Conditions: Renal Transplantation
Keywords: belatacept rabbit antithymocyte globulin alemtuzumab corticosteroid withdrawal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 316
Healthy volunteers: no

Brief summary:
The study purpose is to determine the safety and efficacy of a belatacept-based immunosuppressive regimen (calcineurin inhibitor free) with alemtuzumab or rabbit antithymocyte globulin (rATG) induction and early glucocorticoid withdrawal (CSWD) and a belatacept-based immunosuppressive regimen with tacrolimus-based regimen with rabbit antithymocyte globulin induction and early glucocorticoid withdrawal in renal transplant recipients.

The hypothesis is that a belatacept-based immunosuppressive regimen with alemtuzumab induction, mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and early glucocorticoid withdrawal (Group A) in renal transplant recipients or Belatacept-based immunosuppressive regimen with rabbit antithymocyte globulin induction, MMF/MPA and early glucocorticoid withdrawal (Group B) will lead to less risk of graft loss, patient death, or reduced renal function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with rabbit antithymocyte globulin, MMF/MPA, and early glucocorticoid withdrawal in renal transplant recipients (Group C).

Detailed description:
Renal transplant is the most effective treatment for end-stage renal disease. It provides improved survival and quality of life. Maintenance of a functioning renal transplant mandates lifelong immunosuppressive therapy to prevent immune destruction of the graft. Current immunosuppressive regimens yield 1-year survival rates of 89% for cadaveric and 94% for living-donor grafts. Over time, however, there is progressive loss of both subjects and grafts. Five-year graft survival for cadaveric and living related donor renal transplants is 67% and 80%, respectively.

The most common causes of long-term subject and graft loss in kidney transplant recipients are cardiovascular disease and chronic allograft nephropathy (CAN), respectively. Paradoxically, the principal immunosuppressive therapies for renal transplant, the calcineurin inhibitors (CNIs), cyclosporine (CsA) and tacrolimus, directly contribute to long-term allograft loss and subject death, since they are inherently nephrotoxic and can cause or exacerbate cardiovascular risks including hypertension, hypercholesterolemia, and diabetes mellitus.

There is, therefore, a substantial unmet medical need for new therapies in renal transplant that can provide short-term subject and graft survival comparable to the CNIs without their long-term nephrotoxic, cardiovascular, and metabolic effects. Because belatacept can be administered at the time of engraftment rather than in a delayed fashion, as is frequently necessary with CNIs - especially in those allografts with initial impaired renal function-- it affords immunosuppression in a timely manner. Unlike CNIs, the targeted mechanism of action of belatacept should provide immunosuppression without nephrotoxicity or adverse effects on the cardiovascular/metabolic profile.

Glucocorticoids have been a cornerstone of immunosuppressive therapy for six decades. Although glucocorticoids provide potent suppression of allo-immune responses in humans, their adverse effects including infection, diabetes, weight gain, hypertension, hyperlipidemia, bone disease, dermal thinning, collagen loss in multiple tissues, and cataracts, combined with a lack of available therapeutic monitoring all argue against their continued use in transplantation.

Belatacept represents a potential new treatment option for renal transplant recipients, which addresses the current unmet need for an immunosuppressive treatment that provides short-term outcomes comparable to calcineurin inhibitors (CNIs) with the potential to avoid their renal, cardiovascular, and metabolic toxicities. However, the initial Phase 3 studies exhibited in higher rate of acute rejection and malignancy. The malignancies were associated with recipients who were EBV negative at the time of transplant. All EBV negative patients are precluded from treatment with Belatacept. Due to the limitations of Phase 3 trial designs and the required use of basilixumab induction, it is intuitive that the addition of a potent t cell depleting induction agent may decrease the overall acute rejection rate in patients treated with belatacept.

The current study tests these assumptions with the following immunosuppressive regimens. Group A and B consist of potent T-cell depleting induction agents combined with belatacept. Group C represents the most common immunosuppressive regimen currently utilized in the United States. Each of these regimens include early withdrawal of glucocorticoids along with maintenance mycophenolate mofetil.

Based upon the totality of available evidence, the current study offers a favorable benefit/risk profile to study subjects, and the potential to continue to provide important data for the development of new immunosuppressive regimens that address important unmet needs.

The proposed Phase 4 study is designed to determine whether belatacept, in combination with other immunosuppressive agents (rabbit antithymocyte globulin or alemtuzumab, mycophenolate mofetil/EC mycophenolate sodium), may provide acceptable efficacy and safety in de novo kidney transplant recipients, in a regimen that provides simultaneous CNI freedom and early CSWD.

Arms:
arm 1: Alemtuzumab + belatacept + mycophenolate mofetil /Enteric coated mycophenolate sodium + early cessation of steroids arm 2: Rabbit antithymocyte globulin + belatacept + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids arm 3: Rabbit antithymocyte globulin + tacrolimus + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids

Interventions: intervention 1: Alemtuzumab intervention 2: rabbit antithymocyte globulin intervention 3: Belatacept intervention 4: Tacrolimus intervention 5: Mycophenolate mofetil intervention 6: early cessation of steroids
Intervention descriptions: intervention 1: Alemtuzumab will be dosed on day of transplant (Study Day 1) at dose of 30 mg given intravenously (IV) over a period of 2 hours after induction of anesthesia. Methylprednisolone IV will be administered 30-60 minutes prior to the administration of alemtuzumab. intervention 2: Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg given by days 5-10 post-transplant. It will be administered by local standards of care with the following recommendations. The initial intravenous intra-operative dose will be administered approximately one hour after the methylprednisolone dose. The first dose will be administered so that approximately 25% of the dose is infused prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours. Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte globulin dose will be given to reduce the incidence of infusion reactions. intervention 3: Belatacept will be administered via intravenous (IV) infusion according to the FDA approved dosage recommendations. Subjects randomized to belatacept arms will receive the first dose of IV belatacept (10 mg/kg) within 12-24 hours post reperfusion. The second dose will be given between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 weeks) and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of transplant. intervention 4: Tacrolimus will be administered orally twice daily (BID). The recommended total initial dose of tacrolimus is 0.1 mg/kg/day in two divided doses orally. Tacrolimus should be started post-transplant within 48 hours or when serum creatinine drops lower than 4mg/dL, whichever comes first. The initial targeted trough level of tacrolimus will be 8 - 12 ng/mL for Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter. intervention 5: The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day). Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day). Dose may be increased for African American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 mg/day). intervention 6: Glucocorticoid therapy will be administered as described. Methylprednisolone will be administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below:

Day 1 (day of transplant): 500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B and C) Day 2: 250mg IV Day 3: 125mg IV Day 4: 80mg p.o. Day 5: 60mg p.o. No further steroids

Protocol document:
Prot_SAP_000.pdf: 
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Amendment 8  5/20/2015  
PROTOCOL VERSION DATE:  5/20/2015, Amendment #8 
 
              
   
 
 
CONCEPT 
TITLE:   
A randomized, open label, multicenter study of a belatacept-based early glucocorticoid 
withdrawal regimen with alemtuzumab or rabbit antithymocyte globulin induction 
compared to a tacrolimus-based early glucocorticoid withdrawal regimen with rabbit 
antithymocyte globulin induction in renal transplantation 
 
STUDY PHASE:     Phase 4 
 
 
PRINCIPAL INVESTIGATOR 
 
Name & Title: 
Phone:      
Fax: 
 
          
E-mail:  
          
Institution:                  
 
E. Steve Woodle, MD, FACS (Professor of Surgery, Director-Division of Transplantation) 
(513) 558-6001  
(513) 558-7040 
woodlees@ucmail.uc.edu   
University of Cincinnati College of Medicine 
Department of Surgery - Division of Transplantation 
231 Albert Sabin Way, ML 558 
Cincinnati, OH 45267-0585 
 
 
OTHER INVESTIGATORS 
 
Clinical Research Operations representation 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Rita R. Alloway, PharmD, BCPS, FCCP (Research Professor, Director-Transplant Clinical Research) 
University of Cincinnati College of Medicine – Nephrology/Hypertension 
Office - (513) 558-1568; E-mail - allowarr@ucmail.uc.edu   
 
 
Clinical Site Operations representation – The University Hospital 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Gautham Moglishetty, MD (Assistant Professor) 
University of Cincinnati College of Medicine – Nephrology/Hypertension 
Office - (513) 558-5742; E-mail – mogilig@ucmail.uc.edu   
 
Name & Title: 
Institution: 
Phone & E-mail:    
 
Amit Govil, MD (Assistant Professor) 
University of Cincinnati College of Medicine – Nephrology/Hypertension 
Office - (513) 558-4231; E-mail - govilat@ucmail.uc.edu   
 
Clinical Site Operations representation – The Christ Hospital 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Michael Cardi, MD (Nephrologist) 
Kidney & Hypertension Center (Cincinnati, OH) 
Office - (513) 241-5630; E-mail - mcardi@fuse.net   
 
Name & Title: 
Institution: 
Phone & E-mail:    
 
Adele Rike Shields, PharmD (Research Assistant Professor) 
University of Cincinnati College of Medicine – Surgery (Transplantation) 
Office - (513) 585-2145; E-mail - rikea@ucmail.uc.edu   


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Amendment 8  5/20/2015  
 
Clinical Site Operations representation – California Pacific Medical Center 
 
Name & Title: 
Institution: 
Phone & E-mail:    
V. Ram Peddi, MD (Nephrologist) 
California Pacific Medical Center (San Francisco, CA) 
Office - (415) 600-1060; E-mail – peddir@sutterhealth.org   
 
Clinical Site Operations representation – University of Minnesota 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Arthur J. Matas, MD (Professor of Surgery) 
University of Minnesota Medical Center (Minneapolis, MN) 
Office - (612) 625-6460; E-mail – matas001@umn.edu   
 
Clinical Site Operations representation – University of Wisconsin-Madison 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Dixon Kaufman, MD, PhD (Professor of Surgery) 
University of Wisconsin – Madison (Madison, WI) 
Office - (608) 265-6471; E-mail – kaufman@surgery.wisc.edu  
 
Clinical Site Operations representation – University of Illinois - Chicago 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Patricia West-Thielke, PharmD (Pharmacist – Director of Transplant Research) 
University of Illinois – Chicago (Chicago, IL) 
Office - (312) 996-5695; E-mail – pwest@uic.edu  
 
Clinical Site Operations representation – University of Colorado - Denver 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Alexander Wiseman, MD (Professor of Medicine) 
University of Colorado - Denver (Denver, CO) 
Office - (720) 848-0860; E-mail – alexander.wiseman@ucdenver.edu  
 
Clinical Site Operations representation – Tampa General Hospital 
 
Name & Title: 
Institution: 
Phone & E-mail:    
John Leone, MD (Professor of Surgery) 
Tampa General Hospital (Tampa, FL) 
Office - (813) 844-5660; E-mail – jpleone@tgh.org  
 
HLA laboratory representation 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Alin Girnita, MD (Associate Professor,  Director-Transplant Immunology) 
University of Cincinnati - Hoxworth Blood Center 
Office - (513) 558-1515; E-mail – alin.girnita@uc.edu  
 
Name & Title: 
Institution: 
Phone & E-mail:    
Paul A. Brailey (HLA Laboratory Supervisor) 
University of Cincinnati - Hoxworth Blood Center 
Office - (513) 558-1505; E-mail – paul.a.brailey@uc.edu   
 
Quality of Life Outcomes Assessment representation 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Rebecca Winsett, PhD (Professor of Nursing) 
The University of Tennessee Health Sciences Center 
E-mail – Rebecca.winsett@utmem.edu   
 
 


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Amendment 8  5/20/2015  
Statistical Assessment representation 
 
Name & Title: 
Institution: 
Phone & E-mail:    
Eileen King, PhD 
University of Cincinnati College of Medicine – Division of Biostatistics and 
Epidemiology 
Office – (513)-803-1819; E-mail – eileen.king@cchmc.org 
 
 
STUDY SITE INFORMATION 
 
Description  
 
 Multi-Center (The University Hospital, Cincinnati, OH) 
                          (The Christ Hospital, Cincinnati, OH) 
                          (California Pacific Medical Center, San Francisco, CA) 
                          (University of Wisconsin, Madison, WI) 
                          (University of Minnesota, Minneapolis, MN) 
                          (University of Colorado, Denver, CO) 
                          (University of Illinois, Chicago, IL) 
                          (Tampa General Hospital, Tampa, FL) 
 
 
Competing Studies at Your 
Institution 
 Yes 
 No, this study will take priority enrollment 
 
 
 
SUPPORT REQUESTED (Check all that apply) 
 
 Items requested 
 Drug 
 Funding 
Will funding or study drug be provided from other sources?   
 NO   
 YES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment 8  5/20/2015  
 
 
 
PROTOCOL ACCEPTANCE FORM 
 
 
TITLE:  
A randomized, open label, multicenter study of a 
belatacept-based early glucocorticoid withdrawal 
regimen with alemtuzumab or rabbit 
antithymocyte globulin induction compared to a 
tacrolimus-based early glucocorticoid withdrawal 
regimen with rabbit antithymocyte globulin 
induction in renal transplantation 
 
VERSION: 
 
 
Amendment 8 dated 5/20/2015 
 
STUDY DRUG:  
 
Belatacept 
 
IND: 
 
 
 
IND 115, 270 
 
MEDICAL MONITOR:   
E. Steve Woodle, MD 
 
SPONSOR:  
 
 
University of Cincinnati Medical Center 
 
 
 
 
Dept. of Surgery/Division of Transplantation 
 
 
 
 
231 Albert Sabin Way 
 
 
 
 
Cincinnati, OH 45267-0629 
 
DATE FINAL:   
 
5/202015 
 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
 
Principal-Investigator’s Name (print) 
 
 
 
 
Principal-Investigator’s Signature                                                 Date 
 
 
 
Site 
 
 
Please return a copy of the form to the University of Cincinnati Transplant Regulatory Office and retain the original 
for your study files. 
 


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Amendment 8  5/20/2015  
TABLE OF CONTENTS 
 
I. 
Protocol Synopsis 
 
II.   Clinical Section 
 
1. Background and rationale 
 
2. Purpose and Study Hypothesis 
 
3. Objectives/Endpoints 
 
3.1 Primary Endpoint 
3.2 Secondary and Tertiary Endpoints 
 
4. Study Design 
 
4.1  Patient Population 
 
4.1.1 Inclusion Criteria 
 
4.1.2 Exclusion Criteria 
4.2 Number of Centers and Patients 
4.3 Randomization Procedures 
4.4 Study Duration 
 
5. Study Treatments 
 
5.1 Study Immunosuppressant Treatment Table  
5.2 Individual Immunosuppressive Agent Administration and Monitoring 
 
5.2.1  Alemtuzumab 
5.2.2  Rabbit antithymocyte globulin 
 
5.2.3  Glucocorticoids 
 
5.2.4  Belatacept 
 
5.2.5  Tacrolimus 
5.2.6  Mycophenolate mofetil/Enteric coated mycophenolate 
sodium 
 
5.2.7  Dosage Adjustment Standards 
 
5.2.8  Anti-infective Prophylaxis Recommendations 
 
5.2.9  Reasons for permanent study drug discontinuation 
5.2.10  Discontinuation of study treatment and premature patient 
withdrawal 
 
5.2.11 Study Completion and post-study treatment 
 
5.2.12 Early Study Termination 
 
 
 
6. Laboratory and Clinical Assessments 
 
6.1 Laboratory and Clinical Assessment flowchart 
6.2 Laboratory Assessments by study visit and test 
6.2.1  Baseline/Pretransplant 
 
 
 
 
6.2.2  Day 1 (Day of Transplant) 
 
 
 
 
6.2.3  Day 7, Weeks 2, 4, and 8 
6.2.4  Month 3 
6.2.5 Months 9, 15, and 18 
 
6.2.6 Month 21 


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Amendment 8  5/20/2015  
 
 
 
 
6.2.7 Months 6, 12 and 24 
 
6.3 Clinical Assessments at each Study visit 
6.3.1  General Clinical Assessment 
6.3.2  Graft Function Assessment 
 
6.3.2.1  Initial Renal Function 
 
6.3.2.2  Acute Renal Dysfunction 
 
6.3.2.3  Rejection 
 
 
6.3.2.3.1  Acute Rejection Banff Grade 1a-2a 
 
 
6.3.2.3.2  Acute Rejection Banff Grade >2b 
 
6.3.2.3.3  Antibody Mediated Rejection, Mixed 
Rejection 
6.3.3 
Safety Assessments -  Clinical 
6.3.3.1 Physical Examination 
6.3.3.2 Vital Signs 
6.3.3.3 Laboratory Evaluations 
6.3.3.4 Pregnancy and Assessments of fertility 
6.3.3.5 Tolerability and Acceptability 
6.3.3.6 Appropriateness of Safety Assessments 
6.3.3.7 Special Clinical Safety Assessments 
6.3.3.7.1 
New Onset 
Diabetes Mellitus 
After 
Transplantation 
6.3.3.7.2 
Hyperlipidemia 
6.3.3.7.3 
Hypertension 
6.3.3.7.4 
Framingham Risk 
Assessment and 
Cardiac Events 
6.3.3.7.5 
Infection 
6.3.3.7.6 
Malignancy 
6.3.3.7.7 
Other 
6.3.4 
Quality of Life (QOL)/ Side Effect Assessments 
 
 
6.3.4.1 The Memphis Survey 
6.3.4.2  Modified Transplant Symptom 
Occurrence and Symptom Distress Scale 
Questionnaire (MTSOSDS) 
 
7. Adverse Event Management 
7.1 Definitions 
7.1.1  Adverse Events Related to Immunosuppression 
7.1.2  Serious Adverse Events 
7.1.3  Nonserious Adverse Events 
 
 
 
7.2  Collection and Reporting 
 
 
 
      
  7.2.1  Serious Adverse Event Collecting and Reporting 
                
 
       
  7.2.2  Nonserious Adverse Event Collecting and Reporting 
 
 
 
 
  7.2.3  Adverse Event Flowchart 
 
 
 
7.3  Laboratory Test Abnormalities 
 
 
 
7.4  Overdose 
7.5  Pregnancy 
 
7.5.1  Precautions 
 
7.5.2 Testing Methods and Timing 
 
 
7.5.2.1 Methods for Pregnancy Testing 
 
 
7.5.2.2 Timing of Pregnancy Testing 
 
7.5.3 Pregnancy Reporting 


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Amendment 8  5/20/2015  
 
 
7.5.3.1 Pregnancy Reporting Check List 
 
7.5.4 Pregnancy Counseling 
7.6 Data Safety Monitoring Board (DSMB) 
 
 
 
8. Statistical Analysis Plan 
8.1 Population for analysis 
8.1.1 
Major Protocol Deviations 
8.2 Patient Demographics and Baseline Characteristics 
8.3 Treatments  
8.4 Primary Endpoint Analysis 
8.4.1 
Statistical model, hypothesis, and 
method of analysis 
8.4.2 
Handling of missing 
values/censoring/discontinuations 
8.5 Secondary Endpoint Analysis 
8.6 Tertiary Endpoint Analysis 
8.7 Univariate and Multivariate Analyses 
8.8 Safety Analysis 
8.9 Sample Size Calculation 
8.9.1 
Estimated Event Rates Between Groups 
 
9. Administrative Requirements 
9.1  Good Clinical Practice 
9.2  Ethical Considerations 
9.3  Patient Information and Informed Consent  
9.4  Patient Confidentiality 
9.5  Protocol Compliance 
9.6  Drug Accountability 
9.7  Premature Closure of the Study 
9.8  Record Retention 
9.9  Internal Monitoring Plan 
 
10. Study Progress and Result Dissemination Proposal 
 
III. Bibliography 
 
IV. Appendix I – VIII 
 
 
I  
Labs and Clinical Assessment Flowsheet 
 
 
II  
Study Immunosuppressant Treatment Table 
 
 
III 
Recommended Treatment of Rejection 
 
 
IV  
QOL/Side Effect Assessments 
 
 
V 
NCEP/ATP III Guidelines 
 
 
VI 
JNC VII Guidelines 
 
 
VII 
Framingham Scoring Sheets 
 
 
VIII 
World Medical Association Declaration of Helsinki 
 


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Amendment 8  5/20/2015  
I.        Protocol synopsis 
 
Title of study:   
A randomized, open label, multicenter study of a belatacept-based early glucocorticoid withdrawal 
regimen with alemtuzumab or rabbit antithymocyte globulin induction compared to a tacrolimus-
based early glucocorticoid withdrawal regimen with rabbit antithymocyte globulin induction in 
renal transplantation. 
 
Purpose:   
The study purpose is to determine the safety and efficacy of a belatacept-based 
immunosuppressive regimen (calcineurin inhibitor free) with alemtuzumab or rabbit antithymocyte 
globulin induction and early glucocorticoid withdrawal (CSWD) compared to a tacrolimus-based 
regimen with rabbit antithymocyte globulin induction and early glucocorticoid withdrawal in renal 
transplant recipients. 
 
Study Hypotheses: 
Belatacept-based 
immunosuppressive 
regimen 
with 
alemtuzumab 
induction, 
MMF(mycophenolate mofetil)/MPA (mycophenolic acid), and early glucocorticoid withdrawal  
(Group A) in renal transplant recipients will lead to less risk of graft loss, patient death, or reduced 
renal function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with 
rabbit antithymocyte globulin, MMF/MPA, and early glucocorticoid withdrawal  in renal transplant 
recipients (Group C). 
OR 
Belatacept-based immunosuppressive regimen with rabbit antithymocyte globulin induction, 
MMF/MPA and early glucocorticoid withdrawal (Group B) in renal transplant recipients will lead to 
less risk of graft loss, patient death, or reduced renal function at 12 months as compared to a 
tacrolimus-based immunosuppressive regimen with rabbit antithymocyte globulin, MMP/MPA, 
and early glucocorticoid withdrawal in renal transplant recipients (Group C). 
 
Primary Endpoint:   
The primary endpoint is to ascertain the combinatorial endpoint rate at 12 months as defined as 
• 
Patient Death or Graft Loss or estimated GFR (eGFR) (MDRD) < 45 mL/min 
 
Key Secondary Endpoints: 
Key secondary endpoints will extensively assess efficacy associated with each regimen at 6, 12, 
and 24 months to further quantitate these outcomes. 
• 
Composite endpoint at 6 and 24 months (12 months was selected as the time for 
evaluating the composite endpoint as the primary endpoint, as above) 
• 
Incidence by Banff 2007 criteria of biopsy proven acute rejection (BPAR) stratified by 
type (ACR, AMR, or Mixed rejection) 
• 
Death-Censored Graft Survival 
• 
Proportion of patients with eGFR (MDRD) < 30 mL/min 


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Amendment 8  5/20/2015  
• 
Proportion of patients developing anti-HLA antibodies against the donor (donor specific 
antibodies) (DSA) after transplantation 
 
Tertiary Endpoints: 
Tertiary endpoints will extensively assess additional safety, efficacy and salient endpoints 
associated with each regimen at 6, 12, and 24 months to further quantitate these outcomes. 
• 
Severity of rejection by Banff 2007 criteria, treatment, and outcome of BPAR stratified by 
type (ACR, AMR, or Mixed rejection) 
• 
Proportion of patients requiring anti-lymphocyte therapy for BPAR 
• 
Causes of patient and graft loss 
• 
Incidence, severity and treatment of metabolic and cardiovascular comorbidity (new 
onset diabetes after transplantation [NODAT], exacerbation of preexisting diabetes, 
hyperlipidemias [total serum cholesterol, HDL, LDL, triglycerides], hypertension, number 
of anti-hypertensive medications)  
• 
Patient weight change and BMI from pre-transplant 
• 
Change in Framingham Heart Study Coronary Score Heart Disease Risk Point Total 
• 
Cardiovascular events (myocardial infarction, angina, cerebral vascular accident, 
transient ischemic attack, cardiovascular intervention/procedure or sudden death) 
• 
Incidence of infections and posttransplant malignancies (including PTLD) 
• 
Incidence of leukopenia ( White Blood Cell Count < 2000 cells/uL) 
• 
Incidence of anemia (Hg < 7 g/dL) 
• 
Incidence of proteinuria (elevated protein/creatinine ratio >0.8 grams protein per gram 
creatinine) 
• 
Cumulative total thymoglobulin dosing for induction (mg) 
• 
Renal function assessment by calculated GFR and urine protein creatinine ratio 
• 
Proportion of subjects that remain glucocorticoid-free 
• 
Proportion of subjects on glucocorticoids and mean glucocorticoid dose (mg) 
• 
Patient quality of life (QoL)/Side Effect Assessment 
• 
Incidence of discontinuation of study treatment 
• 
Comparison of immunosuppression-related adverse effects by treatment group. 
• 
To determine the earliest reliable time-point that can be used for prediction of future 
onset of acute rejection and NODAT 
Population:  
Inclusion criteria: 
 
1. Male and female patients ≥ 18 years of age. 


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Amendment 8  5/20/2015  
2. Patient who is receiving a renal transplant from a living or deceased donor.  
3. Female patients of child bearing potential must have a negative urine or serum 
pregnancy test within the past 48 hours prior to study inclusion. 
4. The patient has given written informed consent to participate in the study 
 
Exclusion criteria: 
 
Patients meeting any of the following criteria at baseline will be excluded from study participation. 
 
1. Patient has previously received an organ transplant other than a kidney. 
2. Patient is receiving an HLA identical living donor transplant. 
3. Patient who is a recipient of a multiple organ transplant. 
4. Patient has a most recent cytotoxic PRA of >25% or calculated PRA >50% where 
multiple moderate level HLA antibodies exist and in the opinion of the PI 
represents substantial HLA sensitization. 
5. Patient with a positive T or B cell crossmatch that is due primarily to HLA 
antibodies. 
6. Patient with a donor specific antibody (DSA) as deemed by the local PI to be 
associated with significant risk of rejection. 
7. Patient has received an ABO incompatible donor kidney. 
8. The deceased donor and/or deceased donor kidney meet any of the following 
extended criteria for organ donation (ECD): 
a. Donor age  60 years 
                 OR 
b. Donor age 50-59 years and 1 of the following: 
i. Cerebrovascular accident (CVA) + hypertension + SCr  1.5 
mg/dL OR 
ii. CVA + hypertension OR 
iii. CVA + SCr  1.5 mg/dL OR 
iv. Hypertension + SCr  1.5 mg/dL 
OR 
c. CIT  24 hours, donor age  10 years 
OR 
d. Donation after cardiac death (DCD) 
9. Recipients will be receiving a dual or en bloc kidney transplant. 
10. Donor anticipated cold ischemia is > 30hours. 
11. Recipient that is seropositive for hepatitis C virus (HCV) with detectable Hepatitis 
C viral load are excluded. HCV seropositive patients with a negative HCV viral 
load testing may be included.   
12. Recipients who are Hepatitis B core antibody seropositive are eligible if their 
hepatitis B viral loads are negative.  After transplant, their hepatitis B viral loads 
will be monitored every three months for the first year after transplant.  If hepatitis 
B viral loads become positive, patients will be treated per institutional standard of 
care.  
13. Patients who are Hepatitis B surface antibody seropositive and who receive a 
kidney from a Hepatitis B core surface antibody positive donor may be included. 
14. Recipient or donor is known to be seropositive for human immunodeficiency virus 
(HIV). 
15. Recipient who is seronegative for Epstein Barr virus (EBV). 
16. Patient has uncontrolled concomitant infection or any other unstable medical 
condition that could interfere with the study objectives.  
17. Patients with thrombocytopenia (PLT <75,000/mm3), and/or leucopoenia (WBC < 
2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion. 


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Amendment 8  5/20/2015  
18. Patient is taking or has been taking an investigational drug in the 30 days prior to 
transplant. 
19. Patient who has undergone desensitization therapy within 6 months prior to 
transplant. 
20. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate 
mofetil, alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids. 
21. Patient is receiving chronic steroid therapy at the time of transplant. 
22. Patients with a history of cancer (other than non-melanoma skin cell cancers 
cured by local resection) within the last 5 years, unless they have an expected 
disease free survival of >95%.  
23. Patient is pregnant, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by positive human 
Chorionic Gonadotropin (hCG) laboratory test. 
24. Women of childbearing potential must use reliable contraception simultaneously, 
unless they are status post bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy.  
25. Patient has any form of substance abuse, psychiatric disorder or a condition that, 
in the opinion of the investigator, may invalidate communication with the 
investigator. 
26. Inability to cooperate or communicate with the investigator. 
 
Study design:  
This study is a prospective, randomized, open-label, multicenter safety/efficacy treatment 
study.  
  
Number of centers & patients:  
A total of 315 patients will be consecutively enrolled at eight centers.  Patients receiving a 
renal transplant and meeting enrollment criteria will be randomized 1:1:1 into three groups, 
with 105 patients in each group. Group C is considered the control group and Groups A and 
B are considered the Test Groups. 
 
1) Group A (n = 105): Alemtuzumab + belatacept +  mycophenolate mofetil /Enteric coated 
mycophenolate sodium + early cessation of steroids   
2) Group B (n = 105): Rabbit antithymocyte globulin + belatacept + mycophenolate mofetil 
/Enteric coated (EC) mycophenolate sodium + early cessation of steroids 
3) Group C (n = 105): Rabbit antithymocyte globulin + tacrolimus + mycophenolate mofetil 
/Enteric coated (EC) mycophenolate sodium + early cessation of steroids 
 
 
 


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Study duration:  
The active study duration will be approximately 42 months total with an 18 month enrollment 
period and 24 months of follow-up.  The enrollment period will begin with study drug availability. 
A 3-6 month period before open enrollment will be required for study activation with an additional 
3-6 month period post last follow-up for data analysis. 
 
Immunosuppressive Regimen:  
 
INDUCTION IMMUNOSUPPRESSION 
Group A: 
Alemtuzumab will be dosed on day of transplant (Study Day 1) at dose of 30 mg given 
intravenously (IV) over a period of 2 hours after induction of anesthesia.  Methylprednisolone IV 
will be administered 30-60 minutes prior to the administration of alemtuzumab.   
 
Groups B and C: 
All patients will receive rabbit antithymocyte globulin. 
 
Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-
6.0mg/kg given by days 5-10 post-transplant.  It will be administered by local standards of care 
with the following recommendations.  The initial intravenous intra-operative dose will be 
administered approximately one hour after the methylprednisolone dose.  The first dose will be 
administered so that approximately 25% of the dose is infused prior to revascularization of the 
graft. Subsequent doses will be administered over a minimum of 4 hours.  Premedication with 
acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte globulin 
dose will be given to reduce the incidence of infusion reactions.  
 
MAINTENANCE IMMUNOSUPPRESSION 
Groups A and B will receive belatacept in combination with mycophenolate mofetil/EC 
mycophenolate sodium/early glucocorticoid withdrawal. 
 
Belatacept will be administered via intravenous (IV) infusion according to the FDA approved 
dosage recommendations.  Subjects randomized to belatacept arms will receive the first dose of 
IV belatacept (10 mg/kg) within 12-24 hours post reperfusion.  The second dose will be given 
between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 
weeks) and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 
weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of 
transplant. 
 
Group C will receive tacrolimus in combination with mycophenolate mofetil/EC mycophenolate 
sodium/early glucocorticoid withdrawal 
 
Tacrolimus will be administered orally twice daily (BID). The recommended total initial dose of 
tacrolimus is 0.1 mg/kg/day in two divided doses orally. Tacrolimus should be started post-
transplant within 48 hours or when serum creatinine drops lower than 4mg/dL, whichever comes 


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first.  The initial targeted trough level of tacrolimus will be 8 - 12 ng/mL for Days 1 through 30, 
with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter. 
 
Groups A, B and C will receive mycophenolate mofetil/EC mycophenolate sodium and early 
glucocorticoid withdrawal.   
 
The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-
operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily 
(2000mg/day).  Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily 
(1440 mg/day).  Dose may be increased for African American transplant recipients to 
mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg 
twice daily (2160 mg/day).   
 
These doses of mycophenolate mofetil and EC mycophenolate sodium have shown efficacy, 
pharmacokinetic and pharmacodynamic equivalence. 
 
Subsequent dosage adjustments based on physician discretion are permitted due to toxicity only. 
 
Glucocorticoid therapy will be administered as described.  Methylprednisolone will be 
administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be 
given until Day 5 as below: 
Day 1 (day of transplant):  500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte 
globulin (Groups B and C) 
Day 2: 250mg IV  
Day 3: 125mg IV  
Day 4: 80mg p.o.  
Day 5: 60mg p.o.  
No further steroids 
 
Monitoring of DSA:  
DSA will be monitored in all arms of the study at baseline, 3 months, 6 months, 12 months and 24 
months, and at times of suspected rejection at the central lab.  Local prospective DSA monitoring 
is discouraged if results will impact renal biopsy rate in the absence of renal dysfunction.  The 
remaining serum sample will be utilized for ELISA signature for NODAT. 
 
QPCR assessment for acute rejection signature will be monitored in all arms of the study at 
baseline, 3 months, 6 months, 12 months and 24 months, and at times of suspected rejection at 
the central lab.   
 
 


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Amendment 8  5/20/2015  
Recommended Treatment of Biopsy proven Acute Cellular Rejection (BPACR) Banff Grade 
1a-1b 
Continue current regimen of belatacept or tacrolimus, Solumedrol 7mg/kg (Max 500mg) IV daily X 
3 days.  If improving trend in Scr, then initiate oral Prednisone recycle (Prednisone 200mg X 1, 
Prednisone 160mg X 1, Prednisone 120mg X 1, Prednisone 80mg X 1, Prednisone 40mg X 1, 
Prednisone 20mg X 1, Prednisone 10mg X 1, then discontinue steroids). If no improving trend in 
Scr after 3-5 days of treatment initiation, then repeat biopsy.  If Banff grade is the same or worse, 
then initiate or increase tacrolimus to a goal trough of 10-15 ng/mL or initiate rabbit antithymocyte 
globulin for 7-14 days of CD3 suppression.  If Banff grade is improving or minimal persistent 
rejection, continue oral prednisone recycle. 
 
Recommended Treatment of BPACR Banff Grade >2a 
Continue current regimen of belatacept or tacrolimus, initiate antithymocyte globulin for 7-14 days 
of CD3 suppression.  If no improving trend in Scr after 7 days of treatment initiation, then repeat 
biopsy.  If Banff grade is the same or worse, continue antithymocyte globulin, initiate or increase 
tacrolimus therapy to a goal trough of 10-15 ng/mL and initiate or add corticosteroid therapy.  If 
Banff grade is improving or minimal persistent rejection, continue antithymocyte globulin. 
 
Recommended Treatment of Biopsy proven Antibody mediated rejection (BPAMR) or 
biopsy proven Mixed acute rejection (BPMAR) 
 
May treat BPAMR or BPMAR with a bortezomib-based or IVIG-based protocol.   
 
The following schematic is a guideline for the treatment of BPAMR and BPMAR with bortezomib-
based treatment with rituximab: 
 
Treatment Day 
PRE 
1 
4 
7 
10 
PLASMAPHERESIS 1.5 PV 
  
X 
X 
X 
X 
Methylprednisolone 100 mg IVP or PO 
  
X 
X 
  
  
Methylprednisolone 50 mg IVP or PO 
  
  
  
X 
X 
BORTEZOMIB 1.3 mg/m2 IVP or SC 
  
X 
X 
X 
X 
RITUXIMAB 375 mg/m2 IV 
  
X 
  
  
  
 
 


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Amendment 8  5/20/2015  
Statistical Methods:  
 
Populations for Analysis 
 
Intent-to-Treat (ITT) Analysis - This study will be analyzed as an intent-to-treat analysis at 12 and 
24 months. All patients who were randomized and transplanted (graft is reperfused) will be 
included in the intent to treat population for analysis.  
Following the ITT principle, patients will be analyzed according to the treatment they were 
assigned to at randomization. 
The safety analysis set will consist of all patients who received at least one dose of belatacept in 
Groups A and B and at least one dose of tacrolimus in Group C. Patients will be analyzed 
according to the treatment they have received.  
The per protocol (PP) analysis set will consist of all randomized patients without major protocol 
deviations (PDs) as defined in full protocol.   
 
Statistical Analyses 
The following statistical methods will be used dependent on the type of outcome variable.  For 
continuous variables an Analysis of Variance (ANOVA) will be performed with terms for treatment 
and investigative site.   For time-to-event variables, the Kaplan Meier (KM) survival curves will be 
estimated and the Log Rank test with site as a stratification variable will be performed.   For 
categorical variables, a Cochran-Mantel-Haenzel (CMH) test will be performed with site as the 
stratification variable.  If the cell sizes are sparse, a Fisher’s Exact test will be used.  The 
Hochberg (for KM, CMH) or Tukey-HSD (for ANOVA) adjustment will be used for each endpoint 
to control the alpha level at 5% for comparing the three treatment groups. 
 
 
Sample Size Assessment 
 
The primary endpoint for this trial is the percentage of patients in each treatment group that meet the 
composite endpoint at 12 months as defined as patient death or graft loss or estimated GFR < 45 mL/min.   
It is assumed that the percentage of patients in the Control Group (i.e. Thymo/FK/MMF/CSWD) meeting 
the primary endpoint is 50%.  Each of the test groups will be tested against the control group using 
Kaplan-Meier methodology and the Log-Rank test.  To control the overall experiment-wise error rate at 
5%, the Hochberg method for multiple comparisons will be used.    In this procedure, the p-values for the 
two comparisons will be ordered from largest to smallest.  If the largest p-value is less than α=0.05, then 
both comparisons can be tested at α=0.05.  If the largest p-value is greater than α=0.05, then we cannot 
reject the null hypothesis for that comparison.  We then compare the second largest p-value to α=0.025 
and reject the null hypothesis if the p-value is less than α=0.025.   A sample size of 105 completed 
patients per group will provide at least 80% power to detect an absolute difference of 21% between two 
groups at the two-sided α=0.025 if the percentage of patients meeting the primary endpoint in the control 
group is assumed to be 50%.     
 
 


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II. Clinical Section 
 
1.   
Background and Rationale  
 
Glucocorticoids have been a cornerstone of immunosuppressive therapy for six decades (1).  
Although glucocorticoids provide potent suppression of allo-immune responses in humans, their 
adverse effects including infection, diabetes, weight gain, hypertension, hyperlipidemia, bone 
disease, dermal thinning, collagen loss in multiple tissues, and cataracts, combined with a lack of 
available therapeutic monitoring all argue against their continued use in transplantation.   
 
Initial Efforts with Late Glucocorticoid Withdrawal Under Tacrolimus-based Immunosuppression 
 
Initial experiences with tacrolimus (2-10) indicated that this agent possessed unique and potent 
immunosuppressive properties, which made it a promising agent on which a glucocorticoid free 
immunosuppressive regimen could be developed.  Early reports of glucocorticoid withdrawal 
(CSWD) with tacrolimus involved late CSWD (defined as three months or later post-transplant) 
(11), which was performed following tacrolimus therapy for refractory rejection.  Prior to this 
experience, glucocorticoids could not be withdrawn in patients who were considered to be high 
immunologic risk.  Yet this experience demonstrated that CSWD could be achieved even in 
patients with the most refractory acute renal allograft rejections.   The Pittsburgh experience with 
late CSWD under tacrolimus therapy was later confirmed with experience at another center (12). 
   
Early Glucocorticoid Withdrawal:  Initial Experience 
 
Successes with CSWD tacrolimus rescue therapy led to design and conduct of a number of 
tacrolimus-based de novo CSWD trials dating back to 1995.   Strategies in designing CSWD 
regimens were based on a set of paradigms gleaned from the existing literature and included: 1) 
acute rejection risk is higher the earlier CSWD is attempted following transplantation and also to 
how rapidly CSWD is completed, 2) induction therapy reduces acute rejection risk; 3) the 
magnitude of maintenance immunosuppression reduces acute rejection risk; and 4) historical 
acute-rejection risk factors—particularly recipient African American race have similar effects in 
CSWD (13).   
 
An important feature of these initial tacrolimus-based CSWD immunosuppressive regimens was 
the replacement of azathioprine with mycophenolate mofetil as an antiproliferative agent.  When 
these early CSWD protocols were implemented (14), mycophenolate mofetil had not been used 
in combination with tacrolimus because mycophenolate mofetil pivotal trials were conducted in 
combination with cyclosporine.  In the mycophenolate mofetil pivotal trials, mycophenolate mofetil 
therapy was associated with reduction in acute rejection rates by approximately a third.  
Therefore, it was hypothesized that the tacrolimus/ mycophenolate mofetil maintenance 
immunosuppressive regimen would provide optimal immunosuppression for developing new 
CSWD regimens.   
 
In December 1995 early CSWD under tacrolimus/ mycophenolate mofetil based 
immunosuppression was implemented as primary therapy for de novo kidney transplant 
recipients.  The initial experience with early CSWD under tacrolimus/ mycophenolate mofetil was 
reported in 1998 with demonstration of very low acute rejection rates at that time (21%, which 
was lower than UNOS reported rates at the time) and also with good patient and graft survival 
(14).  Subsequently longer term experience was reported with three-year data that demonstrated 
that early results were maintained without significant reduction in allograft survival over time (15).  
This data provided the first experience demonstrating that excellent three year allograft survival 
could be obtained with early CSWD, which suggested that the problems previously documented 
in the Canadian multicenter trial (increased allograft loss with CSWD), could possibly be 


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Amendment 8  5/20/2015  
overcome when potent maintenance immunosuppressive therapy was employed for early CSWD 
(16).   
 
These initial experiences with early CSWD protocol were remarkable for several reasons.    First, 
it was the first early CSWD regimen using tacrolimus as the CNI, and also was the first early 
CSWD regimen that employed the tacrolimus/ mycophenolate mofetil combination.  Of note, 
today, sixteen years later, the tacrolimus/ mycophenolate mofetil regimen is currently the most 
common maintenance immunosuppressive regimen for early CSWD in renal transplantation.  It is 
important to note that these initial early CSWD protocol represented the first to employ the 
concept of aggressive loading of maintenance immunosuppressive agents in the pre and early 
post-transplant period.  Third, these studies deliberately included African Americans, as they 
were previously excluded from glucocorticoid withdrawal regimens because of their known high 
risk for acute rejection.  Despite this, excellent rejection rates were achieved in African 
Americans.  Of note, our initial trial subsequently became the basis for the design of the first and 
double blind, randomized clinical trial of early CSWD in renal transplantation.  This study will be 
described in detail below.   
 
Simultaneous CSWD and CNI Minimization 
 
An important step in the evolution of CSWD studies was to combine CNI minimization and early 
CSWD.   Before this could be achieved, however, additional experiences had to accumulate with 
early CSWD, particularly with potent T cell depleting induction therapy, so that the potential for 
increased acute rejection rates could be minimized.   By 1999, a substantial experience had been 
accumulated with early CSWD that was adequate to design and conduct the first combined early 
CSWD and CNI minimization regimens.   
 
Combined Early CSWD and Calcineurin inhibitor (CNI) Minimization    
 
The initial CSWD/CNI minimization trial was designed in 2000 and included induction therapy with 
a T-cell-depleting agent that was included to reduce acute rejection risk.  Maintenance 
immunosuppression consisted of low dose cyclosporine, mycophenolate mofetil, sirolimus, and 
complete avoidance of glucocorticoids (CSAV) (17).  Cyclosporine dosing was reduced from the 
early post-transplant period, and in consecutive cohorts, was completely discontinued at earlier 
intervals post-transplant:  first at 12 months, and later at 6, and then 4 months post-transplant.  
The study was also designed to withdraw mycophenolate mofetil at two years, resulting in 
sirolimus monotherapy as maintenance immunosuppression beyond two years post-transplant.  
With a mean of three years follow-up (18) patient survival was 97% and death-censored graft 
survival was 86%, with a one-year acute rejection rate of 14% and a three year acute rejection 
rate of 21%.  90% of patients remained glucocorticoid-free, 87% remained CNI-free.   This study 
showed that early CSWD and CNI minimization could be achieved simultaneously under potent T 
cell depleting induction therapy.    
 
Multicenter CSWD Trials 
 
Astellas Multicenter Randomized, Double Blind Trial Comparing Early CSWD with Chronic 
Glucocorticoid Maintenance Therapy 
 
The Astellas CSWD trial presented the longest blinding period (5 years) of any trial conducted to 
date in transplantation. In designing the Astellas double blinded trial, several features were 
retained from the earlier pilot study of early CSWD conducted under tacrolimus/ mycophenolate 
mofetil based immunosuppression.  These features included:   1) initial and early loading of 
mycophenolate mofetil following transplantation,   2) inclusion of African American transplant 
recipients; and 3) an acceptance of lower WBC counts to minimize reductions in mycophenolate 
mofetil dosing (18).  In the Astellas trial, each transplant center could decide their induction 


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Amendment 8  5/20/2015  
antibody therapy (IL-2 receptor antibody or antithymocyte globulin).  The study excluded patients 
with delayed graft function, high PRA, or repeat transplants in order to achieve a substantial 
degree of homogeneity in the study population.  This trial was also designed to have an extensive 
evaluation of diabetes and other cardiovascular risk factors, including evaluation of new onset 
diabetes after transplantation (NODAT) by multiple definitions and criteria.   The final five year 
results of this study have been reported (19).  The study included adult recipients of deceased 
and living donor kidney transplants.   Patients were randomized to receive prednisone (5 mg/day 
after 6 months post-transplant) or early CSWD, and blinding was maintained for 5 years. 386 
patients were enrolled:  CSWD n= 191, chronic glucocorticoids (CCS) n=195.  All results are 
presented as (CSWD; CCS). No differences were observed at 5 years in the primary end point 
(composite of death, graft loss, or moderate/severe acute rejection) (30/191 (15.7%); 28/195 
(14.4%)), patient death (11/191(5.8%);13/195 (6.7%)), death-censored graft loss (11/191 (5.8%); 
7/195(3.6%)), biopsy confirmed acute rejection (34/191 (17.8%); 21/195(10.8%), p=0.058), 
moderate/severe acute rejection (15/191(7.9%); 12/195 (6.2%)).   
 
Increased biopsy confirmed acute rejection episodes in the CSWD group were primarily 
glucocorticoid-sensitive Banff 1A rejections: the incidence of antibody-treated biopsy confirmed 
acute rejection was similar between groups (11/191(5.8%); 13/195 (6.7%)). No differences in 
renal function were observed at 5 years: mean serum creatinine (1.5 ± 0.6; 1.5 ± 0.7 mg/dL), or 
Cockcroft Gault calculated creatinine clearance (58.6 ± 19.7; 59.8 ± 20.5 mL/min). CSWD was 
shown to be associated with improved serum triglycerides at all time points (except 5 years). 
NODAT was similar with respect to proportions who required treatment (23/107 (21.5%), 18/86 
(20.9%); however, fewer CSWD patients required insulin for NODAT at 5 years (4/107 (3.7%)); 
10/86 (11.6%), P = 0.049). Changes in HgA1c values (from baseline) were lower in CSWD 
patients at all time points except 4 years.  In summary, this five year double blind study 
demonstrated that when compared to chronic glucocorticoid maintenance therapy, early CSWD 
was associated with improvements in several cardiovascular risk parameters with minimal 
increased risk in acute rejection (19). Of note in this study was the impact of induction therapy on 
acute rejection.  This study also highlighted the importance of potent T-cell depleting induction 
therapy, as patients undergoing early CSWD experienced a biopsy confirmed acute rejection of 
14.4% compared to a rate of 24.2% in early CSWD patients receiving IL-2 inhibitor induction. 
 
 
Multicenter Pilot Study of Early (4 day) CSWD under Sirolimus-Based Immunosuppression.   
 
This study was sponsored by Wyeth Ayerst and represented the first prospective trial of early 
CSWD under a sirolimus-based immunosuppressive regimen.  Because this was the first 
experience with this particular immunosuppressive regimen, patients at high risk for acute 
rejection were excluded from study entry (African American recipients and patients with a current 
cytotoxic PRA >25%).  The study was a single limb, open label pilot study.  A major reason for 
conducting this study was to determine whether early CSWD would ameliorate two of the primary 
adverse effects of sirolimus therapy— hyperlipidemia and poor wound healing.   
Immunosuppression induction therapy included IL-2 receptor antibody (Simulect) and 
maintenance immunosuppression included tacrolimus and sirolimus with glucocorticoid cessation 
at four days post-transplant.  The final, 12- month study report has previously been published 
(20).   Patient and graft survival were both 100% at twelve months and the biopsy-proven acute 
rejection rate was 13%.  Relatively small changes were observed in cholesterol and triglycerides 
and new anti-lipid therapy was instituted in only 34% of patients.  This rate of new anti-lipid 
therapy was lower than that reported in the pivotal trials that led to sirolimus approval.   These 
results indicated that CSWD could reduce the observed lipogenic effects of sirolimus.     
 
 
 
 


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Amendment 8  5/20/2015  
TRIMS Multicenter Trial 
 
This multicenter trial was designed to determine the effects of potent T cell depleting induction 
therapy in early CSWD regimens in living donor transplantation (21).   In this study, patients were 
randomized in a 2:1 ratio to receive either CSWD or triple immunosuppression therapy with 
tacrolimus/mycophenolate mofetil/steroids.  No differences occurred in the primary endpoint 
(CSWD 84.4%, triple therapy 74.4%), patient survival (CSWD 100%, triple therapy 93.8%), graft 
survival (CSWD 98.1%, triple therapy 93.8%), or biopsy proven acute rejection (CSWD 13.9% vs. 
triple therapy 19.4%).  This study, therefore demonstrated that early CSWD with potent T cell 
depleting induction therapy could provide results comparable to the most commonly used non-
induction regimen with steroid-based immunosuppressive therapy.  
 
INTAC Multicenter Trial 
 
A recent trial (INTAC) compared alemtuzumab induction with IL-2 receptor antibody induction in 
low risk populations and alemtuzumab with rabbit antithymocyte globulin in populations at high 
risk for acute rejection.  High risk patients were defined as recipients who were African American, 
or had a current PRA>20%, or were a repeat transplant recipient.  Inclusion criteria included 
being adult recipients of living or deceased donor transplants.  Baseline immunosuppression in 
each group included tacrolimus, mycophenolate mofetil, and early CSWD.  At the end of the 
study, acute rejection rates were lower in alemtuzumab patients compared to those receiving IL-2 
receptor antibody induction in the low risk population.   Acute rejection rates were similar in the 
high risk population when comparing alemtuzumab and rabbit antithymocyte globulin (22).   
Therefore, this trial demonstrated that T-cell depleting induction therapy with either rabbit 
antithymocyte globulin or alemtuzumab provided superior acute rejection rates compared to non 
depleting T-cell induction therapy with an IL-2 receptor antibody.  
 
Acute Rejection Risk 
 
This study analyzed and reported multivariate analyses of individual risk factors for acute 
rejection with early CSWD (23).  This analysis revealed that the risk factors for acute rejection 
under early CSWD were similar to those previously reported under other immunosuppressive 
regimens.   The greatest risks were observed for high PRA and repeat transplant recipients 
(patients with a current cytotoxic PRA >25%, or a peak cytotoxic PRA >50%) (23). Also, African 
American and female recipients were at increased risk for acute rejection.  These high risk groups 
are important in designing future trials of CSWD, particularly with respect to inclusion/exclusion 
criteria and stratification and data analysis.  Failures to recognize these higher risk groups have 
led to problems in previous CSWD including the Canadian multicenter trial (1) and the NIH/Roche 
United States double blind trial (24). 
 
This multivariate analysis (23) also showed a 40% reduction in acute rejection risk when T-cell- 
depleting induction therapy was employed.      
 


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Amendment 8  5/20/2015  
Belatacept 
 
Renal transplant is the most effective treatment for end-stage renal disease. It provides improved 
survival and quality of life. Maintenance of a functioning renal transplant mandates lifelong 
immunosuppressive therapy to prevent immune destruction of the graft. Current 
immunosuppressive regimens yield 1-year survival rates of 89% for cadaveric and 94% for living-
donor grafts. Over time, however, there is progressive loss of both subjects and grafts. Five-year 
graft survival for cadaveric and living related donor renal transplants is 67% and 80%, 
respectively. (24) 
The most common causes of long-term subject and graft loss in kidney transplant recipients are 
cardiovascular disease and chronic allograft nephropathy (CAN), respectively. (25, 26) 
Paradoxically, the principal immunosuppressive therapies for renal transplant, the calcineurin 
inhibitors (CNIs), cyclosporine (CsA) and tacrolimus, directly contribute to long-term allograft loss 
and subject death, since they are inherently nephrotoxic and can cause or exacerbate 
cardiovascular risks including hypertension, hypercholesterolemia, and diabetes mellitus. 
There is, therefore, a substantial unmet medical need for new therapies in renal transplant that 
can provide short-term subject and graft survival comparable to the CNIs without their long-term 
nephrotoxic, cardiovascular, and metabolic effects. Because belatacept can be administered at 
the time of engraftment rather than in a delayed fashion, as is frequently necessary with CNIs – 
especially in those allografts with initial impaired renal function-- it affords immunosuppression in 
a timely manner. Unlike CNIs, the targeted mechanism of action of belatacept should provide 
immunosuppression without nephrotoxicity or adverse effects on the cardiovascular/metabolic 
profile.  
Results from analysis of the Phase 3 data confirm that by Year 3: (1) patient and graft survival 
remained comparable between belatacept and CsA, (2) renal function benefits associated with 
belatacept were sustained, and (3) blood pressure was consistently lower in belatacept than in 
the comparator groups, and increases in blood lipids were smaller, in subjects treated with 
belatacept. 
The totality of data in the belatacept renal transplant program, including 36-month results of the 
ongoing Pivotal Phase 3 trials, continues to support a favorable risk-benefit profile for belatacept. 
 
Summary of Results of Belatacept Investigational Program 
A total of 949 subjects have been treated with belatacept (30-minute intravenous [IV] infusion) in 
3 core de novo renal transplant studies: 2 pivotal Phase 3 studies (IM103008 and IM103027) (27, 
33, 28, 35) and one supportive Phase 2 study. (29) in which belatacept dosing regimens (more 
intensive [MI] and less intensive [LI]) were compared with a cyclosporine A (CsA) regimen. 
Efficacy results were consistent in the two pivotal Phase 3 studies and demonstrated comparable 
subject and graft survival at Month 12 between belatacept-treated subjects and CsA-treated 
subjects, with improved renal function, less new onset diabetes mellitus (NODM), lower blood 
pressure and a more favorable lipid profile. Extended follow-up over 3 years demonstrated 


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Amendment 8  5/20/2015  
evidence of ongoing efficacy that did not differ between the 2 belatacept dose regimens (MI and 
LI). Results of the earlier Phase 2 study were consistent with these findings. 
Belatacept is also being evaluated in 3 supportive Phase 2 studies, IM103034, IM103010, and 
IM103045 in combination with different immunosuppressants or in different populations. Studies 
IM103010 and IM103034 are being conducted in renal transplant recipients, and IM103045 is a 
study in liver transplant recipients. These studies have reached their 1-year endpoints. Additional 
studies include a pharmacokinetic (PK) study in renal transplant recipients (IM103047), studies in 
healthy subjects, a study in subjects with rheumatoid arthritis, and investigator-sponsored studies. 
One of the extensions of a liver transplant study was stopped early due to an excess of deaths in 
one of the belatacept groups (less intense regimen with MMF). A causal relationship to belatacept 
could not be clearly established, but it could not be rejected. In consultation with the Independent 
Data Monitoring Committee, BMS decided to terminate the study and recommended that all 
belatacept patients be switched to local standard of liver transplant care. Because of differences 
in patient population and treatment regimens studied, the termination of this Phase 2 belatacept 
liver study is not considered to impact the benefit/risk assessment in renal transplant. (30) 
Pharmacology of Belatacept 
Belatacept is in a new class of immunosuppressive therapy for renal transplant. It is a soluble 
chimeric fusion protein that binds to the B7 molecules on the surface of antigen-presenting cells 
(APCs), inhibiting requisite co-stimulation for T-cell activation. Belatacept differs from existing 
immunosuppressants in the restricted distribution of its molecular target and the specificity of its 
effect. Belatacept was derived from CTLA4Ig (abatacept), a fusion protein consisting of the 
extracellular domain of human CTLA4 fused to a fragment of the Fc domain of a human 
immunoglobulin (Ig) G1 antibody. By binding avidly to CD80/86, CTLA4Ig blocks the interaction of 
the T-cell’s CD28 with the antigen-presenting cell’s CD80/CD86, thus preventing T-cells from 
receiving the required second costimulatory signal. In the absence of this second signal, the T-
cell becomes anergic (unresponsive) or undergoes apoptosis. The binding affinity for murine 
CD80 and CD86 is lower with belatacept than with the parent molecule.  
Preclinical Toxicology of Belatacept 
Data for the parent molecule abatacept is relevant in certain animal species in order to increase 
the understanding of the pharmacology and toxicology of belatacept. Studies that assessed the 
effect of abatacept on host responses against infection in mice suggest that CD28 blockade in 
mice largely preserves innate immunity against most pathogens; however, agents such as 
belatacept that block CD28 may increase the risk of clinical infection by some pathogens that 
require an effective D4+ T cell-mediated immune response for eradication or control, and may 
increase the risk of some virally induced tumors. No drug-related findings were observed in 
standard evaluations of safety pharmacology parameters of cardiovascular, respiratory, and 
neurologic function conducted in monkeys as part of the pivotal, repeat-dose toxicity studies for 
up to 6 months with belatacept or 1 year with abatacept. Belatacept has less activity in rodents 
than abatacept has. Because of abatacept’s similarity to belatacept in structure and mechanism 
of action and its higher activity in rodents, abatacept was used as a more active homolog for 


22 | P a g e  
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belatacept in rodents. Therefore, preclinical studies conducted with abatacept have been used to 
support the safety of belatacept in addition to the studies conducted with belatacept.  
Mutagenesis and Carcinogenesis 
No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a 
mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary 
tumors (in females) occurred. The increased incidence of lymphomas and mammary tumors 
observed in mice treated with abatacept was likely associated with decreased control of murine 
leukemia virus and mouse mammary tumor virus, respectively, in the presence of long-term 
immunomodulation. However, the relevance of these findings to the clinical use of belatacept is 
unknown. In a six-month and one-year toxicity study in cynomolgus monkeys with belatacept and 
abatacept, respectively, no significant toxicity was observed at up to 6 times the exposure 
associated with the maximum recommended human dose (MRHD). Reversible pharmacological 
effects consisted of minimal decreases in serum IgG and minimal to severe lymphoid depletion of 
germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic 
morphologic changes was observed in either study. This was despite the confirmed presence of 
lymphocryptovirus in the abatacept study and presumed presence of this virus in the belatacept 
study. Lymphocryptovirus is known to cause lesions in immunosuppressed monkeys within the 
time frame of these studies. Thus, long-term treatment of monkeys with pharmacologically active 
doses of belatacept did not lead to reactivation of an oncogenic virus. 
Reproductive and Developmental Toxicity 
In rats, belatacept had no undesirable effects on male or female fertility. Belatacept was not 
teratogenic when administered to pregnant rats and rabbits at doses up to 200 mg/kg and 100 
mg/kg daily, respectively, representing approximately 16 and 19 times the exposure associated 
with the MRHD of 10 mg/kg based on area under the concentration time curve (AUC). Belatacept 
administered to female rats daily during gestation and throughout the lactation period was 
associated with infections in a small percentage of dams at all doses (≥ 20 mg/kg, ≥ 3 times the 
MRHD exposure based on AUC), and produced no adverse effects in offspring at doses up to 
200 mg/kg. Belatacept was shown to cross the placenta in rats and rabbits. It is not known 
whether the non-clinical findings in abatacept and belatacept indicate a risk for development of 
autoimmune diseases in humans exposed in utero to abatacept or belatacept. 
Single- and Repeat-Dose Toxicity 
In non-human primate studies, IV administration of belatacept as a single dose up to 90 mg/kg or 
as repeat doses up to 50 mg/kg every other day for 30 days or every week for 6 months was not 
associated with any significant drug-related toxicity. Reversible pharmacologic effects observed 
at all doses consisted of minimal decreases in serum immunoglobulin (Ig)G (no effect on IgM or 
IgA) levels and minimal-to-moderate decreases in the diameter and number of lymphoid germinal 
centers in the spleen and/or lymph nodes, reflective of decreased germinal center activity. No 
evidence of infections or hyperplastic, preneoplastic, or neoplastic changes were observed in the 
peripheral blood cells or lymphoid tissues of any monkey. In the 6-month study, functional activity 
of the immune system was demonstrated at all doses by a robust antibody response to the 


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Amendment 8  5/20/2015  
neoantigen KLH following immunization after an 8-week dose-free period. The no-observable-
adverse effect level (NOAEL) in the 6-month study was 50 mg/kg/weekly, which resulted in 
systemic exposures that were 5.8, 13, and 20 times the exposures observed in subjects given 
belatacept during the first month, fourth month, and maintenance phase of the LI regimen, 
respectively. An increased susceptibility to opportunistic infections observed in juvenile rats on 
abatacept is likely associated with the exposure to abatacept prior to development of memory 
responses. The relevance of these results to humans greater than 6 years of age is unknown, as 
memory responses in patients older than 6 have more time to develop. 
Local Tolerance 
In a local tolerance study in rabbits, belatacept was not significantly irritating when administered 
by IV, paravenous, or intra-arterial injection at the highest concentration intended for use in 
humans (20 mg/mL). In IV repeat-dose studies in monkeys, no significant injection site irritation 
occurred at concentrations of 25 mg/mL. Furthermore, no significant injection site irritation 
occurred following a single SC dose of the IV ready-to-use SC formulation containing Poloxamer 
188 at concentrations up to either 100 or 125 mg/mL. 
Safety Pharmacology 
No adverse cardiovascular, respiratory, or neurological effects have been detected in any of the 
single- or repeat-dose toxicity studies of belatacept when given to monkeys for up to 6 months. In 
these studies, electrocardiograms (ECGs) were obtained near Cmax (3 hours after dosing). In 
addition, no belatacept-related changes were observed in histamine, complement (C3a), TNF-α, 
or IL-6 levels in the plasma or serum, mediators associated with hemodynamic changes and 
anaphylactoid responses. 
Clinical Pharmacology  
Belatacept is a second-generation, higher avidity variant of abatacept (CTLA4-Ig), differing from 
the parent molecule (abatacept) by 2 amino acids within the region that binds CD80 and CD86 
(L104→E and A29→Y). Belatacept shows ~ 2-fold greater binding avidity for human CD80 and 
~ 4-fold greater binding avidity for human CD86 than the parent molecule. Belatacept is 
approximately 5- to 10-fold more potent in vitro on a per-dose basis than abatacept at inhibiting 
human T cell proliferation and T cell cytokine production in response to alloantigen stimulation.  
Clinical Pharmacodynamics of Belatacept 
Belatacept demonstrated concentration-dependent CD86 receptor binding in a steroid avoidance 
phase 2 study in renal transplant recipients who received the belatacept MI regimen.  
The generation of antibodies directed against the donor human leukocyte antigens (HLA) 
antigens (donor-specific antibodies [DSA]) is an essential criterion for the diagnosis of antibody-
mediated rejection, a type of rejection associated with poor outcomes in renal transplant. The 
presence of DSA may also preclude development or signal the absence of functional tolerance, 
leading to chronic rejection. For clinical evaluation of belatacept’s effect on the humoral response 
to the graft, serum samples collected from participants were evaluated for the presence or 


24 | P a g e  
Amendment 8  5/20/2015  
absence of donor-specific alloantibodies. In the Phase 3 clinical studies, fewer belatacept-treated 
subjects had detectable antibodies to donor-specific HLA compared to CsA-treated subjects.  
Human Pharmacokinetics of Belatacept 
Table 1 summarizes the PK parameters of belatacept in healthy adult subjects after a single 10 
mg/kg IV infusion (IM103024), in kidney transplant subjects after multiple 10 mg/kg and 
5 mg/kg IV infusions (IM103100 PK Substudy and IM103047), and in liver transplant subjects 
following Day 84 infusion of belatacept at 10 mg/kg. 
 
Table 1. 
Pharmacokinetic Parameters of Belatacept (5 to 10 mg/kg) Across Studies 
Pharmacokinetic 
Parameters ± SD 
(range)  
Healthy 
subjects (After 
10 mg/kg 
Single Dose)  
N=15  
Kidney 
Transplant 
Subjects (After 10 
mg/kg Multiple 
Doses) N=10  
Kidney Transplant 
Subjects (After 5 
mg/kg Multiple 
Doses) N=14  
Liver Transplant 
Subjects (after 10 
mg/kg Multiple dose)  
Peak 
concentration: 
Cmax (μg/mL) 
300±77  
(190-492) 
247±68  
(161-340) 
139±28  
(80-176) 
209.55±42.57  
(130-287) 
N=11 
AUC*(μg•h/mL)  
26398±5175 
(18964-40684)  
22252±7868  
(13575-42144)  
14090±3860  
(7906-20510)  
20106.93±4359.40  
(14982-27015)  
N=6  
Terminal half-life: 
T-HALF (days) 
9.8±2.8  
(6.4-15.6) 
9.8±3.2  
(6.1-15.1) 
8.2±2.4  
(3.1-11.9) 
8.66±1.3  
(7.01-10.95) 
N=7 
Systemic 
clearance :CLT  
0.39±0.07  
(0.25-0.53) 
0.49±0.13  
(0.23-0.70) 
0.51±0.14  
(0.33-0.75) 
0.46±0.10  
(0.05-0.14) 
N=6 
Volume of 
distribution: Vss  
(L/kg) 
0.09±0.02 
(0.07-0.15)   
0.11±0.03  
(0.067-0.17) 
0.12±0.03  
(0.09-0.17) 
0.11±0.03  
(0.05-0.14) 
N=6 
Source: IM103024 clinical study report (CSR), IM103047 Interim CSR, IM103100 PK Substudy , 
IM103045 CSR 
*AUC=AUC (INF) after single dose and AUC(TAU) after multiple dose, where TAU=4 weeks. 
Values represent mean±SD (range) 
In healthy subjects, the PK of belatacept was linear, and the exposure to belatacept increased 
proportionally after a single IV infusion dose of 1 to 20 mg/kg. The PK of belatacept in de novo 
kidney transplant subjects, liver transplant subject and healthy subjects was comparable. 
Following once every 4 weeks (q4week) IV infusion of 10 mg/kg and 5 mg/kg, there was minimal 
systemic accumulation of belatacept in kidney transplant subjects at steady-state during the 
maintenance phase. Following the administration of LI or MI regimen, Cmin of belatacept gradually 
decreased from the initial phase to the maintenance phase post-transplant, consistent with the 


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Amendment 8  5/20/2015  
decrease dose and dosing frequency of LI or MI regimen and the need to provide maximal 
immunosuppression during the initial period post-transplant as the allograft engrafts. In the LTE 
phase of the Phase 2 Study and two Phase 3 studies, Cmin of belatacept were consistently 
maintained (~4 μg/mL at 4-week schedule) during the maintenance phase up to Month 60 and 
Month 36 post-transplant, respectively. After SC administration (IM103029 and IM103046) in 
healthy subjects, the Tmax of belatacept was reached between 60 and 96 hours, and the exposure 
increased in a dose proportional manner across the dose range of 50 to 250 mg. The absolute 
bioavailability of the SC formulation was estimated to be 79%. 
Metabolism and Elimination  
No studies of the metabolism of belatacept in humans were conducted. Generally, therapeutic 
proteins are cleared through their interactions with specific receptors, as well as interactions with 
the FcgR1 receptors. Proteins are also cleared non-specifically through proteolysis in the Kupffer 
cells in the liver and macrophage activity in the spleen. These non-specific mechanisms of 
clearance are the presumed primary routes of elimination for belatacept. Renal function does not 
play a significant role in the overall clearance of belatacept. One subject who experienced PML 
underwent plasmapheresis for approximately 1.5 hours on two occasions. There was a 79% 
reduction in serum belatacept concentration after 2 cycles of plasmapheresis. Limited data 
suggest that plasmapheresis may accelerate removal of belatacept from systemic circulation.  
Drug-Drug Interaction 
Like most therapeutic proteins, belatacept is not expected to be metabolized by CYP and 
therefore is not expected to have significant interactions with molecules that are metabolized by 
CYP.  
Use with Mycophenolate Mofetil 
In a PK substudy of two Phase 3 studies, the plasma concentrations of mycophenolic acid (MPA) 
were measured in 41 subjects who received fixed MMF doses of 500 to 1500 mg twice daily with 
either belatacept 5 mg/kg or CsA. The mean dose-normalized MPA Cmax and AUC0-12 were 
approximately 20% and 40% higher, respectively, with belatacept co-administration than with 
cyclosporine coadministration, consistent with the fact that inhibition of MPA enterohepatic 
recirculation occurs with CsA but not with belatacept. Therefore, there is a potential change of 
MPA exposure after crossover from cyclosporine to belatacept or from belatacept to CsA in 
subjects concomitantly receiving MMF.  
 
Background Immunosuppressive Therapy with Belatacept 
A cross-study comparison of PK data suggested a lack of effect of background 
immunosuppressive therapy (MMF + corticosteroids) on belatacept PK. Pharmacokinetics of 
belatacept in healthy subjects who received belatacept 5 mg/kg alone were compared with the 
PK in the renal transplant subjects with background immunosuppressive therapy of MMF, 
corticosteroids and basiliximab. Pharmacokinetic parameters of belatacept are comparable with 
respect to Cmax, AUC (INF), T-HALF, CLT, and Vss.  


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Population Pharmacokinetic Analysis 
Population PK analysis confirmed that the PK of belatacept is linear and time-invariant post-
transplant. There was a trend toward higher clearance of belatacept with increasing body weight, 
supporting a weight-based dose of belatacept. Age, gender, race, renal function (measured by 
calculated GFR), hepatic function (measured by albumin), diabetes, and concomitant dialysis did 
not affect clearance of belatacept. Liver transplant subjects with marked abnormalities in liver 
function test post-transplant (defined as aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT] ≥ 5x upper limit of normal [ULN] and bilirubin ≥ 3x ULN) had similar 
belatacept trough concentrations (Cmin) to those who did not have marked abnormalities in liver 
function test. Limited data indicated that proteinuria and neutralizing antibody against belatacept 
did not affect the PK of belatacept in renal transplant subjects.  
Plasma Concentration-Effect Relationship  
The exposure-response (E-R) analyses suggested that the hazard of acute rejection decreases 
with time post-transplant and increases with baseline body weight. 
In the time-to-event exposure-response analysis of acute rejection, no definitive relationship could 
be made between belatacept concentration and acute rejection hazard within the concentrations 
observed in subjects in the 2 belatacept phase 3 studies. Calculated GFR in renal transplant 
subjects did not differ for the 4 quartiles of average belatacept serum concentration (Cavg). These 
relationships suggested that the more intense regimen with twice the exposure to belatacept 
during Months 2 to 6 did not confer additional immunosuppressive benefit beyond that of the less 
intense regimen.  
Graphic E-R analysis suggested that renal transplant subjects with CNS events (CNS PTLD and 
CNS infections, including the 1 renal transplant recipient with PML) tended to have higher Cavg 
during the first 6 months post-transplant compared with subjects who did not have these events. 
Additionally, there was a suggestion of an exposure-response relationship for serious infections; 
the risk of infections increased with higher exposure. Although definitive relationships could not 
be established because of limited data, the exposure-response data, when viewed in totality, 
showed an association between higher belatacept exposure and increased numbers of serious 
infections and CNS events. These data are consistent with the finding that less intense regimen is 
associated with a favorable safety profile compared with the MI regimen.  
Clinical Safety with Belatacept  
The adverse reaction profile associated with immunosuppressive agents is often difficult to 
establish because of the clinical events associated with the underlying disease and the 
concurrent use of multiple medicinal products. 
The frequency of AEs was similar across treatment groups up to Month 36 in the core studies. 
The most common adverse events ( 20% on belatacept treatment) are anemia, diarrhea, urinary 
tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, 
nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.(31,32,39) 


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Safety in Healthy Subjects 
In all the studies in healthy subjects, belatacept was generally well tolerated following single IV 
infusion doses of 0.1 to 20 mg/kg or following single subcutaneous doses of 50 mg to 250 mg. 
There were no deaths or SAEs. No subject discontinued due to AEs during the study. No dose-
related trends in AEs were noted. All AEs were mild to moderate in intensity. There were no 
significant changes in vital signs or ECG parameters. 
Overall, the percentage of healthy subjects that developed antibodies to belatacept was high (up 
to 100%) after receiving single doses of belatacept. However, these findings are not clinically 
relevant, because the incidence of drug-specific antibody formation in renal transplant recipients 
is low when belatacept is a component of multi-dose multi-drug immunosuppressive regimens  
Safety in Core Renal Transplant Studies 
A total of 949 subjects (477 in the MI regimen and 472 in the LI regimen) were treated in the 3 
core de novo renal transplant studies.  
In the pooled analysis, 311 (65%), 328 (70%), and 264 (57%) subjects had at least 36 months of 
exposure to the study medication in the belatacept MI, LI, and CsA groups, respectively. As 
expected in a transplant population, nearly all subjects experienced one or more adverse events 
(AEs). The frequency of serious adverse events (SAEs) was similar across the 3 treatment 
groups. The proportion of subjects with AEs leading to treatment discontinuation was lower in 
both belatacept groups than in the CsA group. 
The cumulative number of deaths was lower in the belatacept LI regimen than with the belatacept 
MI regimen or CsA. The frequency of malignancies was lower with the belatacept LI regimen than 
with the belatacept MI regimen or CsA. The higher frequency in the belatacept MI group was 
driven by more cases of post-transplant lymphoproliferative disorder (PTLD) and squamous cell 
carcinoma of the skin. 
The frequency of AEs leading to discontinuation was lower in both belatacept groups than in the 
CsA group (14%, 15%, and 19% in the belatacept MI, LI, and CsA groups, respectively). Most 
individual AEs leading to discontinuation were reported for no more than 1 subject. AEs leading to 
discontinuation in > 1% of belatacept subjects in either treatment group were transplant rejection, 
CMV infection, renal vein thrombosis, transplant rejection, and complications of transplanted 
kidney. 
Clinically important AEs such as infections, malignancies (including PTLD), graft thrombosis, 
infusional events, proteinuria, and autoimmunity reported in the core studies are described below. 
Drug-Related Adverse Events 
Adverse events considered by the investigator to be related to the study drug were reported up to 
Month 36 in the core studies in 65%, 64%, and 78% subjects in the belatacept MI, LI, and CsA 
groups, respectively. The most common (≥ 2%) drug related AEs in the belatacept-treated 
subjects were UTI, CMV infection, nasopharyngitis, oral herpes, oral candidiasis, herpes zoster, 
upper respiratory tract infection, blood creatinine increased, dyslipidemia, hypercholesterolemia, 


28 | P a g e  
Amendment 8  5/20/2015  
pyrexia, peripheral edema, diarrhea, proteinuria, hypertension, cough, headache, and transplant 
rejection. There were higher frequencies of related AEs of dyslipidemia, increased blood 
creatinine, hypertension, tremor, and hirsutism/hypertrichosis in the CsA group. 
Drug-Related Serious Adverse Events 
The most serious adverse reactions reported with belatacept were PTLD, predominantly central 
nervous system PTLD, and other malignancies, as well as serious infections, including JC virus-
associated progressive multifocal leukoencephalophathy and polyoma virus nephropathy.  
Other Significant Drug-Related Adverse Events 
Post transplant Lymphoproliferative Disorder  
An important risk observed with belatacept was PTLD, with the central nervous system being the 
predominant site of presentation. The overall risk of PTLD was higher in belatacept-treated 
subjects compared with CsA-treated subjects. Most cases of PTLD occurred during the first 18 
months post-transplant. Although the highest risk of PTLD with belatacept was observed in 
Epstein-Barr virus (EBV)-negative subjects, EBV-positive subjects treated with belatacept also 
appeared to be at somewhat higher risk of PTLD than corresponding subjects treated with CsA.  
The risk of PTLD was higher in EBV-seronegative patients compared with EBV-seropositive 
patients. EBV-seropositive patients are defined as those with evidence of acquired immunity 
shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen 
(EBNA). Epstein-Barr virus serology should be ascertained before starting administration of 
belatacept, and only patients who are EBV-seropositive should receive belatacept. Transplant 
recipients who are EBV seronegative, or who have unknown serostatus should not receive 
belatacept. Other known risk factors for PTLD include cytomegalovirus infection and T-cell-
depleting therapy. T-cell-depleting therapies to treat acute rejection should be used cautiously.  
Prophylaxis for CMV is recommended for at least 3 months after transplant. Patients who are 
EBV seropositive and CMV seronegative may be at increased risk for PTLD compared with 
patients who are EBV seropositive and CMV seropositive.  
Progressive Multifocal Leukoencephalopathy  
Progressive multifocal leukoencephalopathy is an often rapidly progressive and fatal opportunistic 
infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with 
belatacept, two cases of PML were reported in patients who were receiving belatacept at higher 
cumulative doses and more frequently than the recommended regimen, along with 
mycophenolate mofetil and corticosteroids; one case occurred in a kidney transplant recipient, 
and the second case occurred in a liver transplant recipient. As PML has been associated with 
high levels of overall immunosuppression, the recommended doses and frequency of belatacept 
and concomitant immunosuppressive agents, including MMF, should not be exceeded. PML is 
usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase 
chain reaction, and/or brain biopsy. Consultation with a specialist (e.g., neurologist and/or 
infectious disease) should be considered for any suspected or confirmed cases of PML. If PML is 


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Amendment 8  5/20/2015  
diagnosed, consideration should be given to reduction or withdrawal of immunosuppression, 
taking into account the risk to the allograft. 
Infections  
Patients receiving immunosuppressants, including belatacept, are at increased risk of developing 
bacterial, viral (CMV and herpes), fungal, and protozoal infections, including opportunistic 
infections. These infections may lead to serious, including fatal, outcomes. Prophylaxis for 
cytomegalovirus is recommended for at least 3 months after transplant. Prophylaxis for 
Pneumocystis jiroveci also is recommended after transplant. Tuberculosis was more frequently 
observed in patients receiving belatacept than cyclosporine in clinical trials. Patients should be 
evaluated for tuberculosis and tested for latent infection prior to initiating belatacept. Treatment of 
latent tuberculosis infection should be initiated prior to belatacept use. 
The frequency of infections including cytomegalovirus infection was similar in the belatacept LI, 
MI, and CsA groups. Serious infections, polyoma virus infection and fungal infections were less 
frequent in the belatacept LI group than in the belatacept MI and CsA groups. Herpes virus 
infections were more frequent in the belatacept MI and LI groups compared with the CsA group. 
Most reports of herpes virus infections were nonserious and did not lead to treatment 
discontinuation. 
Tuberculosis (TB) was more common in both belatacept groups compared with the CsA group. 
Most cases of TB occurred in subjects who currently or previously resided in endemic areas. 
Central nervous system infections were reported at similar rates in the belatacept LI and CsA 
groups, but occurred more frequently in the belatacept MI group. 
Polyoma Virus-Associated Nephropathy  
Two cases of progressive multifocal leukoencephalopathy (PML) have been reported with 
belatacept; both occurred in subjects receiving the belatacept MI regimen, 1 in the renal 
transplant study IM103027 and 1 in the liver transplant study IM103045. Both subjects received 
the MI regimen as well as concomitant immunosuppressive therapy. The MI regimen in the liver 
transplant study is a more intensified regimen compared with the MI regimen in the renal 
transplant studies. In addition, the subject in the liver transplant study was receiving 
mycophenolate mofetil (MMF) at higher than the recommended dose for approximately 6 months. 
No cases of PML have been reported in subjects receiving the LI dose. 
PVAN is associated with serious outcomes, including deteriorating renal function and kidney graft 
loss. Patient monitoring may help detect patients at risk for PVAN. Reductions in 
immunosuppression should be considered for patients who develop evidence of PVAN. 
Immunosuppressant Drugs and Skin Cancer 
Patients receiving any immunosuppressant, including belatacept, are at increased risk of 
developing malignancies (including those of the skin). Exposure to sunlight and ultraviolet (UV) 
light should be limited by wearing protective clothing and using a sunscreen with a high protection 
factor. 


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Amendment 8  5/20/2015  
Drug-Related Deaths 
The table below lists all deaths that occurred in the core studies supporting the kidney transplant 
indication.  
Table 2: 
Summary of All Deaths Reported Up to Database 
Lock: Pooled Core Study Population 
 
 
 
 
Death Reason 
Belatacept More Intense 
Regimen 
N = 477 
Belatacept Less Intense 
Regimen 
N = 472 
Cyclosporine 
N = 476 
 
TOTAL DEATHS 
38 (8.0) 
32 (6.8) 
40 (8.4) 
UNKNOWNa 
2  (0.4) 
 7 (1.5) 
 0 
AES WITH OUTCOME 
OF DEATHb  
36 (7.5) 
25 (5.3) 
40 (8.4) 
TOTAL INFECTIONS 
AND INFESTATIONS 
14 (2.9) 
10 (2.1) 
16 (3.4) 
ACINETOBACTER     
INFECTION 
0 
1 ( 0.2) 
0 
BRONCHOPNEUMO
NIA 
0 1 
1 ( 0.2)  
0 
BRONCHOPULMON
ARY 
ASPERGILLOSIS 
1 
( 0.2)  
 
CEREBRAL 
FUNGAL 
INFECTION 
1 (0.2) 
0 
0 
CRYPTOCOCCOSIS 
0 
1 (0.2) 
0 
CYTOMEGALOVIR
US INFECTION 
1 (0.2) 
0  
0 
DISSEMINATED 
TUBERCULOSIS 
0 
1 (0.2) 
0 
LOBAR 
PNEUMONIA 
0 
0 
1 (0.2) 
LUNG INFECTION 
1 (0.2) 
0 
0 
MENINGITIS 
CRYPTOCOCCAL 
0 
1 ( 0.2) 
0 
MUCORMYCOSIS 
0 
0 
1 (0.2) 
NECROTISING 
FASCIITIS 
0 
1 ( 0.2) 
0 


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Table 2: 
Summary of All Deaths Reported Up to Database 
Lock: Pooled Core Study Population 
 
 
 
 
OSTEOMYELITIS 
1 (0.2) 
0 
0 
PNEUMONIA 
3 (0.6) 
0 
5 (1.1) 
PNEUMONIA 
KLEBSIELLA 
0 
0 
1 (0.2) 
POLYOMAVIRUS-
ASSOCIATED 
NEPHROPATHY 
0 
2 (0.4) 
0 
POSTOPERATIVE 
WOUND INFECTION 
0 
0 
1 (0.2) 
PROGRESSIVE 
MULTIFOCAL 
LEUKOENCEPHALO
PATHY 
1 (0.2) 
0 
0 
PYELONEPHRITIS 
0 
0 
1 (0.2) 
SEPSIS 
4 (0.8) 
4 (0.8) 
2 (0.4) 
SEPTIC SHOCK 
1 (0.2) 
1 (0.2) 
5 (1.1) 
UROSEPSIS 
0 
0 
1 (0.2) 
WEST NILE VIRAL 
INFECTION 
1 (0.2) 
0 
0 
CARDIAC 
DISORDERS    
10 (2.1) 
5 (1.1) 
14 (2.9) 
ACUTE CORONARY      
SYNDROME 
0 
0 
1 (0.2) 
ACUTE 
MYOCARDIAL 
INFARCTION 
1 (0.2) 
0 
0 
AORTIC VALVE 
DISEASE 
1 (0.2) 
0 
0 
ARRHYTHMIA 
1 (0.2) 
0 
0 
ARTERIOSCLEROSIS 
CORONARY ARTERY 
1 (0.2) 
0 
0 
ATRIAL 
FIBRILLATION 
0 
0 
1 (0.2) 
CARDIAC ARREST 
3 (0.6) 
2 (0.4) 
5 (1.1) 
CARDIAC FAILURE 
0 
0 
2 (0.4) 
CARDIAC FAILURE 
CONGESTIVE 
2 (0.4) 
0 
0 


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Table 2: 
Summary of All Deaths Reported Up to Database 
Lock: Pooled Core Study Population 
 
 
 
 
CARDIO-
RESPIRATORY 
ARREST 
2 (0.4) 
0 
3 (0.6) 
INTRACARDIAC 
THROMBUS 
0 
0 
1 (0.2) 
MYOCARDIAL 
INFARCTION 
0 
2 (0.4) 
2 (0.4) 
MYOCARDIAL 
ISCHAEMIA 
0 
0 
2 (0.4) 
PERICARDITIS 
0 
1 (0.2) 
0 
VENTRICULAR 
FIBRILLATION 
0 
0 
1 (0.2 
GENERAL 
DISORDERS AND 
ADMINISTRATION  
 
 
 
SITE CONDITIONS 
7 (1.5) 
3 (0.6) 
1 (0.2) 
CARDIAC DEATH 
0 
1 (0.2) 
0 
DEATH 
0 
1 (0.2) 
0 
MULTI-ORGAN 
FAILURE 
2 (0.4) 
0 
1 (0.2) 
SUDDEN DEATH 
5 (1.0) 
 1 (0.2) 
0 
RESPIRATORY, 
THORACIC AND 
MEDIASTINAL 
 
 
 
DISORDERS 
3 (0.6) 
4 (0.8) 
7 (1.5) 
ACUTE PULMONARY 
OEDEMA 
1 (0.2) 
0 
0 
ACUTE 
RESPIRATORY 
FAILURE 
0 
1 (0.2) 
2 (0.4) 
DYSPNOEA 
0 
1 (0.2) 
1 (0.2) 
HYPOXIA 
0 
0 
1 (0.2) 
INTERSTITIAL LUNG 
DISEASE 
0 
0 
1 (0.2) 
PULMONARY 
EMBOLISM 
0 
0 
2 (0.4) 
PULMONARY 
1 (0.2) 
0 
0 


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Amendment 8  5/20/2015  
Table 2: 
Summary of All Deaths Reported Up to Database 
Lock: Pooled Core Study Population 
 
 
 
 
HYPERTENSION 
PULMONARY 
OEDEMA 
0 
0 
1 (0.2) 
RESPIRATORY 
ARREST 
1 (0.2) 
1 (0.2) 
0 
RESPIRATORY 
FAILURE 
0 
1 (0.2) 
 0 
GASTROINTESTINAL 
DISORDERS 
3 (0.6) 
2 (0.4) 
3 (0.6) 
ABDOMINAL PAIN 
0 
0 
1 (0.2) 
GASTRITIS EROSIVE 
0 
0 
1 (0.2) 
GASTROINTESTINAL 
HAEMORRHAGE 
1 (0.2) 
0 
0 
INGUINAL HERNIA 
OBSTRUCTIVE 
1 (0.2) 
0 
0 
INTESTINAL 
ISCHAEMIA 
1 (0.2) 
0 
0 
INTESTINAL 
OBSTRUCTION 
0 
0 
1 (0.2) 
LARGE INTESTINE 
PERFORATION 
0 
1 (0.2) 
0 
MESENTERIC 
OCCLUSION 
0 
1 (0.2) 
0 
THROMBOSIS 
MESENTERIC 
VESSEL 
1 (0.2) 
0 
0 
NEOPLASMS BENIGN 
MALIGNANT AND  
 
 
 
UNSPECIFIED 
(INCLUDING CYSTS 
AND POLYPS) 
2 (0.4) 
5 (1.1) 
4 (0.8) 
B-CELL LYMPHOMA 
1 (0.2) 
0 
0 
CENTRAL NERVOUS 
SYSTEM 
LYMPHOMA 
0 
1 (0.2) 
0 
EPSTEIN-BARR 
VIRUS-ASSOCIATED  
 
 
 
LYMPHOPROLIFERA
0 
1 (0.2) 
1 (0.2) 


34 | P a g e  
Amendment 8  5/20/2015  
Table 2: 
Summary of All Deaths Reported Up to Database 
Lock: Pooled Core Study Population 
 
 
 
 
TIVE DISORDER  
KAPOSI'S SARCOMA 
0 
0 
1 (0.2) 
LUNG 
ADENOCARCINOMA 
0 
1 (0.2) 
0 
LUNG CANCER 
METASTATIC 
0 
0 
1 (0.2) 
LUNG NEOPLASM 
MALIGNANT 
1 (0.2) 
0 
0 
METASTASES TO 
LIVER 
0 
1 (0.2) 
0 
NON-SMALL CELL 
LUNG CANCER 
0 
1 (0.2) 
0 
SARCOMA 
1 (0.2) 
0 
0 
TRANSITIONAL 
CELL CARCINOMA 
0 
1 (0.2) 
1 (0.2) 
NERVOUS SYSTEM 
DISORDERS 
2 (0.4) 
2 (0.4) 
2 (0.4) 
CEREBELLAR 
SYNDROME 
0 
1 (0.2) 
0 
CEREBROVASCULA
R ACCIDENT 
2 (0.4) 
0 
2 (0.4) 
COGNITIVE 
DISORDER 
0 
1 (0.2) 
0 
a Unknown death reason provided for subjects with death reported only on follow-up page 
b Death reason was provided by adverse events with outcome of death for other subjects 
Table includes all randomized and transplanted subjects from Studies -008 and -027. 
All randomized, transplanted and treated subjects from Study -100. 
Adverse events counting from randomization date for studies -008 and -027 and from transplant date and time for study 
-100. 
56-day counting rule not applied for adverse events with outcome of death. 
MedDRA Version: 13.0 
Clinical Efficacy of Belatacept 
Clinical efficacy is summarized in Table 3, which presents outcomes up to Year 3 in studies 
IM103008 and IM103027. 


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Amendment 8  5/20/2015  
Table 3: 
Key Efficacy Outcomes Up to Year 3 in IM103008 and IM3027 
 
a Imputation Method: No imputation for subjects with graft loss or death, however, if a value was available, it was used 
in the analysis. For other missing data, measured GFR at other time-points or cGFR at the same time point was used 
to impute the missing values at Month 12 or 24.  
b For missing data due to graft loss or death, cGFR after graft loss or death was imputed as 0 (primary analysis) by 
Month 36. 
c Acute rejection is defined as central biopsy proven rejection that was either (1) clinically suspected by protocol 
defined reasons or (2) clinically suspected by other reasons and treated.  
d The 20 % non-inferiority margin was not met in the belatacept MI group. 
 


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Amendment 8  5/20/2015  
Table 4 summarizes key efficacy findings up to Month 12 in study IM103100. 
Table 4: 
Efficacy Findings Up to Month 12 in  Study IMI03100 


 
 
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Amendment 8 5/20/2015 
OVERALL RISK/BENEFIT ASSESSMENT 
Belatacept represents a potential new treatment option for renal transplant recipients, which addresses the current 
unmet need for an immunosuppressive treatment that provides short-term outcomes comparable to calcineurin 
inhibitors (CNIs) with the potential to avoid their renal, cardiovascular, and metabolic toxicities. In the Phase 3 
studies in renal transplant recipients of kidneys from standard or extended criteria donors, belatacept was 
comparable to cyclosporine (CsA) on the proportion of patients who survive with a functioning allograft, and on 
overall mortality. In addition, belatacept resulted in clinically meaningful reductions in the proportions of patients 
with advanced renal dysfunction, defined as CKD stage 4 or 5. While rates of acute rejection (AR) were higher with 
belatacept than CsA, the rates of rejection that led to severe renal dysfunction or graft loss were low. 
The principal risks associated with belatacept are PTLD with CNS involvement and serious infections, including 
PML. The impact of these concerns on the patient and the graft were captured in the primary survival endpoint, 
indicating that, while important, they did not outweigh the overall benefits of belatacept to the patient or the 
allograft.   
Due to differences in patient populations and treatment regimens studied, the termination of the Phase 2 belatacept 
liver study is not considered to impact the benefit/risk assessment in renal transplantation. 
Based upon the totality of available evidence, the current study offers a favorable benefit/risk profile to study 
subjects, and the potential to continue to provide important data for the development of new immunosuppressive 
regimens that address important unmet needs. 
 
 
Initial Experience with Belatacept and Early CSWD/CNI Free Immunosuppression 
 
A major reason to pursue early CSWD and also CNI free immunosuppression is to reduce CV risk in renal 
transplant recipients.  It is well known that renal transplant recipients (and dialysis patients also) are at significantly 
increased risk for cardiovascular disease, and that the primary modifiable risk factors are renal function (GFR)- 
which is modifiable primarily by renal transplantation, obesity (modifiable by medical or surgical weight loss), and 
immunosuppressant-associated exacerbation of CV risk factors.   
 
As noted above, substantial prior studies with early CSWD under modern immunosuppression have shown that CV 
risk can be substantially reduced with an acceptably low risk of acute rejection.   However, renal transplant 
recipients remain at increased CV risk because of the exacerbation of CV risk factors by calcineurin inhibitors -
hypertension, diabetes, and hyperlipidemia are all worsened by calcineurin inhibitors. 
 
Therefore, the next step in optimizing CV-risk profiles of immunosuppressive regimens is to minimize calcineurin 
inhibitor exposure in a steroid free setting.   As noted above, such an approach is reasonable, because 
glucocorticoids and CNIs exert similar effects on cardiovascular risk parameters, and it appears likely that their 
effects may be additive based on results from previous CSWD trials.  Of particular relevance to the proposed 
multicenter randomized CSWD trial with belatacept, is a pilot study of belatacept-based CNI free/CSWD phase 2, 1 
year, randomized, open label, multi-center trial in which recipients of living donor or standard criteria deceased 
donor kidney transplants were randomized 1:1:1 to receive one of three immunosuppressive regimens under early 
CSWD with thymoglobulin induction (26). The control group received tacrolimus/ mycophenolate mofetil, and the 
two belatacept groups both were CNI free:  in one, patients received mycophenolate mofetil and in the other, 
patients received sirolimus. All subjects received thymoglobulin (1.5 mg/kg IV on Days 1, 2, 3, and 4) and 
glucocorticoids (for four days following transplantation). Belatacept dose regimen was the more intense (MI) 
regimen (24, 25).   The primary endpoint was acute rejection at 6 months post-transplantation.    Results are 
presented in the Table below: 
 
 
 


 
 
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Amendment 8 5/20/2015 
Outcome at 12 months  # pts (% of pts) 
Belatacept + 
MMF 
Belatacept + 
Sirolimus 
Tacrolimus + 
MMF 
# patients 
33 
26 
30 
Acute rejection  
4 (12) 
1 (4) 
1 (3) 
Acute rejection at month 6  
5 (15) 
1 (4) 
1 (3) 
Patient and graft survival 
30 (91) 
24 (92) 
30 (100) 
       Death 
1 (3) 
0 
0 
       Graft Loss 
2 (6) 
2 (8) 
0 
Mean cGFR  ml/min/m2 
64 (27) 
62 (31) 
54 (15) 
CNI and steroid free patients 
24 (73) 
18 (69) 
1 (3) 
Steroid free patients 
24 (73) 
20 (77) 
28 (93) 
Mouth ulceration 
2 (6) 
6 (23) 
0 
Wound dehiscence 
0 
0 
3 (10) 
Tremors 
1 (3) 
0 
7 (23) 
 
The single patient death occurred due to pneumonia.  Cardiovascular risk data including hypertension, serum lipids, 
new-onset diabetes after transplant (NODAT) were collected, but data are not yet available. 
In conclusion, this pilot study demonstrated acceptable patient survival, graft survival, and acute rejection rates with 
excellent renal function and cardiovascular outcomes.   
 
Upon review of clinicaltrials.gov, two ongoing trials were identified that incorporated the combination of 
alemtuzumab induction and belatacept maintenance therapy.  The trials are entitled, “Belatacept Post Depletional 
Repopulation to Facilitate Tolerance” (NCT00565773) and “Optimization of Belatacept Usage as a Means of 
Avoiding CNI and Steroids in Renal Transplantation” (NCT01436305).  The current results of first trial initiated in 
2007 were recently summarized in abstract form at the American Transplant Congress, June 2012.  This abstract 
entitled, “Kidney Transplantation Using Alemtuzumab Induction and Belatacept/Sirolimus Maintenance Therapy” 
reported results of 20 patients enrolled with a mean follow-up of >700 days.  The current patient and graft survival 
rate is 100% with a mean serum creatinine at 24 months of 1.2mg/dL with no graft thrombosis.  Personal 
communications with the investigative team confirmed there have been no graft thrombosis in these patients.  In 
addition, the timing of alemtuzumab and belatacept administration was clarified.  Their protocol states that 
alemtuzumab is administered intraoperatively and the belatacept is given within the first 24hrs post transplant.  
Their communications stated that this typically translates to the administration of belatacept at approximately 18hrs 
post alemtuzumab infusions.  They have identified no unexpected SAEs during this trial. 
 
The second trial, “Optimization of Belatacept Usage as a Means of Avoiding CNI and Steroids in Renal 
Transplantation” (NCT01436305) was initiated in September 2011.  This trial compares three treatment arms 
consisting of the following.  Arm 1:  Alemtuzumab induction, MMF and tacrolimus maintenance, Arm 2:  
Alemtuzumab induction, MMF and belatacept maintenance, and Arm 3:  Basiliximab induction, tacrolimus for 3 
months, MMF and belatacept maintenance.  To date 19 patients have been consented to the trial.  Six out of the 19 
were randomized to Arm 2 with Alemtuzumab induction, MMF, and belatacept maintenance however; there have 
been two graft thromboses that occurred in this arm.  The first thrombosis occurred on December 27, 2011, and the 
second on March 28, 2012.  Only one case resulted in graft loss.  In the first case, alemtuzumab was administered 
over 1.5hrs in the OR followed immediately by a belatacept infusion in a living donor kidney transplant recipient. 
The following day, the renal ultrasound confirmed reversal of flow in the renal artery with no visualization of the 
renal vein.  The patient was returned to the OR for re exploration.   The kidney was noted to have a renal vein 
thrombosis, which was treated by explantation, surgical thrombectomy, and re-implantation.   Minimal flow was 
noted following reimplantation.  The patient was also noted to have laboratory evidence of disseminated 
intravascular coagulation at this time. The investigator identified the renal vein thrombosis and allograft loss as 
possibly related to alemtuzumab or belatacept. 
 


 
 
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Amendment 8 5/20/2015 
In the second case a deceased donor kidney transplant recipient received an alemtuzumab infusion over 2 hours 
during the transplant procedure, which was followed by a 30 minute belatacept infusion.  The patient developed 
reduced urine output despite biphasic renal flow on repeated ultrasounds. Upon reexploration, a non-occlusive 
platelet plug was found lining the arterial anastomosis and was removed with renal blood flow re established.  The 
subject currently has a functioning graft and the event has resolved without sequelae.  The investigator considered 
the arterial thrombosis to be possibly related to alemtuzumab and belatacept.   
 
DAIT NIAID, the study sponsor, the manufacturer and ourselves have evaluated these cases and do not believe 
they represent an unanticipated problem that places enrolled subjects at greater risk than previously known or 
recognized.  However, protocol adjustments have been made to mitigate any risk that may be associated with 
thrombosis secondary to co administration of these agents.  Actions that have been taken include the following 
1. Proper timing of methylprednisolone administration 30-60 minutes prior to alemtuzumab administration with 
the induction of anesthesia to minimize any first dose reactions associated with the cytokine release 
syndrome that may occur following alemtuzumab administration. 
2. Administer the first dose of belatacept within 12-24 hours post reperfusion.  The timing will allow for 
adequate separation of administration to identify any potential adverse events associated with either agent 
while not exposing the subjects to additional risks. 
 
The proposed Phase 4 study is designed to determine whether belatacept, in combination with other 
immunosuppressive agents (rabbit antithymocyte globulin, mycophenolate mofetil/EC mycophenolate sodium), may 
provide acceptable efficacy and safety in de novo kidney transplant recipients, in a regimen that provides 
simultaneous CNI freedom and early CSWD. 
 
 


 
 
40 | P a g e  
Amendment 8 5/20/2015 
2.  Purpose and Study Hypothesis  
Purpose:   
The study purpose is to determine the safety and efficacy of a belatacept-based immunosuppressive regimen 
(calcineurin inhibitor free) with alemtuzumab or rabbit antithymocyte globulin induction and early glucocorticoid 
withdrawal (CSWD) compared to a tacrolimus-based regimen with rabbit antithymocyte globulin induction and early 
glucocorticoid withdrawal in renal transplant recipients. 
 
Study Hypotheses: 
Belatacept-based immunosuppressive regimen with alemtuzumab induction, MMF/MPA, and early glucocorticoid 
withdrawal  (Group A) in renal transplant recipients will lead to less risk of graft loss, patient death, or reduced renal 
function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with rabbit antithymocyte 
globulin, MMF/MPA, and early glucocorticoid withdrawal  in renal transplant recipients (Group C). 
OR 
Belatacept-based immunosuppressive regimen with rabbit antithymocyte globulin induction, MMF/MPA and early 
glucocorticoid withdrawal (Group B) in renal transplant recipients will lead to less risk of graft loss, patient death, or 
reduced renal function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with rabbit 
antithymocyte globulin, MMP/MPA, and early glucocorticoid withdrawal in renal transplant recipients (Group C). 
 
3. Objectives/Endpoints: 
3.1 Primary Endpoint:   
Primary Endpoint:   
The primary endpoint is to ascertain the combinatorial endpoint rate at 12 months as defined as 
• 
Patient Death or Graft Loss or estimated GFR (eGFR) (MDRD) < 45 mL/min 
 
3.2 Secondary and Tertiary Endpoints: 
Key Secondary Endpoints: 
Key secondary endpoints will extensively assess efficacy associated with each regimen at 6, 12, and 24 months to 
further quantitate these outcomes. 
• 
Composite endpoint at 6 and 24 months (12 months was selected as the time for evaluating the composite 
endpoint as the primary endpoint, as above) 
• 
Incidence by Banff 2007 criteria of biopsy proven acute rejection (BPAR) stratified by type (ACR, AMR, or 
Mixed rejection) 
• 
Death-Censored Graft Survival 
• 
Proportion of patients with eGFR (MDRD) < 30 mL/min 
• 
Proportion of patients developing anti-HLA antibodies against the donor (donor specific antibodies) (DSA) 
after transplantation 
 
Tertiary Endpoints: 
Tertiary endpoints will extensively assess additional safety, efficacy and salient endpoints associated with each 
regimen at 6, 12, and 24 months to further quantitate these outcomes. 
• 
Severity of rejection by Banff 2007 criteria, treatment, and outcome of BPAR stratified by type (ACR, AMR, 
or Mixed rejection) 
• 
Proportion of patients requiring anti-lymphocyte therapy for BPAR 


 
 
41 | P a g e  
Amendment 8 5/20/2015 
• 
Causes of patient and graft loss 
• 
Incidence, severity and treatment of metabolic and cardiovascular comorbidity (new onset diabetes after 
transplantation [NODAT], exacerbation of preexisting diabetes, hyperlipidemias [total serum cholesterol, 
HDL, LDL, triglycerides], hypertension, number of anti-hypertensive medications)  
• 
Patient weight change and BMI from pre-transplant 
• 
Change in Framingham Heart Study Coronary Score Heart Disease Risk Point Total 
• 
Cardiovascular events (myocardial infarction, angina, cerebral vascular accident, transient ischemic attack, 
cardiovascular intervention/procedure or sudden death) 
• 
Incidence of infections and posttransplant malignancies (including PTLD) 
• 
Incidence of leukopenia ( White Blood Cell Count < 2000 cells/uL) 
• 
Incidence of anemia (Hg < 7 g/dL) 
• 
Incidence of proteinuria (elevated protein/creatinine ratio >0.8 grams protein per gram creatinine) 
• 
Cumulative total thymoglobulin dosing for induction (mg) 
• 
Renal function assessment by calculated GFR and urine protein creatinine ratio 
• 
Proportion of subjects that remain glucocorticoid-free 
• 
Proportion of subjects on glucocorticoids and mean glucocorticoid dose (mg) 
• 
Patient quality of life (QoL)/Side Effect Assessment 
• 
Incidence of discontinuation of study treatment 
• 
Comparison of immunosuppression-related adverse effects by treatment group 
• 
To determine the earliest reliable time-point that can be used for prediction of future onset of acute 
rejection and NODAT 
4. Study Design 
 
4.1 Patient Population:  
 
 
4.1.1 Inclusion criteria: 
 
1. Male and female patients ≥ 18 years of age. 
2. Patient who is receiving a renal transplant from a living or deceased donor. 
3. Female patients of child bearing potential must have a negative urine or serum pregnancy test 
within the past 48 hours prior to study inclusion. 
4. The patient has given written informed consent to participate in the study. 
 
4.1.2 Exclusion criteria: 
 
Patients meeting any of the following criteria at baseline will be excluded from study participation. 
 
1. Patient has previously received an organ transplant other than a kidney. 
2. Patient is receiving an HLA identical living donor transplant. 
3. Patient who is a recipient of a multiple organ transplant. 
4. Patient has a most recent cytotoxic PRA of >25% or calculated PRA >50% where multiple 
moderate level HLA antibodies exist and in the opinion of the PI represents substantial HLA 
sensitization. 
5. Patient with a positive T or B cell crossmatch that is primarily due to HLA antibodies. 
6. Patient with a donor specific antibody (DSA) as deemed by the local PI to be associated with 
significant risk of rejection. 
7. Patient has received an ABO incompatible donor kidney. 
8. The deceased donor and/or deceased donor kidney meet any of the following extended criteria for 
organ donation (ECD): 


 
 
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Amendment 8 5/20/2015 
a. Donor age  60 years 
                 OR 
b. Donor age 50-59 years and 1 of the following: 
i. Cerebrovascular accident (CVA) + hypertension + SCr  1.5 mg/dL OR 
ii. CVA + hypertension OR 
iii. CVA + SCr  1.5 mg/dL OR 
iv. Hypertension + SCr  1.5 mg/dL 
OR 
c. CIT  24 hours, donor age  10 years 
OR 
d. Donation after cardiac death (DCD) 
9. Recipients will be receiving a dual or en bloc kidney transplant. 
10. Donor anticipated cold ischemia is >30hours. 
11. Recipient that is seropositive for hepatitis C virus (HCV) with detectable Hepatitis C viral load are 
excluded. HCV seropositive patients with a negative HCV viral load testing may be included.   
12. Recipients who are Hepatitis B core antibody seropositive are eligible if their hepatitis B viral loads 
are negative.  After transplant, their hepatitis B viral loads will be monitored every three months for 
the first year after transplant.  If hepatitis B viral loads become positive, patients will be treated per 
institutional standard of care.  
13. Patients who are Hepatitis B surface antibody seropositive and who receive a kidney from a 
Hepatitis B core surface antibody positive donor may be included. 
14. Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV). 
15. Recipient who is seronegative for Epstein Barr virus (EBV). 
16. Patient has uncontrolled concomitant infection or any other unstable medical condition that could 
interfere with the study objectives.  
17. Patients with thrombocytopenia (PLT <75,000/mm3), and/or leucopoenia (WBC < 2,000/mm3), or 
anemia (hemoglobin < 6 g/dL) prior to study inclusion. 
18. Patient is taking or has been taking an investigational drug in the 30 days prior to transplant. 
19. Patient who has undergone desensitization therapy within 6 months prior to transplant. 
20. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate mofetil, 
alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids. 
21. Patient is receiving chronic steroid therapy at the time of transplant. 
22. Patients with a history of cancer (other than non-melanoma skin cell cancers cured by local 
resection) within the last 5 years, unless they have an expected disease free survival of >95%.  
23. Patient is pregnant, where pregnancy is defined as the state of a female after conception and until 
the termination of gestation, confirmed by positive human Chorionic Gonadotropin (hCG) laboratory 
test. 
24. Women of childbearing potential must use reliable contraception simultaneously, unless they are 
status post bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.  
25. Patient has any form of substance abuse, psychiatric disorder or a condition that, in the opinion of 
the investigator, may invalidate communication with the investigator. 
26. Inability to cooperate or communicate with the investigator. 
 
4.2  Number of Centers and Patients  
A total of 315 patients will be consecutively enrolled at eight centers.  Patients receiving a renal transplant and 
meeting enrollment criteria will be randomized 1:1:1 into three groups, with 105 patients in each group. Group 
C is considered the control group and Groups A and B are considered the test groups. 
 
4) Group A (n = 105): Alemtuzumab + belatacept +  mycophenolate mofetil /Enteric coated mycophenolate 
sodium + early cessation of steroids   
5) Group B (n = 105): Rabbit antithymocyte globulin + belatacept + mycophenolate mofetil /Enteric coated 
(EC) mycophenolate sodium + early cessation of steroids 
6) Group C (n = 105): Rabbit antithymocyte globulin + tacrolimus + mycophenolate mofetil /Enteric coated 
(EC) mycophenolate sodium + early cessation of steroids 
 
4.3  Randomization Procedures 
 


 
 
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Amendment 8 5/20/2015 
Once the subject has consented and has met all entry criteria (inclusion and exclusion), the subject may be 
randomized.  The randomization will be stratified by center, African American vs. non-African American race, 
and living vs deceased donor.  Adverse Event reporting for all subjects will begin at the time of transplantation, 
not randomization. Each subject who is qualified for treatment will be assigned a unique randomization number.  
Allocation of the randomization will be concealed to all study staff prior to randomization.  There is no blinding 
in this study. 


 
 
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Amendment 8 5/20/2015 
 
 
4.4  Study duration  
The active study duration will be approximately 42 months total with an 18 month enrollment period and 24 months 
of follow-up.  The enrollment period will begin with study drug availability. 
A 3-6 month period before open enrollment will be required for study activation with an additional 3-6 month period 
post last follow-up for data analysis. 
 
 
5.  Study Treatments 
The overall immunosuppressive plan is outlined below in text and table.  
 
Agent/Class 
Group A 
Group B 
Group C 
Induction Agent 
Alemtuzumab 
Antithymocyte globulin 
Antithymocyte globulin 
Belatacept/Tacrolimus 
Belatacept 
Belatacept 
Tacrolimus 
Antiproliferative 
MMF/Myfortic 
MMF/Myfortic 
MMF/Myfortic 
Corticosteroids 
CSWD 
CSWD 
CSWD 
 
 
INDUCTION IMMUNOSUPPRESSION 
Group A: 
Alemtuzumab will be dosed on day of transplant (Study Day 1) at dose of 30 mg given intravenously (IV) over a 
period of 2 hours after induction of anesthesia.  Methylprednisolone IV will be administered 30-60 minutes prior to 
the administration of alemtuzumab.   
 
Groups B and C: 
All patients will receive rabbit antithymocyte globulin. 
 
Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg given by 
days 5-10 post-transplant.  It will be administered by local standards of care with the following recommendations.  
The initial intravenous intra-operative dose will be administered approximately one hour after the 
methylprednisolone dose.  The first dose will be administered so that approximately 25% of the dose is infused 
prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours.  
Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte 
globulin dose will be given to reduce the incidence of infusion reactions.  
 
 
MAINTENANCE IMMUNOSUPPRESSION 
Groups A and B will receive belatacept in combination with mycophenolate mofetil/EC mycophenolate 
sodium/early glucocorticoid withdrawal 
 
Belatacept will be administered via intravenous (IV) infusion according to the FDA approved dosage 
recommendations.  Subjects randomized to belatacept arms will receive the first dose of IV belatacept (10 mg/kg) 
within 12-24 hours post reperfusion.  The second dose will be given between post-transplant days 4 -6 (Study Days 
5-7), and then study days 14, 28, 56, and 84 (12 weeks) and then subjects will receive belatacept at the 
maintenance dose of 5 mg/kg every 4 weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is 
defined as the day of transplant. 
 
Group C will receive tacrolimus in combination with mycophenolate mofetil/EC mycophenolate sodium/early 
glucocorticoid withdrawal 
 
Tacrolimus will be administered orally twice daily (BID). The recommended total initial dose of tacrolimus is 0.1 
mg/kg/day in two divided doses orally. Tacrolimus should be started post-transplant within 48 hours or when serum 


 
 
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Amendment 8 5/20/2015 
creatinine drops lower than 4mg/dL, whichever comes first.  The initial targeted trough level of tacrolimus will be 8 - 
12 ng/mL for Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter. 
 
Groups A, B and C will receive mycophenolate mofetil/EC mycophenolate sodium and early glucocorticoid 
withdrawal.   
 
The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients 
receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day).  Patients receiving EC 
mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day).  Dose may be increased for African 
American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate 
sodium 1080 mg twice daily (2160 mg/day).   
 
These doses of mycophenolate mofetil and EC mycophenolate sodium have shown efficacy, pharmacokinetic and 
pharmacodynamic equivalence. 
 
Subsequent dosage adjustments based on physician discretion are permitted due to toxicity only. 
 
Glucocorticoid therapy will be administered as described.  Methylprednisolone will be administered on Days 1 
through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below: 
Day 1 (day of transplant):  500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B 
and C) 
Day 2: 250mg IV  
Day 3: 125mg IV  
Day 4: 80mg p.o.  
Day 5: 60mg p.o.  
No further steroids 


 
 
46 | P a g e  
Amendment 8 5/20/2015 
 
 5.1. Study Immunosuppressant Treatment Table 
 
 
Belatacept 
(Groups A&B) 
Tacrolimus 
(Group C) 
Induction 
(Group A) 
Induction 
(Groups B&C)  
Steroids  
(All Groups)  
Mycophenolate 
mofetil/EC 
Mycophenolate 
Sodium  
(All Groups) 
 
10 
mg/kg 
5 
mg/kg 
0.1mg/kg/day 
p.o. divided 
twice daily 
Alemtuzumab 
30mg IV 
Rabbit 
antithymocyte 
globulin 
1.5mg/kg IV 
 
 
Day of 
Transplant  
(D1) 
X1 
 
Start 
tacrolimus 
when Scr < 4 
mg/dL or 
within 48 
hours of 
transplant 
 
Goal 
tacrolimus 
trough 8-12 
ng/mL until 
day 30 
X 
X 
Methylpred 
500mg IV 
Introduce 
Mycophenolate 
mofetil/EC 
Mycophenolate 
Sodium on D1  
pre-op.  
  
Mycophenolate 
mofetil 1g p.o. BID 
(EC Mycophenolate 
Sodium 720mg p.o. 
BID).   
 
African 
American recipients 
may receive 
Mycophenolate 
mofetil 1.5 g p.o. 
BID (EC 
Mycophenolate 
Sodium 1080mg p.o. 
BID).   
 
Dose adjustments 
can be made based 
on MD discretion  
D2 
 
 
Subsequent 
thymo doses 
should be 
given so that 
total 
cumulative 
dose of 4-6 
mg/kg is given 
by days 5-10 
Methylpred 
250mg IV 
D3 
 
 
 
Methylpred 
125mg IV 
D4 
 
 
 
Prednisone 
80mg p.o. 
D5 
X2 
 
 
Prednisone 
60mg p.o. 
D6 
 
 
 
No further 
steroids 
D7 
 
 
 
 
D8 
 
 
 
 
D9 
 
 
 
 
D 10 
 
 
 
 
W2 (D14) 
X 
 
 
 
 
D15-D 20 
 
 
 
 
 
D 21-D27 
 
 
 
 
 
W4 (D 28) 
X 
 
 
 
 
W8 (D 56) 
X 
 
Goal 
tacrolimus 
trough 5-10 
ng/mL 
thereafter 
 
 
 
 
W12 ( M 3) 
X 
 
 
 
W16 
 
X 
 
 
W20 
 
X 
 
 
W24 (M 6) 
 
X 
 
 
W28 
 
X 
 
 
W32 
 
X 
 
 
W36 (M 9) 
 
X 
 
 
W40 
 
X 
 
 
W44 
 
X 
 
 
W48 
 
X 
 
 
W52 (M12) 
 
X 
 
 
W56 
 
X 
 
 
W60 
 
X 
 
 
W64 (M 15) 
 
X 
 
 
W68  
 
X 
 
 
W72 
 
X 
 
 
W76 
 
X 
 
 
W80 (M18) 
 
X 
 
 
W84 
 
X 
 
 
W88 
 
X 
 
 
W92 (M21) 
 
X 
 
 
W96 
 
X 
 
 
W100 
 
X 
 
 
W104 (M24) 
 
X 
 
 
1. Initial Belatacept dose will be administered within 12-24 hours post reperfusion  
2. Belatacept dose is to be given once between Study days 5 – 7, with intention of administering as an outpatient.    
 


 
 
47 | P a g e  
Amendment 8 5/20/2015 
5.2  Individual Immunosuppressive Agent Administration and Monitoring 
 
5.2.1 Alemtuzumab Administration 
 
Alemtuzumab will be dosed on day of transplant (Day 1) at dose of 30 mg given intravenously (IV) over a 
period of 2 hours.  Methylprednisolone IV will be administered 30-60 minutes prior to the administration of 
alemtuzumab.  Infusion of the alemtuzumab should not begin until after the surgeon has made an initial 
preoperative assessment, and has concluded that the subject remains a transplant candidate. 
 
5.2.2  Rabbit antithymocyte globulin Administration and Monitoring 
 
Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg 
given by days 5-10 post-transplant.  It will be administered by local standards of care with the following 
recommendations.  The initial intravenous intra-operative dose will be administered approximately one hour 
after the methylprednisolone dose.  Infusion of the rabbit antithymocyte globulin should not begin until after 
the surgeon has made an initial preoperative assessment, and has concluded that the subject remains a 
transplant candidate.  The first dose will be administered so that approximately 25% of the dose is infused 
prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours.  
Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit 
antithymocyte globulin dose will be given to reduce the incidence of infusion reactions.  
 
Rabbit antithymocyte globulin recommended dosage adjustments are as follows. 
 
WBC (cells/µL) and Platelets (cells/µL) 
Reduction in current rabbit 
antithymocyte globulin dose 
WBC > 3000 cells/µL, PLT >100,000 
cells/µL 
None 
WBC <3000 and >2000 cells/µL, PLT 
50,000 – 100,000 cells/µL 
Reduce dose by 50% 
WBC <2000 cells/µL and PLT <50,000 
cells/µL 
Hold until WBC > 2000 cells/µL or PLT > 
50,000 cells/µL 
 
 
5.2.3 Glucocorticoid Administration 
 
Group A, B, and C: 
Glucocorticoid therapy will be administered as described.  Methylprednisolone will be administered on Days 
1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below: 
Day 1 (day of transplant):  500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin 
(Groups B and C) 
Day 2: 250mg IV  
Day 3: 125mg IV  
Day 4: 80mg p.o.  
Day 5: 60mg p.o.  
No further steroids 


 
 
48 | P a g e  
Amendment 8 5/20/2015 
5.2.4  Belatacept Administration and Monitoring 
 
Subjects randomized to either group A or B will receive belatacept via intravenous (IV) infusion according 
to the FDA approved dosage recommendations.  Subjects randomized to belatacept arms will receive the 
first dose of IV belatacept (10 mg/kg) within 12-24 hours post reperfusion.  The second dose will be given 
between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 weeks) 
and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until 
completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of transplant. 
 
Infusion of the initial Study Day 1/Study Day 2 belatacept dose must be given within 12-24 hours post 
reperfusion.  It cannot be administered prior to or concurrently with either induction immunosuppressive 
agent.  Infusion doses will be based on the subject’s actual body weight at study Day 1 (day of transplant), 
and will not be modified during the course of the study, unless there is a change of body weight greater 
than ± 10%. Study drug should be administered to the subject at a relatively constant rate over 30 minutes. 
No additional monitoring will be required during the infusion. 
 
A negative urine or serum pregnancy test is required prior to transplant and every 3 months prior to 
belatacept administration.  Patients are required to report any known pregnancy to the investigator 
immediately.  See Section 7.5. 
 
Commercial belatacept will be provided by the manufacturer for administration during the study period and 
will be considered study drug. 
 
Infusion center services may be offered at belatacept infusion only visits based on each institutions 
preference and where it is feasible. 
 
Belatacept Infusion Visit Table 
 
 
D 
1-2 
D 
5-7 
W 
2 
W 
4 
W 
8 
W12 
M3 
W 
16 
W 
20 
W24 
M6 
W 
28 
W 
32 
W36 
M9 
W 
40 
W 
44 
W 
48 
W52 
M12 
Belatacept 
Infusion 
X1 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
Test 
X2 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
1. Initial Belatacept dose will be administered within 12-24 hours post reperfusion. 
2. Pregnancy test should be done at baseline within 7 days prior to transplant and before patient receives a dose of belatacept 
3. Belatacept dose is to be given once between Study days 5 – 7, with intention of administering as an outpatient   
 
 
W 
56 
W 
60 
W 
64 
M15 
W 
68 
 
W 
72 
W 
76 
 
W 
80  
M18 
W 
84 
W88 
 
W92 
M21 
W 
96 
W 
100 
W 
104 
M24 
Belatacept 
Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
Test 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
5.2.5  Tacrolimus Administration 
 
Patients in Group C will receive tacrolimus.  Tacrolimus will be administered orally twice daily (BID). The 
recommended total initial dose of tacrolimus is 0.1 mg/kg/day in two divided doses orally. Tacrolimus should be 
started post-transplant within 48 hours or when serum creatinine drops lower than 4mg/dL, whichever comes first.  
The initial targeted trough level of tacrolimus will be 8 - 12 ng/mL for Days 1 through 30, with dose reduction to 
achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.  Tacrolimus trough levels will be monitored at each 
study visit time point after tacrolimus is initiated. 
 
 
 


 
 
49 | P a g e  
Amendment 8 5/20/2015 
5.2.6  Mycophenolate mofetil/EC mycophenolate sodium Administration 
 
All patients (Groups A, B, and C) will receive Mycophenolate mofetil/EC mycophenolate sodium first dose will be 
administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily 
(2000mg/day).  Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day).  
These doses of mycophenolate mofetil/EC mycophenolate sodium have shown efficacy, pharmacokinetic and 
pharmacodynamic equivalence.  Dose may be increased for African American transplant recipients to 
mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 
mg/day).   
Subsequent dosage adjustments based on physician discretion are permitted due to toxicity only. 
 
5.2.7  Recommended Dosage Adjustment of Mycophenolate mofetil/EC mycophenolate sodium 
 
Mycophenolate mofetil/EC mycophenolate sodium dosage adjustments are strongly discouraged within the 
first month post-transplant; however, may be permitted by the study investigator.   Dosage adjustments for 
leucopenia are permitted as described in the table below.  
 
WBC cells/µL 
Reduction in current IS dose 
>3000 cells/µL 
None 
<3000 and >2000 cells/µL 
Decrease current dose by 25% 
<2000 with ANC >1000 cells/µL 
Decrease current dose by 50% 
ANC<1000 cells/µL 
Hold until ANC > 1000 cells/µL, GCSF 
may be administered per physician 
discretion 
 
MPA AUCs may be performed in patients with rejection, infection, or leucopenia. 
 
Attempts will be made to avoid drug interactions with any of the immunosuppressants studied.  However, 
when at the physician discretion, the clinical situation necessitates the administration of an interacting drug, 
increased therapeutic drug monitoring will be conducted.  If interacting drugs are co-administered, the 
same targeted levels of immunosuppressant will be the treatment goal. 
 
All options will be exercised to maintain the patient on the randomized immunosuppressive regimen.  
However, some patients may experience dose limiting toxicity requiring adjustments.  The physician will 
use discretion as to how long to continue a patient on the randomized immunosuppressive regimen.  While 
dose adjustments are allowed as described below, deviations from the randomized immunosuppressive 
regimen must be discussed with the principal investigator. These deviations from the randomized 
immunosuppressive regimen would be considered major protocol deviations.  
 
 


 
 
50 | P a g e  
Amendment 8 5/20/2015 
5.2.8  Anti-infective Prophylaxis Recommendations 
 
Anti-infectives will be administered per institution standard of care.  Below is a recommended protocol. 
 
Anti-Infective prophylaxis 
 
Antiviral 
CMV D+/R- 
Valganciclovir1 
450-900mg po QD  
 
365 days 
CMV D+/R+ 
CMV D-/R+ 
CMV D-/R- 
Valganciclovir 1 
225mg po QD or 450mg PO QOD 
90 days 
Antifungal 
All 
Nystatin 
5ml TID swish & swallow 
90 days 
PCP 
All 
Bactrim SS2 
1 po MWF 
365 days 
Sulfa allergic 
Pentamidine 
300mg neb Q 4 weeks 
Sulfa allergic 
Mepron 
1500mg po QD or 750mg BID (true 
sulfa allergy and Pentamidine 
intolerant) 
Other 
Dapsone 
50-100mg po MWF 
 
1 = Valganciclovir renal dose adjustment (Starting Dose = 450mg QD) 
 
CrCl 40-59ml/min = 450mg qd 
 
CrCl 25-39ml/min = 450mg every other day or 225mg qd 
 
CrCl 10-24ml/min = 450mg 2 times a week 
      Valganciclovir renal dose adjustment (Starting Dose = 900mg QD) 
 
CrCl 40-59ml/min = 900mg qd 
 
CrCl 25-39ml/min = 450mg daily 
 
CrCl 10-24ml/min = 450mg every other day or 225mg qd 
2 = If unable to start Bactrim by POD 7, administer alternative PCP prophylaxis 
 
 
 
5.2.9 Reasons for permanent study drug discontinuation 
 
Study drug must be discontinued if the investigator determines that continuing it would result in a significant safety 
risk for that patient.  Reasons for study drug discontinuation are or can be: 
• 
AE(s) (including infections), abnormal laboratory value(s), abnormal test procedure result(s) including ECG 
abnormalities, unsatisfactory therapeutic effect (i.e. demonstrated by acute rejection), graft loss, death, 
significant protocol deviation, withdrawal of consent, or lost to follow-up. 
The following circumstances require study drug discontinuation: 
1. Malignancy (except non-melanoma skin cancer) 
2. Pregnancy 
In addition to these requirements for study drug discontinuation, the investigator should discontinue study drug for a 
given patient if, in his/her professional judgment, it is felt that continuation would be detrimental to the patient’s well-
being. 
 
Patients may withdraw from the study for any reason at any time. 


 
 
51 | P a g e  
Amendment 8 5/20/2015 
 
 
 
5.2.10 Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study treatment or from the study for any reason at any time.  They may 
be considered withdrawn from the study if they state an intention to withdraw, fail to return for visits, or become lost 
to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to determine the primary 
reason for a patient’s premature withdrawal from the study. 
The investigator should discontinue study treatment for a given patient or withdraw the patient from study if, on 
balance, he/she believes that continuation would be detrimental to the patient’s well-being. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study and should continue 
to be followed until the end of the study, unless consent is withdrawn. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal number of newly enrolled 
patients. 
 
5.2.11 Study completion and post-study treatment 
Patients who attend the Month 24 study visit and undergo all study-related procedures and evaluations will be 
deemed to have completed the study.  The only reasons for premature discontinuation from the study are death, 
lost-to-follow-up, or withdrawal of consent (to the study). 
Patients who elect to discontinue participation in the study or those for whom, in the opinion of the investigator, 
continued participation is ill-advised must undergo all End-of-Study/End-of-Treatment procedures and evaluations. 
Early termination/End of Study visit will be the same as the Month 24 visit requirements.    
Patients may permanently discontinue from the study regimen for any reason at any time.  They may be considered 
permanently discontinued from a study regimen (but not the study) if e.g. they state an intention to withdraw 
consent, or fail to return for visits etc.  This may also happen on the initiative of the investigator if necessary for the 
patients’ wellbeing.   
 
Except for discontinuations due to death, loss to follow-up, and withdrawal of consent (to the study), patients who 
discontinue the study regimen should remain in the study (off study regimen) and attend scheduled follow-up visits 
as per schedule of assessments to obtain follow-up information and assessments.  
All patients who permanently discontinue the study regimen will attend the End of Treatment (EOT) visit.   
Every attempt should be made to obtain key endpoint information at the Month 12 and 24 time points.  
All patients who discontinue the study regimen prior to the study completion at Month 24 will be converted to 
immunosuppression treatment as per standard local practice.  No further study drugs will be provided. 
 
 
 
5.2.12 Early study termination 
The study can be terminated at any time for any reason by the Principle Investigator or Bristol-Myers Squibb.  
Should this be necessary, the patient should be seen as soon as possible and treated as described in a 
prematurely withdrawn patient.  The investigator may be informed of additional procedures to be followed in order 
to ensure that adequate consideration is given to the protection of the patient’s interests.  The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
 
 
    


 
 
52 | P a g e  
Amendment 8 5/20/2015 
 
6.   Laboratory and Clinical Assessments 
6.1.  Laboratory and Clinical Assessment Flowchart 
 
Baseline 
Pretxp 
(within 10 
days of txp, 
unless 
indicated 
otherwise) 
Day of 
Trans
plant 
Study Visits 
Time post Transplant [Day (D), Week (W), Month (M)] 
D 1 
D
7 
W
2 
W
4 
W
8 
W 
12 
M3 
W24 
M6 
W
36 
M9 
W
52 
M 
12 
W
64 
M 
15 
W 
80 
M 
18 
W 
92 
M21 
W 
104 
M24 
Study windows 
 
 
±
1 
±
2 
±2 
±3 
±3 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Crossmatch, Tissue 
Typing,  PRA2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serologies4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Chemistries5 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology6 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tacrolimus Trough 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Fasting Lipids7 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Spot Urine 
Protein/Creatnine8 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
HgA1c9 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Pregnancy Test10 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
DSA and ELISA 
assessment11 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
X 
QPCR assessment12 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
X 
Renal Biopsy13 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FRS Score 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
QoL/Side Effect 
Assessments 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical 
Assessments14 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
1. Randomization will occur within 72 hours of transplant.  
2. Screening tests/procedures can be completed within 30 days of transplant.  PRA just needs to be the most recent PRA, not necessarily within 30 days. 
3. Vital signs include BP, weight, and height (including BMI) at baseline visit.  BP and weight only at subsequent visits. 
4. Serologies for CMV, Epstein-Barr, hepatitis B & C and HIV for donor and recipient done at any previous evaluation within one year will be accepted for eligibility criteria as long as it is 
documented. 
5. Serum chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting blood glucose (FBG) with an eGFR (MDRD) assessment. 
6. Hematology includes WBC, Hgb, and platelet count (PLT). 
7. Subjects must be fasting. Lipid testing include total cholesterol, LDL, HDL, triglycerides. 
8. Urinalysis for spot urine protein creatinine ratio. 
9. HgAIc is needed in ALL patients.   This will be used to help assess NODAT and exacerbation of diabetes. 
10. Urine or serum pregnancy tests in women of child bearing potential will be required prior to belatacept infusions at visits on months 3, 6, 9, 12, 15, 18, 21, and 24.     
11.  Anti-donor HLA antibodies (DSA) and ELISA assessment (10ml red top) - additional blood samples are to be obtained at the time of any suspected rejection episode(s).   
12.  QPCR assessment of acute rejection signature (2.5ml Paxgene tube) – additional blood samples are to be obtained at the time of any suspected rejection episode(s) 
13. There are no protocol biopsies.  Implant biopsy will be performed as standard of care.   
14.  Includes assessments of sitting blood pressure (BP), # BP meds and type, weight changes, BMI, smoking, adverse events, CV events, study drug doses, allograft rejection, infection or 
malignancy, insulin or oral anti-diabetic agents, anti-lipid agents, aspirin, need for dialysis, hospitalization, re-transplant status, and other immunosuppressant medications. 
 


 
 
53 | P a g e  
Amendment 8 5/20/2015 
 
 
 
 
 
6.2  Laboratory Assessments by Study Visit and Test 
 
Laboratory evaluations will be performed at certified local laboratories according to the study schedule. The 
only laboratory evaluation that will be performed at the central laboratory is the DSA assessments. 
Required tests are specified in the Laboratory and Clinical Assessment Flowchart. 
 
6.2.1 
Baseline/Pretransplant (Study window within 10 days of transplant, unless indicated 
otherwise) 
Logistic issues surrounding achievement of the following procedures for living donor versus deceased 
donor transplant recipients will vary.  Screening procedures may occur as soon as a potential transplant 
recipient is identified with a viable donor. 
 
- All inclusion/exclusion criteria will be evaluated and supporting documentation for all provided. 
- HLA data such as crossmatch, tissue typing (including A, B, C, DR, and DQ loci if available), PRA testing 
for the donor and recipient will be evaluated based on the most recent PRA available, not necessarily 
within 30 days of transplant. 
- An abbreviated medical history (hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, 
and smoking history and treatments for these conditions) and physical exam including vital signs will be 
provided within 30 days of transplant.   
-Medications of special interest (oral and insulin agents, total # units of insulin, anti-lipid agents, and anti-
hypertensive agents, and aspirin.  
- Vital signs will include sitting blood pressure (systolic and diastolic), height, weight (kg) and body mass 
index (BMI) (kg/m2). 
- Quality of Life/Side Effect Assessment studies performed including MTSOSDS and the Memphis Survey 
- Framingham Risk Score Assessment 
- Baseline laboratory assessments will include the following: 
Serum chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), 
and fasting blood glucose (FBG) with an eGFR (MDRD) assessment. 
Fasting lipid profile (total cholesterol, LDL, HDL, triglycerides) 
HgA1c in ALL patients 
Hematology including a white blood cell count (WBC), hemoglobin (Hg), and platelet count (PLT) 
Serologies for CMV, Epstein-Barr, hepatitis B & C and HIV for donor and recipient done at any 
previous evaluation within one year will be accepted. 
 
Urine or Serum Pregnancy test in women of child bearing potential 
 
Urinalysis for spot urine protein and creatinine ratio 
 
Donor Specific Antibody (DSA) and ELISA assessment for NODAT testing (10ml red top tube) 
 
QPCR assessment of acute rejection (2.5ml PAXgene tube) 
Consent will be obtained prior to transplantation and any study related procedure. 
Randomization will occur within 72hr of transplantation. 
 
6.2.2 
Day 1 (Day of Transplant) 
- Chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting 
blood glucose (FBG) with an eGFR (MDRD) assessment 
- Hematology including a WBC, Hgb, and PLT 
- Routine renal transplant biopsy sample 
- Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, # units of insulin, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant 
status, and other immunosuppressant medications. 
 
6.2.3 
Day 7 (± 1 day), Weeks 2 and 4 (± 2 days), and Week 8 (± 3 days) 
- Chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting 
blood glucose (FBG) with an eGFR (MDRD) assessment 
- Hematology including a WBC, Hgb, and PLT 
- Tacrolimus trough level 


 
 
54 | P a g e  
Amendment 8 5/20/2015 
- Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, # units of insulin, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant 
status, and other immunosuppressant medications. 
 
6.2.4 
Month 3 (± 3 days) 
- Chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting 
blood glucose (FBG) with an eGFR (MDRD) assessment 
- Hematology including a WBC, Hgb, and PLT 
- Urine or Serum Pregnancy test in women of child bearing potential  
- Tacrolimus trough level 
- Donor Specific Antibody (DSA) and ELISA assessment for NODAT testing (10ml red top tube) 
-QPCR assessment of acute rejection (2.5ml PAXgene tube) 
-Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, # units of insulin, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant 
status, and other immunosuppressant medications. 
 
6.2.5 
Month 9 (± 7 days), Month 15 (± 7 days), and Month 18 (± 14 days) 
- Chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting 
blood glucose (FBG) with an eGFR (MDRD) assessment 
- Hematology including a WBC, Hgb, and PLT 
- Urine or Serum Pregnancy test in women of child bearing potential  
- Tacrolimus trough level 
-Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, # units of insulin, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant 
status, and other immunosuppressant medications. 
 
6.2.6 
Month 21 (± 14 days) 
- Urine or Serum Pregnancy test in women of child bearing potential 
 
6.2.7 
Months 6 and 12 (± 7 days), and Month 24 (± 14 days) 
    - Chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting 
    blood glucose (FBG) with an eGFR (MDRD) assessment 
    - Hematology including a WBC, Hgb, and PLT 
 - Fasting lipid profile (total cholesterol, LDL, HDL, triglycerides) 
- Tacrolimus trough level 
   - Urine or Serum Pregnancy test in women of child bearing potential  
- HgA1c  
- Urinalysis for protein creatinine ratio 
- Donor Specific Antibody (DSA) and ELISA assessment for NODAT testing (10ml red top tube) 
-QPCR assessment of acute rejection (2.5ml PAXgene tube) 
- Framingham Risk Score Assessment 
- Quality of Life/Side Effect Assessment studies performed including MTSOSDS and the Memphis Survey 
(Months 12 and 24 only, not required at 6 months) 
- Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, # units of insulin, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant 
status, and other immunosuppressant medications. 


 
 
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6.3  Clinical Assessments at Each Study Visit 
 
6.3.1  General Clinical Assessment 
 
All patients will undergo clinical evaluation by the investigator or the investigator’s designee at the times 
specified in the Laboratory and Clinical Assessment Flowchart.   
 
Clinical Assessment includes sitting blood pressure, weight changes (kg), BMI (kg/m2), smoking, adverse 
events, CV events, study drug doses, allograft rejection, infection or malignancy, insulin or oral anti-diabetic 
agents, anti-lipid agents, aspirin therapy, need for dialysis, hospitalization, re-transplant status, and other 
immunosuppressant medications. 
 
Smoking at the time of transplant is defined as currently smokes, or a significant h/o >20yrs, or quit within 
last year prior to transplant.  Smoking at all post-transplant time points is defined as patient who is currently 
smoking. 
 
6.3.2  Graft Function Assessment 
 
Graft function will be assessed as described below.  Serum creatinine will be assessed immediately post-
operatively to establish initial renal function.  Baseline serum creatinine after the initial post-transplant 
period of 3 to 7 days is defined as the median of 5 consecutive serum creatinine measurements 
immediately preceding the renal allograft biopsy. 
 
6.3.2.1  Initial renal function: 
 
Classified post transplant in the following categories: 
1. DGF(delayed graft function)=Dialysis with in the first 7 days post transplant 
2. OA (oliguric ATN) =<500cc/d UOP and <10% drop SCr by Day 7  
3. NOA (non-oliguric ATN) = >500cc/d and <10% drop SCr by Day 7  
4. DCl (Delayed clearance) = >500cc/d and 10-50% drop SCr by Day 7  
5. Good initial graft function = >50% drop in SCr from baseline by Day 7 
 
6.3.2.2 Acute renal dysfunction 
 
Renal dysfunction will be monitored by serial measurements of serum creatinine. All episodes of renal 
dysfunction, defined as an incremental increase in serum creatinine concentration 20% above baseline or > 
0.3 mg/dl will be evaluated for rejection by renal biopsy and ultrasound, after exclusion of causes other 
than rejection. In cases where renal biopsy is delayed, empiric treatment of rejection with up to 
methylprednisolone 1000mg within 48 hours of biopsy is acceptable. 
 
In addition, a biopsy may be performed in cases that do not meet the above acute renal dysfunction criteria 
but that there is clinical suspicion of rejection determined by the local investigator.   
 
An additional DSA sample should be collected at each biopsy for suspected rejection. 
 
6.3.2.3 Rejection 
 
Biopsy proven Acute Cellular Rejection (BPACR) is defined as: Elevation of serum creatinine of 20% 
above baseline or an absolute increase of > 0.3 mg/dl with renal allograft biopsy showing IA or greater 
grade of rejection by Banff 2007 criteria. 
 
Biopsy proven Antibody Mediated Rejection (BPAMR) is defined as: Elevation of serum creatinine of 
20% above baseline or an absolute increase of > 0.3 mg/dl with renal allograft biopsy meeting Banff 2007 
criteria for AMR.  
 
Biopsy Proven Mixed Acute Rejection (BPMAR) is defined as: Elevation of serum creatinine of 20% 
above baseline or an absolute increase of > 0.3 mg/dl with renal allograft biopsy showing IA or greater 
grade of rejection by Banff 2007 criteria with the presence of either donor specific anti-HLA antibody (DSA) 
or C4d positivity on biopsy. 
 


 
 
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Renal biopsy should be performed in all cases of renal dysfunction (after exclusion of causes other than 
rejection), to confirm a rejection episode.  All patients must have biopsy confirmation of rejection episodes 
either before or within 24 hours of onset of treatment for rejection.   
 
 
Guidelines for Defining Response to Rejection Therapy: 
Baseline Serum Creatinine is the median of the 5 consecutive serum creatinine measurements 
immediately preceding the renal allograft biopsy. 
 
Peak Serum creatinine is the highest value observed within 2 weeks of initiation of anti-rejection 
treatment. 
 
Rejection Reversal is a return of serum creatinine to within 115% of the baseline value, or histologic 
reversal occurring within 14 days of initiation of treatment.   
 
Recurrent Rejection is histologic evidence of rejection noted on a biopsy specimen obtained up to 3 
months after documented rejection reversal. 
 
Refractory Rejection is a rejection that does not obtain histologic rejection reversal or a serum creatinine 
decrease to within 115% of the baseline value within 14 days of initiation of treatment. 
 
Clinically Evident Rejection is a biopsy proven rejection with renal dysfunction defined as increase in 
serum creatinine concentration 20% above baseline or ≥ 0.3 mg/dl above baseline. 
 
Clinically Silent Rejection is a biopsy proven rejection without renal dysfunction. 
 
Progressive deterioration is defined as a refractory rejection causing a progressive decrease in renal 
function leading to graft loss despite treatment. 
 
Glucocorticoid-resistant acute rejection is defined as a biopsy-confirmed acute rejection episode and no 
decrease in serum creatinine after three days of methylprednisolone treatment, OR continued rejection 
documented by renal biopsy within 2 weeks of initiation of methylprednisolone/prednisone treatment (i.e., 
when an initial favorable response to methylprednisolone/prednisone treatment is not sustained, and a 
second biopsy is required to confirm the presence of continued rejection). 
 
Chronic Rejection will be defined as a serum creatinine increase of 30% above baseline or proteinuria > 2 
gm/24hrs with a biopsy demonstrating histologic features of chronic rejection. 
 
All episodes of kidney dysfunction will be evaluated for possible rejection after exclusion of other causes. 
The diagnosis of biopsy proven acute rejection will be based on clinical signs and symptoms and will be 
confirmed histologically using 2007 Banff criteria by the local pathologist.  The biopsy must be obtained 
within 24 hours of starting treatment for the rejection episode.    
 
Residual renal biopsy tissue samples will be stored for analysis as determined scientifically beneficial for 
research related to solid organ transplantation.  Patient samples will be identified by study subject number 
and no other identifiable subject information only for purposes of linking the sample to data previously 
described as collected during the study. 
  
Anti-infective prophylaxis should be administered (as detailed at the time of transplantation) for all patients 
being treated for acute rejection. 
 
If unable to assess response to therapy based on the above guidelines, defer to PI for determining rejection 
response. 
 
The guidelines for treatment of acute rejection are presented in the following sections. 
 
 
 
 
 


 
 
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6.3.2.3.1  BPACR Banff Grade 1a-1bTreatment 
 
Continue current regimen of belatacept or tacrolimus, Solumedrol 7mg/kg (Max 500mg) IV daily X 3 days.  If 
improving trend in Scr, then initiate oral Prednisone recycle (Prednisone 200mg X 1, Prednisone 160mg X 1, 
Prednisone 120mg X 1, Prednisone 80mg X 1, Prednisone 40mg X 1, Prednisone 20mg X 1, Prednisone 10mg X 
1, then discontinue steroids). If no improving trend in Scr after 3-5 days of treatment initiation, then repeat biopsy.  
If Banff grade is the same or worse, then initiate or increase tacrolimus to a goal trough of 10-15 ng/mL or initiate 
rabbit antithymocyte globulin for 7-14 days of CD3 suppression.  If Banff grade is improving or minimal persistent 
rejection, continue oral prednisone recycle. 
 
The following schematic is a guideline for the treatment of Banff 2007 Grade 1a or 1b acute rejections 
 
 
Banff Grade  
1a or 1b 
Continue current 
maintenance IS regimen 
 
Solumedrol 7mg/kg 
(Max 500mg) IV daily X 
3 days and begin oral 
steroid taper. 
Improving trend in 
Serum creatinine 
Oral Prednisone 
Recycle: 
-Prednisone 200mg X 1 
-Prednisone 160mg X 1 
-Prednisone 120mg X 1 
-Prednisone 80mg X 1 
-Prednisone 40mg X 1 
-Prednisone 20mg X 1 
-Prednisone 10mg X 1 
-Discontinue steroids 
No or minimal improvement of 
serum creatinine within 3-5 
days of initiating treatment 
Repeat Biopsy 
Initiate or increase 
tacrolimus dose to a goal 
trough 10-15 ng/mL  
 
or  
 
Start antithymocyte 
globulin for 7-14 days of 
CD3 suppression 
If improving or minimal 
persistent rejection 
If same or greater grade 
of rejection persists 
Continue Oral 
Prednisone Recycle: 
-Prednisone 200mg X 1 
-Prednisone 160mg X 1 
-Prednisone 120mg X 1 
-Prednisone 80mg X 1 
-Prednisone 40mg X 1 
-Prednisone 20mg X 1 
-Prednisone 10mg X 1 
-Discontinue steroids 


 
 
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6.3.2.3.2  Recommended BPACR Banff Grade >2a Treatment 
 
Continue current regimen of belatacept or tacrolimus, initiate antithymocyte globulin for 7-14 days of CD3 
suppression.  If no improving trend in Scr after 7 days of treatment initiation, then repeat biopsy.  If Banff grade is 
the same or worse, continue antithymocyte globulin, initiate or increase tacrolimus therapy to a goal trough of 10-15 
ng/mL and initiate or add corticosteroid therapy.  If Banff grade is improving or minimal persistent rejection, 
continue antithymocyte globulin. 
 
The following schematic is a guideline for the treatment of Banff 2007 2a, 2b or 3 acute cellular rejections 
 
 
Banff Grade ≥ 2a 
-Continue current 
maintenance IS 
regimen 
 
- Antithymocyte 
globulin rejection 
treatment of 1.5mg/kg 
on Day 1 and Day 2 
followed by CD3 
monitoring.  Redose 
antithymocyte globulin 
when CD3>25 for a 
total of 7-14 days of 
CD3 suppression. 
Premedication per 
center protocol. 
Improving trend in 
serum creatinine 
-Observe 
 
-Continue 
antithymocyte 
globulin for 7-14 
days of CD3 
suppression. 
No or minimal improvement of 
serum creatinine within 7 days of 
initiating treatment 
 
Repeat 
Biopsy 
-Observe 
 
-Continue 
antithymocyte  
globulin for 7-14 days 
of CD3 suppression. 
-Continue antithymocyte 
globulin for 7-14 days of 
CD3 suppression. 
 
-Initiate or increase 
tacrolimus therapy to a 
goal trough of 10-15 
ng/mL 
 
-Initiate or add 
corticosteroids. 
Solumedrol 7mg/kg (Max 
500mg) IV daily X 3 days 
and begin oral steroid 
taper. 
If improving or minimal 
persistent rejection 
If same or greater grade 
of rejection persists 


 
 
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6.3.2.3.3  Recommended BPAMR or BPMAR Treatment  
 
May treat BPAMR or BPMAR with a bortezomib-based or IVIG-based protocol.   
The following schematic is a guideline for the treatment of antibody mediated rejection and mixed rejection with 
bortezomib-based treatment with rituximab: 
 
Treatment Day 
PRE 
1 
4 
7 
10 
PLASMAPHERESIS 1.5 PV 
  
X 
X 
X 
X 
Methylprednisolone 100 mg IVP or PO 
  
X 
X 
  
  
Methylprednisolone 50 mg IVP or PO 
  
  
  
X 
X 
BORTEZOMIB 1.3 mg/m2 IVP or SC 
  
X 
X 
X 
X 
RITUXIMAB 375 mg/m2 IV 
  
X 
  
  
  
 
 
6.3.3 
Safety assessments - Clinical 
 
 
 
6.3.3.1 Physical examination and Medical History 
A thorough medical history and physical exam will be performed within 30 days prior to transplant.  
 
 
6.3.3.2 Vital signs 
Height should be recorded on baseline visit or day of transplant (Day 1).  Blood pressure in mmHg and weight in kg 
will be recorded at each clinical assessment time point as indicated in schedule of assessments. BMI should be 
calculated at baseline, month 6, month 12, and month 24. 
 
 
6.3.3.3 Laboratory evaluations 
 
There is no central laboratory for this study, except for the DSA samples.  All laboratory evaluations will be sent 
locally during the study.  Laboratory assessments needed for patient safety during the study will also be performed 
at the local laboratory.    Laboratory samples should be drawn prior to administration of the morning dose of study 
medications.  All samples will be drawn, preferably with the patient in fasting state (recommended more than eight 
hours after the last meal).  Non-fasting blood samples should be clearly identified.  For screening evaluation 
(hematology and blood chemistry) blood samples should be drawn prior to transplantation within 10 days. 
 
Hematology 
 
A white blood cell count, platelet count, and hemoglobin, will be obtained at every visit indicated in schedule of 
assessments (Baseline, Day 1 and 7, Weeks 2, 4, 8, 12, 24, 36, 52, 68, 80, and 104). 
 
Serum Chemistry 
This includes collection of a Serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting blood 
glucose (FBG) and an assessment of renal function by estimated glomerular filtration rate (eGFR) using MDRD as 
described below under renal function.  This will be obtained at every visit indicated in schedule of assessments 
(Baseline, Day 1 and 7, Weeks 2, 4, 8, 12, 24, 36, 52, 68, 80, and 104).   
 
Fasting Lipids 
This includes total cholesterol, high density lipoprotein, low density lipoprotein, and triglycerides.  This will be 
collected at baseline, 6 months, 12 months, and 24 months. 
 
Urinalysis 
A mid-stream spot urine for quantitative protein/creatinine ratio will be performed at baseline, 6 months, 12 months, 
and 24 months.   


 
 
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Renal function 
Renal function will be assessed at each visit by measuring serum creatinine and using this to calculate eGFR using 
the MDRD equation. 
 
MDRD should be calculated using the following equation: 
eGFR (MDRD) (mL/min/1.73m2) = 170 x (SCr)-0.999 * (Age)-0.176 * (BUN)-0.170 * (Alb)0.318 * 0.762 (if female gender) * 
1.180 (if African American race)  
Levey AS, Bosh JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum 
creatinine: A New Prediction Equation.  Ann Intern Med 1999; 130: 461-470. 
Hemoglobin A1c 
New Onset diabetes and exacerbation of preexisting diabetes will be assessed at each visit by evaluating oral and 
insulin agents, total # units of insulin, as well as looking at FBG and HgA1c at baseline, 6, 12, and 24 months. 
Liver Function Tests 
Liver function monitoring will be performed per each institutions standard of care and is not protocol defined.   
Donor specific antibodies (DSA), ELISA for NODAT, and QPCR assessment for acute rejection 
Serum samples (10ml red top tube and 2.5ml Paxgene tube) will be collected as indicated in schedule of 
assessments (Baseline, 3 months, 6 months, 12 months, and 24 months and at times of suspected rejection).   
Blood samples (10 mL) will be collected in a ‘red top clotting tube’ and let the specimen stand at room temperature 
for 30 min until the clot forms. The sample will be centrifuged at 2000 X g for 5 minutes using a swinging bucket 
rotor. The serum will be transferred to TWO cryotubes and will be stored at -80 °C until shipment.  One cryotube 
will be utilized for DSA testing and one crytotube will be utilized for ELISA NODAT testing.   
Blood samples (2.5ml) will be collected in a Paxgene tube and frozen at -80C. This sample will be utilized for 
QPCR assessment for acute rejection 
Patient samples will be identified by study site and subject number and no other identifiable subject information only 
for purposes of linking the sample to data previously described as collected during the study. ALL frozen patient 
samples will be batched shipped to the University of Cincinnati monthly, overnight delivery is not required.  The 
tubes should be labeled as per the shipping manual.  Shipping boxes must conform to the delivery company’s 
biologics requirements.  The shipping address for ALL samples is: 
Stefanie Young/Liz Cole 
UC Health 
University of Cincinnati Physicians 
231 Albert Sabin Way 
MSB Room 1555 
Phone: 513-584-1642 
Fax:  513-584-2149 
Email:  uchtransplant@uc.edu or youngs8@uc.edu or colee@uc.edu 
 
The University of Cincinnati will receive all samples, log, and route to the proper laboratories for analysis.  


 
 
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6.3.3.4 Pregnancy and Assessments of Fertility 
A urine or serum pregnancy test will be performed at the baseline visit within 10 days of transplant and every 3 
months prior to belatacept infusion in women of child bearing potential.  Patients must report any known possible 
pregnancy to the investigator immediately. See Section 7.5. 
 
 
6.3.3.5 Tolerability and Acceptability 
Tolerability of the regimen as measured by percentage of patients requiring dose reduction or discontinuation of 
study group will be assessed. 
 
 
6.3.3.6 Appropriateness of Safety Measurements 
The adverse events of special interest selected are expected for this indication/patient population and may be 
related to immunosuppression and/or comorbid conditions.  Expected events related to immunosuppression are 
those included in the labeling of each immunosuppressive agent utilized.  The following safety measurements will 
be systematically assessed in all patients at each study visit.  Events meeting the definition of serious will be 
reported as a serious adverse event. 
 
 
 
6.3.3.7  Adverse Events of Special Interest 
 
 
 
 
6.3.3.7.1 New Onset Diabetes Mellitus After Transplantation (NODAT): 
In patients who do not have diabetes mellitus prior to transplantation, new onset diabetes mellitus 
is defined by: 
 
1) New requirement for therapy with insulin for > 30 days OR 
2) New use of oral hypoglycemic agents for ≥ 30 days   OR 
3) Any treatment (oral or insulin or other) for ≥ 30 days   OR 
4) FBG > 126 mg/dL x 2 consecutive values   OR 
5) HgAIC ≥ 6.5% at any time point 
 
Periodic assessments of blood glucose control, total # units of insulin, and specific treatment will be 
performed at each study visit. FBG and HbA1c levels at 6 months, 12 months, and 24 months will 
be analyzed to assess for development of NODAT. 
 
 
6.3.3.7.2 Exacerbation of Preexisting Diabetes: 
In patients with preexisting diabetes mellitus at the time of transplantation, the exacerbation of the 
diabetes will be evaluated by analyzing change from baseline at 6, 12, and 24 months in total # 
units of insulin, oral and insulin agents, and FBG, and HgA1c.  Exacerbation will be defined as an 
increase in the total # units of insulin, increase in number of insulin or oral agents, or a worsening 
of control as determined by an increase in HgA1c.  
 
6.3.3.7.3 Hyperlipidemia 
Clinical practice guidelines for the management of dyslipidemias in renal transplant subjects are 
available from the National Cholesterol Education Panel, Adult Treatment Panel III (see Appendix 
V, 36).  Treatment will be initiated based upon those guidelines.  Periodic assessments of 
treatment will be performed at each study visit. Fasting lipids and treatment will be collected at 6, 
12, and 24 months post-transplant to assess for changes in lipid levels. 
 
6.3.3.7.4 Hypertension  
Hypertension will be defined and treated according to Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (see 
Appendix VI, 37). Seated blood pressure should be taken at a resting state.  Treatment will be 
initiated based upon these guidelines.  Blood pressure (systolic and diastolic) and treatment will be 
collected at each required time point in the study and will be specifically analyzed at 6, 12, and 24 
months. 
 
6.3.3.7.5 Framingham Heart Study Coronary Heart Disease Risk Point Total 
A coronary heart disease risk factor assessment will be performed in each patient pre-transplant 
and at 6, 12 and 24 months post-transplant calculated from score sheets in Appendix VII (38).  
Periodic assessments of cardiac events will be performed at each study visit. 


 
 
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Amendment 8 5/20/2015 
 
6.3.3.7.6 Infection 
Periodic assessments of infections will be performed at each study visit. 
Infection is defined as any of the following: 
1)   
Treatment with antimicrobial agent for a specific clinical syndrome (not 
prophylaxis) 
2)   
Positive cultures, pathologic identification of microbial agents, or significant 
serologic changes related to clinical symptoms 
3)   
Typical clinical presentation documented by investigator or appropriate consultant. 
 
 
CMV infection is defined as isolation or identification of CMV from blood or sterile 
site (CMV serum DNA PCR) or positive antigenemia (presence of CMV 
immunoglobulin IgM or fourfold increase in CMV IgG titers) in the absence of 
clinical symptoms. 
 
CMV disease is defined as invasive or symptomatic CMV infection with histological 
evidence of viral cytopathic effect or a positive CMV culture from a deep tissue 
specimen in the setting of suggestive clinical manifestations.  Specimens used for 
diagnosis of CMV disease include liver or lung biopsy, endoscopic mucosal biopsy 
or brushing, bronchoscopic mucosal biopsy or brushing, bronchoalveolar lavage, 
and cerebrospinal fluid.  The presence of positive serum DNA PCR or 
seroconversion in the setting of symptomatic infection is also considered sufficient 
to establish the diagnosis of CMV disease. 
 
 
 
 
BK Virus is defined as one of the following: 
 
 
 
BK viremia -BK viral load is present in the blood by DNA PCR 
 
 
 
BK Nephropathy -BK viral load is present in the blood AND BK in situ hybridization 
 
 
 
is positive on allograft biopsy 
 
 
6.3.3.7.7 Malignancy 
Periodic assessments of malignancy will be performed at each study visit. 
Development of any post-transplant malignancies will be evaluated at 6 months 12 months, and 24 
months. 
 
6.3.3.7.8 Other 
Other safety assessments potentially related to immunosuppression that are expected will be 
captured at each study visit.  These include the following toxicities:  gastrointestinal, hematologic, 
nephrotoxicity, neurotoxicity, electrolyte imbalance, wound healing, bone related, or other as 
assessed by the PI as related to immunosuppression.  Events meeting the definition of serious will 
be reported as a serious adverse event. 
Other safety assessments potentially related to immunosuppression that are unexpected will be 
captured at each study visit as assessed by the PI.  Events meeting the definition of serious will be 
reported as a serious adverse event. 
 
6.3.4   Quality of Life/Side Effect Assessments 
Information captured in these assessments will be analyzed retrospectively and information not included in the 
safety assessment of the protocol.   
 
 
6.3.4.1  The Memphis Survey 
Quality of Life (QoL)/Side Effects will be assessed by the Memphis Survey from the University of 
Tennessee which assesses side effects of transplant medications and will be administered prior to 
transplant and at 12 and 24 months (Appendix IV). 
 
 
 
6.3.4.2  Modified Transplant Symptom Occurrence and Symptom 


 
 
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Amendment 8 5/20/2015 
Distress Scale Questionnaire 
Quality of Life (QoL)/Side Effects will also be assessed by the Modified Transplant Symptom 
Occurrence and Symptom Distress Scale (MTSOSDS) questionnaire that will be administered prior 
to transplant and at 12 and 24 months (Appendix IV). 
 
7 
Adverse Event Management 
 
Any serious adverse event will be reported to the sponsor, and BMS as soon as possible, but no later than 15 
working days.  Unexpected fatal or life-threatening suspected adverse reactions must be reported not later than 7 
calendar days after initial receipt of the information.   
7.1. Definitions 
 
7.1.1. Adverse Events Related to Immunosuppression 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a subject administered immunosuppression.  Adverse events are determined by the PI as 
expected and related to immunosuppression if the adverse event is included in the product labeling.  Adverse 
events as determined by the PI as related to immunosuppression and unexpected may also occur. Adverse event 
reporting will focus on adverse events of special interest.  The adverse events of special interest have been 
detailed within the protocol.    
 
7.1.2. Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see note below for 
exceptions) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event, defined as a medical event that may not be immediately life-threatening or result 
in death or hospitalization but, based on appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention (eg, medical, surgical) to prevent one of the other serious outcomes listed 
above. Examples of such events include but are not limited to intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization.  
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, pathogenic or non-
pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose and cancer are not always serious by regulatory definition, these events must be 
handled as SAEs (See Section 7.5 for reporting pregnancies). 
Any serious adverse event will be reported to the sponsor, and BMS as soon as possible, but no later than 15 
working days via guidelines outlined in the adverse event management section. 
 
Unexpected fatal or life-threatening suspected adverse reactions must be reported not later than 7 calendar days 
after initial receipt of the information.   
 


 
 
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7.1.3. Nonserious Adverse Events 
Nonserious adverse events are all adverse events related to immunosuppression that are not classified as SAEs.  
Non serious adverse event reporting will be focused on adverse events of special interest as detailed in the 
protocol. 
7.2. Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. To prevent reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual symptoms.   
7.2.1. Serious Adverse Event Collecting 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 within 30 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. 
SAEs 
should 
be 
reported 
on 
MedWatch Form 3500A, 
which 
can 
be 
accessed 
at: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM082728.pdf 
All SAEs should be reported locally as per local IRB standards, and simultaneously faxed or e-mailed to 
the sponsor and BMS at: 
Rita Alloway, PharmD 
University of Cincinnati 
Fax Number:  513.558.4944 
Email:  (rita.alloway@uc.edu) 
 
and 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
Additional reporting to the FDA will be the responsibility of the sponsor based upon IND status. 
7.2.2. Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information related to immunosuppression should begin at 
initiation of study drug.  Non serious adverse event reporting will be focused on adverse events of special interest 
as detailed in the protocol.  
 
        


 
 
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7.2.3 Adverse Event Flowchart 
 
 
Is the non serious 
adverse event an 
adverse event of 
special interest ? 
NODAT 
Hyperlipidemia 
Hypertension 
Cardiac Event 
Infection 
Malignancy 
 
Adverse Event 
Does the finding meet 
the definition of a 
Serious Adverse Event? 
Follow Serious Adverse Event 
Reporting Requirements 
YES 
NO (Non Serious Adverse Event) 
YES 
NO 
Follow adverse event of special interest 
reporting requirements. 
Is the non serious 
adverse event related 
to immunosuppression 
based upon the 
judgment of the local 
PI? 
YES 
Follow adverse event reporting 
requirements for events related to 
immunosuppression, ie. GI toxicity, 
hematologic toxicity, nephrotoxicity, 
etc. and determine if expected or 
unexpected.  Expected adverse 
events are those reported in the 
product labeling.  Unexpected adverse 
events are those not previously 
reported. 
NO 


 
 
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7.3. Laboratory Test Abnormalities 
Laboratory abnormalities are not considered adverse events unless serious or otherwise specified.   
 
7.4. Overdose 
In case of over dosage, it is recommended that the patient be monitored for any signs or symptoms of adverse 
reactions, and appropriate symptomatic treatment instituted. Limited data suggest that plasmapheresis may 
accelerate removal of belatacept from systemic circulation.  
Although overdose is not always serious by regulatory definition, these events must be handled as SAEs (See 
section 7.1.2). 
7.5. Pregnancy 
7.5.1. Precautions 
Pregnancy tests may be performed on blood or urine via local laboratory or via investigator provided pregnancy 
kits.  The investigator should ensure that pregnancy kits used for testing are not expired. WOCBP should be 
advised against becoming pregnant or breastfeeding from the beginning of the study until 8 weeks or 5 half lives 
(whichever is greater) after administration of the last dose.  
Female subjects of reproductive potential taking CellCept/Mycophenolate Mofetil/Myfortic will receive contraceptive 
counseling and must agree to use acceptable contraception for the entire 2-year study and for eight weeks 
following study drug discontinuation.  The investigator and/or study staff will discuss appropriate birth 
control/contraception options using the chart below as a guide. 
 
Subjects will be instructed that the use of CellCept/Mycophenolate Mofetil/Myfortic during pregnancy is associated 
with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations and that 


 
 
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CellCept/Mycophenolate Mofetil/Myfortic reduces blood levels of the hormones in the oral contraceptive pill and 
could reduce its effectiveness. 
 
Subjects will be instructed to contact the Investigator immediately if pregnancy is suspected (e.g., missed or late 
menstrual period) while participating in the study or within 8 weeks after stopping participation in this study. The 
investigator will report the pregnancy to the Mycophenolate Pregnancy Reference Registry (1-800-617-8191) and 
the subject will be strongly encouraged to enroll in the pregnancy registry by calling the number above.  In the 
event of a positive pregnancy test the subject will be counseled with regard to whether the maternal benefits of 
mycophenolate treatment may outweigh the risks to the fetus, and will no longer be able to participate in the study.  
The investigator should change the subject’s treatment to a different combination of immunosuppressive drugs, and 
the study medication will be stopped.  The subject will still be required to return for periodic follow-up visits and 
blood work. 
Male subjects will be advised to avoid unprotected sex and sperm donation throughout the study and until sperm 
produced during the period of drug exposure has been cleared. Drug-exposed sperm may be present in the semen 
for 12 weeks following the passage of 5 half lives of the study drug.  Male subjects will be asked to inform the 
investigator immediately if their female partner becomes or suspects she is pregnant while they are enrolled in this 
clinical trial or within 12 weeks following the study drug completion. The subject and his partner will be asked to 
provide information about the pregnancy outcome. The Sponsor has neither set aside any funds for nor does it plan 
to pay for any aspects of obstetrical, child or related care. 
Subjects should be advised to notify the Investigator of any change in birth control method during exposure to 
Study Drug or if they need to take any prescription drug or other medication not prescribed by the Investigator. The 
Investigator should be aware of changes in birth control method so that the use of a study-prohibited contraceptive 
method is identified. 
7.5.2. Testing Methods and Timing 
7.5.2.1. Methods for Pregnancy Testing 
Blood or urine testing is acceptable. Urine pregnancy tests must have a minimum test sensitivity of at least 25 IU/L. 
Kits measuring either total human chorionic gonadotropin (hCG) or the beta (β) fraction.  
7.5.2.2. Timing of Pregnancy Testing  
WOCBP receiving belatacept should be tested at screening and every 3 months while receiving belatacept 
infusions. 
7.5.3. Pregnancy Reporting 
In the event that a WOCBP becomes pregnant during a clinical trial, the implications (on the health of the mother 
and fetus) of treatment suspension must be reviewed and considered. If it is determined that continued treatment is 
desirable, the investigator must immediately notify BMS and the Sponsor of this event in accordance with SAE 
reporting procedures described in Section 7.2.1.  
 


 
 
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7.6 Data Safety Monitoring Board (DSMB) 
 
An independent DSMB will be constituted prior to study initiation and will be comprised of 2 clinicians experienced 
in kidney transplantation and an independent statistician.   The DSMB will monitor ongoing efficacy and safety data 
during the study until the time of its conclusion.   The DSMB charter will outline DSMB constitution, scope, 
operation, and function per relevant FDA Guidance Documents.  
Stopping Criteria: 
Proposed stopping criteria for the DSMB will include CNS PTLD.  The DSMB will be requested to monitor CNS 
PTLD rates for each study limb during the study.   During the study, if 2 more cases of CNS PTLD are noted in 
either Group A or Group B as compared to Group C, the DSMB will review the individual cases and consider halting 
enrollment in the study Group in question.   If enrollment is permanently halted in Group A or B, accrual will 
continue in the remaining belatacept-based study group, and the overall number of subjects treated with belatacept 
would remain the same by adjusting the enrollment ratio to 2:1 with 2 patients in the remaining belatacept arm for 
every one patient in the control arm. 
8.  Statistical Analysis Plan 
 
8.1  Population for Analysis 
 
Intent-to-Treat (ITT) Analysis - This study will be analyzed as an intent-to-treat analysis at 12 and 24 months. All 
patients who were randomized and transplanted (defined as having renal allograft reperfusion) will be included in 
the intent to treat population for analysis.  
Following the ITT principle, patients will be analyzed according to the assigned treatment at randomization. 
Per protocol (PP) analysis: PP analysis set will consist of all randomized patients without major protocol deviations 
(PDs) as defined below and who completed study.  Identification of these protocol deviations are for analysis 
purposes only.  Deviations to the protocol made by the PI are made based upon physician discretion related to the 
optimal individual immunosuppressive management of the study subject reflective of standard of care 
immunosuppressive management and do not represent reportable regulatory protocol deviations since they are 
intended to lower the risk for the individual subject. 
All analyses will be performed on the ITT population and the PP population. 
 
All datasets will remain blinded and there will be no summary of the study by the individual treatment arms with the 
exception of an independent DSMB assessment in the course of an interim/futility analysis.  Data management and 
clean up will be done on blinded data sets. 
 
8.1.1 Major Protocol Deviations: 
1. Thymoglobulin Major Protocol Deviation (Groups B and C): Any patient who receives less than 4mg/kg total 
cumulative thymoglobulin dose for induction. 
2. Alemtuzumab Major Protocol Deviation (Group A): Any patient who receives less than 1 dose of alemtuzumab 
for induction. 
3. Belatacept Major Protocol Deviation (Groups A and B):  Any patient who receives less than 16 doses of 
belatacept at 52 weeks (Month12) or received less than 29 doses of belatacept at End of study Week 104 (Month 
24).   
4. Tacrolimus Major Protocol Deviation (Group C): Any patient who has tacrolimus discontinued for > 7 consecutive 
days. 
5. Mycophenolate Mofetil/Mycophenolate Sodium EC Major Protocol Deviation (All Groups):  Any patient who has 
mycophenolate discontinued for greater than 2 consecutive weeks for reasons other than neutropenia, and 4 
consecutive weeks for any reason. 
6. Glucocorticoids Major Protocol Deviation (All Groups): Any patient who remains on glucocorticoid therapy for > 6 
consecutive weeks. 


 
 
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8. Other Maintenance Immunosuppression (All Groups):  Any patient who has the addition of any other 
maintenance immunosuppressive agent not defined in the protocol for > 4 weeks. 
 
8.2  Patient Demographics, Baseline Characteristics, and Patient Disposition 
Demographic and baseline characteristics of recipients will be summarized by means and standard deviations for 
continuous variables, and by the number and percent of patients for categorical variables. Summaries will be 
performed based on all subjects. 
 
The total number of patients screened and the number of patients who were not randomized will be tabulated by 
reason.  
 
The following descriptive statistics will be calculated by assigned treatment arm and total. Summary statistics (n, 
mean, median, standard deviation (SD), minimum, maximum) will be provided for continuous variables and the 
number and percent of patients for categorical variables.  
 
• 
Patient disposition analysis will include the following for each of the three treatment groups: # Enrolled, # 
Randomized, # Transplanted, # Evaluable, # Not meeting eligibility criteria, # Not receiving study drug 
(belatacept or tacrolimus), # Lost to follow-up, # Withdrawing consent, # Discontinuing study and by reason for 
discontinuation, and # Completing study. 
• 
Protocol Deviations (minor and major) 
• 
Transplant background information: 
o 
Recipient demographics: age, gender, predominant race (African American, Asian, Caucasian, Native 
American, Pacific Islander, other), screening height and weight, and BMI. 
o 
Donor source (living related, living unrelated, deceased).  
o 
Recipient background information: end stage disease leading to transplantation, current dialysis, PRA 
(most recent evaluation, peak evaluation), primary or repeat transplant, PRA evaluation category (0-10%, 
10-25%, 25-50%, 50-75%, >75%), number of HLA mismatches at loci A, B, DR, and DQ, cold ischemia 
time (CIT) (deceased donors only).  
o 
Recipient and donor viral serology for: EBV, CMV, HCV, HBsAg, and HIV (negative, positive, not done, 
missing). 
o 
Medical histories 
 
8.3. Treatments 
The following variables will be analyzed by treatment arm at 12 and 24 months.  For continuous variables an 
Analysis of Variance (ANOVA) will be performed with terms for treatment and investigative site.   For time-to-event 
variables, the Kaplan Meier (KM) curves will be estimated and the Log-Rank test performed with site as a 
stratification variable will be performed.   For categorical variables, a Cochran-Mantel_Haenzel (CMH) test will be 
performed with site as the stratification variable.  If the cell sizes are sparse, a Fisher’s Exact test will be used.  The 
Hochberg (for KM, CMH) or Tukey-HSD (for ANOVA) adjustment will be used for each endpoint to control the alpha 
level at 5% for comparing the three treatment groups.  
• 
duration (days) of exposure to PP study regimen  
• 
% of patients with dose adjustments of MMF/EC MPA 
• 
Reasons for dose adjustments of MMF/EC MPA will be summarized 
• 
% of patients with discontinuation of belatacept in Groups A and B 
• 
% of patients with discontinuation of tacrolimus in Group C 
• 
% of patients with discontinuation of MMF/EC MPA 
• 
% of patients on chronic glucocorticoids 
• 
Mean MMF/EC MPA dose 
• 
Mean tacrolimus dose 
• 
Mean tacrolimus level 
• 
% of patients on belatacept  
• 
% of patients on tacrolimus 


 
 
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• 
Mean daily body weight-adjusted maintenance prednisone equivalent dosages [mg/kg/d]: steroids taken p.o. or 
administered IV or i.m. for the prophylaxis of rejections will be included.  Steroids administered after the 
discontinuation of randomized study medication or administered for treatment of rejection will not be included.  
Inhaled, intra-nasal, and topically administered corticosteroids will not be included. 
 
Prior medications will be defined as drugs taken prior to first dose of study regimen.  Any medication given at least 
once during the period on study regimen is a concomitant medication, including those which start prior to first dose 
of study regimen and continued into the treatment period.  Any medication started after the discontinuation of study 
regimen is not considered a concomitant medication. 
 
 
8.4 Primary Endpoint Analysis 
 
The primary efficacy endpoint is the 12 month incidence of patient death or graft loss or eGFR < 45 mL/min 
(MDRD).     
 
8.4.1 Statistical model, hypothesis, and method of analysis 
 
Time to event analyses will be performed using the Kaplan-Meier estimates and the Log Rank test with site as a 
stratification variable.  To control the overall alpha level at 5% for the two primary comparisons, the Hochberg 
adjustment will be used.  To evaluate the consistency of results for each of the subgroups listed below, a Cox-
Proportional-Hazards model will be performed for each subgroup variable separately.   
The primary endpoint will also be assessed for each study group with the following subgroups: 
o 
African Americans versus Non-African Americans 
o 
Living donors versus Deceased donors 
o 
Male versus female 
o 
Primary transplant versus repeat transplant 
o 
Delayed graft function versus no delayed graft function 
o 
HLA DR mismatch = 0 versus HLA DR mismatch > 0 
o 
HLA DQ mismatch = 0 versus HLA DQ mismatch > 0 
 
The following analysis plan will be performed for the secondary and tertiary endpoints.  For continuous variables an 
Analysis of Variance (ANOVA) will be performed with terms for treatment and investigative site.  For continuous 
variables that are analyzed across all time points, a repeated measures ANOVA will be performed with terms for 
treatment, month, site, treatment by month interaction.  If the interaction term is not significant at the 5% level, it will 
be removed from the model.   For time-to-event variables, the Kaplan Meier (KM) estimates and the Log Rank test 
with site as a stratification variable will be performed.   For categorical variables, a Cochran-Mantel_Haenzel (CMH) 
test will be performed with site as the stratification variable.  If the cell sizes are sparse, a Fisher’s Exact test will be 
used.  The Hochberg (for KM, CMH) or Tukey-HSD (for ANOVA) adjustment will be used for each endpoint to 
control the alpha level at 5% for comparing the three treatment groups. 
In the event that one active treatment arm is discontinued, a blocking factor will be added to all statistical models 
indicating the patients who were enrolled when all treatment arms were enrolling versus when only two treatment 
arms were being enrolled.   To evaluate the consistency of the treatment effect across the blocking factor, the 
treatment by block interaction will be tested for all statistical models. 
 
 
 
8.4.2 Handling of missing values/censoring/discontinuations 
The ‘all events analysis’ using a Kaplan-Meier method considers a patient censored if the patient has no event and 
does not provide information up to the analysis time point x (e.g. x=Day 365 for the Month 12 analysis).  The 
censoring day will be equal to the day of last study contact.  Day of last study contact will be the last visit date in the 


 
 
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x-month database, whichever is earlier. The number of patients at risk at analysis time point x will include all 
patients who completed the study visit associated with time point x (e.g. Month 12) no earlier than x - 2 weeks. 
 
For eGFR, missing values or censoring for death or graft loss will be imputed.  Patients with missing eGFR values 
due to death or graft loss will have their eGFR values imputed as 0, and a last observation carried forward 
imputation will be utilized for other missing values, except if the last eGFR measurement was before an acute 
rejection episode. 
 
Sensitivity analyses will be performed to examine the robustness of the results to the missing data.    The primary 
efficacy endpoint is the 12 month incidence of patient death or graft loss or eGFR < 45 mL/min.   Kaplan-Meier 
estimates and the Log-Rank test will be used to test for differences between groups for the primary endpoint.   For 
patients who are lost to follow-up prior to the 12 month time point, their time-to-event will be censored at the last 
date for which patient status can be determined.   As a sensitivity analysis, the status of the patient will be set to 
“failure” at the date of the last contact with the patient.     Another sensitivity analysis will use multiple imputation 
techniques as discussed in Rubin (Rubin DB.  Multiple imputation for nonresponse in surveys.  New York:  Wiley; 
1987) and Schafer(Schafer JL.  Analysis of Incomplete Multivariate Data.  New York:  Chapman and Hall;  1997.) if 
the patient’s eGFR value is the only unknown component of the primary endpoint.   
 
8.5 Secondary Endpoint Analyses 
The primary efficacy variable will be analyzed as described in the primary objective at Month 24 as a secondary 
endpoint.  
The following actual rates for each secondary efficacy variable will be analyzed at Months 6, 12, and 24 as 
described above: Banff 2007 BPAR (stratified by type: BPAMR, BPACR, and BPMAR) 
• 
Composite endpoint at 6 and 24 months  
• 
Incidence by Banff 2007 criteria of biopsy proven acute rejection (BPAR) stratified by type (ACR, AMR, or 
Mixed rejection) 
• 
Death Censored Graft Survival 
• 
Proportion of patients with eGFR (MDRD) < 30 mL/min 
• 
Proportion of patients developing DSA after transplantation  
 
8.6 Tertiary Endpoint Analyses 
The following efficacy parameters (tertiary endpoints) for each treatment group will be analyzed as described 
above: 
 
• 
BPAR 2a or greater 
• 
Steroid-resistant BPACR 
• 
BPAMR or BPMAR 
• 
Biopsy-proven chronic rejection 
• 
Treatment of all acute rejection episodes (Proportion of patients in each assigned treatment group receiving 
treatment with the following: A) Steroids alone, B) Anti-lymphocyte agents (rabbit antithymocyte globulin, horse 
antilymphocyte globulin, or alemtuzumab), and C) IVIG and/or plasmapheresis and/or bortezomib and /or 
rituximab 
• 
Mean individual component Banff scores at time of BPAR 
• 
Mean composite Banff scores at time of BPAR 
• 
Causes of patient death will be summarized 
• 
Causes of graft loss will be summarized 
• 
Severity of acute rejection episodes using the Banff 2007 grading 
• 
Incidence of leucopenia (WBC < 2000/mm3) 
• 
Incidence of anemia (Hg < 7 g/dL) 
• 
Incidence of proteinuria (elevated protein/creatinine ratio >0.8 grams protein per gram creatinine) 


 
 
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• 
Incidence of infections 
• 
Incidence of post-transplant lymphoproliferative disorder (PTLD)  
• 
Incidence of non-PTLD malignancy 
• 
Proportion of patients in each group remaining glucocorticoid-free 
• 
Patient quality of life changes from baseline will be summarized 
• 
Metabolic and Cardiovascular comorbidities will be analyzed as follows: 
• 
Freedom from Cardiovascular events (myocardial infarction, angina, CVA, TIA, cardiovascular 
intervention/procedure, or sudden death) analyzed. 
• 
NODAT (defined as any one of the following: 1) New requirement for therapy with insulin for > 30 days OR 
2) New use of oral hypoglycemic agents for ≥ 30 days OR 3) Any treatment (oral or insulin or other) 
for  ≥ 30 days OR 4) FBG > 126 mg/dL x 2 consecutive values OR 5) HgAIC ≥ 6.5%) 
NODAT will be analyzed multiple ways.  Each definition will be analyzed for incidence and prevalence.  
Kaplan Meier survival analysis will be used to determine overall NODAT-free per treatment group.  NODAT 
will be analyzed for each treatment group and will be summarized descriptively by frequency distribution for 
categorical variables (Y/N).  Change in HgA1c and FBG from baseline will also be compared between each 
study group.  We will also describe the following per treatment group: 1)% patients on treatment at each 
study visit, 2)% of patients with NODAT at any time point, % patients on treatment at 6, 12, and 24 months  
Exacerbation of Preexisting Diabetes will be analyzed by evaluating changes from baseline in oral and 
insulin agents, changes in total # units of insulin, and change from baseline in FBG, and HgA1c at 6, 12 
and 24 months. 
• 
Treatment of hyperlipidemia (Changes in number and type of agents) 
• 
Treatment of hypertension (Change in number of agents) 
• 
Determine the earliest reliable time-point that can be used for prediction of future onset of acute rejection and 
NODAT 
 
In addition, the following metabolic and cardiovascular endpoints will be analyzed using the repeated measures 
ANOVA as described above: 
• 
Change in SBP from baseline 
• 
Change in DBP from baseline 
• 
Change in total cholesterol from baseline 
• 
Change in LDL from baseline 
• 
Change in HDL from baseline 
• 
Change in Non-LDL from baseline 
• 
Change in Triglycerides from baseline 
• 
Change in weight from baseline 
• 
Change in BMI from baseline 
• 
Change in Framingham Risk Score from baseline 
 
8.7 Outcome analysis 
To evaluate the association between each of the following endpoints and the factors listed below, a logistic 
regression analysis will be performed.    
 
1. Any BPAR  
 
2. Early BPAR (within 6 months) 
 
3. Late BPAR (> 6 months) 
 
4. eGFR < 45 mL/min 
 
5. Death-Censored Graft Loss 
 
6. NODAT 
 
7. Denovo DSA 
 
The factors that may be included, but are not limited to are:  age, race (African American versus non-African 
American), gender (male versus female), donor type (living donor versus deceased donor), treatment assignment 
(Group A versus Group B versus Group C), DGF, DSA, cPRA, PRA, DR mismatch >0, DQ mismatch > 0 and 
repeat transplant. 


 
 
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8.8 Safety Analysis 
All Safety analyses will be performed at 6, 12, and 24 months. 
 
All protocol defined AEs and SAEs will be summarized by treatment group. Select laboratory marked abnormalities 
of interest will also be descriptively summarized. 
 
The safety analysis set will consist of all patients who received at least one dose of belatacept in Groups A and B 
and at least one dose of tacrolimus in Group C. Patients will be analyzed according to the treatment they have 
received.  
Renal function 
The following variables will be analyzed by Fisher’s Exact test.: 
• 
eGFR by MDRD Equation by each study group at 6, 12, and 24 months. 
• 
In patients with and without BPAR (BPAR yes or no) in each of the following groups: 
• 
% of patients with eGFR < 15 mL/min  
• 
% of patients with eGFR 16-29 mL/min 
• 
% of patients with eGFR 30-59 mL/min 
• 
% of patients with eGFR ≥ 60 mL/min  
Adverse events/infections 
The incidence of the following endpoints will be summarized: 
• 
AEs related and expected to immunosuppression by treatment group  
• 
AEs related and unexpected to immunosuppression by treatment group 
• 
SAEs by treatment group 
• 
SAEs rated to have relationship to study drug by treatment group 
• 
Deaths by treatment group 
• 
AEs leading to discontinuation of a study drug by treatment group 
• 
AEs leading to dose adjustment or interruptions of a study drug by treatment group 
• 
Infections by type of infection (viral, bacterial, fungal, and others) 
• 
Serious infections resulting in hospitalization by type of infection 
• 
DGF, OA, NOA, or DCC 
BK-polyoma viremia and nephropathy  
The following variables will be analyzed by Fisher’s Exact test: 
• 
occurrence of BK-polyoma viremia any time post-transplantation 
• 
occurrence of BK-polyoma virus nephropathy any time post-transplantation 
 
EBV or CMV Viremia or Disease  
The following variables will be analyzed by Fisher’s Exact test: 
• 
occurrence of CMV or EBV viremia any time post-transplantation 
• 
occurrence of CMV or EBV disease any time post-transplantation 
 
 
PLTD or Malignancies 
The following variables will be analyzed by Fisher’s Exact test: 
• 
occurrence of PTLD 
• 
occurrence of CNS PTLD 
• 
occurrence of non-PTLD malignancy 
 


 
 
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8.9 Sample Size Calculation 
  
  
Based on the efficacy failure rates seen in belatacept published literature (33, 35), the rate of efficacy failure of the 
control regimen is assumed to be 50% at month 12 in the control arm Group C, we predict an improvement of 21% 
or more between that group and the test groups (Groups A and B). 
 
The primary endpoint for this trial is the percentage of patients in each treatment group that meet the composite endpoint at 
12 months as defined as patient death or graft loss or estimated GFR < 45 mL/min.   It is assumed that the percentage of 
patients in the Control Group (i.e. Thymo/FK/MMF/CSWD) meeting the primary endpoint is 50%.  Each of the test groups 
will be tested against the control group using Kaplan Meier estimates and the Log Rank test.  To control the overall 
experiment-wise error rate at 5%, the Hochberg method for multiple comparisons will be used.  In this procedure, the p-
values for the two comparisons will be ordered from largest to smallest.  If the largest p-value is less than α=0.05, then both 
comparisons can be tested at α=0.05.  If the largest p-value is greater than α=0.05, then we cannot reject the null 
hypothesis for that comparison.  We then compare the second largest p-value to α=0.025 and reject the null hypothesis if 
the p-value is less than α=0.025.   A sample size of 105 completed patients per group will provide at least 80% power to 
detect an absolute difference of 21% between two groups at the two-sided α=0.025 if the percentage of patients meeting 
the primary endpoint in the control group is assumed to be 50%.    
 


 
 
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9.  ADMINISTRATIVE REQUIREMENTS 
9.1  Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization (ICH) for Good 
Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The investigator will be thoroughly familiar 
with the appropriate use of the drug as described in the protocol and Investigator’s Brochure/package insert.  
Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.   
9.2  Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki (Appendix 
VIII).  The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety and well-
being of the patients.  The study will only be conducted at sites where IRB/IEC approval has been obtained.  The 
protocol, Investigator’s Brochure/package insert, informed consent, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB/IEC by the investigator.   
 
9.3  Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the patient or his/her 
guardian or legal representative prior to study participation.  The method of obtaining and documenting the 
informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory 
requirement(s). 
9.4  Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study reports and 
communications will identify the patient by initials and the assigned patient number.  The investigator will grant 
monitor(s), auditors, and regulatory authorities access to the patient’s original medical records for verification of 
data gathered on the data capture records and to audit the data collection process.  The patient’s confidentiality will 
be maintained and will not be made publicly available to the extent permitted by the applicable laws and 
regulations. 
9.5  Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable opinion by the 
IRB/IEC and the appropriate regulatory authorities.  Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable 
opinion of the IRB/IEC.   
Any departures from the protocol must be fully documented in the source documents.   
9.6  Drug Accountability 
Accountability for the drug at all study sites is the responsibility of the principal investigator.  The investigator will 
ensure that the drug is used only in accordance with this protocol.  Drug accountability records indicating the drug’s 
delivery date to the site (if applicable), inventory at the site (if applicable), use by each patient, and return or 
disposal of the drug (if applicable) will be maintained by the clinical site.  Accountability records will include dates, 
quantities, lot numbers, expiration dates (if applicable), and patient numbers.   
 
All material containing belatacept will be treated and disposed of as hazardous waste in accordance with governing 
regulations. 
9.7  Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided by the terminating party.   
 
Circumstances that may warrant termination include, but are not limited to: 
 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient complete and/or evaluable data 


 
 
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Should the study be closed prematurely, all study materials must be returned. 
9.8  Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory requirement(s).   
 
9.8  Internal Monitoring Plan 
The monitoring plan for investigator initiated studies is dictated by the investigator/sponsor.  All monitoring 
responsibility lies with the PI.  An internal monitor will be identified by the Transplant Clinical Research group at the 
University of Cincinnati.  The internal monitor will comply with the Transplant Clinical Research Groups standard 
operating procedures for selection and training of sites, pre qualification monitoring visit, site initiation visit, ongoing 
site visits at least every quarter, and close out monitoring visit.  Monitoring reports generated at each monitor’s visit 
will be reviewed by the PI and presented at the faculty meeting for review by all investigators and other clinical 
research team members at the University of Cincinnati.   
 
10.  Study progress and result dissemination proposal 
 
The following is the proposed abstract and publication strategy which reflects current targets, but may vary based 
upon FDA IND approval.  Study enrollment will begin with the availability of belatacept study drug on site pending 
all regulatory and contractual obligations have been met.  This calendar may be altered based upon study 
enrollment.  The final study report will be consistent with the publication of the two year data.  
 
October 2012 
  
 
Enrolling Patients, FPFV 
March 2015 
 
 
LPFV 
October 2014 
 
 
FPLV  
March 2017 
 
 
LPLV  
July 2017 
 
 
Database lock 
October 2017 
 
 
Final data analysis 
December 2017 
 
Two year data analysis abstract for AST and publication submission 
May 2018 
 
 
Two year data AST presentation 
Dec 2018 (annually to 5 year) 
Annual long-term data analysis for  
AST and International Abstract 
 
 


 
 
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III.  Bibliography   
 
1) 
Hrilick DE. Steroid-free immunosuppression in kidney transplantation: an editorial review. Am J 
Transplant.2002;2:19-24 
2) 
Woodle ES, Perdrizet G, Brunt EM, So SKS, Jendrisak MD, McCullough CS, Vehe KL, White HM, Peters 
MG, Marsh JW.  FK 506: Inhibition of humoral mechanisms of hepatic allograft rejection.  Transplantation, 
54: 377-381, 1992. 
3) 
Phelan DL, Thompson C, Henschell J, Miller L, Woodle ES, Pasque M.  Heart transplantation across 
preformed class I antibody using FK 506.  Human Immunology, 34: 70, 1992. 
4) 
Woodle ES, Marsh JW, Perdrizet GA, So SKS, Jendrisak MD, White HM.  FK 506 rescue therapy: Early 
conversion improves efficacy.  Transplantation Proceedings, 25: 1990-1991, 1993. 
5) 
Woodle ES, Phelan DL, Saffitz JE, Mohanakumar R, Shenoy S, Pasque M.  FK 506: Reversal of humorally-
mediated cardiac allograft rejection in the presence of preformed anti-class I antibody.  Transplantation, 56: 
1271-1275, 1993. 
6) 
Woodle ES, Perdrizet GA, So SKS, White HM, Marsh JW.  FK506 rescue therapy for hepatic allograft 
rejection: Experience with an aggressive approach.  Clinical Transplantation, 9: 45-52, 1995. 
7) 
Woodle ES, Spargo B, Ruebe M, Charette J.  Treatment of acute glomerular rejection with FK 506.  Clinical 
Transplantation, 10: 266-270, 1996. 
8) 
Woodle ES, Thistlethwaite JR, Gordon JH, for the Tacrolimus Kidney Transplant Rescue Study Group.  A 
multicenter trial of FK 506 (tacrolimus) therapy in refractory acute renal allograft rejection.  Transplantation, 
62: 594-599, 1996. 
9) 
Woodle ES, Newell KA, Haas M, Bartosh S, Josephson MA, Millis JM, Bruce DS, Piper JB, Aronson AJ, 
Thistlethwaite JR.  Reversal of accelerated renal allograft rejection with FK 506.  Clinical Transplantation, 11: 
251-254, 1997.  
10) 
Woodle ES, Bruce DS, Josephson M, Newell KA, Piper JB, Millis JM, Cronin D, Whitman G, Ruebe M, 
Thistlethwaite JR.  FK 506 therapy for refractory renal allograft rejection: lessons from liver transplantation.  
Clinical Transplantation, 10: 323-333, 1996. 
11) 
Jordan ML, Naraghi R, Shapiro R, Smith D, Vivas CA, Scantlebury VP, Gritsch HA, McCauley J, Randhawa 
P, Demetris AJ, McMichael J, Fung JJ, Starzl TE.  Tacrolimus for rescue of refractory renal allograft 
rejection.  Transplantation Proceedings. 1998 Jun; 30(4):1257-60. 
12) 
Cronin DC, Bruce DS, Newell KA, Josephson MA, Millis JM, Piper JB, Ruebe M, Kirby M, Thistlethwaite JR, 
Woodle ES.  Tacrolimus therapy for refractory renal allograft rejection: Experience with steroid withdrawal.  
Transplantation Proceedings, 29: 307, 1997. 
13) 
Hricik DE, Whalen CC, Lautman J, Bartucci MR, Moir EJ, Mayes JT, Schulak JA.  Withdrawal of steroids 
after renal transplantation--clinical predictors of outcome.  Transplantation. 1992 Jan; 53(1):41-5.  
14) 
Grewal HP, Thistlethwaite JR, Loss GE, Bruce DS, Siegel CT, Cronin DC, Newell KA, Millis JM, Woodle ES.  
Glucocorticoid cessation 1 week following renal transplantation using tacrolimus/mycophenolate mofetil-
based immunosuppression.  Transplantation Proceedings, 30: 1378-1379, 1998. 
15) 
Buell JF, Kulkarni S, Grewal HP, Kopelan A, Yoshida A, Swanson A, Cronin DC, Bruce DS, Newell KA, 
Thistlethwaite JR, Woodle ES.  Early glucocorticoid cessation at one week following kidney transplant under 
tacrolimus and mycophenolate mofetil (MYCOPHENOLATE MOFETIL) immunosuppression, three year 
follow-up.  Transplantation 69: S134, 2000 (abstract). 
16) 
Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning 
grafts. The Canadian Multicentre Transplant Study Group.  CMAJ 1992 Sep 1; 147(5):645-57. 
17) 
Alexander JW, Stanley LL, Ofstedal TL, First MR, Cardi MA, Safdar S, Mendoza NC, Munda R, Fidler JP, 
Buell JF, Hanaway MJ, Woodle ES.  Transplantation without steroids.  Transplantation Proceedings, 34 (6): 
2076-2078, 2002. 
18) 
Alexander JW, Metze TJ, Goodman HR, Cardi M, Austin J, Goel S, Safdar S, Huang S, Munda R, Fidler J, 
Buell JF, Hanaway MJ, Susskind B, Greenburg N, Trofe J, Alloway RR, Woodle ES.  Simultaneous 
glucocorticoid and calcineurin inhibitor minimization.  Transplantation International, 19 (4): 295-302, 2006. 
19) 
Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P; Astellas Glucocorticoid Withdrawal 
Study Group.  A prospective, randomized, double-blind placebo-controlled multicenter trial comparing early 
(7 day) glucocorticoid cessation versus long-term, low-dose glucocorticoid therapy. Ann Surg. 2008 Oct; 
248(4):564-77. 
20) 
Woodle ES, Vincenti F, Lorber M, Gritsch A, Hricik D, Washburn K, Matas A, Gallichio M, Neylan J.  A 
multicenter pilot study of early (4 day) steroid cessation in renal transplant recipients under Simulect, 
tacrolimus, and sirolimus therapy.  Am J Transplantation, 4: 1-10, 2004. 
21) 
Woodle ES, the TRIMS Study Group.  A randomized, prospective, multicenter comparative study evaluating 
a rabbit antithymocyte globulin-based early glucocorticoid cessation regimen in renal transplantation.  
(TRIMS).  Am J Transplantation, 6(Supp 8): 294, 2006 (abstract).  


 
 
78 | P a g e  
Amendment 8 5/20/2015 
22) 
Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi R, Harrison G, Vandeputte K, Fitzsimmons W, First R, 
Holman J.  Six month results of a multicenter, randomized trial comparing three induction agents 
(alemtuzumab, rabbit antithymocyte globulin and basiliximab) with tacrolimus, mycophenolate mofetil and a 
rapid steroid withdrawal in renal transplantation.  American Transplant Congress 2008 abstract, Am J 
Transplantation, in press. 
23) 
Woodle ES, Alloway RR, Succop P, Thomas M, Buell J, Tevar A, Munda R, Roy-Chaudhury P, Cardi M, 
Trofe J.  Multivariate analysis of risk factors for acute rejection in early glucocorticoid cessation regimens 
under modern immunosuppression.  Am J Transplantation, 5 (11): 2740-4, 2005 
24) 
United Network for Organ Sharing Renal Transplant Registry 1997-2004. Available at 
http://optn.transplant.hrsa.gov/latestData/rptStrat. 
25) 
Paul LC. Chronic allograft nephropathy. a model of impaired repair from injury? Nephrol Dial Transplant. 
2000;15:149-151. 
26) 
Investigator Brochure. Belatacept (BMS-2224818), Version 13.  Bristol-Myers Squibb Research and 
Development Department. 15 December 2010. 
27) 
 (IM103008 CSR). Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression 
Trial (BENEFIT). Bristol-Myers Squibb Company, Mar-2009. Document Control No. 930034309 and 
IM103008 CSR Addendum up to 36 Months. Belatacept Evaluation of Nephroprotection and Efficacy as 
First-line Immunosuppression Trial (BENEFIT). Bristol-Myers Squibb Company, 2010. Document Control No. 
930044447. 
28) 
 (IM103027 CSR). Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression 
Trial - EXTended criteria donors (BENEFIT-EXT). Bristol-Myers Squibb Company, Mar-2009. Document 
Control No. 930030657 and IM103027 CSR Addendum up to 36 Months. Belatacept Evaluation of 
Nephroprotection and Efficacy as First-line Immunosuppression Trial - EXTended criteria donors (BENEFIT-
EXT). Bristol-Myers Squibb Company, 2010. Document Control No. 930046091. 
29) 
 (IM103100 CSR). Open-label, Randomized, Controlled, Multiple-dose Study of Efficacy and Safety of BMS-
224818 as Part of a Quadruple Drug Regimen in Renal Transplant Recipients (12-month analysis). Bristol-
Myers Squibb Company, 2008. Document Control No. 930016865 and IM103100 Interim CSR Long Term 
Extension. Open-label, Randomized, Controlled, Multiple-dose Study of Efficacy and Safety of BMS-224818 
as Part of a Quadruple Drug Regimen in Renal Transplant Recipients. Bristol-Myers Squibb Company, 2008. 
Doc. Control No. 930930028885. 
30) 
 (IM103045 CSR) Evaluation of Belatacept as First-line Immunosuppression in De Novo Liver Transplant 
Recipients. Bristol-Myers Squibb Research and Development; 2006. Document Control No. 930047562.  
31) 
U.S. Prescribing information for Nulojix® (belatacept), Revised 06/2011. Bristol-Myers Squibb.  
32) 
BMS CT DIR GB: 001 18 Jan 2012. 
33) 
F. Vincenti, B. Charpentier, Y. Vanrenterghem, L. Rostaing, B. Bresnahan, P. Darji, P. Massari, G. A 
Mondragon-Ramirez, M. Agarwal, G. Di Russo, C.-S. Lin, P. Garg, C. P. Larsen.   A Phase III Study of 
Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients 
(BENEFIT Study) Am J Transplantation 2010; 10 (3): 535-546. 
34) 
A. Durrbach, J. M. Pestana, T. Pearson, F. Vincenti, V. D. Garcia, J. Campistol, M. del Carmen Rial, S. 
Florman, A. Block, G. Di Russo, J. Xing, P. Garg, J. Grinyó A Phase III Study of Belatacept Versus 
Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT-EXT Study).  Am J 
Transplantation 2010; 10(3):547-557. 
35) 
R Ferguson, J Grinyo, F Vincenti, DB Kaufman, ES Woodle, BA Marder, F Citterio, WH Marks, M Agarwal, D 
Wu, Y. Dong, P Garg.  Immunosuppression with Belatacept-Based, Corticosteroid Avoiding Regimens in De 
Novo Kidney Transplant Recipients.  Am J Transplantation 2011;11:66-76. 
36) 
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in 
Adults (Adult Treatment Panel III) Full Report. JAMA. 2001;285:2486-2497. 
37) 
Chobanian AV, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252. 
38) 
Wilson, PW, et. al. Prediction of Coronary Heart Disease Using Risk Factor Categories. Circulation 1998 97 
(18): 1837-1847. 
39) 
F. Vincenti, C. P. Larsen, J Alberu, B. Bresnahan, VD Garcia, J Kothari, P Lang, E Mancilla Urrea, P 
Massari, G Mondragon-Ramirez, R Reyes-Acevedo, K Rice, L Rostaing, S Steinberg, J Xing, M Agarwal, M 
Harler, B Charpentier.  Three year Outcomes from Benefit, a Randomized, Active Controlled, Parallel-Group 
study in Adult Kidney Transplant Recipients.  Am J Transplantation 2012 Jan;12(1):210-7. 
 


 
 
79 | P a g e  
Amendment 8 5/20/2015 
IV. Appendixes 
Appendix I:  Laboratory and Clinical Assessment Flowchart 
 
Baseline 
Pretxp 
(within 10 
days of txp, 
unless 
indicated 
otherwise) 
Day of 
Trans
plant 
Study Visits 
Time post Transplant [Day (D), Week (W), Month (M)] 
D 1 
D
7 
W
2 
W
4 
W
8 
W 
12 
M3 
W24 
M6 
W
36 
M9 
W
52 
M 
12 
W
64 
M 
15 
W 
80 
M 
18 
W 
92 
M21 
W 
104 
M24 
Study windows 
 
 
±
1 
±
2 
±2 
±3 
±3 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Crossmatch, Tissue 
Typing,  PRA2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serologies4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Chemistries5 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology6 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tacrolimus Trough 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Fasting Lipids7 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Spot Urine 
Protein/Creatnine8 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
HgA1c9 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Pregnancy Test10 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
DSA and ELISA 
assessment11 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
X 
QPCR assessment12 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
 
X 
Renal Biopsy13 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FRS Score 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
QoL/Side Effect 
Assessments 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical 
Assessments14 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
1. Randomization will occur within 72 hours of transplant.  
2. Screening tests/procedures can be completed within 30 days of transplant.  PRA just needs to be the most recent PRA, not necessarily within 30 days. 
3. Vital signs include BP, weight, and height (including BMI) at baseline visit.  BP and weight only at subsequent visits. 
4. Serologies for CMV, Epstein-Barr, hepatitis B & C and HIV for donor and recipient done at any previous evaluation within one year will be accepted for eligibility criteria as long as it is 
documented. 
5. Serum chemistries must include serum creatinine (Scr), albumin (Alb), blood urea nitrogen (BUN), and fasting blood glucose (FBG) with an eGFR (MDRD) assessment. 
6. Hematology includes WBC, Hgb, and platelet count (PLT). 
7. Subjects must be fasting. Lipid testing include total cholesterol, LDL, HDL, triglycerides. 
8. Urinalysis for spot urine protein creatinine ratio. 
9. HgAIc is needed in ALL patients.   This will be used to help assess NODAT and exacerbation of diabetes. 
10. Urine or serum pregnancy tests in women of child bearing potential will be required prior to belatacept infusions at visits on months 3, 6, 9, 12, 15, 18, 21, and 24.     
11.  Anti-donor HLA antibodies (DSA) and ELISA assessment (10ml red top) - additional blood samples are to be obtained at the time of any suspected rejection episode(s).   
12.  QPCR assessment of acute rejection signature (2.5ml Paxgene tube) – additional blood samples are to be obtained at the time of any suspected rejection episode(s) 
13. There are no protocol biopsies.  Implant biopsy will be performed as standard of care.   
14.  Includes assessments of sitting blood pressure (BP), # BP meds and type, weight changes, BMI, smoking, adverse events, CV events, study drug doses, allograft rejection, infection or 
malignancy, insulin or oral anti-diabetic agents, anti-lipid agents, aspirin, need for dialysis, hospitalization, re-transplant status, and other immunosuppressant medications. 


 
 
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Amendment 8 5/20/2015 
Appendix II: Study Immunosuppressant Treatment Table 
 
 
Belatacept 
(Groups A&B) 
Tacrolimus 
(Group C) 
Induction 
(Group A) 
Induction 
(Groups B&C)  
Steroids  
(All Groups)  
Mycophenolate 
mofetil/EC 
Mycophenolate 
Sodium  
(All Groups) 
 
10 
mg/kg 
5 
mg/kg 
0.1mg/kg/day 
p.o. divided 
twice daily 
Alemtuzumab 
30mg IV 
Rabbit 
antithymocyte 
globulin 
1.5mg/kg IV 
 
 
Day of 
Transplant  
(D1) 
X1 
 
Start 
tacrolimus 
when Scr < 4 
mg/dL or 
within 48 
hours of 
transplant 
 
Goal 
tacrolimus 
trough 8-12 
ng/mL until 
day 30 
X 
X 
Methylpred 
500mg IV 
Introduce 
Mycophenolate 
mofetil/EC 
Mycophenolate 
Sodium on D1  
pre-op.  
  
Mycophenolate 
mofetil 1g p.o. BID 
(EC Mycophenolate 
Sodium 720mg p.o. 
BID).   
 
African 
American recipients 
may receive 
Mycophenolate 
mofetil 1.5 g p.o. 
BID (EC 
Mycophenolate 
Sodium 1080mg p.o. 
BID).   
 
Dose adjustments 
can be made based 
on MD discretion  
D2 
 
 
Subsequent 
thymo doses 
should be 
given so that 
total 
cumulative 
dose of 4-6 
mg/kg is given 
by days 5-10 
Methylpred 
250mg IV 
D3 
 
 
 
Methylpred 
125mg IV 
D4 
 
 
 
Prednisone 
80mg p.o. 
D5 
X2 
 
 
Prednisone 
60mg p.o. 
D6 
 
 
 
No further 
steroids 
D7 
 
 
 
 
D8 
 
 
 
 
D9 
 
 
 
 
D 10 
 
 
 
 
W2 (D14) 
X 
 
 
 
 
D15-D 20 
 
 
 
 
 
D 21-D27 
 
 
 
 
 
W4 (D 28) 
X 
 
 
 
 
W8 (D 56) 
X 
 
Goal 
tacrolimus 
trough 5-10 
ng/mL 
thereafter 
 
 
 
 
W12 ( M 3) 
X 
 
 
 
W16 
 
X 
 
 
W20 
 
X 
 
 
W24 (M 6) 
 
X 
 
 
W28 
 
X 
 
 
W32 
 
X 
 
 
W36 (M 9) 
 
X 
 
 
W40 
 
X 
 
 
W44 
 
X 
 
 
W48 
 
X 
 
 
W52 (M12) 
 
X 
 
 
W56 
 
X 
 
 
W60 
 
X 
 
 
W64 (M 15) 
 
X 
 
 
W68  
 
X 
 
 
W72 
 
X 
 
 
W76 
 
X 
 
 
W80 (M18) 
 
X 
 
 
W84 
 
X 
 
 
W88 
 
X 
 
 
W92 (M21) 
 
X 
 
 
W96 
 
X 
 
 
W100 
 
X 
 
 
W104 (M24) 
 
X 
 
 
1. Initial Belatacept dose will be administered within 12-24 hours post reperfusion. 
 
2. Belatacept dose is to be given once between Study days 5 – 7, with intention of administering as an outpatient.    
 


 
 
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Amendment 8 5/20/2015 
Appendix III: Recommended Treatment of Rejection 
 
BPACR Banff Grade 1a-1bTreatment 
 
Continue current regimen of belatacept or tacrolimus, Solumedrol 7mg/kg (Max 500mg) IV daily X 3 days.  If 
improving trend in Scr, then initiate oral Prednisone recycle (Prednisone 200mg X 1, Prednisone 160mg X 1, 
Prednisone 120mg X 1, Prednisone 80mg X 1, Prednisone 40mg X 1, Prednisone 20mg X 1, Prednisone 10mg X 
1, then discontinue steroids). If no improving trend in Scr after 3-5 days of treatment initiation, then repeat biopsy.  
If Banff grade is the same or worse, then initiate or increase tacrolimus to a goal trough of 10-15 ng/mL or initiate 
rabbit antithymocyte globulin for 7-14 days of CD3 suppression.  If Banff grade is improving or minimal persistent 
rejection, continue oral prednisone recycle. 
 
The following schematic is a guideline for the treatment of Banff 2007 Grade 1a or 1b acute rejections 
 
 
Banff Grade  
1a or 1b 
Continue current 
maintenance IS regimen 
 
Solumedrol 7mg/kg 
(Max 500mg) IV daily X 
3 days and begin oral 
steroid taper. 
Improving trend in 
Serum creatinine 
Oral Prednisone 
Recycle: 
-Prednisone 200mg X 1 
-Prednisone 160mg X 1 
-Prednisone 120mg X 1 
-Prednisone 80mg X 1 
-Prednisone 40mg X 1 
-Prednisone 20mg X 1 
-Prednisone 10mg X 1 
-Discontinue steroids 
No or minimal improvement of 
serum creatinine within 3-5 
days of initiating treatment 
Repeat  
Biopsy 
Initiate or increase 
tacrolimus dose to a goal 
trough 10-15 ng/mL  
 
or  
 
Start antithymocyte 
globulin for 7-14 days of 
CD3 suppression 
If improving or minimal 
persistent rejection 
If same or greater grade 
of rejection persists 
Continue Oral 
Prednisone Recycle: 
-Prednisone 200mg X 1 
-Prednisone 160mg X 1 
-Prednisone 120mg X 1 
-Prednisone 80mg X 1 
-Prednisone 40mg X 1 
-Prednisone 20mg X 1 
-Prednisone 10mg X 1 
-Discontinue steroids 


 
 
82 | P a g e  
Amendment 8 5/20/2015 
 
6.3.2.3.2  Recommended BPACR Banff Grade >2a Treatment 
 
Continue current regimen of belatacept or tacrolimus, initiate antithymocyte globulin for 7-14 days of CD3 
suppression.  If no improving trend in Scr after 7 days of treatment initiation, then repeat biopsy.  If Banff grade is 
the same or worse, continue antithymocyte globulin, initiate or increase tacrolimus therapy to a goal trough of 10-15 
ng/mL and initiate or add corticosteroid therapy.  If Banff grade is improving or minimal persistent rejection, 
continue antithymocyte globulin. 
 
The following schematic is a guideline for the treatment of Banff 2007 2a, 2b or 3 acute cellular rejections 
 
 
Banff Grade ≥ 2a 
-Continue current 
maintenance IS 
regimen 
 
- Antithymocyte 
globulin rejection 
treatment of 1.5mg/kg 
on Day 1 and Day 2 
followed by CD3 
monitoring.  Redose 
antithymocyte globulin 
when CD3>25 for a 
total of 7-14 days of 
CD3 suppression. 
Premedication per 
center protocol. 
Improving trend in 
serum creatinine 
-Observe 
 
-Continue 
antithymocyte 
globulin for 7-14 
days of CD3 
suppression. 
No or minimal improvement of 
serum creatinine within 7 days of 
initiating treatment 
 
Repeat 
Biopsy 
-Observe 
 
-Continue 
antithymocyte  
globulin for 7-14 days 
of CD3 suppression. 
-Continue antithymocyte 
globulin for 7-14 days of 
CD3 suppression. 
 
-Initiate or increase 
tacrolimus therapy to a 
goal trough of 10-15 
ng/mL 
 
-Initiate or add 
corticosteroids. 
Solumedrol 7mg/kg (Max 
500mg) IV daily X 3 days 
and begin oral steroid 
taper. 
If improving or minimal 
persistent rejection 
If same or greater grade 
of rejection persists 


 
 
83 | P a g e  
Amendment 8 5/20/2015 
6.3.2.3.3  Recommended BPAMR or BPMAR Treatment  
 
May treat BPAMR or BPMAR with a bortezomib-based or IVIG-based protocol.   
The following schematic is a guideline for the treatment of antibody mediated rejection and mixed rejection with 
bortezomib-based treatment with rituximab: 
 
Treatment Day 
PRE 
1 
4 
7 
10 
PLASMAPHERESIS 1.5 PV 
  
X 
X 
X 
X 
Methylprednisolone 100 mg IVP or PO 
  
X 
X 
  
  
Methylprednisolone 50 mg IVP or PO 
  
  
  
X 
X 
BORTEZOMIB 1.3 mg/m2 IVP or SC 
  
X 
X 
X 
X 
RITUXIMAB 375 mg/m2 IV 
  
X 
  
  
  
 


 
 
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Amendment 8 5/20/2015 
Appendix IV : Quality of Life/Side Effect Assessments 
 
The Memphis Survey 
SIDE EFFECTS BECAUSE OF TRANSPLANT MEDICINES 
 
The following questions describe problems you might be having because of the transplant or the 
medicine you are taking.  For each problem, you will be asked how frequently you experience it 
(the first row) and how troubling it is (the second row).  Please answer every question. 
 
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very 
troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Enlarged gums 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hunger 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Staying asleep 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Weight gain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Increased hair growth 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Infections 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Trembling hands 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
High blood pressure 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Easy bruising 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Loss of interest in sex 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Sexual performance 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Diabetes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


 
 
85 | P a g e  
Amendment 8 5/20/2015 
 
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very 
troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Hair Loss 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Stomach pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Nausea 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Diarrhea 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Vomiting 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stomach gas 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Indigestion 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Mood Changes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Depression 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Nervousness or anxiety 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Irritability 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Anger 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Keeping a positive attitude 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


 
 
86 | P a g e  
Amendment 8 5/20/2015 
 
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very 
troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Feelings of uselessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Being worried 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Worthlessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hopelessness 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to concentrate 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Completing daily errands 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in social activities 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Doing housework 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Doing yardwork 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Performing my job 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in physical activities 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Participating in leisure pastimes 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Driving 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 


 
 
 
87
 
Not  
at all 
Very  
little 
Sometimes 
or 
Moderately 
troubling 
Often 
or 
Very 
troubling 
All the time 
or 
Extremely 
troubling 
 
 
 
 
 
 
Being independent 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Ability to travel on vacations 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Reading 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 
Decreased muscle strength 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Climbing stairs 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Walking 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Bone pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Stiff joints 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Foot pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
Hip pain 
 
 
 
 
 
Do you have this problem? 
□ 
□ 
□ 
□ 
□ 
How troubling is it? 
□ 
□ 
□ 
□ 
□ 
 


 
 
 
88
THE MTSOSDS QUESTIONNAIRE 
 
MODIFIED TRANSPLANT SYMPTOM OCCURRENCE AND SYMPTOM DISTRESS SCALE 
 
Instructions 
Taking medication after transplantation is associated with certain side effects, which may 
or may not be distressing to you.  In this questionnaire, each question is divided into two columns, as shown 
in the example below. 
 
 
 
The left column asks about the occurrence of the side effects. Please indicate how 
frequently or how severely you have experienced a given symptom during the past 4 
weeks by checking off the appropriate answer. 
 
In the right column you will find questions asking you whether these symptoms are 
distressing to you. Please circle the number that corresponds with how distressing this 
symptom is to you. 
 
If a symptom does not occur, answer “never” or “not” in the left column and go 
directly to the next question. 
 
At the end of the questionnaire, you can add additional side effects that you may have 
experienced during the past 4 weeks. Please check if you have completed all items and 
all pages. Please also be sure that you have completed both the right and left column of 
the questionnaire. 
 
Developed to assess occurrence and distress experienced by the side effects of Cyclosporine, 
Tacrolimus, Mycophenolate Mofetil, Azathioprine, Prednisolone, Sirolimus, LEA29Y. 
Partly based on the Transplant Symptom Frequency and Symptom Distress Scale: Lough ME, 
Lindsey AM, Shinn JA, Stotts NA. Life satisfaction following heart transplantation. J Heart 
Transplantation 1985; 4: 446-449 & Lough ME, Lindsey AM, Shinn JA, Stotts NA. Impact of 
symptom frequency and symptom distress on self-reported quality of life in heart transplant 
recipients. Heart Lung 1987; 16: 193-200. 
 


 
 
 
89
During the past 4 weeks (including today): 
 
 


 
 
 
90
 
During the past 4 weeks (including today): 
 
 
 
 


 
 
 
91
 
During the past 4 weeks (including today): 
 


 
 
 
92
During the past 4 weeks (including today): 
 
 
 


 
 
 
93
 
 
During the past 4 weeks (including today): 
 


 
 
 
94
 
During the past 4 weeks (including today): 
 
 
 


 
 
 
95
 
During the past 4 weeks (including today): 
 
 
 


 
 
 
96
 
During the past 4 weeks (including today): 
 
 


 
 
 
97
 
During the past 4 weeks (including today): 
 
 
 


 
 
 
98
 
During the past 4 weeks (including today): 
 
 
 


 
 
 
99
 
During the past 4 weeks (including today): 
 
 


 
 
 
100
 
During the past 4 weeks (including today): 
 
 


 
 
 
101
 
During the past 4 weeks (including today): 
 
 
 
 


 
 
 
102
 
During the past 4 weeks (including today): 
 
 
 
 
 
Please check if you have completed all items and all pages. 
Please also be sure that you have completed both the right and left column of the 
questionnaire. 
 
THANK YOU VERY MUCH FOR YOUR COOPERATION 


 
 
 
103
Appendix V : National Cholesterol Education Panel, Adult Treatment Panel III36 
Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals  
• 
Cigarette smoking  
• 
Hypertension (BP ≥ 140/90 mmHg or on antihypertensive medication)  
• 
Low HDL cholesterol (<40 mg/dL)†  
• 
Family history of premature CHD  
o 
CHD in male first degree relative <55 years  
o 
CHD in female first degree relative <65 years  
• 
Age (men 45 years; women 55 years)  
† HDL cholesterol 60 mg/dL counts as "negative" risk factor; its presence removes one risk factor from the 
total count.  
 
Three Categories of Risk that Modify LDL-Cholesterol 
Goals Risk Category  
LDL Goal (mg/dL) 
CHD and CHD risk 
equivalents  
<100 
Multiple (2+) risk factors 
<130 
Zero to one risk factor 
<160 
 
ATP III Lipid and Lipoprotein Classification  
LDL Cholesterol (mg/dL)  
• 
<100 Optimal  
• 
100-129 Near optimal/above optimal  
• 
130-159 Borderline high  
• 
160-189 High  
• 
190 Very high 
 
HDL Cholesterol (mg/dL) 
• 
<40 Low  
• 
>60 High  
Total Cholesterol (mg/dL)  
• 
<200 Desirable  
• 
200-239 Borderline high  
• 
>240 High Primary 


 
 
 
104
 
LDL Cholesterol Goals and Cut points for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in 
Different Risk Categories  
Risk Category 
LDL Goal 
(mg/dL)  
LDL Level at Which to Initiate 
Therapeutic Lifestyle Changes 
(TLC) (mg/dL)  
LDL Level at Which to 
Consider Drug 
Therapy (mg/dL)  
CHD or CHD Risk 
Equivalents (10-year 
risk >20%) 
<100  
100  
130 (100–129: drug 
optional)  
2+ Risk Factors (10-
year risk 
20%) 
<130  
130  
10-year risk 10–20%: 
130  
 
10-year risk <10%: 
160  
0–1 Risk Factor  
<160  
160  
190 (160–189: LDL-
lowering drug optional)  
LDL Cholesterol Goal and Cut points for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in 
Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%)  
LDL Goal  
LDL Level at Which to Initiate Therapeutic 
Lifestyle Changes (TLC) 
LDL Level at Which to Consider 
Drug Therapy  
<100 
mg/dL  
100 mg/dL  
130 mg/dL (100–129 mg/dL: 
drug optional)  
LDL Cholesterol Goals and Cut points for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in 
Different Risk Categories  
Risk Category 
LDL Goal 
(mg/dL)  
LDL Level at Which to Initiate 
Therapeutic Lifestyle Changes 
(TLC) (mg/dL)  
LDL Level at Which to 
Consider Drug 
Therapy (mg/dL)  
CHD or CHD Risk 
Equivalents (10-year 
risk >20%) 
<100  
100  
130 (100–129: drug 
optional)  
2+ Risk Factors (10-
year risk 
20%) 
<130  
130  
10-year risk 10–20%: 
130  
 
10-year risk <10%: 
160  
0–1 Risk Factor  
<160  
160  
190 (160–189: LDL-
lowering drug optional)  
 


 
 
 
105
Appendix VI : JNC VII Guide to Prevention and treatment of Hypertension Recommendations37 
CVD Risk Factors 
• 
Hypertension*  
• 
Cigarette smoking  
• 
Obesity* (BMI 
30 kg/m2)  
• 
Physical inactivity  
• 
Dyslipidemia*  
• 
Diabetes mellitus*  
• 
Microalbuminuria or estimated GFR <60 ml/min  
• 
Age (older than 55 for men, 65 for women)  
• 
Family history of premature CVD (men under age 55 or women under age 65)  
*Components of the metabolic syndrome.  
Blood Pressure Classification 
BP Classification 
SBP mmHg  
  
DBP mmHg  
Normal  
<120  
and  
<80  
Prehypertension  
120–139  
or 
80–89  
Stage 1 Hypertension  
140–159  
or 
90–99  
Stage 2 Hypertension  
160 
or 
100 
 
Algorithm for Treatment of Hypertension  
  
  
  
  
Initial drug therapy  
BP classification  SBP* mmHg  DBP* mHg 
Lifestyle 
modification  
Without compelling 
indication  
With compelling 
indications 
Normal  
<120  
and <80  
Encourage  
 
  
Prehypertension  
120–139 
or 80–89  
Yes 
No antihypertensive drug 
indicated.  
Drug(s) for compelling 
indications.***  
Stage 1 
Hypertension  
140–159  
or 90–99  
Yes 
Thiazide-type diuretics for 
most. May consider ACEI, 
ARB, BB, CCB, or 
combination.  
Drug(s) for the 
compelling 
indications.***  
Other antihypertensive 
drugs (diuretics, ACEI, 
ARB, BB, CCB) as 
needed.  
Stage 2 
Hypertension  
160  
or 
100  
Yes 
Two-drug combination for 
most** (usually thiazide-
type diuretic and ACEI or 
ARB or BB or CCB).  
Drug(s) for the 
compelling 
indications.*** 
Other antihypertensive 
drugs (diuretics, ACEI, 
ARB, BB, CCB) as 
needed.  
*Treatment determined by highest BP category.  
**Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. 
***Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.  


 
 
 
106
Appendix VII : Framingham Heart Study Coronary Heart Disease Risk Score38 
 
Score Sheet for Males : 
 
 
 
 


 
 
 
107
Score Sheet for Females : 
 
 


 
 
 
108
Appendix VIII : World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, 
Republic of South Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects.  Medical research involving human subjects includes research on identifiable 
human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act only in the patient's interest when providing medical care which 
might have the effect of weakening the physical and mental condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international requirements.  
No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of 
the protections for human subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the 
human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and on adequate laboratory and, where appropriate, animal experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for consideration, 
comment, guidance, and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or any other kind of undue 


 
 
 
109
influence.  This independent committee should be in conformity with the laws and regulations of the 
country in which the research experiment is performed.  The committee has the right to monitor 
ongoing trials.  The researcher has the obligation to provide monitoring information to the committee, 
especially any serious adverse events.  The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest and incentives for subjects. 
5. The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that there is compliance with the principles enunciated in this Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject 
of the research, even though the subject has given consent. 
7. Every medical research project involving human subjects should be preceded by careful assessment 
of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others.  
This does not preclude the participation of healthy volunteers in medical research.  The design of all 
studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits or if there is conclusive proof of positive and beneficial results. 
9. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important when 
the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in which the 
research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimize the impact of the study on the subject's physical and mental integrity 
and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail.  
The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal.  After ensuring that the subject has understood 
the information, the physician should then obtain the subject's freely-given informed consent, 
preferably in writing.  If the consent cannot be obtained in writing, the non-written consent must be 
formally documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the investigation and who is completely independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of giving consent 
or is a legally incompetent minor, the investigator must obtain informed consent from the legally 
authorized representative in accordance with applicable law.  These groups should not be included 
in research unless the research is necessary to promote the health of the population represented 
and this research cannot instead be performed on legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population.  The specific reasons for involving 


 
 
 
110
research subjects with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review committee.  The 
protocol should state that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results.  Negative as well as positive results 
should be published or otherwise publicly available.  Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication.  Reports of experimentation 
not in accordance with the principles laid down in this Declaration should not be accepted for 
publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE 
1. The physician may combine medical research with medical care, only to the extent that the research 
is justified by its potential prophylactic, diagnostic or therapeutic value.  When medical research is 
combined with medical care, additional standards apply to protect the patients who are research 
subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use of 
placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method 
exists. 
3. At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
4. The physician should fully inform the patient which aspects of the care are related to the research.  
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not 
exist or have been ineffective, the physician, with informed consent from the patient, must be free to 
use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering.  Where possible, 
these measures should be made the object of research, designed to evaluate their safety and 
efficacy.  In all cases, new information should be recorded and, where appropriate, published.  The 
other relevant guidelines of this Declaration should be followed.