjects. Clinical study 
report. Bristol Myers Squibb Pharmaceutical Research Institute; 2006. Document 
Control No. 930017678. 
15   Study IM103029: A study to assess the pharmacokinetics, safety, and 
immunogenicity of single doses of belatacept (BMS-224818) administered 
subcutaneously to healthy subjects. Executive summary. Bristol Myers Squibb 
Pharmaceutical Research Institute; 2006. Document Control No. 930018069. 
 


 
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16   Study IM103002: A pilot, multi center, randomized, double-blind, placebo controlled 
study to evaluate the safety, preliminary clinical activity and immunogenicity of 
multiple doses of BMS 188667 and BMS 224818 administered intravenously to 
subjects with rheumatoid arthritis. Clinical study report. Bristol Myers Squibb 
Pharmaceutical Research Institute; 2004. Document Control No. 930001816. 
17  Study IM103024: Study to compare the pharmacokinetics of phase III process C 
belatacept (BMS 224818) to phase II process B belatacept in healthy subjects. 
Clinical study report. Bristol Myers Squibb Pharmaceutical Research Institute; 2006. 
Document Control No. 930018756. 
18   Study IM103100: Open-label randomized, controlled, multiple dose study of efficacy 
and safety of BMS 224818 as part of a quadruple drug regimen in renal transplant 
recipients. Clinical study report (12-month analysis). Bristol Myers Squibb 
Pharmaceutical Research Institute; 2006. Document Control No. 930016865. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 1:  DSMB Charter  
 
Belatacept Therapy for the Failing Renal Allograft (Protocol IM103-133) 
 
Dr. Idelberto R. Badell, M.D., Principal Investigator  
Emory University 
 
The Data Safety Monitoring Board (DSMB) will act in an advisory capacity to monitor 
patient safety and evaluate the efficacy of the intervention. Dr. Idelberto R. Badell, 
Emory University, Atlanta, GA is conducting a clinical trial entitled, Belatacept Therapy 
for the Failing Renal Allograft (Protocol IM103-133).  
At periodic intervals as described in the study protocol, the DSMB responsibilities are to:  
• 
review the research protocol, informed consent documents and plans for data 
safety and monitoring;  
• 
evaluate the progress of the trial, including periodic assessments of data quality 
and timeliness, participant recruitment, accrual and retention, participant risk 
versus benefit, performance of the trial site, and other factors that can affect study 
outcome;  
• 
consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an impact 
on the safety of the participants or the ethics of the trial;  
• 
review clinical center performance, make recommendations and assist in the 
resolution of problems reported by the PI;  
• 
protect the safety of the study participants;  
• 
report on the safety and progress of the trial;  
• 
make recommendations to the the PI, and, if required, to the FDA concerning 
continuation, termination or other modifications of the trial based on the observed 
beneficial or adverse effects of the treatment under study;  
• 
if appropriate, conduct interim analysis of efficacy;  
• 
ensure the confidentiality of the trial data and the results of monitoring  
 
 
 


 
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MEMBERSHIP  
The Data Safety Monitoring Board will consist of 3 members. Two members will 
constitute a quorum. Membership consists of persons completely independent of the 
investigators who have no financial, scientific, or other conflict of interest with the trial. 
The DSMB includes experts in or representatives of the fields of:  
• 
Transplant Surgery,  
• 
Transplant Nephrology 
• 
General nephrology  
• 
Department of Pathology and Laboratory Medicine 
Dr. Avinash Agarwal,  University of Virginia has been selected to serve as the 
chairperson. He is responsible for overseeing the meetings, developing the agenda in 
consultation with the PI. The chair is the contact person for the DSMB.  
 
Board Process  
The first review of data by the DMC will occur either after 10 subjects have been 
enrolled and randomized or approximately 6 months after the first subject is enrolled, 
whichever comes first.   The second review of the data by the DMC will occur either after 
30 subjects have been enrolled or 6 months after the first patient is enrolled, whichever 
comes first.  Subsequent reviews of data by the DMC will occur every 3 months during 
the remainder of the first year and approximately every 6 months thereafter. 
Meetings will be conducted via teleconference and scheduled/coordinated by the site 
study team. Meetings will be attended by the principal investigator and members of 
his/her staff. An emergency meeting of the DSMB may be called at any time at the 
request of the PI or the DMC Chairperson should questions of patient safety arise.  
REPORTS  
Interim Reports. Interim reports will be prepared by the study team and distributed to the 
DSMB at least 3 business days prior to a scheduled meeting. Additions and modifications 
to the content of the reports may be directed by the DSMB. Interim data reports generally 
consist of two parts. Part 1 provides information on study aspects such as accrual, 
baseline characteristics, and other general information on study status. Part 2 may contain 
data on study outcomes, including safety data and depending on the study, perhaps 
efficacy data. Reports are considered confidential. Data files to be used for interim 
 


 
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analyses should have undergone established editing procedures to the extent possible. 
Interim analyses of efficacy data are performed only if they are specified and approved in 
advance and criteria for possible stopping is clearly defined.  
Reports from the DSMB. A formal report from the Chair will be sent to the full DSMB 
within 3 weeks of the meeting. Once approved by the DSMB, the Chair will forward the 
approved minutes to the PI within 6 weeks of each meeting.  
Each report should conclude with a recommendation to continue or to terminate the 
study. This recommendation should be made by formal majority vote. A termination 
recommendation may be made by the DSMB at any time by majority vote. The Chair 
should transmit such a recommendation to the PI as rapidly as possible, by immediate 
telephone if sufficiently urgent. In the event of a split vote in favor of continuation, a 
minority report should be contained within the regular DSMB report. The report should 
not include unblinded data, discussion of the unblinded data, etc.  
Mailings to the DSMB: On a scheduled basis (as agreed upon by the DSMB) blinded 
safety data should be communicated to all DSMB members. Any concerns noted should 
be brought to the attention of the Chair who will take appropriate action.  
Access to Interim Data: Access to the accumulating endpoint data should be limited to as 
small a group as possible. Limiting the access to interim data to the DSMB members 
relieves the investigator of the burden of deciding whether it is ethical to continue to 
randomize patients and helps protect the study from bias in patient entry and/or 
evaluation.  
 
CONFIDENTIALITY  
All materials, discussions and proceedings of the DSMB are completely confidential. 
Members and other participants in DSMB meetings are expected to maintain 
confidentiality. 
 
 
 
 
 
 
 
 
 
 
 


 
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DSMB Membership 
 
Chair: 
 
Avinash Agarwal, MD 
Assistant Professor of Surgery 
University of Virginia 
 
Membership: 
 
Colleen S. Kraft, MD, MSc 
Associate Professor, Department of Pathology and Laboratory Medicine 
Associate Professor, Division of Infectious Diseases 
Emory University Hospital 
 
Wasim A. Dar, MD, PhD 
Assistant Professor of Surgery 
McGovern Medical School University of Texas Houston