Conditions: Proteinuria
Keywords: Proteinuria Kidney transplantation Allograft dysfunction B7-1 Belatacept
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
Background: Proteinuria develops in about 30% of kidney transplant recipients and is a strong predictor of graft loss. The amount of proteinuria has a direct correlation with the risk of graft failure. Novel therapies are urgently needed to reduce proteinuria and prevent graft loss in transplant recipients, since ACE inhibitors carry a number of limitations in the transplant setting, including significant reduction in renal function, anemia and hyperkalemia.

Preliminary data: B7-1 is expressed at significant levels in about 10% of kidney allograft biopsies with predominance in patients with proteinuria.

Hypothesis: We hypothesize that B7-1 targeting therapy may reduce proteinuria and improve graft survival in proteinuric transplant recipients that have B7-1 staining on allografts. In addition, the absence of CNI nephrotoxicity and the potential protective effect of Belatacept on DSA production may be of benefit in this subset of transplant patients.

Objectives:

Primary: Determine the effect of Belatacept conversion in reducing proteinuria by 25% at 12 months in renal transplant recipients (≥1gram/d) that are either B7-1-positive or negative on kidney biopsy.

Secondary: Assess the effect of Belatacept conversion in the percent change of renal function from baseline to 12 months; donor-specific anti-HLA antibodies presence and intensity (MFI); correlation of B7-1 positivity on immunofluorescence on biopsy with B7-1-expression in urine extracellular vesicles; adverse events; acute rejection episodes; blood pressure control; new onset diabetes; hyperlipidemia; graft survival; and patient survival.

Detailed description:
A total of 36 patients will be recruited.

Arms:
arm 1: Belatacept conversion

Interventions: intervention 1: Belatacept
Intervention descriptions: intervention 1: Conversion from calcineurin-inhibitor to Belatacept maintenance immunosuppression.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Page 1 of 19 
 
Belatacept Conversion in Proteinuric Renal Transplant Recipients and B7-1 Positivity 
Status on Biopsy: an Interventional Multi-Center Trial 
 
Version Date: 09-July-2019 
 
 
Short Title: B7-1 Study 
 
 
Institutional (Partners IRB) #2015P000154 
NCT02327403 (clinicaltrials.gov) 
IND 125511 
 
Sponsor: Leonardo Riella, MD, PhD 
Funding Source/Drug Supplier: Bristol-Myers Squibb (BMS) 
BMS ISR Protocol number: IM103-363 
 
 
Study Sponsor/Overall Principal Investigator/IND holder: 
Leonardo V. Riella, MD, PhD 
Brigham and Women’s Hospital (BWH), Harvard Medical School (HMS) 
Transplantation Research Center (TRC), 221 Longwood Ave, Room 303 
Boston, MA 02115 
Ph: 617-710-4600 
FAX: 617-732-5254 
Email: lriella@bwh.harvard.edu 
 
Medical Monitor (MM)/DSMB Chair (available 24/7) : 
Paulo Martins, MD 
508-868-1706 
 
Study Clinical Research Coordinator/Accounts Payable: 
Chelsea Ituah 
BWH CCI 
221 Longwood Ave, Boston, MA 02115 
Office Phone: 617-525-6823 
 
Central Laboratory [(Transplantation Research Center, (TRC)] Technician:  
Sudipta Tripathi, PhD 
Brigham & Women’s Hospital  
Transplantation Research Center, EBRC  
221 Longwood Avenue, Boston, MA  02115 
Office Phone: 617-732-5812 
FAX: 617-732-5254 
Email: Sudipta.Tripathi@childrens.harvard.edu 
 
 
 
 


 
 
Page 2 of 19 
I. Study Synopsis 
 
Background: Proteinuria develops in about 30% of kidney transplant recipients and is a strong 
predictor of graft loss. The amount of proteinuria has a direct correlation with the risk of graft 
failure. Novel therapies are urgently needed to reduce proteinuria and prevent graft loss in 
transplant recipients, since ACE inhibitors carry a number of limitations in the transplant 
setting, including significant reduction in renal function, anemia and hyperkalemia.   
 
Preliminary data: B7-1 is expressed at significant levels in about 10% of kidney allograft biopsies 
with predominance in patients with proteinuria.   
 
Hypothesis: We hypothesize that B7-1 targeting therapy may reduce proteinuria and improve graft 
survival in proteinuric transplant recipients that have B7-1 staining on allografts. In addition, 
the absence of calcineurin inhibitor (CNI) nephrotoxicity and the potential protective effect of 
Belatacept on DSA production may be of benefit in this subset of transplant patients.  
 
Objectives: 
 
Primary: Determine the effect of Belatacept conversion in reducing proteinuria by 25% at 12 
months in renal transplant recipients (≥1gram/d) that are either B7-1-positive or negative on 
kidney biopsy.  
 
Secondary: Assess the effect of Belatacept conversion in the percent change of renal function 
from baseline to 12 months; donor-specific anti-HLA antibodies presence and intensity (MFI); 
correlation of B7-1 positivity on immunofluorescence on biopsy with B7-1-expression in urine 
extracellular vesicles; adverse events; acute rejection episodes; blood pressure control; new 
onset diabetes; hyperlipidemia; graft survival; and patient survival.  
 
Study design:  
 
 
 
Inclusion Criteria: 
1. Male or female adult kidney transplant recipients older than 18 years old 
2. eGFR ≥30 ml/min  
3. ≥6 months after transplantation 
4. Proteinuria ≥1 gram/day in spot urine protein/creatinine ratio  
5. Available biopsy specimen for B7-1 staining at recruitment time. 
6. Ability to provide written informed consent for the study. 
7. Maintenance immunosuppression of CNI (cyclosporine or tacrolimus), antiproliferative agent 
(azathioprine, MMF or MPA) with either steroids or not.  
8. Must be EBV IgG positive 
 
Exclusion Criteria:  
1. Age <18 years 


 
 
Page 3 of 19 
2. eGFR<30 ml/min 
3. active acute cellular rejection (ACR; higher than borderline) or ACR in the previous 6 months; 
active acute antibody-mediated rejection.  
4. recurrent FSGS 
5. EBV IgG negative 
6. patient on mTOR inhibitor (e.g. Everolimus, Sirolimus) 
7. patient only on CNI (cyclosporine or tacrolimus) and steroids 
 
Accrual Goal: 36 subjects, 3 study sites 
Accrual Rate: approximately 2 subjects/month; total of 18 months enrollment; 18 months of follow-up 
First Patient First Visit: 1-March-2015 
 
Statistics: This is a Phase I clinical trial to test the safety and gain further insight into the potential effect 
of Belatacept in proteinuric kidney transplant patients.  We plan to recruit 36 patients, based on the 
feasibility for recruitment in 3 transplant centers and prior literature on recommended sample sizes in a 
Phase I trial.  
 
2. Background:  
 
Although improvements in immunosuppression have led to a 
reduction in acute rejection rates, long-term allograft survival 
remains disappointing, with more than 50% of allografts lost 10 
years after transplantation.  
 
Proteinuria develops in about 30% of kidney transplant 
recipients and is strong predictor of graft loss (1-3). The 
amount of proteinuria has a direct correlation with the risk of 
graft failure (Figure 1). More than 80% of patients with 
proteinuria greater than 1500 mg/d have evidence of allograft 
glomerular 
pathology. 
Among 
these, 
transplant 
glomerulopathy is the leading etiology in about 45% of cases 
followed by recurrent glomerular disease (25%) (4, 5). Patients 
with more than 1 gram/day of proteinuria after transplantation 
carry a dismal prognosis more than 50% of grafts lost after a 
mean follow up of 5 years (4). The proteinuria on these patients 
continues to progress and kidney function deteriorates until grafts are lost with no effective therapy to 
halt this progression, therefore the need to establish novel therapies for this subset of transplant 
patients.  
  
KDIGO guidelines recommend ACEI/ARB in post-transplant proteinuric patients though there is no clear 
evidence that this approach improves renal transplant survival (6, 7). In contrary, ACEI/ARB have been 
associated with significant decrease in renal function, anemia and hyperkalemia post-transplantation. 
Novel therapies are urgently needed to reduce proteinuria and prevent graft loss in transplant recipients. 
 
It has been recently published that Abatacept is able to reduce proteinuria in patients with B7-1–
positive glomerular disease by stabilizing β1-integrin activation in podocytes (8). However, 
prevalence of positive B7-1 staining in renal allografts and a possible role of B7-1 target therapy in the 
treatment of proteinuria post-transplantation remains to be explored. 
  
3. Preliminary Data:  
Figure 1. Risk of graft failure according to 
degree of proteinuria.  


 
 
Page 4 of 19 
 
Using a goat anti-human B7-1 (CD80) antibody, we 
performed immunostaining for B7-1 on frozen sections of 
123 clinically indicated kidney transplant biopsies 
obtained between 2011 and 2012. Fifteen patients had 
≥1+ B7-1 staining on glomeruli at podocyte location 
(Figure 2). The predominant pathologic diagnosis among 
those 
with 
B7-1 
positivity 
was 
transplant 
glomerulopathy (46%). In addition, 27% of patients with 
≥1+ B7-1 staining in their biopsies had nephrotic range 
proteinuria (4 out of 15) and 50% of allograft biopsies 
obtained from patients with nephrotic syndrome stained 
positive for B7-1 (4 out of 8). In sum, B7-1 is expressed 
at significant levels in about 10% of kidney allograft 
biopsies. 
   
 
4. Hypothesis: 
We hypothesize that B7-1 targeting therapy may reduce proteinuria and improve graft survival in 
proteinuric transplant recipients that have B7-1 staining on allografts. In addition, the absence of CNI 
nephrotoxicity and the potential protective effect of Belatacept on DSA production may be of benefit in 
this subset of transplant patients (9, 10). 
 
5. Objectives: 
Primary: Determine the effect of Belatacept conversion in reducing proteinuria by 25% at 12 months 
in renal transplant recipients that have more than 1 gram of proteinuria per day and are either B7-1-
positive or negative on kidney biopsy.  
Secondary: Assess the effect of Belatacept conversion in the percent change of renal function from 
baseline to 12 months; donor-specific anti-HLA antibodies presence and intensity (MFI); correlation of 
B7-1 positivity on immunofluorescence on biopsy with B7-1-expression in urine extracellular vesicles; 
adverse events; acute rejection episodes; blood pressure control; new onset diabetes; hyperlipidemia; 
graft survival; and patient survival.  
 
6. Proposal: 
We propose to perform a multi-center 
study in which adult kidney transplant 
recipients with proteinuria (≥1g/day) 
will be converted from CNI to 
Belatacept (Figure 3) once B7-1 
staining has been performed on 
allograft biopsy (Dr Astrid Weins will 
be performing all stains). This is a 
Phase I study that will aim to enroll 36 
patients in 18-month recruitment time 
involving 3 transplant sites. Other 
inclusion criteria include: eGFR >30 
ml/min, greater than 6 months post-
transplant and EBV IgG positive 
status. Exclusion criteria include: 
age <18 years, eGFR<30 ml/min, 
active acute cellular rejection (ACR; 
higher than borderline) or ACR in the previous 6 months, recurrent FSGS, EBV IgG negative status and 
on mTOR inhibitor as maintenance immunosuppression. 
 
Patients that develop proteinuria after transplant are a heterogenous group with many potential 
Figure 2. B7-1 staining in kidney transplant 
biopsies.  
Figure 3. Study Design. Protocol and outcomes measures are detailed.  


 
 
Page 5 of 19 
underlying etiologies including calcineurin inhibitor toxicity, transplant glomerulopathy, BK nephropathy 
or recurrent glomerular disease (4). Therefore, we decided to enroll 12 patients per center (3 centers 
total) to allow the inclusion of different etiologies of proteinuria and be a feasible study based on our 
inclusion criteria.  
 
By including both B7-1 positive and B7-1 negative patients with proteinuria in the study, we will have 
the best chance of success and it would also allow for future testing for other potential prognostic 
markers in this population. One of the main reasoning’s behind this is that the B7-1 staining is 
undergoing further optimization by Dr. Astrid Weins and a NIH task force, and therefore, restricting our 
recruitment may limit interpretation of the data in case the staining changes. This has been previously 
shown to be most productive approach in biomarker-driven interventions in the cancer field (11). In 
addition, the exact mechanism in which is B7-1 targeting reduce proteinuria is still debated. By including 
both B7-1 positive and B7-1 negative patients with proteinuria, we will be able to assess overall risk 
factors and have a control group with no B7-1 staining treated with Belatacept.  A historical control 
group with patients that fit the inclusion criteria and were managed as standard of care at our institution 
will also be included for comparison. 
 
 
 
 
The primary endpoint of the study will be a 25% reduction in proteinuria from baseline to 12 months. 
This endpoint was extrapolated from studies with ACE inhibitors showing significant benefit in patients 
with kidney disease and proteinuria that reached this endpoint (12). Secondary end-points include: 
percent change of renal function from baseline to 12 months; 
donor-specific anti-HLA antibodies presence and intensity 
(MFI); correlation of B7-1 positivity on immunofluorescence 
on biopsy with B7-1-expression in urine extracellular 
vesicles; adverse events; acute rejection episodes; blood 
pressure control; new onset diabetes; hyperlipidemia; graft 
survival; and patient survival. At 18 months, we will perform 
a chart review to check if patient remained or not on 
Belatacept, their renal function, proteinuria and biopsy-
proven rejection events since trial termination.  
 
 
Developing a urinary biomarker to non-invasively detect 
patients with B7-1 expression on allografts is another 
goal of this study. This will not only allow monitoring of 
treatment effectiveness and serving as secondary end-points 
but will also permit non-invasively screening for B7-1 
positivity in patients in the future. Briefly, we will isolate RNA 
from urinary extracellular vesicles (EVs) of transplanted 
patients and detect B7-1 mRNA using “Droplet Digital” PCR 
system. EVs such as exosomes (40-100 nm in diameter) and 
microvesicles (100-1000 nm) are nanometer-sized vesicles 
released by cells including kidney podocytes to mediate cell-
to-cell communication by delivering proteins and genetic materials such as mRNAs and microRNAs 
(13). We hypothesize that podocytes expressing B7-1 will shed EVs into the urine that will carry B7-1 
mRNA. Dr. Jamil Azzi’s laboratory at the Transplantation Research Center (Co-Investigator) optimized 
the isolation of high quality and quantity of RNA from urinary EVs of transplant patients (Figure 4).  
 
Enrolled patients will have serum and urine collected at time of conversion and 12 months post-
conversion. Urine will be processed for extracellular vesicles (EVs) and mRNA isolation. Samples will 
be stored at minus 80 degrees Celsius freezer until analysis. Future alternative approaches for 
characterization of B7-1 expression on kidney allografts involve determination of urinary B7-1 mRNA 
 
 
 
Figure 4. A, Electron Microscopy of urinary 
exosomes from a kidney transplant recipient 
labeled with exosomal marker, CD63. B, High 
sensitivity RNA analysis of urinary EVs. 
Urinary EVs were isolated from urine (average 
35 ml) of a kidney transplant recipient followed 
by RNA isolation Agilent Bioanalyzer RNA for 
qualitative and quantitative analysis of RNA. 
B 


 
 
Page 6 of 19 
by PCR and laser micro-dissection of glomerulus on biopsy sample followed by measurement of B7-1 
by QT-PCR. 
 
Sample size calculation: This is a Phase I clinical trial to test the safety and gain further insight into 
the potential effect of Belatacept in proteinuric patients.  We plan to recruit 36 patients, based on the 
feasibility for recruitment in 3 transplant centers and prior literature on recommended sample sizes in 
Phase I trials.(14, 15).  
 
Impact: Causes of long-term graft loss are heterogenous and it is clear that the one-size-fits-all 
approach in transplantation is deemed for failure. Therefore, we believe that the identification of 
abnormal B7-1 expression in proteinuric kidney transplant recipients may permit the application of a 
personalized target therapy that will have a higher likelihood of success, avoiding the use of costly 
ineffective agents, minimizing their adverse effects and potentially improving long-term graft survival. 
Lastly, prior work from our laboratory has shown some promising results in B7 targeting in experimental 
models of chronic allograft rejection (16, 17) and more recent work supports an effective role of B7 
targeting in suppressing humoral response through significant reduction in T follicular helper cells (18). 
Both findings support additional pathophysiological mechanisms involving not only podocytes but the 
immune system in contributing to obtain favorable results in this proposed study. 
 
Ethical considerations: 
All study investigators and study staff must follow all appropriate requirements, including Good Clinical 
Practice (GCP), International Conference on Harmonization (ICH), Code of Federal Regulations (CFR), 
and the Partners Human Research Committee (PHRC) Institutional Review Board (IRB).  The study will 
be conducted in compliance of the protocol.  The protocol, all amendments, and the subject informed 
consent will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval/favorable opinion before initiation of the study.  Study personnel must be qualified by 
education, training and experience to perform their respective tasks, and will not utilize personnel for 
whom sanctions have been invoked or where there has been scientific misconduct or fraud. 
Appropriate study personnel will obtain signed and dated informed consent from each study participant.  
[Investigators will ensure that subjects, or their legally acceptable representatives, are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding this clinical research 
study in which they voluntarily participate.  The approved consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.  All relevant safety information regarding 
the dose/schedule of study drug, or any other drugs/procedures in this clinical study must be explained 
in the informed consent document.  Informed consent will also delineate which authorities may have 
direct access to study records and documents.  Consent will also clearly state that although Dr. 
Leonardo Riella is the study sponsor, Bristol-Myers Squibb (BMS) is the study funding source and is 
also supplying study drug for this study.  
 
7. Eligibility: 
7.1 Inclusion Criteria: 
- 
Deceased or living donor adult kidney transplant recipients older than 18 years old 
- 
eGFR >30 ml/min  
- 
>6 months after transplantation 
- 
Proteinuria >1 gram/day in spot urine protein/creatinine ratio  
- 
Available biopsy specimen for B7-1 staining at recruitment time. 
- 
Ability to provide written informed consent for the study. 
- 
Must be EBV IgG positive 
7.2 Exclusion Criteria: 
-     Age <18 years 
- 
eGFR<30 ml/min 
- 
Active acute cellular rejection (ACR; higher than borderline) or ACR in the previous 6 months; 
active acute antibody-mediated rejection. 
- 
Recurrent FSGS 
- 
EBV IgG negative 


 
 
P a g e 7  of 1 9  
- 
P ati e nt o n m T O R i n hi bit or  ( e. g. E v er oli m u s, Sir ol m u s) 
- 
A g e a n d R e pr o d u cti v e St at u s : 
 
7. 3 A g e a n d R e pr o d u cti v e St at u s  
 
•  
W o m e n of c hil d b e ari n g p ot e nti al ( W O C B P) m u st h a v e a n e g ati v e s er u m or uri n e 
pr e g n a n c y t e st ( mi ni m u m s e n siti vit y 2 5 I U/ L or e q ui v al e nt u nit s of H C G) wit hi n 2 4 
h o ur s pri or t o t h e st art of st u d y dr u g.  
 
•  
W o m e n m u st n ot b e br e a stf e e di n g  
 
•  
W O C B P a n d m al e s u bj e ct s wit h r e pr o d u cti v e p ot e nti al m u st a gr e e t o f oll o w i n str u cti o n s 
f or m et h o d( s) of c o ntr a c e pti o n f or t h e d ur ati o n of tr e at m e nt wit h st u d y dr u g a n d f or f o ur 
( 4) m o nt h s p o st-tr e at m e nt c o m pl eti o n. 
 
•  
A z o o s p er mi c m al e s a n d W O C B P w h o ar e c o nti n u o u sl y n ot h et er o s e x u all y a cti v e ar e 
e x e m pt fr o m c o ntr a c e pti v e r e q uir e m e nt s.  H o w e v er , t h e y m u st still u n d er g o pr e g n a n c y 
t e sti n g a s d e s cri b e d i n t hi s s e cti o n. 
 
I n v e sti g at or s s h all c o u n s el W O C B P a n d m al e s u bj e ct s w h o ar e s e x u all y a cti v e wit h W O C B P o n t h e 
i m p ort a n c e of pr e g n a n c y pr e v e nti o n a n d t h e i m pli c ati o n s of a n u n e x p e ct e d pr e g n a n c y I n v e sti g at or s 
s h all a d vi s e W O C B P a n d m al e s u bj e ct s w h o ar e s e x u all y a cti v e wit h W O C B P o n t h e u s e of hi g hl y 
eff e cti v e m et h o d s of c o ntr a c e pti o n.  
 
Hi g hl y eff e cti v e m et h o d s of c o ntr a c e pti o n h a v e a f ail ur e r at e of < 1 % w h e n u s e d c o n si st e ntl y a n d 
c orr e ctl y.  
At a mi ni m u m, s u bj e ct s m u st a gr e e t o t h e u s e of o n e m et h o d of hi g hl y eff e cti v e c o ntr a c e pti o n a s li st e d 
b el o w:  
 
7. 4 HI G H L Y E F F E C TI V E M E T H O D S O F C O N T R A C E P TI O N  
  
•  
M al e c o n d o m s wit h s p er mi ci d e  
•  
H or m o n al m et h o d s of c o ntr a c e pti o n i n cl u di n g c o m bi n e d or al c o ntr a c e pti v e pill s, v a gi n al ri n g, 
i nj e ct a bl e s, i m pl a nt s a n d i ntr a ut eri n e d e vi c e s (I U D s) s u c h a s Mir e n a b y W O C B P s u bj e ct or 
m al e s u bj e ct’ s W O C B P p art n er   
•  
F e m al e  p art n er s  of  m al e  s u bj e ct s  p arti ci p ati n g  i n  t h e  st u d y  m a y  u s e  h or m o n e -b a s e d  
c o ntr a c e pti v e s  a s  o n e  of  t h e  a c c e pt a bl e  m et h o d s  of  c o ntr a c e pti o n  si n c e  t h e y  will  n ot  b e  
r e c ei vi n g st u d y dr u g  
•  
I U D s, s u c h a s P ar a G ar d 
•  
T u b al li g ati o n  
•  
V a s e ct o m y.  
•  
C o m pl et e A b sti n e n c e*  
 
* C o m pl et e a b sti n e n c e  i s  d efi n e d  a s  c o m pl et e  a v oi d a n c e  of  h et er o s e x u al  i nt er c o ur s e  a n d  i s  a n  
a c c e pt a bl e f or m of c o ntr a c e pti o n f or all st u d y dr u g s. F e m al e s u bj e ct s m u st c o nti n u e t o h a v e pr e g n a n c y 
t e st s. A c c e pt a bl e alt er n at e m et h o d s of hi g hl y eff e cti v e c o ntr a c e pti o n m u st b e di s c u s s e d i n t h e e v e nt 
t h at t h e s u bj e ct c h o o s e s t o f or e g o c o m pl et e a b sti n e n c e 
 
At a mi ni m u m, s u bj e ct s m u st a gr e e t o t h e u s e of t w o m et h o d s of c o ntr a c e pti o n, wit h o n e m et h o d b ei n g 
hi g hl y eff e cti v e a n d t h e ot h er m et h o d b ei n g eit h er hi g hl y eff e cti v e or l e s s eff e cti v e a s li st e d b el o w:  
 
7. 5  L E S S E F F E C TI V E M E T H O D S O F  C O N T R A C E P TI O N  
 
•  
Di a p hr a g m wit h s p er mi ci d e  


 
 
Page 8 of 19 
• 
Cervical cap with spermicide 
• 
Vaginal sponge 
• 
Male Condom without spermicide  
• 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
• 
Female Condom*. 
* A male and female condom must not be used together 
 
8. Study Drug: Belatacept (Treatment with Belatacept will continue for 12 months)**: 
Belatacept conversion dosing:  5 mg/kg IV on days 1, 15, 29, 43 and 57, followed by an infusion every 
28 days thereafter. Calcineurin inhibitors (CNI) Taper: CNI dose will remain the same for week 1 and 
then will be tapered by 25% each week and discontinued at the end of week 4 (day 29). 
 
Infusion pre-medications: none 
Duration of Infusion: 30 minutes 
Observation period post-infusion: none 
 
Standard of Care (SOC) Dosing of Belatacept: 
5 x the patient’s weight (in kg) = mg of Belatacept.  Dose then needs to be rounded to the nearest 12.5 
mg increment.  Example:  74 kg patient x 5 = 370 mg; rounded to the nearest 12.5 mg increment = 375 
mg.  At the end of 12 months, study subjects have completed the study drug protocol and they have 
the option to continue on Belatacept treatment, paid for by their medical insurance, or they can switch 
back to a CNI. 
 
**Please see additional important study drug information on pages 11-12. 
 
8.1 Potential Risks of Belatacept 
8.1.1 Acute Rejection 
Acute rejection is expected to be the principle risk in this study. In quantitative terms, the 
magnitude of renal function benefit necessary to offset the risk of incremental acute rejection (up to 
10% based upon historical experience in the conversion setting) is not well characterized. Further, 
opinion among treating clinicians may vary based upon a number of factors, including individual patient 
needs and the clinician’s assessment of the relative importance of rejection versus renal function as 
predictors of long-term outcomes. Thus, it is anticipated that a comprehensive review of the totality of 
safety and efficacy data will be necessary in order to characterize the clinical importance of acute 
rejection. The long-term data is reassuring since even patients that developed an episode of acute 
rejection had improved renal function when compared to CNI regimen at 5 years post-transplant.  
 
8.1.2 Post-transplant Lymphoproliferative Disorder (PTLD)- Black Box Warning 
WARNING:POST-TRANSPLANT 
LYMPHOPROLIFERATIVE 
DISORDER, 
OTHER 
MALIGNANCIES, AND SERIOUS INFECTIONS  
See full prescribing information for complete boxed warning.  
• 
Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), 
predominantly involving the central nervous system (CNS). Recipients without immunity 
to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV 
seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV 
seronegative or with unknown serostatus.  
• 
Only physicians experienced in immunosuppressive therapy and management of kidney 
transplant patients should prescribe NULOJIX.  
• 
Increased susceptibility to infection and the possible development of malignancies may 
result from immunosuppression.  
• 
Use in liver transplant patients is not recommended due to an increased risk of graft loss 
and death.  
 
PTLD is a known complication of immunosuppression in renal transplant recipients. In the core 


 
 
Page 9 of 19 
Belatacept studies in adults, the overall 3-year incidence rate of PTLD in Belatacept was consistent with 
published reports, the highest risk of PTLD with Belatacept was observed in EBV-negative subjects in 
whom a 13-fold increased risk of PTLD relative to EBV-positive patients was observed (9.9% in EBV- 
negative patients vs 0.7% in EBV-positive patients). Based upon these findings, Belatacept is 
contraindicated for use in patients with EBV serostatus negative or unknown. While there was also an 
increased risk in EBV-positive subjects with Belatacept compared to CsA within the studies, the 
absolute risk in this population was low. In addition to EBV-negative serostatus, CMV disease, and use 
of lymphocyte depleting therapy (LDT) for treatment of AR were also associated with an increased risk 
of PTLD in the core Belatacept studies. PTLD in Belatacept-treated patients was unusual in that a 
majority of cases presented in the CNS. The overall proportion of CNS PTLD in the Belatacept groups 
(MI and LI combined) was 9/14 (64%), which is higher than the proportion of CNS PTLD reported in the 
literature: 11% to 13% 32 PTLD should be considered in subjects who develop new neurologic signs or 
symptoms.  
In the Phase 2 Belatacept conversion study, there were no cases of PTLD. 
 
8.1.3 Malignancy 
An increased incidence of malignancy is a recognized complication of immunosuppression in 
recipients of organ transplants. In the Phase 3 studies, overall malignancy rates were similar 
across all treatment groups, with the exception of PTLD. 
In the Phase 2 Belatacept conversion study, the overall rates of malignancies were similar in 
patients converted to Belatacept and those who remained on CNI treatment. 
 
8.1.4 Infection 
Increased susceptibility to infection, including serious and fatal infections may result from the 
use of Belatacept, as with all immunosuppressive therapies. Overall incidences of infections, 
including serious fungal and viral infections, were similar across all therapies in the Phase 3 
IM103008 and IM103027 studies. The most common serious infections across treatment groups were 
urinary tract infection (UTI) and cytomegalovirus (CMV) infections. 
One (1) case of progressive multifocal leukoencephalopathy (PML) has been reported in the 
Belatacept renal transplantation program, in a subject receiving the MI regimen in study IM103027. PML 
should be considered in subjects who develop new neurologic signs or symptoms. 
Tuberculosis (TB) has been more frequently reported in Belatacept-treated patients than 
CsA-treated patients. There were a total of 13 TB cases (12 with Belatacept and 1 with CsA) 
reported in the Phase 3 studies over 36 months. Nearly all cases of TB were reported in subjects who 
currently or previously resided in countries with a high prevalence of TB. It is recommended that all 
patients be screened for TB and treated for any evidence of latent disease prior to initiation of Belatacept 
therapy. 
In the Phase 2 Belatacept conversion study, the overall rates of serious infections were similar in 
patients converted to Belatacept and those who remained on CNI treatment. The most common serious 
infections across treatment groups were urinary tract infection (UTI) and gastrointestinal infections. 
There were higher rates of adverse events due to non-serious viral and fungal infections in patients 
converted to Belatacept. There was one case of TB in a Belatacept-treated subject. 
 
8.1.5 Other Potential Risks 
Other potential risks include clinically relevant peri-infusion-related reactions, early 
post-transplant proteinuria, congestive heart failure or pulmonary edema, and autoimmune 
disorders. These events have been observed infrequently in Belatacept-treated subjects but are being 
closely monitored in all Belatacept clinical trials. 
 
8.1.6 Non-investigational Product 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Tacrolimus (TAC), Cyclosporine A (CsA), 
Mycophenolate Mofetil (MMF) or Mycophenolic Acid (MPA) and corticosteroids. 


 
 
P a g e 1 0  of 1 9  
 
8. 1. 7 D e s cri pti o n of t h e D o s a g e F or m  
B el at a c e pt f or I nj e cti o n, 2 5 0 m g/ Vi al  
B el at a c e pt f or I nj e cti o n, 2 5 0 m g/ Vi al, i s a st eril e n o n -p yr o g e ni c l y o p hili z e d p o w d er. E a c h vi al  
c o nt ai n s 2 7 5 m g of B el at a c e pt, 5 5 0 m g of s u cr o s e, 3 8. 0 m g of s o di u m p h o s p h at e m o n o b a si c  
m o n o h y dr at e, 6. 4 m g of s o di u m c hl ori d e, a n d 1 N s o di u m h y dr o xi d e/ 1 N h y dr o c hl ori c a ci d  
s ol uti o n s uffi ci e nt t o a dj u st p H t o 7. 5. A 1 0 % o v erfill i s i n cl u d e d i n e a c h vi al t o a c c o u nt f or vi al  
n e e dl e s yri n g e ( V N S) h ol d u p.  
 
8. 1. 8 Dr u g Pr o d u ct Pr e p ar ati o n  
C o n stit uti o n a n d dil uti o n of B el at a c e pt f or I nj e cti o n 2 5 0 m g/ Vi al m u st b e p erf or m e d u si n g  
sili c o n e -fr e e di s p o s a bl e s yri n g e s. S uit a bl e fl ui d s f or c o n stit uti o n of t h e l y o p hil e i n cl u d e st eril e 
w at er f or i nj e cti o n ( S W FI), 0. 9 % s o di u m c hl ori d e i nj e cti o n ( N S) or 5 % d e xtr o s e i nj e cti o n  
( D 5 W). Pri or t o I V a d mi ni str ati o n, t h e c o n stit ut e d s ol uti o n i s f urt h er dil ut e d wit h N S or D 5 W t o 
B el at a c e pt c o n c e ntr ati o n s b et w e e n 2 m g/ m L a n d 1 0 m g/ m L. T h e i nf u si o n i s t o b e a d mi ni st er e d  t hr o u g h 
a st eril e, n o n -p yr o g e ni c, l o w pr ot ei n bi n di n g i n -li n e filt er. A d diti o n all y, c ar e m u st b e t a k e n t o e n s ur e t h e 
st erilit y of t h e  pr e p ar e d s ol uti o n, a s t h e dr u g pr o d u ct d o e s n ot c o nt ai n a nti mi cr o bi al pr e s er v ati v e s or  
b a ct eri o st ati c a g e nt s.  
 
8. 1. 9 C o n stit uti o n of t h e L y o p hil e  
E a c h 2 5 0 m g vi al of B el at a c e pt f or I nj e cti o n s h o ul d b e c o n stit ut e d wit h 1 0. 5 m L of a s uit a bl e  
c o n stit uti o n  fl ui d  ( S W FI,  N S  or  D 5 W)  t o  pr o vi d e  a  s ol uti o n  wit h  a  B el at a c e pt  c o n c e ntr ati o n  of  
a p pr o xi m at el y 2 5 m g/ m L. B el at a c e pt f or inj e cti o n, 2 5 0 m g/ Vi al, i s n ot st or e d u n d er v a c u u m.   T o a v oi d 
e x c e s si v e f o a m f or m ati o n i n t h e vi al, sl o wl y i nj e ct t h e c o n st it uti o n fl ui d i nt o t h e vi al wit h t h e str e a m 
dir e ct e d t o w ar d t h e vi al w all a n d n ot i nt o t h e l y o p hili z e d c a k e. T h e vi al s h o ul d  b e g e ntl y s wirl e d a n d 
i n v ert e d u ntil t h e l y o p hil e di s s ol v e s. Alt h o u g h s o m e f o a m m a y r e m ai n o n t h e s urf a c e of t h e c o n stit ut e d 
s ol uti o n, a s uffi ci e nt e x c e s s of B el at a c e pt i s i n cl u d e d i n e a c h vi al t o  a c c o u nt f or wit h dr a w al l o s s e s, t h u s, 
1 0. 0 m L of a 2 5 m g/ m L B el at a c e pt s ol uti o n c a n b e  wit h dr a w n fr o m e a c h vi al. C o n stit ut e d s ol uti o n s of 
B el at a c e pt m a y f o a m, t h er ef or e, s h a ki n g  s h o ul d b e a v o i d e d. 
 
8. 2. 0 Pr e p ar ati o n of t h e I nf u si o n  
Pri or t o I V a d mi ni str ati o n, t h e c o n stit ut e d B el at a c e pt s ol uti o n ( 2 5 m g/ m L) s h o ul d b e f urt h er  
dil ut e d wit h eit h er N S or D 5 W t o fi n al B el at a c e pt c o n c e ntr ati o n s r a n gi n g fr o m 2 m g/ m L t o  
1 0 m g/ m L. L y o p hil e s c o n stit ut e d wit h S W FI m a y b e f urt h er dil ut e d wit h eit h er N S or D 5 W.  
L y o p hil e s c o n stit ut e d wit h N S s h o ul d b e f urt h er dil ut e d wit h N S a n d l y o p hil e s c o n stit ut e d wit h  
D 5 W s h o ul d b e f urt h er dil ut e d wit h D 5 W.  
 
8. 2. 1 H a n dli n g a n d Di s p e n si n g  
T h e  pr o d u ct  st or a g e m a n a g er  s h o ul d e n s ur e  t h at  t h e st u d y dr u g  i s st or e d  i n a c c or d a n c e  wit h t h e  
e n vir o n m e nt al  c o n diti o n s  (t e m p er at ur e,  li g ht,  a n d  h u mi dit y)  a s  d et er mi n e d  b y  B M S.  If  c o n c er n s  
r e g ar di n g t h e q u alit y or a p p e ar a n c e of t h e st u d y dr u g ari s e, t h e st u d y dr u g s h o ul d n ot b e di s p e n s e d 
a n d c o nt a ct B M S i m m e di at el y.  
I n v e sti g ati o n al  pr o d u ct  d o c u m e nt ati o n  m u st  b e  m ai nt ai n e d  t h at  i n cl u d e s  all  pr o c e s s e s  r e q uir e d  t o 
e n s ur e dr u g i s a c c ur at el y a d mi ni st er e d. T hi s i n cl u d e s d o c u m e nt ati o n of dr u g st or a g e,  a d mi ni str ati o n 
a n d, a s a p pli c a bl e,  st or a g e t e m p er at ur e s, r e c o n stit uti o n, a n d u s e of r e q uir e d  pr o c e s s e s ( e . g. r e q uir e d 
dil u e nt s, a d mi ni str ati o n s et s).  
 
8. 2. 2 R e c o m m e n d e d St or a g e C o n diti o n s  
B el at a c e pt  f or  I nj e cti o n  2 5 0  m g/ Vi al  s h o ul d  b e  st or e d  r efri g er at e d  at  2 ° -  8° C  ( 3 6 -4 6 F )  a n d 
pr ot e ct e d fr o m l o n g -t er m e x p o s ur e t o li g ht. T h e r e c o n stit ut e d s ol uti o n s h o ul d b e tr a n sf err e d fr o m t h e 
vi al  t o  t h e  i nf u si o n  b a g  or  b ottl e  i m m e di at el y.  Aft er  f urt h er  dil uti o n  wit h  N S  or  D 5 W  t o   Bel at a c e pt 
c o n c e ntr ati o n s b et w e e n 2 m g/ m L a n d 1 0 m g/ m L, t h e s ol ut i o n s m a y b e st or e d i n pl a sti c, n o n -sili c o ni z e d , 
I V b a g s or gl a s s b ottl e s. If n ot u s e d i m m e di at el y, t h e i nf u si o n s ol uti o n m a y b e st or e d u n d er r efri g er at e d 
c o n diti o n s at 2 ° - 8° C ( 3 6 -4 6 F) a n d pr ot e ct e d fr o m li g ht f or u p  t o 2 4 h o ur s ( a m a xi m u m of 4 h o ur s 


 
 
P a g e 1 1  of 1 9  
of t h e t ot al 2 4 h o ur s c a n b e at r o o m t e m p er at ur e: 2 0 - 2 5 C  [ 6 8-7 7 F ] a n d r o o m li g ht). R e g ar dl e s s 
of st or a g e c o n diti o n, t h e B el at a c e pt i nf u si o n m u st b e  c o m pl et e d wit hi n 2 4 h o ur s of c o n stit uti o n of t h e 
l y o p hil e. 
 
8. 2. 3 Dr u g or d eri n g a n d a c c o u nt a bilit y  ( B M S will b e s hi p pi n g dr u g dir e ctl y t o st u d y sit e s a s 
n e e d e d)  
8. 2. 3. 1 I niti al Or d er s  
F oll o wi n g s u b mi s si o n a n d a p pr o v al of t h e r e q uir e d r e g ul at or y d o c u m e nt s, a s u p pl y of B el at a c e pt  m a y 
b e or d er e d fr o m B M S b y c o m pl eti n g a Dr u g R e q u e st F or m.  ( pl e a s e s e e M O P) T h e fir st r e q u e st m a y 
t a k e pl a c e u p o n sit e a cti v ati o n.  
B el at a c e pt vi al s ( 4 0 m L) ar e s hi p p e d i n q u a ntiti e s of fi v e. T h e i niti al or d er s h o ul d b e li mit e d t o 2 5 vi al s 
( 5 c art o n s of 5 vi al s e a c h). All o w 5 b u si n e s s d a y s f or s hi p m e nt of dr u g fr o m B M S r e c ei pt of t h e Dr u g 
R e q u e st F or m. Dr u g i s pr ot o c ol s p e cifi c, b ut n ot p ati e nt s p e cifi c. All dr u g pr o d u ct will b e s hi p p e d b y 
c o uri er i n a t e m p er at ur e -c o ntr oll e d c o nt ai n er. S hi p m e nt s will b e m a d e fr o m B M S ( T h er e will b e n o 
w e e k e n d or h oli d a y d eli v er y of dr u g s).  
It i s p o s si bl e t h at sit e s m a y h a v e m or e t h a n o n e B el at a c e pt cli ni c al st u d y o n g oi n g at t h e s a m e ti m e. It 
i s i m p er ati v e t h at o nl y dr u g pr o d u ct d e si g n at e d f or t hi s pr ot o c ol n u m b er b e u s e d f or t hi s st u d y. 
 
8. 2. 3. 2 R e -S u p pl y  
Dr u g r e -s u p pl y r e q u e st f or m s h o ul d b e s u b mitt e d el e ctr o ni c all y or b y f a x at l e a st 5 b u si n e s s d a y s b ef or e 
t h e e x p e ct e d d eli v er y d at e.  D eli v eri e s will b e m a d e T u e s d a y t hr o u g h Fri d a y.  W h e n a s s e s si n g n e e d 
f or r e s u p pl y, i n stit uti o n s s h o ul d k e e p i n mi n d t h e n u m b er of vi al s u s e d p er tr e at m e nt d o s e, a n d t h at 
s hi p m e nt s m a y t a k e 1 4 b u si n e s s d a y s fr o m [ B M S or ot h er t hir d-p art y  v e n d or] r e c ei pt of r e q u e st. Dr u g 
i s n ot p ati e nt s p e cifi c. B e s ur e t o c h e c k wit h y o ur p h ar m a c y r e g ar di n g e xi sti n g i n v e sti g ati o n al st o c k t o 
a s s ur e o pti m al u s e of dr u g o n h a n d.  
 
9. St u d y a s s e s s m e nt s a n d pr o c e d ur e s  [ Pl e a s e s e e: S c h e d ul e of E v e nt s ( S O E) o n p a g e  1 9 ]: 
 
9 A . B el at a c e pt I nf u si o n s 
S e e S O E, o n p a g e 1 9 , f or c o m pl et e B el at a c e pt i nf u si o n s c h e d ul e.  
 
  
9 A. 1 B el at a c e pt  I nf u si o n r e a cti o n s** 
 
I n t h e e v e nt of n e w, s eri o u s, a n d u n e x p e ct e d t o xi cit y p ot e nti all y r el at e d t o B el at a c e pt, st u d y 
dr u g a d mi ni str ati o n s h o ul d b e  i nt err u pt e d. T h e i n v e sti g at or m u st i m m e di at el y n otif y t h e m e di c al m o nit or 
( M M).  T h e  s u bj e ct  will  b e  c o n si d er e d  eli gi bl e  t o  r e c ei v e  f urt h er  st u d y  dr u g  tr e at m e nt  o nl y  aft er  
di s c u s si o n wit h t h e m e di c al m o nit or.  
 
 
9 B . E arl y Wit h dr a w al of St u d y Dr u g R e gi m e n – s af et y f oll o w -u p s c h e d ul e:  
S u bj e ct s  i n  w h o m  B el at a c e pt  d o si n g  i s  di s c o nti n u e d  s h o ul d  b e  pl a c e d  o n  a  c o n v e nti o n al 
i m m u n o s u p pr e s si v e r e gi m e n. T o e n s ur e t h e s af et y  of i m m u n o s u p pr e s si o n c o n v er si o n, r e p e at e d bl o o d 
w or k f or cr e ati ni n e a n d dr u g l e v el s will b e p erf or m e d a 1 w e e k, 2 w e e k s a n d 4 w e e k s p o st -c o n v er si o n. 
A s af et y f oll o w -u p cli ni c vi sit 1 m o nt h p o st -c o n v er si o n will b e s c h e d ul e d.  
 
 
9 C . St u d y St o p pi n g R ul e s 
S u bj e ct s M U S T di s c o nti n u e i n v e sti g ati o n al pr o d u ct ( a n d n o n -i n v e sti g ati o n al pr o d u ct at t h e di s cr eti o n of 
t h e i n v e sti g at or) f or a n y of t h e f oll o wi n g r e a s o n s: 
•  
Wit h dr a w al of i nf or m e d c o n s e nt ( s u bj e ct’ s d e ci si o n t o wit h dr a w f or a n y r e a s o n)  
•  
A n y cli ni c al a d v er s e e v e nt ( A E); a b n or m al l a b or at or y t e st r e s ult s s u c h a s r efr a ct or y n e utr o p e ni a 
aft er  i m m u n o s u p pr e s si o n  a dj u st m e nt  ( a b s ol ut e  n e utr o p hil  c o u nt  b el o w  5 0 0),  r efr a ct or y  lif e -
t hr e at eni n g i nf e cti o n; o c c urr e n c e of P T L D; r efr a ct or y a c ut e c ell ul ar r ej e cti o n c o nfir m e d b y ki d n e y 
bi o p s y; or i nt er c urr e nt ill n e s s w hi c h, i n t h e o pi ni o n of t h e i n v e sti g at or, i n di c at e s t h at c o nti n u e d 
p arti ci p ati o n i n t h e st u d y i s n ot i n t h e b e st i nt er e st of t h e s u bj e ct  
•  
Pr e g n a n c y  
•  
L o s s of a bilit y t o fr e el y pr o vi d e c o n s e nt t hr o u g h i m pri s o n m e nt or i n v ol u nt ar y i n c ar c er ati o n f or 


 
 
Page 12 of 19 
treatment of either a psychiatric or physical (e.g., infectious disease) illness  
• 
Missing 2 consecutive Belatacept infusions, unless the subject is receiving lymphocyte-depleting 
therapy or has approval by the medical monitor to remain in the study. Documentation will be 
required. 
• 
Subjects receiving a maintenance dialysis regimen and deemed by the investigator to have 
functional graft loss and therefore do not require immunosuppression. 
 
If PTLD or refractory rejection develops in two or more subjects of the study, the trial will be interrupted.  
 
 
9.1 Site Labs - See SOE, on page 19, for complete labs schedule 
 
Blood Pressure - sitting 
Urinalysis with sediment 
Urine: protein, Urine: creatinine on spot sample; Urine protein/creatinine ratio (calculation) 
Serum Creatinine 
 
9.2 Central Labs: Mechanistics (See SOE, on page 19, for complete Central Labs schedule) 
 
9.2.1 Anti-HLA antibody: recipient’s serum will be tested for the presence of anti-HLA antibodies 
through Luminex single antigen bead assay. In this assay, patient's serum is incubated with microbeads 
coated with purified HLA proteins and then a fluorescent anti-IgG is used for antibody detection. Mean 
fluorescence intensity and donor-specificity of the antibodies present will be determined by correlating 
with known HLA antigens from donor. 
 
9.2.2 Urine B7-1 quantitative: we will isolate RNA from urinary extracellular vesicles (EVs) of 
transplanted patients and detect B7-1 mRNA using “Droplet Digital” PCR system.  
 
9.2.3 B7-1 biopsy staining: Using a goat anti-human B7-1 (CD80) antibody, we will perform 
immunostaining for B7-1 on frozen sections of allograft biopsies. 
 
10. Safety and Reporting: 
 
10.1 Data Safety and Monitoring Board (DSMB) 
A Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the Principal Investigator 
of this study, to monitor participant safety, data quality and evaluate the progress of the study. The Chair 
of the DSMB will also act as the study’s Medical Monitor (MM).  Please see the DSMB Charter, starting 
on Page 17 of this Protocol. 
 
10.2 Definitions 
10.2.1 Adverse Event (AE): 
An AE is any unfavorable medical occurrence in a human subject enrolled in this study regardless of 
its causal relationship to study treatment. This may include:  
• 
Abnormal sign (e.g. finding on physical exam or laboratory finding); 
• 
Symptom; 
• 
Disease. 
 
10.2.2 Serious Adverse Event (SAE): 
An SAE is an adverse event which meets any of the following criteria: 
• 
Results in death; 
• 
Is life threatening (places subject in immediate risk of death from the event as it occurred); 
• 
Requires patient hospitalization or prolongation of existing hospitalization; 
• 
Results in a persistent or significant disability/incapacity; 
• 
Results in a congenital anomaly/birth defect; 


 
 
Page 13 of 19 
• 
Any clinically significant event that based on the judgment of the Investigator may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
10.3 Reporting Requirements 
10.3.1 Adverse Event Reporting Requirements: 
Adverse events should be reported on an ongoing basis in the appropriate eCRF in StudyTRAX.   
 
Study sites should follow their IRB guidelines for reporting these events and document in their Study 
Binders. 
 
10.3.2 Serious Adverse Event Reporting Requirements: 
Serious Adverse Events should be reported to the sponsor within 5 working days/7 calendar days of 
the date that the Study Investigator becomes aware of the event.  Please report in the appropriate 
eCRF AND complete and scan Adverse Event Form (AEF) found in the Manual of Procedures (MOP).  
Please send the scanned Adverse Event Form to the following email address: 
lriella@bwh.harvard.edu. 
 
Study sites should follow their IRB guidelines for reporting these events and document in their Study 
Binders. 
 
10.3.3  Non-SAEs Reporting Requirements: 
The following are not considered SAEs for this study, however they should still be documented in the 
subject binder and eCRF when appropriate (i.e. surgical procedure, adverse event): 
• 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event); 
• 
elective surgery, planned prior to signing consent; 
• 
admissions as per protocol for a planned medical/surgical procedure; 
• 
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy); 
• 
medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases; 
• 
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
 
10.4 IND Safety Reporting Requirements: 
Per 21 CFR 312.32(c)(1)(i), the Sponsor (Dr. Riella) will notify the FDA, Medical Monitor (MM)/DSMB 
Chair, Partners Human Research Committee (PHRC), BMS (drug manufacturer), and all participating 
investigators in an IND Safety Report when an event meets ALL of the following criteria: 
• 
suspected adverse reaction (reasonable possibility of relationship to study drug) 
• 
serious 
• 
unexpected 
Fatal or life-threatening events will be reported as soon as possible, but no later than 7 days of 
occurrence. 
Serious and unexpected events will be reported as soon as possible, but no later than 15 days of 
occurrence. 
 
Study sites should follow their IRB guidelines for reporting these events and document in their Study 
Binders. 
 
 
10.5 Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject is pregnant or 


 
 
Page 14 of 19 
may have been pregnant at the time of study exposure, including during at least 5 half-lives after product 
administration, the investigator must immediately notify Dr. Riella of this event and complete and send 
an Adverse Event Form (AEF) to Dr. Riella within 24 hours of discovery by investigator.  [Dr. Riella will 
then report this AEF to BMS (drug manufacturer) within 24 hours of his knowledge of this event.] 
 
In most cases, the study drug will be permanently discontinued in an appropriate manner (e.g., dose 
tapering if necessary for subject safety). 
 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, the Sponsor 
will consult with BMS representative, and the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject  
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the subject 
unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported on the Adverse Event Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the 
Sponsor within 24 hours of discovery by investigator. Information on this pregnancy will be collected on 
the Adverse Events Form (AEF). 
 
Please send the completed and scanned Adverse Event Form to all of the following email 
addresses: lriella@bwh.harvard.edu . 
 
[Dr. Riella will then report this AEF to BMS (drug manufacturer) within 24 hours of his knowledge of this 
event.] 
 
10.6 Overdose 
All occurrences of overdose must be reported as SAEs (see Section 10.3.2 for reporting details). 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
an SAE (see Section 10.3.2 for reporting details.). 
 
10.7 Potential Drug Induced Liver Injury (DILI) 
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard medical 
practice in identifying and monitoring hepatic issues should be followed. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior 
to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined criteria, 
must be reported as SAEs (see Section 10.9 for reporting details). 
 
Potential drug induced liver injury is defined as:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, including, 
but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of 
other drug(s) known to be hepatotoxic. 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior 
to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined criteria, 
must be reported as SAEs (see Section 10.9 for reporting details). 


 
 
Page 15 of 19 
Potential drug induced liver injury is defined as: [can be defined based on specific study] 
 
10.8 Data Monitoring Committee, Data and Protocol Compliance Monitoring, and Other External 
Committees Please see MOP for information, including how often a site must complete their electronic 
clinical research forms (eCRFs), query resolution guidelines, regulatory binder requirements, and how 
the study data, and protocol compliance, will be monitored by the Sponsor (Dr. Riella/designated study 
managers). 
 
11.Statistics: This is a phase I clinical trial to test the safety and gain further insight to the potential 
effect of Belatacept in proteinuric patients. We plan to recruit 36 patients, based on the feasibility for 
recruitment in 3 transplant centers and prior literature on recommended sample sizes in Phase I trials.  
 
The primary endpoint of the study will be a 25% reduction in proteinuria from baseline to 12 months. 
This endpoint was extrapolated from studies with ACE inhibitors showing significant benefit in patients 
with kidney disease and proteinuria that reached this endpoint (12). For comparison, we will also have 
a historical control group with patients that fit the inclusion criteria and were managed as standard of 
practice on our institution. A logistic regression model will be used to control for key variables such as 
baseline ACEI/ARB use, level of proteinuria, age and gender.  
 
  
For the primary endpoint: Percentage of those patients who have a ≥25% reduction in proteinuria 
from baseline to 12 months will be reported separately for each group. We will compare these 
percentages between the two groups using Fisher’s exact test. In addition, means and standard 
deviations of the actual reduction will be reported separately for each group and will be compared 
between the two groups using a non-parametric test (Wilcoxon rank-sum). These results will also be 
compared to historical controls. A logistic regression model will be used to control for key variables such 
as baseline ACEI/ARB use, level of proteinuria, age and gender. 
 
For the secondary endpoints: Descriptive statistics (means, standard deviations and/or percentages) 
will be reported on percent change of renal function from baseline to 12 months; donor-specific anti-
HLA antibodies presence and intensity (MFI); adverse events; acute rejection episodes; blood pressure 
control; new onset diabetes; and hyperlipidemia. Spearman correlations will be calculated between B7-
1 positivity on immunofluorescence on biopsy with B7-1-expression in urine extracellular vesicles. 
Kaplan-Meyer plots will be used to study graft survival and patient survival and a proportional hazards 
model will be used here to compare survival between treated and historical controls, controlling for the 
baseline covariates above. 
 
 
 
 
 
 


 
 
Page 16 of 19 
 
 
References: 
1. 
Amer H, Cosio F. Significance and management of proteinuria in kidney transplant recipients. 
Journal of the American Society of Nephrology : JASN. 2009;20(12):2490-2. 
2. 
Halimi J-M. Low-grade proteinuria and microalbuminuria in renal transplantation. 
Transplantation. 2013;96(2):121-30. 
3. 
Shamseddin M, Knoll G. Posttransplantation proteinuria: an approach to diagnosis and 
management. Clinical journal of the American Society of Nephrology : CJASN. 2011;6(7):1786-93. 
4. 
Amer H, Fidler M, Myslak M, Morales P, Kremers W, Larson T, et al. Proteinuria after kidney 
transplantation, relationship to allograft histology and survival. American journal of transplantation : 
official journal of the American Society of Transplantation and the American Society of Transplant 
Surgeons. 2007;7(12):2748-56. 
5. 
El-Zoghby Z, Stegall M, Lager D, Kremers W, Amer H, Gloor J, et al. Identifying specific 
causes of kidney allograft loss. American journal of transplantation : official journal of the American 
Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(3):527-35. 
6. 
Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system 
blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant. 2007 
Oct;7(10):2350-60. PubMed PMID: 17845569. 
7. 
Opelz G, Zeier M, Laux G, Morath C, Dohler B. No improvement of patient or graft survival in 
transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 
receptor blockers: a collaborative transplant study report. J Am Soc Nephrol. 2006 Nov;17(11):3257-
62. PubMed PMID: 17035607. 
8. 
Yu C-C, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, et al. Abatacept in B7-1-
positive proteinuric kidney disease. The New England journal of medicine. 2013;369(25):2416-23. 
9. 
Good-Jacobson KL, Song E, Anderson S, Sharpe AH, Shlomchik MJ. CD80 expression on B 
cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell 
generation. Journal of immunology. 2012 May 1;188(9):4217-25. PubMed PMID: 22450810. Pubmed 
Central PMCID: 3331930. 
10. 
Njau MN, Kim JH, Chappell CP, Ravindran R, Thomas L, Pulendran B, et al. CD28-B7 
interaction modulates short- and long-lived plasma cell function. Journal of immunology. 2012 Sep 
15;189(6):2758-67. PubMed PMID: 22908331. 
11. 
Mandrekar SJ, Sargent DJ. Predictive biomarker validation in practice: lessons from real trials. 
Clinical trials. 2010 Oct;7(5):567-73. PubMed PMID: 20392785. Pubmed Central PMCID: 3913192. 
12. 
de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a 
target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney 
international. 2004 Jun;65(6):2309-20. PubMed PMID: 15149345. 
13. 
Lai CP, Breakefield XO. Role of exosomes/microvesicles in the nervous system and use in 
emerging therapies. Frontiers in physiology. 2012;3:228. PubMed PMID: 22754538. Pubmed Central 
PMCID: 3384085. 
14. 
Browne RH. On the use of a pilot sample for sample size determination. Statistics in medicine. 
1995 Sep 15;14(17):1933-40. PubMed PMID: 8532986. 
15. 
Sim J, Lewis M. The size of a pilot study for a clinical trial should be calculated in relation to 
considerations of precision and efficiency. Journal of clinical epidemiology. 2012 Mar;65(3):301-8. 
PubMed PMID: 22169081. 
16. 
Azuma H, Chandraker A, Nadeau K, Hancock WW, Carpenter CB, Tilney NL, et al. Blockade 
of T-cell costimulation prevents development of experimental chronic renal allograft rejection. 
Proceedings of the National Academy of Sciences of the United States of America. 1996 Oct 
29;93(22):12439-44. PubMed PMID: 8901600. Pubmed Central PMCID: 38010. 
17. 
Chandraker A, Azuma H, Nadeau K, Carpenter CB, Tilney NL, Hancock WW, et al. Late 
blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection. The 
Journal of clinical investigation. 1998 Jun 1;101(11):2309-18. PubMed PMID: 9616202. Pubmed 
Central PMCID: 508820. 


 
 
Page 17 of 19 
18. 
Kim EJ, Kwun J, Gibby AC, Hong JJ, Farris AB, 3rd, Iwakoshi NN, et al. Costimulation 
blockade alters germinal center responses and prevents antibody-mediated rejection. Am J 
Transplant. 2014 Jan;14(1):59-69. PubMed PMID: 24354871. 
 
 
DSMB Charter  
Principal Investigator: Leonardo Riella, MD, PhD  
Brigham and Women’s Hospital 
 
The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the Principal 
Investigator of this Investigator-Initiated study, to monitor participant safety, data quality and evaluate 
the progress of the study.  
 
Membership 
DSMB Chair: Andrew Siedlecki, MD [BWH Renal Division] 
Jean Francis, MD (Boston University) 
Paulo Martins, MD PhD (UMass) 
 
DSMB Responsibilities 
The DSMB responsibilities are to:  
 
evaluate the progress of the trial, participant risk versus benefit, performance of the trial sites, 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 study performance, make recommendations and assist in the resolution of problems 
reported by the Principal Investigator; 
  
protect the safety of the study participants; 
 
make recommendations to the Principal Investigator, and, if required, to the Food and Drug 
Administration (FDA) concerning continuation, termination or other modifications of the trial based on 
the observed beneficial or adverse effects of the treatment under study; 
 
The DSMB will discharge itself from its duties when the study is complete. 
 
Board Process  
At each meeting, the DSMB will discuss the protocol, suggested modifications, and establish 
guidelines to study monitoring by the Board. The a designated DSMB Chairperson, in consultation 
with the Principal Investigator and study staff, will prepare the agenda to address the review of study 
materials, and the reporting of adverse events. 
 
Meetings of the DSMB will take place quarterly, until the completion of the study. An emergency 
meeting of the DSMB may be called at any time should participant safety questions or other 
unanticipated problems arise. 
 
Meetings shall be closed to the public because discussions may address confidential participant data. 
Meetings are attended by the Principal Investigator and members of his/her staff. Meetings may be 
convened as conference calls as well as in-person.   
 
Meeting Format 
 
DSMB meetings will consist of open and closed sessions. Discussion held in all sessions is 
confidential. The Principal Investigator and key members of the study team attend the open sessions. 


 
 
Page 18 of 19 
Open session discussion will focus on the conduct and progress of the study, including participant 
accrual, protocol compliance, and problems encountered.  
 
The closed session will be attended by the DSMB members. 
 
Each meeting must include a recommendation to continue or to terminate the study made by a formal 
DSMB majority or unanimous vote. Should the DSMB decide to issue a termination recommendation, 
the full vote of the DSMB is required. In the event of a split vote, majority vote will rule, and a minority 
report should be appended. The DSMB Chair provides the tiebreaking vote in the event of a 50-50 
split vote. 
 
A recommendation to terminate the study may be made by the DSMB at any time by majority vote. In 
the event that the DSMB requires the study to be terminated, the PI will be immediately informed 
about their decision. 
 
Meeting Materials  
 
DSMB interim report templates will be prepared by the study staff, to be reviewed by the DSMB 
members at the first meeting.  Interim data reports generally consist of two parts:  
 
Part 1 - Open Session Report and  
Part 2 - Closed Session Report  
 
Format and content of the reports for both the open and closed sessions and plans for interim 
analyses should be finalized and approved at the initial DSMB meeting, although changes throughout 
the trial may be requested by the Board. 
 
The reports will list and summarize safety data and describe the status of the study.  All meeting 
materials should be sent to the DSMB members at least 1 business day prior to the meeting.  
 
Part 1 - Open Session Reports: Open session reports generally include administrative reports by site 
that describe participants screened, enrolled, completed, and discontinued, as well as baseline 
characteristics of the study population. Other general information on study status may also be 
presented. Listings of adverse events and serious adverse events as well as any other information 
requested by the DSMB may also be in the open session report, but none of the data should be 
presented in an unblinded manner. The DSMB may direct additions and other modifications to the 
reports on a one-time or continuing basis.  
 
Part 2 – Closed Session Report:  Closed session reports generally present the same information as 
presented in the open session but by blinded treatment group. The reports may also contain data on 
study outcomes, including safety data, and depending on the study, perhaps efficacy data. The 
Closed Session reports should be destroyed at the conclusion of the meeting. If the meetings are held 
by telephone, printed copies of the closed reports should be destroyed immediately following the 
meeting.  If a study has an interim analysis, it is also discussed in the closed session. 
 
Reports from the DSMB 
A formal report containing the recommendations for continuation or modifications of the study will be 
prepared by the DSMB Chairperson. Once approved by the DSMB members, the DSMB Chair will 
forward the formal DSMB recommendation to the Principal Investigator, within 2 weeks of the DSMB 
meeting. It is the responsibility of the Principal Investigator to distribute the DSMB recommendation to 
all co-investigators and to ensure that copies are submitted to all the IRBs associated with the study. 
 
Confidentiality  
All materials, discussions and proceedings of the DSMB are completely confidential. Members and 
other participants in DSMB meetings are expected to maintain confidentiality.  


 
 
Page 19 of 19 
 
 
 
B7-1 Study: Schedule of Events (SOE) 
  
Study Visits 
Screening 
Day 1     
60 days 
Day 15 
+ 5 
days 
Day 29 
M 1 
+ 5 
days 
Day 
43     
+ 5 
days 
Day 
57 
M2 
+ 5 
days 
Day 
85 
M3 
+ 5 
days 
Day 
113 
M4 
+ 5 
days 
Day 
141 
M5 
+ 5 
days 
Day 
169 
M6 
+ 5 
days 
Day 
197 
M7 
+ 5 
days 
Day 
225 
M8 
+ 5 
days 
Day 
253 
M9 
+ 5 
days 
Day 
281 
M10 
+ 5 
days 
Day 
309 
M11 
+ 5 
days 
Day 
337 
M12 
+ 5 
days 
 M18      
+ 5 days 
Procedures 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Full Medical 
History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Chart Review 
Only 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
XF 
 Serum or Urine 
Pregnancy Test 
(WOCBP only*) 
X* 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EBV Serologya 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Spot Urine 
Protein/ 
Creatinine Ratioa   
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Urinea,b   
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Cholesterol 
Panela  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Serum Glucosea  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Serum 
Creatininea  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
anti-HLA 
Antibodyc  
Xa  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
B7-1 biopsy 
stainingc  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Research Urinec   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Research Bloodc   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Belatacept 
Infusionsa  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
CNI Taper 
  
Xd 
Xd 
Xe 
  
  
  
  
  
  
  
  
  
  
  
  
AE/SAE Reporting 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
KEY: 
aStandard of Care (SOC) 
bUrine = urinalysis w/sediment AND Spot Urine = Urine:Creatinine & Urine:Protein; AND Urine Protein/Creatinine ratio = calculation needed 
cCentral Lab = send to BWH (transplant research center, 221 Longwood ave) 
dCNI dosing to be tapered 25% of baseline dose PER WEEK (weekly reduction NOT represented on this SOE), dates of reduction must be documented in eCRFs. 
eLast day of CNI; CNI completely stopped after this day. 
f Collect information about last blood pressure, medications, serum creatinine and urine protein/creatinine