Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following Conversion to Nulojix® (Belatacept)-Based Immunosuppression
Phase: PHASE3
Conditions: Kidney Transplantation
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
IM103116
IND Number:
BB 9418
EUDRACT Number
2012-001314-42
Date:
22-May-2012
Revised Date:
18-Apr-2018
Clinical Protocol IM103116
Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following
Conversion to Nulojix® (belatacept)-based Immunosuppression
Revised Protocol Number: 05
Incorporate Amendments 08, 07, 05, 03, 01
Incorporates Administrative Letter 01, 02, & 03
Study Director / Medical Monitor
Martin Polinsky, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg., a Contract 
Research Organization (CRO).
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Clinical Protocol
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BMS-224818
Belatacept
Revised Protocol No.: 05
Date: 18-Apr-2018
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Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Clinical Protocol
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Belatacept
Revised Protocol No.: 05
Date: 18-Apr-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 05
18-Apr-2018
Incorporates Amendment 08
Amendment 08
18-Apr-2018
Update definition of serious breach per company guidelines, clarify
belatacept dosing instructions for skipping of doses to include 
possibility of dosing out of defined visit windows, 
 
, Clarification of “end of infusion” definition, 
allow provision of central lab CNI trough values to sites.
Administrative Letter 
03
17-Oct-2017
To clarify protocol language by aligning the wording in the Time & 
Events Schedule
Administrative Letter 
02
30-May-2017
To correct two typographical errors on the last revised protocol 
version 04.
Revised Protocol 04
07-Apr-2017
Incorporates Amendment 07
Amendment 07
07-Apr-2017
Modification to decrease target enrollment from 600 to 
440 randomized subjects. The clarification of wording for the 
following: the CSPAR endpoint for consistency throughout the 
protocol; the requirement for daily dosing of maintenance 
corticosteroids throughout study participation; to indicate that 
protocol-specified tacrolimus trough levels being locally determined 
for patient management will also be captured in the clinical database; 
the timing for determination of post-belatacept infusion vital signs.  
Limitation of study participation by patients enrolled while receiving 
maintenance immunosuppression with tacrolimus plus mycophenolate 
sodium to approximately one-third (1/3) of all subjects. Provide a 
proviso to allow rescreening of patients who were screen failure 
earlier in the study. Update the definition of menopause; Correction 
of typographical errors and minor edits grammatical inconsistencies 
throughout the protocol. 
Revised Protocol 03
20-Aug-2014
Incorporates Amendment 05
Amendment 05
20-Aug-2014
Modification to the inclusion/exclusion criteria. Modification to the 
MDRD formula, the definition of stable renal function and stable 
immunosuppression regimen. Addition of re-screening subjects. 
Extension of screening period. Decrease the frequency of body weight 
measurements. Minor edits and clarifications throughout the protocol.
Administrative Letter 
01
02-Jul-2014
Change in medical monitor to Martin Polinsky, MD
Revised Protocol 02
04-Sep-2013
Incorporates Amendment 03
Amendment 03
04-Sep-2013
Modification to the inclusion/exclusion criteria.
 
 
Modification to the Renal Biopsy Requirements. Clarification of Live 
Vaccines for subjects. Addition of re-testing for screening creatinine 
labs. Minor edits and clarifications throughout the protocol, including 
table numbering. 
Revised Protocol 01
07-Jan-2013
Incorporates Amendment 01
Amendment 01
07-Jan-2013
Modification to the inclusion/exclusion criteria.
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Belatacept
Revised Protocol No.: 05
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Document
Date of Issue
Summary of Change
 
.
Original Protocol
22-May-2012
Not Applicable
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Belatacept
SYNOPSIS
Clinical Protocol IM103116
Protocol Title: Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following 
Conversion to Nulojix® (belatacept)-based Immunosuppression
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nulojix® (belatacept) will be supplied by BMS. 250mg/vial will be used. Mode of Administration is 
intravenous (IV). Duration of treatment: 24 months
Non-investigational products (Non-IMP) include calcineurin inhibitors (CNI)--tacrolimus (TAC) or cyclosporine 
(CsA) and maintenance background therapies mycophenolate mofetil (MMF) or enteric-coated mycophenolate 
sodium (EC-MPS)/mycophenolic acid (MPA) and corticosteroids. Non-IMP products are standard of care and will 
be supplied locally.
Study Phase: 3b
Research Hypothesis: Formal statistical testing of a research hypothesis will not be performed in this study with 
regard to the primary endpoint of patient and functional graft survival.  Its purpose is to assess the safety and 
efficacy of conversion from CNI (tacrolimus [TAC] or cyclosporine [CsA)]- to belatacept-based maintenance 
immunosuppression in renal allograft recipients with clinically stable function at least 6 months post-transplant.
Objective(s): 
Primary
To evaluate patient and functional graft survival in maintenance renal transplant recipients (6 - 60 months 
post-transplantation) converted from CNI to belatacept-based immunosuppression as compared to those continuing
CNI based immunosuppression at 24 months post-randomization.
Secondary
To evaluate the effect of conversion from CNI to belatacept on the following:
•
Composite of patient and functional graft survival at 12 months post-randomization
•
The incidence and severity of clinically suspected, biopsy proven acute rejection at 12 and 24 months post-
randomization 
•
Renal function as assessed by:
−
Mean change in calculated glomerular filtration rate (cGFR, 4-variable MDRD equation) from baseline 
(defined as most recent measurement prior to the first dose of study drug on Day 1) to 12 and 24 months 
post-randomization (% and absolute)
−
Slopes of cGFR and 1/serum creatinine respectively from baseline as well as from Month 3 to 12 and 
24 months post-randomization
−
Proportion of subjects with > 5% and > 10% improvement over baseline in cGFR at 12 and 24 months 
post-randomization
−
Urine protein/ creatinine ratio (UPCR) at baseline, 3, 6, 12, and 24 months post-randomization
•
Mean change in systolic and diastolic blood pressure and intensity of the anti-hypertensive treatment regimen 
(defined as the total number of antihypertensive medications used to control hypertension) from baseline to 
12 and 24 months post-randomization 
•
Proportion of subjects with donor specific antibodies (DSA) at Baseline/Day 1, Months 12 and 24 
post-randomization
•
Evaluation of symptom occurrence and symptom distress measured with the MTSOSD-59R at baseline, week 6, 
and Months 3, 6, and 12 post- randomization
•
Safety and tolerability of a belatacept in a conversion setting
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Study Design:
This is a randomized, open-label, active-controlled, parallel-group study. Approximately 440 subjects on CNI-based 
regimens will be randomized in a 1:1 ratio to treatment with either belatacept or continued treatment with their 
established CNI. All subjects will also receive a background maintenance immunosuppressive regimen of 
mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS)/mycophenolic acid (MPA), with 
adjunctive daily corticosteroids, according to their immunosuppressive regimen at the time of enrollment. 
Enrollment will be monitored, and if necessary restricted, to ensure no more than 25% of patients are receiving CsA 
at the time of enrollment. In addition, participation by patients receiving the maintenance immunosuppressive 
combination of tacrolimus with mycophenolate sodium will be limited to no more than approximately 1/3 of all 
subjects.
Two cGFR values are required to demonstrate stable renal function prior to randomization, once at the screening 
evaluation and at one additional time point within 2 to 12 weeks prior to screening.  Subjects will be stratified by 
site and screening cGFR (defined as the most recent cGFR between Day -42 and Day 1 prior to randomization). 
Subjects will be stratified by screening cGFR with a 1: 2 ratio (cGFR ≥30 to < 45 mL/min/1.73 m2 or ≥45 to 
≤75 mL/min/1.73m2 ). 
Subjects randomized to belatacept will receive 5 mg/kg intravenous (IV) on Days 1, 15, 29, 43, and 57, and then 
every 28 days thereafter. The CNI dose will be tapered to 40% - 60% of the baseline dose by Day 15, 20% - 30% of 
the baseline dose by Day 22, and will be discontinued by Day 29. 
Subjects randomized to continue their CNI-based regimen will receive doses to achieve trough serum concentrations 
(C0 levels) of 50 - 250 ng/mL (CsA) or 4 - 11 ng/mL (TAC). 
Figure 1:
Study Schematic
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Study Population: 
Key Inclusion Criteria
•
Men and women, ages 18 -75 inclusive
•
Adult recipients of a renal allograft from a living donor or a deceased donor between 6-60 calendar months 
prior to enrollment
•
Receiving a stable regimen of CNI (CsA or TAC), with MMF or EC-MPS/MPA and daily corticosteroids
for ≥1 calendar month prior to randomization. CNI trough (C0) levels must be in the range of 50-250 
ng/ml for CsA and 4-11 ng/ml for TAC.
•
Renal function must have remained stable during the 12 week period prior to Screening, in the opinion of 
the investigator and according to the following criteria:
o
Absence of new onset proteinuria during the 12-week period prior to the Screening evaluation, as 
documented by ≥1+ protein by dipstick or a random-voided urinary protein/creatinine ratio 
≥0.3 mg protein/mg creatinine, identified during the 12-week period prior to Screening in a 
patient without previously diagnosed proteinuria and in the absence of intercurrent illness.
o
In patients with proteinuria documented prior to the 12-week period before Screening, urinary 
protein excretion at the time of the Screening evaluation must be:

≤500 mg/24 hours OR the random urinary protein-to-creatinine ratio (UPr/Cr) must be 
≤0.5:1 mg protein/mg creatinine (≤56.5 mg protein/mmol creatinine) at the Screening 
evaluation in patients with a history of diabetes mellitus; or

≤1,000 mg/24 hours OR the random urinary protein-to-creatinine ratio must be 
≤1.0:1 mg protein/mg creatinine (≤113 mg protein/mmol/creatinine) in non-diabetic 
patients.
•
The calculated GFR (cGFR) must be ≥30 and ≤75 mL/min/1.73 m2, as determined using the 4-variable 
MDRD equation, on two occasions: once at the Screening evaluation and at one additional time point 
between 2 and 12 weeks prior to the Screening evaluation.  If a historical cGFR value is not available, then 
a second cGFR must be obtained at least 2 weeks later during the Screening period;  
•
Negative Interferon Gamma Release Assay (IGRA) such as QuantiFEROΝ®-TB Gold test or 
T- Spoτ®- TB
Key Exclusion Criteria
•
Recipients with EBV serostatus negative or unknown
•
History of any of the following:
o
Treated for biopsy proven AR (BPAR) within 3 calendar months prior to enrollment
o
Antibody-mediated AR
o
Recurrent AR in the current allograft
o
Banff 97 Grade IIA or greater AR (or equivalent), steroid resistant AR or treatment with
lymphocyte-depleting agents, plasmapheresis, or rituximab for AR since the time of 
transplantation of the current allograft
•
Subjects with previous graft loss due to BPAR 
•
Subjects with a positive T-cell lymphocytotoxic cross match 
Study Assessments:
Primary Endpoint(s)
Proportion of subjects who survive with a functional graft at 24 months post randomization.
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Secondary Endpoint(s)
•
Patient and Functional Graft Survival
−
Proportion of subjects who survive with a functional graft at 12 months post-randomization 
•
Acute Rejection
−
The incidence and severity of clinically suspected, biopsy-proven acute rejection at 12 and 24 months 
post-randomization
•
Renal Function
−
Mean change in cGFR (per 4-variable MDRD equation) from baseline to 12 and 24 months 
post-randomization (% and absolute)
−
Slopes of cGFR and 1/serum creatinine respectively from baseline as well as Month 3 to 12 and 24 months 
post-randomization
−
Proportion of subjects with > 5% and > 10% improvement over baseline in cGFR at 12 and 24 months 
post-randomization
−
Urine protein/ creatinine ratio (UPCR) at baseline, 3, 6, 12, and 24 months post randomization
•
Hypertension
−
Mean change in systolic and diastolic blood pressure and intensity of treatment regimen from baseline to 
12 and 24 months post-randomization 
•
Donor Specific Antibodies
•
Proportion of subjects with donor specific antibodies at Baseline/ Day 1, Months 12 and 24 
post-randomization
•
The frequency of symptom occurrence and symptom distress as measured with the MTSOSD-59R at baseline, 
Week 6, and 3, 6, and 12 months post- randomization
•
Safety and tolerability of a belatacept in a conversion setting
−
All adverse events
−
Adverse events of special interest
−
Clinically significant changes in vital signs
−
Laboratory test abnormalities
−
Clinical tolerability of the drug
Statistical Considerations:
Sample Size: Formal statistical testing of a research hypothesis is not being performed in this study. A sample size 
of approximately 220 subjects per treatment group is considered to provide sufficient power to rule out an 
unacceptable difference in patient and graft survival.
With a confidence level (one-sided) of 0.975 and assuming the true rates of patient and graft survival by Month 24 
in both treatment groups is 93%, the sample size of 220 subjects per arm will afford 90% probability to rule out a 
difference of 8.3% (sample size based on 1000 simulations per Newcombe methodology). 
This sample size will provide 93% power to detect a 10% absolute difference of mean percentage change in 
calculated GFR at Month 24 between the belatacept regimen and the CNI regimen assuming a standard deviation of 
30% (alpha 0.05, 2-sided). 
Given a sample size of approximately 220 subjects per treatment group, if the true AR rates by Month 24 are 7% in 
the belatacept regimen and 1% in the CNI regimen, the half width of the 95% confidence interval of the difference 
in AR rate is estimated to be 3.6% (alpha 0.05, 2-sided). With the assumed rates of AR, the confidence interval for 
the difference would be (2.4%, 9.6%). 
Given a sample size of 220 subjects per treatment group, and assuming an event rate of PTLD of 0.74% the 
probability of observing at least 1 event is 80.5%. 
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Analyses:
The primary composite endpoint of patient and graft survival by 24 months will be summarized within each 
treatment group using point estimates of the proportion of patients surviving with a functioning graft, and the 
corresponding 95% CIs. The 95% CIs will also be generated for the difference between the belatacept regimen and 
CNI to assess the effect of belatacept stratified by baseline cGFR.
The incidence and severity of clinically suspected, biopsy proven acute rejection up to 12 and 24 months 
post-randomization will be summarized within each treatment group using point estimates and 95% CIs. The 95% 
CIs will also be generated for the difference in rate of the acute rejection by 12 and 24 months between belatacept 
and CNI stratified by baseline cGFR.
Mean change in cGFR (per 4-variable MDRD equation) from baseline to 12 and 24 months post-randomization (% 
and absolute) will be summarized within each treatment group, point estimates and 95% CIs will also be displayed. 
A point estimate with two-sided 95% CI will be generated for the difference in mean percentage change of cGFR 
from baseline at Month 12 and Month 24, respectively, between belatacept and CNI.
To assess the trend in renal function, a linear mixed model will be used to analyze the mean changes in calculated 
GFR from multiple time-points (baseline and Month 3) to 12 and 24 months for each regimen. A similar analysis in 
1/serum creatinine will also be performed.
The proportion of subjects with ≥ 5% and ≥10% improvement over baseline at 12 and 24 months will be 
summarized respectively.
The time to cGFR < 15 mL/min/1.73m2, graft loss or death from baseline and Month 3, respectively, in each 
treatment group will be summarized using Kaplan-Meier curves.
All the other endpoints will be summarized descriptively by treatment group.
Interim Analysis:
At Month 12 following the last subject randomized, an interim analysis will be performed. The purpose of the 
interim analysis is to obtain study data to assess the evolving benefit risk profile of belatacept conversion at 
12 months post-randomization. Similar methods as those used for the 24 month analyses will be performed for the 
12 month interim analysis. The interim analyses will be descriptive in nature, and no statistical tests will be 
performed.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1
 
 
  
 
 
 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Duration of Study ..................................................................................... 
3.1.2 Overview .................................................................................................. 
3.2 Study Population ............................................................................................... 
3.2.1 Inclusion Criteria ..................................................................................... 
3.2.2 Exclusion Criteria .................................................................................... 
3.2.3 Women of Childbearing Potential ........................................................... 
3.2.4 Re-Screening ............................................................................................ 
 
 
 
 
 
 
 
3.4 Discontinuation of Subjects from Treatment .................................................... 
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3.5 Post Treatment Study Follow up....................................................................... 
3.5.1 Early Termination from Study Medication .............................................. 
3.5.2 Post Study Access to Therapy .................................................................. 
3.5.3 Withdrawal of Consent ............................................................................ 
3.5.4 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.2.1 Description of the Dosage Form..................................................... 
4.1.2.2 Drug Product Preparation .............................................................. 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Phone Visits CNI Subjects ....................................................................... 
4.4 Visit Windows .................................................................................................. 
4.4.1 Dose Modification .................................................................................... 
4.5 Blinding/Un-blinding ........................................................................................ 
4.6 Treatment Compliance ...................................................................................... 
4.7 Destruction and Return of Study Drug ............................................................. 
4.7.1 Destruction of Study Drug ....................................................................... 
4.7.2 Return of Study Drug ............................................................................... 
4.8 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Follow-up Safety Period .......................................................................... 
5.3.2 Vital Signs ................................................................................................ 
5.3.2.1 Standardized Blood Pressure Monitoring ...................................... 
5.3.3 Physical Measurements ........................................................................... 
5.3.4 Physical Examination .............................................................................. 
5.3.5 Laboratory Assessments........................................................................... 
5.3.5.1 Central Laboratory ......................................................................... 
5.3.5.2 Local Laboratory ............................................................................ 
5.3.5.3 Collection, Shipping and Transport ................................................ 
5.3.6 Kidney Allograft Biopsy ........................................................................... 
5.3.7 Diagnosis and Treatment of Acute Rejection ........................................... 
5.3.8 Neurological Examination ....................................................................... 
 
5.3.10 Diagnosis and Treatment of Hypertension ............................................ 
5.3.11 Diagnosis of New Onset Diabetes After Transplant (NODAT) ............. 
 
5.4 Efficacy Assessments ........................................................................................ 
 
 
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6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
 
 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
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APPENDIX 1 BLOOD PRESSURE MEASUREMENT USING AN ANEROID OR 
MERCURY SPHYGMOMANOMETER AND HEART RATE 
MEASUREMENTS REFERENCE ........................................................................ 
APPENDIX 2 THE MTSOSD-59R QUESTIONNAIRE............................................. 
 
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1.3
Objectives(s)
1.3.1
Primary Objective 
To evaluate patient and functional graft survival in maintenance renal transplant recipients 
(6 - 60 months post-transplantation) converted from CNI to belatacept-based immunosuppression
as compared to those continuing
CNI based 
immunosuppression at 24 months 
post-randomization.
1.3.2
Secondary Objectives
To evaluate the effect of conversion from CNI to belatacept on the following:
•
Composite of patient and functional graft survival at 12 months post-randomization
•
The incidence and severity of clinically suspected, biopsy proven acute rejection at 12 and 
24 months post- randomization.
•
Renal function as assessed by:
−
Mean change in calculated glomerular filtration rate (cGFR) (4-variable MDRD
equation) from baseline (defined as most recent measurement prior to the first dose of
study drug on Day 1) to 12 and 24 months post-randomization (% and absolute)
−
Slopes of cGFR and 1/serum creatinine respectively from baseline as well as from Month 
3 to 12 and 24 months post-randomization
−
Proportion of subjects with > 5% and > 10% improvement over baseline in cGFR at 
12 and 24 months post-randomization
−
Urine protein/creatinine ratio (UPCR) at baseline, 3, 6, 12, and 24 months 
post-randomization
•
Mean change in systolic and diastolic blood pressure and intensity of the anti-hypertensive 
treatment regimen (defined as the total number of anti-hypertensive medications used to 
control hypertension) from baseline to 12 and 24 months post-randomization 
•
Proportion of subjects with donor specific antibodies (DSA) at Baseline/ Day 1, Months 12 
and 24 post-randomization
•
Evaluation of symptom occurrence and symptom distress measured with the MTSOSD-59R 
at baseline, Week 6, and Months 3, 6, and 12 post- randomization
•
Safety and tolerability of a belatacept in a conversion setting
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
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 and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS and/or designee immediately. A serious 
breach is a breach of the conditions and principles of Good Clinical Practices (GCP) (occurring 
in any country) in connection with the study or a protocol related to the study, which is likely to 
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affect, to a significant degree, the safety or physical or mental integrity of 1 or more subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approvals / favorable 
opinions from the IRB/IEC for the protocol, consent form, subject recruitment materials, 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates.
The investigator or BMS 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.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
BMS and/or designee will provide the Investigator with an appropriate (ie, Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Investigators must:
1. Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3. Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of 
the study, and after any revisions are completed for new information.
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5. If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally 
be obtained from the subject.
6. Revise the informed consent whenever important new information becomes available that 
is relevant to the subject's consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the USA, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and/or designee and regulatory 
authorities have direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
3.1.1
Duration of Study
Once randomized, the duration of the study is 24 months with a subsequent 8-week follow-up 
period for safety post last dose. In addition, belatacept-treated subjects who discontinue 
treatment or complete the study and do not continue treatment with commercial belatacept post 
study will be seen at 12 and 24 weeks post last dose.
3.1.2
Overview
This is a randomized, open-label, active-controlled, parallel-group study. Approximately 440 
subjects on CNI-based regimens will be randomized in a 1:1 ratio to treatment with either 
belatacept or continued treatment with their established CNI. All subjects will also receive a 
background maintenance immunosuppressive regimen of mycophenolate mofetil (MMF) or 
enteric-coated mycophenolate sodium (EC-MPS)/ mycophenolic acid (MPA), with adjunctive, 
daily corticosteroids, according to their immunosuppressive regimen at the time of enrollment. 
Enrollment will be monitored, and if necessary restricted, to ensure that no more than
approximately 25% of patients are receiving CsA at the time of enrollment. In addition, 
participation by patients receiving the maintenance immunosuppressive combination of 
tacrolimus with mycophenolate sodium will be limited to no more than approximately 1/3 of all 
subjects.
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Eligible patients must have stable renal function for 12 weeks prior to Enrollment, as defined 
below (Section 3.2).
Subjects will be stratified by site and screening cGFR (defined as the most recent cGFR between 
Day -42 and Day 1 prior to randomization). Subjects will be stratified by screening cGFR in an 
approximately 1:2 ratio (≥30 to < 45 mL/min/1.73 m2 or ≥45 to 75 mL/min/1.73 m2).
Subjects randomized to belatacept will receive 5 mg/kg intravenous (IV) on Days 1, 15, 29, 43, 
and 57, and then every 28 days thereafter. The CNI dose will be tapered to 40% - 60% of the 
baseline dose by Day 15, 20% - 30% of the baseline dose by Day 22, and will be discontinued by 
Day 29. 
Subjects randomized to continue their CNI-based regimen will receive doses targeted to achieve
trough serum concentrations (C0 levels) of 50 - 250 ng/mL (CsA) or 4 - 11 ng/mL (TAC). 
(Refer to Figure 3.1.2-1 and Table 3.1.2-1 & Table 3.1.2-2)
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Table 3.1.2-1:
Dosing Schedule - Year 1
M 1
M 3
M 6
M 9
M 12
W0
W2
W4
W6
W8
W12
W16
W20
W24
W28
W32
W36
W40 W44
W48
W52
Randomize to Treatment Arm
D1
D15
D29
D43
D57
Belatacept Dosing ( 5mg/kg)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subjects randomized to receive belatacept will reduce their CNI dose to:
40%-60% of the baseline dose by Day 15
20%-30% of the baseline dose by Day 22
0% of the baseline dose by Day 29
CNI ADMINISTRATION
CsA Dosing
Subjects receiving CsA will be maintained at doses to achieve target trough levels (C0 levels) of 50 - 250 ng/mL.
TAC Dosing
Subjects receiving TAC will be maintained at doses to achieve target trough concentrations of 4 - 11 ng/mL.
Adjunctive Background Immunosuppression
Oral Corticosteroid 
Daily corticosteroid use is required for study enrollment and subjects should not undergo steroid dose adjustment during the 
study unless medically necessary.
MMF or EC-MPS/MPA
Refer to Section 4.3
Subjects May Also Receive:
Antiviral Prophylaxis
(During and after T-Cell 
Depleting Therapy)
It is recommended that subjects who receive a T-cell depleting agent at any time in the trial receive prophylaxis against 
Pneumocystis jiroveci pneumonia (previously called PCP pneumonia), cytomegalovirus exacerbation and other herpes viruses 
and Candida infections for at least 6-12 weeks based upon the KDIGO guidelines and/or in accordance with the local standard 
of care practice.
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Table 3.1.2-2:
Dosing Schedule - Year 2
M 15
M 18
M 21
M 24
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Belatacept Dosing ( 5mg/kg)
X
X
X
X
X
X
X
X
X
X
X
X
X
CNI ADMINISTRATION
CsA Dosing
Subjects receiving CsA will be maintained at doses to achieve target trough levels (C0 levels) of 50 - 250 ng/mL.
TAC Dosing
Subjects receiving TAC will be maintained at doses to achieve target trough concentrations of 4 - 11 ng/mL.
Adjunctive Background Immunosuppression
Oral Corticosteroid 
Daily corticosteroid use is required for study enrollment, and subjects should not undergo steroid dose adjustment 
during the study unless medically necessary.
MMF or EC-MPS/MPA
Refer to Section 4.3. 
Subjects May Also Receive:
Antiviral Prophylaxis
(During and after T-Cell 
Depleting Therapy)
It is recommended that subjects who receive a T-cell depleting agent at any time in the trial receive prophylaxis against 
Pneumocystis jiroveci pneumonia (previously called PCP pneumonia), cytomegalovirus exacerbation and other herpes 
viruses and Candida infections for at least 6-12 weeks based upon the KDIGO guidelines and/or in accordance with the 
local standard of care practice.
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Figure 3.1.2-1:
Study Schematic
3.2
Study Population
The study population includes recipients of a renal allograft from a living donor or a deceased 
(standard criteria and extended criteria) donor transplanted at least 6 months, but not longer than 
60 months prior to enrollment (Study Day -42). 
For entry into the study, the following criteria MUST be met.
3.2.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject or legal representative is willing to provide signed written informed consent
2) Target Population
a) Adult recipients of a renal allograft from a living donor or a deceased donor between 
6 and 60 calendar months prior to enrollment.
b) Receiving a stable regimen of CNI (CsA or TAC), with MMF or EC-MPS/MPA and 
daily corticosteroids for ≥1 calendar month prior to randomization. CNI trough (C0) 
levels must be in the range of 50-250 ng/ml for CsA and 4-11 ng/ml for TAC. [With 
regard to CNI therapy: “receiving a stable regimen” specifically refers to maintaining a 
stable level of exposure to CsA or TAC within the protocol-specified ranges, and not to 
maintaining a stable dose, per se. Thus, changes to the CNI dose made during the 
Screening period to maintain stable exposure do not exclude prospective subjects from 
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study participation, so long as their trough levels remain within the protocol-specified 
range.]
c) Renal function must have remained stable during the 12 week period prior to Screening, 
in the opinion of the investigator and according to the following criteria:
1) Absence of new onset proteinuria during the 12-week period prior to enrollment, 
as documented by ≥1+ protein by dipstick or a random-voided urinary 
protein/creatinine ratio ≥0.3 mg protein/mg creatinine (≥34 mg protein/mmol 
creatinine) in a patient without previously diagnosed proteinuria and in the 
absence of intercurrent illness.
2) In patients with pre-existing proteinuria (proteinuria known to have been present 
prior to the 12-week period before enrollment), urinary protein excretion at the 
time of the Screening evaluation must be:
−
≤500 mg/24 hours OR the random urinary protein-to-creatinine ratio 
(UPr/Cr)
must be ≤0.5:1 mg protein/mg creatinine (≤56.5 mg 
protein/mmol creatinine) at the Screening evaluation in patients with a 
history of diabetes mellitus; or
−
≤1,000 mg/24 hours OR the random urinary protein-to-creatinine ratio 
must 
be 
≤1.0:1 
mg 
protein/mg 
creatinine 
(≤113 
mg 
protein/mmol/creatinine) in non-diabetic patients.
d) The calculated GFR (cGFR) must be ≥30 and ≤75 mL/min/1.73 m2, as calculated using 
the 4-variable MDRD equation 29, on two occasions: once at the Screening evaluation 
and at one additional time point between 2 and 12 weeks prior to the Screening 
evaluation. If a historical cGFR value is not available, then a second cGFR must be 
obtained at least 2 weeks later during the Screening period. Calculated results for cGRF 
should be rounded to the nearest whole number based upon conventional rounding rules.
NOTE: Both serum creatinine determinations should be from the same laboratory unless 
both labs use IDMS-referenced assays.
e) Negative testing for TB by an interferon gamma release assay (IGRA) such as the 
QuantiFERON®-TB Gold test or T- Spot®- TB test, prior to randomization.
3) Age and Reproductive Status
a) Men and women, ages 18 - 75 inclusive
Women of childbearing potential (WOCBP) must use highly effective methods of birth control 
to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner 
that the risk of pregnancy is minimized. Please note: that according to the US product 
information for MMF or EC-MPS/MPA, two reliable forms of contraception must be used 
simultaneously unless abstinence is the chosen method (see package insert).
Acceptable methods of highly effective birth control include:
•
Condom with spermicide
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•
Diaphragm and spermicide
•
Cervical cap and spermicide
•
Oral contraceptives
•
Intrauterine device (IUD)
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours 
prior to the start of study medication. 
c) Women must not be breastfeeding
d) Sexually active fertile men must use highly effective birth control if their partners are 
WOCBP. Men who are sexually active with WOCBP must follow instructions for birth 
control for the entire duration of the study and a minimum of 8 weeks post study drug has 
been completed.
e) Women who are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile; see Section 3.2.3 for the definition of WOCBP).
3.2.2
Exclusion Criteria
1) Target Disease Exceptions 
a) Recipients with EBV serostatus negative or unknown
b) History of any of the following:
1. Treated for biopsy proven AR (BPAR) within 3 calendar months prior to enrollment
2. Antibody mediated AR
3. Recurrent AR in the current allograft
4. Banff 97 Grade IIA or greater AR (or equivalent), steroid resistant AR or treatment 
with lymphocyte-depleting agents, plasmapheresis, or rituximab for AR since the 
time of transplantation of the current allograft
c) Subjects with previous graft loss due to BPAR 
d) Subjects with a positive T-cell lymphocytotoxic cross match
e) Genetically-identical donor recipient pairs (ie, identical twins)
f)
Donor age < 10 years
g) Subjects with underlying renal disease of:
1. Primary focal segmental glomerulosclerosis 
2. Type I or II membranoproliferative glomerulonephritis
3. Atypical hemolytic uremic syndrome (HUS) / thrombotic thrombocytopenic purpura
(TTP)
4. Not applicable per Protocol Amendment 05
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If a subject has ESRD of unknown etiology and/or has no histologically-confirmed 
diagnosis, the subject may be enrolled into the study as long as, in the opinion of the 
investigator, the overall history and clinical findings are not consistent with a likely
diagnosis of underlying primary focal segmental glomerulosclerosis, Type I or II 
membranoproliferative glomerulonephritis, or atypical HUS/TTP. 
h) Subjects with prior non-renal solid organ transplant (subjects undergoing kidney 
re-transplantation are eligible pending other study criteria being met), or subjects 
undergoing multi-organ transplants (eg, kidney-pancreas) or subjects deemed likely to 
have a second solid organ or cell transplant (eg, pancreas or islet transplant) in the next 
3 years by the investigator
i)
Subjects receiving a concurrent solid organ (heart, liver, pancreas) or cell (islet, bone 
marrow, stem cell) transplant 
j)
Subjects receiving paired kidneys (dual or en bloc kidney transplants)
2) Medical History and Concurrent Diseases 
a) Subjects who are or whose allograft donor was known hepatitis C antibody-positive or 
polymerase chain reaction (PCR)-positive for hepatitis C
b) Subjects who are or whose allograft donor was known hepatitis B surface 
antigen-positive or PCR-positive for hepatitis B
c) Subjects and recipients of a graft from a donor with known human immunodeficiency 
virus (HIV) infection
d) Subjects with any active infection [including but not limited to cytomegalovirus (CMV), 
BK or Epstein-Barr virus (as determined by detection of quantifiable viral loads in 
plasma), BKV associated nephropathy, CMV retinitis, CMV colitis, tuberculosis, etc.]
e) Subjects with history of active or untreated latent tuberculosis (TB) or radiographic 
finding consistent with active TB
NOTE: Subjects must be screened for active and latent tuberculosis prior to entry into 
the study. Subjects must have a negative chest x-ray (posterior-anterior and lateral views) 
within the last 6 calendar months prior to screening and a negative IGRA test (such as 
QuantiFERON®-TB Gold test or T- Spot®- TB) done at screening by the central 
laboratory. If equipment for incubation prior to shipment to central lab is not available at 
the site, a local lab IGRA test is acceptable. (Refer to Table 5.1-1)
f)
Subjects whose life expectancy is severely limited by disease state or other underlying 
medical condition
g) Subjects with a history of cancer (other than non-melanoma skin cell cancers cured by 
local resection) within the last 5 years
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h) Female subjects who had a breast cancer screening that is suspicious for malignancy, and 
in whom the possibility of malignancy cannot be reasonably excluded following 
additional clinical, laboratory or other diagnostic evaluations
i)
Subjects with a history of substance abuse (drug or alcohol) within the past 5 years, or 
psychotic disorders that are not compatible with adequate study follow-up
j)
Subjects with active peptic ulcer disease, chronic diarrhea, or gastrointestinal 
malabsorption
3) Physical and Laboratory Test Findings
a) Subjects with laboratory values that meet the following criteria are to be excluded from 
the study:
Hematology:
•
Hemoglobin < 7 g/dL
•
Platelets < 80,000/mm3
•
White blood cell (WBC) count < 3000/mm3 ( < 3 x 109/L)
•
Serum IgG < 400 mg/dL
Chemistry:
•
Bilirubin > 1.5 x upper limit of normal range (ULN); Subjects who have Gilbert’s 
syndrome and have a normal direct bilirubin are permitted 
•
Aspartate aminotransferase (AST) ≥2 x ULN
•
Alanine aminotransferase (ALT) ≥2 x ULN
4) Allergies and Adverse Drug Reaction
a) History of drug or other allergy which in the opinion of the principle investigator makes 
the subject unsuitable for participation in the study 
5) Sex and Reproductive Status
a) Women with a positive pregnancy test on enrollment or prior to study drug 
administration
6) 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
c) Subjects previously treated with belatacept or previously enrolled in a belatacept trial 
with their present allograft, except as specified below (Section 3.2.4)
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d) Subjects currently receiving background immunosuppressive therapy with azathioprine, 
sirolimus or everolimus.
e) Subjects currently receiving immunosuppressive agent(s) (eg, methotrexate, infliximab, 
etanercept, etc) for other indications, such as an autoimmune disease, or subjects with 
co-morbidities that treatment with such agents are likely during the trial.
f)
Subjects who have used any investigational drug within 30 days prior to the Day 1 visit
g) Subjects who are deemed clinically inappropriate for continued CNI therapy (investigator 
discretion).
h) Subjects who, in the opinion of the investigator, have difficult i.v. access.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.2.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone 
(FSH) level > 40 mIU/mL to confirm menopause.*
*Women treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels.
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal. :
3.2.4
Re-Screening 
Subjects who fail screening may be considered for re-screening one time if, in the opinion of the 
investigator, their clinical status has changed such that they may now be eligible for study 
participation per all eligibility criteria. The following are requirements for re-screening:
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1. Medical monitor approval
2. Rescreening is not permitted during the 42-day (initial) screening period following the 
date on which the initial written informed consent is obtained
3. Subjects to be re-screened must sign a new informed consent and be enrolled with a new 
identification number via the IVRS
4. At the discretion of the medical monitor, selected tests, such as chest radiography, will 
not be repeated if previous screening results remain valid per the protocol-defined 
window for that test.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.4
Biopsy Restrictions
Investigators must perform a renal biopsy to assess for acute rejection in subjects who meet 
protocol specified clinical criteria for acute rejection. Renal biopsies performed for medical 
cause are allowed. Renal biopsies performed according to local practice in the absence of clinical 
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suspicion of AR, PTLD or for other medical cause are not permitted. A biopsy of the affected 
organ should be considered when there is suspicion of PTLD. (Refer to Section 5.3)
3.4
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Withdrawal of informed consent (subject’s decision to withdraw for any reason)
•
Any clinical adverse event (AE), abnormal laboratory test results 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
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Missing 
2 
consecutive 
belatacept 
infusions, 
unless 
the 
subject 
is 
receiving 
lymphocyte-depleting therapy or has approval by the BMS/ICON medical monitor to 
remain in the study. Documentation will be required.
•
Subjects who experience functional graft loss (defined herein as resumption of maintenance 
dialysis treatments for > 56 consecutive days), and are deemed by the investigator to no 
longer require immunosuppression.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 3.5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
NOTE: Withdrawal of a subject from study medication does not imply that the subject is 
withdrawn from the study. All patients will be followed through study month 24 for graft 
and subject survival status. 
3.5
Post Treatment Study Follow up
Withdrawal of a subject from study medication does not imply that the subject is withdrawn 
from the study. Subjects will remain in the study and will be contacted annually (either office 
visit or by phone) to confirm graft and vital status. All subjects will be followed for graft and 
survival status through the month 24 study visit. 
3.5.1
Early Termination from Study Medication
An Early Termination visit and safety follow-up visits will be conducted for subjects who 
discontinue study medication during their participation in the study. All procedures listed in 
Table 5.1-2 will be performed.
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The Early Termination visit should occur at the earliest possible date within a 14 day window 
following the discontinuation of belatacept or CNI. If the visit cannot be completed within the 
window (eg, due to hospitalization), the visit should be completed as soon as possible.
Subsequent Follow-up visits should occur as indicated in Table 5.1-2 within a ± 5 day window.
3.5.2
Post Study Access to Therapy
At the completion of the 2-year treatment period or upon premature discontinuation of treatment, 
BMS will not continue to supply study drug to subjects/investigators unless BMS chooses to 
extend the study. The investigator should ensure that the subject receives appropriate standard of 
care.
3.5.3
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. 
Since vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.5.4
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
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4
TREATMENTS
Study drugs include both Non-Investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
•
Study required premedication, and 
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg backbone therapy, rescue medications)
•
Diagnostic agents: given as part of the protocol requirements must also be included in the 
dosing data collection.
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Belatacept
4.1
Study Treatments
Table 4.1-1:
Product Description: Study Treatment
Product Description and Dosage 
Form
Potency
Primary Packaging
(Volume)/ Label 
Type
Secondary 
Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Belatacept for Injection 250 mg / vial
250 mg
Vial / Open Label
Cardboard (SBS 
Carton)
White to off white, 
whole or 
fragmented cake in 
a vial
Refrigerated at 2- 8°
Celsius. Protect from light
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product (IMP) in some 
regions, is defined a pharmaceutical form of an active substance or placebo being tested or used 
as a reference in a clinical study, including products already with a marketing authorization but 
used or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is: Belatacept 250 mg vials
Subjects will receive IV belatacept on Days 1, 15, 29, 43, 57, and then every 28 days thereafter.
4.1.2
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 Enteric-coated Mycophenolate Sodium (EC-MPS)/ 
Mycophenolic Acid (MPA) and corticosteroids.
4.1.2.1
Description of the Dosage Form
Belatacept for Injection, 250 mg/vial
Belatacept for Injection, 250 mg/vial, is a sterile non pyrogenic lyophilized powder. Each vial 
contains 275 mg of belatacept, 550 mg of sucrose, 38.0 mg of sodium phosphate monobasic 
monohydrate, 6.4 mg of sodium chloride, and 1 N sodium hydroxide/1 N hydrochloric acid 
solution sufficient to adjust pH to 7.5. A 10% overfill is included in each vial to account for vial 
needle syringe (VNS) holdup.
4.1.2.2
Drug Product Preparation
Constitution and dilution of Belatacept for Injection 250 mg/vial must be performed using 
silicone-free disposable syringes. Suitable fluids for constitution of the lyophile include sterile 
water for injection (SWFI), 0.9% sodium chloride injection (NS) or 5% dextrose injection 
(D5W). Prior to IV administration, the constituted solution is further diluted to approximately 
100 mL with NS or D5W for a final belatacept concentration between 2 mg/mL and 10 mg/mL. 
The infusion is to be administered through a sterile, non-pyrogenic, low protein binding in-line 
filter. The syringe and in line filter set will be provided by BMS. Additionally, care must be 
taken to ensure the sterility of the prepared solution, as the drug product does not contain 
antimicrobial preservatives or bacteriostatic agents (see product label).
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Belatacept
Constitution of the Lyophile
Each 250 mg vial of Belatacept for Injection should be constituted with 10.5 mL of a suitable 
constitution fluid (SWFI, NS or D5W) to provide a solution with a belatacept concentration of 
approximately 25 mg/mL. Belatacept for Injection, 250 mg/vial, is not stoppered under vacuum. 
To avoid excessive foam formation in the vial, slowly inject the constitution fluid into the vial 
with the stream directed toward the vial wall and not into the lyophilized cake. The vial should 
be gently swirled and inverted until the lyophile dissolves. Although some foam may remain on 
the surface of the constituted solution, a sufficient excess of belatacept is included in each vial to 
account for withdrawal losses, thus, 10.0 mL of a 25 mg/mL belatacept solution can be 
withdrawn from each vial. Constituted solutions of belatacept may foam, therefore, shaking 
should be avoided.
Preparation of the Infusion
Prior to IV administration, the constituted belatacept solution (25 mg/mL) should be further 
diluted to approximately 100 mL with either NS or D5W to final belatacept concentrations 
ranging from 2 mg/mL to 10 mg/mL. Lyophiles constituted with SWFI may be further diluted 
with either NS or D5W. Lyophiles constituted with NS should be further diluted with NS and 
lyophiles constituted with D5W should be further diluted with D5W.
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Recommended Storage Conditions
Belatacept for Injection 250 mg/Vial should be stored refrigerated at 2°- 8°C (36°-46°F), and 
protected from long-term exposure to light. The reconstituted solution should be transferred from 
the vial to the infusion bag or bottle immediately. After further dilution with NS or D5W to 
belatacept concentrations between 2 mg/mL and 10 mg/mL, the solutions may be stored in 
plastic, non siliconized, IV bags or glass bottles. If not used immediately, the infusion solution 
may be stored under refrigerated conditions at 2°- 8°C (36°-46°F) and protected from light for up 
to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20° - 25°C 
[68°-77°F] and room light). Regardless of storage condition, the belatacept infusion must be 
completed within 24 hours of constitution of the lyophile. 
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Belatacept
4.2
Method of Assigning Subject Identification
Subjects will be randomized in a 1:1 fashion to receive belatacept or to continue to receive their 
previous CNI (CsA or TAC). Subjects will be stratified by screening cGFR in a 1: 2 ratio 
(≥30 to < 45 mL/min/1.73 m2 or ≥45 to 75 mL/min/1.73 m2) to maintain similar distributions
across treatment groups. 
Randomization numbers will be assigned in the order in which subjects qualify for treatment, not 
in the order of study enrollment. A randomization schedule will be generated and kept by BMS. 
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 
5-digit subject number beginning with 70001, 70002, 70003, etc. by the interactive voice 
response system (IVRS) for identification throughout the study. This subject number must not be 
reused for any other participant in the study. The physician / coordinator must contact IVRS to 
enroll each subject into a centralized database at the time of signing consent. SAE reporting for 
all subjects will begin at the time of enrollment, immediately after written informed consent is 
obtained.
The subject may be randomized once all entry criteria (inclusion and exclusion) has been met. 
The physician/coordinator must contact IVRS to randomize each subject into a centralized 
database. 
4.3
Selection and Timing of Dose for Each Subject
Administration of Belatacept 
Subjects will receive IV belatacept 5 mg/kg on Days 1, 15, 29, 43, and 57, and every 4 weeks 
thereafter. The infusion dose is to be based on the Day 1 body weight (baseline weight) and will 
not be modified unless there is a change of body weight ≥10% of the Day 1 weight (see 
Section 4.4.1 - Dose Modification). The infusion solution should be administered over a 
period of approximately 30 minutes. 
Home infusion services may be available for belatacept subjects beginning at Week 16
(excluding visits for months 3, 6, 9, 12, 18 and 24) at selected sites where it is feasible and with 
approval from BMS. This visit should occur within the prescribed visit window for the specified 
visit. For details, please refer to the home infusion manual. Subjects participating in home 
infusion visits will also be contacted to assess for AEs and concomitant medications.
Administration of Cyclosporine (CsA)
CsA will be administered according to the package insert. The daily dose of CsA should be 
administered on a consistent schedule in relation to time of day and meals. On study visit days, 
the subject must withhold the morning CsA dose until after trough CsA blood level draws. CsA 
doses should be adjusted to maintain trough serum concentrations in the range of 50 - 250 ng/mL 
as determined by local laboratory assessment and methodology.
For additional prescribing information, see the package insert.
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Belatacept
Administration of Tacrolimus (TAC)
TAC will be administered according to the package insert. The daily dose of TAC should be 
administered on a consistent schedule in relation to time of day and meals. On study visit days, 
the subject must withhold the morning TAC dose until after trough TAC blood level draws. TAC 
doses should be adjusted to maintain trough serum concentrations in the range of 4 - 11 ng/mL as 
determined by the local laboratory assessment and methodology.
For additional prescribing information, see the package insert.
Withdrawal of Calcineurin Inhibitors (CNIs)
Subjects randomized to receive belatacept will reduce their dose of CNI as follows: to 
40% - 60% of the baseline dose by Day 15, 20% - 30% of the baseline dose by Day 22, and will 
discontinue CNI by Day 29.
Corticosteroids
Subjects should be maintained on a stable daily dose of corticosteroids for the duration of the 
study unless a change in the medical condition of the subject warrants adjustment. Withdrawal of 
corticosteroids during the study is not permitted.
Mycophenolate 
Mofetil 
(MMF), 
Enteric-coated 
Mycophenolate 
Sodium 
(EC-MPS)/Mycophenolic Acid (MPA)
All subjects in this study will be treated with MMF or EC-MPS/MPA in addition to belatacept / 
CNI. MMF or EC-MPS/MPA will be administered according to the package insert. Daily MMF 
or EC-MPS/MPA should be administered in 2 divided doses on a consistent schedule in relation 
to the time of day and meals. Intravenous dosing is permitted, if needed, due to inter-current 
illness or other cause, at the investigator’s discretion. The dose and schedule may be adjusted 
determined on the basis of laboratory values and subject tolerability (see below).
Dosing in Subjects Who Develop MMF / EC-MPS/MPA-related Complications or 
Toxicities
For subjects who develop nausea, diarrhea, or other MMF or EC-MPS/MPA-related 
gastrointestinal adverse effects (eg, symptoms fully assessed and deemed not to have an etiology 
other than intolerability to MMF or EC-MPS/MPA), the MMF or EC-MPS/MPA dose may be 
decreased to a level that minimizes these effects.
For subjects who develop neutropenia (absolute neutrophil count < 1.3 x 103/μL), dosing with 
MMF or EC-MPS/MPA should be interrupted or the dose reduced as per the package insert.
For full prescribing information, see the respective package inserts.
Anti-viral / Fungal Prophylaxis
It is recommended that subjects who receive a T-cell depleting agent at any time in the trial 
receive prophylaxis against Pneumocystis jiroveci pneumonia (previously called PCP 
pneumonia), cytomegalovirus exacerbation and other herpes viruses, and Candida infections for 
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Belatacept
at least 6 - 12 weeks based upon the KDIGO guidelines and/or in accordance with the local 
standard of care practice.4
4.3.1
Phone Visits CNI Subjects
Phone visits for CNI subjects may commence at the Week 16 visit (excluding visits for months 
3, 6, 9, 12, 18, and 24). Subjects will be contacted to assess for AEs and concomitant 
medications. This visit should occur within the prescribed visit window for the specified visit.
4.4
Visit Windows
For the purpose of this study, “Week” refers to the end of treatment week (eg. Week4 = Day 29, 
Week 8 = Day 57, etc) 
Visit
Visit Window
Day 15
Target date ± 3 days
Week 4 - Month 6
Target date ± 3 days
Month 7 – Month 24
Target date ± 5 days
Early Termination
Target Date: Within 14 day 
window after discontinuation 
of belatacept or CNI
8, 12, 24 weeks Follow-up
Target date ± 5 days
4.4.1
Dose Modification
The infusion dose is based on the baseline (Day 1) body weight, and will not be modified unless 
there is a change of body weight ≥10% of the Day 1 weight. If an adjustment has been made 
based upon a body weight change, this weight should be considered as a new baseline weight. 
No further adjustment of dose based upon body weight is required, unless the subject has an 
additional body weight change ≥10% from this new baseline measure. The dose should be 
modified starting at the next belatacept infusion visit and the new weight should be considered as 
a new baseline weight. 
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 (refer to section 4.4 above). If 
the belatacept infusion cannot be administered within the visit/infusion window defined in the 
protocol, the infusion may need to be skipped and the next infusion administered within the next 
visit/infusion window. If a belatacept infusion must either be administered outside of the 
protocol-prescribed visit/infusion window or skipped, it is recommended that the investigator 
contact the medical monitor in advance to discuss the circumstances.
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Belatacept
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. Subjects in whom belatacept dosing is discontinued should 
be placed on a conventional immunosuppressive regimen.
Subjects who receive plasmapheresis for the treatment of AR may receive an additional dose(s) 
of belatacept. This decision must be individualized on a case-by-case basis, and the investigator 
must discuss any dose modification with the BMS/ICON medical monitor in advance of such 
modification.
4.5
Blinding/Un-blinding
Not applicable. This study is open label.
4.6
Treatment Compliance
Belatacept will be administered as an IV infusion. All medications specified in this protocol must 
be administered as described within the protocol. All study medications and concomitant 
medication usage must be reported on the appropriate case report form (CRF) pages and any 
deviations from specified administration should be clearly documented.
4.7
Destruction and Return of Study Drug
4.7.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS and/or designee Study Monitor unless study drug containers must be 
immediately destroyed as required for safety, or to meet local regulations (eg, cytotoxics or 
biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS and/or designee upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
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•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS and/or designee Study Monitor 
will make arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.7.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS and/or designee Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
4.8
Retained Samples for Bioavailability / Bioequivalence
Not Applicable
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Belatacept
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Informed Consent
X
Call IVRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
At screening, call IVRS 
to enroll subject & record 
subject # assignment. At 
Day 1, call IVRS to 
randomize subject. CNI 
subjects do not need to 
call IVRS after Day 1 
visit except to report 
discontinuation from 
study drug. 
Inclusion / Exclusion 
Criteria Confirmed
X
X
Subjects who fail 
screening may be 
considered for 
rescreening one time if, in 
the opinion of the 
investigator, their clinical 
status has changed such 
that they may now be 
eligible for study 
participation per all 
eligibility criteria (refer 
to Section 3.2.4).
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Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Chest X-Ray
X*
Chest x-ray (posterior-
anterior and lateral views)
* at the time of, or within 
6 months prior to 
screening
12 Lead 
Electrocardiogram
X
Must be obtained prior to 
randomization.
Full Medical History
X
Physical Exam
X
X
Neurologic Exam
X
X
X
Also required if change in 
neurologic status based 
on clinical signs and 
symptoms is observed
(Sect. 5.3.8)
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Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Vital Signs 
X
X
X
X
X
X
X
X*
X*
X
X*
X*
X
X*
X*
X*
X
BP (sitting position) &
heart rate; temperature & 
respiratory rate will also 
be taken at Screening 
visit.
Measure blood pressure 
and heart rate pre-dose 
and at the end of
infusion for belatacept 
treated subjects * Not 
required for CNI subjects 
at phone visits.
Standardized BP
X
X
X
X
X
X
Refer to Section 5.3.2.1
Height / Weight
X*
X
X
X
X
X
X
X
* Height taken at Day 1 
only. 
Weight prior to infusions
for belatacept treated 
subjects.
Adverse Events 
Monitoring
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
* SAEs should be 
collected from the time 
subject signs informed 
consent.
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Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Peri-Infusion AE 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Following every 
belatacept infusion, 
subject must be contacted 
within 48 hours to 
confirm if they have had 
any adverse event within 
24 hrs of their infusion.
Review Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MTSOSD-R59
X
X
X
X
X
Obtain 
Donor/Recipient
Information
X
Including type of 
allograft, viral (EBV & 
CMV) serologies, T-cell 
cross match, HLA, TB 
screening status and 
demographic data [ if 
available].
CENTRAL LABS
All labs should be drawn 
prior to dosing for 
belatacept treated 
subjects. 
EBV Serology
X
Collect if unknown or 
negative.
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Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Chemistry Panel: 
(Fasting) w/ cGFR
X
X
X
X
X
X
Draw prior to infusion. 
Nothing to eat/drink, 
except water, for 8 hours 
prior to laboratory 
collection.
 
 
TAC/CsA Trough 
Levels
X*
X
X
X
X
X
X
*All subjects - Screening. 
visit. Hold AM dose of 
CNI until trough drawn. 
Only subjects randomized 
to remain on CNI should 
be drawn after screening.
Should also be drawn at time 
of SAR or PTLD/PML.
Refer to section 5.3.5.2
Immunoglobulins & 
Isotypes, IgG1, 2, 3, 4
X*
X
X
X
X
X
X
Also collected at the time 
of graft loss and 
suspected AR.
* No isotypes assessed at 
screening.
CBC with diff
X
X
X
X
X
Hemoglobin A1c
X
X
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Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Urinalysis / Spot 
Urine
X
X
X
X
X
Parameters include 
protein, glucose & blood;
urine protein, creatinine, 
protein /creatinine ratio.
 
 
 
 
 
 
 
 
 
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IM103116
BMS-224818
Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
X
X
 
 
 
 
 
 
 
 
 
 
 
 
X
X
X
 
 
Donor Specific 
Antibodies (DSA)
X
X
Must also obtain for any 
suspected AR.
For belatacept subjects, 
draw prior to infusion.
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IM103116
BMS-224818
Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Immune Cell 
Phenotyping
X
X
USA Subjects Only.
Must also obtain for any 
suspected AR.
For belatacept subjects, 
draw prior to infusion.
Anti-Viral T-cell 
Response
X
X
X
USA Subjects Only.
Must also obtain for any 
suspected PTLD/PML.
For belatacept subjects, 
draw prior to infusion.
Belatacept Infusion 
Visits
X
X
X
X
X
X
X*
X*
X
X*
X*
X
X*
X*
X*
X
Dose based on D1 body 
weight & will not be 
modified unless there is a 
change of ≥10% of the
D1 weight. 
Measure blood pressure 
and heart rate pre-dose 
and at the end of 
infusion for belatacept 
subjects only.
*Home Infusion services 
can begin at Week 16 for 
belatacept subjects if 
approved.
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
CNI Visits
(TAC or CsA)
X
X
X
X
X
X
X
X*
X*
X
X*
X*
X
X*
X*
X*
X
*phone visit permitted -
Assess for AEs & 
concomitant medications. 
Should occur within the 
prescribed visit window 
for the specified visit.
Biopsy
At any time of suspected 
AR /PTLD.
LOCAL LABS
Interferon- gamma
release assay (IGRA) 
X
Refer to Section 3.2.2, 
Exclusion Criteria, 
# 2e NOTE.
If local lab does not
provide this assay (ie, 
QuantiFERON- TB Gold 
or T-Spot-TB), analysis 
should be done at central 
lab. 
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
CsA/TAC Trough
X*
*All subjects-Use local 
lab value for entry 
criteria.
Hold AM dose of CNI 
until trough level drawn. 
Should also be drawn at time 
of SAR/PTLD/PML. Refer 
to section 5.3.5.2
Serum Creatinine 
(to estimate cGFR)
X*
X
X
X
* Two cGFR values are 
required to demonstrate 
stable renal function prior 
to randomization, once at 
the screening evaluation 
and at one additional time 
point within 2 to 12 
weeks prior to screening. 
Should also be drawn if 
there is clinical suspicion 
of AR/PTLD/PML. Refer 
to section 5.3.5.2
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-1:
Screening / Baseline and Study Evaluations - Year 1 (IM103116)
M
1
M
3
M
6
M
9
M
12
Notes 
Screen
a
Randomize/
Baselineb
W
2
W
4
W
6
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52c
Procedure
D -42 D 1 
D 15 D 29 D 43 D 57
Pregnancy Test
X
X
X
X
X
X*
X
X*
X*
X
X*
X*
X
X*
X*
X*
X
All woman of child-
bearing potential 
(WOCBP)
must have urine or serum 
pregnancy test
performed within 24 
hours prior to the first
dose of belatacept, & may 
be performed at either 
screening or baseline 
visit.
Negative pregnancy tests 
are required prior to each 
belatacept infusion. 
A positive urine result 
should be confirmed 
using a quantitative 
serum test performed at a 
local lab.
* Not required for CNI 
subjects at specified 
visits.
a Screening = enrollment (Must occur within 42 days prior to randomization)
b For statistical purposes, Day 1 /Randomization will be considered baseline for all analyses unless noted.
c Information on subject and allograft survival will be collected for all subjects through 12 months post-randomization.
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Call IVRS
X
X
X
X
X
X
X
X
X
X
X
X
X*
* CNI subjects do not need to 
call IVRS except to report 
discontinuation from study 
drug.
Physical Examination
X
Neurologic Exam
X
X
Also required if change in 
neurologic status based on 
clinical signs and symptoms 
is observed (Sect 5.3.8)..
Vital Signs 
X*
X*
X*
X*
X*
X
X*
X*
X*
X*
X*
X*
X
X*
BP (sitting position), heart 
rate, temperature &
respiratory rate will be taken.
Measure blood pressure and 
heart rate pre-dose and at 
the end of the infusion for 
belatacept treated subjects
* Not required for CNI 
subjects at phone visits.
Standardized BP
X
X
Refer to Section 5.3.2.1
Weight
X
X
Weight prior to infusions for 
belatacept treated subjects.
Adverse Events 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Peri-Infusion AE 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Following every belatacept 
infusion, subject must be 
contacted within 48 hours to 
confirm if they have had any 
adverse event within 24 hrs 
of their infusion.
 
X
X
X
X
X
X
X
X
CENTRAL LABS
All labs should be drawn 
prior to dosing for belatacept 
treated subjects. 
Chemistry Panel: w/ c 
GFR
X
X
Nothing to eat/drink, except 
water, for 8 hours prior to 
laboratory collection.
 
TAC/CsA Trough 
Levels
X
X
Hold AM dose of CNI until 
trough drawn. Should also be 
drawn if there is clinical 
suspicion of AR/PTLD/PML. 
Refer to section 5.3.5.2
Immunoglobulins & 
Isotypes, IgG1, 2, 3, 4
X
X
Also collected at the time of 
graft loss and suspected AR.
CBC with diff
X
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Hemoglobin A1c
X
Urinalysis / Spot Urine
X
X
Parameters include protein, 
glucose & blood; urine 
protein, creatinine, 
protein/creatinine ratio.
 
 
 
 
 
 
 
 
 
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
X
X
 
 
 
 
 
 
 
 
 
 
 
 
Gene Expression / 
Transcriptional 
Profiling (mRNA)
X
Must also obtain for any 
suspected AR.
For belatacept subjects, draw 
prior to infusion.
Donor Specific 
Antibodies (DSA)
X
Must also obtain for any 
suspected AR.
For belatacept subjects, draw 
prior to infusion.
Revised Protocol No.: 05
Date: 18-Apr-2018
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Anti-Viral T-cell 
Response
X
USA subjects only.
Must also obtain for any 
suspected PTLD/PML.
For belatacept subjects, draw 
prior to infusion.
Belatacept Infusion 
Visit
X*
X*
X*
X*
X*
X
X*
X*
X*
X*
X*
X*
X
Dose based on D1 body wt & 
will not be modified unless 
there is a change of  ≥10% 
of the D1 weight. 
Measure blood pressure and 
heart rate pre dose and at 
the end of infusion.for 
belatacept subjects only. 
*Home Infusion services can 
begin at Week 16 for 
belatacept subjects. 
(Excluding vists for months
3,6, 9, 12, 18, 24).
CNI Visits
X*
X*
X*
X*
X*
X
X*
X*
X*
X*
X*
X*
X
*allowable phone visit -
Assess for AEs & 
concomitant medications. 
Should occur within the 
prescribed visit window for 
the specified visit.
Revised Protocol No.: 05
Date: 18-Apr-2018
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Clinical Protocol
IM103116
BMS-224818
Belatacept
Table 5.1-2:
Study Evaluations - Year 2 (IM103116)
M
15
M
18
M
21
M
24/ 
ETa
8, 12, 24
Week
Follow-
up
Notes 
Procedure
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
100
W
104
Biopsy
At any time of suspected 
acute rejection or suspected 
PTLD.
LOCAL LABS
Serum Creatinine
Should also be drawn if there 
is clinical suspicion of AR/
PTLD/PML. Refer to section 
5.3.5.2
Pregnancy Test
X*
X*
X*
X*
X*
X
X*
X*
X*
X*
X*
X*
X
X*
Negative pregnancy tests 
(urine or serum) are required 
prior to each belatacept 
infusion. 
A positive urine result should 
be confirmed using a 
quantitative serum test 
performed at a local lab.
8 week post last dose 
(WOCBP).
* Not required for CNI 
subjects at specified visits.
a Information on subject and allograft survival will be collected for all subjects through 24 months post-randomization (at 12 and 24 months).
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Clinical Protocol
IM103116
BMS-224818
Belatacept
5.2
Study Materials
The following study materials will be provided at the study start:
•
On-Site Investigator File (OSIF)
•
Pharmacy Logs
•
Sample source documents, where applicable
•
BMS-224818 Investigator Brochure
•
Site manual of operation for the interactive voice response system (IVRS)
•
Registration worksheets for IVRS
•
Case Report Form (CRF) instructions
•
Laboratory kits and laboratory manual
•
Pregnancy surveillance forms
•
Any other materials as locally required or agreed.
The central laboratory will provide all laboratory-related materials. If required, the investigator 
will need to have a centrifuge, a freezer (-20ºC or below), appropriate containers and dry ice for 
shipment and storage of blood and plasma samples. Enough dry ice, when indicated, should be 
utilized to allow samples to arrive at their designated laboratory in a frozen state.
5.3
Safety Assessments 
Safety assessments will be performed throughout the study as outlined in Table 5.1-1 and Table 
5.1-2. Vital signs will be performed throughout the study. Standard clinical laboratory tests will 
be performed throughout the study and at early termination/ discontinuation, if applicable.
Physical examinations may be performed by a Doctor of Medicine, Doctor of Osteopathy, 
Physician’s Assistant or Nurse Practitioner.
A chest x-ray (CXR) is required for all subjects at the screening visit unless a previous CXR, 
performed within 6 calendar months of enrollment, is negative for any evidence of TB. (See also 
TB exclusion criterion in Section 3.2.2). 
Urine or serum pregnancy tests will be performed prior to dosing for all WOCBP. If any female 
subject becomes pregnant, she will be immediately discontinued from study medication. 
Data for the procedures and assessments specified in this protocol should be submitted on the 
CRF. Lab assessments that are performed and sent to central vendor do not need to be recorded 
on the CRF however, any local lab assessments which are not performed by the central vendor 
but are part of the required study procedures should be entered into the database and recorded on 
a supplemental CRF page.
Additional procedures and assessments may be performed as part of the standard of care 
however data for those assessments should remain in the patient’s medical file and should not be 
provided unless specifically requested from the Sponsor.
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Date: 18-Apr-2018
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Clinical Protocol
IM103116
BMS-224818
Belatacept
5.3.1
Follow-up Safety Period
8-Week Post Last Dose Safety Follow-up Visit 
For belatacept-treated subjects who complete the study and transition to commercially available 
Nulojix®, as well as CNI-treated subjects, the following procedures are required. This visit may 
be conducted by phone.
•
Assess for AEs
•
Concomitant medications 
For belatacept-treated subjects who discontinue belatacept (either prematurely or after week 
104), and return to non-belatacept-based immunosuppression, the following procedures are 
required:
•
Assess for AEs
•
Pregnancy Test (WOCBP only)
•
Immunogenicity
•
PK
•
Concomitant medications 
12-Week and 24-Week Post Last Dose Safety Follow-up Visits 
For belatacept subjects who discontinue belatacept (either prematurely or after week 104), 
completed the study and return to non-belatacept-based immunosuppression for their standard of 
care, the following procedures are required:
•
Assess for AEs
•
Immunogenicity
A ± 5 day window will be allowed for each follow-up visit.
5.3.2
Vital Signs
Vital signs will be recorded as outlined in Table 5.1-1 and Table 5.1-2. Sitting arterial systolic 
and diastolic blood pressure and radial artery pulse rate will be measured. 
5.3.2.1
Standardized Blood Pressure Monitoring
BP measurements should be done soon after the subject’s arrival at the clinic, before 
venipuncture, study medication administration, and any other study procedures scheduled 
for the visit are performed.
Instructions for Subjects
CNI subjects should withhold the AM dose of CNI until after BP measurements are completed 
for the visit.
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Clinical Protocol
IM103116
BMS-224818
Belatacept
No smoking is permitted within 2 hours prior to a BP measurement. No alcoholic beverage 
consumption is permitted within 6 hours prior to a BP measurement. Usual caffeine intake is 
permissible. (Appendix 1)
Standardization of Procedures
BP and heart rate are to be measured with a calibrated automatic BP monitor. If a calibrated 
automatic BP monitor is not available, standardized BP measurements are to be performed with a 
calibrated aneroid device or mercury sphygmomanometer.
At entry, if there is a difference in BP readings between arms, the arm with the higher reading 
should be used. The same arm should be used at all visits for BP measurements throughout the 
study.
The following instructions are standard, irrespective of the device being utilized:
Situate the subject in a quiet environment so that the subject may rest for at least 10 minutes in 
the seated position.
Select an appropriately sized cuff. Bladder width should be at least 40% of the arm 
circumference, and bladder length should be at least 80% of the arm circumference.
With feet flat on the floor, the back against the chair, and with the arm resting on a table or other 
support so that the midpoint of the cuff is at the level of the heart, obtain 3 replicated 
measurements at least 1 minute apart (to permit the release of blood trapped in the arm veins). If 
3 consecutive seated DBP readings are not within 8 mm Hg of each other, an additional 2 BP 
readings must be obtained (total = 5). The mean SBP and DBP from these measurements will be 
used as the subject̓s BP for this assessment.
Record the measurements with the date and time on source documents and appropriate CRF 
pages.
Refer to Appendix 1.
5.3.3
Physical Measurements
Body weight and height will be recorded at the scheduled visits as outlined in Table 5.1-1 and 
Table 5.1-2. The following guidelines will aid in the standardization of these measurements:
•
The same scale should be used to weigh a given patient throughout the study, when possible
•
Scales should be calibrated and reliable; scales should be zeroed just prior to each patient’s 
weigh-in session 
•
A patient should void just prior to being weighed
•
Weight should be recorded before a patient’s meal (if applicable) and at approximately the 
same time each day
•
A patient should be minimally clothed (ie, no shoes or heavy over garments).
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Date: 18-Apr-2018
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Clinical Protocol
IM103116
BMS-224818
Belatacept
5.3.4
Physical Examination
Patients will undergo a routine physical examination during the Screening Phase and at specified 
visits as outlined in Table 5.1-1 and Table 5.1-2.
5.3.5
Laboratory Assessments
Blood and urine samples will be obtained as outlined in Table 5.1-1 and Table 5.1-2 for clinical 
laboratory evaluations. A central laboratory vendor will be utilized for this study and a 
laboratory manual will be provided to each site. Patients should be fasting for a minimum of 
8 hours prior to specified blood draws as outlined in Table 5.1-1 and Table 5.1-2 and 
Section 5.3.5.1. However, if a patient is not fasting at a given visit, the blood draw should still be 
performed, and the non-fasting status should be documented. Analysis of clinical laboratory 
specimens will be performed by a central or local laboratory as specified below.
5.3.5.1
Central Laboratory
Hematology: Complete blood count (CBC with platelet) with differential, HbA1c
Chemistry Panel (Fasting)*: Sodium, potassium, chloride, bicarbonate, calcium; glucose, 
BUN, serum creatinine, uric acid, ALT, AST, LDH, alkaline phosphatase, total protein, albumin, 
total bilirubin, phosphorous and magnesium, C-reactive protein, Calculated GFR (cGFR)
*Note: For clarification, fasting is - nothing to eat/drink, except water, for 8 hours prior to 
procedures required.
Urinalysis (UA)/ Spot Urine (random void):
Parameters include dipstick UA for protein,
glucose and occult blood; urine protein and creatinine concentrations for calculation of a random
urinary protein/creatinine ratio. If occult blood, protein or glucose dipstick results are positive, a
microscopic examination will be done. 
Immunoglobulins: IgG, IgM, and IgA. Total IgG (4 sub-types of IgG: IgG1, IgG2, IgG3, and 
IgG4).
EBV Serology: as outlined in Table 5.1-1 and Lab Manual
 
Anti-viral T-cell Response: as outlined in Table 5.1-1 and Table 5.1-2.
Transcription Profiling (mRNA): as outlined in Table 5.1-1 and Table 5.1-2.
Donor Specific Antibody (DSA): as outlined in Table 5.1-1 and Table 5.1-2.
CsA/TAC Trough: as outlined in Table 5.1-1 and Table 5.1-2.
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IM103116
BMS-224818
Belatacept
IGRA- Interferon gamma release assay: QuantiFERON-TB Gold or T-Spot. Either assay may be 
done at local lab if assay is supported by local lab. If neither assay is available at local lab, assay 
must be done at central lab. A 37ºC incubator is required for processing samples if using the 
central lab. (Refer to lab manual for detailed instructions).
5.3.5.2
Local Laboratory
Collection, processing, storage, transport, and analysis of local laboratory samples should be 
performed based on study site practices. All study-required laboratory results performed by the 
local laboratory are noted below, and must be entered by site personnel onto the appropriate CRF 
pages.
IGRA (Interferon gamma release assay): such as QuantiFERON-TB Gold or T-Spot TB. 
Serum Creatinine: as outlined in Table 5.1-1 and Table 5.1-2. Two cGFR values are required to 
demonstrate stable renal function prior to randomization, once at the screening evaluation and at 
one additional time point within 2 to 12 weeks prior to screening. If a historical value within 12 
weeks of screening is not available, a second cGFR must be obtained prior to randomization. 
(This value must be at least 2 weeks after the screening value). A serum creatinine concentration 
must also be obtained at the time of any episode of suspected acute rejection or PTLD.
Trough CsA/TAC Blood Levels (for CNI-treated Subjects Only): as outlined in Table 5.1-1
and Table 5.1-2. Must also be obtained at the time of suspected acute rejection or PTLD
NOTE: Additional specimens needed for the periodic monitoring of CNI trough levels as part of 
routine clinical patient management, should be obtained and determined locally, per local 
standard of care. The results of the locally determined whole blood tacrolimus trough levels will 
also be collected and entered into the database. 
Pregnancy Test: (serum/urine), as outlined in Table 5.1-1 and Table 5.1-2. A serum or urine 
pregnancy test (minimum sensitivity 25 IU/L of ß-HCG) must be performed at a local laboratory 
for all WOCBP within 24 hours prior to the first dose of study medication (baseline or Day 1). 
Urine or serum pregnancy testing must be performed in all WOCBP within 24 hours prior to 
dosing at all other study visits (including ‘infusion-only’ visits for belatacept subjects). Urine 
pregnancy testing kits will be provided by a central laboratory; serum pregnancy tests should be 
performed at a local laboratory if necessary. If a female subject becomes pregnant, she will be 
discontinued from study medication.
Any laboratory test result that the investigator considers clinically significant must be recorded 
on the appropriate AE page of the CRF.
5.3.5.3
Collection, Shipping and Transport
Collection, processing, transport, and storage of local laboratory clinical specimens will be 
performed based on study site practices. Collection, processing, transport, and storage of central 
laboratory clinical specimens will be detailed in a separate manual to be provided to the 
investigator at or before the time of study initiation.
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5.3.6
Kidney Allograft Biopsy
Investigators must perform allograft biopsies to assess for suspected acute rejection in subjects 
who meet protocol-specified clinical criteria for acute rejection.(Refer to Table 5.3.6-1) Routine 
biopsies performed according to local practice, in the absence of clinical suspicion of acute 
rejection, PTLD or other medical cause are not permitted. 
Table 5.3.6-1:
Criteria for Clinically Suspected AR
1. An unexplained rise of serum creatinine ≥25% from baseline creatinine
2. An unexplained decreased urine output
3. Fever and graft tenderness
4. A reason other than those listed above and the subject was treated for this episode 
Baseline SCr is defined as the average of the 3 preceding SCr values determined by local 
laboratories. Serum creatinine values must be obtained from samples drawn on different days. 
Only local laboratory (as opposed to central laboratory) SCr values will be used for 
establishment of the baseline SCr and for determining rises in SCr that should trigger 
performance of an allograft biopsy.
For all biopsy specimens, the tissue should be stained and graded according to the Banff 97 & 
2007 update to the Banff 97 classification of kidney transplant pathology.31 32 Initial grading of 
allograft biopsies should be performed locally in order to guide acute treatment decisions. All 
allograft biopsies will be reviewed by a central pathologist. These biopsy samples will be 
provided to the central pathologist in a blinded fashion. In cases of disparity in the interpretation 
of the renal graft biopsy, for study analysis purposes, the grading by the central pathologist will 
supersede the local interpretation. If the central pathologist is unable to provide an interpretation, 
the local pathology reading will be used for analysis purposes.
The preparation and shipment of biopsy specimens to the central pathologist will be detailed in a 
separate manual to be provided to the investigator at or before the time of study initiation.
Follow-up Biopsy of a Documented Acute Rejection
Subjects may have a follow-up renal allograft biopsy after a documented acute rejection episode.
5.3.7
Diagnosis and Treatment of Acute Rejection
Signs and symptoms consistent with AR include worsening renal function (≥25% increases from 
baseline SCr) and/or other clinical signs (for example unexplained decreased urine output or 
fever and graft tenderness) (See Table 5.3.6-1 above.). 
Additionally, other factors affecting renal function (eg, dehydration, urosepsis, drug toxicity, 
polyoma viral infection, etc) should be evaluated.
Unless a biopsy is medically contraindicated (eg, hemorrhagic risk and the subject is not able to 
receive plasma/concentrated factors/etc), no subject, including a CNI-treated subject, should be 
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treated for AR without a biopsy to confirm the diagnosis. If a subject is treated for AR without 
biopsy confirmation, this should be clearly indicated on the appropriate CRF pages.
Prior to any treatment for suspected AR, the following procedures/test shall be completed:
a) Kidney allograft biopsy: the tissue should be stained and graded as specified in 
Section 5.3.6.
b) Initial grading of allograft biopsies should be performed locally in order to guide acute 
treatment decisions. The preparation and shipment of biopsy specimens to the central 
pathologist will be detailed in a separate manual to be provided to the investigator at or 
before the time of study initiation.
c) Central laboratory blood samples for determination of the following:
a.
All patients:  serum creatinine concentration, DSA and transcriptional profiling;
b. Subjects at U.S. sites only:  immune cell phenotyping and T-cell response testing; 
c.
All subjects randomized to continue CsA/TAC treatment:  CsA/TAC levels; and 
d. All subjects randomized to belatacept treatment:  Immunogenicity testing and PK 
(trough) samples.
Treatment of suspected AR should be based on the local biopsy reading and should be 
consistent with standard practice.
Definition of Graft Loss
Graft loss is defined as either functional loss or physical loss. Functional loss is defined as either:
•
A sustained level of GFR < 15 ml/min/1.73m2 for ≥4 weeks as determined by the local 
laboratory 
•
Resumption of regularly scheduled dialysis treatments for a period of ≥56 days; or
•
Re-transplantation.
5.3.8
Neurological Examination
Neurologic assessment (examination and history) will be performed at designated time points 
(see Table 5.1-1 and Table 5.1-2). A neurologist is not required for this assessment. The 
neurologic history will include the subject’s description of any new neurological symptoms, such 
as: personality, memory, headaches, pain, seizures, impairment of consciousness, swallowing, 
vision, hearing, language function, coordination, gait, weakness, sensory alterations, sphincter 
disturbance, involuntary movements, time course of any new symptoms (onset and duration), 
corroboration of any complaints with other individuals, medical illnesses, and medications.
The neurologic exam will include assessment of mental status, gait, speech, cranial nerves, 
cerebellar function, deep tendon reflexes, sensory function and motor function. Any new or 
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worsening findings should be reported as an adverse event and evaluated with additional 
modalities and/or neurologic consultation as appropriate. In cases of unexplained neurological 
findings, a magnetic resonance imaging (MRI) study, a computed tomography (CT) scan and a 
cerebrospinal fluid (CSF) examination for John Cunningham (JC) virus should be considered. 
The BMS/ICON medical monitor (or designee) must be contacted.
Any new or worsening findings should be reported as an adverse event and evaluated with a 
follow-up neurologic exam, additional diagnostic modalities and/or neurologic consultation as 
appropriate. Supplemental CRF forms will be provided to collect information confirming 
completion of the neurologic assessment.
 
 
 
 
 
 
 
 
5.3.10
Diagnosis and Treatment of Hypertension
Hypertension will be as defined in this study according to the Seventh Report of the Joint 
National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure for subjects with chronic kidney disease.33,34 Hypertension is defined as SBP ≥130 mm 
Hg or DBP ≥80 mm Hg or SBP < 130 mm Hg and DBP < 80 mm Hg while receiving 
antihypertensive medication or with a medical history of hypertension.
Intensity of treatment regimen is defined as the total number of antihypertensive medications 
used to control hypertension. All antihypertensive medications will be counted for the indication 
of hypertension in subjects with hypertension or controlled hypertension,
since the 
antihypertensive effects are present irrespective of indication. 
5.3.11
Diagnosis of New Onset Diabetes After Transplant (NODAT)
A subject who did not have diabetes prior to randomization and receives an anti-diabetic 
medication for a duration of at least 30 days will be considered to have new onset diabetes.
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Additionally, a subject who meets the criteria below (set forth by a recent international 
consensus guideline)34 and did not have diabetes prior to randomization will be considered to 
have new onset diabetes.
These criteria are summarized as:
•
Symptoms of diabetes plus casual plasma glucose (PG) concentration ≥200 mg/dL 
(11.1 mmol/L)
OR
•
Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
OR
•
2-hour PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (GTT) (75 g 
test)
AND
•
A confirmatory laboratory test based on measurements of venous PG done on another day in 
the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation.
y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.4
Efficacy Assessments
Calculated GFR and Serum Creatinine
Baseline measurements of SCr, albumin, and BUN for the calculated GFR assessment will be 
based on the last measurement prior to first dose on Day 1.
Calculated Glomerular Filtration Rate
Numerous formulae have been developed that incrementally improve the correlation between 
SCr and GFR by accounting for the effect of demographic and biometric factors. For this study, 
the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation will be used to 
estimate GFR. Accordingly, renal function will be estimated using one or the other of the 
following formulae, depending upon whether or not the local laboratory uses an “IDMS (isotope 
dilution mass spectrophotometry)-traceable” automated assay for serum creatinine; that is, an 
assay traceable to the standard reference material (SRM) maintained at the National Institute of 
Standards and Technology (NIST) 29:
•
For laboratories that do use a serum creatinine (SCr) assay that is IDMS-traceable:  
o
GFR (mL/min/1.73 m2) = 175 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x
(1.212 if African American)
•
For laboratories that do not use a serum creatinine assay that is IDMS-traceable29:
o
GFR (mL/min/1.73 m2) = 186 x (SCr) -1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American) 
Data for the procedures and assessments specified in this protocol should be submitted to BMS 
on the CRF. Additional procedures and assessments may be performed as part of standard of 
care; however, data for these assessments should remain in the patient’s medical record and 
should not be provided to BMS, unless specifically requested from the Sponsor. 
 
 
 
 
 
 
 
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5.8.2
Events of Special Interest
Additional CRFs or appropriate source documentation may be required for further clarification 
for the following “events of special interest”:
•
PTLD 
•
PML
•
Malignancies (other than PTLD) including non-melanoma skin carcinomas
•
Tuberculosis Infections (serious and non-serious)
•
CNS Infections (serious and non-serious)
•
Viral Infections (serious)  
•
Infusion related reactions
•
Other reason deemed necessary by the Sponsor
To monitor and better understand these risks, BMS, its collaborators and/or its agents may use 
collected blood samples for JCV, EBV and other immune function-related tests.
5.9
Results of Central Assessments
Blood chemistry, serology and urinalysis results will be provided to the site via an investigator 
portal from the central laboratory. Evaluation of episodes of suspected acute rejection will 
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require real time assessment of serum creatinine, trough CNI levels and histology from the renal 
biopsies; these will be evaluated locally to guide patient management. Local laboratory 
assessments will be reported on the eCRFs.
Central pathology assessment of renal biopsies will not be provided to the sites. These data are 
not immediately available and will not be used for patient management. These data will be used 
for analytical purposes only.
 
 
 
Laboratory data will be summarized and shared with the sites at the end of the study upon 
request.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation 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 (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following:
•
Related: There is a reasonable causal relationship between study drug administration and the 
AE.
•
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
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)
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•
requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status 
(eg, 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 (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 56 days of discontinuation of dosing. If applicable, SAEs must be collected that relate 
to any later protocol-specified procedure.
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
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All events of death, graft loss, malignancy, PTLD, and serious infections (ie, otherwise meeting 
SAE reporting requirements) must be reported to BMS for all randomized subjects until the end 
of the study, irrespective of study drug discontinuation or investigator-deemed causality.
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug and pregnancies must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
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as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including 
during 56 days after product 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 the BMS and/or designee Medical Monitor of this 
event and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 
24 hours and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
For women who become pregnant while using MMF or EC-MPS/MPA in this study, the 
investigator should report the pregnancy to the Mycophenolate Pregnancy Reference Registry 
and should strongly encourage the patient to enroll in the registry. 
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
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6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1. for reporting details).
Potential drug induced liver injury is defined as: 
1. Serum aminotransferase (ALT or AST) elevations to > 3 times the upper limit of 
normal (ULN) for the reference laboratory
AND 
2. Total serum bilirubin elevations to > 2 times the ULN, without initial findings 
consistent with cholestasis (elevated serum alkaline phosphatase), 
AND 
3. Absence of any other readily apparent causes of aminotransferase 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. 
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A Data Monitoring Committee (DMC) will be convened to provide oversight of benefit-risk 
considerations for patients in the study and if necessary make recommendations to BMS to 
ensure the ongoing safety of study subjects.   
The DMC will review accruing unblinded data on key outcomes to include death, graft loss, 
acute rejection, infections, and malignancies in the overall population as well as relevant 
subgroups to better assure an appropriate balance between the potential benefits and risks of 
therapy in the accumulating data set.
A DMC Charter will be prepared, which will include full details on the committee membership, 
responsibilities and how the Committee will function, to include frequency of meetings and types 
of data outputs for review and formal early termination criteria. Appropriate updates will be 
made to the protocol, as well.  
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Formal statistical testing of a research hypothesis is not being performed in this study.
The primary objective of this study is to evaluate patient and functional graft survival in 
maintenance renal transplant recipients converted from CNI to belatacept as compared to 
continuation of CNI based immunosuppression at 24 months post-randomization. A sample size 
of approximately 220 subjects per treatment group is considered to provide sufficient power to 
rule out an unacceptable difference in patient and graft survival. 
With a confidence level (one-sided) of 0.975 and assuming the true rates of patient and graft
survival by Month 24 in both treatment groups is 93%, the sample size of 220 subjects per arm 
will afford 90% probability to rule out a difference of 8.3% (sample size based on 1000 
simulations per Newcombe methodology).36
This sample size will provide 93% power to detect a 10% absolute difference of mean 
percentage change in calculated GFR at Month 24 between the belatacept regimen and the CNI 
regimen assuming a standard deviation of 30% (alpha 0.05, 2-sided). 
Given a sample size of approximately 220 subjects per treatment group, if the true AR rates by 
Month 24 are 7% in the belatacept regimen and 1% in the CNI regimen, the half width of the 
95% confidence interval of the difference in AR rate is estimated to be 3.6% (alpha 0.05, 2-
sided). With the assumed rates of AR, the confidence interval for the difference would be (2.4%, 
9.6%). 
Given a sample size of 220 subjects per treatment group, and assuming an event rate of PTLD of 
0.74% the probability of observing at least 1 event is 80.5%. 
8.2
Populations for Analyses
The primary efficacy data set will include all randomized subjects (ITT). A secondary efficacy 
data set will include all randomized subjects who do not violate terms of the protocol that might 
affect the efficacy outcome (per-protocol). “Per-protocol” analyses will be performed at Month 
24 on the primary endpoint and “key” secondary endpoints (Acute Rejection and Renal 
Function) only if the following occurs:
•
More than 10% of the total number of subjects included into the “ITT” data set at Month 24 
have significant protocol violations/deviations and consequently would be excluded from the 
“per-protocol” data set.
•
Safety analyses will be based on all randomized and treated subjects.
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
Proportion of subjects who survive with a functional graft at 24 months post randomization 
8.3.2
Secondary Endpoint(s)
•
Patient and Functional Graft Survival
o
Proportion of subjects who survive with a functional graft at 12 months 
post-randomization
•
Acute Rejection
o
The incidence and severity of clinically suspected, biopsy proven acute rejection at 12 
and 24 months post-randomization 
•
Renal Function
o
Mean change in cGFR (per 4-variable MDRD equation) from baseline to 12 and 
24 months post-randomization (% and absolute)
o
Slopes of cGFR and 1/serum creatinine, respectively from baseline as well as Month 3 to 
12 and 24 months post-randomization
o
Proportion of subjects with > 5% and > 10% improvement over baseline in cGFR at 
12 and 24 months post-randomization
o
Urine protein/ creatinine ratio (UPCR) at baseline, 3, 6, 12 and 24 months 
post-randomization
•
Hypertension
o
Mean change in systolic and diastolic blood pressure and intensity of treatment regimen 
(defined as the total number of antihypertensive medications used to control 
hypertension) from baseline to 12 and 24 months post-randomization
•
Donor Specific Antibodies (DSA)
o
Proportion of subjects with DSA at Baseline/Day 1, Months 12 and 24 
post-randomization
•
The frequency of symptom occurrence and symptom distress as measured with the 
MTSOSD-59R at baseline, Week 6, and 3, 6, and 12 months post- randomization
•
Safety and tolerability of a belatacept in a conversion setting
o
All adverse events
o
Adverse events of special interest
o
Clinically significant changes in vital signs
o
Laboratory test abnormalities
o
Clinical tolerability of the drug
 
 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics of recipients and donors 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.
8.4.2
Efficacy Analyses
In the primary analysis of subject and graft survival, and calculated GFR, missing data will be 
imputed as described in the statistical analysis plan (SAP). Where it is not explicitly stated, 
analyses will be based upon ITT subjects.
Patient and Functional Graft Survival
The primary composite endpoint of patient and graft survival by 24 months will be summarized 
within each treatment group using point estimates of the proportion of patients surviving with a 
functioning graft, and the corresponding 95% CIs. The 95% CIs will also be generated for the 
difference between the belatacept regimen and CNI to assess the effect of belatacept stratified by 
baseline cGFR. Month 24 analyses will be performed using ITT subjects as well as per-protocol 
subjects.
The composite endpoint of patient and functional graft survival by 12 months 
post-randomization will be summarized using a similar method as for the 24 months analysis.
Acute Rejection
The incidence and severity of clinically suspected, biopsy proven acute rejection up to 12 and 24 
months post-randomization will be summarized within each treatment group using point 
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estimates and 95% CIs. The 95% CIs will also be generated for the difference in rate of the acute 
rejection by 12 and 24 months between belatacept and CNI stratified by baseline cGFR. Month 
24 summaries will be performed using ITT subjects as well as per-protocol subjects.
Additional descriptive sensitivity analyses (for example including borderline events) might be 
performed as specified in the SAP. 
Renal Function
Descriptive summaries of mean calculated GFR (based on the 4-variable MDRD equation) and 
serum creatinine will be provided for each treatment group at baseline, Months 1, 3, 6, 9, 12, 15, 
18, 21, and 24. Changes from baseline and Month 3 to the later time points will be summarized 
as well. Descriptive summaries of mean percent changes in calculated GFR from baseline to 12 
and 24 Months will be provided by treatment group where Month 24 summaries will be based 
upon ITT subjects as well as per-protocol subjects. In addition 95% CI of the means will be 
provided.
A point estimate with two-sided 95% CI will be generated for the difference in mean percentage 
change of cGFR from baseline at Month 12 and Month 24, respectively, between belatacept and
CNI.
The proportion of subjects with ≥5% and ≥10% improvement over baseline at 12 and 
24 months will be summarized respectively.
To assess the trend in renal function, a linear mixed model will be used to analyze the mean 
changes in calculated GFR from multiple time-points (baseline and Month 3) to 12 and 
24 months for each regimen with terms for treatment, time, and calculated GFR at baseline and 
adjusting for important baseline characteristics. A similar analysis in 1/serum creatinine will also 
be performed. 
To diminish the contribution that patients with slower kidney disease progression have on the 
analysis of change in GFR over time and to further evaluate the treatment effect on renal 
function over time.16 The time to cGFR < 15 mL/min/1.73m2, graft loss or death from baseline 
and Month 3, respectively, in each treatment group will be summarized using Kaplan-Meier 
curves.
Urine protein/ creatinine ratio (UPCR) will be summarized descriptively by means and standard 
deviation by treatment group at baseline, 3, 6, 12, and 24 months post-randomization.
Hypertension 
Descriptive summaries of systolic and diastolic blood pressure at baseline, Months 1, 3, 6, 9, 12, 
15, 18, and 24 will be provided for each treatment. Mean change in systolic and diastolic blood 
pressure from baseline to 12 and 24 months will be summarized descriptively. The intensity of 
anti-hypertensive treatment regimens at 12 and 24 months will be summarized descriptively.
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New Onset Diabetes Mellitus After Transplantation (NODAT)
Proportion of subjects who develop NODAT at 12 and 24 months post-randomization will be 
summarized using point estimates and 95% CIs within each treatment group. The 95% CIs will 
also be generated for the difference between the belatacept regimen and CNI.
8.4.3
Safety Analyses
All AEs and SAEs since randomization will be summarized by treatment group using 
proportions and incidence rates normalized by patient-years of exposure. Laboratory marked 
abnormalities will also be descriptively summarized. No statistical tests will be performed for 
AEs or laboratory marked abnormalities.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5
Interim Analyses
At Month 12 following randomization of the last subject, an interim analysis will be performed.
The purpose of the interim analysis is to obtain study data to assess the evolving benefit risk 
profile of belatacept conversion at 12 months post-randomization. All of the above mentioned 
measures at or up to Month 12 will be assessed. Similar methods as those used for the 24-month 
analyses will be performed for the 12-month interim analysis. The interim analyses will be 
descriptive in nature, and no statistical tests will be performed.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
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If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS (and designee) promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, re-location, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug is inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
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•
non-study disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the site does not have an established 
system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 
CRFs will be prepared for all data collection fields except for fields specific to SAEs and 
pregnancy, which will be reported on the paper or electronic SAE form and Pregnancy 
Surveillance form, respectively
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. The investigator must retain 
a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:
•
External Principal Investigator designated at protocol development
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
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and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator or 
BMS as related to the investigational product
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
Term
Definition
AE
Adverse Event
ALT
Alanine aminotransferase
AM
Morning
ANCOVA
Analysis of covariance
APC
Antigen-Presenting Cell
AR
Acute Rejection
AST
Aspartate aminotransferase
BKV
BK virus
BMS
Bristol-Myers Squibb
BMS-188667
CTLA4Ig (abatacept)
BMS-224818
LEA29Y (belatacept)
BP
Blood Pressure
BPAR
Biopsy-Proven Acute Rejection
BUN
Blood Urea Nitrogen
C2
Plasma concentration 2 hours post-dose
CAN
Chronic Allograft Nephropathy
cGFR
calculated Glomerular Filtration Rate
CI
Confidence Interval
CMV
Cytomegalovirus
CNI
Calcineurin inhibitor
CRF
Case Report Form
CRO
Contract research organization
CsA
Cyclosporine A (cyclosporin)
CSBPAR
Clinically-Suspected, Biopsy-Proven Acute Rejection
CSF
Cerebral spinal fluid
CSR
Clinical study report
CXR
Chest X-ray
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
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Term
Definition
D5W
Dextrose 5% in water for injection
DSA
Donor Specific Antibodies
EBER
EBV encoded RNA
EBV
Epstein-Barr virus
ECD
Extended Criteria Donors
EC-MPS
Enteric-coated Mycophenolate Sodium
ESR
Expedited Safety Report
ESRD
End-stage renal disease
EVR
Everolimus
FDA
US Food and Drug Administration
FPG
Fasting plasma glucose
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GTT
Glucose Tolerance Test
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Imunodeficiency Virus
HLA
Human Leukocyte Antigen
HRT
Hormone Replacement Therapy
HUS
Hemolytic Uremic Syndrome
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ID
Identification
IEC
Independent Ethics Committee
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Term
Definition
Ig
Immunoglobulin
IL
Interleukin
IMP 
Investigational Medicinal Product
IGRA
Interferon gamma release assay
IRB 
Institutional Review Board 
IP
Investigational Product
ITT
Intent-To-Treat
IUD
Intrauterine device
i.v.
Intravenous(ly)
IVRS
Interactive Voice Response System
LDL
Low-density lipoprotein
LDT
Lymphocyte depleting therapy
LI
Less intensive
MedDRA
Medical Dictionary of Drug Regulatory Activities
MI
More intensive
MMF
Mycophenolate mofetil 
MPA
Mycophenolic acid
MDRD
Modification of Diet in Renal Disease (study)
MFI
Mean Fluorescent Intensity
mRNA
Messenger ribonucleic acid
MRI
Magnetic resonance imaging
MTSOSD-59R
Modified Transplant Symptom Occurrence and Symptom Distress 
Scale-59R
mTOR
Mammalian target-of rapamycin
NIMP
Non-investigational medicinal product
NKF-K DOQI
National Kidney Foundation Kidney Disease Outcomes Quality 
Initiative
NODAT
New Onset Diabetes After Transplantation
NSS
0.9% normal saline solution
NULOJIX
Commercial belatacept
OSIF
On-site investigator file
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Term
Definition
PCR
Polymerase Chain Reaction
PD
Pharmacodynamics
PG
Plasma Glucose
PK
Pharmacokinetic(s)
PML
Progressive multifocal leukoencephalopathy
PPD
Purified protein derivative
PRA
Panel Reactive Antibodies
PTDM
Post-Transplant Diabetes Mellitus
PTLD
Post-Transplant Lymphoproliferative Disorder
QoL
Quality of Life
RA
Rheumatoid Arthritis
ridit
relative to an identified distribution (analysis)
RO
Receptor occupancy
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SCD
Standard Criteria Donors
SCr
Serum Creatinine
SD
Standard Deviation
SmPc
Summary of Product Characteristics
SOP
Standard Operating Procedure
SRL
Sirolimus
SWFI
Sterile water for injection
TAC
Tacrolimus
TB
Tuberculosis
TG
Triglyceride
UACR
Urinary albumin / creatinine ratio
ULN
Upper limit of normal
UNOS
United Network of Organ Sharing
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Term
Definition
UPCR
Urinary protein/creatinine ratio
USPI
US Package Insert
UTI
Urinary tract infection
VNS
Vial needle syringe
VSS
steady-state volume of distribution
WBC
White blood cells
WOCBP
Women of Childbearing Potential
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APPENDIX 1
BLOOD PRESSURE MEASUREMENT USING AN ANEROID OR 
MERCURY SPHYGMOMANOMETER AND HEART RATE 
MEASUREMENTS REFERENCE
The subject should first rest for at least 10 minutes in the seated position.
1. The accuracy and reliability of blood pressure (BP) measurements will be improved by 
following these standardized steps:
a) Situate the individual in a quiet environment with the feet flat on the floor, the back 
against the chair, and with the arm resting on a table or other support so that the midpoint 
of the cuff is at the level of the heart (see below).
b) Place the manometer near eye level (tilted, floor models excepted), sufficiently close to 
read the calibration markings on the column.
c) Select an appropriately sized cuff. Bladder width should be at least 40% of arm 
circumference; bladder length should be at least 80% of arm circumference (see below 
regarding subjects with large arms).
d) Locate the brachial artery along the inner upper arm by palpation.
e) Wrap the cuff smoothly and snugly around the arm, centering the bladder over the 
brachial artery. The lower margin should be 2.5 cm above the antecubital space. (Do not 
rely on cuff marking; find the center by folding the bladder in half.)
f)
Determine the level for maximal inflation by observing the pressure at which the radial 
pulse is no longer palpable as the cuff is rapidly inflated (palpated systolic) and by adding 
30 mm Hg.
g) Rapidly and steadily deflate the cuff. Then wait 15 to 30 seconds before reinflating.
h) Position the stethoscope over the palpated brachial artery below the cuff at the antecubital 
fossa. Ear pieces should point forward. The bell head of the stethoscope should be 
applied with light pressure, ensuring skin contact at all points. Heavy pressure may 
distort the reading.
i)
Rapidly and steadily inflate the cuff to the maximal inflation level as determined in 
Step F above.
j)
Release the air in the cuff so that the pressure falls at a rate of 2 mm Hg per second.
k) Note the systolic pressure at the onset of at least 2 consecutive beats (Phase I of 
Korotkoff sounds). BP levels should always be recorded in even numbers, and read to the 
nearest 2 mm Hg mark on the manometer.
l)
Record the diastolic pressure at the cessation of the Korotkoff sounds (Phase V). Listen 
for 10 to 20 mm Hg below the last sound heard to confirm disappearance, and then 
deflate the cuff rapidly and completely.
m) Record the subject's position and the arm used for the measurement.
n) Wait 1 minute before repeating the BP measurement (steps I-M) in the same arm to 
permit the release of blood trapped in the arm veins.
Measurements should be made, whenever possible, by the same certified or trained 
person throughout the study.
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Special Pitfalls and Problems:
The Auscultatory Gap
In some subjects, particularly in those with hypertension, the sounds heard over the brachial 
artery when the cuff pressure is high disappear as the pressure is reduced, and then reappear at 
some lower level. This early, temporary disappearance of sound is called the ‘auscultatory gap,’
and occurs during the latter part of Phase 1 and Phase 2. Because this gap may extend over a 
range as great as 40 mm Hg, one may seriously underestimate the systolic pressure or 
overestimate the diastolic pressure, unless its presence is excluded by first palpating for 
disappearance of the radial pulse as the cuff pressure is raised.
Effect of Arm Position
The pressure in the arm increases as the arm is lowered from the level of the heart; conversely, 
raising the arm above this position lowers the pressure measurement. The effect is largely 
explained by hydrostatic pressure or by the effect of gravity on the column of blood. Therefore, 
when measuring indirect blood pressure, the subject's arm should be positioned so that the 
midpoint of the cuff is at the level of the heart. This location of the heart is arbitrarily taken to be 
at the junction of the fourth intercostal space and the lower left sternal border. Attention to the 
position of the cuff in relation to the heart is particularly important when the subject is standing 
upright.
Subjects with Large Arms
In subjects with large upper arms, a longer and wider cuff is needed for adequate compression of 
the brachial artery. A cuff with a bladder width of 40% - 50% of the arm circumference should 
be used in all subjects to assure adequate BP measurements. In subjects with moderately large 
arms, a 15 cm wide cuff will generally be adequate. Determination of forearm BP should not be 
used because of the falsely elevated diastolic readings that occur with this technique.
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