Conditions: Simultaneous Kidney and Pancreas Transplantation
Keywords: transplantation kidney pancreas immunosuppression calcineurin inhibitor (CNI)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if the drug NULOJIX® (belatacept) will minimize the amount of other anti-rejection medications necessary and thereby reduce the long-term side effects caused by the other medications. The researchers also want to learn more about the safety of this treatment and long term health of transplanted pancreases and kidneys.

Detailed description:
Transplant recipients have to take anti-rejection medications to prevent their immune systems (the body's natural defense system against illness) from rejecting their new organs. Most patients who receive a transplanted organ must take these anti-rejection medications for the rest of their lives, or for as long as the transplanted organ continues to work. Taking standard anti-rejection medications for a long time can cause serious side effects, including pancreas and kidney damage. There would be a benefit to finding new anti-rejection medications that work just as well, but could lessen the amount of anti-rejection medications that are taken long term.

Arms:
arm 1: * Induction: 5 day course of methylprednisolone or equivalent;
* Induction: Anti-thymocyte Globulin (Rabbit);
* Maintenance Immunosuppression: Tacrolimus (or generic). The site investigator will identify a starting tacrolimus dose at his or her discretion, in order to achieve the target trough levels, no later than 5 days post-transplantation. Tacrolimus dosing will be initiated on the day of surgery or post-operative day 1 depending upon when during the day the surgery is completed, then adjusted to target trough levels of 8-12 ng/ml during the first 24 weeks post-transplant, then adjusted to target trough levels of 5-8 ng/ml thereafter.
* Maintenance Immunosuppression: Mycophenolate mofetil (or Myfortic (mycophenolate sodium), or generic). arm 2: * Induction: 5 day course of methylprednisolone or equivalent;
* Induction: Anti-thymocyte Globulin (Rabbit);
* Maintenance Immunosuppression: Belatacept
* Maintenance Immunosuppression: Tacrolimus (or generic)- The site investigator will identify a starting tacrolimus dose at his or her discretion, in order to achieve the target trough levels no later than 5 days post-transplantation. Tacrolimus dosing will be initiated on the day of surgery or post-operative day 1 depending upon when during the day the surgery is completed. The dosage will be adjusted to achieve the following therapeutic trough levels: 5-8 ng/ml during the first 24 weeks post-transplant and then 3-5 ng/ml until day 280 (week 40). Subjects may be withdrawn if they meet all the criteria defined below.
* Maintenance Immunosuppression: Mycophenolate mofetil (or Myfortic (mycophenolate sodium), or generic).

Interventions: intervention 1: Belatacept intervention 2: methylprednisolone intervention 3: Anti-thymocyte Globulin (Rabbit) intervention 4: Tacrolimus intervention 5: Mycophenolate mofetil
Intervention descriptions: intervention 1: The first dose of belatacept will be administered approximately 24-48 hours after the last dose of Anti-Thymocyte Globulin (Rabbit). intervention 2: None intervention 3: None intervention 4: There may be an opportunity to withdraw tacrolimus at week 40 intervention 5: Mycophenolate mofetil will be administered at a target dose of 1000 mg by mouth twice daily (e.g., BID) beginning on the day of surgery or post-operative day 1 depending upon when during the day the surgery is completed (maximum MMF dosing is 2G per day). MMF will be adjusted based on clinical complications (such as neutropenia). Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.

Protocol document:
Prot_SAP_000.pdf: 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
 
CLINICAL TRIALS IN ORGAN TRANSPLANTATION (CTOT)  
PROTOCOL CTOT-15 
NIAID GRANT NUMBER:  U01-AI084150 
IND NUMBER: 117364 
Clinical Trials (ct.gov) Number:  NCT01790594 
Optimization of NULOJIX® (Belatacept) Usage as a Means of 
Minimizing CNI Exposure in Simultaneous Pancreas and Kidney 
Transplantation 
 
VERSION 7.0/ June 28, 2016 
 
Study Sponsor: 
    The National Institute of Allergy and Infectious Diseases (NIAID) 
Corporate Supporter:    Bristol-Myers Squibb (BMS) 
PRINCIPAL INVESTIGATOR 
Kenneth Newell, M.D., Ph.D. 
Director, Living Donor Kidney Program  
Emory University   
101 Woodruff Circle, #5105-WMB  
Atlanta, GA 30322 
Phone: 404-727-2489 
Fax:      404-727-3660 
kenneth.newell@emoryhealthcare.org 
MEDICAL MONITOR 
Mark Robien, M.D. 
Medical Officer  
Division of Allergy, Immunology, and 
Transplantation, NIAID 
5601 Fishers Lane, Room 6B29 
Rockville, MD 20852 
Phone: 240-627-3554  
Fax:      240-627-3115 
robienma@niaid.nih.gov 
BIOSTATISTICIAN 
David N. Iklé, Ph.D. 
Senior Statistical Scientist 
Rho Federal Systems Division 
6330 Quadrangle Dr. Suite 500 
Chapel Hill, NC 27517 
Phone:  919-595-6378  
Fax:       919-408-0999  
dikle@rhoworld.com 
 
 
PROTOCOL CHAIR 
 
Peter G. Stock, M.D., Ph.D. 
Professor of Surgery 
University of California, San Francisco 
505 Parnassus Avenue,  
M-884, Box 0780 
San Francisco, CA  94143-0780 
Phone:  415-353-8617 
Fax:       415-353-8974 
Peter.Stock@ucsfmedctr.org 
REGULATORY AFFAIRS 
OFFICER 
Theresa Allio, Ph.D. 
Regulatory Affairs Officer 
Office of Regulatory Affairs,  
DAIT, NIAID, NIH  
6610 Rockledge Drive, Rm 6610  
Bethesda, MD 20892  
Phone: 301-451-0141 
Theresa.allio@nih.gov  
PROJECT MANAGER 
 
Natasha Watson, BSN 
Senior Project Manager 
Division of Allergy, Immunology, 
and Transplantation, NIAID 
5601 Fishers Lane, 6B27 
Rockville,  MD  20852 
Phone: 301-335-8476 
nwatson@niaid.nih.gov   
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol 
Chair, or the Division of Allergy, Immunology and Transplantation; the National Institute of Allergy and Infectious Diseases; 
and the National Institutes of Health. 
                                                                                                                                                           
 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
 
 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol: 
 CTOT-15 
Version/Date:  
7.0/ June 28, 2016 
Title:    Optimization of  NULOJIX® (belatacept) Usage as a Means of Minimizing CNI Exposure in Simultaneous 
Kidney and Pancreas Transplantation 
 
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
 
INSTRUCTIONS:  Please have the Principal Investigator print, sign, and date at the indicated location 
below.  A copy should be kept for your records and the original signature page sent to the NIAID.   
After signature, please return the original of this form by surface mail to:  
DAIT Regulatory Management Center 
Pharmaceutical Product Development 
3900 Paramount Parkway 
Morrisville, NC 27560 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to the principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 21 CFR Parts 50, 56, and 312, and the International Conference on 
Harmonization (ICH) document “Guidance for Industry:  E6 Good Clinical Practice:  Consolidated 
Guidance”.  Further, I will conduct the study in keeping with local, legal, and regulatory requirements.   
 
As the Site Principal Investigator, I agree to conduct “ Optimization of  NULOJIX® (belatacept) Usage as 
a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation ” 
I agree to carry out the study by the criteria written in the protocol and understand that no changes can 
be made to this protocol without written permission of the NIAID. 
 
 
___________________________________ 
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
Study Contacts- Participating Centers 
SITE INVESTIGATOR 
Kenneth Newell, M.D., Ph.D. 
Director, Living Donor Kidney 
Program 
Emory University 
101 Woodruff Circle, #5105-WMB 
Atlanta, GA 30322  
Phone: 404-727-2489 
Fax:      404-727-3660 
E-mail:       kanewel@emory.edu 
 
SITE INVESTIGATOR 
Peter G. Stock, M.D., Ph.D. 
Professor of Surgery 
University of California, San Francisco 
505 Parnassus Avenue,  
M-884, Box 0780 
San Francisco, CA  94143-0780 
Phone: 415-353-8617 
Fax:      415-353-8974 
E-mail:       Peter.Stock@ucsfmedctr.org 
  
SITE INVESTIGATOR 
Roslyn B. Mannon, M.D. 
Professor of Medicine and Surgery 
University of Alabama at Birmingham 
1900 University Boulevard 
THT 611G 
Birmingham, AL 35294 
Phone: 205-934-7220 
Fax:      205-975-0102 
E-mail:        rmannon@uab.edu 
 
SITE INVESTIGATOR 
Jon Odorico, M.D. 
Professor, Division of Transplantation 
University of Wisconsin 
School of Medicine and Public Health 
H4/756 Clinical Science Center 
600 Highland Ave 
Madison, WI 53792 
Phone: 608-263-4768 
Fax:      608-262-6280 
E-mail:        jon@surgery.wisc.edu 
SITE INVESTIGATOR 
Jon Fridell, M.D.  
Surgical Director, Pancreas 
Transplantation  
Professor of Surgery             
Department of Surgery, Organ 
Transplantation          
Indiana University    
550 N University Blvd, UH 4601             
Indianapolis, IN 46202-5250 
Phone: 317-944-4370 
Fax:      317-968-1254 
E-mail:       jfridell@iupui.edu 
 
 
 
 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
Study Contacts- Core Laboratories 
Cellular Core Laboratory 
Christian P. Larsen, M.D., D.Phil 
Division of Transplantation 
Emory University School of Medicine 
101 Woodruff Circle, #5105-WMB 
Atlanta, GA 30322 
Telephone: 404-727-8465 
Fax:             404-727-3660 
Email:         clarsen@emory.org 
Molecular Core Laboratory 
Roslyn B. Mannon, M.D. 
University of Alabama at Birmingham 
1900 University Boulevard 
THT 611G 
Birmingham, AL 35294 
Telephone: 205-934-7220 
Fax:             205-975-0102 
E-mail:        rmannon@uab.edu 
Assays of Allograft Injury Lab 
Roslyn B. Mannon, M.D. 
University of Alabama at Birmingham 
1900 University Boulevard 
THT 611G 
Birmingham, AL 35294 
Telephone: 205-934-7220 
Fax:             205-975-0102 
E-mail:        rmannon@uab.edu 
 
Antibody Core Laboratory 
Howard Gebel, Ph.D. 
Emory University Hospital  
Clinical Laboratories 
1364 Clifton Road, NE 
Room F-149 
Atlanta, GA 30322 
Telephone: 404-712-8199  
E-mail:        hgebel@emory.edu 
Pathology Core Laboratory 
Zoltan G. Laszik, M.D., Ph.D. 
Clinical Professor of Pathology 
Department of Pathology 
University of California San Francisco 
513 Parnassus Avenue, S566 
San Francisco, CA 94143-0102 
Telephone:  415 502 8230 (office)  
Pager: 415-443-6701  
Fax:     415 514 3403  
zoltan.laszik@ucsfmedctr.org 
   
Viral Monitoring Core Laboratory 
Aneesh K. Mehta, M.D. 
Division of Infectious Diseases  
Emory University School of Medicine 
101 Woodruff Circle,  
WMB 2101 
Atlanta, GA 30033 
Telephone: 404-727-8435 
Fax:             404-712-2278 
E-mail:        aneesh.mehta@emory.edu 
Markers of Autoimmunity Core 
Laboratory 
 
Peter Stock, M.D., Ph.D. 
University of California, San 
Francisco  
513 Parnassus Avenue  
HSE520, Box 0780  
San Francisco, CA 94122  
Phone: 415-476-0789  
E-mail: Peter.Stock@ucsfmedctr.org 
 
 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
 
PROTOCOL AMENDMENT 
Prior Version: Version 6.0, Dated May 14, 2016 
Current Version: Version 7.0, Dated June 28, 2016 
 
The following protocol amendment dated June 28, 2016, supersedes all previous 
versions of the protocol CTOT-15, “Optimization of Belatacept Usage as a Means of 
Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation”.   
 
A. Rationale for Protocol Amendment 
Based upon a recommendation by the NIAID Data Safety Monitoring Board, Dr. Newell, 
Dr. Stock and the NIH have decided to halt any further protocol directed low dose CNI 
(Prograf®, tacrolimus) withdrawal. It was observed that there was a higher incidence of 
acute rejection at/around the time of low dose CNI withdrawal. While the rate of 
rejection did not meet the study stopping rule, the temporal relationship between the 
CNI withdrawal and acute rejection warranted sufficient concern to discontinue any 
further CNI withdrawal.  
 
In addition, any subjects in the experimental arm of the study will transition from a 
protocol directed study therapy regimen to a physician directed clinical 
immunosuppressive regimen. The clinical immunosuppressive regimen may include 
belatacept and if so, the subject may continue to receive the study supply of belatacept 
until study completion on August 31, 2016.  
 
B. Informed Consent 
The investigator at each site must inform all active subjects that any further low dose 
CNI withdrawal has been halted and that each subject in the experimental arm will be 
transitioned from a protocol directed study therapy regimen to a physician directed 
clinical immunosuppressive regimen.  The site investigator or designee must explain 
during the re-consent process the reason for the premature discontinuation of study 
therapy and describe in lay terms to the subject and/or the subject’s legal representative 
what is involved in the transition from a protocol mandated therapy regimen to a 
physician directed clinical immunosuppressive regimen as well as the remaining study 
follow-up. The subject and/or the subject’s legal representative, must read, sign, and 
date the informed consent form prior to any study-specific procedures. 
 
A copy of the informed consent must be given to the subject and/or the subject’s legal 
representative.  The subject and/or the subject’s legal representative will be informed 
that participation in the follow-up portion of the study is voluntary and that he/she may 
withdraw from the study at any time, for any reason. 
 
C. Description of Amendment Modifications 
No further subjects in the experimental arm of the study will undergo low dose CNI 
withdrawal. In addition, subjects in the experimental arm will transition from the 
protocol directed study therapy regimen to a physician directed clinical 
immunosuppressive regimen. If the subject, in conjunction with their treating physician, 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
opts to remain on belatacept after being reconsented regarding the new findings, they 
may receive the study supply of belatacept until study completion on August 31, 2016. 
 
Subjects will continue to be followed until study completion based on the existing 
schedule they are following in Appendices 2, 3 or 4.  
 
D. Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21 CRF § 312.62) the investigator is 
required to maintain adequate records of the disposition of the investigational agent, 
including the date and quantity of the drug received, to whom the drug was dispensed 
(participant-by-participant accounting), and a detailed accounting of any drug 
accidentally or deliberately destroyed. Documentation must be present in the site 
pharmacy binder to verify the disposition of the study drug, and the institution’s 
procedures for destruction of the study drug. 
 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
 
 
 
 
 
                        CTOT-15 Protocol Synopsis 
Title 
Optimization of  NULOJIX® (belatacept) Usage as a Means of Minimizing CNI Exposure in 
Simultaneous Kidney and Pancreas Transplantation (CTOT-15) 
Study Design 
This study is a multicenter, prospective, randomized (1:1), open-label, Phase II study to compare a 
NULOJIX® (belatacept) based immunosuppressive regimen to a CNI-based regimen in recipients of 
SPK.  Subjects will be consented and enrolled until a total of 60 subjects are randomized.   
Study Duration 
39 months (21 month accrual period, up to 18 month follow-up period). Subjects will be followed for a 
minimum of 12 months or 60 days post tacrolimus withdrawal. 
Accrual Objective 
60 Randomize (30 per arm); 1:1 to one of two study therapy arms. 
Study Therapy 
Regimen  
Control Arm: 
 Induction:  5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction:  Thymoglobulin® (Anti-thymocyte Globulin (Rabbit)); 
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or Myfortic® 
(mycophenolate sodium), or generic. 
Investigational Arm: 
 Induction: 5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction:  Thymoglobulin® (Anti-thymocyte Globulin (Rabbit));  
 Maintenance Immunosuppression:  NULOJIX® (belatacept); 
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or Myfortic® 
(mycophenolate sodium), or generic. 
Primary Objective 
The primary objective is to evaluate a NULOJIX® (belatacept) based regimen as a means of improving 
long term graft function without increasing the risks of immunologic graft injury by avoiding both CNI 
and corticosteroids.  
Primary Endpoint 
The primary endpoint is mean glomerular filtration rate (GFR) calculated for each treatment group 
using the CKD-EPI equation at 52 weeks. 
Secondary 
Objective 
The secondary objective is to evaluate whether a NULOJIX® (belatacept) based immunosuppression 
regimen with minimal exposure to CNIs achieves superior renal function, improves cardiovascular and 
metabolic risk profiles, and preserves protective immunity in recipients of SPK.  
Secondary 
Endpoints 
Measures of Renal Function and Injury  
The following secondary endpoints will measure renal function and injury at weeks 52: 
1. 
Proportion of subjects with eGFR < 60 mL/min/1.73 m2 measured by CKD-EPI. 
2. 
Change in CKD stages from baseline.  
3. 
Proportion of subjects with defined CKD stage 4 or 5. 
4. 
Mean calculated eGFR using MDRD 4 variable model. 
5. 
 eGFR by CKD-EPI over time based on serum creatinine collected at all visits indicated on the 
Schedule of Events. 
6. 
Incidence of successful discontinuation of tacrolimus in recipients randomized to the NULOJIX® 
(belatacept)t treatment arm (Investigational Arm)  
7. 
The incidence of delayed graft function (DGF- refer to study definitions page). 


Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas 
Transplantation 
Version 7.0 June 28, 2016 
Secondary 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measures of Pancreatic Function and Injury  
The following secondary endpoints will measure pancreatic function and injury at week 52, in addition 
to times of graft dysfunction: 
1. Proportion of subjects with full pancreatic graft function (i.e., insulin independent). 
2. Partial pancreatic graft function (i.e., fasting c-peptide levels >0.3ng.mL (0.1nmol.L), but requiring 
insulin or oral hypoglycemic agents). 
3. Pancreatic loss (i.e., c-peptide value <0.3ng/mL). 
 
Measures of Cardiovascular and Metabolic Parameters 
The following will be measured at baseline, days 28, 84, and weeks 28, 36, and 52, unless otherwise 
stated below. 
1. HbA1c. 
2. Fasting Blood Sugar (FBS). 
3. Standardized blood pressure measurement and use of anti-hypertensive medications. 
4. Fasting lipid profile (Total Cholesterol, non-HDL Cholesterol, LDL, HDL, and triglyceride) and the 
use of lipid lowering medications at baseline, and weeks 28 and 52.  
 
Incidence and Severity of Rejection and Anti-  Donor Reactivity  
These endpoints will be assessed at 52 weeks post-transplant.  Biopsy grading and antibody 
assessments will be performed at the CTOT-15 Core Laboratories.  
1. The incidence and severity of acute cellular rejection defined by the Kidney Banff 2007 criteria and 
Pancreas Banff 2011 criteria within the first 52 weeks. 
2. The severity of first and highest grade of acute cellular rejection in the renal and pancreas biopsies  
3. The incidence of humoral rejection in the renal and pancreas biopsies.  
4. The prevalence of de novo anti-donor antibodies and anti-HLA antibodies. 
5. The type of treatment of rejection. 
 
Safety Outcome Measures  
The following safety outcome measures will be assessed: 
1. The incidence of death, graft loss, or undetectable c-peptide.  
2. The incidence of all adverse events (AEs) and serious adverse events (SAEs). 
3. The incidence of selected AEs and SAEs including: 
o 
Infections requiring hospitalization or systemic therapy,  
o 
BK and CMV viremia (local center monitoring), 
o 
EBV Infection (local center monitoring),  
o 
Malignancy. 
Secondary 
Endpoints- 
Mechanistic 
Samples for Mechanistic studies will be collected as specified on the SOE.   
Immune Reactivity and Function 
1. Multiparameter flow cytometric enumeration and phenotyping of peripheral blood leukocyte 
subsets.  
2. Protective immunity 
a. Viral load monitoring – EBV, CMV, Polyoma BKV & JCV 
b. Quantity and quality of CMV- and EBV- specific T cells and viral-specific antibody. 
3. Anti-donor responses 
a. Donor-specific antibody. 
b. Immunohistochemistry of for-cause renal allograft biopsies. 
c. 
Gene expression, mRNA profiling in blood, urine and tissue. 
4. Serum and urine proteins, selected biomarkers of acute and chronic kidney injury. 
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for enrollment as study participants:  
1. Male or Female, 18-55 years of age at the time of enrollment; 
2. Ability to understand and provide written informed consent; 


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3. Candidate for a primary simultaneous kidney and pancreas allograft with random c-peptide <0.3 
ng/mL.  
4. No known contraindications to study therapy using NULOJIX® (belatacept); 
5. Female subjects of childbearing potential must have a negative pregnancy test upon study entry; 
6. Female and male participants with reproductive potential must agree to use FDA approved 
methods of birth control during participation in the study and for 4 months following study 
completion; 
7. No donor specific antibodies prior to transplant that are considered to be of clinical significance by 
the site investigator; ; 
8. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and admission sera, as 
determined by each participating study center. 
9. A documented negative TB test within the 12 months prior to transplant.  If documentation is not 
present at the time of transplantation, and the subject does not have any risk factors for TB, a TB-
specific interferon gamma release assay (IGRA) may be performed.   
Exclusion Criteria 
Patients who meet any of these criteria are not eligible for enrollment as study participants:  
1. Need for multi-organ transplantation other than a kidney and pancreas 
2. Recipient of previous organ transplant; 
3. Active infection with hepatitis B, hepatitis C, or HIV;  
4. Individuals who have required treatment with systemic prednisone or other immunosuppressive 
drugs within 1 year prior to transplant; 
5. Individuals previously treated with NULOJIX® (belatacept); 
6. Any condition that, in the opinion of the investigator, would interfere with the participant’s ability 
to comply with study requirements; 
7. Use of investigational drugs within 4 weeks of enrollment; 
8. Known hypersensitivity to mycophenolate mofetil (MMF)or any of the drug’s components; 
9. Administration of live attenuated vaccine(s) within 8 weeks of enrollment. 
10. EBV sero-negative recipients or recipients whose EBV status is unknown or ambiguous prior to the 
time of transplantation (refer to Section 6.3). 


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Table of Contents
Study Definitions ................................................................................................................................... 17 
 
Essential Study Components ..................................................................................................... 22 
 
Hypothesis/Research Question ................................................................................................... 22 
 
Primary Objective .......................................................................................................................... 22 
 
Secondary Objective ..................................................................................................................... 22 
 
Primary Endpoint........................................................................................................................... 22 
 
Secondary Endpoints .................................................................................................................... 22 
1.5.1   Measures of Renal Function and Injury ......................................................................22 
1.5.2    Measures of Pancreatic Function and Injury ...............................................................22 
1.5.3   Measures of Cardiovascular and Metabolic Parameters ..............................................23 
1.5.4    Incidence and Severity of Rejection and Anti- Donor Reactivity ...............................23 
1.5.5    Safety Outcome Measures ..........................................................................................23 
 
Mechanistic Secondary Endpoints ............................................................................................. 23 
 
Background and Rationale ......................................................................................................... 24 
2.1 
Background ..................................................................................................................................... 24 
2.2 
Preclinical and Clinical Experience ............................................................................................ 26 
2.2.1   Preclinical Studies .......................................................................................................26 
2.2.2   NULOJIX® (Belatacept) in Clinical Studies .................................................................27 
 
Rationale for Selection of Study Population .......................................................................... 41 
 
Rationale for Investigational Therapeutic Regimen ............................................................. 42 
 
Known and Potential Risks and Benefits to Participants .................................................... 43 
5.1 
Risks of NULOJIX® (belatacept) Therapy ................................................................................ 43 
5.2 
Risks of Thymoglobulin® (Anti-Thymocyte Globulin) Therapy ........................................ 44 
5.3 
Risks of Medrol® (Methylprednisolone) .................................................................................. 46 
5.4 
Risks of Maintenance Immunosuppression Medications ..................................................... 46 
5.4.1   CellCept® (Mycophenolate mofetil - MMF) .................................................................46 
5.4.2   Prograf® (Tacrolimus) .................................................................................................47 
5.5 
Risks of Protocol Mandated Procedures ................................................................................... 47 
5.5.1   Kidney Biopsy .............................................................................................................47 
5.5.2   Blood Draws ................................................................................................................47 
5.6 
Potential Benefits ........................................................................................................................... 47 
6 
Selection of Participants ............................................................................................................. 48 
6.1 
Selection of Centers ....................................................................................................................... 48 
6.2 
Inclusion Criteria ........................................................................................................................... 48 
6.3 
Exclusion Criteria........................................................................................................................... 48 
7 
Study Design ................................................................................................................................ 50 


 
 
Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 11 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 7.0 June 28, 2016 
8 
Study Therapy Regimen ............................................................................................................. 52 
8.1 
Investigational Drug:  NULOJIX® (belatacept) ....................................................................... 55 
8.1.1   Formulation, Packaging, and Labeling ........................................................................55 
8.1.2   Preparation, Administration, and Dosage ...................................................................55 
8.1.3   Handling, Dispensing, and Destruction of NULOJIX® (belatacept) ............................57 
8.1.4   Drug Accountability ....................................................................................................58 
8.2 
Induction and Maintenance Immunosuppression Medications .......................................... 58 
8.3 
Concomitant Medications ............................................................................................................ 58 
8.4 
Prophylactic Medications ............................................................................................................. 58 
8.4.1   Viral Prophylaxis ........................................................................................................58 
8.4.2   PCP Prophylaxis ..........................................................................................................59 
8.5 
Management of Rejection or Graft Loss.................................................................................... 59 
8.6 
Prohibited Medications ................................................................................................................ 59 
8.7 
Modification or Discontinuation of Study Therapy ............................................................... 60 
9 
Criteria for Premature Termination of the Study .................................................................. 61 
9.1 
Participant Withdrawal Criteria .................................................................................................. 61 
9.2 
Study Stopping Rules ................................................................................................................... 61 
9.2.1  Protocol Suspension and Review .................................................................................61 
9.2.2  Continuous Monitoring of Specific Events ...................................................................61 
10 
Study Procedures ......................................................................................................................... 64 
10.1 Enrollment ....................................................................................................................................... 64 
10.2 Screening Visit ............................................................................................................................... 64 
10.3 Study Assessments ........................................................................................................................ 64 
The local center will send the Pathology Core Lab (Dr. Laszik, UCSF) the following: ............ 66 
10.4 Study Treatment Assignment Procedures ................................................................................ 67 
10.4.1 Blinding and/or Randomization .................................................................................67 
11 
Safety Monitoring ........................................................................................................................ 68 
11.1 Overview ............................................................................................................................................ 68 
11.2 Definitions ...................................................................................................................................... 68 
11.2.1 Adverse Event (AE) .....................................................................................................68 
11.2.2 Suspected Adverse Reaction (SAR) .............................................................................68 
11.2.3 Unexpected Adverse Event .........................................................................................69 
11.2.4 Serious Adverse Events ...............................................................................................69 
11.3 Grading and Attribution of Adverse Events ............................................................................ 69 
11.3.1 Grading Criteria ..........................................................................................................69 
11.3.2 Attribution Definitions ...............................................................................................70 
11.4 Collection and Recording of Adverse Events ........................................................................... 70 
11.4.1 Collection Period.........................................................................................................70 
11.4.2 Collecting Adverse Events ..........................................................................................70 
11.4.3 Recording Adverse Events ..........................................................................................71 


 
 
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11.5 Reporting of Serious Adverse Events ........................................................................................ 71 
11.5.1 Reporting of Serious Adverse Events to Sponsor ........................................................71 
11.5.2 Sponsor Reporting to Health Authority ......................................................................72 
11.5.2.1 
Annual Reporting .................................................................................................................... 72 
11.5.2.2 
Expedited Reporting within 15 Calendar Days .................................................................. 72 
11.5.2.3 
Expedited Reporting within 7 Calendar Days .................................................................... 72 
11.5.3 Reporting of Adverse Events to IRBs ..........................................................................72 
11.6 Pregnancy Reporting ..................................................................................................................... 73 
11.7 Reporting of Other Safety Information ..................................................................................... 73 
11.8 Review of Safety Information ..................................................................................................... 73 
11.8.1 Medical Monitor Review .............................................................................................73 
11.8.2 DSMB Review ..............................................................................................................73 
11.8.2.1 
Temporary Halt for Emergency Safety Review .................................................................. 74 
12 
Mechanistic Assays ..................................................................................................................... 75 
12.1 Cellular Assays ............................................................................................................................... 75 
12.1.1 Intracellular Cytokine Staining Viral Phenotyping .....................................................75 
12.1.2 Flow Cytometry ..........................................................................................................76 
12.2 Molecular Assays ........................................................................................................................... 76 
12.2.1 Gene Expression, mRNA Profiling and miRNA Chip Arrays ......................................76 
12.3 Protein Assays of Allograft Injury ............................................................................................. 78 
12.4 Antibody Assays ............................................................................................................................ 79 
12.4.1 Anti-HLA Antibody (Alloantibodies) and Non-HLA Antibodies ................................79 
12.5 Markers of Autoimmunity ........................................................................................................... 79 
12.6 Genomics ......................................................................................................................................... 79 
12.7 Pathology ......................................................................................................................................... 80 
12.7.1 Histology- Renal .........................................................................................................80 
12.7.2 Immunohistochemistry- Renal ....................................................................................80 
12.7.3 Histology- Pancreas ....................................................................................................80 
12.8 Viral Testing ................................................................................................................................... 81 
12.9 Specimen Repository for Future Studies .................................................................................. 81 
13 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ....................... 82 
13.1 Statistical Analyses ................................................................................................................... 82 
13.2 Endpoint Assessments.............................................................................................................. 82 
13.2.1 Primary Clinical Endpoint ..........................................................................................82 
13.2.2 Secondary Clinical Endpoints .....................................................................................83 
13.2.3 Mechanistic Assay Analyses .......................................................................................86 
13.3 Sample Size and Power Calculations .................................................................................. 90 
13.4 Safety Analyses .............................................................................................................................. 90 
13.5 Demographic Data ..................................................................................................................... 90 
13.5.1 Baseline Characteristics and Demographics .................................................................... 90 
13.5.2 Medical History ..........................................................................................................91 


 
 
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13.6 Interim Analyses ........................................................................................................................ 91 
13.7 Reporting Deviations from Original Statistical Plan .................................................. 91 
13.8 Final Study Analysis ................................................................................................................. 91 
14 
Source Data ................................................................................................................................... 92 
14.1 Source Data ..................................................................................................................................... 92 
14.2 Access to Source Data ................................................................................................................... 92 
15 
Quality Control and Quality Assurance .................................................................................. 93 
15.1 Data Handling ................................................................................................................................ 93 
16 
Ethical Considerations and Compliance with Good Clinical Practice .............................. 94 
16.1 Statement of Compliance ............................................................................................................. 94 
16.2 Informed Consent Process ........................................................................................................... 94 
16.3 Privacy and Confidentiality ......................................................................................................... 94 
17 
Publication Policy ........................................................................................................................ 95 
 
List of Figures 
Figure 1.  CTOT-15 Study Design 
 
 
 
 
 
 
 
 
46 
Figure 2.  CTOT-15 Study Arms  
 
 
 
 
 
 
 
 
47 
 
List of Appendices  
Appendix 1:  Schedule of Events (Pre-Transplant to Day 4 Post-Transplant) 
 
 
 
94 
Appendix 2:  Schedule of Events (Recipient) Post -Transplant (Year 1) 
 
 
 
 
95 
Appendix 3:  Schedule of Events (Recipient) Post-Transplant (Year 2) 
 
 
 
 
98   
Appendix 4: Reduced Follow-Up Schedule of Events (Recipient)  
 
 
 
 
99 
Appendix 5: Schedule of Events (Donor)  
 
 
 
 
 
 
 
100 


 
 
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Glossary of Abbreviations 
ACR 
Acute Cellular Rejection 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ALP 
Alkaline Phosphatase 
ALT (SPGT) 
Alanine Aminotransferase 
AMR 
Antibody Mediated Rejection 
ANCOVA 
Analysis of Covariance 
APC 
Antigen Presenting Cells 
AR 
Acute Rejection 
AST (SGOT) 
Aspartate Aminotransferase 
ATG 
Thymoglobulin® (Anti-thymocyte Globulin- Rabbit) 
AUC 
Area Under the Curve 
B-CLL 
B-cell Chronic Lymphocytic Leukemia 
BKV 
BK Polyoma Virus 
BMS 
Bristol-Myers Squibb 
BPAR 
Biopsy-proven acute rejection 
BW 
Body Weight 
CAN 
Chronic allograft nephropathy 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Intervals 
CIT 
Clinical Islet Transplantation 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CKI 
Chronic Kidney Injury 
CTCAE 
Common Terminology Criteria for Adverse Events 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
CNS 
Central Nervous System 
CrCL 
Creatinine Clearance 
CRF 
Case Report Form 
CsA 
Cyclosporine A 
CSBPAR 
Clinically suspected and biopsy-proven acute rejection 
CTOT 
Clinical Trials in Organ Transplantation 
CTOT-C 
Clinical Trials in Organ Transplantation in Children 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DBP 
Diastolic Blood Pressure 
DC 
Dendritic Cells 
DGF 
Delayed Graft Function 
DM 
Diabetes Mellitus 
DNA 
Deoxyribonucleic Acid 
DSA 
Donor Specific Antibody 


 
 
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DSMB 
Data Safety Monitoring Board 
EBV 
Epstein Barr Virus 
ECD 
Extended Criteria Donor 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELISPOT 
Enzyme Linked Immunospot 
FBS 
Fasting Blood Sugar 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed, Paraffin Embedded 
FLP 
Fasting Lipid Profile 
GAD 
Glutamic Acid Decarboxylase 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HbA1c 
Hemoglobin A1c 
HCG 
Human  Chorionic  Gonadotropin 
HDL 
High Density Lipoprotein 
H&E 
Hematoxylin and Eosin (pathology stain) 
HIV 
Human Immunodeficiency Virus 
HLA 
Histocompatibility Antigen 
HUS 
Hemolytic Uremic Syndrome 
IB 
Investigators Brochure 
ICH 
International Conference on Harmonization 
IFTA 
Interstitial Fibrosis and Tubular Atrophy 
IGRA 
TB-specific Interferon Gamma Release Assay 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IV 
Intravenous 
kDa 
kilo Dalton 
LDL 
Low-density Lipoprotein 
LI 
Less Intensive 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MHC 
Major Histocompatibility Complex 
MI 
More Intensive 
MICA 
MHC-class I related chain  
MMF 
Maintenance mycophenolate mofetil 
MMRM 
Mixed Models Repeated Measures 
MOP 
Manual of Procedures 
MPA 
Mycophenolate Acid 
mRNA 
Messenger Ribonucleic Acid 
NCI 
National Cancer Institute 


 
 
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NIAID 
National Institute of Allergy and Infectious Disease 
NIH 
National Institutes of Health 
NK 
Natural Killer cells 
OR 
Odds Ratio 
PAS 
Periodic Acid-Schiff (pathology stain) 
PBMC 
Peripheral Blood Mononuclear Cells 
PCP 
Pneumocystis carinii pneumonia 
PCR 
Polymerase Chain Reaction 
PDT 
Protocol Development Team 
PHI 
Personal Health Identifiers 
PI 
Principal Investigator 
PML 
Progressive Multifocal Leukoencephalopathy 
PRA 
Panel Reactive Antibodies 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PTDM 
Post-transplant Diabetes Mellitus 
PTLD 
Post-transplant Lymphoproliferative Disorder 
RNA 
Ribonucleic Acid 
RR 
Risk Ratio 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SBP 
Systolic Blood Pressure 
SCr 
Serum Creatinine 
SOC 
System Organ Class 
SOE 
Schedule of Events 
SPK 
Simultaneous Pancreas and Kidney Transplantation 
SR 
Suspected Rejection 
SRTR 
Scientific Registry of Transplant Recipients 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TB 
Tuberculosis 
TCR 
T-cell receptor 
TGs 
Triglycerides 
TIB 
Transplant Immunology Branch 
ULN 
Upper Limit of Normal 
USRDS 
United States Renal Data System 
UTI 
Urinary Tract Infection 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 


 
 
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Version 7.0 June 28, 2016 
Study Definitions  
Acute Rejection– 
Kidney  
The endpoint of acute rejection of the kidney allograft will be assessed as in the belatacept 
phase III studies as histologically confirmed rejection as determined by the central pathologist, 
in which there are protocol-defined reasons for clinical suspicion of rejection (unexplained rise 
of serum creatinine ≥25% from baseline, unexplained decrease in urine output; fever and graft 
tenderness; or serum creatinine that remains elevated within 14 days post-transplantation) or 
treatment for acute rejection with other reasons for clinical suspicion. 
Acute Rejection – 
Pancreas 
Histologic evidence of stage 2 or greater rejection on a biopsy performed for clinical conditions 
suspicious for rejection such as, but not limited to, a two-fold increase in serum lipase or 
amylase or suspected rejection with empiric treatment in the absence of a biopsy. 
Antibody Mediated 
Rejection (AMR) 
Diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and 
morphologic evidence of acute tissue injury. 
Banff 2007 Scoring 
Criteria (Kidney)  
1. Normal 
2. Antibody-mediated rejection (may coincide with categories 3, 4, 5 and 6) 
Due to documentation of circulating anti-donor antibody, and C4d or allograft pathology 
C4d deposition without morphologic evidence of active rejection 
C4d+, presence of circulating anti-donor antibodies, no signs of acute or chronic TCMR 
or ABMR (i.e., g0, cg0, ptc0, no PTC lamination).  Cases with simultaneous borderline 
changes or ATN are considered as indeterminate. 
Acute antibody-mediated rejection: 
C4d+, presence of circulating anti-donor antibodies, morphologic evidence of acute 
tissue injury, such as (Type/Grade): 
I. 
ATN-like – C4d+, minimal inflammation 
II. 
Capillary and or glomerular inflammation (ptc/g >0) and/or thromboses 
III. 
Arterial- v3 
Chronic active antibody-mediated rejection: 
C4d+, presence of circulating anti-donor antibodies, morphologic evidence of chronic 
tissue injury, such as glomerular double contours and/or peritubular capillary basement 
membrane multilayering and/or interstitial fibrosis/tubular atrophy and/or fibrous 
intimal thickening in arteries. 
3. Borderline changes: ‘Suspicious’ for acute T-cell mediated rejection (may coincide with 
categories 2 and 5 and 6).  This category is used when no intimal arteritis is present, but 
there are foci of mild tubulitis (t1, t2, or t3) with minor interstitial infiltration (i0, or i1) or 
interstitial infiltration (i2, i3) with mild (t1) tubulitis.  
4. T-cell mediated rejection (may coincide with categories 2 and 5 and 6). 
Acute T-cell-mediated rejection (Type/Grade): 
IA     Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) 
and foci of moderate tubulitis (t2) 
IB     Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) 
and foci of severe tubulitis (t3) 
IIA    Cases with mild-to-moderate intimal arteritis (v1) 
IIB    Cases with severe intimal arteritis comprising >25% of the luminal area (v2) 
III      Cases with ‘transmural’ arteritis and/or arterial fibrinoid change and necrosis of 
medial smooth muscle cells with accompanying lymphocytic inflammation (v3) 
Chronic active T-cell mediated rejection 
‘chronic allograft arteriopathy’ (arterial intimal fibrosis with mononuclear cell infiltration 
in fibrosis, formation of neo-intima) 
5. Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology  


 
 
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(may include nonspecific vascular and glomerular sclerosis, but severity graded by 
tubulointerstitial features). 
Grade I     Mild interstitial fibrosis and tubular atrophy (<25% or cortical area) 
Grade II   Moderate interstitial fibrosis and tubular atrophy 26-50% of cortical area) 
Grade III  Severe interstitial fibrosis and tubular atrophy/ loss (>50% of cortical area) 
6. Other:  Changes not considered to be due to rejection-acute and/or chronic; may include 
isolated g, cg, or cv lesions and coincide with categories 2, 3, 4, and 5. 
Banff 2011 Scoring 
Criteria (Pancreas) 
1. Normal. Absent inflammation or inactive septal, mononuclear inflammation not involving 
ducts, veins, arteries or acini. There is no graft sclerosis. The fibrous component is limited to 
normal septa and its amount is proportional to the size of the enclosed structures (ducts and 
vessels). The acinar parenchyma shows no signs of atrophy or injury. 
2. Indeterminate. Septal inflammation that appears active but the overall features do not 
fulfill the criteria for mild cell-mediated acute rejection. 
3. Acute T-Cell-mediated rejection 
- Grade I/Mild acute T-cell-mediated rejection 
Active septal inflammation (activated, blastic lymphocytes, ± eosinophils) involving 
septal structures: venulitis (sub-endothelial accumulation of inflammatory cells and 
endothelial damage in septal veins, ductitis (epithelial inflammation and damage of 
ducts). Neural/peri-neural inflammation. and/or 
Focal acinar inflammation. No more than two inflammatory foci per lobule with absent or 
minimal acinar cell injury. 
- Grade II/Moderate acute T-cell-mediated rejection (requires differentiation from AMR) 
Multi-focal (but not confluent or diffuse) acinar inflammation (≥3 foci per lobule) with 
spotty (individual) acinar cell injury and drop-out. and/or 
Mild intimal arteritis (with minimal, <25% luminal compromise) 
- Grade III/Severe T-acute cell-mediated rejection 
Diffuse, (widespread, extensive) acinar inflammation with focal or diffuse multicellular 
/confluent acinar cell necrosis. and/or 
Moderate- or severe-intimal arteritis. >25% luminal compromise and/or 
Transmural inflammation-Necrotizing arteritis 
4. Antibody-mediated rejection  
-Confirmed circulating donor-specific antibody (DSA) 
-Morphological evidence of tissue injury (interacinar inflammation/capillaritis, acinar cell 
damage swelling/necrosis/apoptosis/dropout, vasculitis, thrombosis) 
Grade I/Mild acute AMR 
Grade II/Moderate acute AMR 
Grade III/Severe acute AMR 
-C4d positivity in interacinar capillaries (IAC, >5% of acinar lobular surface) 
5. Chronic Active Allograft Arteriopathy- Arterial intimal fibrosis with mononuclear cell 
infiltration in fibrosis 
6.  Chronic Allograft Rejection/Graft Fibrosis 
- Stage I (mild graft sclerosis) 
Expansion of fibrous septa; the fibrosis occupies less than 30% of the core surface but the 
acinar lobules have eroded, irregular contours. The central lobular areas are normal. 
- Stage II (moderate graft sclerosis) 
The fibrosis occupies 30–60% of the core surface. The exocrine atrophy affects the majority 
of the lobules in their periphery (irregular contours) and in their central areas (thin fibrous 
strands criss-cross between individual acin). 
- Stage III (severe graft sclerosis) 
The fibrotic areas predominate and occupy more than 60% of the core surface with only 
isolated areas of residual acinar tissue and/or islets present. 


 
 
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7.  Islet Pathology 
-Recurrence of autoimmune DM (insulitis and/or selective beta cell loss) 
-Islet amyloid (amylin) deposition) 
8. Other histological diagnosis. Pathological changes not considered to be due acute and/or 
chronic rejection. e.g. CMV pancreatitis, PTLD, etc.  
Biopsy Proven 
Acute Kidney 
Rejection (BPAR) 
Banff grade of greater than or equal to 1A with or without clinical symptoms. 
• 
An unexplained rise in serum amylase or lipase 
• 
Treatment for acute rejection with other reasons for clinical suspicion. 
BKV Infection 
A positive BKV infection for the purpose of this study is defined as a level of BKV viremia 
that causes a change in immunosuppression at the local center. 
Clinically 
Suspected and 
Biopsy Proven 
Acute Rejection 
(CSBPAR) in 
Kidney 
Banff grade of greater than or equal to 1A  plus at least one of the following: 
• 
Unexplained rise of serum creatinine ≥25% from baseline; 
• 
Unexplained decrease in urine output;  
• 
Fever and graft tenderness; 
• 
Serum creatinine that remains elevated within 14 days post-transplantation; 
• 
Treatment for acute rejection with other reasons for clinical suspicion. 
Chronic Active 
Antibody-Mediated 
Kidney Rejection  
By the Banff 2007 criteria, C4d+, presence of circulating antidonor antibodies, morphologic 
evidence of chronic tissue injury, such as a glomerular double contours and/or peritubular 
capillary basement membrane multilayering and/or interstitial fibrosis/tubular atrophy 
and/or fibrous initimal thickening in arteries. 
Control Arm 
 Induction:  5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction: Thymoglobulin® (Anti-Thymocyte Globulin- Rabbit);  
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or 
Myfortic® (mycophenolate sodium), or generic. 
Delayed Graft 
Function (DGF) in 
Kidney 
Dialysis in the first week on one or more occasions for any indication other than the 
treatment of acute hyperkalemia in the setting of otherwise acceptable renal function 
Donor Specific 
Antibody Testing  
The donor specific antibody testing include: 
• 
Class I:  A, B, C 
• 
Class II: DR, DQ, DP 
Graft Failure- Renal 
90 consecutive days of dialysis dependency. 
Graft Failure- 
Pancreas 
Return to exogenous insulin therapy or initiation of oral hypoglycemic agents for greater 
than 30 days. 
Insulin 
Independent 
Insulin free. 
Premature 
Termination 
A subject will be terminated prematurely from the study if: 1) the subject withdraws consent, 
2) is lost to follow-up, 3) the investigator or sponsor decision, 4) death, or 5) the subject is 
found to have a positive TB test.   
Protocol Mandated 
Procedures 
Any procedure performed solely for the purpose of this research study, not considered site 
specific standard of care. 
Randomized 
A subject who met all eligibility criteria; met with the study investigator or designee to 
discuss the study purpose, requirements (i.e., time requirements, schedule of events, etc.), 
discussed all risks and benefits, signed the informed consent document and was randomly 
assigned to one of the two treatment groups.  
 
Reduced Follow Up 
Randomized subjects who are no longer following the assigned study therapy regimen, and 
do not meet the criteria for early termination, will continue to participate in the study for 
safety and applicable endpoint assessments.   
Renal Dysfunction 
Two consecutive readings with an increase in serum creatinine of 25% from baseline. 


 
 
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Sensitizing Event 
Defined as a blood transfusion, pregnancy, or an event in the opinion of the Investigator 
would necessitate repeating the PRA. 
Treated Diabetes 
Receipt of any oral medication or insulin for the treatment of diabetes for >14 days 
Tuberculosis  
TB is defined as a positive TB Skin Test (TST/PPD) or a TB-specific interferon gamma release 
assay, such as a QuantiFERON®-TB, QuantiFERON®-TB in tube, or a T-Spot®. 
Withdrawn from 
Study Therapy 
Subjects who prematurely discontinue study treatment will be treated according to the site 
specific standard of care and followed for safety until 52 weeks post-transplant.   
Primary 
Nonfunction (PNF) 
Graft failure that occurs between 3 and 7 days post-transplant. 
Women of Child 
Bearing Potential 
(WOCBP) 
WOCBP includes any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; 
or women on hormone replacement therapy with documented serum follicle stimulating 
hormone level > 35 mIU/mL). Even women who are using oral, implanted, or injectable 
contraceptive hormones or mechanical products such as an intrauterine device or barrier 
methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence 
or where the partner is sterile (e.g., vasectomy), should be considered to be of child bearing 
potential. 
Humoral Rejection 
in Kidney 
Defined as renal dysfunction, the presence of donor specific anti-HLA antibodies, and 
diffuse C4d staining as determined by a central pathologist 
Investigational Arm 
 Induction: 5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction:  Thymoglobulin® (Anti-Thymocyte Globulin- Rabbit);  
 Maintenance Immunosuppression:  NULOJIX® (belatacept); 
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or 
Myfortic® (mycophenolate sodium), or generic. 
 
 
 


 
 
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The Stages of Chronic Kidney Disease (CKD)  
Stage  
GFR* 
Description 
Treatment stage 
1 
90+ 
Normal kidney function but urine 
findings or structural abnormalities 
or genetic trait point to kidney 
disease. 
Observation, control of blood 
pressure.   
2 
60-89 
Mildly reduced kidney function (as 
for stage 1) point to kidney disease. 
Observation, control of blood 
pressure and risk factors. 
3A 
3B 
45-59 
30-44 
Moderately reduced kidney 
function. 
Observation, control of blood 
pressure and risk factors. 
4 
15-29 
Severely reduced kidney function. 
Planning for endstage renal 
failure. 
5 
<15 or on dialysis 
Very severe, or endstage kidney 
failure (sometimes call established 
renal failure). 
Treatment choices. 
*All GFR values are normalized to an average surface area (size) of 1.73m2. 
Suffixes: 
p suffix:  the addition of p to a stage (e.g. 3Ap, 4p) mans that there is a significant proteinuria. 
T -  the addition of T to a stage (e.g. 3AT) indicates that the patient has a renal transplant. 
D – the addition of D to a stage 5 CDK (e.g. 5D) indicates that the patient is on dialysis.  


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Hypothesis/Research Question 
This study will test the hypothesis that a NULOJIX® (belatacept) based regimen using 
Thymoglobulin® (Anti-thymocyte Globulin- Rabbit) induction as a means of minimizing and 
potentially withdrawing calcineurin inhibitors (CNI) will result in comparable rates of rejection and 
achieve 
superior 
renal 
function 
as 
compared 
with 
a 
tacrolimus-based 
maintenance 
immunosuppressive regimen in recipients of simultaneous pancreas and kidney transplants (SPK).   

Primary Objective 
The primary objective is to evaluate a NULOJIX® (belatacept) based regimen as a means of 
improving long term graft function without increasing the risks of immunologic graft injury by 
avoiding both CNI and corticosteroids.  

Secondary Objective 
The secondary objective is to evaluate whether a NULOJIX® (belatacept) based immunosuppression 
regimen with minimal exposure to CNIs achieves superior renal function, improves cardiovascular 
and metabolic risk profiles, and preserves protective immunity in recipients of SPK.  

Primary Endpoint  
The primary endpoint is mean glomerular filtration rate (GFR) calculated for each treatment group 
using the CKD-EPI equation at 52 weeks. 

Secondary Endpoints 
1.5.1      Measures of Renal Function and Injury  
The following secondary endpoints will measure renal function and injury at week 52: 
1.
Proportion of subjects with eGFR < 60 mL/min/1.73 m2 measured by CKD-EPI. 
2.
Change in CKD stages from baseline.  
3.
Proportion of subjects with defined CKD stage 4 or 5. 
4.
Mean calculated eGFR using MDRD 4 variable model. 
5.
 eGFR by CKD-EPI over time based on serum creatinine collected at all visits indicated on the 
Schedule of Events. 
6.
Incidence of successful discontinuation of tacrolimus in recipients randomized to the 
NULOJIX® (belatacept)t treatment arm (Investigational Arm)  
7. 
The incidence of delayed graft function (DGF- refer to study definitions page). 
 Measures of Pancreatic Function and Injury  
The following secondary endpoints will measure pancreatic function and injury at week 52, in 
addition to times of graft dysfunction: 
1.
Proportion of subjects with full pancreatic graft function (i.e., insulin independent). 
2.
Partial pancreatic graft function (i.e., fasting c-peptide levels >0.3ng.mL (0.1nmol.L), but 
requiring insulin or oral hypoglycemic agents). 
3.
Pancreatic loss (i.e., c-peptide value <0.3ng/mL). 


 
 
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1.5.3   Measures of Cardiovascular and Metabolic Parameters 
The following will be measured at baseline, days 28, 84, and weeks 28, 36, and 52, unless otherwise 
stated below. 
1. 
HbA1c. 
2.  Fasting Blood Sugar (FBS). 
3. 
Standardized blood pressure measurement and use of anti-hypertensive medications. 
4. 
Fasting lipid profile (Total Cholesterol, non-HDL Cholesterol, LDL, HDL, and triglyceride) and 
the use of lipid lowering medications at baseline, and weeks 28 and 52.  
1.5.4     Incidence and Severity of Rejection and Anti- Donor Reactivity  
These endpoints will be assessed at 52 weeks post-transplant.  Biopsy grading and antibody 
assessments will be performed at the CTOT-15 Core Laboratories.  
1. 
The incidence and severity of acute cellular rejection defined by the Kidney Banff 2007 criteria 
and Pancreas Banff 2011 criteria within the first 52 weeks. 
2. 
The severity of first and highest grade of acute cellular rejection in the renal and pancreas biopsies  
3.    The incidence of humoral rejection in the renal and pancreas biopsies.  
4.    The prevalence of de novo anti-donor antibodies and anti-HLA antibodies. 
5.   The type of treatment of rejection. 
1.5.5    Safety Outcome Measures  
The following safety outcome measures will be assessed: 
1. 
The incidence of death, graft loss, or undetectable c-peptide.  
2.   The incidence of all adverse events (AEs) and serious adverse events (SAEs). 
3.   The incidence of selected AEs and SAEs including: 
o Infections requiring hospitalization or systemic therapy,  
o BK and CMV viremia (local center monitoring), 
o EBV Infection (local center monitoring), 
o Malignancy. 
1.6 
Mechanistic Secondary Endpoints  
Samples for Mechanistic studies will be collected as specified on the SOE.   
 
Immune Reactivity and Function 
1. 
Multiparameter flow cytometric enumeration and phenotyping of peripheral blood leukocyte 
subsets. ( Emory Cellular Core Laboratory) 
2. 
Protective immunity (Emory Viral Surveillance Core Laboratory) 
a. Viral load monitoring – EBV, CMV, Polyoma BKV & JCV 
b. Quantity and quality of CMV- and EBV- specific T cells and viral-specific antibody. 
3. 
Anti-donor responses 
a. Donor-specific antibody (Emory HLA Clinical Laboratory). 
b.    Immunohistochemistry of for-cause renal allograft biopsies (UCSF Pathology Core Lab).   
d. Gene expression, mRNA profiling in blood, urine and tissue (University of Alabama 
Molecular Core Laboratory).       
4.     Serum and urine proteins, selected biomarkers of acute and chronic kidney injury (University of 
Alabama Protein Assay Core Laboratory).       
 
 
 


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Background 
The overarching aim of CTOT-15 is to investigate a belatacept-based immunosuppressive regimen for 
the purpose of minimizing the dependence of subjects undergoing simultaneous kidney and pancreas 
on CNIs and steroids.   This study will test the hypothesis that the minimization of CNI exposure and 
avoidance of steroids will be facilitated by a belatacept-based regimen using thymoglobulin induction.  
We propose that the minimization of CNIs will lead to superior renal function with comparable rates of 
rejection compared with a tacrolimus-based maintenance immunosuppressive regimen in recipients of 
SPK.  A second goal is to achieve these ends without an increase in viral infections or virus-associated 
malignancies. 
CTOT-15 is designed to complement the CTOT-16 protocol conducted in renal transplants recipients and 
extend a comparable line of investigation to recipients of SPK.  This group is particularly underserved 
with respect to trials examining new immunosuppressive regimens.  In fact, there have been no 
multicenter, randomized, prospective trials in combined pancreas and kidney transplantation since the 
early 1990s.  Thus, immunosuppressive protocols in SPK transplantation are largely devised based on 
experiences with other transplanted organs and reason rather than data.  Data from the 2009 Annual 
Report of the SRTR indicated that in patients transplanted in 2008 immunosuppressive management 
after SPK transplantation is far from standardized with 16 different regimens reportedly used at the time 
of discharge following transplantation.  Induction was used in 83.4% of transplant procedures and CNI 
were the backbone of nearly all regimens with > 90% of recipients receiving tacrolimus or cyclosporine 
at the time of initial discharge. 
CTOT-15 is designed to be a first step in providing the potential benefits of an immunosuppressive 
regimen based on an agent other than a CNI to this underserved patient population.  Currently, SPK 
recipients have no alternatives to CNIs for maintenance immunotherapy.  As a result, 
immunosuppressive protocols remain dependent on these agents despite the long term nephrotoxicity 
and beta cell toxicity associated with these agents.  Furthermore, as abatacept, a precursor of NULOJIX® 
(belatacept), has been shown effective for treatment of the autoimmune disease psoriasis, we believe that 
NULOJIX® (belatacept) may offer unique benefits to pancreas transplant recipients with type I diabetes 
mellitus by acting to control the autoimmune response.  
CTOT-15 will also incorporate a battery of mechanistic assays that are designed to be integrated with 
many of the assays being performed as part of CTOTC-02 and CTOT-16.  These assays compare the 
effects of the belatacept-based regimen on protective antiviral immunity, alloimmunity, and 
autoimmunity.  The study design allows us to focus on how these two different classes of 
immunosuppressive agents affect memory responses including those that predate the transplant and 
those arising from homeostatic lymphocyte repopulation. 
Over the last two decades, the short-term results of organ transplantation have improved steadily in 
large part due to the introduction of increasingly potent immunosuppressants.  Calcineurin inhibitors 
(CNI), such as cyclosporine and tacrolimus, form the backbone of the vast majority of all 
immunosuppressive regimens currently used in abdominal organ transplantation (www.srtr.org).  The 
success of these CNI-based regimens is demonstrated by the ever-decreasing incidence of acute 
rejection and the ever-improving 1-year graft survival following de novo renal and extra-renal 
transplantation.  Disappointingly, this improvement in short-term outcomes has not resulted in 
concomitant improvements in long-term outcomes1,2.  The major factors limiting the long-term survival 
of transplanted kidneys and kidney transplant recipients are the near universal development of 


 
 
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interstitial fibrosis and tubular atrophy (IFTA)3 and the extremely high incidence of cardiovascular 
disease in transplant recipients.  This is particularly true for patients with type 1 diabetes undergoing 
simultaneous kidney and pancreas transplantation. 
It is widely recognized that CNIs are major contributors to the principal causes of the poor long-
term results that still plague transplantation - death from cardiovascular disease and post-
transplant renal failure, be it of the transplant or native kidneys. In the case of renal 
transplantation, virtually all patients develop lesions of CNI-induced nephrotoxicity and 
accelerated renal dysfunction 3. The impact of CNI-induced renal dysfunction is underscored by 
the well-recognized association between preservation of renal function at one year and long-
term graft survival4,5.  In addition to their nephrotoxic properties, CNIs are associated with a 
number of toxicities that increase the risk of death from cardiovascular disease, a factor that 
accounts for 45.7% of all graft losses following renal transplantation (USRDS Annual Report 
1999).  Most importantly, CNI are major contributors to the development of new onset diabetes 
mellitus (DM), the incidence of which approaches 30% following renal and 20% following liver 
transplantation 6,7,8.  These data suggest that CNI would also have a negative impact on beta cell 
function following pancreas transplantation, although SPK recipients remain largely dependent 
on these agents to prevent rejection.    Strikingly, new onset DM after renal transplantation is 
associated with more than a 60% increase in risk of graft failure and an almost 90% increase in 
risk of death9.  CNI also cause and exacerbate hypertension and dyslipidemia, both of which are 
known to accelerate cardiovascular disease10.  Together, these toxicities provide a compelling 
rationale for the identification of immunosuppressive agents that can replace CNI in 
maintenance immunosuppressive regimens following SPK.   
The importance of developing regimens less dependent upon CNI is reflected in the large 
number of studies in renal transplantation designed to avoid or replace CNI with less toxic 
immunosuppressive drugs.  That said, until the recent experience with belatacept identifying 
effective CNI alternatives has proven difficult. For example, attempts to use daclizumab, MMF 
and prednisone based regimens to spare CNI have been associated with excessive rates of 
ACR 11, 12. Similarly, attempts to use sirolimus as a CNI replacement have proven less than ideal. 
In the recent SYMPHONY trial, low-dose sirolimus in combination with Zenapax® (daclizumab) 
induction, MMF and prednisone was inferior to low-dose tacrolimus with respect to GFR, the 
incidence of ACR and the 1-year graft survival.  Intermediate results were obtained in patients 
treated with low-dose CsA13.  These data suggest that replacement of CNI with Rapamune® 
(sirolimus), as a means of avoiding the CNI toxicity may not improve the survival or function of 
renal grafts and likely not provide adequate immunoprotection for SPK subjects. 
Corticosteroids, another widely used class of immunosuppressive agents, are also associated with a 
myriad of metabolic and cardiovascular side effects reported to include weight gain, hypertension, 
glucose intolerance, abnormalities of lipids, cardiovascular and bone disease to name a few.  Several 
immunosuppressive regimens have been reported that avoid steroids thereby achieving favorable 
changes in metabolic profiles while simultaneously achieving acceptably low rates of rejection.  These 
have most frequently used either Thymoglobulin® (anti-thymocyte globulin) or Campath® 
(alemtuzumab) for induction and Prograf® (tacrolimus) and CellCept® (mycophenolate mofetil-
MMF) for maintenance immunosuppression.   
While the potential advantages of minimizing or avoiding both CNI and corticosteroids are both 
obvious and significant, to date there are no large randomized, prospective, multicenter studies 


 
 
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demonstrating either the efficacy or the safety of immunosuppressive regimens that avoid both CNI 
and corticosteroids following kidney and/or pancreas transplantation.  
NULOJIX® (BELATACEPT) IN TRANSPLANTATION 
One promising approach to avoid chronic therapy with CNI is to use the biologic immunosuppressive 
drug NULOJIX® (belatacept).  Belatacept is a new class of immunosuppressive therapy for 
transplantation.  It is a fusion protein that binds to the B7 molecules on the surface of antigen-
presenting cells (APCs) inhibiting the delivery of CD28-dependent 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. It is administered via intravenous infusion.  In the phase II and III, 
studies it has been given monthly during the maintenance phase for up to six years post-transplant.  
Belatacept is a soluble chimeric protein designed to selectively inhibit costimulation of T-cells. T-cells 
require 2 signals for activation. The first signal, which is antigen specific, is delivered by engagement of 
the T-cell receptor (TCR) with antigen presented in context with major histocompatibility complex 
molecules on the APC.  The second, or co-stimulatory signal, is delivered by engagement of co-
stimulatory ligand on the APC with a receptor on the T-cell.  A key co-stimulatory signal is provided 
by the interaction of B7-1 (CD80) and B7-2 (CD86) on APCs with CD28 expressed on T-cells.  In the 
absence of this second signal, the T-cell becomes anergic (unresponsive) or undergoes apoptosis. 
Conversely, if the T-cell becomes fully activated, CTLA4 (CD152) becomes expressed on the cell 
surface.  CTLA4 has a substantially higher avidity than CD28 for CD80 and CD86 (approximately 500- 
to 2,500-fold). The increased avidity of endogenous CTLA4, in comparison with CD28, affords a 
homeostatic mechanism to down-regulate T-cell activity.   
Belatacept was derived from CTLA4Ig (Abatacept, BMS-188667), a novel 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 APCs CD80/CD86, thus preventing T-cells from receiving the required 
second costimulatory signal.  CTLA4Ig has been shown to be efficacious in a wide variety of preclinical 
models and in participants with psoriasis and rheumatoid arthritis. With respect to transplantation, 
CTLA4Ig demonstrated efficacy in rodent models of transplantation, but did not demonstrate 
substantial efficacy in non-human primate models (cynomolgus monkeys).  Therefore belatacept, a 2 
amino acid variant of CTLA4Ig was developed. This alteration resulted in markedly increased binding 
avidity for B7 molecules. Belatacept was subsequently shown to have efficacy in non-human primate 
renal transplant model in which CTLA4Ig was not efficacious7.  Belatacept was also shown to be 
efficacious in Phase 2 clinical trial in de novo renal transplant recipients (Study IM103-100).  
2.2 
Preclinical and Clinical Experience 
2.2.1 
Preclinical Studies 
1. NULOJIX® (belatacept) is a higher avidity CTLA4Ig (abatacept) molecule.  The identification of 
CD28 as a critical costimulatory molecule for T cell activation led to considerable enthusiasm that the 
fusion protein CTLA4-Ig would prove to be as effective in primate and clinical transplantation studies 
as it was in initial rodent studies.  Unfortunately, the potency of this fusion protein was considerably 
less effective in non-human primate renal transplantation models as compared to rodent models.  
Recently, it was shown that the binding affinity of CTLA4-Ig was insufficient to completely block 
CD28/CD86 interactions in in vivo studies.  This may be related to the faster dissociation rate of 
CTLA4-Ig from CD86 as compared to CD80.  High avidity CTLA4-Ig molecules were developed at 


 
 
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Bristol Myers Squibb (BMS) using a mutagenesis and screening strategy of over 2,300 fusion proteins.  
Belatacept was identified as the most potent candidate, as it binds to human CD86 with 4-fold, and to 
CD80 with 2-fold increased avidity.   Belatacept was ten times more potent than CTLA4-Ig at 
inhibiting T cell proliferative responses in vitro.  
2. NULOJIX® (belatacept) prolongs renal allograft survival and synergizes with conventional 
immunosuppression in non-human primates.  Given the promising in vitro and in vivo 
immunosuppressive activity of belatacept, we tested the ability of the molecule to prevent renal 
allograft rejection in non-human primates.  Our initial studies with belatacept monotherapy (> 20 
µg/mL for 90 days post-transplant) demonstrated superior efficacy to CTLA4-Ig (median survival 
time for belatacept group 45d vs. 8d for CTLA4-Ig, p=0.008).  These data indicate that the enhanced 
binding activity of belatacept results in enhanced immunosuppressive activity when compared to the 
parent molecule CTLA4-Ig.  
We found that the combination of belatacept with the chimeric anti-human IL-2R mAb Simulect® 
(basiliximab) led to potentiation of efficacy, with 5 of 6 recipients demonstrating stable serum Cr and 
survival for > 100d.  However, after cessation of belatacept treatment (day 70), all recipients ultimately 
rejected their allografts.  Importantly, no adverse effects related to the administration of belatacept 
(e.g., thrombosis, hypertension, hyperglycemia, or hypercholesterolemia) were observed in any of the 
experimental animals by clinical assessment, by laboratory analysis, or at necropsy7. 
3. NULOJIX® (belatacept) inhibits the development of anti-donor antibody responses.  Despite progressive 
improvements in acute rejection rates in recent years the rate of allograft loss per year has remained 
essentially unchanged.  The development of antibodies specific for donor MHC molecules is thought 
to be an important factor contributing to the process of chronic rejection.  In addition to its possible 
role in the process of chronic rejection the development of antibodies to donor MHC antigens 
following transplantation has a major impact on the prospect of re-transplantation.  To evaluate the 
potential impact of belatacept treatment on this process we examined the development of anti-donor 
antibody responses in the various experimental groups.  Animals treated with basiliximab alone failed 
to develop detectable anti-donor antibodies, presumably because the allograft failed before an 
effective antibody response could be mounted.  Animals treated with MMF and CsA generated strong 
anti-donor antibody responses at the time of rejection (between days 25 and 36).  In contrast, none of 
the animals treated with belatacept developed anti-donor antibodies during therapy, even when 
rejection occurred during belatacept treatment.  Following withdrawal of NULOJIX® (belatacept), 
however, animals from each of the experimental groups developed anti-donor antibodies at the time 
of rejection. 
These data provide evidence that blockade of T-cell costimulatory pathways is a promising strategy 
for the development of potentially less toxic immunosuppressive medications. 
2.2.2 
NULOJIX® (Belatacept) in Clinical Studies 
NULOJIX® belatacept has been evaluated as a CNI-alternative in phase II and phase III studies in renal 
transplantation.  In the phase III BENEFIT trial, one of the largest studies in kidney allograft recipients, 
two NULOJIX® (belatacept) regimens were compared to cyclosporine as the cornerstone of 
maintenance therapy for standard risk recipients from standard risk donors.  All subjects received 
basiliximab induction and maintenance therapy consisting of mycophenolate mofetil (MMF)and 
prednisone.  At 12 months, both belatacept regimens demonstrated similar patient and graft survival as 
a composite endpoint compared with cyclosporine (95% MI; 97% LI; 93% cyclosporine).  Belatacept was 
associated with superior renal function compared with cyclosporine as measured by a composite renal 


 
 
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impairment endpoint (defined as CrCl < 60 ml/min/1.73 m2 or a decrease in CrCl of > 10% between 
months 3 and 12; 55% MI; 54% LI; 78% cyclosporine; P≤ 0.001 MI or LI vs. cyclosporine), and measured 
glomerular filtration rate at Month 12 (65, 63, and 50 mL/min for MI, LI and cyclosporine, respectively; 
P≤ 0.001 MI or LI vs. cyclosporine).  
However, belatacept-treated patients experienced a higher incidence (22% MI; 17% LI; 7% CsA) and 
grade (more frequent grade ≥2) of acute rejection episodes.  Despite this ostensibly more aggressive 
rejection profile, belatacept-treated subjects had very low rates of developing donor-specific antibodies 
that trended toward being lower than the rate observed in the cyclosporine comparison group.  
Importantly, belatacept-treated patients with acute rejection had better renal function at 12 months 
than cyclosporine-treated patients without acute rejection.  In addition, belatacept-treated subjects 
showed a trend toward less chronic allograft nephropathy and improved cardiovascular and metabolic 
profiles (superior blood pressure control and lipid profiles) compared with cyclosporine-treated 
subjects one year post-transplant, despite the increase in early acute rejection.   
Nonetheless, the diagnosis and treatment of acute rejection is associated with morbidity and significant 
expense.  In addition, the higher grades of rejection resulted in more frequent use of T cell depleting 
therapy for rejection, which is a risk factor the development of viral infections and post-transplant 
lymphoproliferative disorder (PTLD).  Therefore, despite the data that suggest that the short-term 
consequences of the higher rates and grades of rejection in belatacept-treated subjects are modest, 
studies designed to optimize the use of NULOJIX® (belatacept) are clearly warranted. 
Given that recipients of pancreas transplants are considered to be at higher immunologic risk and that 
the more than two thirds of SKP recipients transplanted in 2008 were treated with T cell depletion 
therapy (www.ustransplant.org/annual_reports/current/806a_kp.pdf), it will be important to explore 
regimens that incorporate potent induction agents. While for individual studies, the overall safety of 
belatacept and cyclosporine were similar, when data from all phase II and III studies were aggregated, 
more cases of post-transplant lymphoproliferative disorders were reported in the belatacept groups. 
Post-hoc analysis indicated the PTLD risk was highest in EBV sero-negative recipients who received 
kidneys from EBV sero-positive donors. Other risk factors for PTLD included CMV disease and 
treatment of acute rejection with thymoglobulin.  Based on these data, it is apparent that attention to 
measures aimed at reducing the risk of PTLD in belatacept-based regimens such as the avoidance of 
high risk subjects (EBV-negative) will be important in the design of future trials using belatacept. 
Belatacept in steroid-sparing regimens using lymphocyte depletion: There has been an exploratory 
phase II study (IM103-034) to evaluate belatacept as a maintenance agent in place of CNI in two steroid 
avoidance regimens. One regimen evaluated belatacept in combination with mycophenolate mofetil 
while another examined it in combination with sirolimus.  Both regimens included induction therapy 
with thymoglobulin.  Six-month rejection rates were 12 and 4% respectively.  Patient and graft survival 
were high and did not differ between the groups.  Eighty-two and 89% of subjects remained steroid-
free at six months.  This exploratory trial suggests that regimens combining lymphocyte depletional 
induction using induction polyclonal antibody preparation with belatacept may be safe and effective 
in appropriately selected populations.   
The goal of our proposed exploratory study is to determine the safety and efficacy of a regimen 
consisting of induction with Thymoglobulin® (Anti-thymocyte Globulin- Rabbit) and perioperative 
corticosteoids and maintenance with the low intensity regimen of NULOJIX® (belatacept), low dose 
tacrolimus (starting dose of 0.1mg/kg PO BID, followed by target trough levels of 5-8ng/mL during 
the first 24 weeks, and then 3-5 ng/mL until week 40), and MMF (1 gm bid).  Consideration to 
withdrawing tacrolimus at week 40 will be given to recipients who have not experienced biopsy-


 
 
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proven rejection, who have a normal 6 month management kidney biopsy (as is the standard of care at 
our centers), and who do not develop rejection subsequently.  Our comparison group consists of 
recipients treated with our standard of care regimen.  This regimen consists of induction with 
thymoglobulin and perioperative corticosteoids and maintenance with full-dose tacrolimus (targeting 
an initial tacrolimus trough level of 8 – 12ng/mL for the first 24 weeks, followed by 5-8ng/mL 
thereafter) and MMF at 1 gm bid.  
Belatacept was also evaluated as a CNI-alternative in the BENEFIT-EXT study, which assessed whether 
CNI avoidance using belatacept would also benefit recipients of kidneys from extended criteria donors 
(ECD).  As observed in the BENEFIT study, patient and graft survival with belatacept was non-inferior 
to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at Month 12. Fewer belatacept patients reached the 
composite renal impairment endpoint compared with cyclosporine (71% MI, 77% LI, and 85% 
cyclosporine; P=0.002 MI versus cyclosporine; P=0.06 LI versus cyclosporine). The measured 
glomerular filtration rate was 4–7 mL/min higher in the belatacept group compared to the cyclosporine 
group at Month 12. Finally, belatacept was associated with an improved cardiovascular risk profile 
compared to cyclosporine.  
While for individual studies, the overall safety of belatacept and cyclosporine were similar, when data 
from all phase II and III studies were aggregated, more cases of post-transplant lymphoproliferative 
disorders were reported in the belatacept groups. Post-hoc analysis indicated the PTLD risk was 
highest in EBV sero-negative recipients who received kidneys from EBV sero-positive donors. Other 
risk factors for PTLD included CMV disease and treatment of acute rejection with thymoglobulin.  
Based on these data, it is apparent that attention to measures aimed at reducing the risk of PTLD in 
belatacept-based regimens such as the avoidance of high risk participants (EBV-negative) and new 
approaches to avoid the need for thymoglobulin therapy for the treatment of rejection will be 
important considerations in the design of future trials using belatacept. 
Taken together these studies suggest that maintenance therapy with belatacept will provide the best 
alternative to the long-term use of calcineurin-inhibitors following renal transplantation. Belatacept 
achieved excellent one-year patient and graft survival, superior renal function, and an improved 
cardiovascular risk profile. However, unmet needs remain; 1) belatacept-based regimens were 
associated with higher rates and grades of acute rejection and 2) higher rates of PTLD.  Importantly, 
these adverse events associated with belatacept were observed in patients receiving corticosteroids.  
This raises the concern that the avoidance of steroids in patients maintained on belatacept may further 
increase the incidence and severity of rejection and its adverse sequelae.  
Belatacept in calcineurin-inhibitor and steroid free regimens: A pilot trial utilizing thymoglobulin 
induction, and NULOJIX® (belatacept) and sirolimus based maintenance immunosuppression was 
used to protect pancreatic islet cell transplants following transplantation into Type 1 diabetic 
recipients. This regimen avoided the use of steroids and calcineurin-inhibitors to minimize both beta 
cell toxicity as well as nephrotoxicity. All five patients in this trial became insulin independent, and 
remained insulin independent for greater than one year. No patients developed significant side effects 
related to the study drugs, and none were sensitized to alloantigen. Furthermore, there was no 
deterioration in renal function using this regimen which avoided CI (Transplantation 2010; 1594-1601).  
Belatacept in Steroid-sparing regimens: There has been an exploratory phase II study (IM103-034) to 
evaluate belatacept as a maintenance agent in place of CNI in two steroid avoidance regimens. One 
regimen evaluated belatacept in combination with mycophenolate mofetil (MMF) while another 
examined it in combination with sirolimus.    Both regimens included induction therapy with 
thymoglobulin.  Six-month rejection rates were 12 and 4% respectively.  Patient and graft survival was 


 
 
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Version 7.0 June 28, 2016 
high and did not differ between the groups.  Eighty-two and 89% of participants remained steroid-free 
at six months.  These data suggest that belatacept may provide a means to avoid both CNI and 
corticosteroids but indicate that further investigations designed to optimize the regimen are warranted 
in order to achieve rates of rejection comparable to those observed in standard of care CNI-based 
regimens.   
SELECTION OF INDUCTION STRATEGIES TO FACILITATE SAFE AND EFFECTIVE 
STEROID AND CNI-FREE BELATACEPT-BASED MAINTENANCE 
IMMUNOSUPPRESSIVE REGIMENS 
Given the higher rates and grades of rejection associated with the belatacept regimens evaluated 
in the phase3 studies, it is likely that more potent induction strategies than basiliximab will be 
required to facilitate regimens that avoid steroids and calcineurin-inhibitors.  As outlined above 
the phase II (IM103-034) study has shown promise that this may be an achievable goal using 
strategies that include lymphocyte depletion with thymoglobulin.  
Since Type I diabetes is an autoimmune disease, immunosuppressive strategies must target both 
the alloimmune response as well as the recurrent autoimmune response following pancreas 
transplantation.  Since the latter is driven by a memory-cell response, it is imperative that an 
immunosuppressive regimen must target T-cells with memory for islet autoantigen.  Strategies 
using CTLA4-Ig have been effective in blocking the activation of naïve T-cells, but are less 
effective in preventing reactivation of memory cells14,15. The potential need for immunodepletion 
prior to the introduction of co-stimulatory/adhesion blockade is further supported by human 
data suggesting the lack of CD28 expression in effector cells derived from memory CD4+ cells16. 
There are several immunodepleting agents which have been tested and found effective for this 
specific indication, but the most extensive experience has been with rabbit anti-thymocyte 
globulin (Thymoglobulin).  Rabbit ATG is a polyclonal antibody preparation that depletes T and 
B cells following IV administration, and has emerged as the superior agent for induction therapy 
in solid organ transplantation.  Thymoglogulin is the current induction agent for all solid organ 
pancreas transplants performed at UCSF (30/year) and most centers in the US, and is in part 
responsible for the decrease in early rejection rates from 80% to less than 15 % even in steroid 
free regimens17. An early limited human study with equine anti-thymocyte globulin (ATG) with 
new onset Type diabetes mellitus suggested efficacy in prolonging the honeymoon phase18, and 
has prompted a new trial studying the efficacy of Thymoglobulin in the same scenario sponsored 
by the NIH Immune Tolerance Network. Thymoglobulin or ATG, either alone or in combination 
with other agents, has also been used to treat various autoimmune conditions, including 
Wegner’s granulomatosis19, lupus20, multiple sclerosis21 and aplastic anemia22. 
The large clinical experience with Thymoglobulin as a highly effective induction agent for the 
immunogenic solid organ pancreas transplant, as well as evidence that is effective against 
multiple autoimmune diseases, make it an ideal induction agent to be used in conjunction with a 
maintenance regimen focusing on co-stimulatory blockade.  In fact, one of the first clinical islet 
transplantation trials which resulted in long term insulin independence with a single infusion of 
islets utilized Thymoglobulin induction23. Thymoglobulin induction was successfully used in 
another islet transplant study in conjunction with belatacept in a steroid and calcineurin free 
regimen. This trial also resulted in long term insulin independence following islet transplantation, 
and provides the most relevant data suggesting that thymoglobulin induction can provide safe 
and effective immunosuppression following beta cell replacement in the Type I diabetic recipient 
in a regimen based on costimulation blockade24.  


 
 
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As a second approach to facilitate steroid-free belatacept-based regimens we will evaluate an 85 day 
course of induction with low-dose tacrolimus combined with belatacept and mycophenolate mofetil 
(MMF) maintenance therapy.  We have explored a similar approach at the Emory Transplant Center in 
a clinical islet transplant trial using the anti-CD11a mAb, efalizumab. In this study four patients 
received one allogeneic islet infusion.  The immunosuppressive regimen consisted of daclizumab 
induction, induction with a tapering dose of tacrolimus (discontinued at six months), belatacept and 
mycophenolate mofetil.  All four participants achieved insulin independence associated with positive 
determinations of c-peptide and a normalized hemoglobin A1C after a single islet infusion.  Rejection-
free insulin independent survival of 9, 13, 16, and 29 months was observed until efalizumab was 
withdrawn from the regimen following Genzyme’s decision to withdraw it from the market.  
Importantly, none of these 4 patients experienced renal dysfunction associated with the short course of 
tacrolimus (Prograf®).  These results suggest that induction using a low dose of tacrolimus may 
provide protection from acute rejection during the critical early post-transplant period.   
Short-term low-dose tacrolimus combined with belatacept and mycophenolate mofetil has potential 
advantages over T cell depletion approaches with Thymoglobulin® or alemtuzumab.  These include 1) 
the ability to titrate tacrolimus levels and the more rapid reversibility of the immunosuppressive effect 
of tacrolimus relative to thymoglobulin if over immunosuppression is encountered, 3) fewer long-term 
effects on the immune system than T cell depletion approaches, and 4) the avoidance of cytokine 
release-related peri-infusional toxicities.   Two potential disadvantages of this approach include the 
potential for CNI-induced nephrotoxicity and the need for therapeutic drug monitoring.  Based on 
data from the Rapamune Maintenance Regimen Study, the STN study and our observations in our 
islet trial we anticipate that the renal function benefits of belatacept at one year will not be adversely 
affected by a 85 day course of low dose (Prograf®) tacrolimus.  Assessment of these issues will be an 
important focus of our trial.   
In addition to the studies already discussed, belatacept has been studied in three BMS-sponsored 
clinical trials protocols: IM103-001 (completed), IM103 002 (completed), and IM103-100 (completed). 
Protocol IM103-001 was a Phase I, randomized, double blind, placebo-controlled study to assess the 
safety, pharmacokinetics and immunogenicity of escalating doses of intravenously administered 
belatacept in healthy volunteers.  Protocol IM103-002 was a Phase II, randomized, double blind, 
placebo-controlled study to evaluate the safety, preliminary clinical activity, immunogenicity and 
pharmacokinetics of multiple doses of belatacept and CTLA4Ig administered intravenously to 
participants with active rheumatoid arthritis.  IM103-100 was a Phase II, randomized, open-label, 
controlled study to directly compare the safety and preliminary clinical activity of belatacept with 
(Neoral®) cyclosporin in kidney transplant recipients. 
Results of Phase I studies pharmacokinetics and safety of a single dose, dose escalation study of 
belatacept in Healthy Volunteers (IM103-001): 
A single-dose Phase I study with belatacept was performed in 40 healthy volunteers.  Participants 
received single IV infusions of 0.1, 1, 5, 10, or 20 mg/kg belatacept.  At each dose level, 6 participants 
received active drug and 2 received placebo.  Pharmacokinetic sampling and analysis indicated that 
Cmax values increased in a dose-proportional manner and were in a range similar to that observed 
with the parent molecule.  Both Cmax and AUC (area under the curve) appeared to increase in ratio 
comparable to the dose increment ratio.  The half-life ranged between 176 - 210 hr (~7-9 days) between 
the 5 and 20 mg/kg dose levels. Overall, the pharmacokinetics of belatacept appears to be linear 
following intravenous (IV) administration to humans. 


 
 
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Review of the safety data from this trial indicates that single, IV doses of belatacept of 0.1 to 20.0 
mg/kg were well tolerated.  No deaths or serious adverse events were reported. No histamine-like 
peri-infusional AEs were reported.  No clinically significant changes in vital signs or laboratory 
parameters were observed.  There was no evidence for the development of anti-belatacept antibodies. 
Results of a Phase II Study of belatacept in Rheumatoid Arthritis (IM103-002) 
Study IM103-002 was a Phase 2 pilot study that assessed the efficacy, safety, and immunogenicity of 
multiple IV doses of belatacept, CTLA4Ig, and placebo in 214 participants with RA.  Eligible 
participants had a diagnosis of RA for ≤ 7 years, had failed at least 1 disease-modifying anti-rheumatic 
drug therapy, including etanercept, and had active disease (≥ 10 swollen joints, ≥ 12 tender joints, an 
erythrocyte sedimentation rate ≥ 28 mm/h, and morning stiffness ≥ 45 minutes).  Overall, belatacept 
demonstrated dose-dependent efficacy in this participant population, as evidenced by American 
College of Rheumatology scores. With respect to safety, no deaths were reported during the treatment 
or follow-up period (through Day 169), and 12 participants reported SAEs, although no SAEs were 
considered drug related by the investigators. 
Results of a Phase II Study of belatacept in Solid Organ Transplantation (IM103-100) 
Study IM103-100 was a 1-year, partially-blinded, randomized, active-controlled, multiple-dose, 
multicenter non-inferiority study in de novo renal transplant recipients.  All participants received 
basiliximab induction and background maintenance immunosuppression with MMF and 
corticosteroids.  Participants were randomized in a 1:1:1 ratio to treatment with belatacept (more 
intensive [MI] or less intensive [LI] regimens) or CsA (open-label dosed twice daily to achieve a 
specified trough serum concentration range).  Belatacept was administered in a double-blind fashion, 
with the investigator and participant blinded to the identity of the belatacept dose regimen. 
Belatacept participants were dosed with 10 mg/kg on Days 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, and 169 
(MI regimen) or 10 mg/kg on Days 1, 15, 29, 57, and 85 (LI regimen).  Participants were reallocated on 
Days 85 (LI regimen) and 169 (MI regimen) to a 5 mg/kg dose of the drug every 4 or 8 weeks through 
Day 365. 
The primary efficacy variable was the incidence of clinically-suspected and biopsy-proven acute 
rejection (CSBPAR) at 6 months post transplantation.  CSBPAR was defined as an increase in serum 
creatinine (SCr) of at least 0.5 mg/dL compared to the baseline value in the absence of other factors 
known to adversely affect renal function that led the investigator to suspect acute rejection, which was 
then confirmed by centrally-assessed biopsy.  Secondary efficacy variables were the incidence of all 
biopsy-proven acute rejections (BPARs), including those without an increase in SCr of at least 
0.5 mg/dL, as well as the composite endpoints of CSBPAR or presumed acute rejection and BPAR or 
presumed acute rejection at 6 months and 1 year, and death and/or graft loss at 1 year.  ‘Presumed 
acute rejection’ was defined as an elevation in SCr (at least 0.5 mg/dL compared to the baseline value in 
the absence of other factors known to adversely affect renal function) that led the investigator to suspect 
and treat the participant for acute rejection without a biopsy to confirm the diagnosis, or despite a 
biopsy that did not confirm acute rejection.  All biopsies were assessed in a blinded fashion by a central 
pathologist.  The primary cause of graft loss and death was also adjudicated. 
The safety evaluation included AEs (including infections), vital signs, physical examinations, 
electrocardiograms, and laboratory parameters (hematology, biochemistry, and urinalysis). Topics of 
special interest were renal function (GFR, as determined by iohexol clearance, SCr, and calculated 
creatinine clearance or GFR at 1, 6, and 12 months), BP parameters (systolic diastolic pressure [SBP] and 


 
 
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diastolic blood pressure [DBP], presence of hypertension), fasting serum cholesterol and triglycerides 
(TGs), and the presence of post-transplant diabetes mellitus (PTDM). 
The efficacy and safety results for Study IM103-100 study are presented in the following sections.  For 
more detailed information on the efficacy and safety of belatacept, see the Investigator Brochure.  
Overall, the mean duration of exposure was comparable across all 3 treatment groups.  Specifically, 
mean duration of exposure was 300, 308, and 294 days in the belatacept MI and LI groups and the CsA 
group, respectively. 
Acute Rejection 
The primary endpoint, CSBPAR at 6 months, occurred infrequently in all treatment groups.  The 
incidence rate was slightly lower in the belatacept groups than in the CsA group.  The criteria for non-
inferiority to CsA were easily satisfied for both belatacept groups; however, the number of events was 
too small to support any further conclusions regarding the relative efficacy of the 3 regimens.  The 
distribution of events by severity (as indicated by histological grade) was similar across the 3 treatment 
groups.  Identical results were observed at 12 months. 
The secondary endpoint of BPAR occurred 2 to 4 times more frequently than the primary endpoint of 
CSBPAR, indicating that most BPAR were subclinical (i.e., not associated with an increase in 
SCr ≥ 0.5 mg/dL).  These episodes of subclinical rejection were observed on biopsies taken to satisfy the 
protocol requirements, according to local practice, or for other reasons than an increase in SCr ≥ 0.5 
mg/dL. 
BPAR occurred most frequently in the belatacept LI group.  As the rate of CSBPAR was comparable 
across treatment groups, the difference in the rate of BPAR was due to an increase in the number of 
subclinical rejection episodes in the belatacept LI arm.  In addition, reallocation of participants to an 8-
week infusion schedule rather than a 4-week infusion schedule in the maintenance phase was associated 
with an increased frequency of subclinical rejection. 
Overall, the histological severity grade of acute rejection episodes appeared to be similar across the 3 
treatment groups.  While Grade IIB rejection, as assessed by Banff 97 criteria, occurred more frequently 
in the belatacept groups, the number of such events was small, and the belatacept LI: 1.1%-13%; and 
CsA: 0%-6.5%). 
Recurrent Acute Rejection 
Overall, the average number of rejection episodes per participant (~1.2) was similar among the 3 
treatment groups. 
Chronic Allograft Nephropathy (CAN) 
Biopsy specimens were also examined for CAN by an independent blinded central histopathologist 
using Banff 97 working classification of kidney transplant pathology9.  By Month 12, CAN was 
approximately 30%-50%, in relative terms, less common with belatacept than with CsA. 
Participant and Graft Survival 
Death and/or graft loss occurred infrequently in all treatment groups, and was least frequently reported 
in the belatacept LI group.  Most graft losses occurred for technical, rather than immunological, reasons. 
Five deaths (4 in the CsA group and 1 in the belatacept MI group) occurred and were analyzed 
according to the intent-to-treat (ITT) principle.  Two of these deaths – both in the CsA group – occurred 
on therapy or within 56 days of the last dose of study therapy.  Accordingly, these deaths also are 
counted under the prespecified safety conventions. 


 
 
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Three other deaths qualify under the ITT principle, but not under the safety conventions because they 
either never received study drug or the death was an event subsequent to the discontinuation of study 
drug + 56 days.  One death in the CsA group and 1 in the belatacept MI group, occurred > 56 days after 
the last dose of study therapy.  One death in the CsA group occurred in a participant who was 
randomized, but never treated. 
Adverse Events 
Overall Adverse Events 
The overall incidence of AEs is summarized in Table 1A. 
Table 1A: 
Overall Incidence of Adverse Events Through Day 56 After 
Double-blind Period (Randomized, Transplanted and Treated 
Population) - Study IM103-100 
 
No. (%) of Participants 
 
Belatacept 
MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Discontinued Due to Adverse Events 
13 (17.6) 
15 (21.1) 
14 (19.7) 
Related Adverse Events 
43 (58.1) 
40 (56.3) 
50 (70.4) 
Serious Adverse Events 
50 (67.6) 
52 (73.2) 
41 (57.7) 
Related Serious Adverse Events 
20 (27.0) 
23 (32.4) 
21 (29.6) 
Deathsa 
0 
0 
2 (2.8) 
• a 
Includes all deaths up to 56 days after last dose of study therapy, by therapy received. 
CsA = cyclosporine, LI = less intensive, and MI = more intensive. 
The rate of AEs, including AEs resulting in discontinuation, was similar across the 3 treatment 
groups. The rate of SAEs was somewhat higher for both belatacept treatment groups than for the 
CsA treatment group. As described below, this difference is due to an increased number of 
reports of AEs of transplant rejection, not subsequently confirmed as transplant rejection, in the 
belatacept treatment groups. 
 
 


 
 
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The incidence of AEs, by Medical Dictionary for Drug Regulatory Activities (MedDRA) system 
organ class (SOC) and preferred term, is summarized in Table 1B. 
Table 1B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103-100 
 
No. (%) of Participants 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept 
MI 
(N=74) 
Belatacept 
LI 
(N=71) 
CsA 
(N=71) 
Participants with Any Adverse Events 
73 (98.6) 
69 (97.2) 
68 (95.8) 
Blood & Lymphatic System Disorders 
29 (39.2) 
28 (39.4) 
40 (56.3) 
 
Leukopenia 
14 (18.9) 
12 (16.9) 
21 (29.6) 
 
Anemia 
13 (17.6) 
12 (16.9) 
21 (29.6) 
Cardiac Disorders 
10 (13.5) 
10 (14.1) 
10 (14.1) 
Endocrine Disorders 
4 (5.4) 
8 (11.3) 
9 (12.7) 
Gastrointestinal Disorders 
45 (60.8) 
45 (63.4) 
42 (59.2) 
 
Nausea 
19 (25.7) 
18 (25.4) 
16 (22.5) 
 
Diarrhea 
17 (23.0) 
18 (25.4) 
17 (23.9) 
 
Constipation 
16 (21.6) 
22 (31.0) 
20 (28.2) 
 
Vomiting 
11 (14.9) 
14 (19.7) 
11 (15.5) 
General Disorders & Administration Site 
Conds. 
43 (58.1) 
40 (56.3) 
42 (59.2) 
 
Edema Peripheral 
23 (31.1) 
20 (28.2) 
21 (29.6) 
 
Pyrexia 
15 (20.3) 
19 (26.8) 
15 (21.1) 
 
Pain 
7 (9.5) 
6 (8.5) 
9 (12.7) 
 
Fatigue 
6 (8.1) 
6 (8.5) 
9 (12.7) 
 
Edema 
6 (8.1) 
7 (9.9) 
11 (15.5) 
Immune System Disorders 
22 (28.7) 
29 (40.8) 
16 (22.5) 
 
Transplant Rejection 
19 (25.7) 
23 (32.4) 
11 (15.5) 
Infections & Infestations 
54 (73.0) 
52 (73.2) 
53 (74.6) 
 
Urinary Tract Infection 
17 (23.0) 
17 (23.9) 
22 (31.0) 
 
Cytomegalovirus Infection 
11 (14.9) 
10 (14.1) 
13 (18.3) 
 
Nasopharyngitis 
9 (12.2) 
10 (14.1) 
11 (15.5) 


 
 
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Table 1B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103-100 
 
No. (%) of Participants 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept 
MI 
(N=74) 
Belatacept 
LI 
(N=71) 
CsA 
(N=71) 
Injury, Poisoning & Procedural 
Complications 
44 (59.5) 
45 (63.4) 
45 (63.4) 
 
Incision Site Complication 
17 (23.0) 
16 (22.5) 
13 (18.3) 
 
Post Procedural Pain 
14 (18.9) 
17 (23.9) 
15 (21.1) 
 
Graft Dysfunction 
9 (12.2) 
10 (14.1) 
10 (14.1) 
Investigations 
26 (35.1) 
22 (31.0) 
29 (40.8) 
 
Blood Creatinine Increased 
13 (17.6) 
10 (14.1) 
13 (18.3) 
Metabolism & Nutrition Disorders 
36 (48.6) 
35 (49.3) 
42 (59.2) 
 
Hypophosphatemia 
14 (18.9) 
24 (33.8) 
15 (21.1) 
 
Hyperlipidemia 
9 (12.2) 
8 (11.3) 
6 (8.5) 
 
Hypercholesterolemia 
6 (8.1) 
4 (5.6) 
9 (12.7) 
 
Hypokalemia 
5 (6.8) 
5 (7.0) 
9 (12.7) 
Musculoskeletal & Connective Tissue 
Disorders 
26 (35.1) 
20 (28.2) 
20 (28.2) 
 
Arthralgia 
8 (10.8) 
6 (8.5) 
4 (5.6) 
 
Back Pain 
8 (10.8) 
3 (4.2) 
6 (8.5) 
Nervous System Disorders 
26 (35.1) 
20 (28.2) 
26 (36.6) 
 
Headache 
13 (17.6) 
10 (14.1) 
8 (11.3) 
 
Tremor 
8 (10.8) 
10 (14.1) 
14 (19.7) 
Psychiatric Disorders 
18 (24.3) 
27 (38.0) 
20 (28.2) 
 
Insomnia 
12 (16.2) 
19 (26.8) 
17 (23.9) 
Renal & Urinary Disorders 
28 (37.8) 
27 (38.0) 
25 (35.2) 
Reproductive System & Breast Disorders 
7 (9.5) 
12 (16.9) 
7 (9.9) 
Respiratory, Thoracic & Mediastinal 
Disorders 
23 (31.1) 
24 (33.8) 
29 (40.8) 
 
Cough 
7 (9.5) 
8 (11.3) 
11 (15.5) 


 
 
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Table 1B: 
Most Frequent Adverse Events (At Least 10% in Any Group) 
Through Day 56 After Double-blind Period (Randomized, 
Transplanted and Treated Population) - Study IM103-100 
 
No. (%) of Participants 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept 
MI 
(N=74) 
Belatacept 
LI 
(N=71) 
CsA 
(N=71) 
 
Dyspnea 
5 (6.8) 
6 (8.5) 
9 (12.7) 
Skin & Subcutaneous Tissue Disorders 
26 (35.1) 
18 (25.4) 
18 (25.4) 
Vascular Disorders 
27 (36.5) 
29 (40.8) 
29 (40.8) 
 
Hypertension 
16 (21.6) 
17 (23.9) 
22 (31.0) 
Note:  
The number of adverse events for transplant rejections includes investigator-reported transplant  
 
 
rejections, often obtained at the time of biopsy, irrespective of central blinded histological  
 
 
evaluation and/or local evaluation.  
CsA = cyclosporine, LI = less intensive, MedDRA = Medical Dictionary of Drug Regulatory Activities, and MI = more intensive. 
Transplant rejection was reported more commonly with both doses belatacept than with CsA.  
Subsequent evaluation revealed that these reports reflected episodes of suspected acute rejection later 
disproved by central biopsy, as well as episodes that resolved spontaneously without treatment.  All 
reported AEs of transplant rejection were subsequently confirmed by biopsy.  AEs commonly 
observed during CsA treatment, such as anemia, leukopenia, hirsutism, tremor, hypomagnesemia, 
and hypertension, were reported less frequently with belatacept than with CsA in this study.  
Infectious complications occurred with comparable frequency. Pulmonary edema and proteinuria 
were reported more frequently with belatacept than with CsA.   The significance of these events 
requires further evaluation. 
Serious Adverse Events 
SAEs were reported somewhat more frequently in the belatacept treatment groups than in the CsA 
group (see Table 1C).  This difference is accounted for by an increased frequency of reporting acute 
rejection as an AE in the belatacept groups.  Subsequent evaluation revealed that these reports 
reflected episodes of suspected rejection later disproved by central biopsy, as well as episodes that 
resolved spontaneously without treatment. 
Three participants treated with the belatacept MI regimen developed post-transplant 
lymphoproliferative disorder (PTLD).  One case occurred on treatment and the others occurred 2 
months and > 1 year after discontinuation of the study drug.  The participant that developed PTLD 
on treatment was Epstein-Barr virus (EBV) negative and received an EBV positive allograft.  This 
participant was diagnosed with PTLD 9 months after transplantation from a biopsy of a lesion near 
the basal ganglia, and belatacept was discontinued.  The participant died 5 months later from 
Pneumocystis carinii pneumonia and recurrent Cytomegalovirus (CMV) infection while receiving 
dexamethasone and sirolimus.  A second participant was diagnosed with PTLD 4 months after 
transplantation and 2 months after discontinuation of belatacept with initiation of tacrolimus 
(Prograf®).  The diagnosis was based upon a renal allograft biopsy performed for suspected acute 
rejection.  The tumor tissue and urine tested positive for EBV, and retrospective analysis of stored 


 
 
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sera from the recipient tested negative for EBV.  This participant underwent a transplant 
nephrectomy. A final participant received 4 doses of belatacept before discontinuation for a Grade 
IIB rejection, which was treated with a 10-day course of OKT3.  PTLD was diagnosed from an 
excisional biopsy of an anterior cervical lymph node 12 months after discontinuation of study drug. 
Additional information on these cases is provided in the Investigator Brochure. 
One participant treated with the belatacept MI regimen developed breast cancer after 12 months of 
treatment. In retrospect, the baseline mammogram for this participant was abnormal.  No 
participants treated with the belatacept LI regimen developed malignancies.  Two participants 
treated with CsA developed malignancies – squamous cell carcinoma of the skin and thyroid cancer 
– while a third participant developed a parathyroid nodule not yet confirmed to be malignant. 
 
Table 1C: 
Most Frequent (At Least 5% in Any Group) Serious Adverse 
Events Through Day 56 After Double-blind Period 
(Randomized, Transplanted and Treated Population) - Study 
IM103-100 
 
No. (%) of Participants 
MedDRA System Organ Class 
 
Preferred Term 
Belatacept MI 
(N=74) 
Belatacept LI 
(N=71) 
CsA 
(N=71) 
Participants with Any Serious Adverse Events 
50 (67.6) 
52 (73.2) 
41 (57.7) 
Blood & Lymphatic System Disorders 
2 (2.7) 
3 (4.2) 
4 (5.6) 
Gastrointestinal Disorders 
7 (9.5) 
7 (9.9) 
5 (7.0) 
General Disorders & Administration Site Conds. 
5 (6.8) 
8 (11.3) 
7 (9.9) 
 
Pyrexia 
4 (5.4) 
8 (11.3) 
6 (8.5) 
Immune System Disorders 
20 (27.0) 
23 (32.4) 
13 (18.3) 
 
Transplant Rejection 
18 (24.3) 
20 (28.2) 
9 (12.7) 
Infections & Infestations 
17 (23.0) 
12 (16.9) 
18 (25.4) 
 
Cytomegalovirus 
5 (6.8) 
4 (5.6) 
7 (9.9) 
 
Pyelonephritis 
4 (5.4) 
1 (1.4) 
2 (2.8) 
 
Urinary Tract Infection 
2 (2.7) 
0 
4 (5.6) 
Injury, Poisoning & Procedural Complications 
8 (10.8) 
6 (8.5) 
9 (12.7) 
Investigations 
8 (10.8) 
2 (2.8) 
4 (5.6) 
 
Blood Creatinine Increased 
8 (10.8) 
2 (2.8) 
4 (5.6) 
Metabolism & Nutrition Disorders 
1 (1.4) 
2 (2.8) 
4 (5.6) 
Renal & Urinary Disorders 
9 (12.2) 
11 (15.5) 
9 (12.7) 
Respiratory, Thoracic & Mediastinal Disorders 
6 (8.1) 
3 (4.2) 
4 (5.6) 
Vascular Disorders 
3 (4.1) 
5 (7.0) 
8 (11.3) 
• 
CsA = cyclosporine, LI = less intensive, MedDRA = Medical Dictionary of Drug Regulatory Activities, and 
MI = more intensive. 
 


 
 
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IM103-100 Study Follow-Up 
The most recent unpublished analysis of the IM103-100 trial belatacept + CellCept® and low 
dose steroid (5-10 mg prednisone per day) in clinical renal transplantation shows that there are 
75 participants on belatacept and CellCept-based regimens in long-term extension trials from 
the original IM103-100 study with no reports of subsequent post-transplant lymphoproliferative 
disorder in this group. 
Nine of these long-term study participants are being followed at Emory University. Out of the 9, 
one was non-compliant with therapy and had a rejection episode that was successfully reversed. 
Eight of the 9 Emory participants have excellent, stable renal function (mean Cr = 0.80) with up 
to 6 years of follow-up.  
Preliminary results of a multicenter, phase II study to explore the use of Belatacept as a means 
of avoiding the long-term use of both calcineurin inhibitors and corticosteroids in renal 
transplant recipients (CTOT-10) 
CTOT-10 was designed as a multicenter, 
prospective randomized trial to compare 
maintenance immunosuppressive regimens 
consisting of belatacept and MMF to a 
regimen consisting of tacrolimus and MMF.  
All regimens included a perioperative course 
of corticosteroids.  The details of the three 
regimens are shown in the adjacent figure.  
The primary hypothesis was that the use of 
belatacept in place of tacrolimus would 
improve renal function and the metabolic 
profile in patients undergoing a primary 
renal transplant without increasing episodes 
of rejection, significant infections, or 
malignancies.  A total of 19 subjects were enrolled in 3 participating centers between 11/10/11 
and 4/12/12.  The total number of subjects enrolled in each of the 3 groups were Group 1 N = 6, 
Group 2 N = 6, and Group 3 N = 7.  The investigators, after consultation with the NIH Medical 
Officer, chose to pause enrollment in the spring 2012 to allow review of a number of SAEs that 
may have been related to the study regimen.  The SAEs of concern by group were as follows 
(reported at the time of this protocol version):  Group 1 – one episode of intraoperative renal 
artery thrombosis that required thrombectomy but had no adverse sequelae.  Group 2 – one 
episode each of renal artery thrombosis, renal vein thrombosis, and renal artery dissection, each 
of which resulted in graft loss.  Three episodes of acute cellular rejection was reported in two 
patients (Banff grades 1A, 1A and 2B), each episode of rejection responded to therapy with a 
returned to baseline normal renal function.  Group 3 – four episodes of acute rejection in three 
subjects (Banff grades 2A, 2A, 2A, and 2B).  Each of the episodes of rejection responded to 
therapy with a return of renal function to baseline.  Following review by the NIH DSMB and the 
FDA and further deliberation by the investigators and the NIH Medical Officer, enrollment in 
CTOT-10 was permanently halted with the enrolled patients transitioned to a protocol designed 
to gather long-term safety data.   
In considering the potential etiologies of the vascular events, it was felt that the renal artery 
dissection (group 2) that occurred two weeks following the transplant was technical in nature 


 
 
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Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 7.0 June 28, 2016 
and likely related to an unappreciated injury caused by the vascular clamp at the time of 
surgery.  The other 3 vascular events were of uncertain etiology but not felt to have a technical 
component.  Each of the three occurred in patients receiving alemtuzumab and was associated 
with perioperative episodes of relative hypotension and fever.   
With regards to the episodes of acute rejection, two of the four episodes in Group 3 occurred 
shortly after the withdrawal of tacrolimus.  With this in mind, the current protocol (CTOT-15) 
specifies that the administration of tacrolimus in Group 2 be administered to 40 weeks.   


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CTOT-15 will study individuals undergoing de novo simultaneous pancreas and kidney 
transplantation (SPK) from a deceased organ donor.  This study will test the hypothesis that a 
regimen of induction with Thymoglobulin® (anti-thymocyte globulin- Rabbit) followed by 
maintenance with NULOJIX® (belatacept) and minimization or withdrawal of calcineurin 
inhibitors (CNI) will result in comparable rates of rejection and  superior renal function as 
compared with a tacrolimus-based maintenance immunosuppressive regimen in recipients of 
SPK.  
A transplanted pancreas can elicit both an alloimmune response and an autoimmune response 
from the recipient. Individuals undergoing SPK transplantation are presumed to be at greater risk 
of immunologic allograft injury than those that undergo kidney transplant alone; thus, they are 
treated with more aggressive CNI-based immunosuppressive regimens. However, the population 
that presents for SPK is also at higher risk for the morbidities associated with CNI due to the 
consequences of long-standing diabetes. This proposal is an attempt to extend the potential 
benefits of reduced CNI exposure, facilitated by maintenance therapy with NULOJIX® 
(belatacept), to recipients of SPK transplantation.   
 
 
 


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 RATIONALE FOR INVESTIGATIONAL THERAPEUTIC REGIMEN  
Rationale for Co-Stimulation Blockade in Pancreas Transplantation 
The potential efficacy of co-stimulation blockade to minimize or eliminate long term CNI should be 
tested in the setting of pancreas transplantation, as this group is particularly underserved with respect 
to trials examining new immunosuppressive regimens.   As a result of the higher maintenance doses 
of CNI required to prevent rejection of simultaneously transplanted pancreas and kidney transplants 
(SPK), long term function of the kidney allograft is compromised by CNI toxicity.  In patients 
experiencing severe CNI induced toxicities, such as neurotoxicity or Hemolytic Uremic Syndrome 
(HUS), there are no alternative agents for effective immunologic protection.  Finally, the calcineurin 
inhibitors are toxic to beta cells, and the development of strategies to avoid these agents will facilitate 
long term preservation of metabolic function of the pancreas allografts.  For all these reasons, it is 
important to develop an effective strategy for using non-nephrotoxic and non-beta cell toxic co-
stimulation blockade to minimize or eliminate the requirement for CNI. At the same time, the efficacy 
of lymphodepletion followed by co-stimulation blockade in blocking both the alloimmune and 
recurrent autoimmune response can be determined. 
The design of the study is to compare the safety and efficacy of 2 immunosuppressive regimens, 
Refer to Section 8 of the protocol for dosing and administration:  
1. The Control Arm consists of induction with Thymoglobulin (Anti-thymocyte Globulin (Rabbit)) and 
solumedrol (or equivalent). Maintenance immunosuppression will consist of CellCept® 
(mycophenolate mofetil) and Prograf® (tacrolimus). Prograf® (tacrolimus) will not be weaned.  
2. The Investigational Arm will receive induction with Thymoglobulin (Anti-thymocyte Globulin 
(Rabbit)) and solumedrol (or equivalent). Maintenance immunosuppression will consist of NULOJIX® 
(belatacept), Prograf® (tacrolimus) to week 40, and CellCept® (mycophenolate mofetil).   

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Please refer to Manual of Procedures (MOP), study provided Investigator’s Brochure (IB), Package 
Inserts (PI), and to applicable product labeling for known and potential risks to human participants 
associated with the study medication(s). 
All anti-rejection drugs (immunosuppressive medications) may increase the risk of infection, 
lymphoma, post-transplant lymphoproliferative disorder (PTLD), and cancer. Some of these side-
effects may be life-threatening or fatal, and will continue to be closely monitored throughout the study. 
5.1
Risks of NULOJIX® (belatacept) Therapy 
NULOJIX® (belatacept) is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) 
sero negative or with unknown EBV serostatus due to the risk of post-transplant lymphoproliferative 
disorder (PTLD), predominantly involving the central nervous system (CNS) 
 
Potential Risks of belatacept in Renal Transplantation 
Post-transplant Lymphoproliferative Disorder 
In the combined BMS-sponsored Phase 2 (median exposure 74 to 88 months) and Phase 3 studies 
(median exposure of approximately 39 months) in de novo renal transplantation, post-transplant 
lymphoproliferative disorder (PTLD) developed more frequently in patients who received belatacept 
(14 cases out of 949; 1.5% of subjects) than those who received cyclosporine (3 cases out of 476; 0.6%). 
Of the PTLD cases reported with belatacept, all but 1 occurred during the first 18 months post-
transplant.  More than half of the PTLD cases in belatacept-treated patients involved the CNS (9 cases 
out of 14; 65% of belatacept patients). A total of 8 out of 14 patients with PTLD in the belatacept group 
and 3 out of 3 in the cyclosporine group have died.  
The excess risk of PTLD with belatacept was concentrated in EBV negative recipients (approximately 
10-fold higher than that observed in EBV positive recipients). While there was also an increased risk in 
EBV positive subjects with belatacept compared to CsA within the studies, the absolute risk in this 
population was low. In addition to EBV-negative serostatus, CMV disease, and use of lymphocyte 
depleting therapy for treatment of AR were also associated with an increased risk of PTLD in the core 
belatacept studies. Nonetheless, the highest risk of PTLD with belatacept was observed in EBV-
negative subjects. Thus, belatacept should not be administered to belatacept naïve patients who are 
EBV-negative or have unknown EBV serostatus.  PTLD should be considered in subjects who develop 
new neurologic signs or symptoms. 
Malignancy 
An increased incidence of malignancy is a recognized complication of immunosuppression in 
recipients of organ transplants. In the Phase 3 studies, overall malignancy rates were similar across all 
treatment groups, with the exception of PTLD. 
Infection 
Increased susceptibility to infection, including serious and fatal infections may result from the use of 
belatacept, as with all immunosuppressive therapies. Overall incidences of infections, including 
serious fungal and viral infections, were similar across all treatment groups in the Phase 3 studies over 
the 36 month period of observation. The most common serious infections across treatment groups 
were urinary tract infection (UTI) and CMV infections.  
 


 
 
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Progressive Multifocal Leukoencephalopathy (PML) 
One (1) case of progressive multifocal leukoencephalopathy (PML) has been reported in the belatacept 
renal transplantation program, in a subject receiving the MI regimen in study IM103027.   PML should 
be considered in subjects who develop new neurologic signs or symptoms. 
Tuberculosis has been more frequently reported in belatacept-treated patients than CsA-treated 
patients. There were a total of 13 TB cases (12 with belatacept and 1 with CsA) reported in the Phase 3 
studies over 36 months. Nearly all cases of TB were reported in subjects who currently or previously 
resided in countries with a high prevalence of TB.  
Other Potential Risks 
Other potential risks include graft thrombosis, infusion-related reactions, proteinuria, congestive heart 
failure, and autoimmune disorders.  These events have been observed infrequently in belatacept-
treated subjects but are being closely monitored in all belatacept clinical trials. 
 
Potential Risks in Liver Transplantation 
A total of 250 subjects who received a liver transplant were randomized and treated in 5 treatment 
groups (3 belatacept-containing groups and 2 tacrolimus-containing groups): Group 1): Basiliximab + 
Belatacept MI + MMF; Group 2): Belatacept MI + MMF; Group 3): Belatacept LI + MMF; Group 4): 
Tacrolimus + MMF; and Group 5): Tacrolimus. Of these patients, 147 received belatacept. All subjects 
received corticosteroids that could be tapered or discontinued after Month 3 according to institutional 
practice. 
Over the first 12 months of the study, there were 2 cases of post-transplant lymphoproliferative 
disorder (PTLD) reported in the belatacept groups; 1 patient died due to PTLD.  There was 1 fatal 
case of progressive multifocal leukoencephalopathy (PML) in the belatacept more intensive (MI) 
group.  The overall frequency of serious infections was not different between the groups, but there 
was an increase in viral and fungal infections in the belatacept groups versus the tacrolimus groups. 
During the long-term extension phase of the study (beyond 12 months post-transplant), a  higher 
number of deaths was observed in 2 of the 3 belatacept groups (belatacept MI+MMF and belatacept 
LI+MMF) when compared to the tacrolimus+MMF group. The frequencies of death were 12%, 21%, 
and 22% in the basiliximab+ belatacept MI+MMF, belatacept MI+MMF, and belatacept LI+MMF 
groups, respectively, in comparison to 6% in the tacrolimus+MMF group and 14% in the tacrolimus 
group. A causal relationship to belatacept could not be clearly established, but likewise could not be 
rejected. BMS in consultation with the Independent Data Monitoring Committee decided to terminate 
the study and recommend that all belatacept patients be switched to local standard of care.   
5.2 
Risks of Thymoglobulin® (Anti-Thymocyte Globulin) Therapy 
Contraindications:  Thymoglobulin® is contraindicated in patients with history of allergy or 
anaphylaxis to rabbit proteins or to any product excipients, or who have active acute or chronic 
infections which contraindicate any additional immunosuppression. 
Warnings:  Thymoglobulin should only be used by physicians experienced in immunosuppressive 
therapy for the treatment of renal transplant patients. Medical surveillance is required during 
Thymoglobulin infusion. 
Immune-mediated reactions:  Serious immune-mediated reactions have been reported with the use 
of Thymoglobulin and consist of anaphylaxis or severe cytokine release syndrome (CRS). 


 
 
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Fatal anaphylaxis has been reported. If an anaphylactic reaction occurs, the infusion should be 
terminated immediately. Medical personnel should be available to treat patients who experience 
anaphylaxis. Emergency treatment such as 0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) 
subcutaneously and other resuscitative measures including oxygen, intravenous fluids, 
antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated, 
should be provided. Any further administration of Thymoglobulin to a patient who has a history of 
anaphylaxis to Thymoglobulin is not recommended. 
Severe, acute infusion-associated reactions (IARs) are consistent with CRS which is attributed to the 
release of cytokines by activated monocytes and lymphocytes. Severe acute CRS can cause serious 
cardiorespiratory events and/or death. 
IARs may occur following the administration of Thymoglobulin and may occur as soon as the first or 
second infusion during a single course of Thymoglobulin treatment. Clinical manifestations of Infusion-
associated reactions IARs have included some of the following signs and symptoms: fever, chills/rigors, 
dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache. 
IARs with Thymoglobulin are generally manageable with a reduction in infusion rates and/or with 
medications. Serious and fatal anaphylactic reactions have been reported. The fatalities occurred in 
patients who did not receive epinephrine during the event. 
IARs consistent with cytokine release syndrome (CRS) have been reported. Severe and potentially life-
threatening CRS have also been reported. Post-marketing reports of severe CRS have included 
cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary 
edema, myocardial infarction, tachycardia, and/or death). 
During post-marketing surveillance, reactions such as fever, rash, arthralgia, and/or myalgia, indicating 
possible serum sickness, have been reported. Serum sickness tends to occur 5 to 15 days after onset of 
Thymoglobulin therapy. Symptoms are manageable with corticosteroid treatment. 
Infection:  Thymoglobulin is routinely used in combination with other immunosuppressive agents. 
Infections (bacterial, fungal, viral and protozoal), reactivation of infection (particularly 
cytomegalovirus [CMV]) and sepsis have been reported after Thymoglobulin administration in 
combination with multiple immunosuppressive agents. Severe acute infections can be fatal.   
Infections, reactivation of infection, and sepsis have been reported after Thymoglobulin 
administration in combination with multiple immunosuppressive agents. Careful patient monitoring 
and appropriate anti-infective prophylaxis are recommended. 
 
Hematologic Effects:  Thrombocytopenia and/or leukopenia (including lymphopenia and 
neutropenia) have been identified and are reversible following dose adjustments. 
Malignancy: Use of immunosuppressive agents, including Thymoglobulin, may increase the incidence 
of malignancies, including lymphoma or post-transplant lymphoproliferative disease (PTLD). 
Special Considerations for Thymoglobulin Infusion: Reactions at the infusion site can occur and 
may include pain, swelling, and erythema. The recommended route of administration for 
Thymoglobulin is intravenous infusion using a high-flow vein. 
Immunizations:  The safety of immunization with attenuated live vaccines following Thymoglobulin 
therapy has not been studied; therefore, immunization with attenuated live vaccines is not 
recommended for patients who have recently received Thymoglobulin. 
Laboratory Tests:  During Thymoglobulin therapy, monitoring the lymphocyte count (i.e., total 
lymphocyte and/or T-cell subset) may help assess the degree of T-cell depletion (See 


 
 
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Pharmacokinetics and Immunogenicity). For safety, WBC and platelet counts should also be 
monitored. 
Pregnancy- Pregnancy Category C:  Animal reproduction studies have not been conducted with 
Thymoglobulin. It is also not known whether Thymoglobulin can cause fetal harm or can affect 
reproduction capacity. Thymoglobulin should be given to a pregnant woman only if clearly needed. 
Nursing Mothers:  Thymoglobulin has not been studied in nursing women. It is not known whether 
this drug is excreted in human milk. Because other immunoglobulins are excreted in human milk, 
breast-feeding should be discontinued during Thymoglobulin therapy. 
Overdosage of Thymoglobulin may result in leukopenia (including lymphopenia and 
neutropenia) and/or thrombocytopenia.  The Thymoglobulin dose should be reduced by one-
half if the WBC count is between 2,000 and 3,000 cells/mm3 or if the platelet count is between 
50,000 and 75,000 cells/mm3.  Stopping Thymoglobulin treatment should be considered if the 
WBC count falls below 2,000 cells/mm3 or platelets below 50,000 cells/mm3. 
5.3 
Risks of Medrol® (Methylprednisolone) 
Adverse effects of corticosteroid therapy associated with short-term therapy (to three weeks) 
have included sodium retention-related weight gain and fluid accumulation, hyperglycemia and 
glucose intolerance, hypokalemia, gastrointestinal upset and ulceration, reversible depression of 
the hypothalamic-pituitary-adrenal (HPA) axis, and mood changes ranging from mild euphoria 
and insomnia to nervousness, restlessness, mania, catatonia, depression, delusions, 
hallucinations, and violent behavior.  Please refer to the package insert for a complete listing of 
risks associated with Medrol® therapy. 
5.4 
Risks of Maintenance Immunosuppression Medications 
Administration of all immunosuppressive and immunomodulatory therapies used presently to 
prevent rejection of transplanted tissues carry general risks of opportunistic infection and malignancy, 
including lymphoma (~1%), and skin cancers.  These agents are not recommended for nursing 
mothers, and it is recommended (and mandated in the current protocol) that women of childbearing 
potential (WOCBP) use effective contraception before, during and for at least 4 months following 
administration of these agents. 
5.4.1 CellCept® (Mycophenolate mofetil - MMF) 
CellCept® (Mycophenolate mofetil - MMF) is approved (in combination with cyclosporine and 
corticosteroids) as an immunosuppressive agent for renal, cardiac, and hepatic solid organ 
transplantation.  Adverse events reported in > 30% of renal, cardiac or liver transplant patients 
receiving MMF were pain, fever, headache, asthenia, anemia, leukopenia, thrombocytopenia, 
leukocytosis, urinary tract infection, hypertension, hypotension, peripheral edema, 
hypercholesteremia, hypokalemia, hyperglycemia, increased creatinine and BUN, cough, 
hypomagnesaemia, diarrhea, constipation, nausea, vomiting, respiratory infection, dyspnea, lung 
disorder, pleural effusion, tremor and insomnia.   
There is an increased risk of developing lymphomas and other malignancies, particularly of the skin.  
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving MMF 1 - 1.5 
mg BID.  Severe neutropenia developed in up to 2% of renal transplant recipients receiving MMF 1.5 
mg BID.  MMF can cause fetal harm when administered to a pregnant woman.  Cases of progressive 
multifocal leukoencephalopathy (PML), sometimes fatal, and pure red cell aplasia have been reported 


 
 
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in patients treated with MMF.  Gastrointestinal bleeding (requiring hospitalization) has been observed 
in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated 
with MMF 1.5 g BID.  Additional information about MMF can be found in the package insert. 
5.4.2 Prograf® (Tacrolimus)  
Side effects of Prograf® (Tacrolimus) include hypertension, glucose intolerance, peripheral 
neuropathy,   renal insufficiency, abnormal liver function studies, seizures, nausea, vomiting, 
confusion, hypomagnesaemia, tremulousness, neurotoxicity, posterior reversible encephalopathy 
syndrome (PRES), progressive multifocal leukoencephalopathy (PML), interstitial lung disease, BK 
nephropathy, and increased risk of secondary malignancies.  Additional information about 
Tacrolimus can be found in the package insert.  
5.5 
Risks of Protocol Mandated Procedures 
5.5.1 Kidney Biopsy 
This protocol requires an additional core of renal tissue during any for cause biopsy. There is a risk of 
bleeding associated with transplant kidney biopsies. Transient hematuria occurs in 3 to 10% of 
patients and may prolong hospitalization, require bladder catheterization for clot drainage, or in 
approximately 1% of patients, require blood transfusion. Ureteral obstruction from blood clot may 
require percutaneous nephrostomy in <1% of patients. Massive hemorrhage requiring surgical 
exploration, transplant nephrectomy, or arterial embolization occurs in ~0.1 % of patients. Death 
from massive hemorrhage is rare. 
5.5.2 Blood Draws 
The amount of blood that may be drawn from adult subjects for research purposes will not exceed 
10.5mL/kg or 550mL, whichever is smaller, over an eight week period.  All blood samples for the 
mechanistic study will be obtained at the time of scheduled blood draws, so there will be minimal 
additional risk associated with obtaining the study samples.  
The subject may experience some discomfort at the site of the needle entry, bruising, swelling, 
redness, fainting, or local infection. The additional amount of blood could contribute to the 
development of anemia.  The subject’s clinical condition will be taken into consideration to determine 
if research blood tests can be performed. 
5.6 
Potential Benefits 
Potential benefits of a NULOJIX® (belatacept) regimen include avoidance of long term side effects 
associated with the prolonged use of CNI, such as nephrotoxicity, hypertension, dyslipidemia, and 
glucose intolerance, and avoidance of sirolimus-related toxicity such as buccal ulcers and 
dyslipidemia. 
Tacrolimus is known to be directly beta-cell toxic in vitro and in vivo, and has been associated with 
new onset immunosuppression-related diabetes in non-diabetic recipients of solid organ transplants.  
Overall, the administration of thymoglobulin to adult renal transplant patients has been safe and 
effective.  Prolonged depletion of T cells has been achieved but has not been accompanied by 
increased incidence of opportunistic infection or other serious complications.  This treatment has 
generally led to substantial overall reduction in chronic immunosuppression but not tolerance. 


 
 
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6 SELECTION OF PARTICIPANTS 
6.1 
Selection of Centers 
The centers conducting this study have significant experience in SPK transplantation.  
Additional centers may be recruited if enrollment is lower than anticipated.  The team will evaluate 
enrollment progress 6 and 12 months after initiation of the study.  If enrollment is not satisfactory, we 
will expand the number of centers involved to accommodate additional participants.     
6.2 
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for enrollment as study participants:  
1. Male or Female, 18-55 years of age at the time of enrollment; 
2. Ability to understand and provide written informed consent; 
3. Candidate for a primary simultaneous kidney and pancreas allograft with random c-peptide <0.3 
ng/mL.  
4. No known contraindications to study therapy using NULOJIX® (belatacept); 
5. Female subjects of childbearing potential must have a negative pregnancy test upon study entry; 
6. Female and male participants with reproductive potential must agree to use FDA approved methods 
of birth control during participation in the study and for 4 months following study completion; 
7. No donor specific antibodies prior to transplant that are considered to be of clinical significance by 
the site investigator; 
8. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and admission sera, as determined 
by each participating study center. 
9. A documented negative TB test within the 12 months prior to transplant.  If documentation is not 
present at the time of transplantation, and the subject does not have any risk factors for TB, a TB-
specific interferon gamma release assay (IGRA) may be performed.   
6.3 
Exclusion Criteria 
Patients who meet any of these criteria are not eligible for enrollment as study participants:  
1. Need for multi-organ transplantation other than a kidney and pancreas 
2. Recipient of previous organ transplant; 
3. Active infection including hepatitis B, hepatitis C, or HIV;  
4. Individuals who have required treatment with systemic prednisone or other immunosuppressive 
drugs within 1 year prior to transplant; 
5. Individuals previously treated with NULOJIX® (belatacept); 
6. Any condition that, in the opinion of the investigator, would interfere with the participant’s ability 
to comply with study requirements; 
7. Use of investigational drugs within 4 weeks of enrollment; 
8. Known hypersensitivity to mycophenolate mofetil (MMF)or any of the drug’s components; 
9. Administration of live attenuated vaccine(s) within 8 weeks of enrollment. 
10. EBV sero-negative recipients or recipients whose EBV status is unknown or ambiguous prior to the 
time of transplantation 


 
 
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1.  If on subsequent testing the IgG and/or IgM turn positive the subject is eligible.   
2. The subject will be deemed eligible if on subsequent testing the EBNA turns positive or if EBV-
PCR testing is negative.   
Viral Capsid 
Antigen IgG 
Viral Capsid 
Antigen IgM 
EBV Nuclear 
Antigen 
Interpretation 
Belatacept 
Positive 
Negative 
Positive 
Past Infection 
(EBV positive) 
Eligible 
Positive 
Positive 
Positive 
Likely resolved EBV 
(EBV positive) 
Eligible 
Positive 
Negative 
Negative 
Recent EBV vs. EBNA negative past 
infection 
(EBV positive) 
Eligible 
Negative 
Negative 
Negative 
Naïve 
(EBV negative) 
Ineligible 
Negative 
Negative 
Positive 
Possibly a false positive 
Ineligible 1 
Positive 
Positive 
Negative 
Recent infection 
Ineligible 2 


 
 
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7 STUDY DESIGN   
This trial is a prospective, multi-center, open-label, phase II, randomized (1:1) study to compare a 
NULOJIX® (belatacept) based immunosuppressive regimen to a CNI-based regimen in recipients of 
SPK.  Subjects will be consented and enrolled until a total of 60 subjects are randomized.  


 
 
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Version 7.0 June 28, 2016 
 
 
 
 
No 
Subjects Enrolled for 
Assessment of Eligibility            
Randomized & 
Transplanted     
1:1               
Control Arm 
Induction:                  
Thymoglobulin® 
Prednisone 
Maintenance:          
 MMF + Tacrolimus 
N=30 
Subjects 
Terminated 
Without Follow-Up 
Investigational Arm 
Induction:                  
Thymoblogulin® 
Prednisone 
Maintenance:           
MMF + Tacrolimus + 
Belatacept 
N=30 
Eligible for 
Randomization 
& Transplant 
N=60 
Yes 
Primary Endpoint Assessment        
12 Months Post-Randomization 
Subject Eligible 
for Tacrolimus 
Withdrawal? 
No 
Yes 
Tacrolimus Withdrawn 
Following Protocol 
Figure 1: Study Design 
 


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The study therapy regimen includes:  
Control Arm  
 Induction:  5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction: Thymoglobulin® (Anti-thymocyte Globulin (Rabbit));  
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or 
Myfortic® (mycophenolate sodium), or generic. 
Investigational Arm 
 Induction: 5 day course of MEDROL® (methylprednisolone) or equivalent; 
 Induction:  Thymoglobulin® (Anti-thymocyte Globulin (Rabbit)); 
 Maintenance Immunosuppression:  NULOJIX® (belatacept); 
 Maintenance Immunosuppression: Prograf® (tacrolimus), or generic; 
 Maintenance Immunosuppression: CellCept® (mycophenolate mofetil- MMF), or 
Myfortic® (mycophenolate sodium), or generic. 
Prograf®
CellCept®
Thymoglobulin®
Prograf®
or
Group 2
(Investigational)
1 gm bid
Medrol®
T
Group 1
(Control)
Thymoglobulin®
NULOJIX®
T
Induction
Maintenance
Medrol®
Induction
8-12 ng/mL for first 24 weeks
CellCept®
1 gm bid
Maintenance
5-8 ng/mL , thereafter
5-8 ng/mL for 
first 24 weeks
3-5 ng/mL to week 40
10mg/kg days 5, 14, 28, 56 and 84.  
After day 84, 5mg/kg every 4 weeks to completion of study.
Figure 2.  CTOT-15 Study Therapy Regimen 
 


 
 
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Study Therapy Dosage 
CATEGORY 
DRUG 
DOSING 
Investigational  
Agent 
NULOJIX ® 
(belatacept) 
INVESTIGATIONAL ARM:  Participants will receive NULOJIX® (belatacept) 10mg/kg on 
days 5, 14, 28, 56 and 84. After 84 days, subjects will receive belatacept at the 
maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.  
Induction Therapy 
Medrol® 
methylprednisolone 
BOTH STUDY GROUPS:  Methylprednisolone will be administered at a target dose of 500 
mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 
mg day 2 post-transplant, 60 mg day 3 post-transplant, and 30 mg day 4 post-transplant. 
IV methylprednisolone will be administered over no less than 30 minutes in accordance 
with the applicable product labeling.  
Induction Therapy 
Thymoglobulin® 
(Anti-thymocyte 
Globulin (Rabbit)) 
BOTH STUDY GROUPS:  The Thymoglobulin® target dosage is 6mg/kg total over 3 to 4 
days.  The recommended route of administration is intravenous infusion using a high-
flow vein. Thymoglobulin should be infused over a minimum of 6 hours for the first 
infusion and over at least 4 hours on subsequent days of therapy.   The infusion will be 
monitored per the center practice/SOPs. 
Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour 
prior to the infusion will be given per center practice and may reduce the incidence and 
intensity of side effects during the infusion. Medical personnel should monitor patients 
for adverse events during and after infusion. 
Maintenance 
Immunosuppression 
Mycophenolate 
Acid 
BOTH STUDY GROUPS:  CellCept® (Mycophenolate Mofetil- MMF) will be administered 
at a target dose of 1000 mg PO or IV BID beginning on the day of surgery or post-
operative day 1 depending upon when during the day the surgery is completed 
(maximum MMF dosing is 2G per day).  MMF will be adjusted based on clinical 
complications (such as neutropenia).   
Myfortic® (mycophenolate sodium) may be used as a replacement for MMF.   
Mycophenolate sodium will be dosed at 720 mg PO or IV BID. Mycophenolate sodium 
will be adjusted based on clinical complications.   
Maintenance 
Immunosuppression 
Prograf® 
(tacrolimus) 
Tacrolimus may be discontinued or target levels adjusted at the discretion of the 
Investigator.  
CONTROL ARM: The site investigator will identify a starting tacrolimus dose at their 
discretion in order to achieve the target trough levels no later than 5 days post-
transplantation.  Tacrolimus dosing will be initiated on the day of surgery or post-
operative day 1 depending upon when during the day the surgery is completed, then 
adjusted to target trough levels of 8-12 ng/ml during the first 24 weeks post-transplant, 
then adjusted to target trough levels of 5-8 ng/ml thereafter. 
INVESTIGATIONAL ARM: The site investigator will identify a starting tacrolimus dose at 
their discretion, in order to achieve the target trough levels no later than 5 days post-
transplantation.  Tacrolimus dosing will be initiated on the day of surgery or post-
operative day 1 depending upon when during the day the surgery is completed. The 
dosage will be adjusted to achieve the following therapeutic trough levels: 5-8 ng/ml 
during the first 24 weeks post-transplant and then 3-5 ng/ml until day 280 (week 40). 
Subjects may be withdrawn if they meet all the criteria defined below.   
Tacrolimus Withdrawal: Subjects participating in the Investigational Arm will be 
considered eligible for withdraw of tacrolimus once they have reached the week 40 
study visit, if all of the following is met: 
1. No evidence of cellular or antibody mediated rejection in the first 280 days post-
transplant.  
2. Stable renal allograft function as measured by serum creatinine over the preceding 
90 days. 


 
 
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3. Stable pancreatic function as assessed by levels of fasting blood sugars, HbA1c, and 
serum amylase/lipase at week 36 post-transplant.  
4. The absence of donor specific antibody at week 36 post-transplant.   
If eligible for withdrawal, the subject will be weaned off tacrolimus over a 4-8 week 
period. The chart below should be used as a guide based on the current trough level and 
tacrolimus dose.  
Start of withdrawal 
tacrolimus dose 
Initial dose 
reduction 
4 weeks later 
dose 
reduction 
4 weeks later 
0.5 mg q12h (Prograf 
level < 5 ng/ml) 
0.5 mg daily 
Discontinue 
-- 
0.5mg q12h (Prograf 
level > 5 ng/ml) 
0.5 mg daily 
0.5mg every 
other day 
Discontinue 
1mg daily (Prograf level 
< 5 ng/ml) 
0.5 mg daily 
Discontinue 
-- 
1mg daily (Prograf level 
> 5 ng/ml) 
0.5 mg daily 
0.5mg every 
other day 
Discontinue 
1mg q12h (Prograf level 
< 5 ng/ml) 
1 mg daily 
Discontinue 
-- 
1mg q12h (Prograf level 
> 5 ng/ml) 
0.5 mg q12h 
0.5 mg daily 
Discontinue 
2mg q12h (Prograf level 
< 5 ng/ml) 
1 mg q12 
1 mg daily 
Discontinue 
2mg q12h (Prograf level 
> 5 ng/ml) 
1.5 mg q12h 
1 mg q12h 
Discontinue 
3 mg q12h 
2 mg q12h 
1 mg q12h 
Discontinue 
4 mg q12h 
3 mg q12h 
2 mg q12h 
Discontinue 
5 mg q12h 
3 mg q12h 
2 mg q12h 
Discontinue 
6 mg q12h 
4 mg q12h 
2 mg q12h 
Discontinue 
7 mg q12h 
5 mg q12h 
3 mg q12h 
Discontinue 
8 mg q12h 
6 mg q12h 
3 mg q12h 
Discontinue 
9 mg q12h 
6 mg q12h 
3 mg q12h 
Discontinue 
10 mg q12h 
7 mg q12h 
4 mg q12h 
Discontinue 
Monitoring during Prograf® (tacrolimus) weaning and post withdrawal: During the 
weaning period and for 6 weeks following complete withdrawal, weekly safety labs will 
be drawn in order to monitor for early signs of rejection. This includes a serum 
creatinine, fasting glucose, amylase, and lipase. Labs may be performed by the subject’s 
local physician if they are not able to return to the study center. All results should be 
reported back to the site investigator and clinical decisions made accordingly. If any signs 
of rejection are noted, the subject will not continue with tacrolimus withdrawal and 
treatment will be at the discretion of the site investigator.   
Reinstatement of Prograf® (tacrolimus)- Subjects participating in the Investigational Arm 
may have tacrolimus reinstated, at a dose to be determined by the site investigator, if 


 
 
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any of the following events occur: 1 - An acute rejection episode  2- Request of the 
subject or site Investigator. 
8.1 
Investigational Drug:  NULOJIX® (belatacept)  
Nulojix® (belatacept), a selective T-cell costimulation blocker, is a soluble fusion protein 
consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 
domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by 
recombinant DNA technology in a mammalian cell expression system. Two amino acid 
substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4. As a 
result of these modifications, belatacept binds CD80 and CD86 more avidly than abatacept, the 
parent CTLA4-Immunoglobulin (CTLA4-Ig) molecule from which it is derived. The molecular 
weight of belatacept is approximately 90 kilodaltons. 
NULOJIX® (belatacept), along with 1 non-siliconized single-use syringes (Norm-Ject®), will 
be supplied by Bristol-Myers Squibb (Princeton, NJ).  Please refer to section 5.1, and to 
applicable product labeling for known and potential risks to human participants associated 
with the study medication(s). 
NULOJIX® (belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a 
kidney transplant.  NULOJIX® (belatacept) is to be used in combination with basiliximab induction, 
mycophenolate mofetil, and corticosteroids.  NULOJIX® (belatacept) should only be used in subjects 
who are EBV seropositive.  Use of NULOJIX® (belatacept) for the prophylaxis of organ rejection in 
transplanted organs other than kidney has not been established.  The current study will investigate 
the ability of NULOJIX® (belatacept) to facilitate a maintenance regiment that avoids both CNI and 
corticosteroids following SPK transplantation.  
8.1.1 Formulation, Packaging, and Labeling 
NULOJIX® (belatacept) is supplied as a sterile, white or off-white lyophilized powder for 
intravenous administration. Prior to use, the lyophile is reconstituted with a suitable fluid to 
obtain a clear to slightly opalescent, colorless to pale yellow solution, with a pH in the range of 
7.2 to 7.8. Suitable fluids for constitution of the lyophile include SWFI, 0.9% NS, or D5W. Each 
250 mg single-use vial of Nulojix also contains: monobasic sodium phosphate (34.5 mg), sodium 
chloride (5.8 mg), and sucrose (500 mg). 
NULOJIX® (NDC 0003-0371-13) will be provided as open-label commercially available 
supplies.   NULOJIX® is packaged in cases of 6 individually boxed vials and syringes.  Each 
case contains the NDC number, lot number, expiration date, product identity and strength, 
the number of vials, route of administration, and storage requirements.  The study label will 
be affixed to each case and will include the IND number, the protocol number, the Sponsor, 
the Manufacturer, and the statement “New Drug- Investigational Use Only”. 
8.1.2 Preparation, Administration, and Dosage 
NULOJIX® is for intravenous infusion only.  Subjects do not require premedication prior to 
administration of NULOJIX®.  The total infusion dose of NULOJIX® should be based on the actual 
body weight of the patient at the time of transplantation, and should not be modified during the 
course of therapy, unless there is a change in body weight of greater than 10%.   


 
 
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The prescribed dose of NULOJIX ®must be evenly divisible by 12.5 mg in order for the dose to be 
prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. 
Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100.   For example: 
A patient weighs 64 kg. The dose is 10 mg per kg. 
• 
Calculated Dose: 64 kg × 10 mg per kg = 640 mg 
• 
The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 
650 mg. 
• 
The nearest dose to 640 mg is 637.5 mg. 
• 
Therefore, the actual prescribed dose for the patient should be 637.5 mg. 
INVESTIGATIONAL ARM ONLY: Participants will receive NULOJIX® (belatacept) 10mg/kg 
through a peripheral vein on days 5, 14, 28, 56 and 84  After 84 days, subjects will receive NULOJIX® 
(belatacept)  at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.    
Preparation for Administration  
1) Calculate the number of Nulojix vials required to provide the total infusion dose. Each vial 
contains 250 mg of belatacept lyophilized powder.  
2) Reconstitute the contents of each vial of Nulojix with 10.5 mL of a suitable diluent using the 
silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable 
diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in 
water (D5W). 
Note: If the Nulojix powder is accidentally reconstituted using a different syringe than the one 
provided, the solution may develop a few translucent particles. Discard any solutions prepared 
using siliconized syringes. 
3) To reconstitute the Nulojix powder, remove the flip-top from the vial and wipe the top with an 
alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and 
direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial.  
4) To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are 
completely dissolved. Avoid prolonged or vigorous agitation. Do not shake.  
5) The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to 
slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or 
other foreign particles are present.  
6) Calculate the total volume of the reconstituted 25 mg/mL Nulojix solution required to provide the 
total infusion dose.  
Volume of 25 mg/mL Nulojix solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL 
7) Prior to intravenous infusion, the required volume of the reconstituted Nulojix solution must be 
further diluted with a suitable infusion fluid (NS or D5W). Nulojix should be reconstituted with:  
• 
SWFI should be further diluted with either NS or D5W  
• 
NS should be further diluted with NS  
• 
D5W should be further diluted with D5W  
8) From the appropriate size infusion container, withdraw a volume of infusion fluid that is equal to 
the volume of the reconstituted Nulojix solution required to provide the prescribed dose. With the 
same silicone-free disposable syringe used for reconstitution, withdraw the required amount of 


 
 
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belatacept solution from the vial, inject it into the infusion container, and gently rotate the infusion 
container to ensure mixing.  
The final belatacept concentration in the infusion container should range from 2 mg/mL to 10 
mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, 
but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution 
remaining in the vials must be discarded. 
9) Prior to administration, the Nulojix infusion should be inspected visually for particulate matter and 
discoloration. Discard the infusion if any particulate matter or discoloration is observed.  
10) The entire Nulojix infusion should be administered over a period of 30 minutes and must be 
administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a 
pore size of 0.2-1.2 µm).  
• 
The reconstituted solution should be transferred from the vial to the infusion bag or bottle 
immediately. The Nulojix infusion must be completed within 24 hours of reconstitution of 
the Nulojix lyophilized powder. If not used immediately, the infusion solution may be 
stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 
hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C 
[68°-77°F] and room light).  
• 
Infuse Nulojix in a separate line from other concomitantly infused agents. Nulojix should 
not be infused concomitantly in the same intravenous line with other agents. No physical or 
biochemical compatibility studies have been conducted to evaluate the co administration of 
Nulojix with other agents.  
8.1.3 Handling, Dispensing, and Destruction of NULOJIX® (belatacept) 
Care should be taken when handling the injectable drug products. Proper aseptic techniques 
should be used when preparing and administering sterile products such as belatacept. 
Gloves are recommended during constitution process. If belatacept concentrate or solution 
comes in contact with skin or mucosa, immediately and thoroughly wash with soap and 
water. 
NULOJIX® (belatacept) vials are single-use vials and do not contain preservatives.  Therefore 
after reconstitution, the vials should be used immediately whenever possible.  The belatacept 
250 mg vial should be stored under refrigeration (2-8°C), and should be protected from long 
term exposure to light.  Intact vials are stable for at least 1 year under these conditions.   
Reconstituted solutions of belatacept at a concentration of 25 mg/mL are stable for 24 hours 
in the vials if stored at room temperature (15-25°C) and ambient lighting conditions, or under 
refrigeration.  When further diluted with 5% Dextrose for Injection or 0.9% Normal Saline 
Solution to a belatacept concentration as low as 2 mg/mL, solutions may be stored in plastic, 
non-siliconized IV bags for up to 24 hours at room temperature and ambient lighting 
conditions or under refrigeration.  The belatacept infusion must be completed within 24 
hours of constitution of the lyophilized powder. Storage of reconstituted solutions in 
syringes is not recommended due to stability and potential bacterial contamination. 
Belatacept should be stored in a secure area according to local regulations.  It is the responsibility of 
the Investigator to ensure that belatacept is only dispensed to study participants. Belatacept must be 
dispensed only from official study sites by authorized personnel according to local regulations.  The 


 
 
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Investigator should ensure that belatacept is stored in accordance with the environmental conditions 
(temperature, light and humidity) as determined by the Sponsor and defined in the Investigator 
Brochure or SmPC/reference label. 
If an investigational product is destroyed at the site, it is the investigator’s responsibility to ensure 
that arrangements have been made for the disposal, procedures for proper disposal have been 
established according to applicable regulations and guidelines and institutional procedures, and 
appropriate records of the disposal have been documented.  The unused investigational products 
can only be destroyed after being inspected and reconciled by the responsible study monitor. 
8.1.4 Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator is required to 
maintain adequate records of the disposition of the investigational agent, including the date and 
quantity of the drug received, to whom the drug was dispensed (participant-by-participant 
accounting), and a detailed accounting of any drug accidentally or deliberately destroyed. 
Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-
dispensing log will be kept current for each participant.  This log will contain the identification of 
each participant and the date and quantity of drug dispensed.  All records regarding the disposition 
of the NULOJIX® will be available for inspection by the clinical trial monitor. 
8.2 
Induction and Maintenance Immunosuppression Medications 
The following induction and maintenance immunosuppression medications are considered standard 
of care post-transplantation and will be supplied by the hospital pharmacy; Medrol® 
(methylprednisolone), Thymoglobulin® (Anti-Thymocyte Globulin- Rabbit), Mycophenolate Acid, 
and Prograf® (tacrolimus).  Please refer to applicable product labeling for preparation and 
administration instructions and well as known and potential risks.  
8.3 
Concomitant Medications    
Concomitant medications should be administered according to each centers standard of care.  The 
centers will record immunosuppressive and non-immunosuppressive therapy information on an 
eCRF in the study electronic data capture system. 
8.4 
Prophylactic Medications 
8.4.1 Viral Prophylaxis 
CMV Sero Positive Donor and Sero Positive Recipient (D+/R+) 
When tolerating PO or at discharge, subjects will receive Valganciclovir (Valcyte) PO, 900 mg every 
day. Dose adjusted according to renal function.  Treatment is to continue for 85 days post-transplant 
for the prevention of CMV.   
CMV Sero Positive Donor and Sero Negative Recipient (D+/R-) 
When tolerating PO or at discharge, subjects will receive Valganciclovir (Valcyte) PO, 900 mg QD.  
Dose adjusted according to renal function.   Treatment is to continue for 24 weeks post-transplant for 
the prevention of CMV.   
CMV Sero Negative Donor and Sero Positive Recipient (D-/R+) 


 
 
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When tolerating PO or at discharge, subjects will receive Valganciclovir (Valcyte) PO, 900 mg QD. 
Dose adjusted according to renal function.   Treatment is to continue for 85 days post-transplant for 
the prevention of CMV.   
CMV Sero Negative Recipient and Negative Donor (D-/R-) 
When tolerating PO or at discharge, subjects will receive Valacyclovir (Valtrex), 1000 mg PO BID. 
Dose adjusted according to renal function.   Treatment is to continue for 85 days post-transplant for 
the prevention of HSV and VZV.   
 
8.4.2 PCP Prophylaxis 
Any of following regimens, at the discretion of the treating medical team, are acceptable for PCP 
prophylaxis, starting on post-operative day one or when subject is taking oral medications and 
continuing until 1 year post transplant or later based on your institutional standard of care. 
Bactrim TM/Septra ® (Trimethoprim-sulfamethoxazole) single strength (SS; 80/400) administered 
once daily, if GFR >30. If GFR ≤30), single strength administered once a day on every Monday, 
Wednesday, and Friday. If patient is on hemodialysis, single strength administered on the day of 
dialysis after dialysis sessions. 
For participants allergic to or intolerant of sulfa compounds or trimethoprim-sulfmethoxazole 
therapy, and if G6PD level is normal, Aczone ® (Dapsone) 100 mg PO once daily. 
For participants allergic to or intolerant of sulfa compounds or trimethoprim-sulfmethoxazole 
therapy, and is G6PD deficient, Mepron® (Atovaquone) 1500 mg once daily. 
8.5 
Management of Rejection or Graft Loss 
Management of rejection or graft loss is defined by each centers standard of care.  The centers will 
record the treatment information on an eCRF in the study electronic data capture system. Any subject 
who experiences rejection or graft loss following week 52 will continue to follow the schedule 
outlined in Appendix 3 [Schedule of Events (Recipient) Post-Transplant (Year 2)]. 
If a subject experiences rejection either during or after tacrolimus withdrawal, they will complete the 
remaining visits in Appendix 2 (Schedule of Events (Recipient) Year 1) and continue to be followed 
based on Appendix 3 [Schedule of Events (Recipient) Post-Transplant (Year 2)]. 
8.6 
Prohibited Medications 
Prohibited medications for this protocol, except as specifically indicated in this protocol include: 
• Steroid medication (save topicals and prednisone at a dose of ≤ 5 mg daily, or an equivalent 
dose of hydrocortisone, for physiological replacement only) 
• Other investigational products 
• Other immunosuppressive agents not defined in the protocol.   
 
Live vaccines 
 
 


 
 
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8.7 
Modification or Discontinuation of Study Therapy 
Study treatment may be prematurely discontinued at the discretion of the Investigator for any of the 
following reasons: 
1. The subject is unwilling or unable to comply with the protocol. 
2. The subject experiences graft failure.  
3. Any clinical AE, laboratory abnormality or intercurrent illness, which in the opinion of the site 
PI indicates that continued treatment with study therapy is not in the best interest. 
4. Pregnancy. 
5. Two consecutive missed NULOJIX® (Belatacept) infusions. 
Subjects who prematurely discontinue study treatment will be treated according to the site standard 
of care and followed until 52 weeks post-transplant.  Please refer to Reduced Follow-Up Schedule 
(Appendix 4). If subjects discontinue study therapy beyond week 52, they will complete the visits 
outlined in Appendix 3 [Schedule of Events (Recipient) Post-Transplant (Year 2)]. If the subject is 
unable to return to the study center, the data associated with these visits may be obtained from the 
subject’s local physician.  
 


 
 
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9 CRITERIA FOR PREMATURE TERMINATION OF THE STUDY 
9.1 
Participant Withdrawal Criteria 
Participants may be prematurely terminated from study for the following reasons: 
1. The subject elects to withdraw consent from all future study activities, including follow-up. 
2. The participant is “lost to follow-up” (i.e., attempts to reestablish contact have failed). 
3. The participant develops a clinical AE, laboratory abnormality, or intercurrent illness or any 
other event which, in the opinion of the investigator, indicates that continued treatment with 
study therapy and further participation in the study (including obtaining vital status of the 
participant and renal graft) is not in the best interest of the participant. 
4. The participant dies.   
5. The participant is found to be TB positive. 
9.2 
 Study Stopping Rules 
9.2.1 Protocol Suspension and Review 
Study enrollment at all participating sites will be suspended pending expedited review of all pertinent 
data by the institutional review board (IRB), the National Institute of Allergy and Infectious Diseases 
(NIAID), and the NIAID Data Safety Monitoring Board (DSMB), if any one of the following occurs: 
1. Any unexpected fatal or life-threatening AE that is possibly, probably, or definitely related to 
the study treatment regimen (Section 8); 
2. Any event(s) which in the opinion of the Medical Monitor or Protocol Chair indicates the need 
for DSMB review; 
3. Any instance of progressive multifocal leukoencephalopathy (PML). 
In the event of any participant death, the study will pause for review of the event by the medical 
monitor and the protocol chair.  Any death that is not clearly due to non-study causes will result in a 
continued pause in enrollment and DSMB review. “Non-study causes” will include events such as 
deaths due to motor vehicle accidents. 
9.2.2 Continuous Monitoring of Specific Events 
In addition, the incidence of specific safety-related events of particular concern will be continuously 
monitored in each treatment arm throughout the study to determine if any of their observed subject-
based incidence rates exceed a threshold incidence rate of concern pre-specified for each particular 
event.  However, since little is known about what incidence rate to expect for graft loss of either 
pancreas or kidney due to acute or chronic rejection, that rule is based on the incidence of rejection 
events involving one or both allografts in all subjects randomized.   
The following events will be evaluated within each treatment arm, except as noted, and the 
corresponding thresholds of concern are:   
1. Biopsy-proven acute rejection (BPAR) in either pancreas or kidney above 25%. 
2. Pancreas rejection above 20%. 
3. Post-Transplant Lymphoproliferative Disease (PTLD) above 2% at any time. 
4. Incidence of graft loss of either organ due to any rejection above 20% in all randomized 
subjects. 


 
 
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These rules will be implemented by the SACCC, and continuously monitor the occurrence of any of 
these events. If any stopping rule is met, enrollment and randomization will be halted pending 
expedited DSMB review. 
The stopping rules for BPAR and PTLD will be considered to be met if the lower one-sided 95% exact 
confidence limit on the observed incidence rate exceeds the corresponding threshold level of concern 
for that event. The following two tables describe the minimum numbers of events (n) out of selected 
numbers of subjects randomized within each treatment arm (N) which, if equaled or exceeded, would 
satisfy the stopping rule for BPAR and PTLD. 
Table 2: Minimum Numbers of Subjects with Events that Meet the Stopping Rule for BPAR 
in Either Organ in Either Treatment Arm Using a Threshold of 25% 
Number of 
Subjects with 
Event (n) 
Number of Subjects 
Randomized (N) in Either 
Arm 
Observed 
Incidence Rate 
(%) 
Lower 95% 
Confidence Limit 
(%) 
4 
5 
80.00 
34.26 
6 
10 
60.00 
30.35 
8 
15 
53.33 
30.00 
9 
20 
45.00 
25.87 
11 
25 
44.00 
26.99 
13 
30 
43.33 
27.87 
Table 3: Minimum Numbers of Subjects with Events that Meet the Stopping Rule for 
Pancreas Rejection in Either Treatment Arm Using a Threshold of 20% 
Number of 
Subjects with 
Event (n) 
Number of Subjects 
Randomized (N)  
Observed 
Incidence Rate 
(%) 
Lower 95% 
Confidence Limit 
(%) 
4 
5 
80.00 
34.26 
5 
10 
50.00 
22.24 
7 
15 
46.67 
24.37 
8 
20 
40.00 
21.71 
9 
25 
36.00 
20.24 
11 
30 
36.67 
22.11 
Table 4: Minimum Numbers of Subjects with Events that Meet the Stopping Rule for PTLD 
in Either Treatment Arm Using a Threshold of 2% 
Number of 
Subjects with 
Event (n) 
Number of Subjects 
Randomized (N) in Either 
Arm 
Observed 
Incidence Rate 
(%) 
Lower 95% 
Confidence Limit 
(%) 
2 
5 
40.00 
7.64 
2 
10 
20.00 
3.68 
2 
15 
13.33 
2.42 
3 
20 
15.00 
4.22 
3 
25 
12.00 
3.35 
3 
30 
10.00 
2.78 
The stopping rule for graft loss of either organ due to any rejection will be considered to be met 
if the lower one-sided 95% exact confidence limit on the observed incidence rate among all study 
subjects is greater than 20% at any time during the study.   


 
 
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 Table 5: Minimum Numbers of Subjects with Events that Meet the Stopping Rule for GRAFT 
LOSS in All Subjects Randomized at Any Time Using a Threshold of 20% 
Number of 
Subjects with 
Event (n) 
Number of Subjects 
Randomized (N)  
Observed 
Incidence Rate 
(%) 
Lower 95% 
Confidence Limit 
(%) 
5 
10 
50.00 
22.24 
8 
20 
40.00 
21.71 
11 
30 
36.67 
22.11 
13 
40 
32.50 
20.41 
16 
50 
32.00 
21.21 
18 
60 
30.00 
20.37 


 
 
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10 STUDY PROCEDURES 
10.1 Enrollment  
This research study will be explained in lay terms to each potential research subject.  As the part of the 
informed consent process outlined in CFR Title 21 Part 50, the investigator or physician listed on the 
FDA 1572 form will conduct a face-to-face meeting with the study candidate to review all of the 
required elements of informed consent.  The potential study subject will sign an informed consent form 
before undergoing any screening study procedures. Once the informed consent process is complete, the 
subject is considered enrolled in the study. All enrolled subjects will be assigned a unique subject 
number and their disposition must be accounted for at the end of the study. 
10.2 Screening Visit 
The pre-transplant visit (visit 1) will begin at the time consent is obtained until all eligibility criteria are 
available.  Subjects can be approached regarding potential study participation while on the organ 
transplant waiting list, however, the consent process must take place within 60 days of transplant. If 
the subject is consented on the day of transplant, it is at the discretion of the Investigator to ensure 
there is sufficient time to appropriately consent the potential subject. If the subject was consented 
greater than 30 days prior to transplant, the individual obtaining consent must reaffirm the subject's 
willingness to participate.  Refer to Appendix 1, Schedule of Events- Pre-Transplant to Day 4 Post 
Transplant. 
During the screening period the study personnel will review the subject’s medical record for previous 
and current medical history and record the subject’s demographic information (age, gender, and race), 
medications, hematology, chemistry, fasting lipid panel, hemoglobinA1c, and urinalysis.  A serum 
pregnancy test will be conducted on all female subjects of child-bearing potential.  Blood, urine and 
tissue will be collected for research studies. 
During the screening visit, data regarding the donor will be collected; this includes demographics (age, 
gender, and race), cause of death, serum creatinine, HLA, Blood Type, CMV and EBV.  Refer to 
Appendix 5, Schedule of Events – Donor.  A sample of spleen will be requested from the local center 
HLA departments of alloimmune assays. 
10.3 Study Assessments 
Subjects enrolled in this study will be followed for a minimum of 52 weeks post-transplant in order to 
assess the primary endpoint.  Subjects in the Investigational Arm who are eligible and attempt 
tacrolimus withdrawal will be followed for at least 60 days following the withdrawal of tacrolimus. 
Subjects may be followed for up to 18 months (76 weeks) depending upon study completion.  
Subjects will have blood, tissue and urine collected for research studies at the following timepoints: 
• 
Visit 1 (Pre-Transplant to Day 4 Post-Transplant) 
• 
Post-Transplant: Days 28, 84 and Weeks 28, 36, and 52. 
Clinical safety will be monitored through routine physical examinations and appropriate laboratory 
assessments every 4 weeks for the duration of the study. During this period, subjects will have 
repeated clinical/laboratory evaluations, as specified in the Schedule of Events (Appendix 1 through 3, 
Schedule of Events- Recipient and Appendix 4 – Reduced Follow-Up Schedule of Events - Recipient). 
 


 
 
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Infusion Supervision  
In addition to the study visits and procedures listed in Appendix 1-4, participants assigned to the 
Investigational Arm will receive a NULOJIX® (belatacept) infusion on days 5, 14, 28, 56 and 84 post-
transplant. After 84 days, participants in the Investigational Arm will continue NULOJIX® (belatacept) 
infusions every 4 weeks throughout the duration of the study.  The infusion will be administered in a 
center where full resuscitation facilities are immediately available and under close supervision of the 
investigator or infusion center staff.  A history of each infusion and any adverse side effects will be 
recorded and reported to the SACCC using the appropriate case report forms.  Vital signs 
(temperature, blood pressure, pulse, and respiratory rate) will be obtained prior to the start of each 
infusion and again at the end of the infusion.  Additional vital signs will be obtained as clinically 
indicated.  At the discretion of the investigator, the infusion may be discontinued if there is a severe 
reaction to the infusion.     
Clinical Assessments 
Assessments for the development of new adverse events, serious adverse events, infections, rejections, 
graft loss, hospitalizations, new onset diabetes, and malignancies will be completed at each study visit.  
All events will be reported using a designated electronic case report form (eCRF).   
Evaluation of Hemoglobin A1c levels, urinalysis, hematology, chemistry, and pill counts will be 
obtained at Days 28, 84 and Weeks 28, 36, and 52. Additional time points are also specified during Year 
2 of transplant (Appendix 3).  
Infections could influence results of noninvasive testing.  We will therefore record and report 
hospitalizations for infection. Less serious infections that are diagnosed and treated on an outpatient 
basis during the interval between visits and confirmed by pertinent cultures or serologic studies as per 
the local site, will be recorded at each study visit and reported using a designated case report form.  
Undocumented, patient-reported infections (e.g. URI) will not be reported.  Relationships between test 
results and clinical endpoints independent of infections will then be determined in secondary analyses.  
Pregnancy Testing 
Women of child bearing potential (WOCBP) must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, 
WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the 
potential risk factors for an unintentional pregnancy. The subject must sign an informed consent form 
documenting this discussion. 
Pregnancy testing must be performed prior to enrollment and first dose of NULOJIX® (belatacept).  
The results of all pregnancy tests (positive or negative) recorded on the eCRF. All WOCBP MUST 
have a negative serum pregnancy test within 72 hours prior to receiving the first dose of the 
investigational product NULOJIX® (belatacept). The minimum sensitivity of the pregnancy test must 
be 25 IU/L or equivalent units of Human Chorionic Gonadotropin (HCG). If the pregnancy test is 
positive, the subject must not receive the investigational product, and must not be enrolled in the 
study.  All WOCBP should be instructed to contact the investigator immediately if they suspect that 
they might be pregnant (e.g., missed or late menstrual period) at any time during study participation.  
Subjects who become pregnant will be referred to the National Transplant Pregnancy Registry  
(http://www.jefferson.edu/ntpr/). 
For women who become pregnant while using CellCept® or within 6 weeks of discontinuing 
therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate 
Pregnancy Reference Registry (1-800-617-8191) and should strongly encourage the patient to 


 
 
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enroll in the pregnancy registry.  The patient should also be apprised of the potential hazard of 
mycophenolate products to the fetus.  The risks and benefits of CellCept/Myfortic should be 
discussed with the patient.  In certain situations, the patients and her healthcare practitioner may 
decide that the maternal benefits outweigh the risks to the fetus. 
If following initiation of study treatment, it is subsequently discovered that a subject is pregnant or 
may have been pregnant at the time of investigational product exposure, including during at least 56 
days after product administration, the investigational product will be permanently discontinued.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. In addition, the investigator must report on 
the appropriate follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome. Infants should be followed for a minimum of 8 weeks. This pregnancy 
surveillance procedure includes male subjects who fathered a child while receiving study medication; 
however, male subjects do not need to discontinue study medication. 
Viral Monitoring 
The local center will monitor all subjects for CMV and BKV infection by quantitative PCR in the 
blood.  This monitoring will take place at days 28 and 84, and at weeks 28, 52 and 76.  The local center 
investigators will make all treatment decisions.   
For Cause Biopsies - Renal 
The center will perform a biopsy per the discretion of the Investigator in cases of increase in serum 
creatinine, proteinuria, or other clinical symptoms. 
The local center will send the Pathology Core Lab (Dr. Laszik, UCSF) the following:  
• 
5 original stained slides (1-Trichrome or unstained, 1-PAS, 3 H&E) for histology reading. 
• 
The site will send 1 SV40 and 1- immunohistochemistry C4d stained slides, if collected as 
standard of care. 
• 
The remaining portion of the FFPE block will be stored at the local center and sent to the Core 
Pathology when requested for additional immunohistochemistry studies.   
The local center will send the Molecular Core Lab (Dr. Mannon, University of Alabama) the 
following: 
• 
1 core in RNALater for gene expression, mRNA profiling studies. 
Standard of Care or For Cause Biopsies- Pancreas 
The center will perform standard of care biopsies which will be read by the local pathologist using 
Banff criteria.  The data generated from the local center reading will be entered in the study database.  
In addition, once the local pathologist has completed their review of the pathology slides, the site will 
send the original stained slides (1-Trichrome or unstained, 3 H&E, including a C4d and/or SV40, if 
collected) used in that reading to the core pathology laboratory.  The Pathology Core Laboratory will 
scan the slides into an Aperio Scan System, and return the slides back to the local center.   
Glomerular Filtration Rate (GFR) 
Glomerular Filtration Rate (GFR) will be estimated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation and the MDRD 4 variable.  Demographic characteristics; gender, 
age and race are required for calculation in addition to serum creatinine which will be collected as 
specified in the Schedule of Events (SOE).  The equation will be calculated at the SACCC. 


 
 
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Neurological Assessment 
All participants will undergo a neurological exam as specified in the SOE. Subjects will be evaluated 
by their local Neurology consult service for cases with a significantly abnormal exam. 
10.4 Study Treatment Assignment Procedures 
10.4.1 
Blinding and/or Randomization  
This is a randomized, open label study. Subjects will be randomized in an unblinded fashion to one of 
the two study groups in a 1:1 ratio using a web-based randomization system. The randomization 
schedule will not incorporate stratification variables.  However, due to concerns about the potential 
for un-blinded investigators to be biased in their assessments of endpoints, all data analyses and 
reports and all data cleaning activities will be blinded with respect to treatment prior to end-of-study 
database lock, except for safety data reviews by the DSMB.  The study treatment assignments will be 
blinded to all mechanistic core laboratory personnel, including the core pathologist.   


 
 
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11 SAFETY MONITORING 
11.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the 
procedures for appropriately collecting, grading, recording, and reporting that data. Adverse events 
that are classified as serious according to the definition of health authorities must be reported 
promptly (per Section 11.5, Reporting of Serious Adverse Events) to the sponsor, DAIT, NIAID.  
Appropriate notifications must also be made to site principal investigators, Institutional Review 
Boards (IRBs), and health authorities, as applicable.  
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 
21CFR Parts 312 and 320, and applies the standards set forth in the National Cancer Institute (NCI), 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 
(http://ctep.cancer.gov/reporting/ctc.html). 
11.2 Definitions 
11.2.1 Adverse Event (AE) 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related (21 CFR 312.32(a)).  
An adverse event may include any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
product (ICH E6, 1.2).   
For this study, an adverse event will include any untoward or unfavorable medical occurrence 
associated with:   
• 
Study therapy regimen:   
o Induction:  Thymoglobulin® (Anti-thymocyte Globulin- Rabbit); 
o Induction:   Medrol® (methylprednisolone) or equivalent; 
o Maintenance Immunosuppression:  NULOJIX® (belatacept); 
o Maintenance Immunosuppression:  Prograf® (tacrolimus), or generic; 
o Maintenance Immunosuppression:  CellCept® (mycophenolate mofetil), or Myfortic® 
(mycophenolate sodium), or generic. 
• 
Study mandated procedures:  
o Renal Transplant Biopsy:  Any AE occurring within 24 hours after the additional core (study 
mandated) was collected from the for cause biopsy. 
o Blood Draw:  Any AE occurring within 24 hours after a study mandated blood draw. 
11.2.2 Suspected Adverse Reaction (SAR)  
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the investigational drug caused the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 


 
 
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between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug (21 CFR 312.32(a)). 
11.2.3 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the IND.   
“Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation (21 CFR 312.32(a)). 
11.2.4 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of 
either the investigator or DAIT/NIAID, its occurrence places the subject at immediate 
risk of death. It does not include an AE or SAR that, had it occurred in a more severe 
form, might have caused death. 
3. Inpatient hospitalization or prolongation of existing hospitalization 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5. Congenital anomaly or birth defect. 
6. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
In addition to the criteria outlined above, all occurrences of drug induced liver injury (DILI) 
meeting ALL 3 of the defined criteria below must be reported as a SAE:  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
11.3 Grading and Attribution of Adverse Events 
11.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects 
according to the criteria set forth in the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events Version (CTCAE). This document (referred to herein as the NCI-


 
 
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CTCAE manual) provides a common language to describe levels of severity, to analyze and 
interpret data, and to articulate the clinical significance of all adverse events. The NCI-CTCAE 
has been reviewed by the Protocol Development Team (PDT) and has been deemed appropriate 
for the subject population to be studied in this protocol.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the 
NCI-CTCAE manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
Events grade 2 or higher will be collected and recorded for this study. 
11.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study 
procedure(s) will initially be determined by the site investigator and recorded on the appropriate 
AE eCRF.   Final determination of attribution for safety reporting will be determined by 
DAIT/NIAID.  The relationship of an adverse event to study therapy regimen or procedures will 
be determined using the descriptors and definitions provided in the Table below.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-
CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 
Table 6. NCI-CTCAE attribution of adverse events 
Code 
Descriptor 
Relationship (to primary investigational product and/or 
other concurrent mandated study therapy) 
UNRELATED CATEGORY 
1 
Unrelated 
The adverse event is clearly not related. 
 RELATED CATEGORIES 
2 
Possible 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal relationship. 
3 
Definite 
The adverse event is clearly related. 
11.4 Collection and Recording of Adverse Events 
11.4.1 Collection Period 
Adverse events will be collected from the time of first dose of study drug, until he/she 
completes study participation or until 30 days after he/she prematurely withdraws (without 
withdrawing consent) or is withdrawn from the study. 
11.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 


 
 
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• 
Questioning the subject in an objective manner. 
• 
Receiving an unsolicited complaint from the subject. 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an 
adverse event, as defined in Section 11.3, Grading and Attribution of Adverse Events. 
11.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as 
described previously (Section 11.2, Definitions) on the appropriate eCRF regardless of the relationship 
to study therapy regimen or study procedure. 
Certain adverse events occur commonly in this study population and will not be recorded as 
an adverse event, unless it meets the definition of a serious adverse event.     
• 
Occurrence of upper respiratory infection, nasopharyngitis, bronchitis, diarrhea, 
constipation, nausea, vomiting, abdominal pain, hypocalcaemia, hypercalcemia, 
hypercholesterolemia, hypomagnesemia, hyperuricemia, edema, pyrexia, hematuria, 
proteinuria, dysuria, cough, dyspnea,  arthralgia, back pain, hip pain, fracture, 
headache, dizziness, tremor, acne, insomnia, anxiety, depression, stomatitis/aphthous 
ulcers, wound complications, AVF thrombosis, neutropenia, renal impairment, renal 
artery stenosis, incontinence, hydronephrosis, hematoma, lymphocele, 
musculoskeletal pain, alopecia, hyperhidrosis, atrial fibrillation.  
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol 
mandated procedures are not to be reported as an SAE unless hospitalization is prolonged 
due to complications. 
All adverse events must be recorded by the site on the appropriate AE/SAE eCRF within 5 business 
days of the site learning of the adverse event(s).   Please refer to Section 11.5 for reporting of events 
meeting serious criteria.  
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end 
of study participation, or until 30 days after the subject prematurely withdraws (without withdrawing 
consent)/or is withdrawn from the study, whichever occurs first. 
11.5 Reporting of Serious Adverse Events 
11.5.1 Reporting of Serious Adverse Events to Sponsor  
This section describes the responsibilities of the site investigator to report serious adverse events to the 
sponsor via the SACCC eCRF.  Timely reporting of adverse events is required by 21 CFR and ICH E6 
guidelines.  
Site investigators must report all serious adverse events (see Section 11.2.3, Serious Adverse Event), 
regardless of relationship or expectedness within 24 hours of discovering the event. 
For serious adverse events, all requested information on the AE/SAE eCRF should be provided to the 
SACCC.  However, unavailable details of the event should not delay submission of the known 
information.  As additional details become available, the AE/SAE eCRF should be updated and 
submitted. 
 
 


 
 
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11.5.2 Sponsor Reporting to Health Authority 
After an adverse event requiring 24 hour reporting (per Section 11.5.1, Reporting of Serious Adverse 
Events to sponsor) is submitted by the site investigator and assessed by DAIT/NIAID, there are two 
options for DAIT/NIAID to report the adverse event to the appropriate health authorities: 
11.5.2.1 
ANNUAL REPORTING 
DAIT/NIAID will include in the annual study report to health authorities all adverse events classified 
as: 
o Serious, expected, suspected adverse reactions (see Section 11.2.1.1, Suspected Adverse Reaction, 
and Section 11.2.2, Unexpected Adverse Event). 
o Serious and not a suspected adverse reaction (see Section 11.2.2, Suspected Adverse Reaction). 
o Pregnancies not reported as serious adverse events. 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual 
IND Report. 
11.5.2.2 
EXPEDITED REPORTING WITHIN 15 CALENDAR DAYS   
The sponsor, DAIT/NIAID, must notify the appropriate health authorities and all participating 
investigators as soon as possible, or within 15 calendar days if the adverse event is classified as one of 
the following (21CFR312.32 (c)(1)): 
o Serious and unexpected suspected adverse reaction (SUSAR) (see Section 11.2.1.1, Suspected 
Adverse Reaction and Section 11.2, Unexpected Adverse Event).  Expedited reporting of SUSAR’s 
are to include, in an aggregate analysis, specific events that occur more frequently in the 
investigational drug than in a concurrent or control group.  
o Any findings from other studies, whether or not conducted under an IND, and whether or not 
conducted by DAIT/NIAID that suggest a significant risk in humans exposed to NULOJIX® or 
Thymoglobulin®.   This includes findings from animal or in vitro testing that suggest a 
significant risk in humans exposed to the drug.  Ordinarily, such a finding would result in a 
safety-related change in the protocol, informed consent, investigator brochure or other aspects 
of the overall conduct of the trial, will be reported. 
o Increased rate of occurrence of serious suspected adverse reactions.  DAIT/NIAID must report 
any clinically important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or investigator brochure or package insert. 
11.5.2.3 
EXPEDITED REPORTING WITHIN 7 CALENDAR DAYS   
The sponsor, DAIT/NIAID, must notify the appropriate health authorities and all participating 
investigators as soon as possible, or within 7 calendar days, of any unexpected fatal or immediately 
life-threatening suspected adverse reaction.  
11.5.3 Reporting of Adverse Events to IRBs 
All investigators must report adverse events, including expedited reports, in a timely fashion to their 
respective IRBs in accordance with applicable regulations and guidelines. All IND Safety Reports to the 
FDA will be distributed by the sponsor, DAIT/NIAID, or designee to all participating institutions for 
site IRB submission. 
 


 
 
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11.6 Pregnancy Reporting 
The investigator should be informed immediately of any pregnancy in a study subject or a partner of 
a study subject. A pregnant subject should be instructed to stop taking study medication.  The 
investigator should counsel the subject and discuss the risks of continuing with the pregnancy and 
the possible effects on the fetus. Monitoring of the pregnant subject should continue until the 
conclusion of the pregnancy.    
The investigator should report to the SACCC all pregnancies within 1 business day of becoming aware 
of the event using the Pregnancy eCRF.  All pregnancies identified during the study must be followed 
to conclusion and the outcome of each must be reported.  The Pregnancy should be updated and 
submitted to the SACCC when details about the outcome are available.  When possible, similar 
information should be obtained for a pregnancy occurring in a partner of a study subject. 
Information requested about the delivery will include: 
o Expected delivery date and Actual delivery date; 
o Birth weight; 
o Outcome of Pregnancy (i.e., full-term, premature, miscarriage, unknown); 
o Infant status (i.e., any abnormalities). 
Should the pregnancy result in a congenital abnormality or birth defect, an SAE must be submitted to 
the SACCC using the SAE reporting procedures described above. 
11.7 Reporting of Other Safety Information 
An investigator should promptly notify the SACCC when an “unanticipated problem involving risks 
to subjects or others” is identified, which is not otherwise reportable as an adverse event. 
11.8 Review of Safety Information 
11.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor will receive monthly reports from the SACCC compiling new and 
accumulating information on AEs, SAEs, and pregnancies recorded by the sites on appropriate eCRFs.  
In addition, the Medical Monitor will review and triage SAE and pregnancy reports received by the 
SACCC (See Sections 11.5.1, Reporting of Serious Adverse Events to DAIT/NIAID, and 11.6, Pregnancy 
Reporting).   
11.8.2 DSMB Review 
The Data and Safety Monitoring Board (DSMB) will review safety data at least yearly during planned 
DSMB Data Review Meetings.  Data for the planned safety reviews will include, at a minimum, a 
listing of all reported AEs and SAEs.  The DSMB will be informed of an Expedited Safety Report in a 
timely manner. 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called 
upon for ad hoc reviews. The DSMB will review any event that potentially impacts safety at the request 
of the protocol chair or DAIT/NIAID. In addition, the study stopping rules have been established and 
will be monitored in real-time (Section 9.2, Study Stopping Rules).  After careful review of the data, the 
DSMB will make recommendations regarding study conduct and/or continuation. 
 
 
 


 
 
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11.8.2.1 
TEMPORARY HALT FOR EMERGENCY SAFETY REVIEW 
A temporary halt in enrollment will be implemented if an ad hoc DSMB safety review is required.  In 
the event that the study temporarily halts enrollment, no new subjects will be consented or start on 
therapy; and subjects already on study therapy will continue on therapy unless they are the focus of 
the DSMB review.  Subjects in the screening phase of the study may continue to undergo minimal risk 
procedures (e.g. blood tests); all other procedures should be deferred. Randomization will not occur 
until the DSMB review is complete. The health authorities will be notified of any halt in enrollment.  


 
 
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12 
MECHANISTIC ASSAYS 
As discussed in other sections of the protocol, we propose that the substitution of belatacept for 
tacrolimus will result in better preservation of renal function.  However, the results of the phase 
II and phase III studies conducted to date suggest that belatacept, at least as used in those 
studies, may be associated with a slightly increased risk of acute alloimmune-mediated graft 
injury and an increased risk of PTLD, which is most commonly a consequence of an active EBV 
infection.  Consequently, our areas of focus include determinations of renal function, viral 
infections, and alloimmunity.  Mechanistic assays will be paired with clinical measurements in 
an attempt to gain insights into the mechanisms responsible for the hypothesized differences 
between the 2 treatment groups.  
Study participants will be informed that they may be approached about additional clinical 
evaluations or studies that have received the full approval of the NIAID as new evaluations are 
identified.  If additional evaluations or studies are determined to be desirable, this protocol (and 
other appropriate study documents, (e.g., the informed consent and the statistical analysis plan) 
will be amended and submitted to the appropriate regulatory authorities, ethics committees, and 
IRBs for approval.  Each participant’s signature will be obtained on the revised informed consent 
form before additional evaluations are performed.  The specimens from these evaluations may 
be stored up to the end of the grant— approximately 5 years, or longer if the grant is extended. 
12.1 Cellular Assays  
12.1.1 Intracellular Cytokine Staining Viral Phenotyping 
There is ample data to suggest that the number, maturational status and function of virus-
specific T cells is affected by treatment with immunosuppressive agents and that these factors 
are associated with the recipient’s ability to prevent de novo viral infections or reactivation of 
existing latent viruses or control chronic viral infections.  The frequency (percent of virus-specific 
cells for a defined population) as well as the absolute number (using Trucount bead 
methodology) of virus-specific CD8+ and CD4+ T cells will be determined at each time point.  
For recipients of the correct HLA type where dominant peptides have been defined and 
tetramers made, virus-specific cells will be detected by tetramer staining.  For those viruses/ 
MHC combinations where tetramers have yet to be defined or for CD4+ T cells (MHC class II 
tetramers not being available) the number of virus-specific cells will be determined by 
stimulating the cells with a pool of overlapping viral peptides and then staining the cells for 
intracellular expression of IFNγ.  Cells producing IFNγ will be considered to be specific for the 
virus corresponding to the peptide pool used to stimulate the cells.  By gating on the virus-
specific cells, their phenotype can be determined.  Using markers such as CD45RA and CCR7 
CD8+ and CD4+ T cells can be differentiated into different subpopulations that may correlate 
with their maturational status and or functional status including naïve, central memory, effector 
memory, and effector memory RA cells.  Similar characterizations will be performed on the 
entire population of T cells, CD4+ and CD8+ T cells (irrespective of their specificity) in order to 
determine global changes in the T cell repertoire following transplantation.    
The number, frequency, and phenotype of cells specific for the various viruses listed above will 
be correlated with the detection of the various viruses in the blood by PCR (described in 12.2.2) 
and for each of the 2 treatment arms.  Similar analyses will be performed to characterize the 


 
 
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number, frequency, and phenotype of other cell populations in the blood including B cells, NK 
cells, and dendritic cells (DC). 
Stimulating recipient T cells with overlapping pools of viral peptides can be used to compare the 
functional properties of virus-specific T cells as well as to identify them in order to enumerate 
them.  Data derived from viral models suggests that poly-functional T cells are more effective for 
controlling viral infections than are mono-functional cells.  That is, T cells producing both IFNγ 
and TNFα are more effective in mediating protection from viral infections than are cells that 
produce only IFNγ.  The production of other molecules such as IL-2, MIP1β, CD154, perforin, 
and granzyme B has also been reported to be associated with increased functionality.  By 
stimulating recipient blood samples with overlapping peptide pools corresponding to the 
viruses listed above and then performing intracellular cytokine staining for the molecules listed 
above, we will define the functional status of cells from patients in the different treatment groups 
and correlate these findings with the results of the viral load monitoring described in 12.9.    
12.1.2 Flow Cytometry 
Similar to the studies of virus-specific T cells described in 12.2.1, recipient T cells collected at the 
specified time points will be stimulated with donor cells or cell lysates in vitro and the number 
and frequency (percentage) of CD8+ and CD4+ cells responding to donor antigens determined 
based on intracellular staining for IFNγ.  By gating on the IFNγ-positive population the 
phenotype of the donor-specific T cell population can be determined.  Intracellular staining for 
IFNγ, TNFα, IL-2, MIP1β, CD154, perforin, and granzyme B will allow for a determination of the 
functional status of the allo-specific populations.  Data will be analyzed for differences in these 
variables between treatment groups and will be correlated with the development of donor 
specific antibody (DSA), allograft dysfunction (eGFR) and histologic injury (biopsy). 
12.2 Molecular Assays  
12.2.1 Gene Expression, mRNA Profiling and miRNA Chip Arrays 
Studies to quantify the expression of genes in the urine, blood and tissue that have been reported 
to correlate with acute kidney injury (AKI) or chronic kidney injury (CKI) will be performed.  We 
will investigate markers of allograft dysfunction including those associated with immune-
mediated injury, ischemic/stress injury, as well as non-immunologic injuries including 
calcineurin inhibitor toxicity and fibrosis targets.  A list of the gene targets and their function is 
outlined in Table 6.   Recent studies in transplantation indicate further regulation of both 
immune injury as well as fibrosis and scarring. Consequently, total RNA will be analyzed for 
miRNA expression for miR21, miR-29, miR200, miR205, miR124, and further characterization 
using real-time PCR arrays commercially available. 
 
 
 
 
 
 
 
 
 


 
 
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Table 7.  Gene Transcript Array for Kidney Allograft Biopsies 
 
IL-2 
CCL2 
ACTN4  
TLR2 
 
 
IL-4 
CCL3 
AFAP 
TLR4 
  
T cell transcripts 
IL-10 
CCL5 
ANGPT2   
SOD2 
  
costimulation 
IL-17 
CXCL9 
aSMA  
SOD3 
  
B cell 
IFNg 
CXCL11 
BMP7  
HIF1A 
  
matrix, fibrosis, EMT 
IL-23 
CX3CL1 
COL1A1  
HIG2 
  
CNI toxicity 
IL-15 
CCR1 
COL3A1  
HO-1 
 
 
CD3e 
CCR2 
COL4A2  
CAPN1 
 
NK, NKT 
CD4 
CCR5 
CTGF  
MME 
  
Mac 
CD8 
CX3CR1 
CTNNB1  
GPX1 
  
IRI/Stress 
CD28 
CXCR3  
E-cad 
HSPB2 
  
apoptosis 
CD40 
CXCL1 
FGF2  
CTSG  
  
other immune 
activation 
CD40L 
CXCL2 
FN1  
BAX 
  
Chemokines 
CD80 
ITGAM 
HSP47 
BCL2 
  
glomerular injury 
CD86 
ITGAL 
HSPG2  
Caspase 3 
  
Antibody/endothelial 
injury 
CTLA4 
ITGAX 
IGF1  
PARP 
 
 
ICOS 
IGAV 
LAMC2  
FAS 
 
 
ICAM1 
ITGB6 
MMP2 
FASL 
 
 
41BB 
NFKB1 
PAI1  
CIDEB 
 
 
41BBL 
NFKB2 
PDGFB  
TNFSF10 
 
 
CD20 
LTA 
s100A4  
Laminin β2 
 
 
BAFF-R 
LTB 
SPARC  
βIG-H3 
 
 
CD27 
TNF 
TGFB1  
Thrombospondin-
1 
 
 
TACI 
IL-6 
THBS1  
PAI-1 
 
 
CD127/IL7 
IL-13 
TIMP1 
l-arginase 
 
 
IL-5 
IL-8 
TIMP2 
Neph 
 
 
SSP1 
MMP2 
TIMP3 
Pod 
 
 
DES 
SMAD3 
TIMP4 
Gremlin 
 
 
HGF 
MMP7 
VEGF  
C3 
 
 
Osteoprotgenrin 
SMAD7 
VIM  
C4 
 
 
smad2 
MMP9 
WNT1  
CLU  
 
 
b-actin 
gapdh 
18S 
EDN1 
 
 
 
If over time additional markers become of interest, the gene targets may change. Further 
identification of targets and methods to be used will be determined by the results of cooperative 
efforts undertaken by the CTOT and CTOT-C consortia funded by a supplemental application 
for ARRA funding to standardize and cross validate assay methodology and targets, led by Dr. 
Robert Fairchild at the Cleveland Clinic 
 


 
 
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12.3 Protein Assays of Allograft Injury 
We will evaluate both serum (systemic) and urine (local) protein expression specifically looking 
at factors associated with acute and chronic injury of the kidneys in patients undergoing kidney 
allograft transplantation by correlating these putative biomarkers with renal function and biopsy 
material as described in the statistical plan.  The proteins listed include those associated with 
progressive deterioration of renal function in other settings, specifically kidney allograft 
dysfunction.  Positive control proteins or peptides will be included as appropriate.  Urinary 
results will be normalized to creatinine content. Markers for evaluation, their expected disease 
association, and method of measurement are shown in Table 8, as the study progresses this panel 
of markers or the core lab performing the assays may change. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 8.  Proteins for Analysis of Renal Injury in Kidney Transplantation 
Tissue 
Protein 
AKI 
CKI 
CNI 
Toxicity 
Methodology 
Urine 
NGAL 
X 
Unknown 
Unknown 
ELISA 
“AKI” 
NAG 
X 
Unknown 
Unknown 
Colorimetric assay 
 
IL-18 
X 
Unknown 
Unknown 
ELISA 
 
KIM-1 
X 
Unknown 
Unknown 
ELISA 
 
IP-10 
AR 
Unknown 
Unknown 
Luminex 
 
MIG 
AR 
Unknown 
Unknown 
Luminex 
Urine 
CTGF 
No 
association 
X/EMT 
Unknown 
ELISA 
“IF/TA” 
MMP9 
No 
association 
X 
Unknown 
ELISA 
 
Col Iα1 
Unknown 
X 
Unknown 
Western 
 
ColIIIα1 
Unknown 
X 
Unknown 
Western 
 
ColIVα3 
Unknown 
X 
Unknown 
Western 
 
Fibronectin 
Unknown 
X 
Unknown 
Western 
 
ICAM-1 
Unknown 
X 
Unknown 
ELISA 
 
VCAM-1 
Unknown 
X 
Unknown 
ELISA 
 
Laminin β2 
Unknown 
Unknown 
CNI TOX 
ELISA 
 
TGFβ 
No 
association 
X/EMT 
CNI TOX 
ELISA 
 
βIG-H3 
Unknown 
Unknown 
CNI TOX 
Western 
 
Osteoprotogerin 
Unknown 
X 
Unknown 
Luminex 
 
MIP-1d 
Unknown 
X 
Unknown 
Luninex 
Urine 
S100A4 
Unknown 
EMT 
In vitro 
ELISA 
“EMT” 
Vimentin 
Unknown 
EMT 
In vitro 
ELISA 
 
BMP-7 
Unknown 
EMT 
Unknown 
ELISA 
Urine 
Nestin 
Unknown 
Unknown 
CNI TOX 
Western 
“Tox” 
Caspase 1 
Unknown 
Unknown 
CNI TOX 
Colorimetric assay 
 
Caspase 3 
Unknown 
Unknown 
CNI TOX 
ELISA 
Serum 
Cystatin C 
X 
Probable 
Unknown 
ELISA 
 
NGAL 
X 
Unknown 
Unknown 
ELISA 
 
CTGF 
No 
association 
X 
Unknown 
ELISA 


 
 
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Studies to quantify the expression of various cytokines, chemokines and growth factors at the protein 
level will also be undertaken using a standardized, cross-validated approach that will arise from the 
collaborative studies between participating CTOT and CTOT-C consortia described in the preceding 
paragraph.  Sequential serum samples additionally may be analyzed for chemokines and cytokines 
and quantified using the Luminex™ platform. Further target analysis exact assay SOP will be 
developed by the CTOT mechanistic assays consortia headed by Dr. N. Najafian of Brigham and 
Women’s Hospital for this particular assay.     
12.4 Antibody Assays 
12.4.1 Anti-HLA Antibody (Alloantibodies) and Non-HLA Antibodies 
The presence of antibodies reactive to HLA molecules expressed on the renal allograft as well as non-
HLA molecules such as MICA have been associated with both acute and chronic injury to the 
transplanted kidney.  We will determine the presence, and if present the amount, of antibodies 
specific for HLA-A, B, C, DR, DQα, DQβ, and DPβ.  We will use the LuminexTM solid phase testing 
platform.   Serum samples will be collected for analysis at the time of transplantation, days 28 & 84, 
and weeks 28, 36, and 52.  Donor specificity will be assigned based on the HLA type of the donor at 
the loci listed above.   
The frequency and amount of antibodies to MICA will be determined using the approach developed 
by the CTOT/CTOT-C mechanistic assay consortium for detection of antibodies led by E. Reed at 
UCLA.  The de novo development of donor-specific antibodies (DSA) will be compared to functional 
changes (assessed by eGFR) and histologic changes (as demonstrated by biopsy) for the 2 treatment 
groups. 
12.5 Markers of Autoimmunity 
The CTOT-15 study will explore the impact of the autoimmune response on graft function following 
pancreas transplantation. The hypothesis that is being tested is that markers of recurrent autoimmune 
disease will correlate with graft loss as defined by a return to insulin dependence. The details of the 
assay will be worked out at the time of the samples are available based on the needs of the study and 
technology.  The assays for the cellular response against autoantigens are being developed in 
collaboration with the laboratory of Dr. Gerald Nepom (Benaroya Insititute, Seattle).  This work will 
compliment the current work conducted in the Clinical Islet Transplantation (CIT) consortium.   
Whole blood will be collected, and peripheral blood mononuclear cells (PBMCs) and serum will be 
isolated from CTOT-15 participants at baseline, days 28 and 84, weeks 28, 36, and 52. In addition, 
these samples will be collected at the time of suspected rejection, prior to initiating therapy. The 
samples will be stored at the University of California, San Francisco for future analysis of markers of 
autoimmunity.  
12.6 Genomics 
We will isolate and save a DNA sample from each consented patient potentially to use in genomic 
analysis of polymorphisms for cytokine genes. There are several such gene polymorphisms that have 
been associated with increased risk of poor outcome post-transplant.  While our goal is not to test the 
association between various genetic polymorphisms and graft outcome, it is possible that once our 
study is complete there may be questions regarding whether our results are independent of such 


 
 
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polymorphisms and that it would be prudent to maintain small samples for analysis should such 
questions arise. 
As already noted, prior studies using belatacept have been associated with acute rejection rates 
higher than standard therapy and the current study intends to optimize its use to minimize 
rejection or other toxicities.  Analysis of gene polymorphisms in recipients may provide insight 
into allograft outcomes.   Recently, polymorphisms in the CTLA4 gene have been described and 
associated with transplant outcome25.   We will analyze these polymorphisms as well as other 
others related to transplant outcomes26.  DNA will be isolated from the donor and recipient prior 
to treatment and subsequently analyzed.  These results will be analyzed in terms of the primary 
and secondary endpoints of the study. 
12.7 Pathology 
12.7.1 Histology- Renal 
Histologic examination will be performed at UCSF Pathology Laboratory.  The centers will send 5 
original stained slides (1 Trichrome or unstained, 1 PAS and 3 H&E) that were collected at times of 
for-cause biopsy (i.e., increase in serum creatinine, proteinuria, or other clinical symptoms) at the 
discretion of the site Investigator.   
Fibrosis will be assessed using Trichrome and type III collagen stains in the Aperio digital images.  
Biopsy results will be reported using the Banff 2007 classification of renal allograft 
pathology.  Furthermore, morphometric techniques performed on whole slide digital images in the 
central core laboratory will serve as adjunctive data to the routine histologic evaluation. Multivariate 
analysis will seek correlations with changes in any of the morphological parameters including cellular 
infiltration, vasculopathy, and fibrosis. C4d stains will also be performed on all biopsies if not 
performed and/or provided by the participating institution.   
Morphological evaluations will be recorded in a standardized format, according to Banff ’07 criteria.  
Primary data will be sent to the Statistical and Clinical Coordinating Center for final analysis. High-
resolution images of entire sections of all stains from each biopsy will be acquired and archived in an 
Aperio Digital database system.   Slide images will be stored at the UCSF (PI: Dr.  Zoltran Laszik) for 
additional analysis, if needed.  
12.7.2 Immunohistochemistry- Renal 
The centers will send the remaining portion of the formalin fixed, paraffin embedded (FFPE) block at 
times of graft dysfunction/ for cause biopsies.   
Immunohistochemical studies will assess collagen III deposition, subsets of inflammatory cell 
infiltrates, and other molecular markers to be determined in conjunction with genomic, proteomic, 
chemokine, and cytokine data.  Since it is anticipated that the core for immunohistochemistry will be 
small, immunohistochemical stains will be tailored to biomarkers that show promise in the genomic, 
proteomic, chemokine, and cytokine studies.    Remaining tissue will be stored at the UCSF (PI: Dr. 
Zoltran Laszik) until the end of the study (no more than 4 years) for additional analysis, if needed.  
12.7.3 Histology- Pancreas 
Histologic examination will be performed at UCSF. The centers will send stained slides (1- Trichrome 
or unstained slide and 3- H&E) at the times of standard of care and for cause biopsies, if 
available.  Biopsy results will be reported using the Banff 2011 classification of pancreas allograft 


 
 
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pathology.   Slide images will be stored at the UCSF (PI: Dr. Zoltran Laszik) for additional analysis, if 
needed.  
12.8 Viral Testing 
Viral infection following renal transplantation remains a significant source or recipient 
morbidity and mortality as well as a significant cause of allograft dysfunction and loss.  We will 
test and quantify the presence of viremia.  These tests will be completed in batch assay runs by a 
core laboratory, and results will not be available to the clinical centers.  Detection of the 
following viruses will be performed by single assay Quantitative PCR:  CMV, BKV, JCV, HHV6 
and HHV7. EBV will be performed on serum.  In collaboration with the Emory Clinical 
Laboratories we are developing quantitative viral load assays for HHV3 (varicella zoster), HHV6 
(roseola), HHV7 (a potential co-factor for CMV disease), polyoma JC and the recently described 
polyoma WC and KI viruses. If cost-effective multiplexed or low-density arrays are developed, 
we will consider extending our studies to map the patterns of reactivation and viremia with 
these latent/chronic viruses.   
12.9 Specimen Repository for Future Studies 
An attempt will be made to collect amounts of volumes slightly in excess of the minimal 
required amount for the studies currently planned in order to allow specimens to be banked for 
use in new assays that have yet to be optimized of conceived or assays performed by other 
CTOT members not proposed as part of CTOT-15 such as analysis of miRNA, proteomic 
analyses, or ELISPOT.  Appropriate informed consent will be obtained for both the collection 
and banking of samples and specimens.   


 
 
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13 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
13.1 Statistical Analyses 
CTOT-15 is a randomized open-label phase II clinical trial in which subjects who have received a SPK 
transplant are randomized 1:1 to treatment arms receiving (a) Thymoblobulin + methylprednisone 
induction followed by maintenance with tacrolimus + MMF, or (b) Thymoglobulin + 
methylprednisone induction followed by initial maintenance belatacept + MMF + gradually declining 
Tacrolimus so that ultimately they will be maintained entirely on a regime of belatacept and MMF. 
Analysis of the primary endpoint will be based on outcomes measured at 52 weeks post- 
randomization, while analyses of most secondary outcomes will be done on measurements taken at 
day 28, (baseline), day 84, and weeks 28, 36, and 52 post-randomization. The primary study objective 
is to evaluate the belatacept-based maintenance vs. tacrolimus- only maintenance, as a means of 
improving long term graft function without increasing the risks associated with the later of 
immunologic graft injury by avoiding both CNI and corticosteroids associated with the more 
standard tacrolimus maintenance regimen. In addition, this study has a large number of secondary 
clinical and mechanistic objectives.  
13.2 Endpoint Assessments 
13.2.1 Primary Clinical Endpoint 
The primary endpoint will be the week-52 eGFR. Mean eGFR of the belatacept group will be 
compared to the mean eGFR of the tacrolimus reference group within a mixed models repeated 
measures (MMRM) framework , wherein repeated measures of eGFR  at weeks 4, 12, 28, 36 and 52 
will be modeled as a linear function of time (and perhaps other baseline covariates) in the 2 treatment 
groups.  At week-52, a contrast will be made between the eGFR mean of the belatacept group and the 
eGFR mean of the tacrolimus group. ANCOVA assumptions will be evaluated graphically via 
standard residual analyses. If the assumptions fail, a suitable transformation (e.g., natural logarithms) 
will be found and the data will be reanalyzed on the transformed scale. Results will be reported with 
p-values associated with the F-test for each contrast and the corresponding mean treatment 
differences with two-sided 95% confidence intervals. All tests of significance will be two-tailed at the 
0.05 level. 
Estimating the contrasts within the repeated measures framework will provide treatment 
comparisons that are robust to subject dropout bias as long as the dropout pattern is missing at 
random27. Data are missing at random whenever the “missingness” mechanism is a function of 
observable relationships among the nonmissing responses and covariates.  Using the methods of Ma 
et al.28 , we will evaluate the MAR assumption in the data prior to implementing the MMRM 
analysis. If the MAR assumption fails, we will consider more robust alternatives (e.g., pattern mixture 
modeling)29. 
A number of studies have shown RMANCOVA to be superior to analyses of completers or of data 
with LOCF imputations30. Nonetheless, we will  conduct 2 related sensitivity analyses: (1) replace the 
missing week-52 values with the corresponding nonmissing week 36 values of each subject, dropping 
anyone who is missing both week-36 and week-52 and perform the ANCOVA as currently specified; 
(2) include only the completers in the ANCOVA analysis (i.e., exclude all dropouts).  The sensitivity 
analyses will be included as additional secondary analyses. 


 
 
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13.2.2 Secondary Clinical Endpoints 
The secondary endpoints are defined in Protocol section 1.5. 
The protocol defines 28 secondary clinical endpoints. The endpoints are to be computed and 
summarized by treatment and, in a few cases, by day/week and treatment. With the exception of 
specific AEs and lab parameters, proportions or means will be estimated for each treatment arm and 
tested for treatment differences through the use of a statistical model. The particular model to be used 
depends on the scale of measurement of the endpoint.  The accompanying table lists each endpoint 
and its measurement scale (continuous, dichotomous, and ordinal). All tests of significance in all 
analyses will be made at the 0.05 level. 
Dichotomous measures of prevalence and incidence will be analyzed with log-binomial regression 
models, wherein treatment effects will be estimated as relative risk ratios; the reference group will be 
the tacrolimus-thymoglobulin subjects. The log-binomial model (rather than logistic regression) is 
applied for prevalence and incidence analyses because model-based estimates of relative risk (RR) are 
both more desirable and appropriate for non-Poisson events that are expected to occur more 
commonly than in 10% of the cases. In such cases, logistic regression-based odds ratio (OR) estimates 
are poor estimators of the relative risk31,32,33,34. It may be appropriate to treat some of the 
dichotomous outcomes as censored data; if this is the case, we will obtain RR estimates by fitting Cox 
regression models to the data35. 
The single ordinal secondary outcome variable (Banff cell-mediated AR score) will be analyzed in a 
proportional odds model36 which may include additional covariates and interaction terms, as 
appropriate. 
For continuous outcomes, we will test for differences in response means among the treatment arms 
by fitting normal theory analysis of variance (ANOVA) or analysis of covariance (ANCOVA) models 
to the original scores or to some normalizing-variance stabilizing transformation of them. For some 
endpoints, these models may be fit separately by month post-randomization (i.e., time will be treated 
as a by-variable and no repeated measures analysis will be performed). Repeated measures models 
will be fit to HbA1c data and to the slopes of eGFR vs. time regressions. The latter will be estimated 
in a mixed effects repeated measures model in which both treatment-group means (with 95% 
confidence limits) of the individual subject slopes and the individual subject slopes themselves will 
be estimated and tested for equality. Distributions of the individual slopes will be examined 
graphically and compared among the treatment groups.  
Table 9. CTOT-15 primary and secondary clinical response variables  
Response type 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test for 
treatment effects 
 
Primary Endpoint 
Mean GFR at week 52 
(based on CKD-EPI 
Eq.) 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
 Mixed Effects 
Repeated Measures   
ANCOVA  
 
Week-36 LOCF for 
missing week-52 eGFR 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
Mixed Effects 
Repeated Measure 
ANCOVA 
 
Mean GFR at week 52 
(based on CKD-EPI 
Eq.) For Completers 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
Mixed Effects 
Repeated Measure 
ANCOVA 
 


 
 
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Response type 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test for 
treatment effects 
 
Secondary Endpoints 
Renal  Function 
and Injury 
Endpoints 
 
Indicator of week 52 
eGFR<60 mL/min/1.7 
m2  or day 85 – week 52 
eGFR decrease < -10 
mL/min/1.7 m2 
(composite endpoint 
based on CKD-EPI Eq.)  
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
Mean GFR at week 52 
(based on week 52 
MDRD4 values) 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
Mixed Effects 
Repeated Measure 
ANCOVA 
 
Slope of GFR vs. time 
Regression  over day 
85 – week 52, for each 
treatment arm 
continuous 
Slope Mean  
and Std. Error 
or mean + 95% 
CI 
Mixed effects 
Repeated Measures 
ANCOVA 
 
Incidence of successful 
tacrolimus withdrawal 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
 
Incidence of dialysis at 
day 5 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
 
Biopsy-confirmed  
Incidence of  an 
increase of  ≥ 1 
CAN/IFTA grade, 
relative to baseline, at 
each follow-up 
assessment  
Dichotomous 
(Banff score <1 
vs. ≥ 1 ) 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
Prevalence of  
CAN/IFTA grades I, 
II, III at week 52 
Dichotomous 
(1 outcome for 
each grade) 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression 
(1 model per grade) 
Incidence and 
Severity of 
Rejection and 
Anti-donor 
reactivity 
 
Incidence of Acute 
Rejection (AR) of renal 
or pancreatic 
transplant within the 
first 52 weeks 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
 
Banff score  of the 1st 
observed of renal or 
pancreatic AR within 
52 weeks post-
transplant 
Ordered 
categories (3 
levels) 
 
Proportion 
+ 95% CI 
Proportional Odds 
model  
 
Highest Banff score  
observed within 52 
weeks post-transplant 
for either renal or 
pancreatic transplant 
 
Ordered 
categories (3 
levels) 
Proportion 
+ 95% CI 
Proportional Odds 
model  


 
 
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Response type 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test for 
treatment effects 
 
 
Steroid vs. 
nonsteroidal treatment 
for renal or pancreatic 
AR 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
Prevalence of anti-
donor HLA antibodies 
at week 52 for renal or 
pancreatic transplant 
subjects 
dichotomous 
Proportion 
+ 95% CI 
 
Log-binomial or 
Poisson regression  
 
 
Cardiovascular + 
Metabolic 
Fasting blood sugar 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
Separate ANOVA or 
ANCOVA at weeks 
28 and 52  
 
HbA1c (baseline 
through week 52) 
continuous 
Mean and/or 
geometric 
mean + 95% CI 
Mixed effects 
Repeated Measures 
ANCOVA 
 
Blood pressure at 
weeks 28 and 52 
Continuous  
Mean and/or 
geometric 
mean + 95% CI 
at weeks 28 and 
52  
ANCOVA at weeks 
28 and 52, with use of 
blood-pressure drugs 
as a covariate 
 
Use of BP medications 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
 
Fasting lipid profiles at 
weeks 28 and 52 
Continuous  
Mean and/or 
geometric 
mean + 95% CI 
Separate ANOVA or 
ANCOVA at weeks 
28 and 52  
 
Total daily pill count 
continuous 
Mean + 95% CI 
tabulated and 
plotted over 
time, by trt. 
group 
Separate ANOVA or 
ANCOVA at day 85 
and weeks 28 and 52  
(or Poisson Reg) 
Safety (for both 
renal and 
pancreatic 
transplant subjects) 
 
Incidence of death or 
graft loss or 
undetectable C-peptide 
separately and as a 
composite 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
Incidence of  any AE 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
Incidence of  any SAE 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  
 
 
Incidence of  specific 
infectious diseases  (1 
analysis per disease) 
and/or malignancy 
 
dichotomous 
Proportion 
+ 95% CI 
Log-binomial or 
Poisson regression  


 
 
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Response type 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test for 
treatment effects 
 
 
Incidence of specific 
AEs , by NCI CTC 
grade and treatment 
arm 
dichotomous 
proportion 
none 
 
Specific lab parameters 
by treatment arm and 
day/week 
continuous 
N, min, max, 
Mean, std. dev  
none 
 
Change from baseline 
for specific lab 
parameters by 
treatment arm and 
day/week 
continuous 
N, min, max, 
Mean, std. dev  
none 
    
13.2.3 Mechanistic Assay Analyses 
The primary mechanistic objective of CTOT studies is to identify and elucidate pathophysiologic 
and genetic mechanisms that are associated with allograft rejection and how these associations 
may evolve over time and/or differ between therapeutic treatments. In this study, the principal 
objectives of the mechanistic analyses of data from subjects receiving kidney or pancreas 
transplants will include assessment of the association between treatment (i.e., belatacept vs. 
tacrolimus maintenance) and renal function, incidence of viral infection and autoimmunity. 
Ten mechanistic assays are described in Section 12. There are from 1 to 3 separate correlations or 
tests desired for each assay category and these are described in Table 8. The analysis numbers in 
the table refer to the following 10 assays: 
1. Intracellular cytokine staining and viral phenotyping 
2. Flow cytometry 
3. Protein Assays 
4. Gene expression, mRNA profiling 
5. Anti-HLA alloantibodies and non-HLA antibodies 
6. Autoimmunity markers 
7. Genomics (gene polymorphisms) 
8. Renal histology 
9. Renal immunohistochemistry 
10. Pancreatic histology 
11. Viral testing (viral load determination) 
Depending on the scale of measurement of the endpoints, the amount of missing data, and the 
questions of interest, exploratory data analysis (EDA) and/or statistical hypothesis testing and 
modeling will used.  Given the small sample sizes (n=30 in each of 2 treatment arms), modeling 
and testing will generally be restricted to the continuous endpoints where the focus will be 
testing for treatment and time effects on repeated measures of the endpoints.  These types of 
analyses will have sufficient sample sizes to make reasonable inferences; e.g., repeated measures 
ANCOVA tests for differences in gene expression in the treatment arms, over 5 assessment times 
would have to following degrees of freedom for the their error terms: treatment df = 58;  time df 
= 238,  time × treatment = 238.      
  


 
 
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Analysis 
No.  
 Effector cells,  
antibodies, or 
markers (see 
Sect. 12) 
Meas. 
Scale 
Assay 
 
Objective  
Analysis 
Method1 
1a 
Virus-specific T-
cell 
subpopulations  
Continuous. 
(cell counts) 
Cytokine 
staining + 
PCR 
Correlation with 
viral loads 
detected with 
PCR, by visits 
and treatment 
arm  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; treatment x time 
plots; tables of 
summary stats. 
1b 
Virus-specific T-
cell 
subpopulations 
Binary 
Cytokine 
staining + 
PCR 
Comparison of 
prevalence of 
each T-cell type 
by visits and 
treatment arm 
Contingency tables and 
Cochran Mantel 
Haenszel (CMH) tests 
1c 
Virus-specific T-
cell 
subpopulations  
Continuous. 
(cell counts) 
Cytokine 
staining + 
PCR 
Correlation with 
B-cell counts, NK 
cell counts, 
dendritic cell 
counts by visit 
and treatment 
arm  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; treatment x time 
plots; tables of 
summary stats. 
2a 
Donor-reactive T-
cell 
subpopulations  
Continuous. 
(cell counts) 
Flow 
Cytometry 
Look for 
treatment arm 
differences in 
counts, over time  
Random Effects 
repeated measures 
ANCOVA 
(RMANCOVA); 
treatment x time plots 
and random coefficients 
models and plots; tables 
of means and standard 
errors 
2b 
Donor-reactive T-
cell 
subpopulations  
Continuous. 
(cell counts) 
Flow 
Cytometry 
Correlation with 
eGFR, de novo 
anti-donor HLA 
and biopsy 
findings, by visits 
and treatment 
arm  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; treatment x time 
plots; tables of 
summary stats. 
3 
Protein Assays 
 
 
 
 
4a 
Gene expression 
data for > 128 
markers 
Continuous  
Real –time 
PCR 
Identify 
associations 
between specific 
mRNAs and the 
occurrence of 
AKI, CHI, CIT, 
and fibrosis, by 
visit pooled over 
trt  
EDA: various graphical 
comparisons and 
descriptive statistics (by 
visit if there  are enough 
occurrences of AKI, 
CKI, CIT, and/or 
fibrosis  
                                                          
1 Statistical tests (e.g., t-tests) and statistical models (e.g., ANOVA) will only be performed if sample sizes are adequate 


 
 
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Analysis 
No.  
 Effector cells,  
antibodies, or 
markers (see 
Sect. 12) 
Meas. 
Scale 
Assay 
 
Objective  
Analysis 
Method1 
4b 
Gene expression 
data for > 128 
markers  
Continuous  
Real –time 
PCR 
Look for evidence 
of treatment 
differences in the 
occurrence of 
each marker over 
time  
Separate RMANCOVAs 
for each marker; 
treatment x time plots; 
tables of means and 
standard errors by 
marker, treatment arm, 
and visit 
5a 
Anti-HLA and 
non-Anti-HLA 
antibodies 
Continuous  
Luminex 
Characterize the 
occurrence of 
HLA-A, B, C, 
DR, DQα, DQβ, 
DPβ, and anti-
MICA, by 
treatment arm 
and visit  
Separate RMANCOVAs 
for each ab.; treatment x 
time plots; tables of 
means and standard 
errors by antibody, 
treatment arm, and visit 
5b 
Anti-HLA and 
non-Anti-HLA 
antibodies 
Binary (present 
absent)  
Luminex 
Examine 
prevalence 
patterns of HLA-
A, B, C, DR, 
DQα, DQβ, 
DPβ, and anti-
MICA 
Contingency tables and 
CMH tests by marker ; 
treatment x time plots; 
tables of prevalence 
means and stderrs by 
treatment arm and visit 
5c 
De Novo donor-
specific anti-HLA 
antibodies 
Continuous  
Luminex 
Correlation with 
eGFR, and biopsy 
findings (if 
enough are 
done), by visits 
and treatment 
arm  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; treatment x time 
plots; tables of 
summary stats. 
6 
Markers of 
recurrent 
autoimmune 
disease following 
pancreas 
transplant   
Continuous  
TBD 
Compare 
distributions of 
anti-GAD, anti-
insulin and anti-
IA2 between 
subjects with AR 
and no AR  
 
EDA using graphical 
and tabular summaries 
of the data in AR vs. 
non-AR within and 
between subjects. 
7 
Genomic analysis 
of  
polymorphisms 
(SNPs) in 
cytokine genes 
Binary  
TBD 
Determine if 
differences in 
cytokine genetic 
polymorphisms 
are associated 
with AR  
Logistic regression 
analysis for additive 
and recessive 
hypotheses; wherein, 
the predictors are the 
numbers (0,1,2,) of 
recessive alleles for each 
SNP. 
 


 
 
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Analysis 
No.  
 Effector cells,  
antibodies, or 
markers (see 
Sect. 12) 
Meas. 
Scale 
Assay 
 
Objective  
Analysis 
Method1 
7 
Morphological 
markers in 
biospsied kidney 
tissue + CD4 
markers 
Continuous + 
binary 
(present/absent) 
Trichrome, 
H&E, and 
CD4 staining 
Correlation with 
visit 1 – week 52 
changes in Banff 
scores and 
corresponding 
changes in 
several 
morphometric 
features of the 
grafts  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; tables of 
summary stats. 
9 
Renal markers of 
fibrosis and 
inflammation  
Binary (present/ 
absent) 
Immuno-
histochemical 
staining 
Compare  
genomic, 
proteomic, 
cytokine profiles 
in subjects 
with/without the 
renal markers  
Tables of summary 
statistics to compare 
within-subject changes 
in markers and profiles 
between visit 1 and 
week 52.  
10 
Morphological 
markers in 
biospsied 
pancreatic tissue 
+ CD4 markers 
Continuous + 
binary 
(present/absent) 
Trichrome, 
H&E 
Correlation with 
visit 1 – week 52 
changes in Banff 
scores and 
corresponding 
changes in 
several 
morphometric 
features of the 
grafts  
Spearman Rank 
Correlation Coeff., by 
visit and treatment 
group; tables of 
summary stats. 
11a 
Prevalence and 
intensity (viral 
load) of several 
pathogenic 
viruses  
Binary 
(present/absent) 
Quant. PCR 
Prevalence of 
CMV, BKV, JCV, 
HHV6, HH7, and 
EBV 
Contingency tables and 
CMH for treatment 
time differences in 
prevalence of each viral 
species 
11b 
Prevalence and 
intensity (viral 
load) of several 
pathogenic 
viruses  
Continuous  
Quant. PCR 
Viral loads of 
HHV6, 
HHV7,Polyoma 
JC, Polyoma WC, 
and KI   
Separate RMANCOVAs 
on each virus; treatment 
x time plots; tables of 
means and standard 
errors by virus, 
treatment arm and visit 
 
Table 10.  Summary of Mechanistic Data Analyses 
 


 
 
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13.3 Sample Size and Power Calculations 
We have used data from the belatacept phase II and DIRECT studies and from the literature (Grewal 
and Blake 2005) to provide expected values for the GFR standard deviations shown in Table 10 below.  
Sample size calculations for these analyses were performed using NCSS-PASS software. 
In the primary endpoint analysis, we will compare the mean GFR between the study groups at 12 
months. With the sample sizes fixed, a priori, at 30 subjects in each of the two treatment arms, the 
following table shows the smallest treatment mean GFR differences (i.e. effect sizes) we will be able to 
declare significantly different, with 80% power and Type I error rates of 0.05 and 0.10:  
Table 11 – Smallest Detectable Difference in GFR at 12 Months for Different Standard Deviations 
and Alpha Levels 
 
GFR Standard 
Deviation 
Alpha 
Level 
Smallest Detectable 
Difference in GFR 
(mL/min/1.7 m2  ) 
16 
0.05 
12.0 
 
0.10 
10.5 
20 
0.05 
15.0 
 
0.10 
13.0 
24 
0.05 
18.0 
 
0.10 
16.0 
 
This study has been powered to be able to detect minimum detectable differences in the primary 
endpoint at both the 0.05 and 0.10 levels that are clinically relevant as shown in Table 9 above. When 
reporting results of the primary endpoint analysis, we will report a p-value as significant at the 0.10 
level if it is less than 0.10 and as significant at the 0.05 level if it is less than 0.05. As previously stated, 
all secondary endpoint analyses will be performed at the 0.05 level. 
13.4 Safety Analyses  
All adverse events (AEs) and serious adverse events (SAEs) will be classified by body system and 
preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs and SAEs 
will be summarized as the frequency of each event by treatment group.  
Frequency tables by treatment group and category of event (e.g., serious, related to study therapy, 
causing the discontinuation of study therapy) and by NCI-CTCAE grade will be presented. Selected 
laboratory values will also be summarized by treatment group using the mean and standard 
deviation of the change from baseline at scheduled visits. 
13.5 Demographic Data 
13.5.1 Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided for all 
enrolled participants. Demographic data will include age, race, sex, body weight, and height; these 
data will be presented in the following manner:  
• Continuous data (i.e., age, body weight, and height) will be summarized descriptively by 
mean, standard deviation,   median, and range.  


 
 
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• Categorical data (i.e., sex and race) will be presented as enumerations and percentages.  
Statistical presentation for baseline and demographic characteristics will be further defined in the 
statistical analysis plan (SAP). 
13.5.2 Medical History 
Medical history will be collected, including the existence of current signs and symptoms and clinical 
significance for each body system.  
13.6 Interim Analyses 
No interim analyses are planned for this study. Unspecified interim analyses are only conducted if 
they will not adversely affect the integrity of the study or for safety reasons.  
13.7 Reporting Deviations from Original Statistical Plan 
The final study analysis will report the results of the original SAP. Any additional analyses will be 
identified as ad hoc. Clinical study report will be prepared and submitted to the health authority as 
specified in the FDA Guideline for Industry - Structure and Content of Clinical Study Reports - ICH E3 
July 1996.  
13.8 Final Study Analysis  
The final study analysis will report the results of the SAP. Any additional analyses will be identified as 
ad hoc. A final study report will be prepared summarizing the results of analyses of the primary and 
secondary clinical endpoints and the analyses associated with the 12 mechanistic hypotheses. 
 
 


 
 
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14 SOURCE DATA  
14.1 Source Data 
All study data should be verifiable by source documentation.  Most often this will be present in the 
patient’s medical record.  Except in rare instances, study documents (CRFs and data collection tools) 
are not source documents.  “Shadow charts”-duplications of material from the medical record are not 
source documents.   
14.2 Access to Source Data 
The responsibilities of the study sponsor require that they and their representatives as well as the 
health authorities have access to (and may when required by applicable law copy) source documents 
Unless required by the laws that permit copying of records, only the coded identity associated with 
documents or with other participant data may be copied (and all personally identifying information 
must be obscured).  Authorized representatives as noted above are bound to maintain the strict 
confidentiality of medical and research information that is linked to identified individuals.  
 
 


 
 
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15 QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator is required to keep accurate records to ensure that the conduct of the study is fully 
documented.   
The sponsor is responsible for regularly reviewing the conduct of the trial, for verifying adherence to 
the protocol, and for confirming the completeness, consistency, and accuracy of all documented data. 
15.1 Data Handling 
The investigator is required to ensure that all CRFs are completed for every participant entered in the 
trial.    All elements of data entry (i.e., time, date, verbatim text, and the name of the person performing 
the data entry) will be recorded with an audit trail to allow all data changes in the database to be 
monitored and maintained in accordance with federal regulations. 
 
 


 
 
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16 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
16.1 Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in this 
study protocol.  Before study initiation, the protocol and the informed consent documents will be 
reviewed and approved by an appropriate EC or IRB.  Any amendments to the protocol or to the 
consent materials must also be approved before they are implemented. 
16.2 Informed Consent Process  
The consent process provides information about the study to a prospective participant and allows 
adequate time for review and discussion prior to their decision.  The principal investigator or designee 
listed on the FDA 1572 will review the consent and answer questions.  The prospective participant will 
be told that being in the trial is voluntary and that he or she may withdraw from the study at any time, 
for any reason.  All participants (or their legally acceptable representative) must read, sign, and date a 
consent form before undergoing any study procedures.  Consent materials must be presented in 
participants’ primary language. A copy of the signed consent form must be given to the participant. 
The consent process is ongoing.  The consent form must be revised when important new safety 
information is available, the protocol is amended, and/or new information becomes available that may 
affect participation in the study.  
16.3 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant 
will be assigned a unique identification number and these numbers rather than names will be used to 
collect, store, and report participant information.  Site personnel should not transmit documents 
containing personal health identifiers (PHI) to the study sponsor or their representatives. 
 
 


 
 
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17 PUBLICATION POLICY 
The Clinical Trials in Organ Transplantation (CTOT) policy on the publication of study results will 
apply to this trial.  The CTOT Publication Policy is located on the CTOT website at 
www.ctotstudies.org.  
 
 
 
 
 
 
 


 
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Appendix 1:  Schedule of Events – Pre-Transplant to Day 4 Post-Transplant (Visit 1) 
Screening Assessments 
Window 
• Blood Type (A, B, O), Rh Factor 
• HLA Typing (Class I:  A, B, C, Class II:  DR, DP, DQ)  
• Peak PRA, Current PRA or cPRA (within 12 months prior to transplant),Crossmatch 
• Hepatitis B, Hepatitis C, and HIV test results 
• Last reported CMV (IgG, IgM and/or total CMV Ab) and EBV testing (IgG, IgM) 
• Tuberculosis testing (within 12 months prior to transplant).  If documentation is not 
present at the time of transplant, and the subject does not have any risk factors for TB, a 
TB-specific interferon gamma release assay (IGRA) may be performed. 
Retrospective data 
collection, no time limits, 
unless specified.   Repeat 
only if not available. 
• Informed Consent and Assessment of Eligibility 
• Demographics 
• Medical History, Physical exam (BP, Pulse, Temperature, Respiration, Weight) 
• Concomitant Medications 
• Local Labs: Serum Pregnancy Test, Hematology Panel (CBC, differential, platelets), 
Chemistry 12-Panel / CKD-EPI equation, MDRD 4 variable, Serum Amylase, 
Serum Lipase, Fasting Lipid Panel (Total, HDL, LDL, Triglycerides), Hemoglobin 
A1c, Urinalysis 
Within 30 days prior to 
transplant, until time of 
transplant. 
 
• Flow Cytometry (20mL blood in Cyto-Chex Tube)  
• Intracellular Cytokine Staining – Viral Phenotyping (32mL blood in CPT Tube)  
• Markers of Autoimmunity – PBMC (30mL blood in Green-top Tube) 
• Markers of Autoimmunity – serum (5mL blood in Red-top Vacutainer) 
• Gene Expression, mRNA profiling in blood (2.5 mL blood in PAXgene RNA tube) 
• Cytokines and Growth Factors- serum (7mL blood in Red-Top Vacutainer) 
• Serum Proteins – CTGF, TGFbeta (4.5mL blood in CTAD) 
• Urine Proteins – CTGF, TGFbeta (supernatant) 
• Gene Expression, mRNA profiling in urine (urine pellet) 
• Non-HLA Ab, Anti-HLA Ab, DSA (5mL blood in Red-top Vacutainer) 
• Genomics- gene polymorphisms (4mL in Lavender-top EDTA Vacutainer) 
• Viral Monitoring by PCR (CMV, BKV, JCV, HHV6, HHV7) and Viral Assay 
Development (HHV3- varicella zoster, HHV6- roseola, HHV7- cofactor CMV, 
polyoma JC, WC, KI).(plasma from ICS sample) 
Within 48 hours prior to 
transplant 
• Randomization (RhoRand System) 
• Assessment of Events: AE/SAE 
• Solumedrol®( Methylprednisone) : 500mg – Intraoperatively 
• Thymoglobulin® (Anti-thymocyte Globulin – Rabbit) 
• Prograf® (tacrolimus)  
• CellCept® ( mycophenolate mofetil ) 
Day of Transplant 
• Methylprednisolone 250 mg 
• Thymoglobulin® (Anti-thymocyte Globulin – Rabbit) 
Day 1 Post-Transplant 
• Methylprednisolone 125 mg 
• Thymoglobulin® (Anti-thymocyte Globulin – Rabbit) 
Day 2 Post-Transplant 
• Methylprednisolone 60mg 
• Thymoglobulin® (Anti-thymocyte Globulin – Rabbit)  
Day 3 Post-Transplant 
• Methylprednisolone 30mg 
Day 4 Post-Transplant 


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 97 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
Appendix 2.  Schedule of Events (Recipient) Post-Transplant  
 
 
 
DAYS 
WEEKS 
FOR 
CAUSE 
2, 3 
5 
14 
28 
56 
84 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
VISIT NUMBERS 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
VISIT WINDOWS (+/- DAYS) 
 
2 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
5 
5 
GENERAL ASSESSMENTS 
Physical Exam 
BP, Pulse, Temperature, Respiration, Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunosuppressive Meds 
Drug Name and Dose 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Concomitant Medications 
Drug Name (Anti-HTN, Prophylaxis, Anti-Viral) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments of Events 
AE/SAE, Infections, Rejections, Hospital, Graft 
Loss, Malignancies, New Onset Diabetes, Death 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Neurological Assess. for PML 
Hx, mini mental, cranial nerve, motor, cerebellar  
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
LOCAL LABORATORY ASSESSMENTS 
Hematology Panel 
CBC, differential, Platelet 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Chemistry Panel  / GFR 
(CKD-EPI and MDRD)- Renal 
Function 
Serum Creatinine, BUN, glucose, sodium, AST, 
ALT, ALP, bilirubin, albumin, calcium, phosphate 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Chemistry- Pancreatic 
Function 
Serum Amylase, Serum Lipase 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Fasting Lipid Panel 
Total, HDL, LDL, Triglycerides 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
C-Peptide 
C-Peptide 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hemoglobin A1c 
HbA1c 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Urinalysis 
Protein, Glucose, Hematuria, WBC 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Trough Levels 
Tacrolimus trough levels 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral Monitoring 
BKV and CMV by PCR in blood 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Histology- Renal 
Local Read- Banff 2007 Renal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Histology – Pancreas 
Local Read- Banff 2011 Pancreas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NULOJIX® (BELATACEPT) INFUSION DOSING 
 Belatacept Infusion 
• 
Investigational Arm  
IV, 10mg/kg  
X4 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Belatacept  Infusion 
• 
Investigational Arm 
IV, 5mg/kg  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TACROLIMUS DOSING SCHEDULE 
Tacrolimus Dosing  
• 
Control Arm 
Dose adjusted to target trough levels of 8-
12ng/mL to week 24, then 5-8ng/mL thereafter.  
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Tacrolimus Dosing6,7,8   
• 
Investigational Arm 
Dose adjusted to target trough levels 5-8 ng/mL 
to week 24, then 3-5 ng/mL until week 40. 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
stop 
 
 
 
MYCOPHENOLATE MOFETIL DOSING SCHEDULE 
Mycophenolate Mofetil 
1gm BID, Adjusted based on clinical 
complications 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 98 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
 
 
 
DAYS 
WEEKS 
 
FOR 
CAUSE, 
3 
5 
14 
28 
56 
84 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
 
VISIT NUMBERS 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
VISIT WINDOWS (+/- DAYS) 
 
2 
3 
3 
3 
3 
3 
3 
5 
5 
5 
5 
5 
5 
5 
CELLULAR CORE LABORATORY- EMORY UNIVERSITY (PI: CHRISTIAN LARSEN, MD 
Intracellular Cytokine Staining  
32 mL Blood CPT Tube 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
Flow Cytometry 
20-40 mL Blood Cyto-Chex Tube 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
MARKERS OF AUTOIMMUNITY CORE LABORATORY- UCSF (PI: PETER STOCK, MD) 
Markers of Autoimmunity- PBMC 
30 mL Blood Green-Top  Vacutainer 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Markers of Autoimmunity- Serum 
5mL Blood- Red-Top Vacutainer 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
MOLECULAR CORE LABORATORY- UNIVERSITY OF ALABAMA (PI: ROSLYN MANNON, MD) 
Gene Expression, mRNA Profiling  (Blood) 
2.5 mL Blood- PAXgene RNA Tube 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Gene Expression- mRNA Profiling (Urine) 
50-100 mL Urine (Pellet) 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Gene Expression- mRNA Profiling (Tissue) 
1 renal core in RNALater 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ASSAYS OF ALLOGRAFT INJURY LABORATORY- UNIVERSITY OF ALABAMA (PI: ROSLYN MANNON, MD) 
Cytokines and Growth Factors 
7 mL Blood  - Red-Top Vacutainer 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Serum Proteins- CTGF, TGFbeta 
4.5mL Blood- Light Blue CTAD 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Urine Proteins- CTGF, TGFbeta 
50-100 mL Urine (Supernatant) 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
ANTIBODY CORE- EMORY UNIVERSITY SCHOOL OF MEDICINE (PI: HOWARD GEBEL, PHD) 
Non-HLA Ab/Anti-HLA Antibodies / DSA1 
5 mL Blood -  Red-Top Vacutainer  
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
PATHOLOGY CORE LABORATORY- UCSF (PI: ZOLTRAN LASZIK,  MD) 
Histology/Immunohistochemistry - Renal 
5 slides (1-Trichrome or unstained, 1-
PAS, 3-H&E) AND  FFPE tissue 
(remaining block) AND C4d and SV40 
slides (if available) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Histology- Pancreas 
4 slides (1-Trichrome/ unstain, 3-H&E) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VIRAL MONITORING CORE- EMORY UNIVERSITY (PI: ANEESH MEHTA, MD) 
Viral Monitoring by PCR (EBV) AND Viral 
Monitoring Assay Development: BLOOD 
4 mL Blood in EDTA Lavender-top 
Vacutainer Tube  
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
Viral Monitoring by PCR (CMV, BKV, JCV, 
HHV6, HHV7) AND Viral Monitoring Assay 
Development (HHV3 (varicella zoster), HHV6 
(roseola), HHV7 (cofactor CMV), polyoma JC, 
WC,KI): PLASMA 
5mL PPT Tube OR plasma collected 
from the CPT tubes for Intracellular 
Cytokine Staining Viral Phenotyping 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
1. 
If a subject develops anti-donor alloantibodies or de novo anti-HLA (PRA >25%), the test must be repeated on a fresh sample and confirmed within 4 weeks. 
2. 
For Cause Biopsy specimens should be collected at times of graft dysfunction, and prior to initiating therapy.  
3. 
If blood samples are collected for a For-Cause biopsy AND are within 2 weeks of a scheduled visit, then the  samples will also be used for the scheduled visit. 
4. 
The first dose of NULOJIX® (belatacept) will be administered approximately 24-48 hours after the last dose of Thymoglobulin® (Anti-Thymocyte Globulin- Rabbit). 
5. 
The results of the non-HLA Ab/Anti-HLA Antibodies/DSA drawn at week 36 will be sent back to the clinical sites in order to make a decision regarding tacrolimus withdrawal at week 40. 
6. 
At week 40, subjects eligible for withdrawal will be weaned over a 4-8 week period based on the protocol.  
7. 
Tacrolimus dosing will be collected following week 44 on subjects who were not eligible for withdrawal or failed withdrawal.  


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
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Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
8. 
During tacrolimus weaning and for 6 weeks post tacrolimus withdrawal, subjects will have weekly labs that include serum creatinine, fasting glucose, amylase and lipase.  


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 100 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
Appendix 3.  Schedule of Events (Recipient) Post-Transplant (Year 2) 
 
 
WEEKS 
FOR 
CAUSE 2, 3 
56 
60 
64 
68 
72 
76 
 
 
VISIT NUMBERS 
17 
18 
19 
20 
21 
22 
 
VISIT WINDOWS (+/- DAYS) 
5 
5 
5 
5 
5 
5 
GENERAL ASSESSMENTS 
Physical Exam 
BP, Pulse, Temperature, Respiration, Weight 
X 
X 
X 
X 
X 
X 
 
Immunosuppressive Meds 
Drug Name and Dose 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Concomitant Medications 
Drug Name (Anti-HTN, Prophylaxis, Anti-Viral) 
X 
X 
X 
X 
X 
X 
X 
Assessments of Events 
AE/SAE, Infections, Rejections, Hospital, Graft Loss, Malignancies, 
New Onset Diabetes, Death 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Neurological Assess. for PML 
Hx, mini mental, cranial nerve, motor, cerebellar  
 
 
X 
 
 
X 
 
LOCAL LABORATORY ASSESSMENTS 
Hematology Panel 
CBC, differential, Platelet 
 
 
X 
 
 
X 
X 
Chemistry Panel  / GFR (CKD-EPI 
and MDRD)- Renal Function 
Serum Creatinine, BUN, glucose, sodium, AST, ALT, ALP, 
bilirubin, albumin, calcium, phosphate 
 
 
X 
 
 
X 
X 
Chemistry- Pancreatic Function 
Serum Amylase, Serum Lipase 
 
 
X 
 
 
X 
X 
Fasting Lipid Panel 
Total, HDL, LDL, Triglycerides 
 
 
X 
 
 
X 
 
C-Peptide 
C-Peptide 
 
 
 
 
 
X 
X 
Hemoglobin A1c 
HbA1c 
 
 
X 
 
 
X 
 
Urinalysis 
Protein, Glucose, Hematuria, WBC 
 
 
X 
 
 
X 
X 
Trough Levels 
Tacrolimus trough levels 
X 
X 
X 
X 
X 
X 
X 
Viral Monitoring 
BKV and CMV by PCR in blood 
 
 
 
 
 
X 
 
Histology- Renal 
Local Read- Banff 2007 Renal 
 
 
 
 
 
 
X 
Histology – Pancreas 
Local Read- Banff 2011 Pancreas 
 
 
 
 
 
 
X 
NULOJIX® (BELATACEPT) INFUSION DOSING 
Belatacept  Infusion 
• 
Investigational Arm 
IV, 5mg/kg 
X 
X 
X 
X 
X 
X 
 
TACROLIMUS DOSING SCHEDULE 
Tacrolimus Dosing  
• 
Control Arm 
Dose adjusted to target trough levels of 5-8ng/mL. 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Tacrolimus Dosing 1 
• 
Investigational Arm 
Withdrawn by week 48 or dose adjusted based on Investigator 
discretion. 
 
 
 
 
 
 
 
MYCOPHENOLATE MOFETIL DOSING SCHEDULE 
Mycophenolate Mofetil 
1gm BID, Adjusted based on clinical complications 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
 
1. 
Tacrolimus dosing is only collected on subjects who were not eligible for withdrawal or failed withdrawal.  
2. 
For Cause Biopsy specimens should be collected at times of graft dysfunction, and prior to initiating therapy.  
3. 
If blood samples are collected for a For-Cause biopsy AND are within 2 weeks of a scheduled visit, then the samples will also be used for the scheduled visit. 


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 101 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
Appendix 4.  Reduced Follow-Up Schedule of Events (Recipient) 
 
 
DAYS 
WEEKS 
28 
84 
24 
36 
52 
 
VISIT NUMBERS 
4 
6 
9 
12 
16 
 
VISIT WINDOWS (+/- DAYS) 
3 
3 
3 
5 
5 
ASSESSMENTS 
DETAILS 
 
 
 
 
 
GENERAL ASSESSMENTS 
Physical Exam 
Blood Pressure, Pulse, Temperature, 
Respiration, Weight 
X 
X 
X 
X 
X 
Immunosuppressive 
Medications 
Drug Name, Dose, Start and End Date 
→ 
→ 
→ 
→ 
→ 
Assessments of Events 
AE/SAE, Infections, Rejections, 
Hospitalizations, Graft Loss, Malignancies, New 
Onset Diabetes, Death 
→ 
→ 
→ 
→ 
→ 
Neurological Assessments 
for PML 
History, mini mental, cranial nerve, motor, 
cerebellar exam 
X 
X 
X 
X 
X 
LOCAL CLINICAL LAB ASSESSMENTS 
Hematology Panel 
CBC, differential, Platelet  
X 
X 
X 
X 
X 
Chemistry Panel  
Serum Creatinine 
X 
X 
X 
X 
X 
Urinalysis 
Protein, Glucose, Hematuria, WBC 
X 
X 
X 
X 
X 
Viral Monitoring 
BKV and CMV by PCR in blood 
X 
X 
X 
 
 
Viral Monitoring 
CMV by PCR in blood 
 
 
 
 
X 
 
 


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 102 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
Appendix 5.  Schedule of Events (Donor) 
 
Visit 1 
GENERAL ASSESSMENTS 
Demographics  
Age, Race, Gender 
X 
Donor Information 
Deceased-Donor, Cause of Death, 
Serum Creatinine 
X 
LOCAL LABORATORY ASSESSMENTS 
Blood Type 1 
A, B, O 
X 
HLA Typing 1 
 I (A, B, C),  II (DR, DP, DQ) 
X 
Viral Panel 1 
CMV (IgG, IgM and or total CMV 
Ab), EBV (IgG, IgM) 
X 
CORE LABORATORY 
Markers of Autoimmunity 
Spleen 
X 
 
1. 
Retrospective data collection.  Report results available for center specific transplant for CMV, EBV.  If the result is not available/not performed at that center, this is not considered a protocol deviation. 
 
 
 
 


Clinical Trials in Organ Transplantation (CTOT)    CONFIDENTIAL 
Page 103 of 104 
Protocol CTOT-15 
Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
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4 Hariharan, S., B. Kasiske, A. Matas, A. Cohen, W. Harmon, and H. Rabb. 2004. Surrogate markers for long-
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11 Kasiske, B.L., J.J. Snyder, D. Gilbertson, and A.J. Matas. 2003. Diabetes mellitus after kidney transplantation 
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13 Ekberg, H., J. Grinyo, B. Nashan, Y. Vanrenterghem, F. Vincenti, A. Voulgari, M. Truman, C. Nasmyth-
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Optimization of Belatacept Usage as a Means of Minimizing CNI Exposure in Simultaneous Kidney and Pancreas Transplantation 
Version 6.0/ May 14, 2015  
                                                                                                                                                                                                                       
18 Eisenbarth GS, Srikanta S, Jackson R, et al. 1985. Anti-thymocyte globulin and prednisone immunotherapy of 
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22 Di Bona E, Rodeghiero F, Bruno B, et al. 1999. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and 
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23 Hering B, Kandaswamy R, Ansite JD et al. 2005. Single-donor, marginal-dose islet transplantation in patients 
with type I diabetes. JAMA 293: 830-5 
24 Posselt A, Szot S, Frassetto, et al. 2010. Islet transplantation in Type I diabetic patients using calcinuerin 
inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. 
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25 Transplantation. 2001 Sep 15;72(5):935-40 
26 Transplantation. 2009 Feb 15;87(3):393-6 
27 Molenberghs, G. and M. Kenward. 2007. Missing Data in Clinical Studies. J. Wiley & Sons. West Sussex, 
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28 Ma G, A. Troxel, D. Heitjan. An index of local sensitivity to nonignorable dropout in longitudinal modeling. 
Stat Med 2005;24:2129–2150 
29 Pauler DK, McCoy S, Moinpour C. 2003.: Pattern mixture models for longitudinal quality of life studies in 
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34 Zou, G. 2004. A Modified Poisson Regression Approach to Prospective Studies with Binary Data.  American 
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35 Barros AJ and V.N. Hirakata VN. 2008. Alternatives for logistic regression in cross-sectional studies: an 
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ICF_001.pdf: 
 
 
INFORMED CONSENT TEMPLATE (RECIPIENT) 
VERSION: 7.0 – June 28, 2016 
Page 1 of 3 
 
TEMPLATE INFORMED CONSENT ADDENDUM 
PROTOCOL: CTOT-15 
 
Optimization of NULOJIX® (Belatacept) Usage as a Means of Minimizing 
CNI Exposure in Simultaneous Pancreas and Kidney Transplantation  
 
 (All Institutions or organizations who define themselves as “covered entities” should implement HIPAA 
Privacy Rule regulations, (45 CFR part 160, subparts A&E of part 164.)   
 
PRINCIPAL INVESTIGATOR 
(Insert site Principal Investigator as well as other subinvestigator if desired.) 
 
YOUR PARTICIPATION IS VOLUNTARY 
The purpose of this consent addendum is to inform you of new findings as well as changes to 
the research study “Optimization of NULOJIX® (Belatacept) Usage as a Means of Minimizing 
CNI Exposure in Simultaneous Pancreas and Kidney Transplantation”. It was observed that 
there were a high number of rejection episodes that occurred at or around the time of low dose 
Prograf (tacrolimus withdrawal), therefore, the decision has been made to stop any further 
Prograf (tacrolimus) withdrawal as a part of the study.  
In addition, active study participants in the experimental arm currently follow the study therapy 
regimen outlined in the study protocol. From this point forward, study participants will be 
transitioned onto a clinical immunosuppressive regimen, based on a discussion between the 
study participant and his/her study physician. This drug regimen may include belatacept and if 
so, you will be able to receive the study drug supply of belatacept until the study ends on August 
31, 2016. 
No changes will be made to subjects in the control arm and/or study participants currently in 
reduced follow-up.   
A total of 43 study participants were randomized, from 5 centers in the United States. Study 
participants who have not yet reached study completion will be asked to continue following their 
existing schedule, along with research blood draws, until the study ends. 
STUDY FOLLOW UP 
Study participants will be asked to continue their existing follow-up schedule until study 
completion in August 2016. All clinical labs and research blood draws currently on the schedule 
will still be drawn in order to continue following your transplanted kidney and pancreas.   
VOLUNTARY WITHDRAWAL FROM STUDY 
You may decide to withdraw from the study at any time.  If you decide to withdraw, there is no 
penalty or loss of benefits in your routine medical care or any other benefit(s) that you would 
otherwise be entitled to receive.   
 
CONFIDENTIALITY 


Clinical Trials in Organ Transplantation (CTOT) 
 
CONFIDENTIAL 
Protocol Identification Number:  CTOT -15 
 
INFORMED CONSENT Addendum 
VERSION: 7.0 – June 28, 2016 
Page 2 of 3 
 
Your medical and research records will be confidential to the extent permitted by law.  Efforts will 
be made to keep your personal information private.  However, we cannot guarantee complete 
confidentiality.  You will be identified by a code, and personal information from your records will 
not be released without your written permission.  You will not be identified in any publication about 
this study. 
Medical and research records may be reviewed by the National Institute of Allergy and Infectious 
Diseases, including its representatives, agents, employees, contractors, and other persons 
assisting in conducting, monitoring or analyzing the study.  In addition, the U.S. Food and Drug 
Administration, or other health authorities, and the study drug manufacturer may review your 
medical and research records for regulatory purposes. 
A description of this clinical trial is available on http://www.ClinicalTrials.gov, as required by U.S. 
law.  This web site will not include information that can identify you.  At most, the web site will 
include a summary of the results.  You can search this Web site at any time.  
 
PROBLEMS OR QUESTIONS   
 I can call … 
 At … 
 If I have questions or 
concerns  
<Insert PI Name> 
 Phone:<Insert Phone> 
 General questions about the study 
 Principal Investigator 
 Pager:   <Insert Pager> 
 Research-related injuries or  
  
 
 
 emergencies 
  
 
Beeper # 
 Any research-related concerns or  
  
 
 
 complaints 
<Insert Research Nurse>  
 Phone:<Insert Phone> 
 General questions about the study 
 Research Nurse 
 Pager: <Insert Pager> 
 Research-related injuries or emergencies 
  
 Beeper #  
 Any research-related concerns or  
  
  
 
 complaints 
<Insert IRB> 
 Phone:<Insert Phone> 
 Rights of a research subject 
 Use of protected health information 
 Compensation in event of research-related 
injury 
 Any research-related concerns or complaints 
 If investigator/study contact cannot be reached  
 
 
 
 
  If I want to speak with someone other than the 
Investigator, Study Contact or research staff 
 
 
 
 


Clinical Trials in Organ Transplantation (CTOT) 
 
CONFIDENTIAL 
Protocol Identification Number:  CTOT -15 
 
INFORMED CONSENT Addendum 
VERSION: 7.0 – June 28, 2016 
Page 3 of 3 
 
SIGNATURE PAGE  
(Site may use the site-specific signature page if required) 
 
Please sign below if you agree to take part in this study.  
 
You have read the informed consent and/or had it explained to you 
 
You were given the opportunity to ask questions about the information, and 
 
You voluntarily agree to take part in the study 
 
 
_________________  
_____________________ 
 
______________ 
Research Subject’s Name Research Subject’s Signature 
Date 
(Typed or printed) 
 
OR 
____________________ 
______________________  
_______________ 
Research Subject’s Legal Legal Guardian’s Signature 
Date 
Guardian/Representative 
(Typed or printed) 
 
____________________ 
______________________  
________________ 
Witness’s Name and title Witness’s Signature 
 
Date 
(Typed or printed) 
 
(A witness to the research subject’s signature is required.) 
 
Signature of person explaining and obtaining the consent: 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title 
 
Signature 
 
 
 
Date 
(Typed or printed) 
       
(NOTE:  This consent form with the original signatures MUST be retained on file by the principal 
investigator.  A copy must be given to the research subject.  A copy should be placed in the research 
subject’s medical record, if applicable.)