Conditions: Kidney Transplant
Keywords: Kidney Transplantation infliximab Tissue Donors Remicade Induction Therapy Deceased Donor Kidney Transplant Recipients
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 290
Healthy volunteers: no

Brief summary:
During transplant surgery, there is a period of time when a donated kidney is removed from a donor's body and stored until the time of the transplant surgery. The storage procedure results in buildup of various proteins within the kidney that can injure the donated kidney after it is transplanted. One of these proteins is tumor necrosis factor-alpha (TNF-alpha).

The purpose of this study is to evaluate whether taking infliximab, which blocks tumor necrosis factor alpha (TNF-alpha), just prior to transplant surgery, along with usual transplant medicines will protect the donated kidney from damage caused by TNF-alpha and help keep the transplanted kidney healthy for a longer period of time.

Detailed description:
This is a Phase 2, multicenter, randomized, double blind (masked), placebo-controlled, 2-arm clinical trial of 300 deceased donor kidney transplant recipients. Participants will be randomized (1:1) to the experimental or control arm (150 subjects per arm).

Arms:
arm 1: rATG is co-administered with anti-TNFa (infliximab/Remicade®) plus maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone. arm 2: Rabbit anti-thymocyte globulin (rATG/Thymoglobulin®) plus placebo (Sterile normal saline) induction followed by maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone.

Interventions: intervention 1: Infliximab intervention 2: Methylprednisolone intervention 3: Mycophenolate Mofetil intervention 4: Tacrolimus intervention 5: Thymoglobulin® intervention 6: Acetaminophen intervention 7: Loratadine intervention 8: Placebo for Infliximab intervention 9: Prednisone intervention 10: Diphenhydramine
Intervention descriptions: intervention 1: A single dose, of 3mg/kg infusion intervention 2: 500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion intervention 3: Administered at a target dose of 2000mg daily, as tolerated, until study closure intervention 4: Administered at a target dose of 0.1mg/kg BID, post-op, then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op and finally adjusted to target trough levels of 5-8ng/ml until study closure intervention 5: Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated intervention 6: 30 to 60 minutes prior to the start of the infusion

* Tylenol, 600 to 1000mg by mouth or
* Suppository form intervention 7: 30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth intervention 8: A single dose is volume matched to Infliximab (250mL) infusion intervention 9: Prednisone will be administered peri-operatively according to center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg every other day by 3 months post-transplant thereafter until study closure. intervention 10: 30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Protocol document:
Prot_000.pdf: 
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CLINICAL TRIALS IN ORGAN TRANSPLANTATION (CTOT) 
CTOT-19 
Randomized Controlled Trial of Infliximab (Remicade®) Induction Therapy 
For Deceased Donor Kidney Transplant Recipients 
SHORT TITLE: Effects of Inhibiting Early Inflammation in Kidney Transplant Patients 
 
VERSION 9.0/April 27, 2020 
Study Sponsor(s):  The National Institute of Allergy and Inf ectious Diseases (NIAID) 
NIAID Funding Mechanism: 
U01 AI063594-11 
IND Sponsor/Number: 
NIAID/124633 
Clinicaltrials.gov#: 
NCT02495077 
 
PRINCIPAL INVESTIGATOR 
PETER S. HEEGER, MD 
Icahn School of Medicine at Mount 
Sinai 
Recanati Miller Transplant Institute 
Annenberg Bldg., 2366B, 
Room 1243 
1 Gustave L. Levy Place 
New York, NY 10029 
Phone: 212-241-6324 
Fax: 
212- 987-0389 
Email: peter.heeger@mssm.edu 
PROTOCOL CHAIR 
DONAL D E. HRICIK, MD 
Division of Nephrology & Hypertension 
University Hospitals of Cleveland 
11100 Euclid Avenue, Room 8124 
Lakeside Building 
Cleveland, OH 44116 
Phone: 216-844-8060 
Fax: 
216-844-8060 
E-mail: Donald.Hricik@uhhospitals.org 
MEDICAL MONIT OR 
JONAH ODIM, MD 
Transplantation Branch (TB) 
Division of Allergy Immunology & 
Transplantation (DAIT) 
National Institutes of Allergy & Infectious 
Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane, Rm 6B21, Mail Stop 9827 
US Mail: Bethesda, MD 20892-9827 
FedEx, UPS: Rockville, MD 20852 
Direct Line: 240-627-3540 
Fax Line: 
240-627-3115 
Email address: odimj@niaid.nih.gov 
BIOSTATISTICIAN 
KAREN KESLER, PHD 
Senior Statistical Scientist 
Rho Federal Systems 
2635 E NC Hwy 54 
Durham, NC 27713 
Phone: 919-595-6244 
Fax: 
919-595-4291 
E-mail: karen_kesler@rhoworld.com 
PROJECT MANAGE R 
HELENA DIOP 
Transplantation Branch (TB) 
Division of Allergy Immunology & 
Transplantation (DAIT) 
National Institutes of Allergy & Infectious 
Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane, Room 6B22 Mail Stop 9827 
US Mail: Bethesda, MD 20892-9827 
FedEx, UPS: Rockville, MD 20852 
Direct Line: 240-627-3497 
Fax Line: 
240-627-3115 
Email address: dioph@niaid.nih.gov 
SENIOR REGULATORY OFFICER 
JULIA GOLDSTEIN, MD 
Office of Regulatory Affairs (ORA) 
Division o f Allergy, Immunology & 
Transplantation (DAIT) 
Nation al Institute o f Allergy & Infectious 
Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane, Rm 7B29 Mail Stop 9828 
US Mail: Bethesda, MD 20892-9827 
FedEx, UPS: Rockville, MD 20852 
Direct Line: 240-627-3509 
Fax Line: 
301-480-1537 
Email address: goldsteinj@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, National Institute of Allergy and Infectious Diseases of the National 
Institutes of Health. 


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INVESTIGATOR SIGNATURE PAGE 
Protocol: CTOT-19 
Version/Date: 
VERSION 9.0/April 27, 2020 
Title: Randomized Controlled Trial of Infliximab (Remicade®) Induction Therapy 
For Deceased Donor Kidney Transplant Recipients 
Study Sponsor: The National Institute of Allergy and Inf ectious Diseases (NIAID) 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated 
location below. A copy should be kept for your records and the original signature page sent. 
After signature, please return the original of this form by surface mail to: 
PPD, Inc. 
3900 Paramount Parkway 
Morrisville, NC 27560 
Attn: CTOT DAIT Regulatory Management Center 
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) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, 
and in the International Conference on Harmonization (ICH) document Guidance for Industry: 
E6 Good Clinical Practice: Consolidated Guidance dated April 1996. Further, I will conduct 
the study in keeping with local legal and regulatory requirements. 
As the site Principal Investigator, 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 the written 
permission of the IRB and NIAID. 
 
Site Principal Investigator (Print) 
 
 
Site Principal Investigator (Signature) 
Date 


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Protocol Synopsis 
 
Title 
Randomized Controlled Trial of Infliximab Induction Therapy 
For Deceased Donor Kidney Transplant Recipients 
Short Title 
Effects of inhibiting early inflammation in kidney transplant patients 
Clinical Phase 
Phase II 
Number of Sites 
15 
Health Authority 
Applications/ 
Sponsor Number 
NIAID/US IND 124633 
NIAID/HC CTA File # HC6-24-C185918, Control #185918 
Study Objectives 
The objective of the study is to determine the efficacy of intravenous infliximab 
administered at the time of transplantation, prior to reperfusion, on 2-year 
kidney transplant survival and function. 
Study Design 
This is a Phase II, Multicenter, randomized, double blind, placebo-controlled, 2- 
arm clinical trial of 300 deceased donor kidney transplant recipients. Subjects 
will be randomized 1:1 to the experimental or control arms (150 subjects per 
arm). 
Primary 
Endpoint(s) 
The difference between the mean 24-month eGFR (modified MDRD) in the 
experimental vs. control arms. 
Secondary 
Endpoint(s) 
Efficacy Endpoints 
1. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) 
within 
a) 6 months and 
b) 2 years of transplant 
2. BANFF grades of first Acute Cellular Rejections (ACR) within 6 months of 
transplant 
3. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or 
borderline rejection within 
a) 6 months and 
b) 2 years of transplant 
4. Proportion of subjects with biopsy proven acute antibody mediated 
rejection (AMR) within 6 months and 2 years of transplant 
5. Proportion of subjects with biopsy proven acute antibody mediated 
rejection AMR or suspicious for AMR within 
a) 6 months and 
b) 2 years of transplant 
6. BANFF grades of first AMR within 6 months of transplant 
7. Proportion of subjects with BANFF chronicity scores >or equal 2 on 24-month 
biopsy 
8. Change in BANFF chronicity scores between implantation and 24 month 
biopsies 


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9. eGFR (as measured by both MDRD and CKD-EPI) 
a) Change in eGFR between 3 months and 24 months 
b) Change in eGFR between post-transplant nadir and 24 months 
c) eGFR on days 7, 30, 90, and 180 post-transplant 
10. Proportion of subjects with: 
a) Death or graft failure within 2 years 
b) Only graft failure within 2 years 
11. Each of the following: 
a) Proportion of subjects that required at least one dialysis treatment 
within the first week after transplantation 
b) Number of dialysis sessions in the first 8 weeks post-transplantation. 
c) Duration of DGF defined as time from transplantation to the last 
required dialysis treatment 
d) The incidence of primary non-function (PNF), defined as for dialysis- 
dependency for more than 3 months or an eGFR 20 ml/min or less at 90 
days post-transplant 
e) Change from baseline (immediately after surgery) in serum creatinine 
and serum creatinine concentration at 24, 48, and 72 hours. 
12. Days from transplantation until event (ACR, AMR, or hospitalization for 
infection and or malignancy) 
13. Rate of Slow Graft Function (SGF): 
a) The proportion of patients with a serum creatinine of more than 3 
mg/dL at day 5 post-transplant, 
b) Creatinine reduction ratio (CRR) on day 2 
c) Creatinine reduction ratio (CRR) on day 5 
d) The proportion of patients whose day 5 serum CRR was less than 70% 
e) The proportion of patients whose day 2 serum CRR was less than 30% 
f) Proportion of subjects who need dialysis after 1 week. 
Safety/Complication Endpoints 
1. Proportion of subjects with: 
a) Any infection requiring hospitalization or resulting in death 
b) Mycobacterial or fungal infections 
2. Proportion of subjects with CMV viremia that require a change in 
immunosuppression or anti-viral treatment as per standard of care at the 
site 
3. Proportion of subjects with BK viremia that require a change in 
immunosuppression or anti-viral treatment as per standard of care at the 
site 
4. Proportion of subjects with malignancy 
5. Proportion of subjects with impaired wound healing manifested by wound 
dehiscence, wound infection, or hernia at the site of the transplant incision. 


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Mechanistic Endpoints 
1. Sensitivity, specificity, PPV, and NPV of biomarkers, including PRT, urinary 
CXCL9, blood genomic profile, and 3 month allograft genomic profile 
(alone and/or in combination) to predict: 
a) Incident biopsy-proven acute rejection. 
b) Graft loss 
c) Chronic graft injury, as measured by 2-year eGFR 
2. Each of the following: 
a) Inflammatory gene expression profiles 
b) Frequency of donor reactive T-cells 
c) Frequency and function of Treg 
d) Proportion of subjects with de novo DSA within 24 months 
e) Fibrogenic gene expression profiles 
f) Amount of peritubular capillary loss by histology 
Ancillary Endpoints 
1. Percentage of predicted prednisone bottle openings as measured by a 
medication event monitoring system (MEMS®) in the first 3 months post- 
transplantation 
2. Standard deviation of the monthly tacrolimus trough levels from 6 months 
post-transplantation to 2 years post-transplantation 
Accrual 
Objective 
300 patients will be enrolled and randomized into the two treatment groups 
(150 Experimental arm, 150 Control Arm) across approximately 10 participating 
centers. 
Study Duration 
5 years (3-year accrual period + 2 year follow up period) 
• 
24 months for primary and majority of secondary endpoints 
• 
5 years with Reduced follow-up to assess patient and graft survival and 
serum creatinine 
Treatment 
Description 
There are two arms/groups in this study, the Experimental Group and the Control 
Group. Each group will receive the following: 
• 
Experimental Group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) 
is co-administered with anti-TNFa (infliximab/Remicade®) followed by 
maintenance therapy with tacrolimus, either Mycophenolate Mofetil/MMF 
or Mycophenolate Acid/MPA (or their generic equivalents) and prednisone 
• 
Control group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) plus 
placebo (Sterile normal saline) induction followed by maintenance therapy 
with tacrolimus, either Mycophenolate Mofetil/MMF or Mycophenolate 
Acid/MPA (or their generic equivalents) and prednisone 


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Inclusion Criteria 
1. Adult (>18 years of age) male and female recipients (all races and 
ethnicities) 
2. Subject must be able to understand and provide consent 
3. Recipients of deceased donor kidney transplants (including re-transplants) 
4. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and 
current sera as determined by each participating study center. 
5. Donor kidneys from deceased donors and donors after cardiac death 
(DCD) with Kidney Donor Profile Indices (KDPI) ranging from >20 to <95 
6. Female participants of childbearing potential must have a negative 
pregnancy test upon study entry 
7. Subjects must have a negative test result for latent tuberculosis (TB) 
infection (PPD, QuantiFERON, ELISPOT) . 
Subjects who have a negative test result for latent TB infection within 1 year 
of transplant date are eligible for enrollment and no further action is 
required. 
Subjects who have a negative test for latent TB infection that is greater 
than 1 year old are eligible for enrollment but are required to have a 
repeat test prior to transplantation. Samples for testing latent TB infection 
can be obtained during the hospital admission for the transplant but must 
be collected prior to the initiation of immunosuppression and prior to 
transplant. The results of this repeat test will determine the next step. 
• 
If the test is negative, no further action is required 
• 
If the test is positive, lost, indeterminant or unavailable the subject 
must be treated for latent TB infection (if the subject is enrolled, 
received study drug/placebo and transplanted). 
o Treatment for latent TB infection is required for all in this group. 
o The treatment regimen (including the specific drug, dose and 
duration of treatment) will be determined by the local 
Infectious Disease team. 
• 
If the subject has no latent TB testing available, then the subject 
cannot be enrolled 
Subjects may be enrolled if they have not had a test for latent TB infection 
within one year of the transplant if samples for the test are collected prior to 
the administration of immunosuppressive drugs and prior to transplant. 
Refer to Section 8.1.1 for additional information. 
Exclusion Criteria 1. Inability or unwillingness of a participant to give written informed consent or 
comply with study protocol 
2. Recipients of living donor transplants 
3. Presence of other transplanted solid organs (heart, lung, liver, pancreas, 
small intestines) or co-transplanted organ 
4. HIV+ recipients 
5. EBV IgG negative recipients 


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6. Hepatitis B surface antigen positive kidney transplant recipients 
7. Hepatitis B core antibody positive kidney transplant recipients 
8. Hepatitis B negative kidney transplant recipients that receive transplant from 
Hepatitis B core antibody positive donor 
9. Hepatitis C virus positive (HCV+) patients who are either untreated or have 
failed to demonstrate sustained viral remission for more than 12 months after 
anti-viral treatment 
10. Recipients with a previous history of invasive fungal infection 
11. Recipients with a previous history of active TB disease 
12. Recipients with a positive test for latent TB infection (PPD, QuantiFERON, 
ELISPOT), regardless of previous therapy. 
13. Any severe infection at the time of transplantation. Severe infection 
determination will be made by the local site investigator. 
14. Severe congestive heart failure (NYHA functional class III or higher) 
15. Subjects with a known hypersensitivity to any murine/ mouse proteins. 
16. Subjects with any history of receiving any anti-TNF products 
17. Subjects in whom rATG or infliximab might not be tolerated 
18. Subjects with less than 3000/mm3 WBC 
19. Subjects with less than 100,000/mm3 platelets counts 
20. Subjects with systolic blood pressure <100 mm/Hg 
21. Subjects with symptomatic orthostatic hypotension or currently requiring 
Midodrine for blood pressure support. 
22. Subjects from or who have traveled to endemic areas with a history of active 
histoplasmosis or with a chest x-ray consistent with previous active 
histoplasmosis (no serological testing required). 
Endemic regions 
determined by site based on local standard of care 
23. Subjects currently or formerly residing in regions of the US that are highly 
endemic for coccidioidomycosis, and who have a positive serologic test for 
coccidioidomycosis. Endemic regions determined by site based on local 
standard of care. * 
* (Subjects currently or formerly residing in regions of the US that are 
highly endemic for coccidioidomycosis, and who have a negative 
pre-transplant serologic test for coccidioidomycosis are eligible for 
enrollment only if they receive fluconazole 200 mg/day for the 
duration of the study. Serologic testing for coccidioidomycosis is 
required for subjects that currently or formerly resided in regions that 
are highly endemic for coccidioidomycosis only, per the site’s 
standard of care). 
24. Recipients are excluded if the local site decides to treat the recipient with 
fluconazole because of diagnosis or suspicion of fungal infection in the 
donor. 
25. Subjects that receive IVIG treatment within 3 months of transplant or planned 
IVIG treatment peri-transplant. 
26. Use of an investigational agent within 4-weeks prior to study entry 


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Study Stopping 
Rules 
Satisfaction of any of the following stopping rules at any time during the post- 
transplant (treatment) follow-up will trigger an ad hoc DSMB Safety Review. 
• 
Any single occurrence of a life-threatening or fatal AE that is possibly, 
probably, or definitely related to either the investigational agent 
(infliximab/infliximab placebo) or a study mandated procedure. 
Across both treatment arms: 
• 
Incidence of PTLD of 1% or more subjects 
• 
Incidence of Adverse Events for tuberculosis active disease of 1% or more 
subjects 
• 
Incidence of invasive fungal infection of 3% or more subjects 
• 
Incidence of coccidioidomycosis of 1% or more subjects 
• 
Incidence of histoplasmosis of 1% or more subjects 
• 
Incidence of death of 10% or more subjects 
Within either treatment arm: 
• 
Incidence of infection of any type requiring hospitalization of 40% or more 
subjects 
• 
Incidence of graft loss of 20% or more subjects 
• 
Incidence of BPAR (Banff Grade 1 or higher) or AMR based on local read of 
25% or more subjects 


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Study Contacts: Participating Centers 
 
University Hospitals of Cleveland 
Mount Sinai School of Medicine 
Yale University 
Donald Hricik, MD 
Madhav Menon, MD 
Richard Formica, Jr., MD 
University Hospitals of Cleveland 
Icahn School of Medicine at Mount 
Yale University School of 
Division of Nephrology 
Sinai 
Medicine 
11100 Euclid Avenue 
Recanati Miller Transplant Institute 
Department of Medicine 
Room 8124 Lakeside Building 
Annenberg Building, Floor 23 
Division of Nephrology 
Cleveland OH 44106-5048 
1468 Madison Avenue 
FMP 107, PO Box 208029 
Phone: (216) 844 8060 
New York, NY 10029 
New Haven CT06520-8029 
Fax: (216) 844 5204 
Phone: (212) 
Phone: (203) 785-4184 
Dhricik@Aol.Com 
Fax: (212) 987-0389 
Madhav.Menon@Mssm.Edu 
Fax: (203) 785-7068 
Richard.Formica@Yale.Edu 
University of Manitoba 
University of Manitoba 
University of California, 
David Rush, MD, FRCPC, FACP, FASN Peter Nickerson, MD 
Los Angeles 
University of Manitoba Health 
University of Manitoba, 
Suphamai Bunnapradist, MD 
Sciences Centre, 
Health Sciences Centre, 
UCLA 
820 Sherbrook Street, GE421 
Transplant Immunology Laboratory 
200 UCLA Medical Plaza 
Winnipeg, MB Canada R3A 1R9 
777 William Avenue 
Los Angeles, CA 90055 
Phone: (204) 787-3437 
Winnipeg, Manitoba, Canada R3A 
Phone: (310) 794-8516 
Fax: (204) 787-3326 
1R9 
Bunnapradist@Mednet.Ucla.Edu 
Drush@Exchange.Hsc.Mb.Ca 
Phone: (204) 789-1125 
Fax: (204) 783-6780 
 
Peter.Nickerson@Med.Umanitoba.Ca 
Cleveland Clinic 
University of Michigan 
Washington University 
Emilio Poggio, MD 
Randall Sung, MD 
Tarek Alhamad, MD, MS, FACP, 
The Cleveland Clinic 
University of Michigan 
FASN 
Glickman Urological Institute 
2926D Taubman Center 
Medical Director, Pancreas 
9500 Euclid Ave, Q7-103 
1500 E. Medical Center Drive 
Transplant 
Cleveland OH 44195 
Ann Arbor, MI 48109-5331 
Assistant Professor of Medicine 
Phone: (216) 444-5383 
Phone: (734) 936-8363 
Division of Nephrology 
Fax: (216) 444-8372 
Fax: (734) 232-1915 
Washington University in St. Louis/ 
Poggioe@Ccf.Edu 
Rssung@Med.Umich.Edu 
Barnes Jewish Hospital 
660 S. Euclid Avenue. Cb 8126 
St. Louis, Mo 63110 
Phone: (314) 362-8259 
Fax: (314) 362-2713 
 
Talhamad@Wustl.Edu 
Emory University 
University of California San Francisco 
University of Maryland 
Kenneth Newell, MD 
Flavio Vincenti, MD 
Jonathan S. Bromberg, MD, PhD 
1364 Clifton Road Suite E426 
Professor of Clinical Medicine 
Professor of Surgery & 
Atlanta, GA 30322 
Transplant Services 
Microbiology and Immunology 
Phone: (404) 727-2489 
University of California At San 
Vice Chair for Research 
Fax: (404) 712-2999 
Francisco 
University of Maryland School of 
KANEWEL@EMORY.EDU 
505 Parnassus Avenue, Rm #M884 
San Francisco, CA 94118-0780 
Medicine 
22 S. Greene St., S8B06 
Phone: (415) 353-1322 
Baltimore, MD 21201 
FLAVIO.VINCENTI@UCSFMEDCTR.ORG 
Office: (410) 328-6430 
FAX: (410) 328-0401 
 
JBROMBERG@SOM.UMARYLAND.EDU 


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University of Alabama 
Roslyn B. Mannon, MD 
Professor of Medicine and Surgery 
University of Alabama At 
Birmingham 
1900 University Boulevard THT 643 
Birmingham, Al 35294 
Phone: (205) 934-7220 
Fax: (205) 975-0102 
RMANN ON@UAB MC.ED U 
Toronto General Hospital 
Kathryn Tinckam MD, MMSc, FRCPC, 
FAST 
Toronto General Hospital – 
Peter Munk Building 
11th Floor, Room 187 
585 University Ave, 
Toronto, On Canada 
M5g 2n2 
Phone: (416) 340-4800 Ext.8225 
Fax Number: (416) 340-3252 
KATHRYN.TINCKAM@UHN.CA 
University of Wisconsin 
David Foley, MD 
600 Highland Ave. 
H4/766 CSC 
Madison, Wi 53792 
United States 
Phone: (608) 263-3343 
FOLEY@SURGER Y.WISC.EDU 
Johns Hopkins University 
Daniel C. Brennan, MD 
Professor, Medical Director & 
Co-Director of The Comprehensive 
Transplant Center 
1830 East Monument St., Suite 416 
Baltimore, MD 21287 
Phone: 410-955-7658 
Fax Number: 410-367-2259 
dbrenna4@jhmi.edu 


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Study Contacts: Core Laboratories 
 
 
ADMINISTRATIVE CORE 
Peter Heeger, MD 
Icahn School of Medicine at 
Mount Sinai 
Recanati Miller Transplant Institute 
Annenberg Building, Floor 23-04, 
Box 1243 
1 Gustave L. Levy Place 
New York, NY 10029 
Phone: (212) 241-6324 
Fax: (212) 987-0389 
Peter.heeger@mssm.edu 
CELLULAR/IMMUNOLOGY CORE 
Peter Heeger, MD 
Icahn School of Medicine at 
Mount Sinai 
Recanati Miller Transplant Institute 
Annenberg Building, Floor 23-04, 
Box 1243 
1 Gustave L. Levy Place 
New York, NY 10029 
Phone: (212) 241-6324 
Fax: (212) 987-0389 
Peter.heeger@mssm.edu 
HUMORAL ANTIBODY CORE 
Peter Nickerson, MD 
University of Manitoba, 
Health Sciences Centre, 
Transplant Immunology Laboratory 
777 William Avenue 
Winnipeg, Manitoba, 
Canada R3A 1R9 
Phone: (204) 789-1125 
Fax: (204) 783-6780 
peter.nickerson@med.umanitoba.ca 
GENOMICS CORE 
Barbara Murphy, MD 
Icahn School of Medicine at 
Mount Sinai 
Recanati Miller Transplant Institute 
Annenberg Building, Floor 23-04, 
Box 1243 
1 Gustave L. Levy Place 
New York, NY 10029 
Phone: (212) 241-6324 
Fax: (212) 987-0389 
barbara.murphy@mssm.edu 
HISTOLOGY CORE 
Ian Gibson, MD 
University of Manitoba 
Canadian Blood Services 
777 William Avenue 
Winnipeg, MB R3E 3R4 Canada 
Phone: (204) 787-1791 
Fax: (204) 783-6780 
igibson@exchange.hsc.mb.ca 
MOLECULAR IMMUNOLOGY CORE 
Robert Fairchild, PhD 
Cleveland Clinic Foundation 
NB3-59 Lerner Research Institute 
9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: (216) 444-3146 
Fax: (216) 444-8372 
FAIRCHR@CCF.ORG 
GFR CORE 
Emilio Poggio, MD 
The Cleveland Clinic 
Glickman Urological Institute 
9500 Euclid Ave, Q7-103 
Cleveland OH 44195 
Phone: (216) 444-5383 
Fax: (216) 444-8372 
poggioe@ccf.edu 


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Table of Contents 
Glossary of Abbreviations ................................................................................................................... 18 
Study Definitions Page ....................................................................................................................... 22 
1. 
Study Hypotheses/Objectives .......................................................................................................28 
1.1. 
Hypotheses........................................................................................................................... 28 
1.2. 
Primary Objective.................................................................................................................. 28 
1.3. 
Secondary Objective(s)....................................................................................................... 28 
2. 
Background and Scientific Rationale..........................................................................................30 
2.1. 
Background .......................................................................................................................... 30 
2.2. 
Rationale for Selection of Investigational Product or Intervention..................................... 31 
2.3. 
Preclinical Experience .......................................................................................................... 32 
2.4. 
Clinical Studies..................................................................................................................... 33 
3. 
Study Design.................................................................................................................................34 
3.1. 
Description of Study Design................................................................................................. 34 
3.2. 
Primary Endpoint .................................................................................................................. 36 
3.3. 
Secondary Endpoint ............................................................................................................ 36 
3.4. 
Stratification, Randomization, and Blinding/Masking......................................................... 37 
Blinding........................................................................................................................... 38 
Unblinding Authorization................................................................................................. 38 
Reporting Unblinding Events ........................................................................................ 38 
4. 
Selection of Participants and Clinical Sites/Laboratories ...........................................................39 
4.1. 
Rationale for Study Population............................................................................................. 39 
4.2. 
Inclusion Criteria ................................................................................................................... 39 
4.3. 
Exclusion Criteria ................................................................................................................... 40 
4.4. 
Selection of Clinical Sites/Labs ........................................................................................... 42 
5. 
Known and Potential Risks and Benefits to Participants..............................................................43 
5.1. 
Risks of Investigational Product, Remicade® (Infliximab) ................................................... 43 
5.2. 
Risks of Investigational Product or Intervention cited in Medical Literature ...................... 48 
5.3. 
Risks of Other Protocol Specified Medications ..................................................................... 48 
Risks of Thymoglobulin...................................................................................................... 48 
Risks of Maintenance Immunosuppression Medications............................................... 49 
Risks of Methylprednisolone and Prednisone ............................................................... 49 


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Risks of Mycophenolic Acid Derivative (either Mycophenolate Mofetil/MMF or 
Enteric-coated Mycophenolic Acid/MPA) ................................................................................. 49 
Risks of Tacrolimus............................................................................................................ 50 
Risk of Prophylactic INH Therapy for Latent TB Infection ............................................... 50 
5.4. 
Risks of Study Procedures ..................................................................................................... 50 
Risks of Blood Draw (Venipuncture) ............................................................................... 50 
Risk of Protocol-Directed Biopsy ................................................................................... 51 
5.5. 
Potential Benefits ................................................................................................................. 51 
6. 
Investigational Agents................................................................................................................. 52 
6.1. 
Investigational Agent: Remicade® (Infliximab) .................................................................. 52 
Remicade® (Infliximab) Indications and Usage........................................................... 52 
Remicade® (Infliximab) Formulation, Packaging, Labeling and Storage ................... 52 
Dosage, Preparation and Administration ...................................................................... 53 
Contraindications............................................................................................................ 54 
Drug Interactions............................................................................................................ 55 
Special Populations Use ............................................................................................... 56 
Infusion Supervision ....................................................................................................... 56 
6.2. 
Investigational Agent: Placebo ........................................................................................... 56 
Dose, Preparation, Administration and Storage ........................................................... 57 
Infusion Supervision ....................................................................................................... 57 
6.3. 
Drug Accountability ............................................................................................................... 58 
6.4. 
Toxicity Prevention and Management .................................................................................. 58 
6.5. 
Premature Discontinuation of Investigational Agent .......................................................... 58 
7. 
Other Medications ....................................................................................................................... 59 
7.1. 
Concomitant Medications ................................................................................................... 59 
Protocol-Mandated Medications .................................................................................. 59 
Other permitted concomitant medications .................................................................. 59 
7.2. 
Prophylactic Medications ..................................................................................................... 59 
Infection Prophylaxis ..................................................................................................... 59 
7.3. 
Prohibited Medications ......................................................................................................... 60 
7.4. 
Rescue Medications.............................................................................................................. 60 
8. 
Study Procedures ........................................................................................................................ 61 
8.1. 
Screening/Enrollment............................................................................................................ 61 


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Testing and Prophylaxis for Latent TB Infection .............................................................. 61 
8.2. 
Baseline Visit......................................................................................................................... 61 
8.3. 
Study Therapy Regimen........................................................................................................ 62 
Pre-Medications.............................................................................................................. 63 
Remicade®/Placebo..................................................................................................... 64 
Thymoglobulin................................................................................................................ 64 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA ...................................... 64 
Tacrolimus (Prograf®)..................................................................................................... 64 
Prednisone..................................................................................................................... 64 
8.4. 
Follow-up Study Visits........................................................................................................... 64 
8.5. 
MEMS®................................................................................................................................. 65 
8.6. 
Additional Clinical Data Collection ..................................................................................... 65 
8.7. 
Modification of Immunosuppression Protocol ..................................................................... 65 
8.8. 
Unscheduled Visits............................................................................................................... 65 
8.9. 
Unscheduled Study Visits after Month 24 Post-Transplant................................................... 65 
8.10. 
Reduced Follow-Up.......................................................................................................... 65 
8.11. 
COVID-19 Pandemic-Study Follow-up ............................................................................. 65 
8.12. 
Standard Study Visit Windows ........................................................................................... 66 
8.13. 
COVID-19 Pandemic Study Visit Window ......................................................................... 67 
9. 
Mechanistic  Assays ..................................................................................................................... 68 
9.1. 
Overview............................................................................................................................... 68 
9.2. 
Cellular Immunology Core ................................................................................................... 68 
T and B Cell Phenotyping by Flow Cytometry................................................................ 68 
T Cell Functional Assays (ELISPOT) and Archived PBMC for CyTOF Analysis................ 68 
TCR Sequencing Substudy ............................................................................................ 69 
T Regulatory Cells Substudy........................................................................................... 70 
Urinary Chemokine Protein and Necroptosis Markers ................................................. 70 
9.3. 
Genomics Analysis Core Laboratory.................................................................................... 71 
mRNA Profiling, Gene Expression in Blood .................................................................... 71 
mRNA Profiling, Gene Expression Profiles in Tissue ....................................................... 71 
Genomics Analysis ........................................................................................................ 72 
Cell Free DNA Analysis .................................................................................................. 72 
9.4. 
Molecular Immunology Core Lab ....................................................................................... 73 


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Nanostring Analysis ....................................................................................................... 73 
mRNA Profiling, Gene Expression Profiles in Urine Pellet................................................ 73 
9.5. 
Pathology Core Lab ............................................................................................................ 73 
Histology ........................................................................................................................ 74 
TNFR1 Expression Patterns in Renal Allografts ................................................................ 74 
Immunofluorescence/IHC ............................................................................................... 74 
9.6. 
Humoral Core Lab................................................................................................................ 75 
Anti-HLA Antibodies and Donor Specific Antibodies .................................................... 75 
9.7. 
Glomerular Filtration Rate (GFR) Core Lab.......................................................................... 75 
9.8. 
Mechanistic Studies Data Analysis Plan .............................................................................. 76 
9.9. 
Sample Collection................................................................................................................ 77 
10. 
Biospecimen Storage .............................................................................................................. 78 
11. 
Criteria for Participant and Study Completion and Premature Study Termination .............. 79 
11.1. 
Participant Completion .................................................................................................... 79 
11.2. 
Participant Withdrawal Criteria ....................................................................................... 79 
11.3. 
Participant Replacement ................................................................................................. 79 
11.4. 
Follow-up after Early Study Withdrawal ............................................................................ 79 
11.5. 
Stopping Rules.................................................................................................................. 79 
12. 
Safety Monitoring and Reporting ............................................................................................ 83 
12.1. 
Overview ........................................................................................................................... 83 
12.2. 
Definitions .......................................................................................................................... 83 
Adverse Event (AE) .................................................................................................... 83 
Suspected Adverse Reaction (SAR) ........................................................................ 83 
Unexpected Adverse Event ...................................................................................... 83 
Serious Adverse Event (SAE) ..................................................................................... 84 
12.3. 
Grading and Attribution of Adverse Events ................................................................... 84 
Grading Criteria ......................................................................................................... 84 
Attribution Definitions ................................................................................................. 85 
12.4. 
Collection and Recording of Adverse Events ................................................................ 86 
Collection Period........................................................................................................ 86 
Recording Adverse Events ........................................................................................ 87 
12.5. 
Reporting of Serious Adverse Events and Adverse Events.............................................. 87 
Reporting of Serious Adverse Events to Sponsor ...................................................... 87 


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Reporting to Health Authority ................................................................................... 87 
Reporting of Adverse Events to IRBs/IECs ................................................................ 88 
12.6. 
Pregnancy Reporting ....................................................................................................... 88 
12.7. 
COVID-19 Reporting .......................................................................................................... 89 
12.8. 
Reporting of Other Safety Information............................................................................. 89 
12.9. 
Review of Safety Information ............................................................................................ 89 
Medical Monitor Review ........................................................................................... 89 
DSMB Review .............................................................................................................. 89 
13. 
Statistical Considerations and Analytical Plan ....................................................................... 91 
13.1. 
Overview ........................................................................................................................... 91 
13.2. 
Endpoints ........................................................................................................................... 91 
13.3. 
Measures to Minimize Bias ............................................................................................... 93 
13.4. 
Analysis Plan ...................................................................................................................... 93 
Analysis Populations ................................................................................................... 93 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .................................................... 93 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) .................................... 95 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ................................... 95 
Analyses of Safety Endpoints..................................................................................... 98 
Descriptive Analyses .................................................................................................. 99 
13.5. 
Interim Analysis ................................................................................................................. 99 
13.6. 
Sample Size Calculations ................................................................................................. 100 
14. 
Identification and Access to Source Data ........................................................................... 101 
14.1. 
Source Data .................................................................................................................... 101 
14.2. 
Access to Source Data ................................................................................................... 101 
15. 
Quality Assurance and Quality Control ................................................................................ 102 
15.1. 
Quality Assurance .......................................................................................................... 102 
15.2. 
Quality Control ............................................................................................................... 102 
16. 
Protocol Deviations................................................................................................................ 103 
16.1. 
Protocol Deviation Definitions ........................................................................................ 103 
16.2. 
Reporting and Managing Protocol Deviations ............................................................. 103 
17. 
Ethical Considerations and Compliance with Good Clinical Practice ................................ 104 
17.1. 
Statement of Compliance .............................................................................................. 104 
17.2. 
Informed Consent Process ............................................................................................ 104 


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17.3. 
Privacy and Confidentiality ............................................................................................ 104 
18. 
Publication Policy .................................................................................................................. 105 
19. 
References............................................................................................................................. 106 
Appendix 1. Recipient Schedule of Events .....................................................................................112 
Appendix 2. Donor Schedule of Events.......................................................................................... 119 
Appendix 3. Reduced Follow-up Schedule of Events ................................................................... 120 
Appendix 4. Reduced Follow-up Schedule of Events (Withdrawn/Terminated Subjects) ............ 121 


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Glossary of Abbreviations 
 
 
ACR 
Acute Cellular Rejection 
AE 
Adverse Event 
AHG 
Anti-human Globulin 
ALP 
Alkaline Phosphatase 
ALT (SGPT) 
Alanine Aminotransferase 
AMR 
Antibody Mediate Rejection 
ANCOVA 
Analysis at Covariance 
Anti -TNFa-mAb 
Anti-Tumor Necrosis Factor Alpha-monoclonal antibody 
APC 
Antigen Presenting Cells 
AR 
Acute Rejection 
AST (SGOT) 
Aspartate Aminotransferase 
ATG 
Anti-Thymocyte Globulin (Thymoglobulin®) 
AUC 
Area Under the Curve 
BPAR 
Biopsy Proven Acute Rejection 
BID 
Twice Daily 
BKV 
BK Polyoma Virus 
BMP7 
Bone Morphogenic Protein 7 
CBC 
Complete Blood Count 
CD4, 8, etc. 
Cluster of Differentiation 4, 8, etc. 
CDC 
Complement Dependent Cytotoxicity Assay 
CFR 
Code of Federal Regulations 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CMH 
Cochran-Mantel-Haenszel 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitors 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRR 
Creatinine Reduction Ratio 
CS 
Corticosteroids 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTOT 
Clinical Trials in Organ Transplantation 


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CV 
Cardiovascular Disease 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DGF 
Delayed Graft Function 
DNA 
Deoxyribonucleic Acid 
DSA 
Donor Specific Antibody 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein Barr Virus 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISPOT 
Enzyme Linked Immunospot 
EMT 
Epithelial-Mesenchymal Transition 
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practice 
H&E 
Haematoxylin and Eosin 
HLA 
Human Leukocyte Antigen 
HPLC 
High Performance Liquid Chromatography 
HTN 
Hypertension 
ICH 
International Conference on Harmonization 
IF/TA 
Interstitial Fibrosis/Tubular Atrophy 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IND 
Investigational New Drug 
INF-γ 
Interferon gamma 
IoR 
Investigator of Record 
IR Injury 
Ischemia Reperfusion Injury 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
MDRD 
Modification of Diet in Renal Disease 


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MESF 
Molecular Equivalents of Fluorescence 
MFI 
Mean Fluorescent Intensity 
MHC 
Major Histocompatibility Complex 
MI 
Multiple Imputation 
MMF 
Mycophenolate Mofetil (CellCept®) 
MOP 
Manual of Procedures 
MPA 
Mycophenolate Acid (Myfortic®) 
mRNA 
Messenger RNA 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NR 
Not Reported 
OI 
Opportunistic Infections 
OR 
Operating Room 
PAS 
Periodic Acid-Schiff 
PBL 
Peripheral Blood Lymphocytes 
PBMC 
Peripheral Blood Mononuclear Cells 
PCA 
Principal Components Analysis 
PCR 
Polymerase Chain Reaction 
PP Sample 
Per Protocol Sample 
PHI 
Personal Health Identifiers 
PI 
Principal Investigator 
PNF 
Primary Non-Function 
PRA 
Panel Reactive Antibody 
PRT 
Panel Reactive T-cell 
QOD 
Every Other Day 
qRT-PCR 
Quantitative Real Time Polymerase Chain Reaction 
RA 
Rheumatoid Arthritis 
rATG 
Rabbit Anti-Thymocyte Globulin (Thymoglobulin®) 
RMSE 
Root Mean Squared Error 
RNA 
Ribonucleic Acid 
ROC 
Receiver Operating Characteristics 
ROS 
Reactive Oxygen Species 
RR 
Relative Risk 
RTE 
Recent Thymic Emigrants 


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SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
sCr 
Serum Creatinine 
SD 
Standard Deviation 
SGF 
Slow Graft Function 
SOE 
Schedule of Events 
SOP 
Standard Operating Procedure 
SRTR 
Scientific Registry of Transplant Recipient 
TAC 
Tacrolimus 
TB 
Tuberculosis 
TB 
Transplantation Branch 
TNFa 
Tumor Necrosis Factor Alpha 
TNFR: Fc 
Tumor Necrosis Factor Receptor: Fc Fusion Protein 
UNOS 
United Network for Organ Sharing 
URI 
Upper Respiratory Infection 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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Study Definitions Page 
 
 
Acute 
Cellular 
Rejection 
Based on BANFF 2007 Scoring Criteria. Grade 1A or higher. 
1. Normal 
2. Borderline changes: 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. 
3. 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) 
4. Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology 
(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) 
5. 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. 
Acute 
Rejection 
Based on BANFF 2007/2013 Scoring Criteria. Any episode of rejection that meets 
the criteria for ACR and/or ABMR. 


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Antibody 
Mediated 
Rejection (ABMR) 
Based on BANFF 
2013 Criteria 
Acute/Active ABMR (all three features must be present for diagnosis)1, 2 
1. Histologic evidence of acute tissue injury, including one or more of the 
following: 
• 
Microvascular Inflammation (g>03 and/or ptc>0) 
• 
Intimal or transmural arteritis (v>0)4 
• 
Acute thrombotic microangiopathy, in the absence of any other 
cause 
• 
Acute tubular injury, in the absence of any other apparent 
cause 
2. Evidence of current/recent antibody interaction with vascular 
endothelium, including at least one of the following: 
• 
Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF 
on frozen sections, or C4d>0 by IHC on paraffin sections) 
• 
At lease moderate microvascular inflammation (Ig + ptc>2)5 
• 
Increased expression of gene transcripts in the biopsy tissue 
indicative of endothelial injury, if thoroughly validated6 
3. Serologic evidence of donor-specific antibodies (DSAs) (HLA or other 
antigens) 
These lesions may be clinically acute, smoldering or subclinical. Biopsies 
showing two of the three features except those with DSA and C4d without 
histologic abnormalities potentially related to ABMR or TCMR (C4d staining 
without evidence of rejection) may be designated as “suspicious” for 
acute/active ABMR. 
Chronic, active ABMR; all three features must be present for diagnosis1,7 
1. Morphologic evidence of chronic tissue injury, including one or 
more of the following: 
• 
Transplant glomerulopathy (TG) (cg>0)8, if no evidence of 
chronic thrombotic microangiopathy 
• 
Severe peritubular capillary basement membrane multi-layering 
(requires EM)9 
• 
Arterial intimal fibrosis of new onset, excluding other causes10 
2. Evidence of current/recent antibody interaction with vascular 
endothelium, including at least one of the following: 
• 
Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF 
on frozen sections, or C4d>0 by IHC on paraffin sections) 
• 
At least moderate microvascular inflammation ([g+ptc]>2)5 
• 
Increased expression of gene transcripts in the biopsy tissue 
indicative of endothelial injury, if thoroughly validated6 
3.  Serologic evidence of DSAs (HLA or other antigens) 
C4d staining without evidence of rejection; all three features must be 
present for diagnosis11 
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on 
frozen sections, or C4d>0 by IHC on paraffin sections) 
2. g=0, ptc=0, cg=0 (by light microscopy and by EM if available), v=0; 
no TMA, no peritubular capillary basement membrane multi- 


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layering, no acute tubular injury (in the absence of another 
apparent cause for this) 
3. No acute cell-mediated rejection (Banff 97 type 1A or greater) or 
borderline changes 
 
cg, Banff chronic glomerulopathy score; EM, electron microscopy; ENDAT, 
endothelial activation and injury transcript; g, Banff glomerulitis score; GBM, 
glomerular basement membrane; IF, immunofluorescence; IHC, 
immunohistochemistry; ptc, peritubular capillary; TCMR, T cell–mediated rejection; 
v, Banff arteritis score. 
1. For all ABMR diagnoses, it should be specified in the report whether the lesion 
is C4d-positive (C4d2 or C4d3 by IF on frozen sections; C4d>0 by IHC on 
paraffin sections) or without evident C4d deposition (C4d0 or C4d1 by IF on 
frozen sections; C4d0 by IHC on paraffin sections). 
2. These lesions may be clinically acute, smoldering or subclinical. Biopsies 
showing two of the three features, except those with DSA and C4d without 
histologic abnormalities potentially related to ABMR or TCMR (C4d staining 
without evidence of rejection; see footnote 11, below) may be designated as 
‘‘suspicious’’ for acute/active ABMR. 
3. Recurrent/de novo glomerulonephritis should be excluded. 
4. It should be noted that these arterial lesions may be indicative of ABMR, TCMR 
or mixed ABMR/TCMR. ‘‘v’’ lesions are only scored in arteries having a 
continuous media with two or more smooth muscle layers. 
5. In the presence of acute TCMR, borderline infiltrates or evidence of infection, 
ptc >2 alone is not sufficient to define moderate microvascular inflammation 
and g must be >1. 
6. At present the only validated molecular marker meeting this criterion is ENDAT 
expression (4), and this has only been validated in a single center (University of 
Alberta). The use of ENDAT expression at other centers or other test(s) of gene 
expression within the biopsy as evidence of ABMR must first undergo 
independent validation as was done for ENDAT expression by Sis et al (4). 
7. Lesions of chronic, active ABMR can range from primarily active lesions with 
early TG evident only byEM(cg1a) to those with advanced TG and other 
chronic changes in addition to active microvascular inflammation. In the 
absence of evidence of current/recent antibody interaction with the 
endothelium (those features in the Second Section), the term active should be 
omitted; in such cases DSA may be present at the time of biopsy or at any 
previous time post-transplantation. 
8. Includes GBM duplication by EM only (cg1a) or GBM double contours by light 
microscopy. 
9. >7 layers in one cortical peritubular capillary and >5 in two additional 
capillaries (17), avoiding portions cut tangentially. 
10. While leukocytes within the fibrotic intima favor chronic rejection, these are 
seen with chronic TCMR as well as chronic ABMR, and are therefore helpful 
only if there is no history of TCMR. An elastic stain may be helpful as absence 
of elastic lamellae is more typical of chronic rejection and multiple elastic 
lamellae are most typical of arteriosclerosis, although these findings are not 
definitive. 
11. The clinical significance of these findings may be quite different in grafts 
exposed to anti-blood-group antibodies (ABO-incompatible allografts), where 
they do not appear to be injurious to the graft (18,19) and may represent 
accommodation. However, with anti-HLA antibodies such lesions may 
progress to chronic ABMR (20) and more outcome data are needed. 


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BANFF Chronicity 
Scores 
Change in IFTA (Ci+Ct)> 2 between baseline and 24 months post- 
transplant 
Biopsy Proven 
Acute Rejection 
(BPAR) 
Banff grade of greater than or equal to 1A with or without clinical 
symptoms. 
BK Viremia 
The protocol definition of BK Viremia will be based on Center-dependent 
definition of a viral load resulting in a change of immunosuppression. 
Chronic Kidney 
Disease 
Epidemiology 
Collaboration 
(CKD-EPI) Equation 
GFR = 141 × min (sCr /k, 1)α × max(sCr /κ, 1)-1.209 × 0.993Age × 1.018 [if 
female] × 1.159 [if black] 
Clinically 
Indicated Biopsy 
Any biopsy performed for a clinically indicated reason as determined by 
the local investigator 
Cold Ischemia 
Time 
Sites will defer to their SOC practices 
Congestive Heart 
Failure 
The NYHA functional Class II or higher criteria will be used to determine 
congestive heart failure for this protocol. 
Creatinine 
Reduction Ratio 
(CRR) 
([Cr1 – CrX] × 100) / Cr1, where Cr1 and CrX represent serum creatinine on 
day one and day X post-transplant respectively 
Cytomegalovirus 
(CMV) Viremia 
Based on Center-dependent definition of a viral load resulting in a change 
of immunosuppression 
Delayed Graft 
Function (DGF) 
Determined locally. The need for at least one dialysis treatment in the first 
week after transplantation. Duration of DGF is defined from 
transplantation to the last required dialysis treatment 
Estimated 
Glomerular 
Filtration Rate 
(eGFR) 
Determined centrally. Will be measured by both the modified MDRD and 
CKD-EPI equations 
Graft Loss/Failure 
(Other than 
Primary (Graft) 
Non-Function) 
The need for post-transplant dialysis for more than 56 days. Date of dialysis 
is the day of the 1st dialysis treatment. 
Impaired Wound 
Healing 
Manifested by wound dehiscence, wound infection, or hernia at the site of 
transplant incision 
Intent-to-Treat 
Sample 
All randomized subjects who receive the Remicade®/Placebo infusion. 
This sample will be used for efficacy and safety summaries/analyses. 


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Invasive Fungal 
Infection 
Defined by the presence of a fungus in blood (determined by fungal 
blood culture), normally sterile site (other than mucous membrane; 
determined by culture) or in tissue (determined either by histology or by 
tissue culture). 
Exclusions include: 
• 
Uncomplicated cystitis resulting from Candida or non-Candida 
yeast 
• 
Cutaneous, nail, or mucosal (e.g. thrush) infections resulting from 
Candida or non-Candida yeast or from cutaneous pathogens such 
as tinea pedis, trichophyton, epidermopyhton, and microsporum 
species 
Malignancy 
Determined locally. Any malignancy including squamous cell 
carcinoma/skin cancers and PTLD 
Modification of 
Diet in Renal 
Disease (MDRD) 
Equation 
GFR (mL/min/1.73 m2) = 175 × (sCr)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if African American) 
Per Protocol (PP) 
Sample 
All randomized subjects who receive the Remicade®/Placebo infusion 
who are compliant with their medications and do not have any major 
protocol deviations. 
Primary 
Non-Function 
Dialysis-dependency for more than 3 months or an eGFR 20 ml/min or less 
at 90 days post-transplant 
Protocol Mandated 
Procedures 
Any procedure performed solely for the purpose of this research study (not 
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. 
Screening Sample 
All subjects who are enrolled in the study. This sample will be used for 
disposition summaries. 
Serious Infectious 
Complications 
Any infection requiring hospitalization or resulting in death 
Slow Graft Function 
(SGF) 
Defined as one of the following: 
• 
A serum creatinine of more than 3mg/dL at day 5 post-transplant 
• 
Serum creatinine reduction ratio less than 70% at post-operative 
day 5 
• 
Serum creatinine reduction ratio less than 30% at 48 hours post- 
transplant 
Rate of SGF is defined as the proportion of subjects with serum creatinine 
of more than 3mg/dL at Day 5 post-transplant and/or creatinine reduction 
ratio (CRR) on Day 2 and Day5 


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Study Therapy 
Regimen 
The investigational therapeutic regimen and all protocol required 
therapies 
Tuberculosis (TB) 
Active Disease 
Clinical evidence of active tuberculosis with positive tuberculosis cultures 
as determined by the clinical site. 
Tuberculosis (TB) 
Exposure 
Positivity/Latent TB 
Infection 
For this protocol, tuberculosis exposure positivity is defined as subjects with 
a positive test for tuberculosis exposure (PPD, QuantiFERON, ELISPOT). 
Tuberculosis exposure is not the same as active tuberculosis disease. 
Warm Ischemia 
Time (Recipient) 
Time from allograft removal from the ice bucket or perfusion pump in the 
recipient operating room to vascular unclamping (following completion of 
anastomoses), and reperfusion 
Warm Ischemia 
Time (Donor) 
a) Time from extubation to pronouncement of death 
b) Time from pronouncement of death to cross-clamp 


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1. Study Hypotheses/Objectives 
1.1. Hypotheses 
Ischemia followed by reperfusion (I-R) of a kidney transplant results in up-regulated TNFa 
production within the allograft. The I-R induced TNFa plays a crucial role in amplifying allograft 
inflammation by enhancing activation, expansion and graft infiltration of donor-reactive T cells 
and B cells (the latter of which also produce donor-reactive antibodies), while simultaneously 
inhibiting regulatory T cell induction and function. Together with early TNFa-mediated induction 
of a fibrogenic molecular profile in the graft, these early post-transplant, TNFa-dependent 
processes have prolonged, detrimental, pro-inflammatory consequences that injure the 
transplanted organ. This hypothesis predicts that peritransplant TNFa blockade (initiated intra- 
operatively, prior to graft reperfusion) will have a profound effect by preventing amplification of 
the downstream pro-inflammatory and pro-fibrogenic responses, thereby reducing costly injury in 
deceased donor grafts. As a consequence, blocking TNFa at the time of transplantation will 
improve both short-term and long-term outcomes in recipients of deceased donor kidney 
transplants. 
1.2. Primary Objective 
The objective of the study is to determine the efficacy of adding intravenous infliximab 
administered at the time of transplantation (prior to reperfusion) to rATG and standard 3-drug 
immunosuppression on 2-year kidney transplant function. 
1.3. Secondary Objective(s) 
Secondary Objectives 
 
 
Efficacy Objectives 
To determine the efficacy of intravenous infliximab administered at the time of transplantation 
(prior to reperfusion) plus rATG followed by TAC, MMF, and prednisone on 
1. 
Incidence of biopsy-proven acute cellular rejection 
2. 
Severity of acute cellular rejection based on Banff criteria 
3. 
Incidence of biopsy-proven acute cellular rejection or borderline rejection 
4. 
Incidence of biopsy-proven acute humoral rejection 
5. 
Incidence of biopsy-proven acute humoral rejection or suspicious for AMR 
6. 
Severity of acute humoral rejection based on Banff criteria 
7. 
Incidence of chronic allograft injury 
8. 
Progression of chronic allograft injury 
9. 
Change in renal function over the 24 months of the study 
10. Allograft survival rate 
11. Incidence of delayed graft function 
12. Time to events (ACR, AMR, graft failure, or hospitalization for infection and/or malignancy) 
13. Incidence of Slow Graft Function (SGF) 


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Safety /Complication Objectives 
To determine the complication rate of intravenous infliximab administered at the time of 
transplantation (prior to reperfusion) plus rATG followed by TAC, MMF/MPA, and prednisone as 
measured by: 
1. Incidence of serious infectious complications 
2. Incidence of CMV viremia 
3. Incidence of BK viremia 
4. Incidence of malignancy 
5. Incidence of impaired wound healing 
Mechanistic objectives 
1. To define the utility of previously identified, noninvasive biomarkers as risk assessment, 
diagnostic, and predictive testing strategies for outcomes (acute rejection, graft loss, and 
eGFR at 2 years) in higher risk recipients of deceased donor kidney allografts including 
(alone or in some combination) 
a) Panel of reactive T cell (PRT) assays 
b) Urinary chemokine and urinary PCR assays 
c) Gene expression profiles in peripheral blood 
d) Gene expression profiles in graft tissue 
2. To test the effects of induction therapy with ATG plus anti-TNFa mAb on graft inflammation, 
donor reactive immunity and graft pathology including 
a) Effects of intraoperative anti-TNFa mAb on post-transplant inflammation 
b) Effects of intraoperative anti-TNFa mAb on donor-reactive effector T cells 
c) Effects of intraoperative anti-TNFa mAb on regulatory T cells 
d) Effects of intraoperative anti-TNFa mAb on donor specific antibody 
e) Effects of intraoperative anti-TNFa mAb on fibrogenic gene profiles in the allograft 
f) Effects of intraoperative anti-TNFa mAb on peritubular capillary loss 
Ancillary objectives 
1. To determine the prevalence of non-adherence to immunosuppressive therapy as 
measured by a medication event monitoring system (MEMS®) for prednisone in the first 3 
months post-transplantation and as measured by the standard deviation of the monthly 
tacrolimus troughs from 6 months post-transplantation to 2 years post-transplantation in 
both infliximab and control groups. 


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2. Background and Scientific Rationale 
2.1. Background 
Kidney Graft and Patient Survival 
Despite impressive reduction in rates of acute kidney graft rejection (AR), the widespread use of 
calcineurin inhibitors and accompanying immunosuppressive medication, including induction 
therapy, has had only a modest impact on prolonging transplant survival, particularly in recipients 
of deceased donor organs. In f act, the average life span of kidney allograft recipients may be 
decreasing, with death with a functioning graft [50% due to cardiovascular (CV) disease] as the 
most common cause of graft loss (1, 2). Multiple factors are implicated in post-transplant mortality 
but the influence of renal dysfunction on CV status is an important suspected etiology. Chronic 
immune-mediated injury to the graft is common, and post-transplant kidney function is strongly 
associated with both the incidence and risk of CV death, independent of other known risk f actors 
(3). 
 
Current standard of care immunosuppression for kidney transplantation 
Standard of care immunosuppression for deceased donor kidney transplantation in most North 
American centers, consists of induction therapy with rabbit anti-human thymocyte globulin (rATG 
or Thymoglobulin®) and triple maintenance therapy with tacrolimus, either mycophenolate 
mofetil or enteric-coated mycophenolate sodium, and corticosteroids (SRTR Annual Report 2010). 
rATG is a polyclonal antibody derived from immunization of rabbits with human thymocytes. The 
final product includes antibodies against CD2, CD3, CD4, CD8, CD11A, CD18, CD25, CD44, CD45, 
HLA-DR, and HLA class I heavy chains, and is effective in preventing cellular immune responses 
against a variety of antigenic stimuli (4). In a randomized trial of 72 kidney transplant recipients, 
rATG was superior to horse anti-thymocyte globulin resulting in lower rates of acute rejection (4% 
versus 25%) and producing more sustained lymphopenia (5). Two randomized trials have 
compared the overall effectiveness of rATG to anti-interleukin 2 receptor antibodies in patients 
deemed to be “high risk” (6, 7). The inclusion criteria for these two studies differed, but are broadly 
encompassed by those of the current protocol. In each study, ATG proved to be superior to anti- 
interleukin 2 receptor antibodies in preventing acute rejection, supporting the use of ATG as 
standard of care for this high-risk population. 
 
In the above-described studies of ATG in high-risk kidney allograft recipients, DGF rates were less 
than 1%, raising the possibility that polyclonal antibodies may prevent DGF. A randomized study 
of 58 deceased donor kidney transplant recipients managed with either intraoperative or 
postoperative rATG found significantly less DGF in the group receiving intraoperative treatment 
(8). Interestingly, the incidence of DGF was lower for rATG-treated patients in the study by Noel et 
al (7), although not in the larger study by Brennan et al (6). rATG does not completely mitigate 
the development of DGF and its role in mollifying IR injury remains unclear, supporting the need 
to test additional agents. Adhesion molecules, cytokines, chemokines and their receptors 
contribute to IR injury and their blockade by a polyclonal antibody may mitigate the 
development of DGF. This theoretical benefit of polyclonal agents forms the basis for their initial 
administration intra-operatively, prior to revascularization of the allograft. 
Ischemia reperfusion injury and kidney transplantation 
Increasing evidence implicates inflammatory events related to ischemia and reperfusion (IR) injury 
occurring immediately after transplantation of deceased donor organs as impacting short- and 
long-term survival. Delayed graft function, the forme fruste of post-transplant IR injury, results in 
acute renal failure manifested by post-transplantation oliguria and requires dialytic support. DGF 


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is associated with increased allograft immunogenicity, elevated risk of acute rejection episodes, 
and decreased long-term survival (9, 10). The incidence of DGF averages 30% of all deceased 
donor kidney transplants (9, 10). The development of DGF post-transplant strongly correlates with 
poorer kidney graft survival and with the subsequent development of chronic allograft 
nephropathy or IF/TA (11, 12). One study of 126 cadaveric kidney transplant recipients 
demonstrated that while patients with immediate graft function had a 90% 5-year graft survival, 
those with DGF for more than 9 days had a 5-year graft survival of 50% (11). A meta-analysis found 
that patients who experienced DGF had a higher risk of acute rejection [RR 1.38 (95% CI 1.29– 
1.47), P < 0.001] and worse long-term renal function (13). In addition, DGF is associated with 
prolonged hospitalization, higher transplantation costs and adverse effects on the rehabilitation 
of transplant recipients (14). Prolonged ischemic times are associated with increased incidence 
of delayed kidney graft function (10, 15). Longer cold ischemic storage times for kidney grafts are 
also associated with increased incidence of acute rejection episodes and the development of 
graft fibrosis and arteriopathy (10, 16, 17). Thus, DGF is both an outcome following kidney 
transplantation and a predictor for long-term graft function. 
 
Mechanistic studies of IR injury and associated inflammation in animal models and humans 
(reviewed in (10)) indicate that reperfusion of an ischemic organ, whether or not it causes 
delayed graft function, induces an intense inflammatory response in the tissue. This inflammation 
is initiated by the production of reactive oxygen species (ROS) that activate the vascular 
endothelium of the tissue to express adhesion molecules, produce complement components (18- 
21), and release a variety of pro-inflammatory cytokines (22, 23), including IL-1, IL-6, TNFa, and pro- 
inflammatory chemokines and complement. The released pro-inflammatory molecules and 
cytokines, including TNF a activate the vascular endothelium to mobilize selectins and von 
Willebrand factor to the luminal membrane and upregulate surface expression of integrin ligands. 
TNFa also initiates the activation of interstitial dendritic cells and their emigration from tissue sites 
of inflammation to the peripheral lymphoid organs draining the inflammatory sites where they 
activate donor antigen-reactive T cells to become effector T cells. Together, these processes 
provide an immunogenic, pro-inflammatory environment that facilitates the induction and 
function of adaptive immune responses ultimately resulting in graft failure. 
Animal studies performed by multiple groups have shown that blocking TNFa signaling (including 
studies of subjects with TNFR polymorphisms), among other early pro-inflammatory mediators (e.g. 
complement activation) can significantly attenuate tissue injury (24-27). While each of these 
pathways contributes to inflammation, acute injury and graft dysfunction, it is possible to 
significantly dampen the effects by blocking one pathway. These data show synergistic 
interactions of the overlapping pro-inflammatory mechanisms, and highlight the concept that 
inhibiting one relevant mechanism can dampen the entire vicious cycle of inflammation and 
have important protective consequence. The published findings strongly implicate TNFa as a key 
driver of early post-transplant inflammation that contributes to late allograft injury and loss. Thus, 
the overarching goal of the proposed study is to test the efficacy of blocking post-transplant TNFa 
on early and late outcomes following deceased donor kidney transplantation. 
2.2. Rationale for Selection of Investigational Product or Intervention 
Following the recognition that TNFa plays a crucial role in the pathogenesis of rheumatoid arthritis 
(RA), multiple TNFa blocking agents were developed and tested in humans (28). In 2014, five TNF 
blocking agents are FDA approved for human use: infliximab, a mouse/human chimeric anti- TNFa 
mAb (administered IV, half-life of 8-10d); adalimumab and golimumab, fully humanized anti-TNF 
mAbs (administered SC, half-lives 7-20 d); certolizumab, which is a PEGylated anti- TNFa Fab 
fragment (administered SC half-life 14 d); and etanercept, a TNFR2:Fc fusion protein that binds 


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TNFa and lymphotoxin f amily members (administered SC half-life 4 d). Approved indications for 
TNFa blockade include treatment of RA, Crohn’s disease, ankylosing spondylitis, and psoriasis. 
Accumulating data indicate strong safety profiles for each of these agents, but chronic TNFa 
blockade is associated with increased risks for infection including reactivation of tuberculosis (TB) 
and other invasive fungal infections. There is controversial evidence indicating that chronic TNFa 
blockade can inhibit wound healing [current recommendations are that patients on chronic TNFa 
blockade stop the treatment prior to surgery (28, 29)]. TNFa blocking agents have been tested as 
chronic therapies in large trials to treat heart failure without efficacy, and with some evidence of 
paradoxical worsening of heart disease (30). These latter results, possibly due to chronic inhibition 
of anti-inflammation (protective) TNFR2 signaling have resulted in a relative contraindication for 
chronic TNFa blockade in RA patients with heart f ailure. Autoimmune hepatitis has been 
described as an uncommon complication of chronic TNFa blockade (see package insert). 
In our proposed studies we will restrict administration of anti- TNFa mAb to a single perioperative 
dose. We will use infliximab over other TNFa blockers because: a) it is FDA approved for use in 
humans (albeit not in transplant recipients) and it is effective in RA and Crohn’s disease; b) it is the 
only agent administered IV such that high levels can be achieved if given in the OR; c) its relatively 
short half-life (8-10 days) so as to block TNFa during and after reperfusion injury for only up to 
several weeks post-transplant, thereby increasing the likelihood of blocking post-transplant 
inflammation without significantly increasing long term infectious risk; and d) its cost is affordable. 
2.3. Preclinical Experience 
Anti- TNFa mAb inhibits post-transplant inflammation and prolongs allograft survival in rodents. 
Experiments performed in mice by the Fairchild lab [Co-I, member of this consortium] 
demonstrated that a single dose of anti- TNFa mAb at the time of allograft reperfusion has multiple 
protective consequences (24). It attenuates many components of the early post-transplant 
inflammation including production of neutrophil and macrophage chemoattractants and the 
infiltration of these leukocyte populations as well as donor-reactive memory CD8 T cells into the 
allograft within the first 48 hours post- transplant. These CD8 memory T cells reactive to donor class 
I MHC molecules produce IFNy within 24 hours of allograft reperfusion (24) and are important 
contributors to the establishment of an inflammatory milieu in the allograft that f acilitates the 
infiltration of effector T cells primed in the spleen into the allograft. Peri-transplant administration 
of a single dose of anti-TNFa antibody also has a profound effect in inhibiting alloreactive CD4 
and CD8 T cell priming. Interstitial dendritic cell emigration from tissue inflammatory sites is 
promoted by TNFα (31, 32)suggesting this as a mechanism accounting for the decreased effector 
CD4 and CD8 T cell priming in the anti-TNFa treated recipients. TNFa upregulates class I/II MHC 
(31, 33) so that neutralization in allograft recipients may also decrease the immunogenicity of  the 
graft dendritic cells as well as the antigenicity of the graft itself. 
Administration of anti-TNFa antibodies with CyA, anti-CD40L or anti-CD4 mAb prolonged heart 
and small bowel survival in rodent models that was associated with delayed T cell infiltration into 
the allografts (33-37). Brouard and colleagues extended these mechanistic findings to show that 
anti- TNFa mAb administered to MHC mismatched rat heart transplant recipients, at the time of 
the transplant: a) decreased graft inflammation and extended graft survival and b) strikingly 
prevented induction of anti-donor MHC IgG antibodies (38). The latter occurred without 
detectable effects on Th1 or Th2 cytokines suggesting a specific effect on inhibiting T cell help to 
B cells, a possible mechanism that warrants further testing. TNF blockade with a TNFR:Fc fusion 
protein was tested with and without cyclosporine in a small number of cynomolgus monkey 
kidney transplant recipients (39).  Acute rejection was delayed from 5 to 11 days with TNF 


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blockade alone and to ~35 days in animals treated with CYA plus TNF blockade (10 days in CYA 
alone treated animals). No significant off target effects were noted in this short-term study. 
Together, the preclinical data support the conclusion that blocking TNFa at the time of the 
transplant has profound effects on immediate post-transplant inflammation, and on subsequent 
T and B cell alloimmunity and graft outcome, supporting the need to test the effects of early TNFa 
blockade in human transplant recipients, as proposed herein. 
2.4. Clinical Studies 
Studies of human heart transplant biopsies showed elevated TNFa mRNA and protein expression 
early post-transplant and unrelated to rejection grade or serum levels (40) consistent with the 
concept that TNFa is produced in the graft as part of the IR injury response. TNFa blocking agents 
have been tested, to our knowledge, in 2 reports of human solid organ transplant recipients. Kirk 
and Mannon used chronic therapy with infliximab plus Campath 1H in an attempt to induce 
kidney transplant tolerance in a small number of patients (41). While the therapy was deemed 
safe, it was not efficacious in the protocol employed: all patients ultimately developed rejection. 
The Bogaev group used etanercept as chronic therapy to prevent ventricular hypertrophy in 49 
heart transplant recipients (42), again demonstrating safety when administered with other 
immunosuppressants, and showing some efficacy in preventing ventricular hypertrophy. No 
wound healing problems were reported. Importantly, none of the studies have attempted to use 
TNFa blockade as solely an induction therapy to dampen inflammation and its downstream 
consequences, as we propose herein. Etanercept has also been used in association as induction 
therapy (given on day 0, 3, 7 and 10), with and without concomitant ATG, in islet transplant 
recipients with evidence of efficacy and without significant infectious complications (43-45). 
Finally, the group from Berlin (Schnachtner et al, WTC 2014 Abstract #1365) recently reported their 
experience combining an anti-TNF antibody with a T cell-depleting antibody in 40 kidney re- 
transplant recipients who were “sensitized” based on the presence of donor-reactive T cells prior 
to transplantation. Compared to a control group of 40 “non-sensitized” re-transplant patients 
treated with conventional immunosuppression, the group treated with anti-TNF actually had 
significantly better 5-year graft survival (p=0.02). There were no differences in acute rejection and, 
notably, no differences in septic complications or in rates of CMV, BK, or EBV viremia. Together, 
the preclinical data, the established safety profile of the class of drugs in general and in small 
numbers of transplant patients support the protocol in which we will test the additive efficacy of 
TNFa blockade with infliximab, in addition to rATG induction plus standard 3 drug maintenance 
immunosuppression for deceased donor kidney transplant recipients. 


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3. Study Design 
3.1. Description of Study Design 
This is a phase II, multicenter, randomized, double blind, and placebo-controlled, 2-arm study of 
300 deceased donor kidney transplant recipients randomized 1:1 to the experimental and control 
arms (150 patients per arm). Subjects in the control arm will be treated with rATG plus placebo 
(sterile normal saline) induction followed by tacrolimus, a mycophenolic acid derivative (either 
MMF or enteric coated MPA), and corticosteroids. Subjects in the experimental arm will receive 
infliximab plus rATG induction followed by tacrolimus, a mycophenolic acid derivative (either MMF 
or enteric coated MPA), and corticosteroids. Please refer to the study therapy regimen below. 
 
Please refer to Section 8-Study Procedures for additional details regarding dosing and 
administration. 
 
Study Therapy Regimen 
Experimental 
Arm 
• 
Remicade® (Infliximab) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o 
Generic equivalent 
o 
An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their generic 
equivalents 
• 
Methylprednisolone or generic equivalent 
Control 
Arm 
• 
Placebo (Normal Saline for Injection) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o 
Generic equivalent 
o 
An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their generic 
equivalents) 
• 
Methylprednisolone or generic equivalent 
 
Estimated GFR (eGFR) will be calculated using the MDRD formula based on serum creatinine 
performed centrally at the Cleveland Clinic, Cleveland, OH, GFR core laboratory, (Poggio PI). 
Pathology analyses of graft tissue will be performed at the Pathology core lab at University of 
Manitoba at Winnipeg (Gibson, PI). Anti-HLA antibody testing will occur at the core HLA lab at 
the University of Manitoba at Winnipeg (Nickerson, PI). Mechanistic studies will be performed at 
2 additional core laboratories at the Cleveland Clinic, Cleveland OH (Fairchild, PI) and the Icahn 
School of Medicine at Mount Sinai, NY, NY (Heeger, PI). 
Medication Adherence 
Non-adherence to immunosuppressive medications is known to be associated with inferior 
allograft outcomes. Hence, short- and long-term adherence to immunosuppressives will be 
monitored during the study. During the first 3 months post-transplantation, prednisone adherence 
will be monitored using a medication event monitoring system (MEMS®). Subjects will be asked 
to transfer their prednisone to a MEMS® bottle for the 3-month duration after transplant. Long- 
term tacrolimus adherence will be quantified using the standard deviation of the monthly 
tacrolimus troughs from 6 months post-transplantation to 2 years post-transplantation. 


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3.2. Primary Endpoint 
The primary endpoint is the difference between the mean 24-month eGFR (modified MDRD) in 
the experimental vs. control groups. 
3.3. Secondary Endpoint 
The secondary endpoints include efficacy, safety and mechanistic endpoints. See table below. 
 
Secondary Endpoints 
 
Efficacy Endpoints 
1. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) within 
a) 6 month and 
b) 2 years of transplant 
2. BANFF grades of first Acute Cellular Rejections (ACR) within 6 month of transplant 
3. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline 
rejection within 
a) 6 month and 
b) 2 years of transplant 
4. Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR) 
within 6 months and 2 years of transplant 
5. Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or 
suspicious for AMR within 
a) 6 months and 
b) 2 years of transplant 
6. BANFF grades of first AMR within 6 months of transplant 
7. Proportion of subjects with BANFF chronicity scores >or equal 2 on 24-month biopsy 
8. Change in BANFF chronicity scores between implantation and 24 month biopsies 
9. eGFR (as measured by both MDRD and CKD-EPI) 
a) Change in eGFR between 3 months and 24 months 
b) Change in eGFR between post-transplant nadir (lowest eGFR in first 6 months) and 24 
months 
c) eGFR on days 7, 30, 90, and 180 post-transplant 
10. Proportion of subjects with: 
a) Death or graft failure within 2 years 
b) Only graft failure within 2 years 
11. Each of the following: 
a) Proportion of subjects that required at least one dialysis treatment within the first week 
after transplantation 
b) Number of dialysis sessions in the first 8 weeks post-transplantation. 
c) Duration of DGF defined as time from transplantation to the last required dialysis 
treatment 
d) The incidence of primary non-function (PNF), defined as dialysis-dependency for 
more than 3 months or an eGFR 20 ml/min or less at 90 days post-transplant 
e) Change from baseline (immediately after surgery) in serum creatinine and serum 
creatinine concentration at 24, 48, and 72 hours. 
12. Days from transplantation until event (ACR, AMR, or hospitalization for infection and or 
malignancy) 


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13. Rate of Slow Graft Function (SGF): 
a) The proportion of patients with a serum creatinine of more than 3 mg/dL at day 5 
post-transplant, 
b) Creatinine reduction ratio (CRR) on day 2 
c) Creatinine reduction ratio (CRR) on day 5 
d) The proportion of patients whose day 5 serum CRR was less than 70% 
e) The proportion of patients whose day 2 serum CRR was less than 30% 
f) Proportion of subjects who need dialysis after 1 week. 
Safety/Complication Endpoints 
1. Proportion of subjects with: 
a) Any infection requiring hospitalization or resulting in death 
b) Mycobacterial or fungal infections 
2. Proportion of subjects with CMV viremia that require a change in immunosuppression or 
anti-viral treatment as per standard of care at the site 
3. Proportion of subjects with BK viremia that require a change in immunosuppression or 
anti-viral treatment as per standard of care at the site 
4. Proportion of subjects with malignancy 
5. Proportion of subjects with impaired wound healing manifested by wound dehiscence, 
wound infection, or hernia at the site of the transplant incision. 
Mechanistic Endpoints 
1. Sensitivity, specificity, PPV, and NPV of biomarkers, including PRT, urinary CXCL9, blood 
genomic profile, and 3-month allograft genomic profile (alone and/or in combination) to 
predict: 
a) Incident biopsy-proven acute rejection. 
b) Graft loss 
c) Chronic graft injury, as measured by 2-year eGFR 
2. Each of the following: 
a) Inflammatory gene expression profiles 
b) Frequency of donor reactive T-cells 
c) Frequency and function of Treg 
d) Proportion of subjects with de novo DSA within 24 months 
e) Fibrogenic gene expression profiles 
f) Amount of peritubular capillary loss by histology 
Ancillary Endpoints 
1. Percentage of predicted prednisone bottle openings as measured by a medication 
event monitoring system (MEMS®) in the first 3 months post-transplantation 
2. Standard deviation of the monthly tacrolimus trough levels from 6 months post- 
transplantation to 2 years post-transplantation 
 
3.4. Stratification, Randomization, and Blinding/Masking 
Subjects will be randomized 1:1 through a computer program administered by the data 
coordinating center to either the treatment (infliximab) or control (saline) arm in a blinded fashion 
and using a standard randomization process. Only the study pharmacist at each center will be 
unblinded. Randomization will be stratified by enrollment site. 


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Blinding 
This is a double-blinded study; therefore, medication assignments will be unknown to the study 
participants as well as to the site clinical personnel. Only the site research pharmacist will have 
access to the unblinded randomization assignment and schedule for that site. In the event that 
the subject undergoes a life-threatening infusion reaction, then the study subject and the treating 
physician will be unblinded to treatment assignment. Safety events that do not occur during an 
infusion of the study drug, but that in the opinion of the investigator cannot be adequately treated 
without knowledge of the group assignment can also be cause for unblinding. IND safety reports 
will be reported to the FDA, DSMB, and IRBs in an unblinded fashion. 
Unblinding Authorization 
Emergency unblinding of a participant for safety purposes is to be handled through the site 
Investigators, the NIAID medical monitor, and the site pharmacist. Whenever possible the NIAID 
medical monitor should be notified prior to and involved in the decision to unblind. In all cases, 
including when the medical monitor is not notified prior to the decision to unblind, prompt 
notification and reporting is required. Except in the case of a life-threatening infusion reaction, a 
request to unblind a study subject should be based in the belief that knowledge of the treatment 
assignment is necessary in order to treat the patient appropriately. In the case of a life- 
threatening infusion reaction every effort should be made to contact the NIAID medical monitor 
prior to the unblinding, however ultimately the site Investigator must act in the study subject’s best 
interest. 
Reporting Unblinding Events 
Any unblinding event will require a full written report. The report should include 1) a brief 
description of the medical events which led to the decision to unblind, 2) the name of medical 
monitor who was notified and the date and time of notification, and 3) the justification for 
unblinding the subject. If the unblinding occurred in a situation other than the infusion of the study 
drug, the report should indicate how knowledge of the treatment assignment was expected to 
influence therapeutic decisions. All unblinding information will be reported to the DSMB and will 
be included in the final study report to the FDA. 
During site visits, the site monitor must verify that the DAIT NIAID medical monitor of the trial was 
notified and that a written account (described above) was completed. 


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4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
Our intention is to recruit patients at moderately high risk for DGF, acute rejection and, poorer 
long-term graft function and survival. This strategy is based on the notion that an effective 
intervention in a moderately high-risk population will is more likely to improve outcomes than in 
low risk patients. On the other hand, limiting the study to very high-risk patients could hamper 
enrollment and reduce the generalizability of the study’s results. Study enrollment will be limited 
to male and female adult recipients of all races and ethnicities that received HLA mismatched 
deceased donor kidney-only transplants. The inclusion criteria are based on the Kidney Donor 
Profile Index. In this new allocation scheme KDPI <20 will be the best kidneys which we want to 
avoid for this study. By setting KDPI > 20, and by restricting our study to adults, we expect mean 
KDPI to be 50-60 and average CIT >20hrs. Excluding KDPI >95 will exclude the highest risk kidneys 
and those most likely to go to oldest (e.g. octogenarians) recipients, a population that differs from 
the majority of transplants recipients and which we do not feel are appropriate for this study due 
to a) higher infectious risks from over immunosuppression) and b) are least likely to benefit 
because of poor kidneys. 
 
 
 
4.2. Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants: 
1. Adult (>18 years of age) male and female recipients (all races and ethnicities) 
2. Subject must be able to understand and provide consent 
3. Recipients of deceased donor kidney transplants (including re-transplants) 
4. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and current sera as 
determined by each participating study center. 
5. Donor kidneys from deceased donors and donors after cardiac death (DCD) with Kidney 
Donor Profile Indices (KDPI) ranging from >20 to <95 
6. Female participants of childbearing potential must have a negative pregnancy test upon 
study entry 


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7. Patients must have a negative test result for latent tuberculosis (TB) infection (PPD, 
QuantiFERON, ELISPOT). 
Subjects who have a negative test result for latent TB infection within 1 year of transplant 
date are eligible for enrollment and no further action is required. 
Subjects who have a negative test for latent TB infection that is greater than 1 year old 
are eligible for enrollment but are required to have a repeat test prior to transplantation. 
Samples for testing latent TB infection can be obtained during the hospital admission for 
the transplant but must be collected prior to the initiation of immunosuppression and prior 
to transplant. The results of this repeat test will determine the next step. 
• 
If the test is negative, no further action is required 
• 
If the test is positive, lost, indeterminant or unavailable the subject must be treated 
for latent TB infection (if the subject is enrolled, received study drug/placebo and 
transplanted). 
o Treatment for latent TB infection is required for all in this group. 
o The treatment regimen (including the specific drug, dose and duration of 
treatment) will be determined by the local Infectious Disease team. 
• 
If the subject has no latent TB testing available, then the subject cannot be 
enrolled 
Refer to Section 8.1.1 for additional information. 
4.3. Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study 
participants: 
1. Inability or unwillingness of a participant to give written informed consent or comply 
with study protocol 
2. Recipients of living donor transplants 
3. Presence of other transplanted solid organs (heart, lung, liver, pancreas, small 
intestines) or co-transplanted organ 
4. HIV+ recipients 
5. EBV IgG negative recipients 
6. Hepatitis B surface antigen positive kidney transplant recipients 
7. Hepatitis B core antibody positive kidney transplant recipients 
8. Hepatitis B negative kidney transplant recipients that receive transplants from 
Hepatitis B core antibody positive donor 
9. Hepatitis C Virus positive (HCV+) patients who are either untreated or have f ailed 
to demonstrate sustained viral remission for more than 12 months after anti-viral 
treatment 
10. Recipients with a previous history of invasive fungal infection 
11. Recipients with a previous history of active TB disease 
12. Recipients with a positive test for latent TB infection (PPD, QuantiFERON, ELISPOT), 
regardless of previous therapy. (Refer to Section 8 for additional information) 
13. Any severe infection at the time of transplantation. Severe infection determination will be 
made by the site investigator 
14. Severe congestive heart failure (NYHA functional class III or higher) 
15. Subjects with a known hypersensitivity to any murine/ mouse proteins. 
16. Subjects with any history of receiving any anti-TNF products 


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17. Subjects in whom rATG or infliximab might not be tolerated 
18. Subjects with less than 3000/mm3 WBC 
19. Subjects with less than 100,000/mm3  platelets counts 
20. Subjects with systolic blood pressure <100 mm/Hg 
21. Subjects with symptomatic orthostatic hypotension or currently requiring Midodrine 
for blood pressure support 
22. Subjects from or who have traveled to endemic areas with a history of active histoplasmosis 
or with a chest x-ray consistent with previous active histoplasmosis (no serological testing 
required). Endemic regions determined by site based on local standard of care. 
23. Subjects currently or formerly residing in regions of the US that are highly endemic for 
coccidioidomycosis, and who have a positive serologic test for coccidioidomycosis. 
Endemic regions determined by site based on local standard of care.* 
* (Subjects currently or formerly residing in regions of the US that are highly endemic for 
coccidioidomycosis, and who have a negative pre-transplant serologic test for 
coccidioidomycosis are eligible for enrollment only if they receive fluconazole 200 
mg/day for the duration of the study. Serologic testing for coccidioidomycosis is only 
required for subjects that currently or formerly resided in regions that are highly endemic 
for coccidioidomycosis, per the site’s standard of care.) 
24. Recipients are excluded if the local site decides to treat the recipient with fluconazole 
because of diagnosis or suspicion of fungal infection the donor. 
25. Subjects that receive IVIG treatment within 3 months of transplant or planned IVIG 
treatment peritransplant. 
26. Use of an investigational agent within 4-weeks prior to study entry 
 
 
Figure1. Guide to Areas Endemic for Histoplasmosis and Coccidioidomycosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T 


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Areas Endemic for Coccidioidomycosis 
 
 
 
4.4. Selection of Clinical Sites/Labs 
Patients will be enrolled at 15 sites within our consortium (US and Canada). Thirteen domestic US 
sites: Barnes/Jewish Hospital/Washington University St Louis Mo, University Hospitals Case Medical 
Center, Cleveland OH, Cleveland Clinic, Cleveland, OH, Emory University Hospital, Atlanta GA, 
Mount Sinai Hospital NY, NY, University of California Los Angeles, Los Angeles, CA, University of 
California San Francisco, San Francisco, CA, University of Michigan Medical Center, Ann Arbor, 
MI, Yale New Haven Hospital, New Haven, CT, University of Alabama, Birmingham, AL , University 
of Wisconsin, Madison, WI, the University of Maryland, Baltimore, MD and Johns Hopkins University, 
Baltimore, MD. University of Manitoba, Winnipeg, in Manitoba, Canada and Toronto General 
Hospital in Ontario, Canada are the only international sites participating in this protocol. 
Additional clinical sites may be recruited if enrollment is lower than anticipated. 
The core laboratories that will be used in the study are the following: the Cleveland Clinic, 
Cleveland, OH, GFR core laboratory (Emilio Poggio, PI) will be the serum creatinine core, 
pathology analyses of graft tissue will be performed at the Pathology core lab at University of 
Manitoba at Winnipeg (Ian Gibson, PI). Anti-HLA antibody testing will occur at the core HLA lab 
at the University of Manitoba at Winnipeg (Peter Nickerson, PI). Mechanistic studies will be 
performed at 2 additional core laboratories at the Cleveland Clinic, Cleveland OH (Robert 
Fairchild, PI) and the Icahn School of Medicine at Mount Sinai, NY, NY (Peter Heeger, PI). 


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5. Known and Potential Risks and Benefits to Participants 
5.1. Risks of Investigational Product, Remicade® (Infliximab) 
According to the package insert, the most common side effects of infliximab (occurring in > 10% 
of patients) are infections, infusion-related reactions, headache, and abdominal pain. In clinical 
trials, infections occurred in 36% of patients receiving infliximab versus 25% of patients receiving 
placebo. The most common infections were upper respiratory tract infections. Rare but serious 
infections include reactivation of latent tuberculosis, invasive fungal infections, and reactivation 
of hepatitis B. Approximately 18% of patients experience infusion reactions, including fever and 
chills (3%) and either chest pain, hypotension or hypertension (1%). Rare anaphylactic reactions 
have been reported. Other rare but serious side effects include malignancy (including lymphoma 
and non-melanoma skin cancers), hepatotoxicity, worsening of pre-existing heart f ailure, 
cytopenias, demyelination syndrome, and a lupus like syndrome (approximately 20% of patients 
develop new anti-dsDNA antibodies but symptoms of lupus are rare). Most of the side effects 
reported above occurred in patients receiving multiple doses of infliximab. Subjects will receive 
one dose of infliximab in this study. The presence of active infection is a contraindication to 
administering the drug. 
Adverse effects during administration of Remicade® (infliximab) have included flu-like symptoms, 
headache, dyspnea, hypotension, transient fever, chills, gastrointestinal symptoms, and skin 
rashes. Anaphylaxis might occur at any time during REMICADE® infusion. Approximately 20% of 
REMICADE®-treated patients in all clinical trials experienced an infusion reaction compared with 
10% of placebo-treated patients. Prior to infusion with REMICADE®, pre-medication will be 
administered to participants. Pre-medication will include antihistamines (anti-H1 +/- anti-H2) and 
acetaminophen. 
During infusion, mild to moderate infusion reactions may improve following slowing or suspension 
of the infusion, and upon resolution of the reaction, reinitiating at a lower infusion rate and/or 
therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For 
patients that do not tolerate the infusion following these interventions, REMICADE® should be 
discontinued. 
During or following infusion, patients who have severe infusion-related hypersensitivity reactions 
should be discontinued from further REMICADE® treatment. The signs and symptoms of the 
reaction should dictate the management of severe infusion reactions. 
REMICADE® at doses >5 mg/kg should not be administered to participants with moderate to 
severe heart failure. Participants in this protocol will receive one 3mg/kg dose of REMICADE®. In 
a randomized study evaluating REMICADE® in patients with moderate to severe heart failure 
(New York Heart Association [NYHA] Functional Class III/IV), REMICADE® treatment at 10 mg/kg 
was associated with an increased incidence of death and hospitalization due to worsening heart 
failure [see product labeling: Warnings and Precautions and Adverse Reactions]. 
REMICADE® should not be re-administered to participants who have experienced a severe 
hypersensitivity reaction to REMICADE®. Additionally, REMICADE® should not be administered to 
participants with known hypersensitivity to inactive components of the product or to any murine 
proteins. 


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Serious Infections 
Patients treated with REMICADE® are at increased risk for developing serious infections involving 
various organ systems and sites that may lead to hospitalization or death. 
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic 
organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, 
legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers. 
Patients have frequently presented with disseminated rather than localized disease. 
Treatment with REMICADE® should not be initiated in patients with an active infection, including 
clinically important localized infections. Patients greater than 65 years of age, patients with co- 
morbid conditions and/or patients taking concomitant immunosuppressive medications such as 
corticosteroids or methotrexate may be at greater risk of infection. 
The risks and benefits of treatment should be considered prior to initiating therapy in patients: 
• With chronic or recurrent infection 
• Who have been exposed to tuberculosis 
• With a history of an opportunistic infection 
• Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as 
histoplasmosis, coccidioidomycosis, or blastomycosis 
• With underlying conditions that may predispose them to infection. 
Tuberculosis 
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in 
patients receiving REMICADE®, including patients who have previously received treatment for 
latent or active tuberculosis. Patients should be evaluated for tuberculosis risk f actors and tested 
for latent infection prior to initiating REMICADE® and periodically during therapy. 
 
Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been 
shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater 
with tuberculin skin testing should be considered a positive test result when assessing if treatment 
for latent tuberculosis is needed prior to initiating REMICADE®, even for patients previously 
vaccinated with Bacillus Calmette-Guerin (BCG). 
Anti-tuberculosis therapy should also be considered prior to initiation of REMICADE® in patients 
with a past history of latent or active tuberculosis in whom an adequate course of treatment 
cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk 
factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of 
tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is 
appropriate for an individual patient. 
Tuberculosis should be strongly considered in patients who develop a new infection during 
REMICADE® treatment, especially in patients who have previously or recently traveled to 
countries with a high prevalence of tuberculosis, or who have had close contact with a person 
with active tuberculosis. 
Monitoring 
Patients should be closely monitored for the development of signs and symptoms of infection 
during and after treatment with REMICADE®, including the development of tuberculosis in 
patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for 
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REMICADE® should be discontinued if a patient develops a serious infection or sepsis. A patient 
who develops a new infection during treatment with REMICADE® should be closely monitored, 
undergo a prompt and complete diagnostic workup appropriate for an immunocompromised 
patient, and appropriate antimicrobial therapy should be initiated. 
 
Invasive Fungal Infections 
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection 
should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal 
therapy should be considered while a diagnostic workup is being performed. Antigen and 
antibody testing for histoplasmosis may be negative in some patients with active infection. 
When feasible, the decision to administer empiric antifungal therapy in these patients should be 
made in consultation with a physician with expertise in the diagnosis and treatment of invasive 
fungal infections and should take into account both the risk for severe fungal infection and the 
risks of antifungal therapy 
Malignancies 
Malignancies, some f atal, have been reported among children, adolescents and young adults 
who received treatment with TNF-blocking agents (initiation of therapy > 18 years of age), 
including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin’s 
and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including 
rare malignancies that are usually associated with immunosuppression and malignancies that are 
not usually observed in children and adolescents. The malignancies occurred after a median of 
30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients 
were receiving concomitant immunosuppressive medications. These cases were reported post- 
marketing and are derived from a variety of sources, including registries and spontaneous post- 
marketing reports. 
 
Lymphomas 
In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma 
have been observed among patients receiving a TNF blocker compared with control patients. In 
the controlled and open-label portions of REMICADE® clinical trials, 5 patients developed 
lymphomas among 5707 patients treated with REMICADE® (median duration of follow-up 1.0 
years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In 
rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 10 patient- 
years of follow-up, which is approximately three-fold higher than expected in the general 
population. In the combined clinical trial population for rheumatoid arthritis, Crohn’s disease, 
psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were 
observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four- 
fold higher than expected in the general population. Patients with Crohn’s disease, rheumatoid 
arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic 
exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the 
general population for the development of lymphoma, even in the absence of TNF-blocking 
therapy. Cases of acute and chronic leukemia have been reported with post-marketing TNF- 
blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker 
therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the 
general population for the development of leukemia. 
 
Hepatosplenic T-cell lymphoma (HSTCL) 
Post marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, 
have been reported in patients treated with TNF blockers including REMICADE®. These cases have 


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had a very aggressive disease course and have been fatal. All reported REMICADE® cases have 
occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent 
and 
young 
adult 
males. 
All 
of 
these 
patients 
had 
received 
treatment 
with 
the 
immunosuppressants azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or 
prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to REMICADE® or 
REMICADE® in combination with these other immunosuppressive medications. When treating 
patients with inflammatory bowel disease, particularly in adolescents and young adults, 
consideration 
of 
whether 
to 
use 
REMICADE® 
alone 
or 
in 
combination 
with 
other 
immunosuppressive medications should take into account a possibility that there is a higher risk of 
HSTCL with combination therapy versus an observed increased risk of immunogenicity and 
hypersensitivity reactions with REMICADE® monotherapy from the clinical trial. 
 
Skin cancer 
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker 
therapy, including REMICADE® [see Adverse Reactions (6.2)]. Periodic skin examination is 
recommended for all patients, particularly those with risk factors for skin cancer. 
Other Malignancies 
 
In the controlled portions of clinical trials of some TNF-blocking agents including REMICADE®, more 
malignancies (excluding lymphoma and non-melanoma skin cancer [NMSC]) have been 
observed in patients receiving those TNF-blockers compared with control patients. During the 
controlled portions of REMICADE® trials in patients with moderately to severely active rheumatoid 
arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque 
psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) 
among 4019 REMICADE®-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 
patient-years among REMICADE®-treated patients vs. a rate of 0.11/100 patient-years among 
control patients), with median duration of follow-up 0.5 years for REMICADE®-treated patients 
and 0.4 years for control patients. Of these, the most common malignancies were breast, 
colorectal, and melanoma. The rate of malignancies among REMICADE®-treated patients was 
similar to that expected in the general population whereas the rate in control patients was lower 
than expected. 
 
In a clinical trial exploring the use of REMICADE® in patients with moderate to severe chronic 
obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and 
neck origin, were reported in REMICADE®-treated patients compared with control patients. All 
patients had a history of heavy smoking [see Adverse Reactions (6.1)]. Prescribers should exercise 
caution when considering the use of REMICADE® in patients with moderate to severe COPD. 
 
Psoriasis patients should be monitored for non-melanoma skin cancers (NMSCs), particularly those 
patients who have had prior prolonged phototherapy treatment. In the maintenance portion of 
clinical trials for REMICADE®, NMSCs were more common in patients with previous phototherapy. 
The potential role of TNF-blocking therapy in the development of malignancies is not known [see 
Adverse Reactions (6.1)]. Rates in clinical trials for REMICADE® cannot be compared to rates in 
clinical trials of other TNF-blockers and may not predict rates observed in a broader patient 
population. Caution should be exercised in considering REMICADE® treatment in patients with a 
history of malignancy or in continuing treatment in patients who develop malignancy while 
receiving REMICADE®. 


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Hepatitis B Virus Reactivation 
Use of TNF blockers, including REMICADE®, has been associated with reactivation of hepatitis B 
virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation 
occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports 
have occurred in patients concomitantly receiving other medications that suppress the immune 
system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection 
before initiating TNF blocker therapy, including REMICADE®. For patients who test positive for 
hepatitis B surf ace antigen, consultation with a physician with expertise in the treatment of 
hepatitis B is recommended. Adequate data are not available on the safety or efficacy of 
treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker 
therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with 
TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection 
throughout therapy and for several months following termination of therapy. In patients who 
develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate 
supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV 
reactivation is controlled is not known. Therefore, prescribers should exercise caution when 
considering resumption of TNF blocker therapy in this situation and monitor patients closely. 
 
Hepatotoxicity 
Severe hepatic reactions, including acute liver f ailure, jaundice, hepatitis and cholestasis, have 
been reported rarely in post-marketing data in patients receiving REMICADE®. Autoimmune 
hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred 
between 2 weeks to more than 1 year after initiation of REMICADE®; elevations in hepatic 
aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. 
Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or 
signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or 
marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® 
should be discontinued, and a thorough investigation of the abnormality should be undertaken. 
In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients 
receiving REMICADE® without progression to severe hepatic injury. 
 
Patients with Heart Failure 
REMICADE® has been associated with adverse outcomes in patients with heart failure, and should 
be used in patients with heart f ailure only after consideration of other treatment options. The 
results of a randomized study evaluating the use of REMICADE® in patients with heart failure 
(NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg 
REMICADE®, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 
mg/kg. There have been post-marketing reports of worsening heart failure, with and without 
identifiable precipitating f actors, in patients taking REMICADE®. There have also been rare post- 
marketing reports of new onset heart failure, including heart failure in patients without known pre- 
existing cardiovascular disease. Some of these patients have been under 50 years of age. If a 
decision is made to administer REMICADE® to patients with heart f ailure, they should be closely 
monitored during therapy, and REMICADE® should be discontinued if new or worsening symptoms 
of heart failure appear. 
 
Hematologic Reactions 
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a f atal 
outcome, have been reported in patients receiving REMICADE®. The causal relationship to 
REMICADE® therapy remains unclear. Although no high-risk group(s) has been identified, caution 


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should be exercised in patients being treated with REMICADE® who have ongoing or a history of 
significant hematologic abnormalities. All patients should be advised to seek immediate medical 
attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., 
persistent fever) while on REMICADE®. Discontinuation of REMICADE® therapy should be 
considered in patients who develop significant hematologic abnormalities. 
 
Hypersensitivity 
REMICADE® has been associated with hypersensitivity reactions that vary in their time of onset 
and required hospitalization in some cases. Most hypersensitivity reactions, which include 
urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of REMICADE® 
infusion. However, in some cases, serum sickness-like reactions have been observed in patients 
after initial REMICADE® therapy (i.e., as early as after the second dose), and when REMICADE® 
therapy was reinstituted following an extended period without REMICADE® treatment. Symptoms 
associated with these reactions include fever, rash, headache, sore throat, myalgias, 
polyarthralgias, hand and f acial edema and/or dysphagia. These reactions were associated with 
a marked increase in antibodies to infliximab, loss of detectable serum concentrations of 
infliximab, and possible loss of drug efficacy. 
 
REMICADE® should be discontinued for severe hypersensitivity reactions. Medications for the 
treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids 
and/or epinephrine) should be available for immediate use in the event of a reaction. 
In rheumatoid arthritis, Crohn’s disease and psoriasis clinical trials, re-administration of REMICADE® 
after a period of no treatment resulted in a higher incidence of infusion reactions relative to 
regular maintenance treatment. In general, the benefit-risk of re-administration of REMICADE® 
after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, 
should be carefully considered. In the case where REMICADE® maintenance therapy for psoriasis 
is interrupted, REMICADE® should be reinitiated as a single dose followed by maintenance 
therapy. 
 
Neurologic Reactions 
REMICADE® and other agents that inhibit TNF have been associated in rare cases with CNS 
manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms 
and/or radiographic evidence of central nervous system demyelinating disorders, including 
multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain- 
Barre syndrome. Prescribers should exercise caution in considering the use of REMICADE® in 
patients with these neurologic disorders and should consider discontinuation of REMICADE® if 
these disorders develop. 
5.2. Risks of Investigational Product or Intervention cited in Medical Literature 
Use of infliximab has been associated with impaired wound healing. There are also rare reports of 
autoimmune hepatitis. 
5.3. Risks of Other Protocol Specified Medications 
Risks of Thymoglobulin 
Thymoglobulin is indicated for the treatment of renal transplant acute rejection in conjunction 
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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). 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, 
vasoactive 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. 
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. 
 
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). 
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. 
Risks of Methylprednisolone and Prednisone 
Adverse effects of corticosteroid therapy associated with short-term therapy 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. Long-term use of prednisone may be associated with hypertension, 
hyperlipidemia, weight gain with Cushingoid features, osteopenia, and skin changes including 
acne and easy bruisability. 
Risks of Mycophenolic Acid Derivative (either Mycophenolate Mofetil/MMF or 
Enteric-coated Mycophenolic Acid/MPA) 
Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium are approved (in 
combination with cyclosporine and corticosteroids) as immunosuppressive agents for renal, 


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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, hypercholesterolemia, hypokalemia, hyperglycemia, increased creatinine 
and BUN, cough, hypomagnesaemia, diarrhea, constipation, nausea, vomiting, respiratory 
infection, dyspnea, lung disorder, pleural effusion, tremor and insomnia. The side effect profile of 
enteric-coated mycophenolate sodium is similar to those of MMF. 
 
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 (including spontaneous abortion in the first trimester 
and can cause congenital malformations in the offspring of women who are treated during 
pregnancy) when administered to a pregnant woman. Cases of progressive multifocal 
leukoencephalopathy (PML), sometimes fatal and pure red cell aplasia have been reported 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. 
Risks of Tacrolimus 
Side effects of 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. 
Risk of Prophylactic INH Therapy for Latent TB Infection 
Subjects with a positive test for Latent TB Infection should receive prophylactic therapy. 
Hepatotoxicity has been seen in 10-20% of patients that receive INH therapy. Liver function tests 
should be monitored to determine the need for reduction or cessation of the prescribed dose. 
Allergic reactions such as skin rash can occur but are uncommon. Alcohol should be avoided 
during treatment with INH. 
5.4. Risks of Study Procedures 
Risks of Blood Draw (Venipuncture) 
The amount of blood that may be drawn from adult subjects for research purposes will not exceed 
10.5mL/kg or 550 mL; 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 discomf ort 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 


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Risk of Protocol-Directed Biopsy 
A renal transplant biopsy will be performed for this protocol according to the following schedule: 
 
 
Protocol-Directed Biopsies 
1.  Pre-implantation biopsy 
Day of Transplant/Visit 01 
2.  3 month surveillance biopsy 
Month 3 post-transplant/ Visit 10 
3.  24 month biopsy 
Month 24 post-transplant/Visit 14 
 
 
There is a risk of bleeding associated with percutaneous 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. Potential Benefits 
This study may show that infliximab, in combination with rATG, results in a decreased incidence 
and severity of ischemia reperfusion injury and delayed graft function, a decreased incidence of 
acute rejection, higher glomerular filtration rates, and increased graft survival rate compared to 
patients receiving placebo. The mechanistic studies may delineate the immune mechanisms 
underlying these potentially beneficial effects of infliximab, but will also add to a more general 
understanding of biomarkers and their role in predicting outcomes in kidney transplant recipients. 
The results of this study could influence future care of transplant patients. Participants in this study 
may benefit from the close follow-up dictated by the study protocol. 


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6. Investigational Agents: 
The investigational agents for this trial are Remicade® (infliximab) and placebo (0.9% Sterile 
Normal Saline). Details describing the product labeling, supply, storage, monitoring and 
accountability are outlined in the Investigational Pharmacy Manual. 
6.1. Investigational Agent: Remicade® (Infliximab) 
The investigational agent that will be used in this study is Remicade® (Infliximab). Remicade® 
(infliximab) is manufactured by Janssen Biotech, Inc. Janssen Biotech, Inc. is part of the Janssen 
Pharmaceutical Companies of Johnson & Johnson. Remicade® is a drug approved by both FDA 
and Health Canada. Please refer to the product labeling for known and potential risks to human 
participants.  The study therapy regimen for each arm is outlined in the table below. 
Table1. Study Therapy Regimen 
 
Experimental 
Arm 
• 
Remicade® (Infliximab) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o Generic equivalent 
o An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their 
generic equivalents) 
• 
Methylprednisolone or generic equivalent 
Control 
Arm 
• 
Placebo (Normal Saline for Injection) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o Generic equivalent 
o An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their 
generic equivalents) 
• 
Methylprednisolone or generic equivalent 
Please refer to section 8.0 Study Procedures for additional dosing and administration details. 
 
Remicade® (Infliximab) Indications and Usage 
Remicade® (infliximab) is a tumor necrosis factor (TNF) blocker indicated for treatment of Crohn’s 
Disease, ulcerative colitis, rheumatoid arthritis in combination with methotrexate, ankylosing 
spondylitis, psoriatic arthritis, and plaque psoriasis. Use of Remicade® (infliximab) in the setting of 
solid organ transplantation as a TNF blocker has not been established, and thus is not approved 
by Health Authorities for use for this indication. 
Remicade® (Infliximab) Formulation, Packaging, Labeling and Storage 
Infliximab, the active ingredient in REMICADE®, is a chimeric IgG1κ monoclonal antibody 
(composed of human constant and murine variable regions) specific for human tumor necrosis 
factor-alpha (TNFα). It has a molecular weight of approximately 149.1 kilodaltons. Infliximab is 
produced by a recombinant cell line cultured by continuous perfusion and is purified by a series 
of steps that includes measures to inactivate and remove viruses. 
Remicade® is supplied as a 100mg vial (100mg lyophilized infliximab in a 20mL vial for injection). 
Remicade® is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following 
reconstitution with 10 mL of Sterile Water for Injection, USP, and the resulting pH is approximately 
7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 


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mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium phosphate, 
dihydrate. No preservatives are present. 
Each Remicade® 20mL vial is individually packaged in a carton. Remicade® is supplied in an 
accumulator carton containing 10 vials. Each single dose vial contains 100mg of infliximab for 
final concentration volume of 10mL. 
Remicade® will be purchased using funds from the Investigator grant (U01-AI063594) and 
distributed by EMINENT Services Corporation (Frederick, MD). 
Storage and Stability 
REMICADE® must be refrigerated at 2° C to 8° C (36° F to 46° F). Do not use REMICADE® beyond 
the expiration date (Exp) located on the carton and the vial. This product contains no 
preservative. 
Dosage, Preparation and Administration 
Dosage and Administration 
Remicade® (infliximab)/placebo will be given as a single 3mg/kg intravenous pre-perfusion dose, 
beginning after initiation of the corticosteroid infusion. Actual body weight will be used to 
calculate the dose. Remicade®/placebo must be given through a dedicated intravenous line. Do 
not infuse Remicade® concomitantly with another IV solution or IV medication. 
• 
If the subject does not experience an adverse event during the first 30 minutes of the 
infusion, then Thymoglobulin® infusion will be initiated through a separate line from the 
Remicade® infusion. 
• 
The Remicade®/placebo infusion should be administered over a period of greater than 2 
hours and may continue beyond reperfusion (unclamping of the arterial anastomosis). 
• 
Whenever possible, Remicade®/Placebo and rabbit ATG should be administered through 
two separate IV lines. 
• 
If only a single IV line with a single port is available, the rabbit ATG infusion should begin 
only after the Remicade®/Placebo infusion has stopped and only after the line has been 
flushed with saline. 
• 
If the only available venous access is a multiport central venous catheter, rabbit ATG can 
be started 30 minutes after initiation of Remicade®/Placebo through a separate port, but 
only if that catheter has multiple exit ports. 
Pre-medications may attenuate infusion-related events. See the list of pre-medications in the 
table 
below. 
Please 
refer 
to 
the 
Investigational 
Pharmacy 
Manual 
for 
additional 
Remicade®/Placebo dosage, preparation, administration and storage details. 
Participants will receive a standard of care dose of corticosteroids prior to transplantation. 
Table 2. Pre-Medications-Experimental Arm 
Pre-Medications-Experimental Arm 
Acetaminophen 
Antihistamines: 
Claritin (Loratadine) or Benadryl (Diphenhydramine) 
Methylprednisolone or its Generic Equivalent 
Please refer to Section 8 Study Procedures for additional dosing and administration details. 


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Preparation 
Remicade® should be prepared by the site pharmacist using appropriate aseptic techniques. 
Discard any unused portion left in the vial. Parenteral drug products should be inspected visually 
for particulate matter and discoloration prior to administration. 
 
Remicade® is intended for use under the guidance and supervision of a physician. The 
reconstituted infusion solution should be prepared by a trained medical professional using aseptic 
technique by the following procedure: 
1. Calculate the dose, total volume of reconstituted REMICADE® solution required and the 
number of REMICADE® vials needed. Each REMICADE® vial contains 100 mg of the 
infliximab antibody. 
2. Reconstitute each REMICADE® vial with 10 mL of Sterile Water for Injection, USP, using a 
syringe equipped with a 21-gauge or smaller needle as follows: 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 Sterile Water for Injection, 
USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the 
lyophilized powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the 
solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 
minutes. The solution should be colorless to light yellow and opalescent, and the solution 
may develop a few translucent particles, as infliximab is a protein. Do not use if the 
lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign 
particles are present. 
3. Dilute the total volume of the reconstituted REMICADE® solution dose to 250 mL with sterile 
0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of 
reconstituted REMICADE® from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or 
bag. Slowly add the total volume of reconstituted REMICADE® solution to the 250 mL 
infusion bottle or bag. Gently mix. The resulting infusion concentration should range 
between 0.4 mg/mL and 4 mg/mL. NS. In order to maintain the blinding of the study 
treatment, amber bag/bottle covers will be used to administer both infliximab and 
placebo. See the pharmacy manual for additional details. 
4. The REMICADE® infusion should begin within 3 hours of reconstitution and dilution. The 
infusion must be administered over a period of not less than 2 hours and must use an 
infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 
µm or less). The vials do not contain antibacterial preservatives. Therefore, any unused 
portion of the infusion solution should not be stored for reuse. 
5. No physical biochemical compatibility studies have been conducted to evaluate the co- 
administration of REMICADE® with other agents. REMICADE® should not be infused 
concomitantly in the same intravenous line with other agents. 
6. Parenteral drug products should be inspected visually before and after reconstitution for 
particulate matter and discoloration prior to administration, whenever solution and 
container permit. If visibly opaque particles, discoloration or other foreign particulates are 
observed, the solution should not be used. 
Contraindications 
REMICADE® at doses >5 mg/kg should not be administered to patients with moderate to severe 
heart f ailure. In a randomized study evaluating REMICADE® in patients with moderate to severe 
heart failure (New York Heart Association [NYHA] Functional Class III/IV), REMICADE® treatment at 
10 mg/kg was associated with an increased incidence of death and hospitalization due to 
worsening heart failure [Refer to the product labeling]. 


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REMICADE® should not be re-administered to patients who have experienced a severe 
hypersensitivity reaction to REMICADE®. Additionally, REMICADE® should not be administered to 
patients with known hypersensitivity to inactive components of the product or to any murine 
proteins. 
Drug Interactions 
Use with Anakinra or Abatacept 
An increased risk of  serious infections was seen in clinical studies of other TNFα-blocking agents 
used in combination with anakinra or abatacept, with no added clinical benefit. Because of the 
nature of the adverse reactions seen with these combinations with TNF-blocker therapy, similar 
toxicities may also result from the combination of anakinra or abatacept with other TNFα-blocking 
agents. Therefore, the combination of REMICADE® and anakinra or abatacept is not 
recommended [Refer to the product labeling]. 
 
Use with Tocilizumab 
The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including 
REMICADE®, should be avoided because of the possibility of increased immunosuppression and 
increased risk of infection. 
Use with Other Biological Therapeutics 
The combination of REMICADE® with other biological therapeutics used to treat the same 
conditions as REMICADE® is not recommended [Refer to the product labeling]. 
 
Methotrexate (MTX) and Other Concomitant Medications 
Specific drug interaction studies, including interactions with MTX, have not been conducted. The 
majority of patients in rheumatoid arthritis or Crohn’s disease clinical studies received one or more 
concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were 
non-steroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. 
Concomitant Crohn’s disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA 
and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in 
approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant 
MTX use may decrease the incidence of anti-infliximab antibody production and increase 
infliximab concentrations. 
 
Immunosuppressive Medications 
Patients with Crohn’s disease who received immunosuppressive medication tended to 
experience fewer infusion reactions compared to patients who were not. [Refer to the product 
labeling]. Serum infliximab concentrations appeared to be unaffected by baseline use of 
medications for the treatment of Crohn’s disease including corticosteroids, antibiotics 
(metronidazole or ciprofloxacin) and aminosalicylates. 
 
Cytochrome P450 Substrates 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, 
IL-1, IL-6, IL-10, and IFN) during chronic inflammation. Therefore, it is expected that for a molecule 
that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be 
normalized. Upon initiation or discontinuation of REMICADE® in patients being treated with 
CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warf arin) or 
drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose 
of the drug product may be adjusted as needed. 


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Live Vaccines/ Therapeutic Infectious Agents 
It is recommended that live vaccines not be given concurrently with REMICADE® [Refer to the 
product labeling]. It is recommended that therapeutic infectious agents not be given 
concurrently with REMICADE®. 
Special Populations Use 
Pregnancy 
Pregnancy Category B- It is not known whether REMICADE® can cause fetal harm when 
administered to a pregnant woman or can affect reproduction capacity. REMICADE® should be 
given to a pregnant woman only if clearly needed. Because infliximab does not cross-react with 
TNFα in species other than humans and chimpanzees, animal reproduction studies have not been 
conducted with REMICADE®. No evidence of maternal toxicity, embryotoxicity or teratogenicity 
was observed in a developmental toxicity study conducted in mice using an analogous antibody 
that selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in 
pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal 
pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects 
in animal reproduction studies. 
As with other IgG antibodies, REMICADE® crosses the placenta and has been detected up to 6 
months in the serum of infants born to female patients treated with REMICADE® during 
pregnancy. Consequently, these inf ants may be at increased risk of infection, and caution is 
advised in the administration of live vaccines to these infants [Refer to the product labeling] 
Nursing Mothers 
It is not known whether REMICADE® is excreted in human milk or absorbed systemically after 
ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because 
of the potential for adverse reactions in nursing inf ants from REMICADE®, women should not 
breast-feed their infants while taking REMICADE®. A decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to 
the mother. 
Infusion Supervision 
Remicade® will be administered in a hospital environment where full resuscitation f acilities are 
immediately available and under close supervision of the investigator or designated safety 
accessor. The intravenous infusion will be supervised by the clinical staff (i.e., clinical nurse, 
physician) at the participating institutions. A history of  each infusion and any adverse side effects 
will be recorded and reported to the Clinical Research Organization (CRO) using the appropriate 
case report forms. 
Vital signs (temperature, blood pressure, pulse, and respiratory rate) will be obtained prior to the 
start of each Remicade® infusion and every 15 minutes for the first hour of the infusion, every 30 
minutes until the end of the infusion, and every hour thereafter for a total of 3 hours after the 
infusion. After the infusion, the IV line should remain in the participant for at least 1 hour to enable 
the administration of drugs, if necessary. Additional vital signs may then be obtained as clinically 
indicated. 
6.2. Investigational Agent: Placebo 
Placebo is considered an investigational agent in this study. The placebo is 0.9% sterile normal 
saline for injection (0.9% NS). 
US sites will use only sterile normal saline that is produced by an FDA registered facility as 
designated by the presence of a National Drug Code (NDC) number on product labeling. 


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Canada sites will use only sterile normal saline that is associated with a valid DIN and is of 
compendial quality intended for human use. 
Product information including manufacturer, lot number, and expiration date will be captured in 
the pharmacy log at each clinical center. 
Dose, Preparation, Administration and Storage 
Dosage and Administration 
Placebo will be given as a single intravenous pre-perfusion dose, volume matched (250ml) to 
Remicade®, administered in the operating room. The infusion should be administered over a 
period of 2 hours or longer. Do not infuse placebo concomitantly with another IV solution or IV 
medication. Placebo should be given through a dedicated line. Placebo can be administered 
at the same time as Thymoglobulin as long as placebo is given in a separate, dedicated 
intravenous line. Pre-medications may attenuate infusion-related events. See Pre-Medications 
table 
below. 
Please 
refer 
to 
the 
Investigational 
Pharmacy 
Manual 
for 
additional 
Remicade®/Placebo dosage, preparation, administration and storage details. Participants will 
receive a standard of care dose of corticosteroids prior to transplantation. 
 
Table 3. Pre-Medications-Control Arm 
 
Pre-Medications-Control Arm 
Acetaminophen 
Antihistamines: 
Claritin (Loratadine) or Benadryl (Diphenhydramine) 
Methylprednisolone or its Generic Equivalent 
Please refer to section 8.0 Study Procedures for additional dosing and administration details. 
 
Preparation, Storage and Stability 
The Pharmacist of Record will prepare and label the placebo infusion bags (260mL bag) using site 
clinical stock 0.9% NS In order to maintain the blinding of the study treatment, amber bag/bottle 
cover will be used to administer both infliximab and placebo. See the pharmacy manual for 
additional details. Placebo will be prepared and stored using the standard procedures at each 
institution’s Investigational Pharmacy. Placebo should be prepared using appropriate aseptic 
techniques. 
Infusion Supervision 
Remicade® and Placebo will be administered in a hospital environment where full resuscitation 
facilities are immediately available and under close supervision of the investigator or designated 
safety accessor. The intravenous infusion will be supervised by the clinical staff (i.e., clinical nurse, 
physician) at the participating institutions. A history of each infusion and any adverse side effects 
will be recorded and reported to the Clinical Research Organization (CRO) using the appropriate 
case report forms. 
Vital signs (temperature, blood pressure, pulse, and respiratory rate) will be obtained prior to the 
start of each Placebo infusion and every 15 minutes for the first hour of the infusion, every 30 
minutes until the end of the infusion, and every hour thereafter for a total of 3 hours after the 
infusion. After the infusion, the IV line should remain in the participant for at least 1 hour to enable 


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the administration of drugs, if necessary. Additional vital signs may then be obtained as clinically 
indicated. 
6.3. Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) and Canadian regulations 
(C.05.012) the investigator will 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. 
The study site will maintain records for receipt, storage, use, and disposition. 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 investigational product will be available for inspection. 
Any partially used, expired, or product remaining at the end of the study may be destroyed 
according to the center’s standard operating center. If a center does not have an SOP for drug 
destruction, then the product will be returned to the CTOT drug distribution center for destruction. 
6.4. Toxicity Prevention and Management 
During infusion, mild to moderate infusion reactions may improve following slowing or suspension 
of the infusion, and upon resolution of the reaction, reinitiating at a lower infusion rate and/or 
therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For 
participants that do not tolerate the investigational agent following these interventions, the 
infusion should be discontinued. 
6.5. Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant if the participant has severe 
infusion-related hypersensitivity or an infusion related reaction. During or following infusion, 
participants who have severe infusion-related hypersensitivity reactions should be discontinued 
from further investigational agent administration. The management of severe infusion reactions 
should be dictated by the signs and symptoms of the reaction. 
Study therapy may also be prematurely discontinued for any participant if the investigator 
believes that the study treatment is no longer in the best interest of the participant, if the subject 
is judged non-compliant, or due to other safety concerns. Participants that prematurely 
discontinue the study therapy regimen will remain in the study until study closure. 


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7. Other Medications 
7.1. Concomitant Medications 
 
Protocol-Mandated Medications 
Study Therapy Regimen 
The study therapy regimen is outlined in the table below. 
Please refer to section 8.0 Study 
Procedures for additional dosing and administration details. 
 
Study Therapy Regimen 
Experimental 
Arm 
• 
Remicade® (Infliximab) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin, Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o 
Generic equivalent 
o 
An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their 
generic equivalents) 
• 
Methylprednisolone or generic equivalent 
Control 
Arm 
• 
Placebo (Normal Saline for Injection) 
• 
Thymoglobulin® (Anti-Thymocyte Globulin, Rabbit) 
• 
Tacrolimus (Prograf®) or one of the following: 
o 
Generic equivalent 
o 
An equivalent once-daily formulation of Tacrolimus 
• 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their 
generic equivalents) 
• 
Methylprednisolone or generic equivalent 
 
Other permitted concomitant medications 
Concomitant medications are not defined by the CTOT-19 study; this is defined by each centers 
standard of care. Information regarding Immunosuppressant use will be collected during study 
visits. Please refer to Appendix 1 (Schedule of Events) for additional details. 
7.2. Prophylactic Medications 
Infection Prophylaxis 
CMV Prophylaxis 
• 
Sero-Negative Donor and Recipient 
These subjects will not receive CMV prophylaxis mandated by the protocol. Treatment will be 
dictated by the standard of care at each site. 
• 
Sero-Positive Donor and Negative Recipient 
When tolerating PO or at discharge, subjects will receive Valganciclovir (Valcyte®) PO, 450 to 
900 mg QD. Dose adjusted according to renal function, for 6 months post- transplant as per 
local site standard of care. 
• 
Sero-Positive Recipient with donor that is either sero-positive or sero-negative 
When tolerating PO or at discharge, subjects will receive Valganciclovir (Valcyte®) PO, 450 to 
900 mg QD. Dose adjusted according to renal function, for 3 months post- transplant as per 
local site standard of care. 


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Table 4 below summarizes the protocol mandated CMV prophylaxis based on the CMV status of 
the donor and recipient prior to transplant. 
 
Table 4. Donor/Recipient CMV Status and Prophylaxis 
 
Donor 
CMV 
Recipient 
CMV 
CMV Prophylaxis 
+ 
- 
• When tolerating PO or at discharge, subjects will receive Valganciclovir 
(Valcyte*) PO, 450 to 900 mg QD. 
• Dose adjusted according to renal function, for 6 months post- transplant as 
per local site standard of care. 
- 
+ 
• 
When tolerating PO or at discharge, subjects will receive Valganciclovir 
(Valcyte*) PO, 450 to 900 mg QD. 
• 
Dose adjusted according to renal function, for 3 months post- transplant as 
per local site standard of care. 
+ 
+ 
• 
When tolerating PO or at discharge, subjects will receive Valganciclovir 
(Valcyte*) PO, 450 to 900 mg QD. 
• 
Dose adjusted according to renal function, for 3 months post- transplant as 
per local site standard of care. 
- 
- 
• 
These subjects will not receive CMV prophylaxis mandated by the 
protocol. Treatment will be dictated by the standard of care at each site. 
 
All sites will use PCR based assays to diagnose CMV. Treatment of symptomatic CMV disease will 
be treated per the local center standard of care. 
7.3. Prohibited Medications 
The use of any other Investigational Drugs is prohibited. Participants should not use an 
investigational agent within 4-weeks prior to study entry and for the duration of the protocol. 
7.4. Rescue Medications 
Subjects suspected of having a rejection episode on the basis of clinical signs, symptoms or on 
the basis of laboratory tests will have a renal ultrasound and will undergo a renal transplant biopsy. 
The local pathologist at the participating clinical site will make rejection diagnoses. A sample of 
blood, urine and a portion of the biopsy will be collected and sent to a CTOT-19 Core laboratory 
for mechanistic studies. 
Acute cellular rejection or acute humoral rejection (C4d+) detected on any biopsy will be treated 
per local practice. 


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8. Study Procedures 
8.1. Screening/Enrollment 
The research study will be explained in lay terms to each potential research participant. As part 
of the informed consent process outlined in CFR Title 21 Part 50 and ICH E6 GCP Guidance, the 
investigator or physician listed on the FDA 1572 or Investigator of Record Form will conduct a 
meeting with the study candidate to review all of  the required elements of informed consent. The 
potential participant will sign an informed consent form before undergoing any study procedures. 
After the informed consent has been signed and the participant meets entry criteria, the 
participant will be enrolled in the study. Once enrolled, the participant will be assigned a unique 
participant number. Participants enrolled in the study will be followed for approximately 24 
months after their transplant surgery. 
Testing and Prophylaxis for Latent TB Infection 
All enrolled subjects must have a negative test result for latent TB infection. Subjects who have a 
positive test result for latent TB infection at any time prior to enrollment are not eligible for 
enrollment, even if they completed a full course of treatment. Any subject with a history of active 
TB disease are not eligible for enrollment. 
All enrolled subjects should be evaluated for new risks of exposure to latent TB infection since their 
last test. If there are new risks of exposure to latent TB infection since the last test, these subjects 
should not be enrolled without sufficient time to get a latent TB infection test result prior to 
enrollment. 
Once it has been determined that there are no new risks of exposure to latent TB infection since 
the last test for latent TB infection, subjects who have a negative test result for latent TB infection 
within 1 year of transplant date are eligible for enrollment and no further action is required. 
Subjects who have a negative test for latent TB infection that is greater than 1 year old are eligible 
for enrollment but will need to repeat the test. Samples for testing latent TB infection can be 
obtained during the hospital admission for the transplant but must be collected prior to the 
initiation of immunosuppression and prior to transplant. The results of this repeat test will determine 
the next step. 
• 
If the test is negative, no further action is required 
• 
If the test is positive, lost, indeterminant or unavailable the subject must be treated for 
latent TB infection (if the subject is enrolled, received study drug/placebo and 
transplanted). Treatment is required for all in this group. 
o The treatment regimen (including the dose and duration of treatment) will b e 
determined by the local Infectious Disease team. 
■ 
Rif ampin-based prophylaxis is discouraged due to a drug-drug 
interaction with tacrolimus and other drugs metabolized by the 
cytochrome P450 system. 
• 
If the subject has no evidence of latent TB testing available, then the subject cannot 
be enrolled. 
8.2. Baseline Visit 
Subjects will have their baseline visit prior to transplant. During this visit blood, urine and tissue will 
be collected from participants. 


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Randomization 
Randomization will occur after enrollment, prior to transplant surgery. Participants will be 
randomized to either the Treatment group (receive Remicade®) or the Control Group (receive 
placebo). The site personnel will enter the information in the web-based system. This action will 
generate an automatic email and/or faxed communication to the site staff indicating successful 
randomization. 
 
This is a blinded study so participants and the study team will not know the treatment assignment 
of the participant. Only the research pharmacist will receive a communication identifying the 
treatment assignment. Randomization treatment assignments will be generated by the SACCC 
statisticians and stored on the SACCC server. The SACCC will maintain a central web-based 
randomization system. 
8.3. Study Therapy Regimen 
Table 5 below summarizes the study therapy regimen defined by this protocol. Please refer to 
the Appendices for additional information. 


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Table 5. Study Therapy Regimen Summary 
 
Study Therapy Regimen Summary 
Pre-Meds 
(Acetaminophen, Antihistamines & Methylprednisolone) 
• 
All pre-meds must be administered up to 4 hours prior to transplant and prior to start of 
Remicade® infusion 
o Acetaminophen 
■ 
600mg to 1000mg given by mouth, suppository or IV 
o Antihistamines (either can be used) 
■ 
Claritin/Loratadine 10mg given by mouth or IV 
■ 
Benadryl/Diphenhydramine 25 to 50mg given by mouth or IV 
o Methylprednisolone 
■ 
500mg given by IV 
Remicade® (Infliximab) or Placebo 
• 
Initiated prior to reperfusion. 
• 
Administered over a period greater than 2 hours 
o Remicade®-single dose, 3mg/kg infusion 
o Placebo- single dose, volume matched to Remicade® (250mL) infusion 
Thymoglobulin® (Rabbit ATG) 
• 
Initiated on the day of transplant 
• 
Administered daily with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their generic equivalent) 
• 
Initiated no later than 48 hours post-transplant 
• 
Administered at a target dose of 2000mg daily, as tolerated, until study closure 
Tacrolimus (or its generic equivalent) 
• 
Initiated no later than 48 hours post-transplant 
• 
Administered at a target dose of 0.1mg/kg per day divided into BID dosing (0.05 mg/kg BID), or 
an equivalent starting dose of a once-daily formulation of tacrolimus post-op 
o Then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op 
o Finally adjusted to target trough levels of 5-8ng/ml until study closure 
Prednisone (or its generic equivalent) 
• 
Prednisone administered perioperatively according to center standard of practice 
• 
Prednisone should be gradually tapered to no less than 5 mg QD or 10 mg QOD by 3 months post- 
transplant. 
Pre-Medications 
Participants 
will 
receive 
all 
pre-medications 
(antihistamines 
acetaminophen 
and 
methylprednisolone) up to 4 hours prior to transplant followed by either the investigational drug 
or placebo based on randomization assignment. When necessary, intravenous formulations may 
be used for pre-medications. Methylprednisolone 500 mg will be administered by intravenous 
infusion beginning up to 4 hours prior to or at the initiation of the transplant operation, and prior 
to initiating the infusions of Remicade®/placebo or thymoglobulin. 


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Remicade®/Placebo 
Remicade® is administered as a single 3mg/kg intravenous pre-perfusion dose. Placebo is 
administered as a single, intravenous, pre-perfusion, volume matched to Remicade® (250mL) 
dose. 
• 
Actual body weight will be used in the calculation. 
• 
Do not infuse Remicade® or placebo concomitantly with another IV solution or IV 
medication. 
• 
Remicade® and Placebo infusions should be administered through a separate, dedicated 
intravenous line. 
• 
The Remicade® and Placebo infusions should be administered in the operating room, over 
a period greater than 2 hours. 
 
Please refer to protocol Section 6.1 Investigational Agent: Remicade® and Section 6.2 
Investigational Agent: Placebo for additional details regarding Remicade®/Placebo dosing, 
administration, preparation and storage. 
Thymoglobulin 
Thymoglobulin will be initiated on the day of transplant. It will be administered at a dose of 1.5 
mg/kg daily (as tolerated) with the intention of achieving a total dose of 4.5 to 6.0 mg/kg total 
dose. Subjects who receive less than 4.5mg/kg total dose will continue in the study until study 
closure. Receiving less than 4.5 mg/kg will not be considered a deviation from the protocol. 
Thymoglobulin can be administered at the same time as Remicade® or Placebo as long as 
Remicade® or Placebo is given through a separate, dedicated intravenous line. 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or its generic equivalent) will be 
administered at a target dose of 2000 mg daily until study closure. MMF/MPA will be adjusted 
based on clinical complications. If participants cannot tolerate MMF/MPA (or its generic 
equivalent) or is outside the target dose range, this will not be considered a protocol deviation. 
Tacrolimus (Prograf®) 
Tacrolimus (or its generic equivalent) will be initiated no later than 48 hours post-transplant and 
administered at a dose of 0.1 mg/kg per day divided into BID dosing (0.05 mg/kg BID) or an 
equivalent dose of a once-daily tacrolimus postoperatively, then adjusted to target trough levels 
of 8-12 ng/ml during the first 3 months post-transplant, and then adjusted to target trough levels 
of 5-8 ng/ml thereafter until study closure. 
Prednisone 
Prednisone or its generic equivalent should be administered perioperatively according to center 
practice. Methylprednisolone (SOLU-MEDROL) can be administered perioperatively according to 
center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg QOD 
by 3 months post-transplant thereafter until study closure. 
8.4. Follow-up Study Visits 
Subjects will have study visit everyday up to 7 days while they are in the hospital after their 
transplant surgery. Blood and/or urine samples will be collected during scheduled visits. Protocol 
mandated biopsies will be performed on the day of transplant, month 3 and month 24 post- 
transplant. 


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8.5. MEMS® 
Prior to discharge, subjects will be given a MEMS® cap and bottle to store their prednisone 
medication. Subjects will utilize the MEMS® from the time they are discharged from the hospital 
after transplant surgery until 3 months post-transplant. Subjects will return MEMS® cap and bottle 
to the research team once they have reached the 3-month post-transplant visit. 
 
Please refer to Appendix 1 for detailed information regarding assessments. 
8.6. Additional Clinical Data Collection 
In addition to data collected during study visits, Tacrolimus trough levels will be collected every 
month from 1 month post-transplantation until the end of the study period. 
8.7. Modification of Immunosuppression Protocol 
At the discretion of the site investigator, immunosuppression protocols may be modified for clinical 
reasons. This would not be considered a protocol deviation. 
8.8. Unscheduled Visits 
If disease activity increases or other concerns arise between regularly scheduled visits, 
participants should be instructed to contact study personnel and may be asked to return to the 
study site for an “unscheduled” visit. 
8.9. Unscheduled Study Visits after Month 24 Post-Transplant 
Once sibjects complete the last planned study visit at month 24 after your kidney transplant the 
subject may continue to have study visits every 6 months up to 5 years after your transplant. This 
portion of the research study is optional. During these visits, a review of the medical record to 
determine graft status and a sample of blood will be collected for research. 
8.10. Reduced Follow-Up 
Subjects that withdraw or terminate from the study early or experience graft loss will follow a 
reduced follow-up schedule. 
Subjects that experience graft loss can remain in the study until study closure. These subjects will 
be followed on a reduced schedule. Please refer to Appendix 3 for details. 
For subjects who withdraw or terminate from the study early, the last study visit should be 
considered the final study visit. Please refer to Appendix 4 for details regarding data collection. 
8.11. COVID-19 Pandemic-Study Follow-up 
During the COVID-19 pandemic sites should use the COVID-19 Study Visit Windows outlined below. 
The COVID-19 Pandemic Study Visit Windows will remain in effect until each center reinstitutes 
standard protocols and allows participants to come into their center for their standard clinic 
and/or research visits. If there is a re-emergence of the COVID-19 pandemic, these changes may 
be reinstituted to accommodate site restrictions. 


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8.12. Standard Study Visit Windows 
 
STUDY VISIT WINDOWS 
VISIT 
Post- 
Transplant 
VISIT 
NO. 
VISIT WINDOW 
Study visits should take place within the time limits specified below 
Day 0 
00 
• 
Blood and urine samples should be collected prior to perfusion 
o The specimens (urine and blood) may be collected up to 4 months prior to 
transplant, while the subject is on the wait list for transplant. If the transplant 
occurs greater than 4 months after screening sample collection, then the site 
should collect the specimens prior to transplant/perfusion. Missed screening 
samples (visit 00) will not be considered a protocol deviation. 
• 
Latent TB infection test must occur within 1 year prior to transplant 
o If latent TB infection test results are not available within 1 year of transplant, sites 
must collect sample for latent TB test prior to the initiation of immunosuppression 
and prior to transplant with the understanding that results may not be available 
until after transplant surgery. 
o Section 8.1.1 Testing and Prophylaxis for Latent TB Infection, provides instructions 
on how to proceed based on test results. 
Days 
1 to 7 
01 
02 
03 
04 
05 
06 
07 
• 
+ 12 hours 
• 
After transplant, urine samples (for Urinary Chemokines and Necroptosis Markers and 
mRNA Profiling, Gene Expression) will be collected daily until subject is discharge 
from hospital. 
• 
Subjects will have study visits daily while they are hospitalized post-transplant up to 
Day 7. If a subject is discharged prior to Day 7 the day of discharge will be the last 
study visit until Day 14. 
• 
There are no study visits from Day 8 to Day 13. 
o 
Note: If discharge occurs prior to Day 7, then complete the discharge 
visit/core labs (using Kit #3) at the time of the discharge. Any remaining 
core labs due between discharge and Day 7 are not required. 
■ 
Example: If discharge occurs at Day 4, use the Kit #3 to complete 
the core labs at Day 4. The Day 4, 5, 6, and 7 core labs (Kit#2) are 
not required. 
o 
Note: If discharge occurs after Day 7, then complete the Day 7 core labs 
(Kit#3) on Day 7. No further core labs should be collected until Month 1. 
■ 
Example: If discharge occurs at Day 9, use the Kit #3 to complete 
the core labs at Day 7. There are no scheduled visits between Day 
8 to 14. The next time a protocol visit is due is Day 14, and the next 
time core labs are due is Month 1 (Kit #4). 
Day of 
Discharge 
07 
• 
Day 3 to Day 7 
Day 14 
08 
• 
+ 7 Days 
Month 1 
09 
• 
-7 Days/+ 21 days 
Month 3 
10 
• 
+ 14 days 
Month 6 
11 
• 
+ 21 days 


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VISIT 
Post- 
Transplant 
VISIT 
NO. 
VISIT WINDOW 
Study visits should take place within the time limits specified below 
Month 12 
12 
• 
+ 21 days 
Month 18 
13 
• 
+ 21 days 
Month 24 
14 
• 
+ 1 month 
Tacrolimus 
Trough levels 
07, 
09-14, 
UV1 
• 
+ 2 weeks 
• 
Collected monthly from Month 1 to Month 24 
Unscheduled 
Visit 1 
UV1 
• 
Day of unscheduled biopsy 
Unscheduled 
Visit 2 
UV2 
• 
Between 2 to 6 weeks after UV1 visit 
Unscheduled 
Visit 3 
UV3 
• 
+ 2 months 
Final Study 
Visit 
FV 
• 
Day of the visit 
 
8.13. COVID-19 Pandemic Study Visit Window 
 
COVID-19 PANDEMIC STUDY VISIT WINDOWS 
VISIT 
Post-Transplant 
VISIT NO. 
VISIT WINDOW 
Study visits should take place within the time limits specified below 
Month 12 
12 
• 
- 21 days/+ 4 months 
Month 18 
13 
• 
- 21 days/+ 5 months 
Month 24 
14 
• 
- 1 month/+ 6 months 
Tacrolimus Trough 
levels 
07, 09-14, 
UV1 
• 
+/- 2 weeks 
• 
Collected monthly from Month 1 to Month 24 
Unscheduled Visit 1 
UV1 
• 
Day of unscheduled biopsy 
Unscheduled Visit 2 
UV2 
• 
Between 2 to 6 weeks after UV1 visit 
Unscheduled Visit 3 
UV3 
• 
+/- 2 months 
Final Study Visit 
FV 
• 
Day of the visit 


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9. Mechanistic Assays 
9.1. Overview 
Previous work by our group and others has identified multiple biomarkers that strongly correlate 
with, or predict, episodes of acute rejection and/or poor late graft function in low risk recipients 
of living donor kidneys. We will validate the utility of these markers in larger populations of 
deceased donor graft recipients and in the context of a clinically applicable testing frequency. 
The biomarker analyses will be supplemented by studies to address mechanisms of anti-TNFa mAb 
effects on recipient inflammation and alloimmunity. Our hypothesis predicts that neutralization of 
TNFa at the time of renal transplantation will dampen IR-induced inflammation and result in 
weaker anti-donor T cell immunity, preservation of Treg number/function, limiting production of 
DSA and endothelial injury and preventing induction of fibrogenesis, together resulting in better 
graft outcomes. 
9.2. Cellular Immunology Core 
The Cellular Immunology Core laboratory is located at Icahn School of Medicine at Mount in New 
York, NY (PI: Dr. Peter Heeger, MD). Selective validations will be done at the Cleveland Clinic (PI: 
Dr. Robert Fairchild) 
T and B Cell Phenotyping by Flow Cytometry 
We hypothesize that addition of anti-TNFa to rATG as induction therapy will dampen post- 
transplant inflammation thereby improving ATG-induced depletion, limiting re-expansion and 
function of donor reactive memory T cells, and preventing induction of new donor reactive T cells, 
which together will result in decreased acute and chronic allograft injury and improved graft 
outcome. We will test the hypothesis first, by performing comprehensive, serial, multicolor flow 
cytometric phenotyping on PBMC from each patient using standardized flow cytometric 
approaches. Patterns of depletion and reconstitution will be compared between the 2 study arms 
and correlated with clinical outcomes. We will assess frequencies of CD4 and CD8, naïve and 
memory T cells as well as Treg and B cell subsets as each time point. Blood samples will be 
collected pre and serially post-transplant, as outlined in the Schedule of Events (appendix 1). 
Samples will be stained using antibody panels shown in Table 6 and analyzed by flow cytometry. 
Depending upon available cells we will also stain for NKG2D and chemokine receptors CXCR3 
and CCR6 on the T cell subsets. 
Table 6. Antibody panels for Flow Cytometric Analyses 
 
Because intracellular expression of pSTAT3 
has been reported by others to be a useful 
marker of effector T cell function in 
patients with multiple sclerosis (among 
other 
diseases) 
while 
Treg 
pSTAT5 
expression correlates with Treg function 
(46-49), we will include these 2 markers in 
our  analyses  as  indirect  measures  of 
function. 
T Cell Functional Assays (ELISPOT) and Archived PBMC for CyTOF Analysis 
Evidence suggests that effector and/or memory T cells reactive to donor antigens and or to a 
panel of alloantigens as measured by IFNy ELISPOT assays are detrimental to graft survival. In 
previous studies we showed that pre- (and post-) transplant frequency of anti-donor memory T 
fluorochrome 
TruCount 
T Cell 
Treg 
B Cell 
FITC 
CD16 
CD45RA 
CD45RA 
IgG 
PE 
CD19 
CCR7 
CD25 
CD24 
PerCP6Cy565 
CD45 
CD3 
CD3 
IgD 
PE6Cy7 
CD3 
CD28 
CD127 
CD38 
APC 
CD56 
CD27 
CCR4 
CD27 
APC6Cy7 
CD8 
CD8 
CD19 
Pacific Blue 
CD4 
CD4 
CD4 
IgM 
Krome Orange 
CD14 
CD14/CD19 CD14/CD19 CD14/CD3 


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cells in peripheral blood, as determined by an IFNy ELISPOT assay directly correlates with the risk 
of developing AR (within 6 mo. Post-transplant) and decreased 12 mo. GFR (50-55). These findings 
have been subsequently validated by our group and several others using independent patient 
cohorts (56-59). Completion of ELISPOT assays requires ~36 hours, a time frame which essentially 
precludes using anti-donor ELISPOT testing to make clinical decisions regarding use of, or therapy 
for, deceased donor transplants. In an effort to circumvent this practical issue and to develop a 
screening test for alloreactive T cell memory (analogous to the panel of reactive antibody, PRA, 
screening test for humoral immunity), we developed and validated the “panel of reactive T cells,” 
or PRT, assay (60-62). In the PRT, PBMC from transplant candidates (e.g. dialysis patients on the 
transplant waiting list) are tested in IFNy ELISPOT assays against a panel of HLA disparate B cell 
stimulator lines. Our goals here are to a) prospectively validate the pre-transplant PRT as an 
independent risk assessment tool in deceased donor transplant recipients and b) to compare the 
results of the PRT to anti-donor responses as predictors of outcomes in study population. Using 
serially collected post-transplant blood samples we will assess the impact of anti-TNFa induction 
therapy on the strength of the post-transplant anti-donor T cell immune responses over time. 
Based on new data published by the Fairchild group that CD28neg effector T cells are important 
mediators of allograft injury and that this population of cells only produce IFNy in ELISPOT assays if 
stimulated with IL-15 (63) we will perform side by side PRT and anti-donor ELISPOT assays with and 
without recombinant IL-15 compare the results and determine how well the results of each assay 
correlate with outcomes. Readouts will be both IFNy and Granzyme B ELISPOTs. 
We will obtain blood samples in heparinized green top tubes pre-transplant (pre-induction) and 
serially post-transplant and will perform PRT and anti-donor ELISPOT assays with and without IL-15 
as published. In vitro expanded B cell lines will be used as stimulator cells for these assays. HLA 
typed B cells will be expanded from donor and or recipients within the study population. PRT 
assays will be done with the same panel of up to 8 stimulator lines for each patient at each time 
point. As it is anticipated that donor tissue will only be obtainable from a subset of the deceased 
donors in this study, anti-donor immunity will only be assessed in a subset of recipients (anticipated 
to be ~30% of the total enrollees). 
In exploratory studies, we will use 1-2 million PBMCs obtained from these cells or from the cells 
obtained in 9.3 below to evaluate expression >30 concurrent markers by CyTOF analysis and to 
assess B cell reactivity in vitro to allo-, auto- and infectious antigens. 
TCR Sequencing Substudy 
We have recently demonstrated that biologically-relevant donor-reactive T cell clones can be 
identified by high-throughput sequencing of recipient T cells proliferating in an anti-donor MLR 
and expanded compared to unstimulated T cell populations100. In patients achieving tolerance 
by combined kidney and bone marrow transplantation, the number of circulating donor- 
reactive CD4 T cell clones declined over time, whereas conventional transplant patients 
showed an increase in these clones in the circulation. We hypothesize, therefore, that a decline 
in these donor-specific CD4 clones at one year compared to pre-transplant blood may identify 
patients who are operationally “tolerant” and whose graft outcomes at two years will be 
excellent. We hypothesize that there may be more frequent reductions in these clones in the 
infliximab-treated group than the controls, though this hypothesis cannot be addressed until the 
study is completed, due to the double-blind study design. We also hypothesize that a high level 
of expansion of donor-specific Tconv and lack of expansion of donor-specific Tregs will be 
associated with the presence of rejection episodes. Conversely, high levels of expansion of 
donor-specific Tregs and/or conversion of donor-reactive CD4 Tconv to Tregs post-transplant 
may be associated with the absence of rejection. We have been able to detect CFSE-low CD4 


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cells in the anti-donor MLR that appear in the sorted Treg fraction of transplant patients (Figs. 
1,2) as well as donor-reactive T cells that appear in the sorted Tconv fraction pre-transplant and 
in the Treg fraction post-transplant (Fig.2). Thus, donor-specific Tregs may be identified and 
tracked with this method. 
 
Furthermore, in pilot studies we have 
detected donor-specific TCR DNA in 
urine of kidney transplant patients prior 
to and during rejection episodes but 
have not detected such DNA in urine 
of patients without rejection episodes. 
We hypothesize that the presence of 
donor-reactive TCR DNA in the urine 
may be a diagnostic marker and/or 
predictor of rejection. We propose a 
substudy to obtain preliminary data 
relevant to these hypotheses in 10 
subjects. This work will be performed 
at Columbia University (Megan Sykes, 
MD). 
 
1) The degree of expansion or reduction of donor-reactive CD4 TCRs in the circulating T cell 
pool at 6 and/or 12 months correlates with graft outcomes at 2 years. 
2) Expansion of donor-specific Tregs or conversion of donor-reactive Tconv to Tregs post- 
transplant correlates with excellent graft function and absence of rejection. 
The presence of donor-reactive TCR DNA in the urine predicts and/or correlates with the 
presence of rejection. 
T Regulatory Cells Substudy 
The flow cytometric analyses will determine the effect of anti-TNFa induction on Treg frequencies. 
To assess impact of anti-TNFa on Treg function, in a subset of patients in each group (n=10 per 
group without anemia) we will isolate 50-100 cc of blood to perform functional analyses of Treg 
suppressive capacity to verify the correlations between phenotype and function. We will flow sort 
CD4+CD25hiCD127lo T cells and test them in in vitro suppression assays (64), using effector T cells 
from normal controls as the responders. We will quantify DNA methylation of the Foxp3 gene (65) 
and phosphorylation (66) using commercial assays in selected samples as an indirect measure of 
Foxp3 stability of the Treg. Only participants from the Cleveland Clinic, University Hospitals of 
Cleveland/Case Western, and Mount Sinai will be included in this Substudy. 
Urinary Chemokine Protein and Necroptosis Markers 
Urinary chemokine assays will be performed at Icahn School of Medicine at Mount Sinai in New 
York, NY (PI: Dr. Peter Heeger, MD). 
One goal of these studies is to determine the effectiveness of the anti-TNFa mAb in attenuating 
TNFa-mediated inflammation and its associated downstream sequelae. Urinary chemokines, 
including CXCL9, CXCL10 are elevated immediately post-transplant as a reflection of ischemia 
reperfusion injury. We hypothesize that anti-TNFa induction therapy will limit post-transplant 
inflammation and ischemia reperfusion injury. To test this we will serially collect urine samples over 
the first month post-transplant and test supernatants for CXCL9 and CXCL10 (among other 


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potential markers), perform time dependent analyses and compare the results between the 
experimental and the control groups. 
A second goal of these studies is to validate the utility of urinary CXCL9 as a biomarker for ongoing 
or incipient acute rejection in a high-risk study population. We previously showed that in low risk 
kidney allograft recipients urinary CXCL9measurements are an accurate noninvasive approach 
to diagnosing acute cellular (but not humoral rejection) and can detect subclinical allograft injury 
(with a stable creatinine) that will develop over time into clinically evident rejection (67). Our goal 
herein is to determine the utility of serial urinary CXCL9 measurements to: a) diagnose and or 
predict incipient, clinically evident, biopsy proven acute rejection, b) to assess whether the type 
(cellular and or antibody) and/or grade of rejection impacts diagnostic/predictive utility, and c) 
to define causes of false positive results (predicted to be infection and resolving IR injury). Urine 
samples will be obtained from each patient at each site at predefined time points between 
transplantation and 6 months post-transplant because the majority of rejections occur during the 
first 6 months. We will also obtain urine samples at the time of a biopsy performed for evaluation 
of acute kidney dysfunction. 
Urine supernatants will be sent to a core lab and frozen in aliquots. Samples will be tested by ELISA 
for urinary CXCL9, CXCL10 and additional markers. Pilot data indicate that values > 200 mg/dl 
represents a positive test indicative of ongoing or incipient rejection. Results will be correlated 
with clinical evidence of rejection (we will not direct therapy based on the results of the assays). 
As we have previously shown that urinary infections including BK virus infections lead to increases 
in urinary CXCL9, we will correlate the urinary CXCL9 results with tests for BK and UTI. 
9.3. Genomics Analysis Core Laboratory 
The Genomics Core Lab is located at the Icahn School of Medicine at Mount Sinai, NY, NY (PI: Dr. 
Barbara Murphy). 
mRNA Profiling, Gene Expression in Blood 
We will isolate RNA from PBLs and perform RT-PCR (or nanostring). There is some evidence that 
these markers may be useful for predicting AR in renal allograft recipients. We will include these 
studies to confirm published findings and to test whether recurrent detection of these markers is 
associated with the development of the late endpoints. Blood samples will be collected in 
PAXgene RNA tubes. Results will be correlated with pathological interpretation of the 3-month. 
biopsy (core lab) and with incipient biopsy proven rejection. 
mRNA Profiling, Gene Expression Profiles in Tissue 
We also hypothesize that chronic allograft injury manifested pathologically as progressive 
interstitial fibrosis and tubular atrophy (IF/TA) is initiated early post-transplant by a pro- 
inflammatory environment, compounded by T cell and antibody mediated injury. Our hypothesis 
is that anti-TNFa induction will dampen early post-transplant inflammation and prevent or 
attenuate induction of a fibrogenic gene profile in the allograft that ultimately leads to chronic 
allograft injury. This hypothesis predicts that differences in molecular signatures indicating fibrosis 
are likely to be present prior to the histological development of the injury and that they will be less 
prevalent (and or occur later) in patients treated with anti-TNFa induction. Data in animal models 
of liver and renal fibrosis and clinical studies clearly implicate a role for TNFa and for TNF receptor 
1 signaling in the instigation of this fibrogenesis (154-159). We will test this hypothesis by evaluating 
gene expression profiles in urine between the treatment and control arms, and comparing the 
results to the pathological analysis of IF/TA progression between implantation and 24 mo. (as well 
as with eGFR which is likely to correlate with the IF/TA progression). 


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Molecular analyses of the graft tissue will be performed for 2 purposes: a) to determine the effects 
of anti-TNFa induction therapy on intragraft inflammation at 3 months and b) to validate a 
molecular biomarker that predicts incipient rejection. 
a) Effects of anti-TNFa induction on intragraft inflammation. To supplement the urinary gene 
expression profiling described above and to directly test the effects of anti-TNFa on graft 
tissue, we will make RNA from a portion of the 3-month protocol biopsy from each patient 
and perform qPCR (or nanostring) to quantify gene expression of inflammatory and 
profibrotic genes (same as those described in section 8.1.4). For each gene, we will 
compare the results between the experimental and control groups and will also determine 
the strength of the correlations between urinary gene expression patterns and intragraft 
gene expression patterns. 
b) In unpublished work from co-I B Murphy, analysis of RNA obtained prospectively from 3 mo. 
surveillance transplant biopsies in patients with stable renal function at 3 mos. showed that 
molecular profiles in the graft at 3 mo. predict subsequent 12 mo. chronic injury, 
independent of clinical and histopathological parameters. This genomic biomarker of 20 
differentially regulated genes (some up-regulated, others down-regulated) strongly 
correlate with chronic allograft damage at 1 year, but importantly not with fibrosis at 3 mo. 
Statistical analysis of this preliminary panel reveals an average AUC score of multiple 
iterations of ROC curves of 0.947 within 95% confidence interval 0.942-0.952. Our goal here 
is to independently validate and refine the gene set as a biomarker for incipient rejection. 
We will prospectively test the predictive value of the gene set expressed in the 3-month 
biopsy RNA using the new cohort from this deceased donor kidney transplant trial and will 
test the impact of anti-TNFa therapy on the utility of the biomarker. We will isolate RNA from 
surveillance/protocol biopsies obtained at 3 mos. from our study cohort (control and anti- 
TNFa treatment arms). We will perform qRT-PCR on each RNA sample to detect expression 
levels of the minimal gene set (10-20 genes) as a biomarker. We will test the strength of the 
relationship of this intragraft gene expression profile biomarker with: a) 12m eGFR, b) 24m 
eGFR and c) change in histology scores between implantation and 24 months accounting 
for confounders (see statistical analysis below). 
Genomics Analysis 
In unpublished work, Dr. Murphy (Co-Investigator) and colleagues, using a set of 147 kidney 
transplant recipients identified a 100-gene set from peripheral blood obtained at 3 months post- 
transplant that strongly correlated with subclinical acute cellular rejection (ACR) of 3 mo. 
surveillance biopsies. Our goal here is to test the diagnostic utility of this peripheral blood derived 
RNA biomarker for ongoing and incipient acute cellular rejection in this new deceased donor 
cohort, and to test whether the therapy with anti-TNFa impacts the diagnostic/predictive utility. 
Cell Free DNA Analysis 
Blood samples will be obtained in Streck Cell-Free DNA BCT tubes to perform cell-free plasma DNA 
analysis. Streck Cell-Free DNA BCT tubes contain a formaldehyde-free preservative in Cell-Free 
DNA BCT that stabilizes white blood cell, preventing the release of genomic DNA, allowing 
isolation of high-quality cell free DNA. Samples will be collected and shipped to the Genomics 
Core Laboratory for processing. Samples will be provided to CareDx, Inc. for final analysis. 
CareDx, Inc. (Brisbane, CA) is a commercial stage company that develops, markets and delivers 
a diagnostic surveillance solution for transplant recipients to help clinicians make personalized 
treatment decisions throughout a transplant patient’s lifetime. 


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9.4. Molecular Immunology Core Lab 
The Molecular Core laboratory is located at the Cleveland Clinic, Cleveland OH (PI: Dr. Robert 
Fairchild). 
Nanostring Analysis 
We will isolate RNA from PBLs and perform RT-PCR and Nanostring analysis. Blood samples will 
be collected in PAXgene RNA tubes, and shipped to the Genomics Core Lab (PI: Barbara 
Murphy). The samples will be processed and shared with the Molecular Immunology Core lab. 
mRNA Profiling, Gene Expression Profiles in Urine Pellet 
To further determine the effectiveness of the anti-TNFa mAb in attenuating TNFa-mediated 
inflammation and its associated downstream sequelae, we will study and compare urinary RNA 
expression of a panel of selected molecules relevant to IR injury and are known to be up- 
regulated by TNFa (Table 7). 
Table 7. Genes to be studied in Graft tissue and urine 
We will examine and compare: urinary cellular RNA 
expression 
profiles 
and 
urinary proteins peri- 
transplant, in the control and treatment arms. For 
cost containment purposes, we will use quantitative 
real time PCR (qPCR) or nanostring technology as the 
primary methodology. Urine samples from each 
patient obtained at the predefined time points 
(Schedule of Events, Appendix 1) will be pelleted and 
the cellular sediment homogenized in RNA Lysis 
Solution. We will not differentiate or separate immune 
cells from intrinsic renal cells in this process. RNA will 
be isolated from biopsy samples or urine cells and 
reversed transcribed using random hexamers in our 
published and validated SOPs. qPCR will be done as 
published (68) using primers for the mouse BAK gene to establish a standard curve and normalized 
to 18S. The expression levels of each gene will be expressed as copy number per µg of the control 
BAK standard. Additional inflammatory and fibrosis genes will be assessed by nanostring once 
the procedures have been optimized and validated (exploratory analyses). 
We will compare the results between treatment groups and all laboratory results will be correlated 
with graft outcomes, specifically endpoints related to early graft function (DGF, immediate graft 
function, slow graft function, see Endpoints in Sections 3.2 and 3.3), testing the hypothesis that 
dampening ischemia IR-inflammation improves outcome (e.g. prevents DGF). 
We will isolate urine cell RNA obtained serially post-transplantation to measure RNA for genes 
encoding proteins involved in the progression of interstitial graft fibrosis including TGFb, n- 
cadherin, a-smooth muscle actin, connective tissue growth f actor, vimentin, fibronectin, collagen 
I, collagen III, MMP-2, BMP7 (among others) in urine cells using qPCR as described above and 
published (109). The findings will be correlated with the degree of chronic injury and will be 
compared between the groups of patients in the 2 study arms. 
9.5. Pathology Core Lab 
The Pathology Core laboratory is located at the University of Manitoba in Winnipeg, Manitoba, 
Canada (PI: Dr. Ian Gibson, MD). 
Cytokines: TNFa, IL-1, -6, -8, -15, -18 
Chemokines: CCL2, CCL3, CCL5, 
CXCL-9, -10 CCR2 
Complement components: C3, fB, C5, 
C5aR, C3aR, DAF 
Other: ICAM-1, TLR4, HMGB1 
Control: succinyl dehydrogenase 
(SDHA) 


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Histology 
Our hypothesis is that the anti-TNFa induction therapy will lower the incidence of acute T cell and 
antibody mediated rejection and result in improved 2-year graft histology (lower chronicity 
scores). 
Graft tissue will be obtained pre-transplant (prior to implantation), at 3 months post-transplant and 
at 2 years post-transplant. Histologic examination will be done at the University of Manitoba at 
Winnipeg site. Biopsy results will be reported using the Banff ’07 schema for acute rejection and 
chronic allograft injury. The centers will send renal tissue (1-1.5 wedge or core tissue s in a pre- 
filled formalin jar). If tissue cannot be sent to the Histology Core Lab, then the site should send or 
stained slides (3 PAS, 1 Trichrome or unstained and 1 H&E). 
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 archived in 
an Aperio Digital database system. Slide images will be stored at the University of Manitoba at 
Winnipeg (PI: Dr. Ian Gibson) for additional analysis, if needed. 
TNFR1 Expression Patterns in Renal Allografts 
We will test the hypothesis that the efficacy of anti-TNF therapy will depend upon the state of the 
kidney at the time of transplantation. Specifically, the prediction is that transplanted kidneys 
expressing high levels of TNFR1 but low levels of TNFR2 and DR3 have less pre-existing injury and 
are less likely to manifest DGR. Some patients still develop DGF and this is the group of patients 
who would benefit from anti TNF therapy. In contrast, those transplanted kidneys expressing low 
levels of TNFR1 but high levels of DR3 and TNFR2 (i.e., those with ischemia-reperfusion injury) are 
more likely to develop DGF and less likely to show benefits of anti-TNF therapy. We plan to assess 
the expression patterns of TNFR1, TNFR2 and DR3 by multicolor immunofluorescence staining on 
pre-implantation FFPE biopsies and correlate the findings with clinical variables. A portion of renal 
allograft tissue collected at implantation will be shared with Yale School of Medicine (Jordan 
Prober, MD). 
Immunofluorescence/IHC 
Peritubular capillary (PTC) loss induced by IR correlates with interstitial inflammation and 
subsequent fibrosis in animal models of renal disease (75), in native kidneys with progressive 
dysfunction (76) and in kidney transplants (77). PTC loss as quantified by endothelial cell 
immunostaining for CD31 and CD34, has been reported to increase between baseline and 3 
months post-transplant more often in recipients of deceased donor kidneys (more so in recipients 
of brain dead donors than in recipients of donors after cardiac death) than in living donor kidneys, 
in recipients of older donors, and in recipients with early immunological events (77). Furthermore, 
PTC loss occurs more commonly in recipients who develop DGF, in whom serum levels of the 
soluble VEGF-R1 levels are elevated (78). As we hypothesize that these processes will be 
dampened by perioperative anti-TNFa, our working model predicts that PTC loss will be prevented 
in patients in the treatment group. We will compare the change in PTC density of biopsy tissue 
by immunofluorescence or IHC between baseline and 3 mos. in a subset of patients from each 
arm of the study that have developed DGF (or SGF) or have had good function as controls. As 
PTC loss correlates with subsequent fibrosis (77), we will determine whether PTC density at 3 months 
correlates with the prevalence and/or intensity of interstitial fibrosis at 2 years. Tissue obtained for 
Histology (described above) will be shared to complete the Immunofluorescence/IHC work. If 
tissue is not received from the local center, they will send the core pathology 3 unstained slides 
mounted on positively-charged glass slides (e.g. Superfrost Plus treated slides), 1 C4d stained slide 


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and 1 SV-40 stained slide. If the C4d and SV-40 stained slides were not prepared at the local 
center, then a total of 5 unstained slides will be sent to the core pathologist. 
Primary data will be sent to the CTOT Statistical and Clinical Coordinating Center for final analysis. 
High-resolution images of entire sections of all stains from each biopsy will be archived in an Aperio 
Digital database system.  Slide images will be stored at the University of Manitoba at Winnipeg 
(PI: Dr. Ian Gibson) for additional analysis, if needed. 
9.6. Humoral Core Lab 
The Humoral core lab is located at the University of Manitoba at Winnipeg, (PI: Dr. Peter 
Nickerson). 
Anti-HLA Antibodies and Donor Specific Antibodies 
Preexisting and de novo post-transplant donor specific antibodies (DSA) can be pathogenic and 
contribute to acute and chronic allograft injury. We hypothesize that blocking early inflammatory 
events post-transplant with anti-TNFa induction therapy will prevent de novo alloantibody 
formation in human transplant recipients. 
Serum samples will be collected from recipients at predefined time point, divided into aliquots 
and store at -80 C. For these analyses, serum samples will be obtained prior to transplantation, 
every 3 months post transplantation, as well as at the time of indication biopsies. We will use 
standardized methods (79) to define kinetics, specificities and quantity (median fluorescence 
intensity, MFI) of DSA in each patient. The HLA specificity, class I vs. II, and approximate titer of 
the anti-HLA IgG will be determined using Luminex single HLA class I and class II antigen 
microbeads in combination with phycoerythrin (PE) secondary antibody conjugates for the 
detection of human IgG. To minimize any prozone effect (interfering factors which mask the 
antibody strength (MFI) serum samples will be treated with or without EDTA as part of the 
evaluation to assess if there is an MFI increment with EDTA treatment. The Luminex beads will be 
analyzed using the LABScan™ 100 flow analyzer and an analysis program will assist in the 
assignment of the reaction strength (MFI). We will compare the incidence of de novo DSA 
between the control and experimental arms and assess the correlations de novo DSA and 
outcomes. 
We will also collect serum samples in the early post-transplant time period (days 1-5) and measure 
TNFa levels by ELISA as another approach to test the hypothesis that anti-TNFa mAb induction 
therapy limits post-transplant inflammation. 
9.7. Glomerular Filtration Rate (GFR) Core Lab 
All creatinine values will be performed at the core lab at the Cleveland Clinic foundation (PI: Dr. 
Emilio Poggio, MD) for standardization. 
GFR analysis will be calculated by the Chronic Kidney Disease Epidemiology Collaboration 
equation (CKD-EPI). This method uses a serum sample for creatinine at month 6 post-transplant, 
then months 6 and 18 post-randomization. To accomplish this in a uniform manner, serum samples 
will be collected as part of the protocol at these time points and creatinine values will be 
determined at a single site (CCF). Demographic characteristics, gender, and race are required 
for calculation. 


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9.8. Mechanistic Studies Data Analysis Plan 
We will test, validate and expand our biomarker panel to predict and diagnose incipient ACR 
and to determine the accuracy of early post-transplant markers to define individuals most at risk 
for late graft dysfunction. This evaluation will be based primarily on examining the Receiver 
Operating Characteristic (ROC) Curves generated for each candidate biomarker and the 
associated classification accuracy in terms of sensitivity and specificity (as well as positive and 
negative predictive value). We will also explore combining the candidate biomarkers to 
determine whether there are distinct combinations of biomarkers that may improve performance 
relative to individual biomarkers. The ROC curve puts different biomarkers on a common relevant 
scale and shows the entire range of possible performance. The information in these curves, 
describing the overall potential performance of each biomarker, will be quantified by the area 
under the curve (AUC-ROC) and its associated 95% confidence interval using the nonparametric 
method of Hanley and McNeil (80). Cut points, based on optimizing sensitivity and specificity, will 
be determined, and based on the ROC curves. The sensitivity and specificity so obtained (and 
also the positive and negative predictive values) will serve as the primary summaries of the 
predictive ability of each biomarker. 
Logic regression (81-83) will be used to construct Boolean combinations of biomarkers, 
dichotomized into indicator variables using the optimized cut points referred to above. Logic 
regression is an adaptive regression methodology that attempts to construct predictors as 
Boolean combinations of binary covariates. This method determines a classification algorithm that 
identifies predictive rules for combining biomarkers by searching the space of possible rules for an 
optimal rule. The optimal rule is one that minimizes a specified objective function; in this case, 
misclassification of progression. Cross-validation will be used to select the optimal number of trees 
and leaves, and the resulting score used to construct an ROC curve. The AUC for this curve will 
be computed with the associated confidence interval determined using a bootstrap percentile 
method. This “combination” AUC-ROC will be qualitatively compared to those obtained from the 
individual biomarkers. Multiple logistic regression models will quantify the association of the 
biomarkers to risk, and assess the potential confounding effects of key characteristics such as age, 
sex, race, treatments and comorbidities. 
Our hypothesis that anti-TNFa limits activation of donor reactive immunity and prevents initiation 
and progression of graft fibrosis by dampening early inflammation within the allograft will be 
assessed by a series of linear mixed models. Models will be fit sequentially, with specific models fit 
to address specific elements of the hypothesized mechanism. Initially we will use regression 
models to quantify the extent to which infliximab, when added to therapy with ATG, reduces 
“early” inflammation at the time of transplantation, measured both by cellular reactivity in blood 
and from post-implantation biopsies. Corresponding linear regression models will assess 
differences between treatment groups with respect to inflammation measures at 24 mos., and 
mixed linear models will be used to assess the inflammation measures over the entire time course 
subsequent to the “early” evaluation. Additionally, proportional odds models will be used to assess 
treatment differences in ordinal grade of graft fibrosis at 24 mos. and, through a generalized 
estimating equation (GEE) approach, over time. A finding of reduced inflammation with 
combination therapy would be consistent with our mechanistic hypothesis. Further confirmation 
would be a finding that the estimated benefit for added infliximab therapy at 24 hours and times 
subsequent the “early” assessment were diminished after adjusting for the “early” measures of 
inflammation. The adjusted estimate will be based on models that include the “early” measures 
as covariates in the assessment of treatment on 24 hour measures and on the entire time course. 
A formal statistical analysis plan is being prepared separately 


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Sample Size: Our sample size will allow precise estimation of sensitivity and specificity, especially 
for those biomarkers that perform well. For sensitivities and specificities in the range of 0.80 to 0.90, 
this sample size (300 subjects) ensures that the associated standard error is in the range of 0.02 to 
0.03. 
9.9. Sample Collection 
The mechanistic studies schedule of events is located in Appendix 1 & 2-Schedule of Events of this 
protocol. 


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10. Biospecimen Storage 
Biological specimens (whole blood, plasma, serum, urine supernatant, urine pellet) obtained 
under this protocol may be used in future assays to reevaluate biological responses as additional 
research tests are developed over time. These specimens will be collected at time points already 
scheduled for the core mechanistic studies, in order to allow specimens to be stored for use in 
new assays that have yet to be optimized or conceived, or assays performed by other CTOT 
consortium members for cross-validation studies. Appropriate informed consent will be obtained 
for both the collection and storing of samples. The specimens from these evaluations may be 
stored beyond the funding period. During the funding period, samples will be identifiable, which 
means samples will be coded with a subject ID number that could be directly linked to the subject 
and the subject’s medical record. When the funding period is over, samples will be anonymized, 
which means a sample that was previously identifiable, has had all identifiers removed and can 
no longer be linked back to the subject or the subject’s medical record by any means. 


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11. Criteria for Participant and Study Completion and Premature Study 
Termination 
11.1. Participant Completion 
 
11.2. Participant Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow- 
up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts 
to reestablish contact with the participant have failed). 
3. The participant dies. 
4. The Investigator no longer believes participation is in the best interest of the participant. 
11.3. Participant Replacement 
Participants that are randomized but did not receive the investigational agent will be replaced. 
Participants who received the investigational agent and subsequently withdrew consent or are 
withdrawn will not be replaced. 
11.4. Follow-up after Early Study Withdrawal 
If a participant is withdrawn from the study for any reason, the participant may be asked to 
complete a final visit and/or final assessments. Please refer to Appendix 4 for details regarding 
final visit assessments. 
11.5. Stopping Rules 
Study enrollment at all participating clinical sites will be temporarily 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 Saf ety Monitoring Board (DSMB) 
upon satisfaction of any of the following stopping rules at any time during the post-transplant 
(treatment) follow-up period: 
• 
Any single occurrence of a life-threatening or f atal AE that is possibly, probably, or definitely 
related to either the investigational agent (infliximab/infliximab placebo) or a study 
mandated procedure. 
 
Across both treatment arms 
• 
Incidence of PTLD of 1% or more subjects 
• 
Incidence of Adverse Events for tuberculosis active disease of 1% or more subjects 
• 
Incidence of invasive fungal infection of 3% or more subjects 
• 
Incidence of coccidioidomycosis of 1% or more subjects 
• 
Incidence of histoplasmosis of 1% or more subjects 
• 
Incidence of death of 10% or more subjects 
 
Within a given treatment arm 
• 
Incidence of infection of any type requiring hospitalization of 40% or more subjects 
• 
Incidence of graft loss of 20% or more subjects 
• 
Incidence of BPAR (Banff Grade 1 or higher) or AMR based on local read of 25% or more 
subjects 


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These thresholds of concern will be continuously monitored by the SACCC throughout the study 
to determine if any of their observed subject-based incidence rates exceed the pre-specified 
incidence rate of concern for each particular event. They will be implemented by comparing the 
exact lower 95% confidence limit on the currently observed subject-level incidence rate to the 
threshold rate described for that event in the stopping rule. If the lower confidence limit is greater 
than the threshold, the stopping rule will be considered to have been met and the Medical 
Monitor, DSMB and study PI will be notified. 
The following are tables illustrating, for each stopping rule, the minimum numbers of subjects with 
the respective event that would meet the stopping rule for selected numbers of subjects. 
Table 8a: Minimum Numbers of Subjects with the Event in All Randomized Subjects that meet the 
Stopping Rule for PTLD, Adverse Events for Tuberculosis Active Disease, Coccidioidomycosis 
& Histoplasmosis disease with a Threshold of Concern of 1% 
 
Number of Subjects 
with Event 
Number of Randomized 
Subjects Total 
Cumulative Incidence Rate 
(%) 
Lower 95% Exact 
Confidence Limit (%) 
1 
5 
20.00 
1.02 
2 
30 
6.67 
1.20 
3 
80 
3.75 
1.03 
4 
130 
3.08 
1.06 
5 
190 
2.63 
1.04 
6 
260 
2.31 
1.01 
 
Table 8b- Minimum Numbers of Subjects with the Event in All Randomized Subjects that meet the 
Stopping Rule for Incidence of Invasive Fungal Infections of 3% or More 
 
Number of Subjects 
with Event 
Number of 
Randomized Subjects 
Total 
Cumulative Incidence 
Rate (%) 
Lower 95% Exact Confidence 
Limit (%) 
7 
110 
6.36 
3.02 
9 
150 
6.00 
3.17 
11 
190 
5.79 
3.28 
12 
230 
5.22 
3.04 
14 
270 
5.19 
3.16 


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Table 9: Minimum Numbers of Subjects with the Event in All Randomized Subjects 
That meet the Stopping Rule for Death with a Threshold of Concern of 10% 
 
Number of Subjects 
with Event 
Number of Randomized 
Subjects Total 
Cumulative Incidence Rate 
(%) 
Lower 95% Exact 
Confidence Limit (%) 
4 
10 
40.00 
15.00 
7 
30 
23.33 
11.50 
10 
50 
20.00 
11.27 
16 
100 
16.00 
10.30 
22 
150 
14.67 
10.14 
28 
200 
14.00 
10.14 
34 
250 
13.60 
10.17 
 
Table 10: Minimum Numbers of Subjects with the Event in Either Randomized Treatment Arm 
That meet the Stopping Rule for Infection of any type requiring Hospitalization 
With a Threshold of Concern of 40% 
 
Number of Subjects 
with Event 
Number of Randomized Subjects 
in Either Treatment Arm 
Cumulative 
Incidence Rate (%) 
Lower 95% Exact 
Confidence Limit (%) 
8 
10 
80.00 
49.31 
17 
30 
56.67 
40.16 
27 
50 
54.00 
41.48 
36 
70 
51.43 
40.99 
45 
90 
50.00 
40.88 
54 
110 
49.09 
40.89 
62 
130 
47.69 
40.20 
 
Table 11: Minimum Numbers of Subjects with the Event in Either Randomized Treatment Arm 
That meet the Stopping Rule for Graft Loss with a Threshold of Concern of 20% 
 
Number of Subjects 
with Event 
Number of Randomized Subjects 
in Either Treatment Arm 
Cumulative 
Incidence Rate (%) 
Lower 95% Exact 
Confidence Limit (%) 
5 
10 
50.00 
22.24 
11 
30 
36.67 
22.11 
16 
50 
32.00 
21.21 
21 
70 
30.00 
21.06 
25 
90 
27.78 
20.11 
30 
110 
27.27 
20.36 
35 
130 
26.92 
20.59 


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Table 12: Minimum Numbers of Subjects with the Event in Either Randomized Treatment Arm 
That meets the Stopping Rule for BPAR (Banff Grade 1 or higher) or AMR 
Based on local read with a Threshold of Concern of 25% 
 
Number of Subjects 
with Event 
Number of Randomized Subjects 
in Either Treatment Arm 
Cumulative 
Incidence Rate (%) 
Lower 95% Exact 
Confidence Limit (%) 
6 
10 
60.00 
30.35 
13 
30 
43.33 
27.87 
19 
50 
38.00 
26.51 
25 
70 
35.71 
26.19 
30 
90 
33.33 
25.12 
36 
110 
32.73 
25.34 
42 
130 
32.31 
25.54 
 
After a review of the data, the DSMB will make recommendations regarding study conduct 
and/or continuation. 


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12. Safety Monitoring and Reporting 
12.1. 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 those data. 
Adverse events that are classified as serious according to the definition of health authorities must 
be reported promptly (per Section 12.5, Reporting of Serious Adverse Events and Adverse Events) 
to the sponsor, DAIT/NIAID. Appropriate notifications will also be made to site principal 
investigators, Institutional Review Boards (IRBs)/Institutional Ethics Committees (IECs) and health 
authorities. 
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 Division 5 of the Canadian Food and Drug Regulations 
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). 
12.2. Definitions 
Adverse Event (AE) 
Any untoward or unf avorable medical occurrence associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the research 
(modified from the definition of adverse events in the 1996 International Conference on 
Harmonization E-6 Guidelines for Good Clinical Practice) (from OHRP "Guidance on Reviewing 
and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events 
(1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 ). 
Suspected Adverse Reaction (SAR) 
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 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)/ICHE2A). 
Suspected adverse reactions associated with the study therapy regimen or study procedures are 
collected and reported to the sponsor. The sponsor will relay any suspected adverse reactions to 
the DSMB, as appropriate. 
Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the package insert or is not listed at the specificity, severity or rate of occurrence that has been 
observed; or 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 package insert 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)] Division 5 of the Canadian Food and Drug 
Regulations and ICH E2A} 


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For events assessed in association with kidney biopsy, an AE or suspected adverse reaction is 
considered “unexpected” if it is not listed in the protocol or is not listed at the specificity, severity 
or rate of occurrence that has been observed. 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or Sponsor DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a), 
Division 5 of the Canadian Food and Drug Regulations and ICH E2A): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either 
the investigator or Sponsor [add DAIT/NIAID or other Sponsor, if applicable], 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. 
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. 
12.3. Grading and Attribution of Adverse Events 
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 (CTCAE). This document (referred to herein as the NCI-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 Chair(s), Principal Investigator, etc. 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: 
Table 13. NCI-CTCAE Adverse Event Grading Scale 
 
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 
For this trial, only events that are ≥ 3 will be recorded as adverse events. Additionally, all events 
that meet serious criteria will be recorded as AEs/SAEs, regardless of severity grade. 


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For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not 
limited to, a radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent 
adverse event is defined as an increase in grade from baseline or from the last post-baseline value 
that doesn’t meet grading criteria. Changes in grade from screening to baseline will also be 
recorded as adverse events, but are not treatment-emergent. If a specific event or result from a 
given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, then an 
abnormal result would be considered an adverse event if changes in therapy or monitoring are 
implemented as a result of the event/result. 
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 electronic case report form (AE/SAE 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 12.2. 
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 14. Attribution of Adverse Events 
 
 
Code 
Descriptor 
Relationship (to primary investigational product and/or other 
concurrent mandated study therapy or study procedure) 
UNRELATED CATEGORY 
1 
Unrelated 
The adverse event is clearly not related: there is insufficient 
evidence to suggest a causal relationship. 
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. 


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• 
Blood Draw 
• 
Biopsy 
Procedures 
For this study, attribution assessment for the study therapy regimen and study mandated 
procedures would be made when an adverse event/Serious Adverse Event is recorded. 
 
Table 15. Study therapy regimen 
 
Experimental Arm 
• Investigational Agent 
o Remicade® (Infliximab) 
• Standard of Care Immunosuppression 
o Thymoglobulin® (Anti-Thymocyte Globulin-Rabbit) 
o Tacrolimus (Prograf®) or equivalent, or an equivalent 
starting dose of a once-daily formulation of tacrolimus 
o Mycophenolate Mofetil/MMF or Mycophenolate 
Acid/MPA (or their generic equivalents) 
o Prednisone or generic equivalent 
Control Arm 
• Standard of Care Immunosuppression 
o Placebo 
o Thymoglobulin® (Anti-Thymocyte Globulin-Rabbit) 
o Tacrolimus (Prograf®) or equivalent, or an equivalent 
starting dose of a once-daily formulation of tacrolimus 
o Mycophenolate Mofetil/MMF or Mycophenolate 
Acid/MPA (or their generic equivalents) 
o Prednisone or generic equivalent 
 
Table 16. Study mandated procedures 
 
 
12.4. Collection and Recording of Adverse Events 
Collection Period 
Adverse events will be collected from the initiation of the investigational treatment until one of 
the following time points: a subject completes study participation or 45 days after he/she 
prematurely withdraws (without withdrawing consent) or is withdrawn from the study. 
After Month 24/Visit 14 
After Month 24/Visit 14 sites will only report grade 3 or higher AEs and any SAE regardless of 
severity that occur within 24 hours after a protocol mandated procedure of blood draw. 
 
Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject 
• 
Interviewing the subject [e.g., using a checklist, structured questioning, diary, etc.] 
• 
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 12.3, Grading and Attribution of Adverse Events. 


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Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as 
described previously (Section 12.2, Definitions) on the appropriate AE/SAE eCRF regardless of the 
relationship to study therapy regimen or study procedure. 
• 
COVID-19 infections of any grade 
 
 
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. 
• 
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, anemia, lymphocytopenia 
• 
An elective hospitalization or hospital admission for the purpose of conducting protocol- 
mandated procedures is not to be reported as an SAE unless the hospitalization is 
prolonged due to complications. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the 
end of study participation, or until 45 days after the subject prematurely withdraws (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first. 
12.5. Reporting of Serious Adverse Events and Adverse Events 
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, Division 
5 of the Canadian Food and Drug Regulations and ICH E6 guidelines. 
Site investigators will report all serious adverse events (see Section 12.2.3, 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 will be provided. 
However, unavailable details of the event will not delay submission of the known information. As 
additional details become available, the AE/SAE eCRF will be updated and submitted. 
Reporting to Health Authority 
After an adverse event requiring 24-hour reporting (per Section 12.5.1, 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 
(Annual Reporting and Expedited Reporting). 
12.5.2.1 Annual Reporting 
DAIT/NIAID will include in the annual study report to health authorities all adverse events classified 
as: 


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• 
Serious, expected, suspected adverse reactions (see Section 12.2.1.1, Suspected Adverse 
Reaction, and Section 12.2.2, Unexpected Adverse Event) 
• 
Serious and not a suspected adverse reaction (see Section 12.2.2, Suspected Adverse 
Reaction) 
• 
Pregnancies 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the 
Annual IND Report. 
12.5.2.2 Expedited Safety Reporting 
This option, with 2 possible categories, applies if the adverse event is classified as one of the 
following: 
Category 1: Serious and unexpected suspected adverse reaction (SUSAR) 
(See Section 12.2.1.1, Suspected Adverse Reaction and Section 12.2, Unexpected Adverse Event 
and 21 CFR 312.32(c) (1)i, Division 5 of the Canadian Food and Drug Regulations and ICH E2A). 
The sponsor shall report any suspected adverse reaction that is both serious and unexpected. 
The sponsor shall report an adverse event as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the study drug and the adverse event, such 
as: 
1. A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, or Stevens-Johnson Syndrome); 
2. One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture); 
3. An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
 
Category 2: Any findings from studies that suggests a significant human risk 
The sponsor shall report any findings from other epidemiological studies, analyses of adverse 
events within the current study or pooled analysis across clinical studies or animal or in vitro testing 
(e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest a significant risk in humans 
exposed to the drug that would result in a safety-related change in the protocol, informed 
consent, investigator brochure or package insert or other aspects of the overall conduct of the 
study. 
 
DAIT/NIAID shall notify the appropriate health authorities (FDA and Health Canada) and all 
participating investigators of Expedited Safety Reports within 15 calendar days; unexpected f atal 
or immediately life-threatening suspected adverse reaction(s) shall be reported as soon as 
possible or within 7 calendar days. 
Reporting of Adverse Events to IRBs/IECs 
All investigators shall report adverse events, including expedited reports, in a timely fashion to their 
respective IRBs/IECs in accordance with applicable regulations and guidelines. All Safety Reports 
to the FDA and Health Canada shall be distributed by DAIT/NIAID or designee to all participating 
institutions for site IRB/IEC submission. 
12.6. Pregnancy Reporting 


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The investigator shall be informed immediately of any pregnancy in a study subject or a partner 
of a study subject. A pregnant subject will not be infused. The investigator shall counsel the subject 
per site standard of care. 
The investigator shall report to the SACCC and DAIT/NIAID all pregnancies within 1 business day 
of becoming aware of the event using the Pregnancy eCRF. All pregnancies identified during 
the study shall be followed to conclusion and the outcome of each must be reported. The 
Pregnancy eCRF shall be updated and submitted to SACCC and DAIT/NIAID when details about 
the outcome are available. When possible, similar information shall be obtained for a pregnancy 
occurring in a partner of a study subject. 
Information requested about the delivery shall include: 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 
minutes, and 24 hours after birth, if available 
• 
Any abnormalities. 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, 
and medically indicated abortion will be considered an SAE. Pregnancies reported as SAEs will 
be submitted to the SACCC, DAIT/NIAID, the FDA and Health Canada using the SAE reporting 
procedures described above. 
12.7. COVID-19 Reporting 
COVID-19 is an event of medical importance. Centers must report any instance of COVID-19 
infection as a Serious Adverse Event. If none of the standard criteria for a serious event are met, 
the event should still be reported as an SAE due to its medical importance. This event should be 
reported (entered on the AE/SAE form) within 24 hours of awareness even if the event does not 
meet serious criteria. 
12.8. Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB/ IEC as well as the SACCC using the AE/SAE form 
when an “unanticipated problem involving risks to subjects or others” is identified, which is not 
otherwise reportable as an AE. 
12.9. Review of Safety Information 
The PI, the DAIT/NIAID Medical Monitor, and the NIAID/DAIT Transplant DSMB will review safety 
data on an ongoing basis. Enrollment and initiation of study treatment may be suspended at any 
time if any of these reviews conclude there are significant safety concerns. 
Medical Monitor Review 
DAIT/NIAID Medical Monitor shall receive monthly reports from the SACCC compiling new and 
accumulating information on AEs, SAEs, and pregnancies recorded by the study sites on 
appropriate eCRFs. 
In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE 
and pregnancy reports received by the SACCC (See Sections 12.5.1, Reporting of Serious Adverse 
Events to Sponsor, and 12.6, Pregnancy Reporting). 
DSMB Review 


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12.8.2.1 Planned DSMB Reviews 
The Data and Safety Monitoring Board (DSMB) shall 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. 
12.8.2.2 Ad hoc DSMB Reviews 
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 study principal investigator or DAIT/NIAID. Additionally, satisf action of any of 
the stopping rules listed in Section 11.5 will trigger an ad hoc DSMB Safety Review. 
12.8.2.3 Temporary Suspension of Enrollment/Drug Dosing for Ad Hoc DSMB Safety 
Review 
A temporary halt in enrollment, randomization and administration of Remicade®/infliximab or 
Remicade®/infliximab placebo will be implemented if an ad hoc DSMB safety review is required. 


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13. Statistical Considerations and Analytical Plan 
13.1. Overview 
CTOT-19 is a Phase 2, randomized, double blind, controlled clinical trial in which 300-deceased 
donor kidney transplant recipients will be randomized 1:1 to the experimental or control arms. 
Each group will receive rATG induction in combination with either infliximab or placebo pre- 
reperfusion followed by maintenance therapy consisting of tacrolimus, either MMF or enteric 
coated MPA, and prednisone. The objective of the study is to determine the efficacy of 
intravenous infliximab administered at the time of transplantation on 2-year kidney transplant 
survival and function. 
13.2. Endpoints 
As described in section 2, the study endpoints are outlined in the table below. 
 
Endpoints 
Primary Endpoint 
The difference between the mean 24-month eGFR (modified MDRD) in the experimental vs. 
control arms. 
Secondary Endpoints (Efficacy, Safety and Mechanistic Endpoints) 
Efficacy Endpoints 
1. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) within 
a) 6 month and 
b) 2 years of transplant 
2. BANFF grades of first Acute Cellular Rejections (ACR) within 6 month of transplant 
3. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline 
rejection within 
a) 6 month and 
b) 2 years of transplant 
4. Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR) 
within 6 months and 2 years of transplant 
5. Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or 
suspicious for AMR within 
a) 6 months and 
b) 2 years of transplant 
6. BANFF grades of first AMR within 6 months of transplant 
7. Proportion of subjects with BANFF chronicity scores >or equal 2 on 24-month biopsy 
8. Change in BANFF chronicity scores between implantation and 24 month biopsies 
9. eGFR (as measured by both MDRD and CKD-EPI) 
a) Change in eGFR between 3 months and 24 months 
b) Change in eGFR between post-transplant nadir (lowest eGFR in first 6 months) and 24 
months 
c) eGFR on days 7, 30, 90, and 180 post-transplant 
10. Proportion of subjects with: 
a) Death or graft failure within 2 years 
b) Only graft failure within 2 years 


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11. Each of the following: 
a) Proportion of subjects that required at least one dialysis treatment within the first 
week after transplantation 
b) Number of dialysis sessions in the first 8 weeks post-transplantation. 
c) Duration of DGF defined as time from transplantation to the last required dialysis 
treatment 
d) The incidence of primary non-function (PNF), defined as for dialysis-dependency for 
more than 3 months or an eGFR 20 ml/min or less at 90 days post-transplant 
e) Change from baseline (immediately after surgery) in serum creatinine and serum 
creatinine concentration at 24, 48, and 72 hours. 
12. Days from transplantation until event (ACR, AMR, or hospitalization for infection and or 
malignancy) 
13. Rate of Slow Graft Function (SGF): 
a) The proportion of patients with a serum creatinine of more than 3 mg/dL at day 5 
post-transplant, 
b) Creatinine reduction ratio (CRR) on day 2 
c) Creatinine reduction ratio (CRR) on day 5 
d) The proportion of patients whose day 5 serum CRR was less than 70% 
e) The proportion of patients whose day 2 serum CRR was less than 30% 
f) Proportion of subjects who need dialysis after 1 week. 
Safety/Complication Endpoints 
1. Proportion of subjects with: 
a) Any infection requiring hospitalization or resulting in death 
b) With mycobacterial or fungal infections 
2. Proportion of subjects with CMV viremia that require a change in immunosuppression or 
anti-viral treatment as per standard of care at the site 
3. Proportion of subjects with BK viremia that require a change in immunosuppression or 
anti-viral treatment as per standard of care at the site 
4. Proportion of subjects with malignancy 
5. Proportion of subjects with impaired wound healing manifested by wound dehiscence, 
wound infection, or hernia at the site of the transplant incision. 
Mechanistic Endpoints 
1. Sensitivity, specificity, PPV, and NPV of biomarkers, including PRT, urinary CXCL9, blood 
genomic profile, and 3-month allograft genomic profile (alone and/or in combination) to 
predict: 
a) Incident biopsy-proven acute rejection. 
b) Graft loss 
c) Chronic graft injury, as measured by 2-year eGFR 
2. Each of the following: 
a) Inflammatory gene expression profiles 
b) Frequency of donor reactive T-cells 
c) Frequency and function of Treg 
d) Proportion of subjects with de novo DSA within 24 months 
e) Fibrogenic gene expression profiles 
f) Amount of peritubular capillary loss by histology 


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Ancillary Endpoints 
1. Percentage of predicted prednisone bottle openings as measured by a medication 
event monitoring system (MEMS®) in the first 3 months post-transplantation 
2. Standard deviation of the monthly tacrolimus trough levels from 6 months post- 
transplantation to 2 years post-transplantation 
 
13.3. Measures to Minimize Bias 
Randomization will be carried out with fixed block sizes and stratification by enrolling center to 
balance the intervention assignments. In order to avoid center-specific measurement error, 
mechanistic assays will be performed in central laboratories where the lab personnel will be 
blinded to the randomization status of the study subject. All endpoints are predefined. We will 
also attempt to enroll all consecutive patients fulfilling inclusion criteria. 
13.4. Analysis Plan 
All analyses will be detailed in a statistical analysis plan. All analyses will be performed using the 
SAS System version 9.3 (or higher). 
Analysis Populations. 
• 
Intent-to-Treat (ITT) Sample – All transplanted and randomized subjects who receive the 
infliximab/placebo infusion. This sample will be used for efficacy and some safety analyses. 
Transplanted subjects who receive an infusion, but have no additional follow up will be 
used in this population 
• 
Per Protocol (PP) Sample – All randomized subjects who receive the infliximab/placebo 
infusion who are compliant with their medications and do not have any major protocol 
deviations that preclude analysis of the primary endpoint. 
• 
Safety Sample - All subjects who receive any infliximab/placebo infusion. This sample will 
be used for some safety summaries/analyses. 
• 
Delayed Graft Function (DGF) Sample –All subjects with delayed graft function. This is 
defined as any dialysis in the first 7 days. This sample will be used for all DGF related 
analyses. 
• 
Screening Sample – All subjects who are enrolled in the study. This sample will be used for 
disposition summaries. 
Subjects will be analyzed in the group to which they were randomized, regardless of the treatment 
received. 
Primary Analysis of Primary Endpoint(s)/Outcome(s) 
All subjects in the ITT sample will be used for the primary analysis. Mean eGFR of each of the two 
treatment arms will be compared within a restricted maximum likelihood repeated measures 
model (MMRM) framework, wherein repeated measures of eGFR at months 1, 3, 6 12, 18, and 24 
will be modeled using fixed effects of treatment group, collection time point, and the interaction 
between time point and treatment group. A random subject effect will also be included in the 
model to appropriately adjust for the correlation of having multiple eGFR values for each subject. 
The following material presents the notation and the model. 
Let 
 
t index the two treatment arms, t = 1 for placebo control, i.e., rATG induction in combination with placebo; 
t = 2 for experimental treatment arm, i.e., rATG induction in combination with infliximab; 


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$
s index subjects within treatment arms, s = 1, 2, … , Nt= number of subjects in treatment arm t whose data 
are in the ITT Analysis Set of Data (the data from the subjects in the ITT Analysis Set of Subjects or “ITT 
Analysis Population”); 
m index the post-randomization measurement or evaluation occasions, with m = 1 ↔ month 1 evaluation, 
m = 2 ↔ month 3 evaluation, m = 3 ↔ month 6 evaluation, m = 4 ↔ month 12 evaluation, m = 5 ↔ month 
18 evaluation, and m = 6 ↔ month 24 evaluation. 
Ytssm = eGFR value from subject number s (s=1, 2, …, Nt ) within treatment arm t (t = 1 for placebo control, 
i.e., rATG induction in combination with placebo; t = 2 for experimental treatment arm, i.e., rATG 
induction in combination with infliximab), m = 1 ↔ month 1 evaluation, m = 2 ↔ month 3 evaluation, m = 
3 ↔ month 6 evaluation, m = 4 ↔ month 12 evaluation, m = 5 ↔ month 18 evaluation, and m = 6 ↔ month 
24 evaluation. 
The MMRM for Ytssm is, for the values of t, s, and m given above: 
 
!!"# = #!# + %!" + &!"# 
 
where 
 
μtm = E[Ytsm] is the population mean eGFR for subjects treated with treatment t and followed for the time 
indicated by the index m; 
δts is the random effect on eGFR associated with subject s in treatment arm t; 
 
εtsm = Ytssm –(μtm + δts) is the random component in the eGFR measurement from subject s in treatment arm t 
at evaluation occasion m. 
 
Assumptions: 
 
• 
Each μtm is an unknown, fixed constant parameter; an MMRM will be used to estimate the values of the 
μtm. 
• 
Each δts is a random variable that is stochastically independent of each other δt’s’ where (t,s) ≠ (t’,s’); 
E[δts]=0, '
% = ()*(%!") for each combination of t and s 
• 
Each εtsm is a random variable that is stochastically independent of each other εt’s’m’ where (t,s,m) ≠ 
(t’,s’, m’); E[εtsm]=0, '
% = ()*(& 
) for each combination of t, s, and m. 
& 
!"# 
It follows that ()*[!!"#] = '
% + '
% and Cov[! 
, ! 
] = 4 '
% for m≠m’. That is, the expected-value 
$ 
& 
!"#  !"#' 
$ 
component of the MMRM is a cell means model and the covariance component is a compound symmetric 
model. 
Let τ denote the “treatment effect at 24 months”, defined as 5 = #%,) − #*,), i.e., the difference in 24-month 
population mean eGFR for the experimental treatment minus the corresponding placebo mean. τ is a 
parameter of primary interest; the MMRM will be used to estimate τ. 
The primary null and alternative hypotheses are: 7+: 5 = 0 vs. 7, : 5 ≠ 0. The MMRM will be used to test 
these hypotheses at the α = 0.05 Type I error rate. 
SAS PROC MIXED (ver. 9.3 or higher) will be used to fit the MMRM to the data, estimate the 
parameters, and test the primary hypotheses along with others. 


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The mean eGFR at 24 months will also be summarized and the difference will be presented with 
a 95% confidence interval. Additional graphical summaries of the eGFR over time will be used to 
further illustrate any differences between the two treatment groups. MMRM assumptions will be 
evaluated graphically via standard residual analyses. If the assumptions fail, a suitable 
transformation (e.g., natural logarithms) will be utilized and the data will be reanalyzed on the 
transformed scale. Results associated with the F-test for the contrast and the corresponding mean 
treatment difference with two-sided 95% confidence intervals will be reported. Missing data will 
not be imputed for the primary analysis; however, a sensitivity analysis will be employed to assess 
the impact of missing data due to subjects who terminate the study early. 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) 
Because subject drop-outs represent an important area to carefully examine, (86) we propose to 
compare 1) the proportion of subjects who drop out prior to the 24-month visit (i.e., premature 
withdrawals), 2) the timing of premature withdrawals, and 3) reasons for premature withdrawals. 
These comparisons will look for differences between treatment groups that could indicate that 
the missing at random (MAR) assumption in the primary analysis model does not hold. 
Additionally, we will utilize the methods of Ma et al (87) to provide an objective index of the level 
of non-ignorable missingness. 
If the MAR assumption f ails, we will perform a sensitivity analysis to examine the impact of the 
missing data on our inference. The first sensitivity analysis will use a pattern mixture model (PMM) 
fitted via multiple imputation (88), and is an example of a “controlled imputation” method (85, 
89) and will implement a jump to control (89) approach. For subjects who drop out of the study, 
this method imputes missing values for both treatment groups from the placebo population, which 
reduces any bias away from the null hypothesis of no difference between treatment groups. 
Additionally, we will perform a second sensitivity analysis that imputes a single point for subjects 
(in either treatment group) that have had a graft loss or have died. Specifically, subjects who 
have a graft loss prior to 24 months would have an eGFR of 10 imputed for their remaining eGFR 
collection time points. Subjects who die with a functioning kidney would have a “last observation 
carried forward” imputation, which means that we would impute their last known eGFR prior to 
death for all remaining eGFR collection time points. This final eGFR would be based on the central 
evaluation of eGFR if the collection time was within 1 month of death and on a local assessment 
of eGFR if the last collection for the central labs was more than 1 month from death. 
A third sensitivity analysis will compare the eGFR at 24 months between the two treatment arms 
using a Wilcoxon test. Subjects who experience death or graft loss will be given the worst ranks. 
Subjects who are missing their 24-month eGFR due to other causes will receive a rank based on 
an imputed eGFR from the model used in the primary analysis. 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
The secondary endpoints are to be computed and summarized by treatment and, where 
appropriate, by day/month and treatment. Continuous variables will be summarized using means 
and standard deviations or, if appropriate, medians and inter-quartile ranges, and categorical 
variables will be summarized using frequencies and percentages. 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 (Table 
17) lists each endpoint and its measurement scale (continuous, dichotomous, and ordinal). 
Secondary analyses are considered descriptive. 


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Longitudinal continuous variables will be modeled using a MMRM similar to the one used to 
analyze the primary endpoint. Non-longitudinal continuous variables will be analyzed using an 
ANOVA (e.g. change from baseline in eGFR). Dichotomous measures of prevalence and 
incidence will be analyzed using a chi-square test. Time to event variables will be analyzed by 
fitting Cox regression models to the data (90). The change in BANFF cell-mediated AR score will 
be analyzed using a generalized McNemar’s test. 
Table 17. Summary of Proposed Analyses for CTOT-19 Secondary Clinical 
Endpoints 
 
Response 
Type 
(Sample) 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test 
for treatment 
effects 
Incidence 
and Severity 
of Rejection 
Endpoints 
(ITT, PP) 
Proportion of subjects with 
biopsy proven acute 
cellular rejection (BPAR) 
within a) 6 month and b) 2 
y of transplant 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
BANFF grades of first Acute 
Cellular Rejections (ACR) 
within 6 month of transplant 
categorical 
Table 
Chi-square test 
Proportion of subjects with 
biopsy proven acute 
antibody mediated 
rejection (AMR) within 6 
months and 2 y of 
transplant 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
BANFF grades of first AMR 
within 6 months of 
transplant 
categorical 
Table 
Chi-square test 
Proportion of subjects with 
BANFF chronicity scores >or 
equal 2 on 24 month biopsy 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Change in BANFF chronicity 
scores between 
implantation and 24 month 
biopsies 
Categorical 
Shift table 
Generalized 
McNemar’s test 
Days from transplantation 
until event (ACR, AMR, or 
hospitalization for infection 
and or malignancy) 
Time to event 
Kaplan-Meier 
estimates 
Cox model 
Renal 
Function 
Endpoints 
(ITT, PP) 
Change in eGFR (as 
measured by both MDRD 
and CKD-EPI) between 3 
months and 24 months 
continuous 
Mean + 95% CI 
ANOVA 
Change in eGFR (as 
measured by both MDRD 
and CKD-EPI) between 
post-transplant nadir 
(lowest eGFR in first 6 
months) and 24 months 
continuous 
mean + 95% CI 
ANOVA 


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Estimated GFR (as 
measured by both MDRD 
and CKD-EPI) on days 7, 30, 
90, and 180 post-transplant 
continuous 
mean + 95% CI 
MMRM, 
(repeated time 
effect; fixed 
effects of 
treatment, time 
and treatment 
by time 
interaction) 
Graft Failure 
Endpoints 
Proportion of subjects with 
death or graft failure within 
2 years 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects with 
only graft failure within 2 
years 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Delayed Graft 
Function 
Endpoints 
(DGF Sample) 
Proportion of subjects that 
required at least one 
dialysis treatment within the 
first week after 
transplantation 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Number of dialysis sessions 
in the first 8 weeks post- 
transplantation 
continuous 
mean and/or 
geometric mean 
+ 95% CI 
Poisson regression 
Duration of DGF defined as 
time from transplantation to 
the last required dialysis 
treatment 
continuous 
mean and/or 
geometric mean 
+ 95% CI 
ANOVA 
The incidence of primary 
non-function (PNF), defined 
as dialysis-dependency for 
more than 3 months or an 
eGFR 20 ml/min or less at 90 
days post-transplant 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Change from baseline 
(immediately after surgery) 
in serum creatinine and 
serum creatinine 
concentration at 24, 48, 
and 72 hours 
continuous 
mean + 95% CI 
ANOVA 
Proportion of patients with 
total 24-hour urine output of 
more t00 ml on days 2, 3 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Slow Graft 
Function 
(ITT, PP) 
The proportion of patients 
with a serum creatinine of 
more than 3 mg/dL at day 
5 post-transplant 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Creatinine reduction ratio 
(CRR) on day 2 
ratio 
mean + 95% CI 
ANOVA 
Creatinine reduction ratio 
(CRR) on day 5 
ratio 
mean + 95% CI 
ANOVA 
The proportion of patients 
whose day 5 serum CRR 
was less than 70% 
dichotomous 
proportion + 95% 
CI 
Chi-square test 


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The proportion of patients 
whose day 2 serum CRR 
was less than 30% 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects who 
need dialysis after 1 week 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
 
 
We will test a biomarker panel to predict and diagnose incipient ACR and to determine the 
accuracy of early post-transplant markers to define individuals most at risk for late graf t 
dysfunction and chronic graft injury. This panel will include reactive T cell (PRT) assays, urinary 
chemokine, urinary PCR assays, gene expression profiles in peripheral blood, and gene expression 
profiles in graft tissue. If the comparison of the biomarkers between the two treatment groups (see 
previous paragraph) yields no differences, we will utilize the entire study population. If, however, 
we find an influence of the infliximab on the biomarkers, we will limit this investigation to the control 
subjects. This evaluation will be based primarily on examining the Receiver Operating 
Characteristic (ROC) Curves generated for each candidate biomarker and the associated 
classification accuracy in terms of sensitivity and specificity as well as positive and negative 
predictive value. We will also explore combining the candidate biomarkers to determine whether 
there are distinct combinations of biomarkers that may improve performance relative to 
individual biomarkers. 
Our hypothesis that anti-TNFa limits activation of donor reactive immunity and prevents initiation 
and progression of graft fibrosis by dampening early inflammation within the allograft will be 
assessed by a series of linear mixed models. The assays to assess these effects will include T cell 
(PRT) assays, urinary chemokine, urinary PCR assays, gene expression profiles in peripheral blood, 
gene-expression profiles in graft tissue, donor-reactive effector T cells, markers of inflammation, 
regulatory T cells, donor specific antibody, fibrogenic gene profiles, and peritubular capillary loss. 
Models will be fit sequentially, with specific models fit to address specific elements of the 
hypothesized mechanism. Initially we will use regression models to quantify the extent to which 
infliximab, when added to therapy with ATG, reduces “early” inflammation at the time of 
transplantation, measured both by cellular reactivity in blood and from post-implantation 
biopsies. Corresponding linear regression models will assess differences between treatment 
groups with respect to inflammation measures at 24 mos., and mixed linear models will be used 
to assess the inflammation measures over the entire time course subsequent to the “early” 
evaluation. Additionally, proportional odds models will be used to assess treatment differences in 
ordinal grade of graft fibrosis at 24 mos. and, through a generalized estimating equation (GEE) 
approach, over time. 
Should chance imbalances occur despite randomization, estimates of treatment effects on 
primary and some secondary outcomes will be obtained from multivariable models that include 
the treatment factor, the potential confounders and statistically significant interactions between 
the covariates and the treatment f actor. In particular, the two ancillary adherence measures, the 
standard deviation of tacrolimus trough levels and the MEMS® percentage of predicted 
medication use will be included in the analysis of potential confounding variables. 
Analyses of Safety Endpoints 
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. 


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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. 
Specific AEs of interest include infections, hospitalizations, malignancies, and wound healing. The 
accompanying table (Table X) lists each of these AE endpoints and its measurement scale 
(continuous, dichotomous, and ordinal) as well as the summary statistics and the statistical model 
that will be used to compare the endpoints between treatment groups. 
Table 18. Summary of Proposed Safety Endpoints and Analyses for CTOT-19 
 
Response 
Type 
(Sample) 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test 
for treatment 
effects 
Safety 
Endpoints 
(ITT) 
Proportion of subjects with a) 
any infection requiring 
hospitalization or resulting in 
death b) mycobacterial or 
fungal infections 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects with 
CMV viremia that require a 
change in 
immunosuppression or anti- 
viral treatment as per 
standard of care at the site 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects with 
BK viremia that require a 
change in 
immunosuppression or anti- 
viral treatment as per 
standard of care at the site 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects with 
malignancy 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
Proportion of subjects with 
impaired wound healing 
manifested by wound 
dehiscence, wound 
infection, or hernia at the site 
of the transplant incision 
dichotomous 
proportion + 95% 
CI 
Chi-square test 
 
Descriptive Analyses 
Disposition of subjects will be summarized by treatment group (including the number of subjects 
who complete the study, number lost to follow-up, number withdrawn from study, times to lost to 
follow-up, and reasons for discontinuation). Baseline and demographic subject characteristics 
will also be summarized by treatment group. Other clinical characteristics will be summarized by 
treatment group and study visit as needed. 
13.5. Interim Analysis 
There are no planned interim analyses for this study. 


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13.6. Sample Size Calculations 
Primary endpoint of eGFR (MDRD) at 24 months: Data from published studies employing similar 
control arms with deceased donor allograft recipients induced with ATG on CNI, MMF and 
prednisone (BENEFIT trial among others) indicate 24 mo. GFRs range from 55-70 ml/min with s.d. 
~23-27 ml/min. Conservatively assuming a s.d. of 25 ml/min, 130 patients per arm will provide 90% 
power to detect a difference of 10 ml/min in eGFR between groups using a two-sided two-sample 
t-test at an alpha level of 0.05. We will be able to detect smaller differences in eGFR should the 
size of the s.d. be less than 25 mL/min. Note that in our preliminary assessment of eGFRs in CTOT- 
01, the mean ± s.d. 6 mo. values were 57.7± 17.1, a lower s.d. that would permit detection of eGFR 
differences of < 8 ml/min between groups with 90% power. 
 
Assuming a 15% dropout rate (10% due to death or graft loss, 5% for other reasons) we require 150 
patients per arm. Based on a sample size of 300 (150 patients/arm), power calculations for 
selected secondary endpoints are given in Table 18. 
Table 19. Power for secondary endpoint analyses 
 
Secondary Endpoint 
Expected 
Outcome in 
Control Group 
Expected outcome in 
treatment group 
(80%/90% power) 
Detectable Risk- 
Reduction 
(80%/90% Power) 
BPAR at 12 months 
15% 
5.3%/4.1% 
65%/73% 
Graft loss at 12 months 
10% 
2.3%/1.4% 
77%/86% 
SGF 
23% 
10.9%/9.3% 
53%/60% 
DGF 
40% 
24.9%/22.7% 
38%/43% 
(BPAR: Biopsy Proven Acute Rejection, SGF: Slow Graft Function, DGF: Delayed Graft Function) 


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14. Identification and Access to Source Data 
14.1. Source Data 
Source documents and source data are considered to be the original documentation where 
subject information, visits consultations, examinations and other information are recorded. 
Documentation of source data is necessary for the reconstruction, evaluation and validation of 
clinical findings, observations and other activities during a clinical trial. 
14.2. Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, as well 
as to relevant health authorities. Authorized representatives as noted above are bound to 
maintain the strict confidentiality of medical and research information that may be linked to 
identified individuals. 


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15. Quality Assurance and Quality Control 
15.1. Quality Assurance 
The sponsor will review site processes for quality management of the protocol prior to enrollment 
at each clinical center, to include processes for data and biological specimen 
collection. Expectations will be communicated to each site regarding study conduct. In 
addition, all study staff are required to have GCP and ICH training. 
15.2. Quality Control 
A quality control plan for electronic data capture and data management will be created by 
the data center and will be reviewed by the sponsor prior to study onset. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 
The Sponsor will develop a risk-based monitoring plan to direct study monitoring. Sponsor 
monitors will follow written Standard Operating Procedures (SOPs) to verify that the clinical trial is 
conducted, data are generated, and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 


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16. Protocol Deviations 
16.1. Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the 
protocol; no deviations from the protocol are permitted. Any change, divergence, or departure 
from the study design or procedures constitutes a protocol deviation. As a result of any deviation, 
corrective actions will be developed by the site and implemented promptly. 
Major Protocol Deviation - A Major Protocol Deviation is a deviation from the IRB approved 
protocol that may affect the subject's rights, safety, or well-being and/or the completeness, 
accuracy and reliability of the study data. In addition, protocol violations include willful or 
knowing breaches of human subject protection regulations, or policies, any action that is 
inconsistent with the NIH Human Research Protection Program’s research, medical, and ethical 
principles, and a serious or continuing noncompliance with federal, state, local or institutional 
human subject protection regulations, policies, or procedures. 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or 
departure from the study design or procedures of a research protocol that does not have a major 
impact on the subject's rights, safety or well-being, or the completeness, accuracy and reliability 
of the study data. Non-Major Protocol Deviations will not be collected in this study. 
16.2. Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol 
deviations as directed by the study Sponsor. However, protocol deviations may also be identified 
during site monitoring visits or during other forms of study conduct review. 


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17. Ethical Considerations and Compliance with Good Clinical Practice 
17.1. 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 the IRB or Ethics Committee. The IRB, 
Ethics Committee or relevant health authority (FDA or Health Canada) will also approve any 
amendments to the protocol or to the consent materials before they are implemented. 
17.2. Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will 
allow adequate time for review and discussion prior to his/her decision. The principal site 
investigator or a study physician designee listed on the 1572, must conduct a meeting with the 
potential study participant to review all of the required elements of informed consent, review the 
consent form and answer questions. The conversation between investigator or their physician 
designee and the potential study participant must be documented in participant’s medical 
record. The study physician designee listed on the 1572 must be a medical doctor licensed to 
practice medicine in the United States for US sites and possess appropriate licenses to practice 
medicine in Canada for the Canadian sites. Coordinators, nurses, physician assistants, nurse 
practitioners, non-physicians listed on the 1572 and other support staff may provide additional 
trainings and discussions to potential study participants, but cannot serve as the physician 
designee listed above. 
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) will read, sign, and date a consent form before undergoing any study procedures. 
Consent materials will be presented in participants’ primary language. A copy of the signed 
consent form will be given to the participant. 
The consent process will be ongoing. The consent form will 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. 
17.3. 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 will not transmit 
documents containing personal health identifiers (PHI) to the study sponsor or their 
representatives. 


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18. Publication Policy 
The CTOT policy on the publication of study results will apply to this trial. The CTOT Publications 
Policy is located on the CTOT website at www.ctotstudies.org. 


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44. Gangemi A, Salehi P, Hatipoglu B, Martellotto J, Barbaro B, Kuechle JB et al. Islet 
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45. Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T et al. Single-donor, 
marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 2005;293:830-835. 
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47. Betts BC, Abdel-Wahab O, Curran SA, St Angelo ET, Koppikar P, Heller G et al. Janus kinase-2 
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51. Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE. Pre-transplant IFN- 
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enzyme-linked immunosorbent spot assay for post-transplant alloreactivity as a potentially 
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53. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA et al. 
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55. Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N et al. Enzyme linked 
immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal 
function in kidney transplant recipients. Am J Transplant 2003;3:878-884. 
56. Nather BJ, Nickel P, Bold G, Presber F, Schonemann C, Pratschke J et al. Modified ELISPOT 
technique--highly significant inverse correlation of post-Tx donor-reactive IFNgamma- 
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57. Nickel P, Presber F, Bold G, Biti D, Schonemann C, Tullius SG et al. Enzyme-linked 
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alloreactive T cells correlate with graft function in longstanding renal transplant recipients. J 
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59. Kim SH, Oh EJ, Kim MJ, Park YJ, Han K, Yang HJ et al. Pretransplant donor-specific interferon- 
gamma ELISPOT assay predicts acute rejection episodes in renal transplant recipients. 
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60. Poggio ED, Augustine JJ, Clemente M, Danzig JM, Volokh N, Zand MS et al. Pretransplant 
cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute 
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61. Poggio ED, Clemente M, Hricik DE, Heeger PS. Panel of reactive T cells as a measurement of 
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63. Traitanon O, Gorbachev A, Bechtel JJ, Keslar KS, Baldwin WM, 3rd, Poggio ED et al. IL-15 
induces alloreactive CD28(-) memory CD8 T cell proliferation and CTLA4-Ig resistant memory 
CD8 T cell activation. Am J Transplant 2014;14:1277-1289. 
64. Akimova T, Kamath BM, Goebel JW, Meyers KE, Rand EB, Hawkins A et al. Differing effects of 
rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant 
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65. van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS. Cutting edge: 
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of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury. Am J Transplant 
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68. Keslar KS, Lin M, Zmijewska AA, Sigdel TK, Tran TQ, Ma L et al. Multicenter evaluation of a 
standardized protocol for noninvasive gene expression profiling. Am J Transplant 
2013;13:1891-1897. 
69. Duerrschmid C, Crawford JR, Reineke E, Taffet GE, Trial J, Entman ML et al. TNF receptor 1 
signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis. J Mol Cell 
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70. Therrien FJ, Agharazii M, Lebel M, Lariviere R. Neutralization of tumor necrosis factor-alph a 
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71. Osawa Y, Hoshi M, Yasuda I, Saibara T, Moriwaki H, Kozawa O. Tumor necrosis factor-alpha 
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72. Liew R, Khairunnisa K, Gu Y, Tee N, Yin NO, Naylynn TM et al. Role of tumor necrosis factor- 
alpha in the pathogenesis of atrial fibrosis and development of an arrhythmogenic substrate. 
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signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic 
target. Proc Natl Acad Sci U S A 2013;110:E928-937. 
74. Borthwick LA, Corris PA, Mahida R, Walker A, Gardner A, Suwara M et al. TNFalpha from 
classically activated macrophages accentuates epithelial to mesenchymal transition in 
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75. Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and 
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of peritubular capillaries after kidney transplantation. J Am Soc Nephrol 2011;22:1024-1029. 
78. Chapal M, Neel M, Le Borgne F, Meffray E, Carceles O, Hourmant M et al. Increased soluble 
flt-1 correlates with delayed graft function and early loss of peritubular capillaries in the 
kidney graft. Transplantation 2013;96:739-744. 
79. Reed EF, Rao P, Zhang Z, Gebel H, Bray RA, Guleria I et al. Comprehensive assessment and 
standardization of solid phase multiplex-bead arrays for the detection of antibodies to HLA. 
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Graphical Statistics 2003;12:475-511. 
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85. Little R, Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics 
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87. Ma G, Troxel AB, Heitjan DF. An index of local sensitivity to non-ignorable drop-out in 
longitudinal modelling. Stat Med. 2005 Jul 30;24(14):2129-50. 
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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
GENERAL ASSESSMENTS 
Informed Consent, 
Screening 
Study Enrollment- 
Inclusion/Exclusion 
Criteria 
X 
Randomization 
Assignment received 
X 
Medical History 
All Body Systems 
X 
X 
X 
X 
X 
Medical Record Review 
Graft Status 
X 
Physical Exam/ 
Vital Signs 
Height, Weight, 
Temperature, Blood 
Pressure, Pulse 
X 
X 
X 
X 
X 
Concomitant 
Medications 
Drug Name 
X 
X 
X 
X 
X 
X 
X 
Warm Ischemia Time 
Warm Ischemia Time 
(Recipient) 
Warm Ischemia Time 
(DCD Donors only) 
X 
Cold Ischemia Time 
(Defined by site SOC 
practices) 
X 
Delayed Graft 
Function/Dialysis 
Hemodialysis 
(# of days) 
Peritoneal Dialysis 
(# of days) 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Assessment of Events 
AE/SAE, Infections, 
Rejections, 
Hospitalizations, Graft 
Loss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY MEDICATIONS 
Investigational 
Agent/Placebo 
Total Dose 
X 
Thymoglobulin 
Drug Name, Total Dose 
Administered 
X 
Mycophenolate Mofetil 
/Mycophenolic Acid 
(or generic equivalents) 
Drug Name, Total Daily 
Dose 
X 
X 
X 
X 
X 
X 
Tacrolimus 
(or generic equivalent) 
Drug Name, Total Daily 
Dose 
X 
X 
X 
X 
X 
X 
Tacrolimus (or generic 
equivalent)5 
(Only Trough levels) 
Drug Name, Trough 
Levels 
(Collected monthly from 1-24 
months post-transplant) 
X 
X 
X 
X 
X 
X 
X 
X 
Prednisone 
(or generic equivalent) 
Drug Name, Total Daily 
Dose 
X 
X 
X 
X 
X 
X 
X 
Pneumocystis Infection 
Prophylaxis 
Drug Name, Total Daily 
Dose 
X 
X 
X 
X 
X 
X 
X 
CMV Infection 
Prophylaxis 
Drug Name, Total Daily 
Dose 
X 
X 
X 
X 
X 
X 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Medication Event 
Monitoring System 
(MEMS®)-Prednisone 
(Given to Subject before 
discharge from the hospital) 
Assess accurate use of 
MEMS® Cap by Subject 
X 
X 
LOCAL LABORATORY ASSESSMENTS 
Blood Type 
A, B, O, Rh 
X 
HLA Typing 
I (A, B, C), II (DR, DP, 
DQ) 
X 
PRA 
Peak and Current 
(Calculated) 
(Flow Based, Cellular, 
ELISA, Luminex) 
X 
Crossmatch 
T-Cell and B-Cell 
(Flow Cytometry) 
X 
Pregnancy Test 
Urine or Serum 
X 
Hematology Panel 8 
CBC, Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel 8 
Creatinine, BUN, 
glucose, sodium, AST, 
ALT, ALP, bilirubin, 
albumin, calcium, 
phosphate, magnesium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Sample 
Urine Protein, 
Urine Creatinine, 
Urine Protein to 
Creatinine Ratio 
(Calculated from above) 
X 
X 
X 
X 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
CMV Matching 
Donor and Recipient 
Status prior to transplant 
X 
Viral Monitoring 
BKV by PCR in blood, 
Viral load 
X 
X 
X 
X 
Tuberculosis Testing 
QuantiFERON, PPD, 
ELISPOT 
X10 
Local Histology Read 
X7 
X7 
X 
Standard of Care 
Biopsies 11 
Biopsy Results, Treatment 
provided (if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CORE MECHANISTIC ASSESSMENT 
CELLULAR IMMUNOLOGY CORE –ICAHN SCHOOL OF MEDICINE AT MSSM (PI: PETER HEEGER) 
T and B Cell 
Phenotyping by Flow 
Cytometry 
(FLO) 
10 mL Blood 
Cyto-Chex ® Tubes 
2 x 5mL tubes 
X 
X 
X 
X 
X 
X 
X 
T Cell Functional Assays 
(ELISPOT) / CyTOF Assay 
(ELI) 
30 mL Blood 
Green-Top – 
Sodium Heparin 
3x 10mL tubes 
X 
X 
X 
X 
T Regulatory Cells Sub- 
study 
(CCF, UHC/Case 
Western, MSSM)1 
(REG) 
26 mL Blood 
Green-Top – 
Sodium Heparin, 
2x 10mL tubes; 
1x 6mL tube 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Urinary Chemokines and 
Necroptosis Markers6, 8 
(USC) 
50-100ml Urine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for Necroptosis 
Markers, donor and 
mitochondrial DNA, and 
other Inflammatory 
Markers 
(PIM) (PTA) 
2 mL Blood 
Lavender-top (EDTA) 
Tube 
Remaining EDTA Plasma 
Tube Archived 
X 
X 
X 
X 
X 
X 
GENOMICS ANALYSIS CORE – ICAHN SCHOOL OF MEDICINE AT MSSM (PI: BARBARA MURPHY) 
mRNA Profiling, Gene 
Expression (Blood) 
(BGE) 
2.5 mL Blood 
PAXgene RNA 
1 x 2.5mL tube 
X 
X 
X 
X 
X 
X 
X 
X 
X 
mRNA Profiling, Gene 
Expression (Tissue) 
(TGE) 
1 Core/Wedge Tissue 
X2 
X 
X 
 
X 
Genomics (SNP analysis, 
epigenetics, CDR3 TCR 
sequencing) Archived 
(GEN) 
4mL Blood 
Lavender-top (EDTA) 
Tube 
1 x 4mL tube 
X 
X 
X 
X 
X 
X 
 
X 
X 
Cell Free DNA Analysis 
(CFD) 
10 mL Blood 
Streck Cell Free DNA 
BCT 
1x10mL tube 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
MOLECULAR IMMUNOLOGY CORE – CLEVELAND CLINIC (PI: ROBERT FAIRCHILD) 
Nanostring Analysis 
(sample shared from the 
mRNA Profiling- blood) 
(NSA) 
2.5mL Blood 
PAXgene RNA 
1x2.5mL tube 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
mRNA Profiling, Gene 
Expression (Urin e Pellet) 6, 8 
(UPR) 
50-100ml Urine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HISTOLOGY CORE – UNIVERSITY OF MANITOBA (PI: IAN GIBSON) 
Histology 
(1 Co re/Wedge Tissue in 
Formalin Jar- Core to be 
shared with IHC) 
(HIS) 
*** If tissue core cannot be 
sent to the Core Pathology 
Lab, then the site should 
send (1) H&E, (3) PAS, and 
(1) Trichrome or unstained 
slide3 
X2 
X 
X 
X 
Immunohistochemistry 
(1 Core/Wed ge Tissue in 
Formalin Jar- Core to be 
shared with HIS) 
(IHC) 
*** If tissue core cannot be 
sent to the Core Pathology 
Lab, then the site should 
send 
(3) unstained slides, (1) C4d 
stained, (1) SV-40 stained 
If C4d and/or SV-40 are not 
available, then the site will 
send an unstained slide in 
its place (5 slides total for 
Immunohistochemistry) 3 
X2 
X 
X 
X 


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APPENDIX 1. CTOT-19 SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
HUMORAL ANTIBODY CORE – UNIVERSITY OF MANITOBA (PI: PETER NICKERSON) 
Anti-HLA Antibodies, 
Donor Specific 
Antibodies 
(DSA) (ALO) 
5 mL Blood 
Red-Top (No Additive) 
Tubes 
1 x 5mL tubes 
X 
X 
X 
X 
X 
 
X 
HLA Typing for Epitope 
Analysis (EPI-R) 
4mL Blood 
X 
GLOMERULAR FILTRATION RATE (GFR) CORE –CLEVELAND CLINIC (PI: EMILIO POGGIO) 
eGFR by MDRD 
(GFR) 
5ml Blood 
Red-Top (No Additive) 
Tubes 
1 x 5mL tubes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
T Regulatory Cells Sub-study will be performed at a subset of centers (Cleveland Clinic, Case Western/UHC, and Mount Sinai SOM). These centers will 
receive a separate Sub-study kit for this blood collection. 
2. 
Day 0 (implantation biopsy) can be a wedge biopsy or 2 cores. 
3. 
If unstained slides are shipped, these should be prepared and mounted on positively-charged glass slides (e.g. Superfrost Plus treated slides). 
4. 
The UV3 visit will occur in subjects whom have reached the month 24 visit, however the study is still actively enrolling or following subjects. Subjects will be 
seen every 6 months until the last subject has completed their last visit (LSLV). 
5. 
Trough levels will be collected monthly from Month 1 to Month 24. 
6. 
After transplant, urine will be collected daily until subject is discharge from hospital. If subject is unable to produce urine it will not constitute a deviation. 
7. 
Collected if available. 
Would not constitute a deviation if not available. 
8. 
Subjects will have study visits every day while they are hospitalized post-transplant up to Day 7/Visit 07. If a subject is discharged prior to Day 7/Visit 07 the 
day of discharge will be the last study visit until Day 14. There are no study visits Day 8 to Day 13. 
9. 
Day 0 is defined as the day when the initial Thymoglobulin administration ends. Day 1 is at least 12 hours after Day 0 
10. TB exposure test sample should be drawn pre-transplant. 
11. Collect Standard of Care/Surveillance biopsy results when performed post-transplant, throughout the study follow-up period. Additionally, collect if subject 
was treated and treatmen t provided. 


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Appendix 2. Donor Schedule of Events 
Assessments 
Day of 
Transplant 
Visit 00 
Donor Demographics 
Age, Ethnicity, Gender, CMV status, Cause of Death, DCD/Non-DCD, 
Cold Ischemia Time, HLA Typing, KDPI Score (including components), 
Kidney Pumped/Not Pumped, Renal Resistive Index 
X 
Mechanistic Sample Collection 
Donor Sample Collection for HLA 
Typing for Epitope Analysis 
4mL Blood in a Lavender-top EDTA Tube or 
20µL of DNA at a concentration of 20ng/µL. 
• The purity should be between 1.6 to 1.9 
X 
Donor Sample Collection for 
Genomics 
4mL Blood in a Lavender-top EDTA Tube or 
20µL of DNA at a concentration of 20ng/µL. 
• The purity should be between 1.6 to 1.9 
X 
Donor Sample Collection for T Cell 
Functional Assays 
Spleen, Lymph node or Blood1 
• 1st Priority: Spleen Tissue 
• 2nd Priority: 30ml Blood in Green Top Sodium Heparin Tubes 
• 3rd Priority: Lymph Nodes 
X 
1.  Th e donor samples will be collected  when  th e transplant center is able to o btain th e samples. At a minimum, th e transplant center is req uired to collect 
the sample for the HLA Typing for Epitope Analysis (EPI-D), as this is required  for th e planned  study analysis. Th e transplant center may o btain this sample 
from the HLA Histocompatibility Laboratory at their center. 


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APPENDIX 3. CTOT-19 REDUCED FOLLOW-UP SCHEDULE OF EVENTS 
ASSESSMENTS 
Days 
Post-transplant 
Months 
Post-transplant 
Clinically 
Indicated 
Biopsy 
Clinically 
Indicated 
Biopsy 
Follow-Up 
Every 6 
months 
to study 
end4 
Days/Months Post-transplant 
09 
1 
2 
3 
4 
5 
6 
7/ 
Discharge8 
14 
1 
3 
6 
12 
18 
24 
UV1 
UV2 
UV3 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
ASSESSMENTS 
Assessment of 
Events 
AE/SAE, Infections, Death, 
Malignancies 
X 
X 
X 
Physical Exam 
Height, Weight, Temperature, 
Blood Pressure, Heart Rate 
X 
X 
X 
Immunosuppressive 
Medications 
Drug Name, Dose Total Daily 
Dose 
X 
X 
X 
Anti HLA Antibodies 
Results of test that are done 
as part of clinical care 
(If not done, not a deviation) 
X 
X 
X 


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APPENDIX 4. REDUCED FOLLOW-UP SCHEDULE OF EVENTS 
(Withdrawn/Terminated  Subjects) 
ASSESSMENTS 
FINAL VISIT 
Visit Number 
FV 
Assessment of Events 
AE/SAE, Infections, Rejections, Death, Malignancies, Graft Loss 
X 
Physical Exam 
Height, Weight, Temperature, Blood Pressure, Heart Rate 
X 
Immunosuppressive Medications 
Drug Name, Dose Total Daily Dose 
X 
Anti HLA Antibodies 
Results of test that are done as part of clinical care 
(if not done, not a deviation) 
X 
 

SAP_001.pdf: 
CTOT-19 STATISTICAL ANALYSIS PLAN 
 
Randomized Controlled Trial of Infliximab (Remicade®) Induction 
Therapy For Deceased Donor Kidney Transplant Recipients 
 
CTOT-19 
VERSION: 
1.0 
DATE: 
14 December 2021 
SPONSOR: 
Division of Allergy, Immunology, and Transplantation 
National Institute of Allergy and Infectious Diseases – NIH 
5601 Fishers Lane 
Rockville, MD 20852 
Telephone:  (301) 496-5717 
Fax:  (301) 402-3573 
 
 
PREPARED BY: 
Rho 
2635 E. NC Hwy 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
 
 


Clinical Trials in Organ Transplantation 
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Protocol No. CTOT-19 
14 December 2021 
 
 
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CTOT-19 STATISTICAL ANALYSIS PLAN 
ACKNOWLEDGMENT AND SIGNATURE SHEET 
 
CTOT-19 
 
 
 
 
 
Signature and Date: 
 
 
 
 
__________________________________ 
 
Donald Hricik, MD 
Protocol Chair 
 
 
 
 
Signature and Date: 
 
 
 
 
__________________________________ 
 
Peter Heeger, MD 
Principal Investigator 
 
 
 
 
Signature and Date: 
 
 
 
 
__________________________________ 
 
Jonah Odim, MD, PhD 
NIAID Medical Monitor 
 
 
 
 
Signature and Date: 
 
 
 
 
__________________________________ 
 
Karen Kesler, PhD 
Rho Scientist 
 
 
 
 
Signature and Date: 
 
 
 
 
__________________________________ 
 
Brian Armstrong, MPH 
Rho Statistician 
 
 
 


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Document History 
 
Version 
 
Date 
 
Change(s) 
 
Author 
0.1 
05 May 2021 
Initial Draft 
Brian Armstrong 
0.2 
25 May 2021 
Revised Draft 
Brian Armstrong 
0.3 
24 August 2021 
Revised Draft 
Brian Armstrong 
0.4 
02 December 2021 
Revised Draft 
Brian Armstrong 
1.0 
14 December 2021 
Final revisions 
Brian Armstrong 


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Table of Contents 
 
1. 
PROTOCOL SYNOPSIS ........................................................................................... 5 
2. 
INTRODUCTION ..................................................................................................... 10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................... 10 
4. 
ANALYSIS SAMPLES ............................................................................................ 10 
5. 
STUDY SUBJECTS ................................................................................................ 11 
5.1. 
Disposition of Subjects ................................................................................. 11 
5.2. 
Demographic and Other Baseline Characteristics ......................................... 11 
6. 
STUDY OPERATIONS ............................................................................................ 11 
6.1. 
Protocol Deviations ...................................................................................... 11 
6.2. 
Treatment Adherence................................................................................... 11 
7. 
ENDPOINT EVALUATION ...................................................................................... 12 
7.1. 
Overview of Efficacy Analysis Methods ......................................................... 12 
7.1.1. Multicenter Studies .................................................................................. 12 
7.1.2. Assessment Time Windows ..................................................................... 12 
7.2. 
Primary Endpoint.......................................................................................... 12 
7.2.1. Computation of the Primary Endpoint ....................................................... 12 
7.2.2. Primary Analysis of the Primary Endpoint ................................................. 13 
7.2.3. Sensitivity Analyses of the Primary Endpoint ............................................ 13 
7.2.4. Additional Analyses of the Primary Endpoint ............................................ 14 
7.3. 
Secondary Endpoints ................................................................................... 14 
7.3.1. Secondary Clinical Endpoints................................................................... 14 
7.3.2. Safety and Complication Endpoints .......................................................... 19 
7.3.3. Secondary Mechanistic Endpoints............................................................ 20 
7.4. 
Exploratory Endpoints .................................................................................. 21 
8. 
SAFETY EVALUATION .......................................................................................... 21 
8.1. 
Overview of Safety Analysis Methods ........................................................... 21 
8.2. 
Adverse Events ............................................................................................ 21 
8.3. 
Deaths and Serious Adverse Events............................................................. 22 
8.4. 
Clinical Laboratory Evaluation ...................................................................... 22 
8.5. 
Vital Signs and Other Observations Related to Safety ................................... 23 
8.5.1. Vital Signs ............................................................................................... 23 
8.5.2. Other Safety Measures ............................................................................ 23 
9. 
OTHER ANALYSES ............................................................................................... 23 
10. 
INTERIM ANALYSES AND DATA MONITORING ................................................... 23 
11. 
REFERENCES........................................................................................................ 23 
 


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1. 
PROTOCOL SYNOPSIS ........................................................................................... 6 
2. 
INTRODUCTION ..................................................................................................... 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................... 11 
4. 
ANALYSIS SAMPLES ............................................................................................ 11 
5. 
STUDY SUBJECTS ................................................................................................ 12 
6. 
STUDY OPERATIONS ............................................................................................ 12 
7. 
ENDPOINT EVALUATION ...................................................................................... 13 
8. 
SAFETY EVALUATION .......................................................................................... 22 
9. 
OTHER ANALYSES ............................................................................................... 24 
10. 
INTERIM ANALYSES AND DATA MONITORING ................................................... 24 
11. 
REFERENCES........................................................................................................ 24 
 
 


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1. 
PROTOCOL SYNOPSIS 
Title 
Randomized Controlled Trial of Infliximab Induction Therapy For Deceased Donor 
Kidney Transplant Recipients 
Short Title 
Effects of inhibiting early inflammation in kidney transplant patients 
Clinical Phase 
Phase II 
Number of Sites 
15 
Health Authority 
Applications/ 
Sponsor Number 
NIAID/US IND 124633 
NIAID/HC CTA File # HC6-24-C185918, Control #185918 
Clinicaltrials.gov # NCT02495077 
Study Objectives The objective of the study is to determine the efficacy of intravenous infliximab 
administered at the time of transplantation, prior to reperfusion, on 2-year kidney 
transplant survival and function. 
Study Design 
This is a Phase II, multicenter, randomized, double blind, placebo-controlled, 2-arm 
clinical trial of 300 deceased donor kidney transplant recipients. Subjects will be 
randomized 1:1 to the experimental or control arms (150 subjects per arm). 
Primary 
Endpoint(s) 
The difference between the mean 24-month eGFR (modified MDRD) in the 
experimental vs. control arms. 
Secondary 
Endpoint(s)  
Efficacy Endpoints 
1. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) within  
a) 6 months and  
b) 2 years of transplant 
2. BANFF grades of first Acute Cellular Rejections (ACR) within 6 month of 
transplant 
3. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or 
borderline rejection within  
a) 6 months and  
b) 2 years of transplant 
4. Proportion of subjects with biopsy proven acute antibody mediated rejection 
(AMR) within 6 months and 2 years of transplant 
5. Proportion of subjects with biopsy proven acute antibody mediated rejection AMR 
or suspicious for AMR within  
a) 6 months and  
b) 2 years of transplant 
6. BANFF grades of first AMR within 6 months of transplant 
7. Proportion of subjects with BANFF chronicity scores ≥ 2 on 24 month biopsy 
8. Change in BANFF chronicity scores between implantation and 24 month biopsies 
9. eGFR (as measured by both MDRD and CKD-EPI) 
a) Change in eGFR between 3 months and 24 months  
b) Change in eGFR between post-transplant nadir and 24 months 
c) eGFR on days 7, 30, 90, and 180 post-transplant 
10.   Proportion of subjects with: 
a) Death or graft failure within 2 years 
b) Only graft failure within 2 years 


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11.  Each of the following: 
a) Proportion of subjects that required at least one dialysis treatment within the 
first week after transplantation 
b) Number of dialysis sessions in the first 8 weeks post-transplantation. 
c) Duration of DGF defined as time from transplantation to the last required 
dialysis treatment  
d) The incidence of primary non-function (PNF), defined as for dialysis-
dependency for more than 3 months 
e) Change from baseline (immediately after surgery) in serum creatinine and 
serum creatinine concentration at 24, 48, and 72 hours. 
12. Days from transplantation until event (ACR, AMR, or hospitalization for infection 
and or malignancy)  
13. Rate of Slow Graft Function (SGF): 
a) The proportion of patients with a serum creatinine of more than 3 mg/dL at 
day 5 post-transplant,  
b) Creatinine reduction ratio (CRR) on day 2 (defined as the first creatinine on 
day 2 divided by the first creatinine after surgery)  
c) Creatinine reduction ratio (CRR) on day 7 (defined as the first creatinine on 
day 7 divided by the first creatinine after surgery  
d) The proportion of patients whose day 5 serum CRR was less than 70%  
e) The proportion of patients whose day 2 serum CRR was less than 30%  
f) Proportion of subjects who need dialysis after 1 week. 
 
Safety/Complication Endpoints 
1. Proportion of subjects with:  
a) Any infection requiring hospitalization or resulting in death  
b) Mycobacterial or fungal infections  
2. Proportion of subjects with CMV viremia that require a change in 
immunosuppression or anti-viral treatment as per standard of care at the site 
3. Proportion of subjects with BK viremia that require a change in 
immunosuppression or anti-viral treatment as per standard of care at the site 
4. Proportion of subjects with malignancy 
5. Proportion of subjects with impaired wound healing manifested by wound 
dehiscence, wound infection, or hernia at the site of the transplant incision. 
 
Mechanistic Endpoints 
1. Sensitivity, specificity, PPV, and NPV of biomarkers, including PRT, urinary 
CXCL9, blood genomic profile, and 3 month allograft genomic profile (alone and/or 
in combination) to predict: 
a) Incident biopsy-proven acute rejection. 
b) Graft loss 
c) Chronic graft injury, as measured by 2-year eGFR 
2. Each of the following: 
a) Inflammatory gene expression profiles 
b) Frequency of donor reactive T-cells 
c) Frequency and function of Treg 
d) Proportion of subjects with de novo DSA within 24 months 
e) Fibrogenic gene expression profiles 
f) Amount of peritubular capillary loss by histology 
 
Ancillary Endpoints 


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1. Percentage of predicted prednisone bottle openings as measured by a medication 
event monitoring system (MEMS®) in the first 3 months post-transplantation 
2. Standard deviation of the monthly tacrolimus trough levels from 6 months post-
transplantation to 2 years post-transplantation 
Accrual 
Objective 
300 patients will be enrolled and randomized into the two treatment groups (150 
Experimental arm, 150 Control Arm) across approximately 10 participating centers. 
Study Duration 
5 years (3 year accrual period + 2 year follow up period) 
• 
24 months for primary and majority of secondary endpoints 
• 
5 years with Reduced follow-up to assess patient and graft survival and serum 
creatinine 
Treatment 
Description  
There are two arms/groups in this study, the Experimental Group and the Control Group. 
Each group will receive the following: 
• Experimental Group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) is co-
administered with anti-TNFa (infliximab/Remicade®) followed by maintenance 
therapy with tacrolimus, either Mycophenolate Mofetil/MMF or Mycophenolate 
Acid/MPA (or their generic equivalents) and prednisone 
• Control group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) plus placebo 
(Sterile normal saline) induction followed by maintenance therapy with tacrolimus, 
either Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their generic 
equivalents) and prednisone  
Inclusion Criteria 1. Adult (>18 years of age) male and female recipients (all races and ethnicities) 
2. Subject must be able to understand and provide consent 
3. Recipients of deceased donor kidney transplants (including re-transplants) 
4. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and current sera 
as determined by each participating study center. 
5. Donor kidneys from deceased donors and donors after cardiac death (DCD) with 
Kidney Donor Profile Indices (KDPI) ranging from >20 to <95 
6. Female participants of childbearing potential must have a negative pregnancy test 
upon study entry 
7. Subjects must have a negative test result for latent tuberculosis (TB) infection 
(PPD, QuantiFERON, ELISPOT). Subjects who have a negative test result for latent 
TB infection within 1 year of transplant date are eligible for enrollment and no further 
action is required. Subjects who have a negative test for latent TB infection that is 
greater than 1 year old are eligible for enrollment but are required to have a repeat 
test prior to transplantation. Samples for testing latent TB infection can be obtained 
during the hospital admission for the transplant but must be collected prior to the 
initiation of immunosuppression and prior to transplant. The results of this repeat test 
will determine the next step. 
• 
If the test is negative, no further action is required 
• 
If the test is positive, lost, in determinant or unavailable the subject must 
be treated for latent TB infection (if the subject is enrolled, received study 
drug/placebo and transplanted). 


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o Treatment for latent TB infection is required for all in this group. 
o The treatment regimen (including the specific drug, dose and duration 
of treatment) will be determined by the local Infectious Disease team. 
• 
If the subject has no latent TB testing available, then the subject cannot be 
enrolled 
Subjects may be enrolled if they have not had a test for latent TB infection within one 
year of the transplant if samples for the test are collected prior to the administration of 
immunosuppressive drugs and prior to transplant. 
Exclusion 
Criteria 
1. Inability or unwillingness of a participant to give written informed consent or comply 
with study protocol 
2. Recipients of living donor transplants 
3. Presence of other transplanted solid organs (heart, lung, liver, pancreas, small 
intestines) or co-transplanted organ 
4. HIV+ recipients 
6. Hepatitis B surface antigen positive kidney transplant recipients 
7. Hepatitis B core antibody positive kidney transplant recipients 
8. Hepatitis B negative kidney transplant recipients that receive transplant from     
Hepatitis B core antibody positive donor 
9. Hepatitis C virus positive (HCV+) patients who are either untreated or have failed to 
demonstrate sustained viral remission for more than 12 months after anti-viral 
treatment 
10. Recipients with a previous history of invasive fungal infection 
11. Recipients with a previous history of active TB disease 
12. Recipients with a positive test for latent TB infection (PPD, QuantiFERON, 
ELISPOT), regardless of previous therapy. 
13. Any severe infection at the time of transplantation. Severe infection determination 
will be made by the local site investigator. 
14. Severe congestive heart failure (NYHA functional class III or higher) 
15. Subjects with a known hypersensitivity to any murine/ mouse proteins 
16. Subjects with any history of receiving any anti-TNF products 
17. Subjects in whom rATG or infliximab might not be tolerated 
18. Subjects with less than 3000/mm3 WBC 
19. Subjects with less than 100,000/mm3 platelets counts 
20. Subjects with systolic blood pressure <100 mm/Hg 


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21. Subjects with symptomatic orthostatic hypotension or currently requiring Midodrine 
for blood pressure support. 
22. Subjects from or who have traveled to endemic areas with a history of active 
histoplasmosis or with a chest x-ray consistent with previous active histoplasmosis (no 
serological testing required). Endemic regions determined by site based on local 
standard of care 
23. Subjects currently or formerly residing in regions of the US that are highly endemic 
for coccidioidomycosis, and who have a positive serologic test for coccidioidomycosis. 
Endemic regions determined by site based on local standard of care. * 
 * (Subjects currently or formerly residing in regions of the US that are highly 
endemic for coccidioidomycosis, and who have a negative pre-transplant 
serologic test for coccidioidomycosis are eligible for enrollment only if they receive 
fluconazole 200 mg/day for the duration of the study. Serologic testing for 
coccidioidomycosis is required for subjects that currently or formerly resided in 
regions that are highly endemic for coccidioidomycosis only, per the site’s 
standard of care). 
24. Recipients are excluded if the local site decides to treat the recipient with 
fluconazole because of diagnosis or suspicion of fungal infection in the donor. 
25. Subjects that receive IVIG treatment within 3 months of transplant or planned IVIG 
treatment peri-transplant. 
26. Use of an investigational agent within 4-weeks prior to study entry 
Study Stopping 
Rules 
Satisfaction of any of the following stopping rules at any time during the post-transplant 
(treatment) follow-up will trigger an ad hoc DSMB Safety Review. 
 
• Any single occurrence of a life-threatening or fatal AE that is possibly, probably, or 
definitely related to either the investigational agent (infliximab/infliximab placebo) or a 
study mandated procedure. 
 
Across both treatment arms: 
•  Incidence of PTLD of 1% or more subjects 
• Incidence of Adverse Events for tuberculosis active disease of 1% or more 
subjects 
•  Incidence of invasive fungal infection of 3% or more subjects 
•  Incidence of coccidioidomycosis of 1% or more subjects 
•  Incidence of histoplasmosis of 1% or more subjects 
•  Incidence of death of 10% or more subjects 
Within either treatment arm: 
•  Incidence of infection of any type requiring hospitalization of 40% or more  
subjects 
•  Incidence of graft loss of 20% or more subjects 
•  Incidence of BPAR (Banff Grade 1 or higher) or AMR based on local read of 
25% or more subjects 
 
 


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2. 
INTRODUCTION 
This statistical analysis plan includes pre-planned analyses related to the study objectives 
outlined in the protocol. 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following analyses and reporting conventions will be used: 
• 
Categorical variables will be summarized using counts (n) and percentages (%) and will be 
presented in the form “n (%).”  Percentages will be rounded to one decimal place. 
• 
Numeric variables will be summarized using n, mean, standard deviation (SD), median, 
minimum (min), maximum (max).  The min/max will be reported at the same level of 
significance as original data.  The mean and median will be reported at one more significant 
digit than the precision of the data, and SD will be reported at two more significant digits 
than the precision of the data. 
• 
The median will be reported as the average of the two middle numbers if the dataset 
contains an even number of observations. 
• 
Test statistics including t and z test statistics will be reported to two decimal places.  
• 
P-values will be reported to three decimal places if greater than or equal to 0.001.  If less 
than 0.001, the value will be reported as “<0.001.”  A p-value can be reported as “1.000” 
only if it is exactly 1.000 without rounding.  A p-value can be reported as “0.000” only if it is 
exactly 0.000 without rounding. 
If departures from these general conventions are present in the specific evaluations section of 
this SAP, then those conventions will take precedence over these general conventions.  
4. 
ANALYSIS SAMPLES 
Intent-to-Treat (ITT) Sample – The ITT sample is all transplanted and randomized subjects 
who receive the infliximab/placebo infusion. This sample will be used for efficacy and some 
safety analyses. Transplanted subjects who receive an infusion, but have no additional follow up 
will be used in this population.  Subjects will be assigned to the treatment they were randomized 
to, regardless of which treatment they received.  
Per-Protocol (PP) Sample – The PP sample is the subset of subjects from the ITT sample who 
receive the entire infliximab/placebo infusion, complete the full induction protocol, are compliant 
with their medications, and do not have any major protocol deviations that preclude analysis of 
the primary endpoint. 
Safety Sample - All subjects who receive any infliximab/placebo infusion. This sample will be 
used for most safety summaries/analyses.  Subjects will be assigned to the treatment they 
received, regardless of what they were randomized to.  
Delayed Graft Function (DGF) Sample –All subjects with delayed graft function. This is 
defined as any dialysis in the first 7 days. This sample will be used for all DGF related analyses. 
Screening Sample – All consented subjects will constitute the screening sample.  This sample 
will be used for disposition summaries. 
 
 
 


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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects  
The disposition of all subjects will be summarized in tables and presented in listings, as needed, 
using the screening sample.  A consort diagram will also be constructed to serve as a visual 
depiction of the flow of subjects through the study. 
The numbers and percentages of subjects enrolled, randomized, and transplanted will be 
displayed by treatment group and overall.  The number of subjects in each analysis sample will 
be presented.  Additionally, the numbers and percentages of subjects who complete the study 
or terminate early, along with reasons for early termination, will be summarized.  Other 
information relevant to disposition will be summarized by treatment group and study visit as 
needed. 
5.2. 
Demographic and Other Baseline Characteristics  
Summary descriptive statistics, with no formal group comparisons, for baseline and 
demographic characteristics will be reported for the ITT sample by treatment group and overall.  
These characteristics, to the extent known, will also be summarized for subjects who were 
screened but were not eligible for study participation.  Characteristics to be summarized are 
identified below.  Additional relevant characteristics may be included. 
• 
Recipient: age, race, ethnicity, sex, primary reason for transplant, cPRA%, dialysis 
pre-transplant, length and modality of pre-transplant dialysis, EBV and CMV 
serology status, pump perfusion status, resistive index 
• 
Donor: age, race, ethnicity, sex, cause of death, donation after cardiac death, CMV 
serology status, KDPI, cold ischemia time 
6. 
STUDY OPERATIONS 
6.1. 
Protocol Deviations 
Only major protocol deviations were collected for this study.  Protocol deviations will be listed 
by site with information such as type of deviation, date of occurrence, and the reason for the 
deviation.  Protocol deviations may also be summarized in tabular format by type of deviation. 
6.2. 
Treatment Adherence 
Treatment Groups: 
Experimental Group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) is co-
administered with anti-TNFa (infliximab/Remicade®) followed by maintenance therapy 
with tacrolimus, either Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their 
generic equivalents) and prednisone 
Control Group: rabbit anti-thymocyte globulin (rATG, Thymoglobulin) plus placebo 
(Sterile normal saline) induction followed by maintenance therapy with tacrolimus, either 
Mycophenolate Mofetil/MMF or Mycophenolate Acid/MPA (or their generic equivalents) 
and prednisone 
Randomization occurred after enrollment and prior to transplant surgery. Participants were 


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randomized to either the Experimental group (receive Remicade®) or the Control Group 
(receive placebo). This was a blinded study so participants and the study team did not know the 
treatment assignment of the participant during the course of a subject’s participation.  
Adherence will be summarized for the ITT sample.  Infusion status will be classified as complete 
or partial and also reported as the percentage of expected dose received, if needed.  These 
variables will then be summarized in a table using appropriate statistics and subject-level details 
will be presented in a listing. 
7. 
ENDPOINT EVALUATION 
7.1. 
Overview of Efficacy Analysis Methods 
7.1.1. 
Multicenter Studies 
Study subjects were recruited from 15 study sites.  Since randomization was carried out using 
fixed block sizes and stratified by enrolling site, study data will be analyzed as a whole, and no 
formal accommodation for site-to-site variation will be made. 
7.1.2. 
Assessment Time Windows 
Allowable visit windows are detailed in Section 8 of the protocol.   
Unscheduled visits may also occur throughout the study at the time of an unscheduled (i.e., for 
cause) biopsy.  A follow-up visit will be conducted 2-6 weeks after an unscheduled biopsy visit. 
Additionally, subjects may have semi-annual (± 2 months) visits between months 24 and 60 
post-transplant, up until the last transplanted subject completes 24 months of follow-up.  These 
visits are only intended to collect a core lab specimen for eGFR, graft status, and, in some 
cases, a local creatinine result. 
Generally, all data will be included in analyses, regardless of time of assessment.  Exceptions to 
this include when the endpoint has a built in time component (e.g., within 24 months), in which 
case only data collected up to and including the protocol-specified upper window of time for the 
corresponding visit may be included.  Endpoint-specific windows are specified in the 
subsections below.  
7.2. 
Primary Endpoint 
The primary endpoint is the difference between the mean 24-month eGFR in the experimental 
vs. control arms. 
7.2.1. 
Computation of the Primary Endpoint 
All post-transplant serum creatinine results received from the central laboratory and collected at 
protocol visits at month 1, 3, 6, 12, 18, and 24 will be used to estimate GFR via the Modification 
of Diet in Renal Diseases (MDRD) equation.  Any creatinine sample collected on or after the 
date of graft failure will be excluded from the eGFR calculation.  
MDRD equation for eGFR (mL/min/1.73m2): 
175 × (SCr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) 
SCr=serum creatinine measured in mg/dL from the central laboratory 
Age=age in years, rounded down to the nearest integer, at time of the SCr collection 


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Only data for subjects with known values of sex and race will be included in the evaluation of 
the primary endpoint.  Subjects who reported race as ‘Unknown or Not Reported’ will be 
considered non-African American when calculating eGFR. 
7.2.2. 
Primary Analysis of the Primary Endpoint 
All subjects in the ITT sample will be used for the primary analysis.  Mean eGFR of each of the 
two treatment arms will be compared within a restricted maximum likelihood repeated measures 
model (MMRM) framework, wherein repeated measures of the available eGFRs (as outlined in 
section 7.2.1) will be modeled using fixed effects of treatment group, collection time point, and 
the interaction between time point and treatment group.  A random subject effect will also be 
included in the model to appropriately adjust for the correlation of having multiple eGFR values 
for each subject. 
Let 𝜏𝜏 denote the “treatment effect at 24 months”, which will be defined as the difference in 24-
month population mean eGFR for the experimental treatment minus the corresponding placebo 
mean.  𝜏𝜏 is a parameter of primary interest; the MMRM will be used to estimate 𝜏𝜏.   
The primary null and alternative hypotheses are:  𝐻𝐻0: 𝜏𝜏= 0 vs. 𝐻𝐻𝐴𝐴: 𝜏𝜏≠0.  The MMRM will be 
used to test these hypotheses at the α= 0.05 Type I error rate. 
SAS PROC MIXED (ver. 9.4 or higher) will be used to fit the MMRM to the data, estimate the 
parameters, and test the primary hypothesis along with others. 
An example of SAS code to be used for the analysis of the primary endpoint: 
Proc mixed; 
   class trtnm(ref=‘Placebo’) subjid; 
   model gfrmdrd=trtnm colldy trtnm*colldy / ddfm=kr; 
   random intercept colldy / subject=subjid type=<xx>; 
   lsmeans trtnm / at colldy=730 cl pdiff; 
   estimate ‘Experimental vs. Control at M24’ trtnm 1 -1 
      trtnm*colldy 730 -730 / cl; 
run; 
The type=<xx> covariance structure used will be determined following an evaluation of the 
AIC, AICC, and BIC model fit statistics for several candidate covariance structures (e.g., 
Unstructured, Toeplitz, and Variance components).  The best fitting covariance structure will be 
used in the final model.  
The estimated mean eGFR at 24 months, treatment group difference, and two-sided 95% 
confidence intervals will be summarized.  Results associated with the F-test for the 
contrast/estimate will be reported.  Additional graphical summaries of the eGFR over time will 
be used to further illustrate any differences between the two treatment groups.  MMRM 
assumptions will be evaluated graphically via standard residual analyses.  If the assumptions 
fail, a suitable transformation (e.g., natural logarithms) will be utilized and the data will be 
reanalyzed on the transformed scale.  Missing data will not be imputed for the primary analysis; 
however, a sensitivity analysis will be employed to assess the impact of missing data due to 
subjects who terminate the study early or experience graft loss. 
7.2.3. 
Sensitivity Analyses of the Primary Endpoint 
The impact of early terminations will be assessed by looking for differences between the 
treatment groups in the proportion of subjects who terminate the study before completing the 


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month 24 visit, the timing of early terminations, and the reasons for early termination.  These 
comparisons will allow for determination of whether or not the missing at random (MAR) 
assumption holds.  Additionally, we will utilize the methods of Ma et al (2) to provide an 
objective index of the level of non-ignorable missingness.  If the MAR assumptions fails, various 
sensitivity analyses will be employed to examine the impact of missing data on the primary 
analysis. 
The first sensitivity analysis will use a pattern mixture model fitted via multiple imputation (3), 
and is an example of a “controlled imputation” method (1, 4) and will implement a jump to 
control (4) approach.  For subjects who drop out of the study, this method imputes missing 
values for both treatment groups from the placebo population, which reduces any bias away 
from the null hypothesis of no difference between treatment groups. 
A second sensitivity analysis will impute a single point for subjects (in either treatment group) 
that have had a graft loss or have died.  Specifically, subjects who have a graft loss prior to 24 
months will have an eGFR of 10 imputed for their remaining eGFR collection time points.  
Subjects who die with a functioning kidney will have a “last observation carried forward” 
imputation, which means that we would impute their last known eGFR prior to death for all 
remaining eGFR collection time points.  This final eGFR will be based on the central evaluation 
of eGFR if available and the collection time was within 1 month of death; otherwise, a local 
assessment of eGFR will be used, if available. 
A third sensitivity analysis will compare the eGFR at 24 months between the two treatment 
groups using a Wilcoxon test.  Subjects who experience death or graft loss will be given the 
worst ranks.  Subjects who are missing their 24-month eGFR due to other causes will receive a 
rank based on an imputed eGFR from the model used in the primary analysis. 
7.2.4. 
Additional Analyses of the Primary Endpoint 
If alternative eGFR equations are published in a peer-reviewed journal following conclusion of 
this trial and the required data inputs were collected for this trial, the primary model will be rerun 
using eGFRs calculated via one or more of these alternative equations. 
Furthermore, the following additional analyses of the primary endpoint are planned. 
• 
A two-sample t-test will be used to compare group means of eGFR at 24 months post-
transplant.  This analysis will include only the month 24 (± 1 month) eGFR values. 
• 
The two-sample t-test will be repeated using local creatinines, in lieu of central 
creatinines, when calculating eGFR. The same ± 1 month window will be applied. 
• 
The following analyses will use the same model as the primary analysis with data 
substitutions as follows: 
o Include central creatinines from the post-month 24 visits;  
o Substitute available local creatinines into the eGFR calculation at time points 
where a central creatinine result was not available via separate models with and 
without post-month 24 visits.  All local creatinine values collected on or after the 
month 1 visit that are not within +/- 7 days of an available central creatinine result 
will be included in these models. 
o Use only local creatinines, in lieu of central creatinines, and separate models with 
and without post-month 24 visits. 
• 
All analyses noted above may be repeated using eGFRs calculated via one or more of 
the alternative equations, if published and available. 
7.3. 
Secondary Endpoints 
7.3.1. 
Secondary Clinical Endpoints 


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The secondary endpoints will be summarized by treatment and, where appropriate, by time 
point and treatment.  Treatment groups will be compared through the use of appropriate 
statistical methods.  The particular method used will depend on the scale of measurement of the 
endpoint.  The accompanying table lists each endpoint, the applicable analysis sample, 
measurement scale (continuous, dichotomous, or ordinal), and the summary statistics and 
statistical model to be used for treatment group comparisons.  Rejection and renal function 
endpoints will be based on central laboratory results; graft failure, delayed graft function, and 
slow graft function endpoints will be based on data recorded in the clinical database.  Endpoints 
denoted with a ‘#’ were not part of the protocol-specified endpoints and were added during 
finalization of this document. 
Secondary analyses will be considered descriptive. 
 
Summary of Proposed Analyses for Secondary Clinical Endpoints 
Response Type 
(Sample) 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to test for 
treatment effects 
Incidence and 
Severity of 
Rejection 
Endpoints 
(ITT, PP) 
Note: All biopsies (protocol, clinically indicated, and standard of care) will be utilized for 
rejection endpoints. 
 
Proportion of subjects with 
biopsy proven acute 
cellular rejection (BPAR) 
within a) 6 months and b) 2 
years of transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using a 
window of +21 days at 
month 6. Month 24 will 
use a window of + 1 
month if the biopsy 
occurred before 
01MAR2020. Otherwise, 
the +6 month window 
used during the COVID-
19 pandemic will be 
used for month 24. 
 
BANFF grades of first 
Acute Cellular Rejections 
(ACR) within 6 months of 
transplant, among subjects 
who have ACR 
categorical 
Table 
Chi-square test using a 
window of +21 days at 
month 6 
 
Proportion of subjects with 
BPAR or borderline 
rejection within a) 6 months 
and b) 2 years of transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
the same windows as 
outlined for BPAR 
 
Proportion of subjects with 
biopsy proven acute 
antibody mediated 
rejection (AMR) within a) 6 
months and b) 2 years of 
transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
the same windows as 
outlined for BPAR 


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BANFF grades of first AMR 
within 6 months of 
transplant, among subjects 
who have acute AMR 
categorical 
Table 
Chi-square test using a 
window of +21 days at 
month 6 
 
Proportion of subjects with 
biopsy proven AMR or 
suspicious for AMR within 
a) 6 months and b) 2 years 
of transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
the same windows as 
outlined for BPAR 
 
# Proportion of subjects 
with locally treated 
rejection, defined as 
treatment administered for 
rejection based on clinical 
signs or biopsy findings, 
within a) 6 months and b) 2 
years of transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
the same windows as 
outlined for BPAR 
 
Proportion of subjects with 
BANFF chronicity scores ≥ 
2 on 24 month biopsy 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
the biopsy reported from 
Visit 14/Month 24 
 
Change in BANFF 
chronicity scores between 
implantation and 24 month 
biopsies 
categorical 
Table 
CMH test using the 
difference of M24 minus 
BL categorized as 0, 1, 
2, or 3+. 
 
Days from transplantation 
until event (ACR, AMR, or 
hospitalization for infection 
and or malignancy) 
time to event 
Kaplan-
Meier 
estimates 
Kaplan-Meier model with 
log-rank test 
Renal Function 
Endpoints  
(ITT, PP) 
Note: Any creatinine sample collected on or after the date of graft failure will be 
excluded from the eGFR calculation for renal function endpoints. 
 
Change in eGFR (as 
measured by both MDRD 
and CKD-EPI1) between 3 
months and 24 months 
continuous 
mean + 95% 
CI 
T-test using the 3 and 
24 month scheduled 
collections. Change 
calculated two ways 
using M24 – M3: (1) 
using the M3 (+/- 14 
days) and M24 (+/- 1 
month) collections and 
(2) using all M3 and M24 
collections, regardless of 
timing post-transplant. 


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# Change in eGFR (as 
measured by both MDRD 
and CKD-EPI1) between 6 
months and 24 months 
continuous 
mean + 95% 
CI 
T-test using the 6 and 
24 month scheduled 
collections. Change 
calculated two ways 
using M24 – M6: (1) 
using the M6 (+/- 21 
days) and M24 (+/- 1 
month) collections and 
(2) using all M6 and M24 
collections, regardless of 
timing post-transplant. 
 
Change in eGFR (as 
measured by both MDRD 
and CKD-EPI1) between 
post-transplant nadir 
(lowest eGFR in first 6 
months) and 24 months 
continuous 
mean + 95% 
CI 
T-test using scheduled 
collections from the first 
6 months and month 24. 
Nadir will be calculated 
two ways using the 
values from month 1 to 
month 6: (1) using only 
collections from M1 (-7 
days) to M6 (+21 days) 
and (2) using any 
collections from the M1 
visit through the M6 visit, 
regardless of timing 
post-transplant. The M1 
eGFR value will be 
excluded from the nadir 
determination for any 
subject with DGF. Then 
change will be 
calculated two ways 
using M24 – nadir: (1) 
using nadir #1 and M24 
(+/- 1 month) collections 
and (2) using nadir #2 
and all M24 collections, 
regardless of timing 
post-transplant. 
 
In addition to the planned analysis as indicated above for each of the endpoints (i.e., 
change in eGFR from month 3 to month 24, month 6 to month 24, and the 6 month 
nadir to month 24), an exploratory analysis will report the changes estimated using the 
same MMRM used for analysis of the primary endpoint. 
 
Estimated GFR (as 
measured by both MDRD 
and CKD-EPI1) on days 7, 
30, 90, and 180 post-
transplant 
continuous 
mean + 95% 
CI 
MMRM, same as used 
for analysis of the 
primary endpoint to 
generate estimates at 
days 30, 90, and 180. 
Day 7 eGFR value will 
be added to the model 
to generate an estimate 
at day 7. 


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Graft Failure 
Endpoints 
 
(ITT, PP) 
Proportion of subjects with 
death or graft failure within 
2 years 
dichotomous 
proportion + 
95% CI 
Chi-square test using a 
window of +1 month 
 
Proportion of subjects with 
only graft failure within 2 
years 
dichotomous 
proportion + 
95% CI 
Chi-square test using a 
window of +1 month 
Delayed Graft 
Function 
Endpoints  
(ITT, PP) 
Proportion of subjects that 
required at least one 
dialysis treatment within 
the first week after 
transplantation 
dichotomous 
proportion + 
95% CI 
Chi-square test 
(ITT) 
Number of dialysis 
sessions in the first 8 
weeks post-transplantation 
continuous 
mean and/or 
geometric 
mean + 95% 
CI 
Poisson regression 
(DGF) 
Duration of DGF defined as 
time from transplantation to 
the last required dialysis 
treatment 
continuous 
mean and/or 
geometric 
mean + 95% 
CI 
T-test 
(ITT, PP) 
The incidence of primary 
non-function (PNF), 
defined as dialysis-
dependency for more than 
3 months  
dichotomous 
proportion + 
95% CI 
Chi-square test using 
only subjects who are 
still on study at 3 months 
post-transplant (i.e., day 
90) 
(ITT, PP) 
Change from baseline 
(immediately after surgery) 
in serum creatinine at 24, 
48, and 72 hours 
continuous 
mean + 95% 
CI 
MMRM with treatment 
group, visit number, and 
their interaction term as 
independent variables 
Slow Graft 
Function 
(ITT, PP)  
Note: Any subject who experienced DGF will be excluded from assessment of SGF 
endpoints. 
 
The proportion of subjects 
with a serum creatinine of 
more than 3 mg/dL at day 
5 post-transplant 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
creatinine from the 
discharge visit, if subject 
discharged prior to day 5 
 
Creatinine reduction ratio 
(CRR) on day 2 (defined as 
the first creatinine on day 2 
divided by the first 
creatinine after surgery) 
ratio 
mean + 95% 
CI 
T-test 
 
Creatinine reduction ratio 
(CRR) on day 5 (defined as 
the first creatinine on day 5 
divided by the first 
creatinine after surgery) 
ratio 
mean + 95% 
CI 
T-test using creatinine 
from the discharge visit, 
if subject discharged 
prior to day 5 
 
The proportion of subjects 
whose day 5 serum CRR 
was less than 70% 
dichotomous 
proportion + 
95% CI 
Chi-square test using 
creatinine from the 
discharge visit, if subject 
discharged prior to day 5 


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The proportion of subjects 
whose day 2 serum CRR 
was less than 30% 
dichotomous 
proportion + 
95% CI 
Chi-square test 
 
Proportion of subjects who 
need dialysis after 1 week 
dichotomous 
proportion + 
95% CI 
Chi-square test 
Alloantibody 
Endpoints 
(ITT, PP) 
# Proportion of subjects with 
de novo DSA within 24 
months 
dichotomous 
proportion + 
95% CI 
Chi-square test applying 
the same window as 
outlined for the BPAR 
endpoint to the 
alloantibody samples 
1 CKD-EPI equation: 141 x min(Scr/k,1)a x max(Scr/k,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if 
black], where Scr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is -0.329 for 
females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum 
of Scr/k or 1. 
 
7.3.2. 
Safety and Complication Endpoints 
The safety sample will be used for analysis of all post-transplant safety endpoints.  The specific 
clinical safety events of interest are infections, hospitalizations, malignancies, and wound 
healing.  The table below lists each safety endpoint, the analysis sample, measurement scale 
(continuous, dichotomous, or ordinal), and the summary statistics and statistical model that will 
be used for treatment group comparisons.  All safety endpoints will be assessed during the first 
24 months post-transplant, using a window of +1 month. 
 
Summary of Proposed Analyses for Safety Endpoints 
Response 
Type 
(Sample) 
Response 
Measurement 
Scale 
Summary 
Statistics 
Models to 
test for 
treatment 
effects 
Safety 
Endpoints 
 
(Safety) 
Proportion of subjects 
with any infection 
requiring hospitalization 
or resulting in death 
dichotomous 
proportion + 
95% CI 
Chi-square 
test  
 
Proportion of subjects 
with mycobacterial or 
fungal infections 
dichotomous 
proportion + 
95% CI 
Chi-square 
test  
 
Proportion of subjects  
with CMV viremia that 
require a change in 
immunosuppression or 
anti-viral treatment as 
per standard of care at 
the site 
dichotomous 
proportion + 
95% CI 
Chi-square 
test 
 
Proportion of subjects 
with BK viremia that 
require a change in 
immunosuppression or 
anti-viral treatment as 
per standard of care at 
the site 
dichotomous 
proportion + 
95% CI 
Chi-square 
test 
 
Proportion of subjects 
with malignancy 
dichotomous 
proportion + 
95% CI 
Chi-square 
test 


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Proportion of subjects 
with impaired wound 
healing manifested by 
wound dehiscence, 
wound infection, or 
hernia at the site of the 
transplant incision 
dichotomous 
proportion + 
95% CI 
Chi-square 
test 
 
7.3.3. 
Secondary Mechanistic Endpoints 
Appendix 1 of the protocol contains the mechanistic assay collection schedule. 
The following mechanistic endpoints will be assessed using the ITT sample. 
• 
Sensitivity, specificity, PPV, and NPV of biomarkers, including PRT, urinary CXCL9, 
blood genomic profile, and 3-month allograft genomic profile (alone and/or in 
combination) to predict: 
o Biopsy-proven acute rejection 
o Graft loss 
o Chronic graft injury, as measured by 2-year eGFR 
• 
Each of the following: 
o Inflammatory gene expression profiles 
o Frequency of donor reactive T-cells 
o Frequency and function of Treg 
o Fibrogenic gene expression profiles 
o Amount of peritubular capillary loss by histology 
We will test a biomarker panel to predict and diagnose incipient ACR and to determine the 
accuracy of early post-transplant markers to define individuals most at risk for late graft 
dysfunction and chronic graft injury. This panel will include reactive T cell (PRT) assays, urinary 
chemokine, urinary PCR assays, gene expression profiles in peripheral blood, and gene 
expression profiles in graft tissue. If the comparison of the biomarkers between the two 
treatment groups (see previous paragraph) yields no differences, we will utilize the entire study 
population. If, however, we find an influence of the infliximab on the biomarkers, we will limit this 
investigation to the control subjects. This evaluation will be based primarily on examining the 
Receiver Operating Characteristic (ROC) Curves generated for each candidate biomarker and 
the associated classification accuracy in terms of sensitivity and specificity as well as positive 
and negative predictive value. We will also explore combining the candidate biomarkers to 
determine whether there are distinct combinations of biomarkers that may improve performance 
relative to individual biomarkers. 
Our hypothesis that anti-TNFa limits activation of donor reactive immunity and prevents initiation 
and progression of graft fibrosis by dampening early inflammation within the allograft will be 
assessed by a series of linear mixed models. The assays to assess these effects will include T 
cell (PRT) assays, urinary chemokine, urinary PCR assays, gene expression profiles in 
peripheral blood, gene-expression profiles in graft tissue, donor-reactive effector T cells, 
markers of inflammation, regulatory T cells, donor specific antibody, fibrogenic gene profiles, 
and peritubular capillary loss. Models will be fit sequentially, with specific models fit to address 
specific elements of the hypothesized mechanism. Initially we will use regression models to 
quantify the extent to which infliximab, when added to therapy with ATG, reduces “early” 
inflammation at the time of transplantation, measured both by cellular reactivity in blood and 
from post-implantation biopsies. Corresponding linear regression models will assess differences 
between treatment groups with respect to inflammation measures at 24 mos., and mixed linear 
models will be used to assess the inflammation measures over the entire time course 


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subsequent to the “early” evaluation. Additionally, proportional odds models will be used to 
assess treatment differences in ordinal grade of graft fibrosis at 24 mos. and, through a 
generalized estimating equation (GEE) approach, over time. 
7.4. 
Exploratory Endpoints 
The following exploratory endpoints will be assessed using the ITT sample. 
Variable: Standard deviation of the monthly tacrolimus trough levels from 6 months post-transplant to 
2 years post-transplant 
Analysis: Among subjects who have at least 3 outpatient tacrolimus trough levels collected that 
are at least 3 months (i.e., greater than or equal to 3 months) post-transplant, an estimate of the 
standard deviation of tacrolimus levels will be produced for each subject beginning at month 6 
post-transplant.  This estimate will be a rolling estimate (continually re-assessed with each 
subsequent outpatient trough level) and may use up to 1 year worth of trough levels at any 
given time.  The estimated standard deviations will be analyzed within the same MMRM 
framework as the primary endpoint.  The estimated mean of the standard deviation at 2 years 
post-transplant, treatment group difference, and two-sided 95% confidence intervals will be 
summarized.  Additionally, a cross-sectional analysis will be performed using only the month 24 
estimated standard deviation for each subject with available data and will estimate the mean of 
the standard deviation, treatment group difference, and two-sided 95% confidence intervals for 
comparison to the MMRM results. 
Variable: Percentage of predicted prednisone bottle openings as measured by a medication event 
monitoring system (MEMS®) in the first 3 months post-transplant 
Analysis:  The number and percentage of subjects who participated in the MEMS study will be 
summarized at day 14 and months 1 and 3 post-transplant by treatment group and overall.  
Additionally, the number of pauses in the use of the MEMS cap at months 1 and 3 will be 
determined for each subject participating in the MEMS study and summarized by treatment 
group and overall. 
8. 
SAFETY EVALUATION 
8.1. 
Overview of Safety Analysis Methods 
All safety analyses will be carried out using the safety sample and percentages will be 
calculated based on the number of subjects in the safety sample, unless otherwise noted.  
Missing safety information will not be imputed.  These analyses will not be stratified by site.  
Safety will be analyzed in each treatment group through the reporting of AEs, vital signs, and 
changes in routine laboratory measures. 
Listings will be prepared, as needed, for all safety measurements.  All listings will be sorted in 
order of treatment, subject identifier, and time point of assessment (e.g., visit and/or time). 
8.2. 
Adverse Events 
Per the protocol, only non-serious AEs with a severity grade of 3 or higher were collected, and 
all serious AEs were collected.  All AEs were classified by system organ class (SOC) and 
preferred term (PT), according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1.  The severity of AEs was classified using the National Cancer Institute’s (NCI’s) 


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Common Toxicity Criteria for Adverse Events (CTCAE) version 4.  Each AE was recorded once 
at the highest severity. 
AEs were collected for each subject from the initiation of investigational treatment through study 
completion or early termination.  Based on this reporting period, all AEs will be considered 
treatment-emergent.  All data tabulations will be stratified by treatment group. 
An overall summary table will be developed to report the number of events and the number and 
percentage of subjects having at least one event in the following categories: 
• 
AEs 
• 
AEs indicated as serious 
• 
AEs with an outcome of death 
• 
AEs that were assessed as being related to infliximab/placebo, thymoglobulin, tacrolimus, 
MMF, prednisone, blood draw, or biopsy 
• 
AEs by severity 
In general, when reporting on the relationship of an adverse event to study drug and 
procedures, the DAIT medical monitor assessment of relationship will be used for all serious 
AEs and the site investigator assessment of relationship will be used for all non-serious AEs.  
This convention will apply even when AEs are summarized in aggregate (i.e., serious and non-
serious AEs pooled together). 
Additionally, the classification of AEs by MedDRA SOC and PT will be summarized for each 
treatment group and overall.  Summary tables will present the total number of events as well as 
the number and percentage of subjects experiencing at least one event in each SOC/PT 
combination. 
Separate data listings may be generated for treatment-related AEs and AEs leading to study 
drug discontinuation. 
8.3. 
Deaths and Serious Adverse Events 
Serious adverse events (SAEs) will be summarized in a manner consistent with that described 
in Section 8.2, and when appropriate SAEs may be summarized in the same table as all AEs. 
Separate listings detailing each death, including time to and cause of death, will also be 
created. 
8.4. 
Clinical Laboratory Evaluation 
Clinical laboratory measurements include serum chemistry, hematology, and urine.  Results 
will be converted to standardized units where possible.  For numeric laboratory results, 
descriptive statistics of laboratory values and the change from baseline of laboratory values will 
be summarized for each treatment group and overall.  For any categorical laboratory results, 
the number and percentage of subjects reporting each result will be presented for each 
treatment group and overall.   
In addition, or in lieu of summary statistics, clinical laboratory data may be plotted to show 
patterns over time.  For each test with a numeric result, data will be plotted either as a 
spaghetti plot where each subject’s values will be plotted and connected by line segments, 


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forming one line per subject, or as box plots over time and stratified by treatment group.  Tests 
with qualitative results will not be plotted. 
Separate listings of laboratory data over time may also be created. 
8.5. 
Vital Signs and Other Observations Related to Safety 
8.5.1. 
Vital Signs 
Descriptive statistics of vital sign measures will be summarized by time point for each treatment 
group and overall.  Since pre-infusion (i.e., baseline) vitals were not collected, no summary of 
change from baseline will be presented.  Additionally, or in lieu of summary statistics, vital sign 
measures may be plotted over time by treatment group with individual lines for each subject. 
Separate listings of vital sign data over time may also be created. 
8.5.2. 
Other Safety Measures 
If present, a listing will be produced detailing any reported instances of PTLD or other 
malignancies. 
9. 
OTHER ANALYSES 
Non-immunosuppressive medications reported on the CRF will be categorized for analysis as 
prior, concomitant, or after study treatment by comparing the medication start and stop dates 
with the study drug infusion start and stop date/time.  Prior medications will have both the 
medication start and stop dates prior to the study drug infusion date.  After medications will have 
both the medication start and stop dates after the study drug infusion date.  All other 
medications will be classified as concomitant, indicating that use of the medication overlapped 
with use of the study drug infusion. 
The number and percentage of subjects receiving prior, concomitant, and after medications will 
be presented overall and by medication class within each treatment group for the ITT sample. 
Medications will be captured in the following categories: beta blockers, diuretics, ACE/ARB 
inhibitors, anti-adrenergics, calcium channel blockers, other antihypertensives, statins, non-
statins, insulin (rapid-acting, short-acting, intermediate-acting, long-acting), oral hypoglycemia 
agents, hemapoietic support, and aspirin.  
10. 
INTERIM ANALYSES AND DATA MONITORING 
No interim statistical analyses were planned.  However, the progress of the study was 
monitored by the Data and Safety Monitoring Board (DSMB).  The DSMB formally reviewed the 
safety data at least yearly in open and/or closed sessions.  
In addition, safety data was reviewed by the DSMB when an event occurred that was of 
sufficient concern to the DAIT medical monitor or protocol chair to warrant review, or when an 
event occurred that could contribute to a protocol-specified stopping rule. 
11. 
REFERENCES 
1. Little R, Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics 
1996;52:1324-1333. 
2. Ma G, Troxel AB, Heitjan DF. An index of local sensitivity to non-ignorable drop-out in 
longitudinal modelling. Stat Med. 2005 Jul 30;24(14):2129-50. 


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3. Kenward M, Multiple Imputation and its Application James Carpenter, ISBN: 978-0-470-
74052-1 February 2013. 
4. Carpenter, J. R., and Kenward, M. G. , Multiple Imputation and its Application (Statistics 
in Practice), Wiley. 2010.