Clinical trial NCT04066114
Conditions: Living-Donor Kidney Transplant Kidney Transplant Recipients
Keywords: adult living-donor kidney transplant recipients novel immunosuppressive (IS) therapy regimen lulizumab pegol (BMS-931699) CD28 and IL-6 biologic blockade CD28 and IL-6 receptor antagonists T regulatory cells (Treg) modulation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-12-11; Completion date: 2023-09-14
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety of using lulizumab pegol with tocilizumab, belatacept, and everolimus in kidney transplant recipients.

Detailed description:
This research study is for adults who are planning to have a kidney transplant from a living donor.

In Brief:

Those who have a transplant take immunosuppressive therapy to prevent the body from rejecting the transplanted organ. Rejection occurs when the body's defense system (immune cells) recognizes the transplant as a foreign object. These immune cells and the substances they produce can damage the transplanted kidney. It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible.

Most transplant doctors in the United States give a combination of two or three drugs to prevent rejection. People with a transplant must take these drugs every day. Although kidney transplant recipients usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and avoid the side effects that the current drugs can cause.

This study will test a new combination of four drugs to evaluate whether this combination is safe for kidney transplant recipients:

* lulizumab pegol (BMS-931699)
* tocilizumab
* belatacept and
* everolimus.

Belatacept and everolimus are already approved for use as anti-rejection drugs in kidney transplant recipients. Lulizumab pegol and tocilizumab act on specific molecules (specifically CD28 and interleukin 6, respectively) on immune cells: these actions are different from how the older rejection drugs work.

Summary: This is a prospective multicenter open-label clinical trial of 10 living donor kidney transplant recipients. Safety of lulizumab pegol (BMS-931699) in the context of a novel immunosuppressive regimen (anti-thymocyte globulin (rabbit) (ATG), steroids,) Nulojix® (belatacept), Actemra® (tocilizumab), and Zortress®(everolimus)) will be assessed. Study participation involves a minimum of one year of follow-up post-transplant.

\*\*\* IMPORTANT NOTICE: \*\*\* The National Institute of Allergy and Infectious Diseases and the Clinical Trials in Organ Transplantation (CTOT) do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Arms: arm 1: lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus)
Interventions: intervention 1: lulizumab pegol intervention 2: antithymocyte globulin (rabbit) intervention 3: methylprednisolone intervention 4: tocilizumab intervention 5: Prednisone intervention 6: everolimus intervention 7: belatacept intervention 8: mycophenolate mofetil intervention 9: mycophenolic acid
Intervention descriptions: intervention 1: 25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11) intervention 2: Study participants are administered four doses of rabbit anti-thymocyte globulin, total dose 6 mg/kg given in divided doses on the day of transplantation and days 1-3. intervention 3: 500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2 intervention 4: 8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24) intervention 5: Beginning on Day 3 post transplantation, taken orally: 60 mg daily

* Days 4 through 10: 30 mg daily
* Days 11 through 17: 20 mg daily
* Days 18 through 24: 10 mg daily
* After Day 24: continued taper of dose to final maintenance dose of 5 mg, per protocol intervention 6: Initial dose of 0.75 mg taken orally twice daily on Day 14 days after transplantation. Dose will be titrated to target trough levels 3-8 ng/mL. intervention 7: 5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52) intervention 8: mycophenolate mofetil is started no later than one day after transplant at 1000mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do no tolerate everolimus can stay on or switch back to mycophenolate mofetil 1000 mg twice daily and remain in trial. intervention 9: mycophenolic acid is started no later than one day after transplant at 720mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do not tolerate everolimus can stay on or switch back to 720 mg twice daily of mycophenolic acid and remain in trial.

Protocol documents:
ICF_000.pdf: 
National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 1 of 8 
 
 
 
 
 
1. 
TITLE OF CLINICAL RESEARCH STUDY 
“Regulatory T Cell Modulation in Kidney Transplantation with Biologic Blockade of Dual Effector Pathways, CD28 
and IL-6” 
Protocol Number:   CTOT-24 
Short Title:  Treg Modulation with CD28 and IL-6 Receptor Antagonists 
 
2. 
YOUR PARTICIPATION IS VOLUNTARY 
We will explain this research study to you.  You have the right to ask questions.   
Research is different from regular medical care.  When you receive standard medical care, your physician makes 
decisions based only on what is in your best interest. When you are in a research protocol, your physician is still 
bound to act in your best interest, but some medical decisions will be directed by the research study. 
• 
Taking part in this study is your decision. 
• 
You may change your mind about being in this study at any time. 
• 
You will be given a copy of this consent form for your records 
 
3. 
PRINCIPAL INVESTIGATOR 
(Insert site Principal Investigator as well as other investigators if desired.) 
 
4. 
KEY INFORMATION FOR THE STUDY 
This document contains information that will help you decide whether to take part in a research study.  We 
encourage you to read the entire document.  All the information is important, but here are some key points to 
help you understand the study.  Additional information is available in the document, in the sections noted in 
italics, below.  
 
• 
This research study is for people who will receive a kidney transplant from a living donor.  The living 
donor is also asked to participate by giving blood for research tests.   
• 
The study will see if a new combination of 5 anti-rejection drugs is safe and will prevent rejection of the 
transplanted kidney with fewer side effects than the standard treatment. While each drug has been used 
separately in humans and has been found to be safe, this combination of drugs will be used for the first 
time in this study.   See Section 5, Introduction and Background; and Section 6, Purpose of the Study  
• 
The study requires donors to make 1 office visit for a blood draw.  See Section 7B, Study Overview/Visit 
Schedule 
• 
Study donors will have one extra blood draw that is not part of routine care for kidney transplant donors.  
• 
The risks of blood draws are pain, bruising, infection, redness, and swelling at the sight of needle entry.  
There is a chance you may feel dizzy while your blood is being drawn.  
• 
There is no direct medical benefit to you from being in this study.  The information learned from this 
study might someday benefit future kidney transplant recipients.  See Section 10, Potential Benefits 
• 
The risk of kidney rejection for the recipient could be higher, lower, or remain the same compared to 
standard of care. 
 
5. 
INTRODUCTION/BACKGROUND 
This research study is for adults who are planning to have a kidney transplant from a living donor. 
 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 2 of 8 
 
 
 
People who have a transplant take immunosuppressive drugs (IS) to prevent the body from rejecting the 
transplanted organ.  Rejection occurs when the body’s defense system (immune cells) recognizes the transplant 
as a foreign object.  These immune cells and the substances they produce can damage the transplanted kidney.  
It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible. 
 
Most transplant doctors in the United States give two or three drugs by mouth to prevent rejection.  People with 
a transplant must take these drugs every day.  These drugs can have several long-term side effects including 
damage to the kidney (which shortens the life of the kidney). New or worsening of conditions such as high blood 
sugar (diabetes), high blood pressure, and high cholesterol can also occur.  Although kidney transplant recipients 
usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and 
long-term side effects while extending the life of the kidney.  
 
This study will test five drugs to see if this combination is safe for kidney transplant recipients.  The table below 
shows the five drugs, how each is given, and the current use: 
 
Drug Name 
How Drug is Given 
Use of Drug  
Lulizumab 
Injection under the skin 
(sub-cutaneous or SC) 
Research studies in animals, healthy volunteers, 
research in subjects with lupus, and Sjogren’s 
Tocilizumab 
SC injection 
FDA approved for treatment of arthritis, research in 
subjects with kidney and heart transplant 
Belatacept 
Injection in a vein 
(intravenously or IV) 
FDA approved for preventing rejection in kidney 
transplant recipients 
Everolimus 
By mouth 
FDA approved for preventing rejection in kidney 
transplant recipients 
Mycophenolate Mofetil 
By mouth 
FDA approved for preventing rejection in kidney 
transplant recipients 
 
Belatacept, Everolimus, and mycophenolate mofetil are already approved for use as anti-rejection drugs in 
kidney transplant recipients. Lulizumab and tocilizumab block the activity of immune cells and target different 
immune cells than the older rejection drugs. 
 
Studies have shown that tocilizumab and lulizumab are successful in preventing rejection in animals with 
transplanted organs.  The combination of lulizumab and tocilizumab has not been used in humans so far.  
However, based on the animal studies, the study team thinks this drug combination can work well in humans 
with a transplant.  This study will help find out if this drug combination can prevent rejection without causing bad 
side effects in kidney transplant patients.      
 
6. 
PURPOSE OF THE STUDY 
The purpose of this study is to see if it is safe to use lulizumab with tocilizumab, belatacept, and everolimus in 
kidney transplant recipients. The study team will look for effects, both good and bad, that the drug combination 
will have in the kidney recipient. 
 
 
 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 3 of 8 
 
 
 
7. 
STUDY COMPONENTS 
A. Number of Study Sites and Participants 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).  The lead study doctor 
is Dr. Flavio Vincenti at the University of California, San Francisco.  Dr. <insert site principal investigator name> is 
in charge of the study at <insert institution>.  Up to <insert expected number for your site> subjects will be 
enrolled at <insert institution>.  We plan to treat 10 kidney transplant recipients in this study at 7 transplant 
centers in the United States.   
 
B. 
Study Overview/Visit Schedule 
There will be a screening visit to see if your recipient qualifies for the study.  Your recipient’s eligibility to 
continue in the study might change, depending on laboratory test results. You will be asked to have a blood draw 
and information collected from your chart after it is confirmed your recipient is eligible to be in the study. 
 
C. 
Study Procedures 
Blood Draw 
All kidney donors have blood drawn as part of the evaluation to donate and to check on your health status after 
donation.  If possible, the study will have research blood drawn when you are already coming to the transplant 
center. 
 
Donor blood collected for research will be used to obtain donor cells.  These cells will be stored and used by 
researchers to see whether the recipient’s immune system is reacting to the donor at different times during the 
study. 
 
You will not have more than 3 ½ tablespoons (50 ml) of extra blood drawn for research tests.   
 
With any laboratory sample, there is a chance of collection tube breakage, shipping problems, and/or other 
human error that can ruin the collected specimen.  If this happens, your study team will let you know and ask 
permission for a 2nd blood draw.  If needed, the second blood draw amount will be no more than the first time. 
 
8. 
RISKS AND DISCOMFORTS 
A. Risks of Study Procedures 
Blood Draw 
The risks of blood draws are pain, bruising, infection, redness, and swelling at the sight of needle entry.  There is 
a chance you may feel dizzy while your blood is being drawn.  Blood collection for research may be delayed or 
canceled if you have severe anemia (low red blood cell count).  Your doctor will treat your anemia if needed as 
normally would occur in your care as a kidney transplant recipient. 
 
9. 
POTENTIAL BENEFITS    
There will be no direct medical benefit to you for being in this study.  The information learned from this study 
might someday benefit future kidney transplant recipients. 
 
10. ALTERNATIVES TO PARTICIPATION 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 4 of 8 
 
 
 
Your doctor will talk with you about this study and other options available to you and your kidney recipient.  Your 
decision to participate in this study will not affect the care you would otherwise receive.   
 
11. NEW FINDINGS  
Your doctor will tell you about any new findings from this or other research that may affect your willingness to 
allow testing and use of your cells for this study.  If new information is provided to you, we will ask for your 
consent to continue in the study. 
 
12. VOLUNTARY WITHDRAWAL FROM STUDY 
You may decide to withdraw consent at any time during this study.  If you decide to withdraw, there is no penalty 
or loss of benefits in your routine medical care or any other benefit(s) that you would otherwise be entitled to 
receive.  Your doctor or research staff will destroy your samples at your request.   
 
13. REASONS WHY YOU MAY BE TAKEN OFF STUDY WITHOUT YOUR CONSENT 
You may be removed from the study without your consent at any time.  Reasons why you may be removed from 
the study include, but are not limited to, the following:      
• 
Your study doctor determines that it is in your best interest not to take part.   
• 
You are unable to complete required study procedures. 
• 
The study is stopped by the Institution, the Sponsor, or health authorities. 
 
14. COSTS TO THE SUBJECT (YOU) 
There will be no charge to you, your health insurance company, or your recipient’s insurance company for any 
costs which are done specifically for this study.    
 
15. PAYMENTS (REIMBURSEMENT) 
You will receive no payment for taking part in this study. 
  (or) 
You will receive (insert amount) to cover the travel and parking cost for your visit to the transplant center to give 
your blood specimen. (Specify what test/procedures will result in compensation, as well as the amount. Explain 
the method of prorating the payment(s)) 
 
(Payments are pro-rated and not held until completion of the study. If participant payments are tied to 
completion of specific study benchmarks, these stipulations should be noted in this section as well as other 
reimbursement specific to the study -i.e. parking, meal tickets, etc.    
 
16. RESEARCH-RELATED INJURY  
<Insert your IRB required language.> 
If are hurt or get sick from something that was done as part of this study, doctors at the clinic or hospital can 
arrange for emergency medical care. The Hospital does not offer financial compensation or payment for injuries 
due to participation in this research. No funds have been set aside to compensate you in the event of injury.  
Your insurance company will be billed for the costs of any care for injuries.  
  
In case of injury resulting from this study, you will not lose any legal rights by signing this form. 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 5 of 8 
 
 
 
17. CONFIDENTIALITY  
Your medical and research records will be confidential to the extent permitted by law.  Efforts will be made to 
keep personal information private.  However, we cannot guarantee complete confidentiality.   
 
As an NIH funded study, you are further protected through a policy that prevents the investigator from disclosing 
sensitive study information that would lead to your identity. This does not prevent you or a family member from 
voluntarily releasing information about yourself or your involvement in this research.                      
 
You will be identified by a code, and personal information from your records will not be released without your 
written permission.  You will not be identified in any publication or in the sharing of your data about this study.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law.  This 
web site will not include information that can identify you.  At most, the Web site will include a summary of the 
results.  You can search this Web site at any time.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include:   
• 
the National Institute of Allergy and Infectious Diseases, (NIAID) sponsor of the research  
• 
NIAID representatives, agents, employees, contractors, and other persons assisting in conducting, 
monitoring or analyzing the study   
• 
the U.S. Food and Drug Administration  
• 
other State and Local health authorities 
 
 
18. STORING INFORMATION/DATA FOR FUTURE STUDIES  
As a NIH-sponsored clinical study, we are expected, as described in the Funding Opportunity Announcement 
and/or Terms of Award, to share research data with the scientific community.  We will store information 
resulting from this study in a central data repository. Data is information organized for a reason, like this study.  A 
central data repository is a place that collects and stores data from many different studies.  The purpose of this 
collection is to make scientific information available for future studies which may help future patients. Your data 
may be stored indefinitely.  Any information released to a central data repository will not contain traditional 
information such as name, birthdate, address, etc. that is considered your personal information. 
 
19. PROBLEMS OR QUESTIONS   
If you ever have questions about this study or in case of research-related injuries, you should contact Dr. <Insert 
name> at <Telephone Number>, or if you have questions about research subjects’ rights you can call <Insert the 
name and title of the appropriate country/site-specific person> at <Insert the number>, or if you prefer, direct 
your questions to the following address: <Insert address of IRB patient representative here>. 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 6 of 8 
 
 
 
SIGNATURE PAGE  
 (Site may use the site-specific signature page if required) 
 
Please sign below if you agree to take part in this study.  
  
• 
you have read the informed consent and/or had it explained to you 
• 
you were given the opportunity to ask questions about the information, and 
• 
you voluntarily agree to take part in the study 
 
 
_________________ 
         
_____________________      
           ______________ 
Research Subject’s Name 
Research Subject’s Signature 
           Date 
(Typed or printed) 
 
 
Signature of person(s) explaining and obtaining the consent: 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title  
Signature 
 
 
 
Date 
(Typed or printed)   
 
____________________ 
____________________ 
 
_________________ 
Name and Title  
Signature 
 
 
 
Date 
(Typed or printed)   
 
  
(NOTE:  This consent form with the original signatures MUST be retained on file by the principal investigator.  A 
copy must be given to the research subject.  A copy should be placed in the research subject’s medical record, if 
applicable.)       


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 7 of 8 
 
 
 
20. STORAGE OF SAMPLES and/or INFORMATION FOR FUTURE USE  
(This consent is optional, and agreement is not required for participation in the study) 
We are asking your permission to store samples of biological specimens (e.g., cells) collected for this study to be 
used in the future for tests that are not yet planned. These tests may or may not be related to the study of 
transplantation.     
 
Some information about a research specimen will always be linked to it (also see section 6c, Genetic 
Information).  For example, researchers might know a sample is from a kidney transplant recipient.  Because of 
this, allowing for specimens to be stored for future use also means allowing for the linked information to be 
stored and used when the specimens are needed. 
 
Genetic Testing on Stored Samples 
Your samples may be used to look at genetic information in relation to kidney transplantation (for example, the 
rejection process).  However, your samples could also be used in studies that are not related to transplantation 
(for example, the immune system as a whole).   
 
Confidentiality 
All samples will be labeled with a randomly assigned unique barcode.  They will not contain personal information 
like name, initials, or date of birth.  Reports on these stored samples and genetic tests will not be given to your 
study doctor and they will not be in your medical record.  Doctors will not know that your samples are being used 
for other studies and it will not affect your routine medical care. 
 
Benefits of Stored Material and Genetic Testing 
There is no benefit to you from the storage of samples and information.  However, the use of your samples and 
information may help researchers learn more about your disease or the genetics related to a specific condition.   
 
Samples will be stored at the core laboratories involved in this trial.  If you agree, your samples and information 
may be stored for an unknown length of time. 
 
Risks of Stored Material and Genetic Testing 
Although your stored research samples will not be sold, the information obtained from the research performed 
on your samples may in the future lead to the development of commercial products.  You will not receive any 
money from research using your stored samples and information 
There may be unknown risks associated with the storage of samples and information.    For example, if the future 
research involves genetic testing it is possible that it could be traced back to you because your genes are specific 
to you. We will make every attempt to protect your confidentiality and to make sure that your personal identity 
does not become known.    
 
Making a Decision for Stored Human Subject Material and Genetic Testing  
Your decision regarding the storage of samples or the information resulting from the analysis of your samples will 
not affect your ability to participate in this study.   
 
 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Donor Consent Template 
CTOT-24 Donor Consent Template 
 
Version 5.0/ October 26, 2021 
Page 8 of 8 
 
 
 
Please indicate your response below: 
Choose yes or no to allow the storage and sharing of your sample (cells) and information for genetic tests.      
 
   Yes       
  No    
 
 
                                   _______________________ 
 
     
 
      Initials of Research Subject 
 
Choose yes or no to allow the storage and sharing for future use of remaining sample (cells) and information for 
other research tests not currently planned (not genetic).  
 
 
   Yes       
  No    
 
 
                                    _______________________ 
 
        
      Initials of Research Subject 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Recipient Consent Template 
CTOT-24 Recipient Consent Template 
 
Version 5.0/ October 26, 2021 
 
Page 1 of 15 
 
 
 
 
 
1. 
TITLE OF CLINICAL RESEARCH STUDY 
“Regulatory T Cell Modulation in Kidney Transplantation with Biologic Blockade of Dual Effector Pathways, CD28 
and IL-6” 
Protocol Number:  CTOT-24 
Short Title:  Treg Modulation with CD28 and IL-6 Receptor Antagonists 
 
2. 
YOUR PARTICIPATION IS VOLUNTARY 
We will explain this research study to you.  You have the right to ask questions.   
Research is different from regular medical care.  When you receive standard medical care, your physician makes 
decisions based only on what is in your best interest. When you are in a research protocol, your physician is still 
bound to act in your best interest, but some medical decisions will be directed by the research study. 
• 
Taking part in this study is your decision. 
• 
You may change your mind about being in this study at any time. 
• 
You will be given a copy of this consent form for your records 
 
3. 
PRINCIPAL INVESTIGATOR 
(Insert site Principal Investigator as well as other investigators if desired.) 
 
4. 
KEY INFORMATION FOR THE STUDY 
This document contains information that will help you decide whether to take part in a research study.  We 
encourage you to read the entire document.  All the information is important, but here are some key points to 
help you understand the study.  Additional information is available in the document, in the sections noted in 
italics, below.  
 
• 
This research study is for people who will receive a kidney transplant from a living donor. 
• 
The study will see if a new combination of 5 anti-rejection drugs is safe and will prevent rejection of the 
transplanted kidney with fewer side effects than the standard treatment.  While each drug has been used 
separately in humans and has been found to be safe, this combination of drugs will be used for the first 
time in this study.  See Section 5, Introduction and Background; and Section 6, Purpose of the Study  
• 
The study requires participants to make 18 office or hospital visits over a one-year period.  See Section 
7B, Study Overview/Visit Schedule 
• 
Study participants will have to see a nurse or study team member to get a study drug injection every 
week for 12 weeks (about 3 months); then every other week until 24 weeks (about 6 months after 
transplant).  Study participants will also have a study drug infusion about once a month during the study. 
See Section 7B, Study Overview/Visit Schedule 
• 
Study participants will have procedures that are not part of routine care for kidney transplant recipients. 
These include: 
o 
<Customize per site standard of care> An extra kidney biopsy, in which a piece of the 
transplanted kidney is removed with hollow needle 
o 
Extra urine and blood collections.  See Section 7C, Study Procedures 
• 
The risks of the study drugs used in combination are not known.  However, the risks of anti-rejection 
drugs in general include cancer and serious infections.  There is also a risk for rejection of the 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Recipient Consent Template 
CTOT-24 Recipient Consent Template 
 
Version 5.0/ October 26, 2021 
 
Page 2 of 15 
 
 
 
transplanted kidney if the drug combination does not work as expected.  See Section 8A, Risks of Study 
Drugs 
• 
There might be no direct medical benefit to you for being in this study.  The information learned from 
this study might someday benefit future kidney transplant recipients.  See Section 10, Potential Benefits 
 
5. 
INTRODUCTION/BACKGROUND 
This research study is for adults who are planning to have a kidney transplant from a living donor. 
 
People who have a transplant take immunosuppressive drugs (IS) to prevent the body from rejecting the 
transplanted organ.  Rejection occurs when the body’s defense system (immune cells) recognizes the transplant 
as a foreign object.  These immune cells and the substances they produce can damage the transplanted kidney.  
It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible. 
 
Most transplant doctors in the United States give two or three drugs by mouth to prevent rejection.  People with 
a transplant must take these drugs every day.  These drugs can have several long-term side effects including 
damage to the kidney (which shortens the life of the kidney).  New or worsening of conditions such as high blood 
sugar (diabetes), high blood pressure, and high cholesterol can also occur.  Although kidney transplant recipients 
usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and 
long-term side effects while extending the life of the kidney.  
 
This study will test a new combination of five drugs to see if this combination is safe for kidney transplant 
recipients.  The table below shows the five drugs, how it is given, and the current use:  
 
Drug Name 
How Drug is Given 
Use of Drug  
Lulizumab 
Injection under the skin (sub-
cutaneous or SC) 
Research studies in animals, healthy volunteers, 
research in subjects with lupus, and Sjogren’s 
Tocilizumab 
SC injection 
FDA approved for treatment of arthritis, 
research in subjects with kidney and heart 
transplant 
Belatacept 
Injection in a vein 
(intravenously or IV) 
FDA approved for preventing rejection in kidney 
transplant recipients 
Everolimus 
By mouth 
FDA approved for preventing rejection in kidney 
transplant recipients 
Mycophenolate Mofetil 
By mouth 
FDA approved for preventing rejection in kidney 
transplant recipients 
 
Belatacept, everolimus, and mycophenolate mofetil are already approved for use as anti-rejection drugs in 
kidney transplant recipients. Lulizumab and tocilizumab block the activity of immune cells and target different 
parts of the immune system than the older rejection drugs. 
 
Studies have shown that tocilizumab and lulizumab are successful in preventing rejection in animals with 
transplanted organs.  The combination of lulizumab and tocilizumab has not been used in humans so far.  
However, based on the animal studies, the study team thinks this drug combination can work well in humans 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Recipient Consent Template 
CTOT-24 Recipient Consent Template 
 
Version 5.0/ October 26, 2021 
 
Page 3 of 15 
 
 
 
with a transplant.  This study will help find out if this drug combination can prevent rejection without causing bad 
side effects in kidney transplant patients.      
 
6. 
PURPOSE OF THE STUDY 
The purpose of this study is to see if it is safe to use lulizumab with tocilizumab, belatacept, everolimus and 
myophenolate mofetil in kidney transplant recipients. The study team will look for effects, both good and bad, 
that the drug combination will have in the kidney recipient. 
 
7. 
STUDY COMPONENTS 
A. Number of Study Sites and Participants 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).  The lead study doctor 
is Dr. Flavio Vincenti at the University of California, San Francisco.  Dr. <insert site principal investigator name> is 
in charge of the study at <insert institution>.  Up to <insert expected number for your site> subjects will be 
enrolled at <insert institution>.  We plan to treat 10 kidney transplant recipients in this study at 7 transplant 
centers in the United States.   
 
B. 
Study Overview/Visit Schedule 
There will be a screening visit to see if you qualify for the study.  Your eligibility to continue in the study might 
change, depending on laboratory test results.  
 
The study will start when you have your kidney transplant, and you will receive study drugs for one year after the 
transplant.  We will also collect additional information about your kidney function and overall health status two 
years after transplant.  Study participants will have: 
• 
23 study visits for blood draws, vital signs, physical exam, and to meet with a study team member. You 
will also get medications at some of these study visits.  Study visits usually take about 1-2 hours to 
complete.  
• 
13 medication visits to get study drugs.  Medication visits for Lulizumab or tocilizumab SC injections 
usually take about 30 minutes to complete.  Medication visits for Belatacept IV infusions will usually take 
less than 1 hour to complete.  The schedule for each drug is: 
o 
Lulizumab SC injections on day 1 after transplant, then every week for the first 12 weeks after 
transplant.   
o 
Tocilizumab IV on day 2 after the transplant, then SC injections every other week for the first 6 
months after transplant (week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24)  
o 
Belatacept IV injections every month starting at 12 weeks after transplant.   
• 
Everolimus by mouth twice a day starting at 2 weeks after transplant 
As described in the Kidney Biopsy section, you might have extra visits to the transplant center if your 
doctor thinks a kidney biopsy is needed. 
Visits early after transplant will occur while you are still in the hospital.  After your hospital stay from transplant 
surgery, study and medication visits will be combined to save time whenever possible.   
The following table summarizes the study.  Visits marked with (*) are times when you will be asked to go to the 
transplant clinic even if you are not in the study.   
 
 Additional details about study procedures are in other sections of this document.  


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Study or Medication Visit After Transplant 
Blood Draw 
Physical 
Exam/ 
Vital Signs 
Kidney 
Biopsy 
Medication  
Luli = lulizumab 
Toci = tocilizumab 
Bela = belatacept 
SC = Sub-Cutaneous 
IV = Intravenous 
Research 
Lab Tests 
Hospital 
Lab Tests 
Screening Visit  
 
X 
X 
 
 
Time Point 
Study 
Visit 
Medication 
Visit 
 
 
 
 
 
Transplant Day 
X 
X 
X 
 
X 
 
 
Day 1 
X 
X  
 
X 
X 
 
Luli SC 
Day 2 
X 
X  
 
X 
 
 
Toci IV 
Day 7/ Week 1 
X 
 X  
 
X 
X 
 
Luli SC 
Day 14/ Week 2 
X 
X  
 
X 
X 
 
Luli & Toci SC 
Week 3 
 
X 
 
X 
 
 
Luli SC 
Day 28/ Week 4 
X 
 
X 
X 
X 
 
Luli & Toci SC 
Week 5 
 
X 
 
X 
 
 
Luli SC 
Week 6 
X 
 
 
X 
X 
 
Luli & Toci SC 
Week 7 
 
X 
 
X 
 
 
Luli SC 
Week 8 
X 
X   
 
X 
X 
 
Luli & Toci SC 
Week 9 
 
X 
 
X 
 
 
Luli SC 
Week 10 
X 
X    
 
X 
X 
 
Luli & Toci SC 
Week 11  
 
X 
 
X 
 
 
Luli SC 
Week 12 
X 
X  
X 
X 
X 
 
Toci SC & Bela IV 
Week 14 
X 
X    
 
X 
X 
 
Toci SC  
Week 16 
 
X 
 
 
 
 
Toci SC & Bela IV 
Week 18 
X 
X 
 
X 
X 
 
Toci SC 
Week 20 
 
X 
 
 
 
 
Toci SC & Bela IV 
Week 22 
X 
X  
 
X 
X 
 
Toci SC  
Week 24 
 
X 
 
 
 
 
Toci SC & Bela IV 
Week 26 
X 
 
X 
X 
X 
X 
 
Week 28 
 
X 
 
 
 
 
Bela IV 
Week 30 
X 
 
 
X 
X 
 
 
Week 32 
 
X 
 
 
 
 
Bela IV 
Week 36 
X 
X  
 
X 
X 
 
Bela IV 
Week 40 
 
X 
 
 
 
 
Bela IV 
Week 42 
X 
 
X 
X 
X 
 
 
Week 44 
 
X 
 
 
 
 
Bela IV 
Week 48 
 
X 
 
 
 
 
Bela IV 
Week 52 
X 
X  
X 
X 
X 
 
Bela IV 
2 years 
Medical records review and data collection 
 
Possible Extra Visits 
 
 
X 
X 
X 
X 
 
 


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C. 
Study Procedures 
Blood Draw 
All transplant patients have blood drawn as part of their routine care.  Whenever possible, the study will use test 
results from your routine blood work (Hospital Lab Tests) for the study without drawing more blood.  In addition 
to local lab testing, you will have blood drawn for research tests.  (See Study Schedule).   
 
Blood collected for research will be examined for the following: 
• 
T Cells – Different types of T cells will be identified in the blood and compared at different time points.  
• 
Antibodies – Antibodies form when the immune system identifies something foreign, such as an organ 
transplant.  We will be looking for antibodies to your kidney donor.    
• 
Gene Expression – Researchers will look at when certain genes are turned on or off when the kidney is 
working normally, and when there is inflammation or rejection. 
• 
Biomarkers – Researchers will look for certain molecules in the blood to see if any correlate with the 
kidney’s health. 
 
You will not have more than 6 tablespoons (87.5 ml) of extra blood drawn for research tests at a single visit.   
 
Kidney Biopsy 
A kidney biopsy is a procedure in which a small piece of kidney tissue is removed with a needle so that it can be 
examined under a microscope.   Kidney tissue is needed for research tests at the following times:   
• 
Visit 14/ 26 Weeks (about 6 months) after transplant    
<Customize per site standard of care surveillance biopsy schedule> 
A biopsy is done at this time even in people who are not in the study.  However, some of the tissue samples from 
the biopsy will be used for this study.  No additional needle sticks are needed for the study. 
OR 
Up to two needle passes will be made to collect tissue samples for this study.   For each time point listed above, 
kidney tissue about ¾ - 1 inch in length and the width of a pencil lead will be collected for research tests. 
 
Kidney tissue collected for research will be examined for the following: 
• 
Changes in the number of cells or cell type seen.   
• 
Other evidence of a change in the health of the kidney. 
• 
Gene Expression – Researchers will look for evidence that certain genes are turned on or off  
 
Possible Extra Visits 
There are different reasons when extra visits might be needed during the study.  Examples include: 
• 
Collection tube breakage, shipping problems, and/or other human error that can ruin laboratory samples.  This may 
require new samples to be collected.   
• 
Your screening visit may have to be repeated if your transplant is delayed, to ensure you still qualify for the study. 
 
If an extra visit is required, your study team will let you know and ask permission for repeating research procedures.  If any 
laboratory tests need to be repeated, the blood draw amount will be no more than the first time.  
 
In addition, you might have a ‘for-cause’ kidney biopsy done during the study.  For example, your doctor may 
perform a biopsy if kidney function tests are abnormal.  No extra kidney tissue will be collected for this study at 


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the time of a for-cause or other routine biopsy (not study related) but we will use the same sample for research 
tests.  Less than 2 tablespoons (27.5 ml) of blood will be collected for the study you have a for-cause biopsy. 
 
Urine Collection 
You will be asked to collect 100 ml (less than ½ cup) of urine in a cup for study tests.  Researchers will look for 
molecules in the urine that might provide information about the health of the kidney.  
 
D. Study Drugs 
This section describes drugs you will have during the study.  Your study doctor will talk to you about the best 
combination of medications to take at the end of the study.  You might continue with some of the study drugs or 
switch to other ones. 
 
Lulizumab  
Lulizumab is a new drug not yet approved for use in kidney transplant recipients.  Lulizumab is known to work 
against CD28 cell activity which may play a part in rejection.  So far, lulizumab has been studied in animals, 
healthy human volunteers, and patients with diseases called lupus and Sjogren’s.  The study in lupus showed that 
lulizumab is safe but not effective for that disease.  It is not known if lulizumab is helpful in Sjogren’s, but no 
safety concerns were seen in that study.  The next step is to see if the drug works as researchers think it will in 
people with kidney transplants. 
 
Lulizumab is given with a small needle under your skin (SC injection).  You will get the first dose one day after 
transplant and then every week for 12 weeks.  You will have to return to the transplant center to get the 
injections. 
 
Actemra® (tocilizumab) 
Tocilizumab is FDA approved to treat rheumatoid arthritis and reactions to certain types of cancer treatments.  
Tocilizumab works against IL6, a molecule that can help cause organ rejection in addition to inflammation (your 
body’s reaction to injury or infection) which is seen in other diseases.  Tocilizumab has been used in small studies 
to fight rejection in people with kidney transplants and was found to be safe.  There is a study using tocilizumab 
in heart recipients.  However, there is still more to be learned about how the drug works in people with 
transplants because larger studies have not yet started or are still ongoing. 
 
You will receive the first dose 2 days after transplant as an IV infusion. Tocilizumab is also given as a SC injection.  
After you leave the hospital, you will have 12 more tocilizumab injections SC every other week (week 2, 4, 6, 8, 
10, 12, 14, 16, 18, 20, 22, 24 after transplant).  
 
Nulojix® (belatacept) 
Belatacept is a FDA-approved anti-rejection medication used after kidney transplantation.   Although belatacept 
is not as widely used as other anti-rejection medications, it is well studied and used in thousands of kidney 
transplant patients. Belatacept is not generally used in combination with the drugs in this study. 
 
Belatacept is given as an intravenous (through the vein, IV) solution about once a month.  Each infusion takes 
about 30 minutes.  The first dose will be given at the time of transplant and then monthly until the end of the 


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study.  You will be monitored closely during and after each infusion.  It is important for you to keep all your 
appointments for belatacept infusions to prevent rejection.    
 
Zortress® (Everolimus) 
Everolimus is a FDA-approved anti-rejection medication used after kidney transplantation.  Although everolimus 
is a newer drug and not as widely used as other anti-rejection medications, it has been well studied and used in 
thousands of kidney transplant patients.  You will start taking everolimus about 2 weeks after transplantation. 
 
Everolimus is taken by mouth twice a day (morning and evening).  The dose of everolimus is changed based on 
levels of the drug in your blood. 
 
Cellcept® (Mycophenolate Mofetil -MMF) or Myfortic® (Mycophenolic Acid -MPA) 
MMF and MPA are both FDA-approved anti-rejection medications used after organ transplantation.  These 
medications are also widely used “off-label” to treat other diseases.  MMF and MPA are medications with the 
same active ingredient, and one or the other is usually given with at least one other drug to prevent rejection 
after organ transplantation.  You will likely be prescribed MMF or MPA even if you are not in this study.  Your 
doctor will decide whether MMF or MPA is better for you.  In this study, MMF or MPA will be given starting on 
the day of transplantation for about 2 weeks.  MMF or MPA will be discontinued when Everolimus drug levels are 
high enough.   The study team will give instructions for medication dose changes. 
   
8. 
RISKS AND DISCOMFORTS 
A. Risks of Study Procedures 
Blood Draw 
The risks of blood draws are pain, bruising, infection, redness, and swelling at the sight of needle entry.  There is 
a chance you may feel dizzy while your blood is being drawn.  Blood collection for research may be delayed or 
canceled if you have severe anemia (low red blood cell count).  Your doctor will treat your anemia if needed as 
normally would occur in your care as a kidney transplant recipient. 
 
Kidney Biopsy 
Risks of a biopsy include bleeding in or around the kidney that can lead to a fall in blood pressure and rise in 
heart rate. This may require a blood transfusion, or very rarely, lead to a need for surgery or loss of the kidney. 
Additional risks include pain and bleeding at the site of biopsy, infection, discomfort and bloodstained urine. 
 
Urine Collection 
There are no known risks of urine collection. 
 
Genetic Information 
Genetic information will be recorded from the specimen collected for this study.  However, the specimen will be 
used in experiments planned for this study only.  Your sample will not be looked at for other genetic conditions, 
genetic cloning, or paternity testing.  However, basic genetic information about you will be known to researchers 
(e.g. sex, racial or ethnic group).  We will keep all information recorded private as much as possible.  However, 
because genetic information is unique to you, complete confidentiality cannot be guaranteed.   
B. 
Risks of Study Drugs 


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Anti-rejection drugs suppress or weaken the body’s response to reject a transplanted organ.  However, these 
drugs generally affect the entire immune system and not just the transplanted kidney.  Because people with 
transplants must take anti-rejection drugs, the risks exist even if you are not in this study.   
 
You will take some drugs (like Thymoglobulin, prednisone and myophenolate mofetil) as a study participant even 
if you are not in the study.  However, you will receive belatacept and everolimus as a study participant which 
might not be prescribed to you if you are not in the study.  It is not known whether the combination of drugs 
used in this study will change that risk – it may be lower than, the same as, or greater than standard anti-
rejection drugs.   
 
Opportunistic Infections:   Opportunistic infections are infections that occur more frequently and are more severe 
in people with weakened immune systems, including kidney transplant recipients who must take immune 
suppressing drugs.  Serious fungal infections have been reported in people using tocilizumab, belatacept, and 
everolimus.  People using these types of drugs are also at higher risk for bacterial, viral, and other infections.   
 
PTLD:  Taking immune suppressing drugs increases the risk of post-transplant lymphoproliferative disorder (PTLD) 
more than other anti-rejection drugs.  PTLD is a type of cancer (tumor) that can develop in transplant recipients 
because they are required to take drugs that suppress the immune system over a long period of time.  PTLD is 
the most common type of cancer after transplant but occurs in less than 1% of adults who receive kidney 
transplants.  In lymphoproliferative disorders like PTLD, lymphocytes (a type of white blood cell) grow 
abnormally.  PTLD is almost always linked with a virus called Epstein Barr (EBV), the virus responsible for 
infectious mononucleosis (known as mono).  The risk of PTLD is highest if a patient has his/her first EBV infection 
after kidney transplant and lower if a patient has had a previous EBV infection prior to kidney transplantation and 
has developed immunity.  You have evidence of previous EBV infection.  This study only enrolls patients who 
have had previous EBV infection.  
 
Cancer:  People taking anti-rejection drugs that weaken the immune system are at higher risk of getting cancer.  
Although also very rare, the second most common type of cancer after transplantation is skin cancer.  All 
participants will be monitored for this or other complication as part of the study.  After the study, you will be 
monitored for cancer as part of routine care after transplant.        
 
PML:  Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection caused by JC virus.  
People with weakened immune systems are at risk for getting PML.  PML can result in death or sever disability.  
There is no known treatment or cure for PML. 
 
Other serious infections:  Serious infections including tuberculosis and BK virus can occur in people taking anti-
rejection drugs.  Because of the weakened immune system, these and other infections caused by bacteria, 
viruses, or fungi can cause illness that may lead to death.  The BK virus can affect how your kidney works and 
cause your transplanted kidney to fail. 
 
Rejection:  It is possible that the combination of study drugs can increase the risk of rejection.  Typically, rejection 
can be treated in kidney transplant recipients.  There is, however, no experience in treating rejection that 
happens when using the study drugs.  Your kidney tests will be monitored very closely to ensure early diagnosis 
of kidney rejection. 


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There have been 3 subjects who experienced rejection after starting the drugs in this study.  The study team 
stopped the study each time this occurred, then reviewed and changed the study to make it less likely for 
rejection to occur.  The study’s data safety monitoring board, as well as each participating site’s institutional 
review board reviewed each study change and agreed that the study can proceed. 
 
Lulizumab  
Lulizumab is a new drug so there is not as much information about side effects as for drugs that have been used 
longer.  The most frequent side effects reported in a study of 108 healthy volunteers receiving lulizumab are: 
headache, feeling hot, pain in the mouth and throat, back pain, itchiness, and upper respiratory infection.  Seven 
of these study participants had infusion reactions.  18 people who received lulizumab also had minor 
abnormalities in liver tests.   
 
In a larger study of 346 patients with lupus, serious events happened in one out of ten participants receiving 
lulizumab.  Side effects related to lulizumab include: high blood pressure, shingles (herpes zoster), abscess 
(bacterial skin infection with a pocket of pus under the skin), lung and respiratory infections, serum sickness 
(fever, muscle aches, feeling unwell without infection), and systemic inflammatory response syndrome (fever, 
nausea, vomiting, diarrhea, muscle aches, abnormal blood cell counts without infection).  There were no deaths 
related to lulizumab. 
 
Information about any side effects will be recorded for this study.  
 
Actemra® (tocilizumab) 
Tuberculosis:  People taking tocilizumab are at higher risk of getting tuberculosis (TB).  TB is an infection mainly 
affecting the lungs.  People who get TB must take several types of medications for many months to cure the 
infection.  TB can be very serious and difficult to treat in kidney transplant recipients because of the ongoing 
need for immune suppressing drugs.  You must have a negative TB test or have completed treatment for TB to be 
in this study.   
 
Ruptured Bowel:  People in studies using tocilizumab have had ruptured bowel, usually after problems with an 
existing disease called diverticulitis (inflamed and/or infected bowel). 
 
Drug Reaction:  Anaphylaxis leading to death has been reported in people after being given tocilizumab by IV.  
Anaphylaxis is a severe, potentially life-threatening allergic reaction.  The reaction can occur within seconds or 
minutes after exposure to a drug or other substance you are allergic to.  You will receive the first dose of 
tocilizumab by IV while in the hospital.  The rest of the study doses will be given by SC injection.  You will be 
monitored for anaphylaxis and other reactions after the first injection in the hospital.   
 
Side effects for people taking tocilizumab every other week to treat rheumatoid arthritis are listed below.  The 
number next to the side effect is the percentage of people who had the side effect. 
• 
Injection site reactions, such as redness and swelling at the site of needle entry (7%)  
• 
Low white cell count (4%) 
• 
Abnormal liver tests (3%), also see below about liver failure 
• 
High cholesterol level (20%) 


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There have been extremely rare instances (2 in a million patients) of liver failure in people using tocilizumab.  
Your liver tests will be monitored closely during the study.  The study team will pause or stop tocilizumab and/or 
other medications, as needed, if your liver tests are abnormal. 
 
9. 
Pregnancy 
You cannot take part in this study if:   
• 
You are pregnant or breastfeeding 
• 
You or your partner plan to get pregnant in the next 12 months. 
 
Study drugs and procedures involved in this research project may involve unexpected risks to your unborn or 
nursing child. If you are female of childbearing potential, a pregnancy test will be done before you start the study 
and will also be done about every 4 weeks for the first year.  
 
If you are female of childbearing potential and take part in this study, you must agree to use birth control during 
the study. You and the study team will discuss acceptable methods of birth control.  Male participants must 
agree to always use condoms during any sexual activity for at least the first three months while taking lulizumab. 
 
If you become pregnant while participating in this study, or if you think that you may be pregnant, you must 
contact the study team immediately. 
 
The study doctor will talk to you about your care.    
 
10. POTENTIAL BENEFITS    
There might be no direct medical benefit to you for being in this study.  The information learned from this study 
might someday benefit future kidney transplant recipients. 
 
Some subjects may benefit if inflammation in the transplanted kidney can be decreased.   
 
11. ALTERNATIVES TO PARTICIPATION 
Your doctor will talk with you about this study and other options available to you.  Your decision to participate in 
this study will not affect the care you would otherwise receive.   
 
12. NEW FINDINGS  
Your doctor will tell you about any new findings from this or other research that may affect your willingness to 
allow testing and use of your cells for this study.  If new information is provided to you, we will ask for your 
consent to continue in the study. 
 
13. VOLUNTARY WITHDRAWAL FROM STUDY 
You may decide to withdraw consent at any time during this study.  If you decide to withdraw, there is no penalty 
or loss of benefits in your routine medical care or any other benefit(s) that you would otherwise be entitled to 
receive.  Your doctor or research staff will destroy your samples at your request.   
 
14. REASONS WHY YOU MAY BE TAKEN OFF STUDY WITHOUT YOUR CONSENT 


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You may be removed from the study without your consent at any time.  Reasons why you may be removed from 
the study include, but are not limited to, the following:      
• 
Your study doctor determines that it is in your best interest not to take part.   
• 
You are unable to complete required study procedures.The study is stopped by the Institution, the 
Sponsor, or health authorities. 
 
15. COSTS TO THE SUBJECT (YOU) 
There will be no charge to you, your health insurance company, or your recipient’s insurance company for any 
costs which are done specifically for this study.    
16. PAYMENTS (REIMBURSEMENT) 
You will receive no payment for taking part in this study. 
  (or) 
You will receive (insert amount) to cover the travel and parking cost for your visit to the transplant center to give 
your blood specimen. (Specify what test/procedures will result in compensation, as well as the amount. Explain 
the method of prorating the payment(s)) 
 
(Payments are pro-rated and not held until completion of the study. If participant payments are tied to 
completion of specific study benchmarks, these stipulations should be noted in this section as well as other 
reimbursement specific to the study -i.e. parking, meal tickets, etc.    
 
17. RESEARCH-RELATED INJURY  
<Insert your IRB required language.> 
If are hurt or get sick from something that was done as part of this study, doctors at the clinic or hospital can 
arrange for emergency medical care. The Hospital does not offer financial compensation or payment for injuries 
due to participation in this research. No funds have been set aside to compensate you in the event of injury.  
Your insurance company will be billed for the costs of any care for injuries.  
  
In case of injury resulting from this study, you will not lose any legal rights by signing this form. 
 
18. CONFIDENTIALITY  
Your medical and research records will be confidential to the extent permitted by law.  Efforts will be made to 
keep personal information private.  However, we cannot guarantee complete confidentiality.   
 
As an NIH funded study, you are further protected through a policy that prevents the investigator from disclosing 
sensitive study information that would lead to your identity. This does not prevent you or a family member from 
voluntarily releasing information about yourself or your involvement in this research.                      
 
You will be identified by a code, and personal information from your records will not be released without your 
written permission.  You will not be identified in any publication or in the sharing of your data about this study.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law.  This 
web site will not include information that can identify you.  At most, the Web site will include a summary of the 
results.  You can search this Web site at any time.  


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Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include:   
• 
the National Institute of Allergy and Infectious Diseases, (NIAID) sponsor of the research  
• 
NIAID representatives, agents, employees, contractors, and other persons assisting in conducting, 
monitoring or analyzing the study   
• 
the U.S. Food and Drug Administration  
• 
other State and Local health authorities 
 
19. STORING INFORMATION/DATA FOR FUTURE STUDIES  
As a NIH-sponsored clinical study, we are expected, as described in the Funding Opportunity Announcement 
and/or Terms of Award, to share research data with the scientific community.  
We will store information resulting from this study in a central data repository. Data is information organized for 
a reason, like this study.  A central data repository is a place that collects and stores data from many different 
studies.  The purpose of this collection is to make scientific information available for future studies which may 
help future patients. Your data may be stored indefinitely.  Any information released to a central data repository 
will not contain traditional information such as name, birthdate, address, etc. that is considered your personal 
information. 
 
20. PROBLEMS OR QUESTIONS   
If you ever have questions about this study or in case of research-related injuries, you should contact Dr. <Insert 
name> at <Telephone Number>, or if you have questions about research subjects’ rights you can call <Insert the 
name and title of the appropriate country/site-specific person> at <Insert the number>, or if you prefer, direct 
your questions to the following address: <Insert address of IRB patient representative here>. 


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SIGNATURE PAGE  
 (Site may use the site-specific signature page if required) 
 
Please sign below if you agree to take part in this study.  
  
• 
you have read the informed consent and/or had it explained to you 
• 
you were given the opportunity to ask questions about the information, and 
• 
you voluntarily agree to take part in the study 
 
 
_________________ 
         
_____________________      
           ______________ 
Research Subject’s Name 
Research Subject’s Signature 
           Date 
(Typed or printed) 
 
 
Signature of person(s) explaining and obtaining the consent: 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title  
Signature 
 
 
 
Date 
(Typed or printed)   
 
____________________ 
____________________ 
 
_________________ 
Name and Title  
Signature 
 
 
 
Date 
(Typed or printed)   
 
  
(NOTE:  This consent form with the original signatures MUST be retained on file by the principal investigator.  A 
copy must be given to the research subject.  A copy should be placed in the research subject’s medical record, if 
applicable.)       


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21. STORAGE OF SAMPLES and/or INFORMATION FOR FUTURE USE  
(This consent is optional, and agreement is not required for participation in the study) 
We are asking your permission to store samples of biological specimens (e.g., cells) collected for this study to be 
used in the future for tests that are not yet planned. These tests may or may not be related to the study of 
transplantation.     
 
Some information about a research specimen will always be linked to it (also see section 6c, Genetic 
Information).  For example, researchers might know a sample is from a kidney transplant recipient.  Because of 
this, allowing for specimens to be stored for future use also means allowing for the linked information to be 
stored and used when the specimens are needed. 
 
Genetic Testing on Stored Samples 
Your samples may be used to look at genetic information in relation to kidney transplantation (for example, the 
rejection process).  However, your samples could also be used in studies that are not related to transplantation 
(for example, the immune system as a whole).   
 
Confidentiality 
All samples will be labeled with a randomly assigned unique barcode.  They will not contain personal information 
like name, initials, or date of birth.  Reports on these stored samples and genetic tests will not be given to your 
study doctor and they will not be in your medical record.  Doctors will not know that your samples are being used 
for other studies and it will not affect your routine medical care. 
 
Benefits of Stored Material and Genetic Testing 
There is no benefit to you from the storage of samples and information.  However, the use of your samples and 
information may help researchers learn more about your disease or the genetics related to a specific condition.   
 
Samples will be stored at the core laboratories involved in this trial.  If you agree, your samples and information 
may be stored for an unknown length of time. 
 
Risks of Stored Material and Genetic Testing 
Although your stored research samples will not be sold, the information obtained from the research performed 
on your samples may in the future lead to the development of commercial products.  You will not receive any 
money from research using your stored samples and information 
There may be unknown risks associated with the storage of samples and information.    For example, if the future 
research involves genetic testing it is possible that it could be traced back to you because your genes are specific 
to you. We will make every attempt to protect your confidentiality and to make sure that your personal identity 
does not become known.    
 
Making a Decision for Stored Human Subject Material and Genetic Testing  
Your decision regarding the storage of samples or the information resulting from the analysis of your samples will 
not affect your ability to participate in this study.   
 
 


National Institute of Allergy and Infectious Diseases (NIAID) 
Division of Allergy, Immunology and Transplantation (DAIT) 
Recipient Consent Template 
CTOT-24 Recipient Consent Template 
 
Version 5.0/ October 26, 2021 
 
Page 15 of 15 
 
 
 
Please indicate your response below: 
Choose yes or no to allow the storage and sharing of your sample (cells) and information for genetic tests.      
 
   Yes       
  No    
 
 
                                   _______________________ 
 
     
 
      Initials of Research Subject 
 
Choose yes or no to allow the storage and sharing for future use of remaining sample (cells) and information for 
other research tests not currently planned (not genetic).  
 
 
   Yes       
  No    
 
 
                                    _______________________ 
 
        
      Initials of Research Subject 
 
 
 
 
 
 
 
 
 
 

Prot_SAP_002.pdf: 
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Clinical Trials in Organ Transplantation 
CTOT-24 
Regulatory T Cell Modulation in Kidney Transplantation with  
Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 
Treg Modulation with CD28 and IL-6 Receptor Antagonists 
VERSION NUMBER 5.0/ October 26, 2021 
Study Sponsor(s): 
 
 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism:  
 
U01AI113362  
 
IND Sponsor/Number:  
 
 
NIAID/139185 
Study Drug Manufacturer/Provider: 
Bristol Myers Squibb (BMS IM128-046) 
PRINCIPAL INVESTIGATOR 
Flavio Vincenti, MD 
Clinical Professor of Medicine & Surgery 
Depts. Medicine & Surgery 
University of California at San Francisco 
505 Parnassus Avenue, Rm #M884 
San Francisco, CA 94118-0780 
Phone:  415-353-1322 
E-mail:  flavio.vincenti@ucsf.edu 
PROTOCOL CHAIR  
Sindhu Chandran, MD 
Associate Professor of Medicine 
Division of Nephrology 
Department of Medicine 
University of California at San 
Francisco 
400 Parnassus Avenue, Seventh Floor 
San Francisco, CA 94143 
Phone:  415-353-8374 
E-mail:  sindhu.chandran@ucsf.edu 
 
MEDICAL MONITOR 
Megan Morsheimer, MD, MPH 
Medical Officer 
Clinical Transplantation Branch 
Division of Allergy Immunology and 
Transplantation, NIAID, NIH 
5601 Fishers Lane, 6B19 
Bethesda, MD 20852-9827 
Phone:  301-761-7579 
E-mail:  megan.morsheimer@nih.gov 
BIOSTATISTICIAN 
Karen Kessler 
Senior Research Scientist 
Rho, Inc.  
6330 Quadrangle Drive 
Chapel Hill, NC 27517 
Phone: 919-595-6244 
E-mail: karen_Kesler@rhoworld.com 
 
PROJECT MANAGER 
Tina Sledge, RN 
Nurse Consultant/Project Manager 
Clinical Transplantation Branch 
Division of Allergy, Immunology, and 
Transplantation, NIAID, NIH 
5601 Fishers Lane, 6B28 
Bethesda, MD 20852-9827 
Phone:  240-627-3561 
E-mail:  sledget@niaid.nih.gov   
REGULATORY OFFICER 
Julia Goldstein, MD 
Office of Regulatory Affairs 
Division of Allergy, Immunology, 
and Transplantation, NIAID, NIH 
5601 Fishers Lane, 7B29 
Bethesda, MD 20852 
Phone:  240-627-3509 
E-mail:  goldsteinj@niaid.nih.gov 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol Chair, or 
the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases of the National Institutes of 
Health. 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol: 
 CTOT-24 
Version/Date:  
 5.0/ October 26, 2021  
  
Title:   Regulatory T Cell Modulation in Kidney Transplantation with Biologic Blockade of 
Dual Effector Pathways, CD28 and IL-6  
IND Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
 
Return Signed Form to: 
The original signature page must be kept for your records. Return an electronic PDF copy of the signed 
signature page (*as described below) to the DAIT Regulatory Management Center via the applicable DAIT 
RMC email address for the protocol/network. 
  
If PPD is not the Regulatory Management Center for this protocol, e.g., for an Investigator Initiated clinical 
trial, contact the DAIT Regulatory Officer for instructions on where to send the completed signature page. 
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. 
*The site Principal Investigator should sign and date at the indicated location below. A written 
signature/date is acceptable (e.g., scanned and sent via email as a PDF version). An electronic signature is 
also acceptable (e.g., sent via email as a PDF version). 
 
____________________________________     
Site Principal Investigator (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                       Date 


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Protocol Synopsis 
Title 
Regulatory T Cell Modulation in Kidney Transplantation with Biologic 
Blockade of Dual Effector Pathways, CD28 and IL-6 
Short Title 
Treg Modulation with CD28 and IL-6 Receptor Antagonists 
Clinical Phase 
Phase I/II 
Participating Sites 
Cleveland Clinic 
Duke University  
Northwestern University 
University of Alabama at Birmingham 
University of California at San Francisco 
University of Colorado 
University of Nebraska 
IND Sponsor/Number   
NIAID/ IND# 139185 
ClinicalTrials.gov Number 
NCT04066114 
Study Objective  
This trial will be a pilot, proof of concept trial to evaluate the safety and 
mechanisms of transplant immune regulation via Tregs. 
Study Design 
Multi-center, non-randomized, single arm, prospective trial with an 
investigational product (lulizumab pegol (BMS-931699) in the context of a 
novel immunosuppression regimen  
Primary Endpoint 
The primary safety endpoint is the proportion of participants who remain 
free of biopsy-proven acute T-cell mediated or antibody-mediated rejection 
as defined by Banff criteria at 6 months after transplantation.  Clinical 
rejection occurring prior to 6 months, defined as treated rejection without 
biopsy confirmation will be included as acute rejection with respect to the 
endpoint. 
Secondary Endpoint  
The secondary safety endpoint is the proportion of participants who remain 
free of biopsy-proven acute T-cell mediated or antibody-mediated rejection 
as defined by Banff criteria at or before 12 months after transplantation.  
Clinical rejection occurring prior to 12 months, defined as treated rejection 
without biopsy confirmation will be included as acute rejection with respect 
to the endpoint. 
Accrual Objective 
10 subjects 
Study Duration 
27-month accrual, 24-month follow-up 
 
 


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Treatment Description  
Participants will receive the following study drugs, with day 0 defined as the 
date of kidney transplantation: 
• 
ATG (IV) 6 mg/kg given in divided doses on days 0 to 3  
• 
Methylprednisolone (IV) 500 mg on day 0, 250 mg on day 1, 125 mg 
on day 2 
• 
Prednisone (PO) 60 mg on day 3, 30 mg on day 4, then taper to 5 mg 
daily by day 28 (See Section 7.2.4) 
• 
Lulizumab pegol 25 mg on day 1, then 12.5 mg (SC) weekly until day 
77 
• 
Tocilizumab 8 mg/kg (IV) on day 2, then 162 mg (SC) every 2 weeks 
until day 168 
• 
Belatacept (IV) 5 mg/kg every 4 weeks starting day 84 
• 
Mycophenolate mofetil 1000 mg bid starting on day 1, stopped when 
everolimus level is within therapeutic range.  
• 
Everolimus (PO) starting at 0.75 mg BID on day 14, titrated to 
maintain trough level 3-8 ng/ml 
Inclusion Criteria 
1. Able to understand and provide informed consent 
2. Agreement to use highly effective (<1% failure rate) methods of 
contraception (see study definitions). Female participants of child-bearing 
potential must consult with their physician and determine the most 
suitable method(s) from this list to be used for 12 months while on study 
drug regimen.  
3. Male or female, 18 to 70 years 
4. Recipient of primary, non-HLA identical living donor kidney transplant 
5. No donor specific antibodies prior to transplant that are considered to be 
of clinical significance by the site investigator 
6. EBV positive serology  
7. CMV positive serology, unless donor-recipient pair are both CMV negative  
8. Negative testing for latent TB infection within 3 months prior to 
transplant.  Testing should be conducted using either a PPD or interferon-
gamma release assay (i.e. QuantiFERON-TB, T-SPOT.TB).  Patients with a 
positive test for latent TB infection must complete appropriate therapy 
for LTBI.  A subject is considered eligible only if they have a negative test 
for LTBI within 3 months prior to transplant OR they have appropriately 
completed LTBI therapy prior to transplant.  Latent TB infection treatment 
regimens should be among those endorsed by the CDC (Division of TB 
Elimination, 2016). 
9. In the absence of contraindication, vaccinations must be up to date for 
hepatitis B, influenza, pneumococcal, varicella and herpes zoster, and 
MMR.  
10. Hepatitis C Virus Ab positive subjects with negative HCV PCR are eligible if 
they have spontaneously cleared infection or are in sustained virologic 
remission for at least 12 weeks after treatment (see exclusion 13). 
11. Negative SARS-CoV2 PCR testing within 2 weeks of transplant. 


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Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Prisoners or subjects who are compulsorily detained.  
2. Inability or unwillingness of a participant to give written informed 
consent or comply with study protocol 
3. Candidate for a multiple solid organ or tissue transplants   
4. Prior history of organ or cellular transplantation 
5. Known to have idiopathic FSGS as the underlying cause of ESRD   
6. Requirement for uninterrupted anticoagulation therapy, including Plavix 
7. Known hypersensitivity to mTOR inhibitors or contraindication to 
everolimus (including history of wound healing complications) 
8. History of severe allergic and/or anaphylactic reactions to humanized or 
murine monoclonal antibodies  
9. Hypersensitivity to rabbit proteins or rabbit Anti-thymocyte Globulin 
(ATG) 
10. Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol 
(BMS-931699),  
11. HIV infected subjects, including those who are well controlled on anti-
retrovirals 
12. Positive HBsAg or HBcAB serology  
13. Hepatitis C virus antibody positive (HCVAb+) subjects who have failed to 
demonstrate sustained viral remission for more than 12 weeks (after 
anti-viral treatment) 
14. Patients with a previous history of active Tuberculosis (TB)  
15. Known active current viral, fungal, mycobacterial or other infections 
(including, but not limited to tuberculosis and atypical mycobacterial 
disease, Hepatitis B and C, and herpes zoster)  
16. Donor or recipient residing in areas where annual incidence is ≥21 
cases/100,000 for coccidioidomycosis according to current CDC map: 
(https://www.cdc.gov/fungal/diseases/coccidioidomycosis/images/valle
y-fever-map-2017.jpg). Donor or recipients residing in zones with annual 
incidence of <21 cases/100,000 will not require additional screening.  
17. History of malignancy except treated basal cell cancer of the skin  
18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia 
purpura  
19. History of demyelinating disorders (e.g., multiple sclerosis, chronic 
inflammation demyelinating polyneuropathy)  
20. History of gastrointestinal perforations, active inflammatory bowel 
disease or diverticulitis  
21. Any previous treatment with alkylating agents such as chlorambucil, or 
with total lymphoid irradiation;  
22. Receipt of a live vaccine within 30 days prior to transplantation  
23. Past or current medical problems or findings from physical examination 
or laboratory testing that are not listed above, which, in the opinion of 
the investigator, may pose additional risks from participation in the 
study, may interfere with the participant’s ability to comply with study 
requirements or that may impact the quality or interpretation of the 
data obtained from the study.  
24. Severe hyperlipidemia (total cholesterol >350 mg/dL, LDL >190 mg/dL, 
or triglycerides >500 mg/dL) 


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25. Transaminase levels elevated more than 1.5 times the upper limit of 
normal (ULN) within 7 days prior to enrollment. 
26. ANC less than 2,000 per mm3 within 7 days prior to enrollment   
27. Platelet count less than 100,000 per mm3 within 7 days prior to 
enrollment  
28. More than 50% CD8+/ CD28- T-cells in peripheral blood 
29. Positive pregnancy test in women of child bearing potential, currently 
breastfeeding, or planning to become pregnant during the timeframe of 
the study or follow-up period. 
30. Participation in any other studies with investigational drugs or regimens 
in the preceding year 
31. cPRA greater than or equal to 20%, as determined by each participating 
site’s laboratory 
32.  
Study Stopping Rules 
The study may be prematurely terminated for the following reasons: 
1. When 5 or more treated participants receive less than 80% of the 
expected total number of doses of either lulizumab pegol (BMS-931699) 
or tocilizumab  
2.  Banff 2A or higher grade acute cellular rejections in any one of the first 5 
participants in the first 6 months post-transplant. 
3.   Antibody-mediated rejection (of any grade) in any one of the first 5 
participants in the first 6 months post-transplant (Table 6) 
4.  Any TB or invasive fungal infection  
5. Any diagnosis of PTLD or PML 
6. Any graft loss  
7. Any death  
8. Grade 4 infections in two participants 
Additionally, an expedited safety review will also be conducted by the DSMB if 
there are ≥2 episodes of acute rejection in 2 subjects at any time during the 
study. During the process of data collection for the safety review and analysis 
by the DSMB, enrollment will be paused in the study, but others study 
operations can continue including the recruitment of potential participants, 
provision of study drug to previously enrolled participants. 
 
 
 
 


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Study Contacts: Participating Centers 
 
SITE PRINCIPAL INVESTIGATOR 
Emilio Poggio, MD 
Director, Clinical Research of Kidney 
Transplant Program 
Department of Nephrology & 
Hypertension 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: 216-444-6771 
Email: poggioe@ccf.org 
 
SITE PRINCIPAL INVESTIGATOR 
Allan Kirk, MD, PhD 
Department of Surgery Chairman 
Professor of Surgery 
Duke University 
2301 Erwin Road 
DUMC 3704 
Durham, NC 27710 
Phone:  919-681-3445 
E-mail:  allan.kirk@duke.edu 
 
SITE PRINCIPAL INVESTIGATOR 
John Friedewald 
Professor of Medicine & Surgery 
Northwestern University 
Feinberg School of Medicine  
Arkes Family Pavilion Suite 1900 
676 N Saint Clair 
Chicago, IL 60611 
Phone: 312-695-8900 
Email:  
jfriedewald@northwestern.edu 
SITE PRINCIPAL INVESTIGATOR 
Scott Davis, MD 
Assistant Professor, Medicine-Renal 
Med Diseases/Hypertension 
University of Colorado 
Anschutz Transplant Services 
1635 Aurora Ct 
7th Floor 
Phone: 720-848-0005 
Email:  
SCOTT.DAVIS@CUANSCHUTZ.EDU 
SITE PRINCIPAL INVESTIGATOR 
Clifton Kew II, MD 
Professor of Medicine & Surgery 
Director of Research, Alabama 
Transplant Center 
University of Alabama, Birmingham 
1900 University Boulevard 
THT 611G 
Phone:  205-934-7200 
E-mail:   ckew@uab.edu 
 
SITE PRINCIPAL INVESTIGATOR 
Flavio Vincenti, MD 
Clinical Professor of Medicine & 
Surgery 
Depts. Medicine & Surgery 
University of California at San 
Francisco 
505 Parnassus Avenue, Rm #M884 
San Francisco, CA 94118-0780 
Phone:  415-353-1322 
E-mail:  flavio.vincenti@ucsf.edu 
 
 
SITE PRINCIPAL INVESTIGATOR 
Roslyn Mannon, MD 
Professor of Medicine 
Associate Chief of Research 
Division of Nephrology  
University of Nebraska MC 
983040 Nebraska Medical Center 
Omaha, NE 68198-3040 
Phone: 402-559-9227 
Email:  Roslyn.mannon@unmc.edu 
 
 
 
 
 


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Study Contacts: Core Laboratories  
 
Rajalingam Raja, PhD, D (ABHI) 
Main Hospital Level B,  
CPMC Davies Campus 
University of California, San Francisco 
45 Castro Street 
San Francisco, CA 94114 
Phone: 415-476-3883  
Email: Rajalingam.Raja@ucsf.edu 
 
 
 
 
CELLULAR ASSAY CORE 
Qizhi Tang, PhD 
Professor  
Director, Transplantation Research 
Lab 
University of California, San 
Francisco 
San Francisco, CA 94143-0780 
Phone: 415-476-1739 
Email: Qizhi.Tang@ucsf.edu  
GRAFT IMMUNOFLUORESCENCE STAINING/ 
AND GENE EXPRESSION 
Zoltan Laszik, MD, PhD 
Professor of Clinical Pathology 
Department of Pathology, Box 0102 
University of California, San Francisco 
513 Parnassus Avenue, Room S566 
San Francisco, CA 94143-0102 
Phone: 415-502-8230 
Email: zoltan.laszik@ucsf.edu 
PERIPHERAL BLOOD GENE EXPRESSION/ URINE 
CYTOKINE ANALYSIS 
Minnie Sarwal, MD 
Professor  
Department of Surgery 
513 Parnassus Ave. Med Sci 
San Francisco, CA  94143 
Phone: 415-502-7921 
Email:  minnie.sarwal@ucsf.edu 
 
 
 
 
 
 
HLA ANTIBODY TESTING FOR DSA 
 
 
 
 


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1. Table of Contents 
1. 
Table of Contents ............................................................................................................................................................ 9 
1. 
Study Hypotheses/Objectives ....................................................................................................................................... 18 
1.1 
Hypothesis ............................................................................................................................................................. 18 
1.2 
Primary Objective .................................................................................................................................................. 18 
1.3 
Secondary Objective ............................................................................................................................................. 18 
2. 
Background and Rationale ............................................................................................................................................ 19 
2.1 
Background and Scientific Rationale ..................................................................................................................... 19 
2.2 
Rationale for Anti-CD28 Therapy ( lulizumab pegol (BMS-931699)) .................................................................... 19 
2.3 
Rationale for tocilizumab, a Humanized Antibody to the IL6R ............................................................................. 20 
2.4 
Rationale for belatacept and everolimus Based Maintenance Immunosuppression ........................................... 21 
2.5 
Preclinical Experience with lulizumab pegol (BMS-931699) ................................................................................. 22 
2.6 
Clinical Studies with lulizumab pegol (BMS-931699) ............................................................................................ 23 
2.7 
Clinical Studies with Tocilizumab in Kidney Transplantation ................................................................................ 23 
2.7.1 
Tocilizumab Dose Selection for CTOT-24 ...................................................................................................... 24 
3. 
Study Design .................................................................................................................................................................. 26 
3.1 
Description of Study Design .................................................................................................................................. 26 
3.2 
Primary Endpoint .................................................................................................................................................. 27 
3.3 
Secondary Endpoint .............................................................................................................................................. 27 
3.4 
Mechanistic Endpoints .......................................................................................................................................... 27 
4. 
Selection of Participants and Clinical Sites/Laboratories.............................................................................................. 28 
4.1 
Rationale for Study Population ............................................................................................................................. 28 
4.2 
Inclusion Criteria ................................................................................................................................................... 28 
4.3 
Exclusion Criteria ................................................................................................................................................... 28 
4.4 
Selection of Clinical Sites ....................................................................................................................................... 29 
5. 
Known and Potential Risks and Benefits to Participants .............................................................................................. 31 
5.1 
Risks of lulizumab Pegol (BMS 931699) ................................................................................................................ 31 
5.1.1 
Risks of lulizumab pegol (BMS-931699) from Studies in Healthy Volunteers .............................................. 31 
5.1.2 
Risks of lulizumab pegol (BMS-931699) from Studies in Patients with Disease ........................................... 32 
5.2 
Risks of Actemra® (tocilizumab) ............................................................................................................................ 33 
5.3 
Risks of Other Protocol Specified Medications ..................................................................................................... 36 
5.3.1 
Risks of ATG, steroids, belatacept, everolimus, and mycophenolate mofetil .............................................. 36 
5.4 
Reproductive Risks ................................................................................................................................................ 36 


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5.5 
Risks of Study Procedures ..................................................................................................................................... 36 
5.5.1 
Risks of Blood Draws ..................................................................................................................................... 36 
5.5.2 
Risks of Kidney Transplant Biopsy ................................................................................................................. 36 
5.6 
Potential Benefits .................................................................................................................................................. 36 
6. 
Investigational Agent .................................................................................................................................................... 38 
6.1 
lulizumab Pegol (BMS 931699) ............................................................................................................................. 38 
6.1.1 
Formulation, Packaging, and Labeling .......................................................................................................... 38 
6.1.2 
Dosage, Preparation, and Administration ..................................................................................................... 38 
6.2 
Drug Accountability ............................................................................................................................................... 39 
6.3 
Toxicity Prevention and Management .................................................................................................................. 39 
6.4 
Premature Discontinuation of Investigational Agent ........................................................................................... 39 
6.5 
Study Drug Access ................................................................................................................................................. 40 
7. 
Immunosuppressive Regimen ....................................................................................................................................... 41 
7.1 
Induction Immunosuppression ............................................................................................................................. 41 
7.1.1 
Thymoglobulin .............................................................................................................................................. 41 
7.1.2 
Methylprednisolone ...................................................................................................................................... 41 
7.2 
Maintenance Immunosuppression ....................................................................................................................... 41 
7.2.1 
Actemra® (tocilizumab) ................................................................................................................................. 41 
7.2.2 
Nulojix® (belatacept) ..................................................................................................................................... 45 
7.2.3 
Zortress® (everolimus) .................................................................................................................................. 45 
7.2.4 
Maintenance Corticosteroids ........................................................................................................................ 46 
7.2.5 
Mycophenolate Mofetil/Mycophenolic Acid ................................................................................................ 46 
7.3 
Treatment of Rejection ......................................................................................................................................... 46 
8. 
Other Medications ........................................................................................................................................................ 47 
8.1 
Anti-Infective Prophylactic Medications ............................................................................................................... 47 
8.2 
Prohibited Medications/Products ......................................................................................................................... 47 
8.2.1 
Non-Leukoreduced Blood Products .............................................................................................................. 47 
8.3.2 
Vaccinations .................................................................................................................................................. 47 
8.3.3 
Cytochrome P450 3A4 and P-gp ................................................................................................................... 47 
9. 
Study Mandated Procedures ........................................................................................................................................ 48 
9.1 
Renal Transplant Biopsy ........................................................................................................................................ 48 
9.2 
Blood Draws .......................................................................................................................................................... 48 
10. 
Study Visits ................................................................................................................................................................ 49 


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10.1 
Enrollment ............................................................................................................................................................. 49 
10.2 
Donor Visit ............................................................................................................................................................ 49 
10.3 
Screening/Baseline Visit ........................................................................................................................................ 49 
10.4 
Study Visits ............................................................................................................................................................ 49 
10.4.1 
Medication Schedule ..................................................................................................................................... 49 
10.4.2 
Follow-Up Visits............................................................................................................................................. 49 
10.5 
Unscheduled Visits/ Clinically Indicated Biopsies ................................................................................................. 49 
10.6 
Visit Windows ....................................................................................................................................................... 49 
11. 
Mechanistic Assays ................................................................................................................................................... 50 
11.1 
Peripheral Blood Assays ........................................................................................................................................ 50 
11.1.1 
Multiparameter Flow Cytometry (MFC): ...................................................................................................... 50 
11.1.2 
Alloreactive T cell Frequency (ATF) assay ..................................................................................................... 50 
11.1.3 
Donor Antigen Stimulated Gene Expression ................................................................................................. 51 
11.1.4 
In Vitro Treg Suppression .............................................................................................................................. 52 
11.1.5 
Kidney Solid Organ Response Test (KSORT) .................................................................................................. 52 
11.1.6 
HLA Antibody Testing for DSA ....................................................................................................................... 53 
11.2 
Biopsy assays ......................................................................................................................................................... 53 
11.2.1 
Graft Histology .............................................................................................................................................. 54 
11.2.2 
Multi-parameter Immunofluorescence and In Situ Hybridization ................................................................ 54 
11.2.3 
Gene Expression by Nanostring .................................................................................................................... 54 
11.3 
Urinary Biomarkers of Graft Inflammation and Rejection .................................................................................... 55 
11.3.1 
Urine Cytokine Analysis ................................................................................................................................. 55 
12. 
Biospecimen Storage................................................................................................................................................. 56 
13. 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 57 
13.1 
Participant Stopping Rules and Withdrawal Criteria ............................................................................................ 57 
13.2 
Participant Replacement ....................................................................................................................................... 57 
13.3 
Follow-up after Early Study Withdrawal ............................................................................................................... 57 
13.4 
Study Stopping Rules............................................................................................................................................. 57 
14. 
Safety Monitoring and Reporting ............................................................................................................................. 59 
14.1 
Overview ............................................................................................................................................................... 59 
14.2 
Definitions ............................................................................................................................................................. 59 
14.2.1 
Adverse Event (AE) ........................................................................................................................................ 59 
14.2.2 
Suspected Adverse Reaction (SAR) ............................................................................................................... 59 


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14.2.3 
Unexpected Adverse Event ........................................................................................................................... 59 
14.2.4 
Serious Adverse Event (SAE) ......................................................................................................................... 59 
14.2.5 
Other Significant Adverse Events .................................................................................................................. 60 
14.3 
Grading and Attribution of Adverse Events .......................................................................................................... 60 
14.3.1 
Grading Criteria ............................................................................................................................................. 60 
14.3.2 
Attribution Definitions .................................................................................................................................. 61 
14.4 
Collection and Recording of Adverse Events ........................................................................................................ 62 
14.4.1 
Collection Period ........................................................................................................................................... 62 
14.4.2 
Collecting Adverse Events ............................................................................................................................. 62 
14.4.3 
Recording Adverse Events ............................................................................................................................. 62 
14.5 
Reporting of Serious Adverse Events and Adverse Events ................................................................................... 62 
14.5.1 
Reporting of Serious Adverse Events to Sponsor .......................................................................................... 62 
14.5.2 
Reporting to Health Authority ...................................................................................................................... 62 
14.5.3 
Reporting of Adverse Events to IRBs/IECs .................................................................................................... 64 
14.6 
Pregnancy Reporting ............................................................................................................................................. 64 
14.7 
Reporting of Other Safety Information ................................................................................................................. 65 
14.8 
Review of Safety Information ............................................................................................................................... 65 
14.8.1 
Medical Monitor Review ............................................................................................................................... 65 
14.8.2 
DSMB Review ................................................................................................................................................ 65 
15. 
Statistical Considerations and Analytical Plan .......................................................................................................... 66 
15.1 
Overview ............................................................................................................................................................... 66 
15.2 
Measures to Minimize Bias ................................................................................................................................... 66 
15.3 
Analysis Plan .......................................................................................................................................................... 66 
15.3.1 
Analysis Populations. .................................................................................................................................... 66 
15.3.2 
Analysis of Primary Endpoint ........................................................................................................................ 66 
15.3.3 
Analysis of Secondary Endpoint .................................................................................................................... 67 
15.3.4 
Analyses of Exploratory Endpoint(s)/Outcome(s)......................................................................................... 67 
15.3.5 
Descriptive Analyses ..................................................................................................................................... 67 
15.4 
Interim Analyses .................................................................................................................................................... 67 
15.5 
Sample Size Considerations .................................................................................................................................. 67 
16. 
Quality Assurance and Quality Control ..................................................................................................................... 68 
17. 
Identification and Access to Source Data ................................................................................................................. 69 
17.1 
Source Data ........................................................................................................................................................... 69 


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17.2 
Access to Source Data ........................................................................................................................................... 69 
18. 
Protocol Deviations ................................................................................................................................................... 70 
18.1 
Protocol Deviation Definitions .............................................................................................................................. 70 
18.2 
Reporting and Managing Protocol Deviations ...................................................................................................... 70 
19. 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 71 
19.1 
Statement of Compliance ..................................................................................................................................... 71 
19.2 
Informed Consent Process .................................................................................................................................... 71 
19.3 
Privacy and Confidentiality ................................................................................................................................... 71 
20. 
Publication Policy ...................................................................................................................................................... 72 
21. 
 References ................................................................................................................................................................ 73 
Appendix 1.  Donor Schedule of Events ................................................................................................................................ 76 
Appendix 2. Recipient Schedule of Events ............................................................................................................................ 77 
Appendix 3.  Recipient Medication Schedule ....................................................................................................................... 78 
Appendix 4.  Schedule of Events for Reduced Follow Up ..................................................................................................... 79 
 
 


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Glossary of Abbreviations 
ACR 
Acute Cellular Rejection 
AMR 
Antibody Mediated Rejection 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FSGS 
Focal Segmental Glomerulosclerosis 
GCMS 
Gas Chromatography-Mass Spectrometry 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IL6 
Interleukin 6 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISH 
In Situ Hybridization 
MHC 
Major Histocompatibility Complex 
MMF 
Mycophenolate Mofetil 
MOP 
Manual of Procedures 
MPA 
Mycophenolic Acid 
NIAID 
National Institute of Allergy and Infectious Diseases 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PRA 
Panel Reactive Antibody 


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RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TCR 
T Cell Receptor 
Treg 
T Regulatory Cells 
WOCBP 
Women of Childbearing Potential 
 


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Study Definitions Page 
Acute T cell Mediated 
Rejection 
Banff 2007 Type 1A or higher and clinical treatment for acute rejection. 
Central reading will be utilized when accounting for study stopping rule and 
for safety endpoint. 
Acute Antibody 
Mediated Rejection 
Diffusely positive staining for C4d, presence of circulating anti-donor 
antibodies, and morphologic evidence of acute tissue injury. 
Contraception, Highly 
Effective 
Women of Childbearing Potential: 
Highly effective methods of contraception have a failure rate of <1% when 
used consistently and correctly.  
• 
Progestogen only hormonal contraception associated with inhibition 
of ovulation 
• 
Hormonal methods of contraception including oral contraceptive 
pills containing a combination of estrogen + progesterone, vagina 
ring, injectables, implants and intrauterine devices (IUDs) 
• 
Non-hormonal IUDs 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner  
• 
Intrauterine hormone-releasing system (IUS) 
• 
Complete abstinence 
 
Male Participants: 
Male participants will be required to always use a latex or other synthetic 
condom during any sexual activity (e.g. vaginal, anal, oral) with WOCBP; even 
if the participants have undergone a successful vasectomy or if their partner 
is already pregnant or breastfeeding. Males should continue to use a 
condom until one month after the last dose of lulizumab. Withdrawal (coitus 
interruptus) and/or the use of a spermicide without a condom are not 
acceptable methods of contraception or fetal protection. 
Graft Failure 
90 consecutive days of dialysis dependency 
Investigational Agent 
lulizumab pegol (BMS-931699) 
Lost to Follow-up 
Subject who cannot complete study visits due to inability to reach the 
subject, subject relocation, etc. 
Protocol Mandated 
Procedures 
Any procedure performed solely for this research study (not site-specific 
SOC).   
Site Principal 
Investigator 
Lead investigator listed on the FDA 1572 at a participating center who is 
responsible for the conduct of the study at that center. 
Study Termination 
Subjects who complete the study, are lost to follow up, withdraw consent, or 
die during the study.  Data and specimens will no longer be expected from 
subjects who are terminated from the study. 
Study Therapy 
The investigational agents and all protocol required interventions and 
medications.  


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Withdrawal from 
Therapy 
Subject who stops study therapy prior to protocol described duration. 
Women of Childbearing 
Potential 
A woman is considered fertile following menarche and until becoming post-
menopausal* unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
*A post-menopausal state is defined as 12 months of amenorrhea in a 
woman over age 45 years in the absence of other biological or physiological 
causes. In addition, females under the age of 55 years must have a serum 
follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause. 
 
 
 
 
 
 
 
 
 


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1. Study Hypotheses/Objectives 
This trial will be a pilot, proof of concept trial with emphasis on safety and mechanistic assays examining transplant 
immune regulation via Tregs. 
1.1 Hypothesis 
The CTOT-24 investigators hypothesize that interleukin 6 (IL6) blockade is synergistic with co-stimulation blockade, 
decreasing the potential for activation of effector T cells while at the same time minimizing or reversing the negative 
effect of CD28 inhibition on Tregs.     
1.2 Primary Objective 
This study will evaluate the safety of the investigational agent lulizumab pegol (BMS-931699), administered with an 
immunosuppressive regimen that includes tocilizumab, in adult living-donor kidney transplant recipients in the first 6 
months after transplantation.   
1.3 Secondary Objective 
This study will also evaluate the safety of the study therapy regimen in adult living donor kidney transplant recipients 6 
to 12 months after transplantation.   


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2. Background and Rationale  
2.1 Background and Scientific Rationale 
 A significant problem that continues to challenge transplant physicians is the need to develop immunosuppression 
strategies that can usher in a tolerant state without the risks associated with conditioning regimens or the threat of graft 
versus host disease (GVHD) associated with infused stem cells.  Other challenges include maintenance of the stability of 
the tolerant state and the availability of reproducible biomarkers for tolerance. 
Combining CD28 inhibition with blockade of other co-stimulation tracts or other co-activation pathways has been shown 
to induce long-term graft acceptance in experimental transplants (Kirk, 1997) (Larsen, 2005) (Zhao, 2012). Co-
stimulation inhibition with CTLA4Ig or its second-generation sister drug, belatacept, inhibits T cell activation in vitro and 
induces anergy but neither agent by itself has been shown to induce tolerance in experimental or clinical organ 
transplantation (Larsen, 2005) (Kirk, 2014).  While tolerance has been demonstrated only in small animals, based on the 
mechanism of action of IL6 and CTLA4-Ig, their combined inhibition may result in a Treg-mediated tolerogenic 
environment. 
CTOT-24 will use a novel therapeutic approach to combine anti-CD28 therapy using lulizumab pegol (BMS-931699) 
initially, followed by Belatacept, along with inhibition of the IL6 pathway by tocilizumab, an anti-IL6R monoclonal 
antibody. 
2.2 Rationale for Anti-CD28 Therapy ( lulizumab pegol (BMS-931699)) 
A major disadvantage of CTLA4-Ig or belatacept is that binding to CD80/CD86 not only blocks CD28 mediated T cell 
activation but also prevents activation of the inhibitory pathways through CTLA4 and PDL1 (Linsley, 1993).  Furthermore, 
belatacept blocks the suppressor activity of Tregs mediated by CTLA4 (Riella, 2012) (Zhang, 2013).  The absence of the 
dual CTLA4 mediated “beneficial” as well as the detrimental effect on Tregs effects have been suggested to contribute to 
the high rejection rate and increased severity of rejections in kidney transplantation associated with belatacept 
(Vincenti, 2012). Higher rates of acute rejection were observed in the BENEFIT Trial in the more intense regimen of 
belatacept vs. the lower intensity regimen (lower dose and exposure) and are believed to be related to greater inhibition 
of the CTLA4 pathway at higher dose (Vincenti, 2012).  Another intriguing finding was observed with the abatacept 
(CTLA4-Ig) treated psoriasis patients: at very high dose, CTLA4-Ig reversed the suppression of antibody response to KHL 
vaccine, while maintaining efficacy (Abrams, 1999). One explanation for this observation is that at lower doses of CTLA4-
Ig, there is predominant inhibition of the CD28 pathway but at higher dose, the inhibitory CTLA4 pathway is blocked; 
similar to the better efficacy observed in the less intense regimen in BENEFIT Trial than the higher intensity regimen.  
The development of non-agonist anti-CD28 monoclonal antibodies that bind and block CD28 activation but allow 
CD80/CD86 to interact freely with receptors of the inhibitory pathways on T effector and Tregs is an important advance 
in co-stimulation blockade that overcomes this disadvantage (Poirier, 2010) (Salomon, 2000) (Suchard, 2013) (Vanhove, 
2003). Indeed, selective CD28 blockade unlike CTLA4-Ig/belatacept has been shown to preserve regulatory function 
through CTLA4 mediated signaling (Linsley, 1993) (Riella, 2012) (Poirier, 2010). 
This study uses a novel anti-CD28 receptor antagonist immunoglobulin light chain variable region (VK) domain antibody 
developed by Bristol-Myers Squibb (BMS 931699 or lulizumab pegol).  Lulizumab pegol (BMS-931699) is a potent 
inhibitor of T-cell activation, lacking costimulatory or agonist activity as measured by T-cell proliferation or cytokine 
release.  In cynomolgus monkeys, the ability of BMS-908613-P40Br (surrogate of lulizumab pegol (BMS-931699)) to 
inhibit the antibody response to T-cell dependent antigens in was evaluated as a measure of PD activity. There was a 
strong relationship between CD28 receptor occupancy (RO) and in vivo PD responses. After a single SC dose of BMS-


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908613-P40Br, the IgG response (area under the average IgG response-time curve up to Day 29) to keyhole limpet 
hemocyanin (KLH) was inhibited by ~0%, 79%, and 97%, with corresponding average CD28 RO of 26%, 62%, and 86%, at 
0.05, 0.5, and 5 mg/kg, respectively. Following weekly repeated doses, the bioavailability of lulizumab was 
approximately 63% to 105%.  
CD28 target engagement by lulizumab pegol (BMS-931699) in human whole blood has also been measured. Blood 
treated ex vivo with Lulizumab pegol (BMS-931699) demonstrated RO potency values that correlate closely with the in 
vitro functional assays, suggesting that saturation of CD28 is strongly correlated with inhibition of T-cell activation. CD28 
RO and inhibition of a T-cell dependent antibody response were evaluated to assess the PD of lulizumab pegol (BMS-
931699) in the SAD Study IM128001 in healthy humans following a single IV or SC dose of lulizumab pegol (BMS-
931699). RO confirmed target engagement in a concentration-dependent manner with the majority of subjects reaching 
at least 80% RO for an average duration of at least 2 weeks at doses of 9 mg and above. Inhibition of a neo-antigen 
(KLH)-induced T-cell dependent antibody response was evaluated only in the 9, 25, and 100 mg IV dose groups. In the 
control placebo group, anti-KLH IgG antibodies were detectable in approximately half of the individuals by 2 weeks after 
KLH immunization. In all active treatment groups tested (9, 25, and 100 mg), the IV administration of Lulizumab pegol 
(BMS-931699) inhibited or delayed the generation of detectable anti-KLH IgG antibodies. The nonclinical data suggest 
that 80% RO for 2 weeks is needed for maximum immunosuppression as measured by anti-KLH IgG suppression 
following antigen challenge and as levels of RO fall below 80%, the immunosuppressive activity lessens and anti-KLH 
antibody formation rises. Results from the SAD study substantiated this premise. 
Peripheral whole blood RO was assessed in the MAD Study IM128003 at baseline and after each dose of lulizumab pegol 
(BMS-931699) or placebo. A time- and dose-dependent effect on the maximal amount and duration of occupancy after 
multiple doses of lulizumab pegol (BMS-931699) was observed. Data from the MAD RO measurements are consistent 
with SAD, nonclinical animal experiments, and ex vivo human blood experiments. CD28 RO by lulizumab pegol (BMS-
931699) on both CD4 and CD8 T cells was similar with respect to dose and time or exposure. Irrespective of dose level, 
after the first dose, maximum mean RO occurred 48 hours post dose and was similar, ranging from 93.32% to 95.43%, 
and was sustained above 90% (range: 90.90% to 94.25%) 7 days after the first dose. Seven days (168 hours) after the 
administration of the last dose (third dose for the 6.25-mg biweekly treatment and fifth dose for the 12.5- and 37.5-mg 
weekly treatments), mean RO ranged from 88.00% to 94.67%. Fourteen days (336 hours) after the last dose, mean RO 
was > 80%, which gradually tapered to approximately < 3%, 7%, and 30% for the 6.25-mg biweekly, 12.5-mg weekly, and 
37.5-mg weekly treatments, respectively, 56 days (1,344 hours) post last dose. For this reason, we have selected the first 
dose of lulizumab pegol (BMS-931699) to be 25 mg, followed by weekly doses of 12.5 mg SC in this study, with the goal 
of consistently maintaining RO>80% and thereby aiming for maximal clinical efficacy.  The drug had a favorable safety 
profile with no evidence of cytokine release in both phase 1 studies noted above (Shi, 2017).   
2.3 Rationale for tocilizumab, a Humanized Antibody to the IL6R 
IL6 is a pleotropic cytokine produced by multiple cells and plays an important role in alloimmune responses and allograft 
injury (Jordan, 2017).  IL6 regulates inflammation and the development, maturation and activation of T cells, B cells and 
plasma cells.  In experimental transplantation, IL6 has been shown to regulate allograft rejection and tolerance (Zhao, 
2012). 
IL6 deficient mice have decreased lymphocyte proliferation, increased percentage of Treg cells and greater suppression 
function as compared to wild type mice.  Although wild type 57 B56 recipients treated with CTLA4-Ig rejected fully MHC 
mismatched BALB/c heart transplants, treatment of IL6 deficient mice with CTLA4-Ig resulted in graft acceptance (see 
Figure 1) (Zhao, 2012). In the same study, indefinite graft survival was observed only in animals treated with CTLA1g and 


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anti-IL6 (Figure 2) (Kirk, 1997). IL6 inhibition promoted transplant tolerance by limiting effector T cell expansion, and by 
promoting Treg function. 
 
A.                                                                                                B. 
 
 
Figure 1. Graft Survival in IL-6 deficient Mice 
 A. Effect of IL-6 deficiency on allograft tolerance. IL-6−/− and WT B6 recipients of fully MHC-mismatched BALB/c hearts were treated 
with a single dose of CTLA4Ig (0.25mg) on the day of transplantation. IL-6 deficiency facilitates allograft tolerance. Survival of BALB/c 
cardiac allografts is significantly prolonged in IL-6−/− recipients, when compared to WT controls (n = 4–7 per group) [3].  B. In vivo 
neutralization of IL-6 inhibits rejection and facilitates allograft survival with costimulation blockade in wild-type recipients. Survival of 
fully MHC-mismatched BALB/c cardiac allografts in WT C57BL/6 recipients treated with CTLA4Ig and either anti-IL-6 mAb (n = 5) or 
control IgG (n = 8). Data are presented as a Kaplan–Meier curve [3]. 
In preliminary analysis of FFPE cores of kidney biopsies by Nanstring from renal transplant recipients in the CTOT-21 
(NCT02711826) trial, subjects with acute cellular and humoral rejection had increased level of intragraft IL6 transcripts 
(Figure 2).  An increase in IL6 message was also noted in patients with subclinical inflammation on kidney biopsy. 
 
Figure 2. IL-6 Expression in Kidney Transplant 
Box distribution of IL-6 expression in kidney transplant 
recipients with and without rejection 
  
 
 
 
 
2.4 Rationale for belatacept and everolimus Based Maintenance Immunosuppression 
At 6 months, tocilizumab will be discontinued, and participants will be henceforth on belatacept (every 4 weeks), 
everolimus, and prednisone, a regimen which we have shown previously to be safe and effective for long term 
maintenance (Wojciechowski, 2017). As in our previously described experience, everolimus will be used to with 
belatacept based on data indicating that mTOR inhibition may provide synergistic immunosuppression when coupled 


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with costimulation blockade.  In non-human primate models of renal and islet transplantation the combination of 
CTLA4-Ig and sirolimus successfully prevented rejection and prolonged graft survival (Lo D. A., 2013) (Lowe, 2013). In 
addition to our clinical experience cited above, other clinical studies have demonstrated the safety and efficacy of 
belatacept in combination with lymphodepletion and mTOR inhibition (Ferguson, 2011) (Kirk, 2014).   
2.5 Preclinical Experience with lulizumab pegol (BMS-931699) 
Lulizumab pegol (BMS-931699) binds to human and cynomolgus monkey CD28 but does not bind to mouse CD28. This 
domain antibody is specific for CD28 and does not bind to the closely related CTLA-4. It is a potent inhibitor of T-cell 
activation and is a pure antagonist as determined by in vitro agonist, costimulation, and cross-linking experiments.  
Surrogate CD28 dAbs that recognize mouse CD28, with potencies similar to lulizumab pegol (BMS-931699), were used to 
evaluate the impact of direct inhibition of CD28 in murine models of lupus, experimental allergic encephalomyelitis, and 
collagen induced arthritis and were found to be efficacious. Intended PD effects in cynomolgus monkeys have been 
demonstrated in vivo with BMS-908613-P40Br (inhibition of T-cell-dependent antibody response) and with lulizumab 
pegol (BMS-931699) (decreases in peripheral blood Tregs, B cells, serum IgG, and cortical lymphocytes in various lymph 
nodes, which is reflective of decreased germinal center activity). In vitro, lulizumab pegol (BMS-931699) and BMS-
908613-P40Br showed similar binding affinities for human CD28 and similar potency in in vitro mixed-lymphocyte 
reaction assays. In monkeys, there was a strong relationship between CD28 receptor occupancy and in vivo PD 
responses. 
The cynomolgus monkey was selected as the toxicology species because lulizumab pegol (BMS-931699) binds 
comparably to macaque CD28, is pharmacologically active in monkeys, and does not cross-react with rodent CD28. The 
preclinical safety assessments that support the clinical development of lulizumab pegol (BMS-931699) include: 
1. 
Single-dose pharmacokinetic PK/PD studies conducted with BMS-908613-P40Br in monkeys to support the 
rationale for selection of the minimal anticipated biological effect level (MABEL) dose. There were no adverse 
drug related findings including any effects on plasma cytokines or peripheral blood T cell counts with doses up to 
5 mg/kg 
2. 
Single-dose exploratory toxicity study in mice with BMS-1m74-14982-S60C-P40Br to assess potential toxicity of 
CD28 antagonism in a rodent model.  Doses up to 18 mg/kg were not associated with any adverse drug related 
findings. 
3. 
Good Laboratory Practice (GLP) 1- and 6-month repeat-dose toxicity studies of lulizumab pegol (BMS-931699) in 
cynomolgus monkeys. In the 1-month repeat dose study, reductions in Tregs and cortical lymphocytes in lymph 
nodes were expected pharmacologic effects, while minimal/slight vacuolation in various tissues was attributed 
to the PEG moiety of lulizumab pegol (BMS-931699). All lulizumab pegol (BMS-931699)-related effects showed 
partial to complete resolution following an 8-week recovery period with the exception of vacuolation in the 
choroid plexus epithelium and pituitary gland. In the 6-month repeat dose study, findings were similar with the 
addition of lymphoma was noted in 1 female at 1 mg/kg/week that was considered secondary to lulizumab 
pegol (BMS-931699)-induced immunosuppression in cynomolgus monkeys latently infected with 
lymphocryptovirus (LCV). Based on this finding, a no-observed-adverse-effect-level (NOEL) was not determined 
in this study. 
4. 
Exploratory in vitro study of potential lulizumab pegol (BMS-931699)-related effects (cytokine release, T-cell 
activation/proliferation) on human T cells. Purified human T cells were incubated with lulizumab pegol (BMS-


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931699) or the superagonist anti-CD28 monoclonal antibody trans-Golgi network (TGN) 5.11A1. There were no 
lulizumab pegol (BMS-931699)-related effects, while TGN 5.11A1 induced both cytokine release and cellular 
activation. 
5. 
GLP human tissue cross-reactivity study to demonstrate target distribution and inform of any potential 
unexpected epitope/tissue binding. Binding of lulizumab pegol (BMS-931699) was limited to mononuclear cells 
in most human tissues. As CD28 is expressed primarily by T cells, the staining of blood lymphocytes and 
mononuclear cells throughout the human tissue panel was expected reactivity. 
Of note, in both the single-dose exploratory PK and PD studies, and repeat-dose monkey toxicity studies, 
immunogenicity occurred with low incidence, and the presence of the anti-drug antibodies did not affect the PK, PD, or 
toxicokinetics of lulizumab pegol (BMS-931699) in monkeys. No adverse irritation or local intolerance was observed at 
the lulizumab pegol (BMS-931699) IV or SC injection sites in either the 5-week or the 6-month studies in monkeys using 
lulizumab pegol (BMS-931699) concentrations and injection rates greater than or equal to those recommended for 
human use. 
All the available preclinical evidence demonstrates that lulizumab pegol (BMS-931699) is an anti-CD28 antagonist and T-
cell costimulation inhibitor lacking any agonist activity and was safe and well tolerated in cynomolgus monkeys.  
2.6 Clinical Studies with lulizumab pegol (BMS-931699) 
There have been two randomized controlled clinical trials of lulizumab pegol (BMS-931699) in patients with disease: 
1. Study IM128027 in patients with active systemic lupus: n=346, route SC; the study was terminated based on lack 
of efficacy observed in the interim analysis. 
2. Study IM128035 in patients with moderate to severe primary Sjogren’s syndrome: n=18, route SC; the study was 
terminated due to unfavorable safety profile with the dose of the comparator drug (a BTK inhibitor) as 
determined from an interim analysis of another study in subjects with rheumatoid arthritis. 
In the first study, IM128027, 346 subjects were randomized and treated with one of the following treatments utilizing a 
1:1:1:1:1 randomization scheme: lulizumab pegol (BMS-931699) administered 12.5 mg weekly, 12.5 mg every 2 weeks, 5 
mg every 2 weeks, 1.25 mg every 2 weeks, or placebo. The study was comprised of a placebo-controlled short-term 
period (Part 1 and Part 2) and a long-term extension (LTE) period. Treatment duration was up to 24 weeks (169 days) in 
the short-term period. The LTE period of the study remained blinded but did not have a placebo arm. Of the 346 
subjects who were randomized and treated, 258 subjects completed the placebo controlled short-term period, and 212 
subjects entered the LTE period of the study.  
2.6.1 
Lulizumab pegol (BMS-931699) Dose Selection for CTOT-24 
In CTOT-24, subjects will receive lulizumab pegol (BMS-931699) 25 mg (SC) on study day 1 (post-operative day 1), 
followed by 12.5 mg (SC) weekly through day 77.  Dose selection was based on PK/PD data as presented in section 2.5, 
which includes favorable safety data in non-human primates with doses up to 5 mg/kg.  Peri-transplant induction with 
twice the maintenance dose has been chosen due to the importance of preventing early alloimmunity.  Assuming an 
average 70kg adult, the 25mg induction dose is 0.36mg/kg/dose, more than an order of magnitude less than that safely 
tolerated in the non-human primate model.  The weekly maintenance dosing is consistent with the dose utilized in the 
aforementioned two clinical studies, IM128027 and IM128035.   Adverse events in the placebo-controlled dose 
escalation IM128027 trial is presented in Table 2 in 5.1.2 
2.7 Clinical Studies with Tocilizumab in Kidney Transplantation  


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An ongoing, randomized controlled study at UCSF (NCT02108600) assigns subjects with intragraft inflammation at 6 
months to either monthly treatments with tocilizumab (8 mg/kg IV) or control (no additional therapy), with a follow-up 
kidney biopsy 6 months later.  At the time of CTOT-24 protocol development, 27/48 have been enrolled in the study.   
Dr. Jordan at Cedars Sinai Hospital has treated 36 patients with chronic antibody mediated rejection with tocilizumab (8 
mg/kg monthly, maximum 800 mg per dose, for 6-25 months) without any major complications (Choi, 2017). 
Tocilizumab both in IV and subcutaneous preparations are currently approved for therapy in rheumatoid arthritis.  So 
far, it appears from our ongoing trial as well as Dr. Jordan’s study to be safe when added to standard of care therapy. It 
has been observed that patients with rheumatoid arthritis who received tocilizumab had a significant increase in 
circulating Tregs (Kikuchi, 2015) (Thiolat, 2014).  Preliminary results of the UCSF trial in the first 18 patients who have 
completed at least 6 months in the study indicate that this increase is seen in kidney transplant patients on 
immunosuppression, as well (Figure 3). Also, patients who received tocilizumab showed a significant reduction of IFN-γ 
and IL17 in stimulated CD4 T cells when compared to the control group at month 6 (Figure 3).  This modulatory effect of 
IL6 blockade may counteract the adverse effect of CD28 blockade on Tregs. An additional advantage for the study is that 
tocilizumab can be administered subcutaneously, rendering the combination therapy easier to implement.   
A. 
 
B. 
 
Figure 3. Circulating Treg Frequency in Kidney Transplant Recipients after Tocilizumab 
A. Circulating Treg frequency in kidney transplant recipients on immunosuppression who received tocilizumab for 6 months 
compared to controls who did not receive tocilizumab. B. IFN-γ + IL-17 secretion in CD4+ T cells stimulated by PMA/ 
Ionomycin for 4 hours in tocilizumab treated patients and control at 6 months. 
2.7.1 
Tocilizumab Dose Selection for CTOT-24 
In CTOT-24, the dose of tocilizumab used will be 8 mg/kg for the first dose followed by 162 mg SC every 2 weeks. The 
dose of 8 mg/kg IV every 4 weeks or 162 mg SC every other week is the approved dose for tocilizumab according to the 
label for the treatment of rheumatoid arthritis. This dosing regimen is based on clinical studies with the 4 mg per kg and 
IF N g + IL 1 7 +  in  C D 4
B a s e lin e
M o n th  6
0 .0
0 .1
0 .2
0 .3
T o cilizu m a b
C o n tro l


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8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of tocilizumab which showed decreases in 
levels of C-reactive protein to within normal ranges were seen as early as week 2. Greatest improvements in the 
pharmacodynamic parameters were observed with 8 mg/kg. The dose of 8 mg/kg IV every 4 weeks was used by Dr. 
Jordan in patients with chronic AMR as well as in our study of subclinical graft inflammation and appears to be relatively 
safe and well tolerated.  The second and subsequent doses will be given subcutaneously at 162 mg every 2 weeks based 
on efficacy demonstrated in clinical studies of rheumatoid arthritis.   


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3. Study Design 
3.1 Description of Study Design  
CTOT-24 is a multi- center, open-label, pilot, single arm clinical trial which aims to enroll 10 living donor renal transplant 
recipients to evaluate the safety of lulizumab pegol (BMS 931699) in the context of a novel immunosuppressive regimen 
using anti-thymocyte globulin (rabbit) (ATG), steroids,) Nulojix® (belatacept), Actemra® (tocilizumab), mycophenolate 
mofetil (MMF) and Zortress®(everolimus) (Table 1 and Figure 4).  Study participants will be enrolled prior to 
transplantation.  The primary endpoint will be evaluated at 6 months and study participants will continue to be followed 
for 24 months after transplantation. The study plans to complete enrollment within a 27 month period. 
Participants receive induction with ATG and methylprednisolone and are initially maintained on tocilizumab and 
prednisone. Lulizumab pegol (BMS-931699) is administered on the day after transplantation and weekly until 3 months; 
after which lulizumab pegol (BMS-931699) will be replaced with belatacept every 4 weeks.  MMF will be started on the 
day after transplant to reduce the risk of acute rejection during the initial weeks when tocilizumab has not achieved its 
full effect on reducing effector T cell function and increasing Tregs. Zortress® (everolimus) is added at 14 days post-
transplant to reduce the impact on wound healing during the first two weeks. MMF will be discontinued once the 
everolimus level is within the therapeutic range.  Tocilizumab will be discontinued at 6 months, and participants will be 
maintained on belatacept, everolimus, and prednisone.   
Participants undergo protocol biopsies at 6 months after transplant.  At 3, 6, 9 and 12 months they will also undergo a 
battery of mechanistic assays to identify changes in the immune profile and correlate their emergence and evolution 
with different components of the study regimen.   
Table 1. Study drugs  
Study Drug 
Dosing 
Anti-thymocyte globulin, rabbit (ATG)  6 mg/kg (IV) total dose, given in divided doses on days 0-3 
Methylprednisolone  
Prednisone  
500 mg (IV) on day 0, 250 mg on day 1, 125 mg on day 2 
60 mg on day 3, 30 mg on day 4, then taper to 5 mg daily by day 28 
(See Section 7.2.4) 
Lulizumab pegol (BMS 931699) 
25 mg (SC) on day 1 
12.5 mg (SC) weekly till day 77 
Actemra® (tocilizumab) 
8 mg/kg (IV) on day 2 
162 mg (SC) every 2 weeks till day 168 
Nulojix® (belatacept) 
 
 
5 mg/kg (IV) every 4 weeks starting day 84 
Mycophonelate mofetil  
1000 mg PO bid started on day 1, then discontinued once everolimus 
level is within therapeutic range 
Zortress®(everolimus)*  
Start at 0.75 mg (PO) bid on day 14, titrate to maintain level 3-8 
ng/ml 
*Participants who do not tolerate everolimus will be switched to mycophenolate mofetil 1000 mg BID, PO  


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Figure 4.  Study Scheme 
 
3.2 Primary Endpoint 
The primary safety endpoint is the proportion of participants who remain free of biopsy-proven acute T-cell mediated or 
antibody-mediated rejection as defined by Banff criteria at 6 months after transplantation.  Clinical rejection occurring 
prior to 6 months, defined as treated rejection without biopsy confirmation, will be included as acute rejection with 
respect to the endpoint. 
3.3 Secondary Endpoint 
The secondary safety endpoint is the proportion of participants who remain free of biopsy-proven acute T-cell mediated 
or antibody-mediated rejection as defined by Banff criteria at 12 months after transplantation.  Clinical rejection 
occurring prior to 12 months, defined as treated rejection without biopsy confirmation, will be included as acute 
rejection with respect to the endpoint. 
3.4 Mechanistic Endpoints 
1. 
Frequency of circulating Tregs at 3, 6 and 12 months post-transplant  
2. 
Treg suppressive activity at 3, 6 and 12 months post-transplant using irradiated donor PBMC as stimulators and 
measuring cytokine production in response to anti-CD3 and anti-CD28 
3. 
Alloreactive T cell frequency at 3, 6 and 12 months post-transplant 
4. 
Expression of T cell checkpoint inhibition related genes at 3, 6 and 12 months post-transplant 
Comparisons of mechanistic data will be made within the cohort of participants enrolled in this study across different 
time points.     


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4. Selection of Participants and Clinical Sites/Laboratories 
4.1 Rationale for Study Population 
This study aims to enroll 10 recipients of HLA mismatched living donor kidney recipients with PRA <50% and no DSA. 
Since this study is testing a novel CNI-free immunosuppression regimen, only those at low risk for rejection will be 
enrolled to maximize participant safety. This population is similar to the population that was enrolled in the BENEFIT 
study (NCT00256750) to test a novel belatacept-based immunosuppressive regimen. It has been shown that that CD28- 
T-cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation, and will therefore not be 
susceptible to CD28 blockade (Lo D. W., 2011) (Xu, 2014) (Shoji, 2018). Therefore, patients with a high proportion of 
CD28-1 cells among the circulating CD8T cells will be excluded from this study due to their increased risk of 
costimulation blockade resistant rejection. On the other hand, HLA matched living donor recipients have excellent 
outcomes irrespective of immunosuppressive regimens and therefore will also be excluded from the study.    
4.2 Inclusion Criteria 
Individuals who meet all the following criteria are eligible for enrollment as study participants:  
1. 
Able to understand and provide informed consent 
2. 
Agreement to use highly effective (<1% failure rate) methods of contraception (see study definitions). Female 
participants of child-bearing potential must consult with their physician and determine the most suitable 
method(s) from this list to be used for 12 months while on study drug regimen.  
3. 
Male or female, 18 to 70 years 
4. 
Recipient of primary, non-HLA identical living donor kidney transplant 
5. 
No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site 
investigator 
6. 
EBV positive serology  
7. 
CMV positive serology, unless donor-recipient pair are both CMV negative  
8. 
Negative testing for latent TB infection within 3 months prior to transplant.  Testing should be conducted using 
either a PPD or interferon-gamma release assay (i.e. QuantiFERON-TB, T-SPOT.TB).  Subjects with a positive test 
for latent TB infection must complete appropriate therapy for LTBI.  A subject is considered eligible only if they 
have a negative test for LTBI within 3 months prior to transplant OR they have appropriately completed LTBI 
therapy prior to transplant.  Latent TB infection treatment regimens should be among those endorsed by the 
CDC (Division of TB Elimination, 2016). 
9. 
In the absence of contraindication, vaccinations must be up to date for hepatitis B, influenza, pneumococcal, 
varicella and herpes zoster, and MMR.  
10. Hepatitis C Virus Ab positive subjects with negative HCV PCR are eligible if they have spontaneously cleared 
infection or are in sustained virologic remission for at least 12 weeks after treatment (see exclusion 13). 
11. Negative SARS-COV2 PCR testing within 2 weeks of transplant. 
4.3 Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants:  
1. 
Prisoners or subjects who are compulsorily detained. 
2. 
Inability or unwillingness of a participant to give written informed consent or comply with study protocol 
3. 
Candidate for a multiple solid organ or tissue transplants   
4. 
Prior history of organ or cellular transplantation 


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5. 
Known to have idiopathic FSGS as the underlying cause of ESRD   
6. 
Requirement for uninterrupted anticoagulation therapy, including Plavix 
7. 
Known hypersensitivity to mTOR inhibitors or contraindication to everolimus (including history of wound 
healing complications) 
8. 
History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies  
9. 
Hypersensitivity to rabbit proteins or rabbit Anti-thymocyte Globulin (ATG) 
10. 
Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol (BMS-931699),  
11. 
HIV infected subjects, including those who are well controlled on anti-retrovirals 
12. 
Positive HBsAg or HBcAb serology 
13. 
Hepatitis C virus antibody positive (HCVAb+) subjects who have failed to demonstrate sustained viral 
remission for more than 12 weeks (after anti-viral treatment) 
14. 
Subjects with a previous history of active Tuberculosis (TB)  
15. 
Known active current viral, fungal, mycobacterial or other infections (including, but not limited to 
tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster)  
16. 
Donor or recipient residing in areas where annual incidence is ≥21 cases/100,000 for coccidioidomycosis 
according to current CDC map (https://www.cdc.gov/fungal/diseases/coccidioidomycosis/images/valley-
fever-map-2017.jpg). Donor or recipients residing in zones with annual incidence of <21 cases/100,000 will 
not require additional screening. 
17. 
History of malignancy except treated basal cell cancer of the skin  
18. 
History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura  
19. 
History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating 
polyneuropathy)  
20. 
History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis  
21. 
Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation;  
22. 
Receipt of a live vaccine within 30 days prior to transplantation  
23. 
Past or current medical problems or findings from physical examination or laboratory testing that are not 
listed above, which, in the opinion of the investigator, may pose additional risks from participation in the 
study, may interfere with the participant’s ability to comply with study requirements or that may impact the 
quality or interpretation of the data obtained from the study.  
24. 
Severe hyperlipidemia (total cholesterol >350 mg/dL, LDL >190 mg/dL, or triglycerides >500 mg/dL) 
25. 
Transaminase levels elevated more than 1.5 times the upper limit of normal (ULN) within 7 days prior to 
enrollment  
26. 
ANC less than 2,000 per mm3 within 7 days prior to enrollment   
27. 
Platelet count less than 100,000 per mm3 within 7 days prior to enrollment  
28. 
More than 50% CD8+/ CD28- T-cells in peripheral blood 
29. 
Positive pregnancy test in women of child bearing potential, currently breastfeeding, or planning to become 
pregnant during the timeframe of the study or follow-up period. 
30. 
Participation in any other studies with investigational drugs or regimens in the preceding year 
31. 
cPRA greater than or equal to 20%, as determined by each participating site’s laboratory 
 
4.4 Selection of Clinical Sites 
The primary study site will be UCSF. Other sites will include Cleveland Clinic, Duke University, University of Alabama at 
Birmingham (UAB), and the University of Colorado. All sites perform 40-120 living donor kidney transplants per year 


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allowing easily for the target enrollment of 10 subjects within the projected enrollment period of 12 months. All centers 
also have long experience with the use of belatacept based immunosuppression in kidney transplant recipients.  


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5. Known and Potential Risks and Benefits to Participants 
5.1 Risks of lulizumab Pegol (BMS 931699) 
The known risks of lulizumab pegol (BMS-931699) are primarily derived from four randomized blinded placebo-
controlled studies: two in healthy volunteers (Shi, 2017) and two in patients with disease. 
5.1.1 
Risks of lulizumab pegol (BMS-931699) from Studies in Healthy Volunteers 
There have been two randomized blinded placebo-controlled studies in healthy volunteers: 
1. 
SAD (single ascending dose study), BMS study IM128001: n=156, with 108 subjects receiving the active drug 
(0.01-100 mg IV or 9, 25, or 50 mg SC).  
2. 
MAD (multiple ascending dose study), BMS study IM128003: n=24, with 18 subjects receiving the active drug  
(6.25 mg every 2 weeks, 12.5 mg weekly, or 3.75 mg weekly SC for 5 weeks). 
In the SAD study, the most frequently reported AE was headache (n = 17 [15.7%] for lulizumab pegol (BMS-931699) vs. n 
= 4 [8.3%] for placebo). Acute infusion reactions occurred in 7 subjects.  Four subjects were discontinued from the study 
due to AEs of acute infusion reaction within 60 minutes of initiation of IV infusion of lulizumab pegol (BMS-931699).  The 
most commonly reported symptoms were flushing, feeling hot, erythema, and ocular hyperemia.  All events were of 
moderate (grade 2) intensity.  The symptoms were reversible on cessation of administration and initiation of standard 
treatment.  There were no clinically relevant changes in vital signs following administration of lulizumab pegol (BMS-
931699).  Also, no clinically meaningful changes were observed in pro-inflammatory cytokines following a single dose of 
lulizumab pegol (BMS-931699), confirming the lack of CD28 receptor agonistic activity in humans. 
Two subjects experienced SAEs. One subject in part 1 experienced acute renal failure due to severe dehydration on day 
16 following administration of 25 mg lulizumab pegol (BMS-931699) SC; this condition was not attributed to study drug 
and fully resolved.  One subject in part 2 had a perforated appendix 7 days after receiving a partial dose of lulizumab 
pegol (BMS-931699) on day 1.  This event was not attributed to lulizumab pegol (BMS-931699). 
Isolated, asymptomatic ALT increases (with 41 U/L considered ULN) were seen in 20 (18.5%) subjects following 
administration of lulizumab pegol (BMS-931699) and 6 (12.5%) subjects following administration of placebo in the SAD 
study.  
During the MAD study, infections and infestations occurred in 5 (27.8%) subjects following administration of lulizumab 
pegol (BMS-931699) (versus 0 in the placebo group). No correlation was observed between exposure and infection rate. 
One subject in the 12.5-mg lulizumab pegol (BMS-931699) weekly group experienced 2 infective episodes: oral herpes 
on day 40 followed, after 7 days, by an upper respiratory infection; in both episodes the severity was classified as mild. 
One subject receiving 12.5 mg lulizumab pegol (BMS-931699) weekly presented with a furuncle of mild severity on day 
69. One subject receiving 37.5 mg lulizumab pegol (BMS-931699) weekly presented on day 89 with a peritonsillar 
abscess of moderate severity, which required antibiotic treatment with 500 mg amoxicillin 3 times a day for 10 days. 
One subject receiving 37.5 mg lulizumab pegol (BMS-931699) weekly had a mild viral infection on day 81.  One SAE 
occurred that was considered possibly related to lulizumab pegol (BMS-931699).  A subject receiving 6.25 mg lulizumab 
pegol (BMS-931699) every 2 weeks required hospitalization on day 49 for cellulitis that developed in his right hand after 
damage of the skin at the base of his third finger. The hospitalized patient was treated with IV antibiotics, and the lesion 
was surgically drained. The traumatic skin damage in his right hand is a potential inciting factor for the cellulitis. 
However, it could not be excluded that lulizumab pegol (BMS-931699) might have made the subject more susceptible to 
the subsequent infection. Therefore, the SAE was considered possibly related to the study drug.   


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Three discontinuations due to AEs were reported.  One discontinuation occurred in the placebo group due to a mild 
increase in transaminases to < 2 times ULN. One subject in the 12.5-mg and 1 in the 37.5-mg lulizumab pegol (BMS-
931699) weekly group discontinued due to moderate injection-site reactions. The most frequently occurring AEs were 
headache and nausea, and were mild to moderate in severity. 
5.1.2 
Risks of lulizumab pegol (BMS-931699) from Studies in Patients with Disease 
Safety data for the IM128027 placebo-controlled short-term Lupus trial (a period of 24 weeks and up to 42 days post last 
dose of the short-term treatment period or the start of LTE treatment, whichever occurred first, are summarized below. 
Data from the LTE are still being analyzed. 
Table 2. Summary of subjects with AEs reported during the short-term period, all treated subjects, Study IM128027 
 
Placebo 
 
N=71 
lulizumab pegol (BMS-931699) 
1.25 mg every 2 weeks 
N=70 
5 mg every 2 weeks 
N=68 
12.5 mg every 2 weeks 
N=68 
12.5 mg weekly 
N=69 
Deaths 
0 
2 (2.9) 
0 
0 
0 
SAEs 
6 (8.5) 
8 (11.4) 
9 (13.2) 
5 (7.4) 
5 (7.2) 
Related SAEs 
1 (1.4) 
0 
5 (7.4) 
3 (4.4) 
3 (4.3) 
Discontinued due 
to SAEs 
1 (1.4) 
5 (7.1) 
4 (5.9) 
2 (2.9) 
3 (4.3) 
AEs 
62 (87.3) 
59 (84.3) 
60 (88.2) 
56 (82.4) 
59 (85.5) 
Related AEs 
19 (26.8) 
19 (27.1) 
29 (42.6) 
30 (44.1) 
33 (47.8) 
Discontinued due 
to AEs 
3 (4.2) 
9 (12.9) 
9 (13.2) 
5 (7.4) 
8 (11.6) 
 
During the short-term period, there were 2 deaths in the 1.25 mg every 2 weeks group: 1 death due to cerebral 
hemorrhage and 1 death due to complications of a SLE flare, both deemed unrelated to investigational product by the 
investigator. Overall, the number of AEs and SAEs that were related to treatment was higher in the 5 mg every 2 weeks, 
12.5 mg every 2 weeks, and 12.5 mg weekly dose groups. A total of 33 subjects experienced SAEs during the short-term 
period. The only SAE experienced by ≥ 2 subjects in one of the lulizumab pegol (BMS-931699)-treated groups, by 
preferred term, was SLE; in the placebo group, cellulitis and lupus nephritis were experienced by ≥ 2 subjects. The 
following SAEs were considered related to study medication by the investigator: cellulitis (placebo), herpes zoster (12.5 
mg every 2 weeks), hypertension (12.5 mg every 2 weeks), lung infection (12.5 mg weekly), lupus enteritis (5 mg every 2 
weeks), optic neuritis (12.5 mg weekly), pleurisy (5 mg every 2 weeks), respiratory tract infection (5 mg every 2 weeks), 
serum sickness (5 mg every 2 weeks), SC abscess (12.5 weekly), SLE (5 mg every 2 weeks), and systemic inflammatory 
response syndrome (12.5 every 2 weeks).  
With respect to infusion and injection site reactions, 35 subjects (4 of 71 subjects who received placebo and 31 of 275 
subjects who received lulizumab pegol (BMS-931699)) experienced 123 AEs (12 in subjects who received placebo and 
111 in subjects who received lulizumab pegol (BMS-931699)) of local injection site reactions. These events were mostly 
mild and considered related to study medication. There were 2 SAE injection reactions reported. First, there was an SAE 
that was reported as serum sickness (Grade 2 / moderate) in the lulizumab pegol (BMS-931699) 5 mg every 2 weeks 
group occurring approximately 4 weeks after initiating study therapy and 1 day after the most recent dose, which was 
considered to be related to study drug by the investigator and Sponsor. The subject reported feeling unwell, dizzy, and 
feverish with muscle aches. The event resolved with treatment. The second case was a subject in the lulizumab pegol 
(BMS-931699) cohort that received 12.5 mg every 2 weeks.  The subject was hospitalized for systemic inflammatory 
response syndrome (Grade 3/severe) shortly after receiving the second dose of lulizumab pegol (BMS-931699); the 
event was considered related to study drug. This subject presented with fevers and diarrhea, was found to have SIRS, 


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underwent hospitalization for 3 days and was treated empirically with antibiotics (no microbial etiology identified). The 
event was considered resolved, and study drug was discontinued. 
In the second study, IM128035, subjects with Primary Sjögren’s Syndrome were randomized 1:1:1 to receive either BMS-
986142 350 mg PO daily and SC placebo injection, lulizumab pegol (BMS-931699) 12.5 mg SC once weekly and oral 
placebo, or oral and SC placebo for 12 weeks. A total of 45 subjects were enrolled into the study, and 18 subjects were 
randomized to treatment. Five subjects were treated with lulizumab pegol (BMS-931699), 6 subjects were treated with 
BMS-986142, and 7 subjects received placebo. Three of these 18 subjects completed the double-blind treatment period; 
2 placebo-treated subjects and 1 lulizumab pegol (BMS-931699)-treated subject. There were no deaths in this study. No 
serious or severe AEs were noted in the lulizumab pegol (BMS-931699) arm of the study.  Collectively, the data from the 
above studies demonstrate that lulizumab pegol (BMS-931699) has an acceptable safety profile.  
5.2 Risks of Actemra® (tocilizumab)  
Most common adverse reactions (incidence of at least 5%) are upper respiratory tract infections, nasopharyngitis, 
headache, hypertension, increased ALT, injection site reactions. 
Serious Infections 
The package insert includes a “black box” warning about serious infections, including tuberculosis.  Serious and 
sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic 
pathogens have been reported in patients receiving immunosuppressive agents including Actemra® for rheumatoid 
arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, 
gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, 
aspergillosis, candidiasis, and pneumocystosis were reported with Actemra®. Other serious infections, not reported in 
clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with 
disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as 
methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. 
Patients with known active current viral, fungal, mycobacterial or other infections (including, but not limited to 
tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster) will be excluded from 
participation in this study. 
Patients will be closely monitored for the development of signs and symptoms of infection during and after treatment 
with Actemra®, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase 
reactants. Actemra® will be held if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient 
who develops a new infection during treatment with Actemra® will undergo a prompt and complete diagnostic workup 
appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and be closely monitored  
Tuberculosis  
Patients will be evaluated for tuberculosis risk factors and have a test for latent infection within 3 months prior to 
enrollment in the study, conducted using either a PPD or interferon-gamma release assay (i.e. QuantiFERON-TB, T-
SPOT.TB). Those with a history of active TB will be excluded from participation. Those with a positive test for latent TB 
infection must have completed appropriate therapy for LTBI; treatment regimens should be among those endorsed by 
the CDC (Division of TB Elimination, 2016). Only those patients will be enrolled who have a negative test for LTBI within 3 
months prior to transplant OR have appropriately completed LTBI therapy prior to transplant.   
Viral Reactivation  


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Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation 
were observed in clinical studies with Actemra®. No cases of Hepatitis B reactivation were observed in the trials; 
however, patients who screened positive for hepatitis were excluded. Study participants will be required to have 
evidence of immunity to varicella.  
Gastrointestinal Perforations 
Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in 
RA patients. Patients with a history of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis 
will be excluded from participation in the study. Patients presenting with new onset abdominal symptoms will be 
promptly evaluated for early identification of gastrointestinal perforation. 
Laboratory Parameters  
Neutropenia  
Treatment with Actemra® was associated with a higher incidence of neutropenia. Infections have been uncommonly 
reported in association with treatment-related neutropenia in long-term extension studies and post-marketing clinical 
experience.  See section 7.2.1.4, Toxicity Prevention and Management for Tocilizumab. 
 
Thrombocytopenia  
Treatment with Actemra® was associated with a reduction in platelet counts. Treatment-related reduction in platelets 
was not associated with serious bleeding events in clinical trials.  See section 7.2.1.4, Toxicity Prevention and 
Management for Tocilizumab. 
 
Elevated Liver Enzymes and Hepatotoxicity  
Treatment with Actemra® was associated with a higher incidence of transaminase elevations. These elevations did not 
result in apparent permanent or clinically evident hepatic injury in clinical trials.  Increased frequency and magnitude of 
these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Actemra®. 
In one case, a patient who had received Actemra® 8 mg/kg monotherapy without elevations in transaminases 
experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in 
combination with Actemra®. Transaminases normalized when both treatments were held, but elevations recurred when 
MTX and Actemra® were restarted at lower doses. Elevations resolved when MTX and Actemra® were discontinued.  See 
section 7.2.1.4, Toxicity Prevention and Management for Tocilizumab. 
 
The Marketing Authorization Holder identified eight cases as tocilizumab related moderate to severe drug-induced liver 
injury including acute liver failure, hepatitis and jaundice. This serious hepatic injury occurred between 2 weeks to more 
than 5 years after initiation of tocilizumab with median latency of 98 days. In these eight cases, two cases of acute liver 
failure required liver transplantation. In the context of total world-wide tocilizumab exposure of approximately 
1,066,849 patients (882,370.3PY) up to 10th April 2018, serious hepatotoxicity events are considered rare. The benefit-
risk profile of tocilizumab in the approved indications remains favorable. 
 
 
 
Lipid Abnormalities  
Treatment with Actemra® was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL 
cholesterol, and/or HDL cholesterol. Lipid parameters will be assessed approximately 4 to 8 weeks following initiation of 


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Actemra® therapy, then at approximately 24-week intervals. Participants will be managed according to the local 
standard of care. 
 
Immunosuppression 
The impact of treatment with Actemra® on the development of malignancies is not known. During the 24 week 
controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRA-IV compared to 8 
malignancies in the control groups. Exposure adjusted incidence of malignancies was similar in the ACTEMRA-IV group 
(1.32 events per 100 patient-years and in the placebo + DMARD group (1.37 events per 100 patient-years). Actemra® is 
an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. 
 
Hypersensitivity Reactions, Including Anaphylaxis 
Hypersensitivity reactions, including anaphylaxis, have been reported in association with Actemra® and anaphylactic 
events with a fatal outcome have been reported with intravenous infusion of Actemra®. Anaphylaxis and other 
hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in 
the 6-month controlled trials of intravenous Actemra®, 0.2% (8 out of 4009) of patients in the intravenous all-exposure 
RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of 
patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous Actemra®, 1 out of 
112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA 
controlled trial with intravenous Actemra®, 0 out of 188 patients (0%) in the Actemra® all-exposure population 
experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment 
discontinuation included generalized erythema, rash, and uticaria. Injection site reactions were categorized separately. 
In the post-marketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in 
patients treated with a range of doses of intravenous Actemra®, with or without concomitant arthritis therapies. Events 
have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred 
both with and without previous hypersensitivity reactions and as early as the first infusion of Actemra®.   
 
Those with known hypersensitivity to Acetmra® will be excluded from this study. The first dose of Actemra® will be 
administered IV in the hospital with appropriate medical support to manage anaphylaxis and the participant will be 
monitored for at least 24 hours afterward. Subsequent doses will be given SC and participant will be advised to seek 
immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other 
hypersensitivity reaction occurs, the administration of Actemra® will be stopped immediately and Actemra® will be 
discontinued permanently.  
 
Demyelinating Disorders 
The impact of treatment with Actemra® on demyelinating disorders is not known, but multiple sclerosis and chronic 
inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Patients with a history of 
demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy) will be excluded 
from participation in this study. Participants will be monitored during the study for signs and symptoms potentially 
indicative of demyelinating disorders. 
 
 
 
 


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5.3 Risks of Other Protocol Specified Medications 
5.3.1 
Risks of ATG, steroids, belatacept, everolimus, and mycophenolate mofetil 
ATG, steroids, belatacept, everolimus, and MMF are considered standard of care maintenance IS medications in kidney 
transplantation and the risks of these drugs are well described.  The risks of the specific regimen in this protocol, which 
includes lulizumab pegol (BMS-931699) and Actemra®, are unknown.  
5.4 Reproductive Risks 
Investigators shall counsel women of child bearing potential, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy and when applicable, the 
potential of fetal toxicity occurring due to transmission of study drug, present in seminal fluid, to a developing fetus, 
even if the participant has undergone a successful vasectomy or if the partner is pregnant. Investigators will also counsel 
study participants about the risks of embryo toxicity and teratogenicity with everolimus and Mycophenolate.  
Investigators shall advise on the use of highly effective methods of contraception (see Study Definitions).   
5.5 Risks of Study Procedures  
5.5.1 
Risks of Blood Draws 
Risks of blood draw or venipuncture are typically minimal with temporary local discomfort. More serious risks would 
include ecchymosis and, rarely, localized infection. The anticipated amount of blood for mechanistic assays in this study 
is not more than 67.5 ml for a single visit.  The amount of blood that may be drawn from adult participants for research 
purposes will not be more than 10.5 mL/kg or 550 mL, whichever is smaller, over an eight-week period.  The 
participant’s clinical condition will be taken into consideration to determine if research blood tests can be performed. 
5.5.2 
Risks of Kidney Transplant Biopsy 
This study requires one research biopsy approximately 6 months after transplant.  There is a risk of bleeding associated 
with transplant kidney biopsies. Transient hematuria occurs in 3 to 10% of patients and may prolong hospitalization, 
require bladder catheterization for clot drainage, or require blood transfusion in approximately 1% of patients. 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. 
5.6 Risks of Coronavirus Disease 2019 (COVID-19)  
Early reports indicate an increased risk of critical illness and mortality in kidney transplant recipients infected with SARS-
CoV-2, possibly due to chronic immunosuppression and co-existing conditions (Akalin, 2020); (Pereira, 2020). Given that 
both lulizumab pegol (BMS-931699) and Actemra® are associated with increased risk of infection in general, it is possible 
that study therapy may increase the risk of developing symptomatic severe COVID-19 illness in subjects who would have 
otherwise been asymptomatic. 
All subjects will be screened for active infection with 2019-nCoV RT-PCR prior to study entry and prior to receiving the 
first dose of the study therapy. Those with a history of positive result for 2019-nCoV RT-PCR at any time in the past will 
be excluded from participation. 
Subjects will be asked to report any fever, cough or other new symptoms immediately to the study team. The study 
therapy will be discontinued immediately in any subject (symptomatic or asymptomatic) with a positive result for 2019-
nCoV RT-PCR during the study. Results of standard of care screening for COVID-19 and testing for SARS-CoV-2 which 


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occur in any subject during the study will be collected. Subjects who are in quarantine (Akalin, 2020) for possible 
exposure to SARS-CoV-2 will not receive the study therapy or undergo study-related procedures until they complete the 
quarantine period and have a negative result for 2019-nCoV RT-PCR; such subjects may be asked to conduct study 
follow-up visits remotely during the quarantine period, if possible. 
5.7 Potential Benefits 
This study might not provide direct or immediate benefit to study participants. 


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6. Investigational Agent 
6.1 lulizumab Pegol (BMS 931699) 
6.1.1 
Formulation, Packaging, and Labeling 
A previous publication described the discovery and preclinical characterization of a domain antibody (dAb), lulizumab 
pegol, that binds to the CD28 receptor and blocks this signaling pathway (Suchard, 2013). Lulizumab pegol (BMS-
931699) was generated using phage display and affinity maturation through the diversification of a selected subset of 
amino acid residues. Monomeric anti-CD28 domain antibodies were formatted with polyethylene glycol (PEG). 
Lulizumab pegol (BMS-931699) is a potent inhibitor of T-cell proliferation and cytokine production. Unlike the first-
generation T-cell stimulation inhibitor abatacept (a cytotoxic T lymphocyte–associated antigen-4-immunoglobulin [CTLA-
4Ig] fusion protein that binds with different affinities to CD80 and CD86 on antigen-presenting cells) (Linsley, 1993), 
lulizumab pegol (BMS-931699) is equipotent at inhibiting  both CD80- and CD86-driven T-cell proliferation. No agonist 
activity, as measured by preclinical T-cell proliferation or cytokine release, has been observed with lulizumab pegol 
(BMS-931699). 
6.1.2 
Dosage, Preparation, and Administration 
Dosage Form 
Lulizumab injection, 12.5 mg/Vial (12.5 mg/mL) 
Lulizumab injection for SC administration is a clear to slightly opalescent, colorless to pale yellow solution, essentially 
free of particulate matter on visual inspection. The drug product is a single use, preservative-free, ready-to-use solution, 
contained in a 3-cc type I glass vial, closed with a 13-mm stopper and sealed with a 13-mm aluminum seal.  
Each vial of the drug product contains the labeled amount of lulizumab, sorbitol, sodium phosphate monobasic, sodium 
phosphate dibasic, and water for injection. Sodium hydroxide solution may be added to adjust the solution pH to 5.9. A 
30% overfill is included in each vial to account for vial, needle, and syringe (VNS) holdup. 
Drug Product Preparation and Administration 
To assure the sterility of the prepared solutions, the vials are single use. Because solutions of lulizumab may foam, 
shaking or excessive agitation of the vials should be avoided. Additionally, care must be taken to ensure the sterility of 
the prepared solution, as the drug product does not contain antimicrobial preservatives or bacteriostatic agents. 
Lulizumab injection is administered via SC route either undiluted or diluted in 0.9% Sodium Chloride Injection (normal 
saline [NS]) to concentration range of 0.5-5 mg/ml. Dosing solutions of lulizumab concentration 5 mg/mL are prepared 
by direct injection of NS into the original drug product vial. Dosing solutions with lulizumab concentration lower than 5 
mg/ml are prepared by injection of the drug product into an IV bag containing NS. A conventional, commercially 
available, disposable sterile plastic syringe of appropriate size should be used for the preparation and dilution of dosing 
solutions. Care must be taken to maintain the sterility of the prepared solutions. A 21-gauge, 1.5-inch sterile needle is 
recommended for withdrawal of the product from the vial or IV bag containing diluted lulizumab. A 27-gauge, 0.5-inch 
sterile needle is recommended for subsequent SC dosing. A sterile, commercially available, disposable 1-cc luer-lock 
polycarbonate syringe should be used for withdrawal and administration of the SC doses.  
Subjects will be administered lulizumab pegol (BMS-931699) 25 mg SC on day 1 after transplantation then 12.5 mg SC 
weekly until day 77.  
 


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Recommended Storage and Use Conditions 
lulizumab pegol (BMS-931699) injection should be stored refrigerated at 2⁰—8⁰ C (36⁰—46⁰ F) with protection from light 
and freezing.  Prepared vials and syringes may be stored for up to 24 hours in a refrigerator, 2°to 8°C (36° to 46°F), and 
up to 4 hours of the 24-hour period may be at room temperature, 15°C to 25°C (59°F to 77°F). The prepared syringes and 
vials should be protected from light.  Prior to administration, the drug product should reach room temperature by 
storing unrefrigerated for approximately 30 minutes before use. 
6.2 Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) 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. 
Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-dispensing log will be kept 
current for each participant.  This log will contain the identification of each participant and the date and quantity of drug 
dispensed. 
All records regarding the disposition of the investigational product will be available for inspection. 
6.3 Toxicity Prevention and Management 
Infusion reactions are not expected, since the drug administration will be via the SC route. In the MAD study as well as 
study IM128027, injection site reactions were observed to be infrequent, low-grade and self-limiting (Shi, 2017). 
Participants will be monitored for 24 hours after the 1st dose for injection site reactions.  
Two serious adverse events related to lulizumab infusion were noted in IM128027: serum sickness and systemic 
inflammatory response syndrome.  These events were delayed reactions occurring hours after receiving several doses of 
the investigational agent.  Both subjects required hospitalization and the reactions resolved with treatment.   
There has been no clinical experience with overdose of lulizumab pegol (BMS-931699). Treatment of overdose of 
lulizumab pegol (BMS-931699) should consist of general supportive care. There is no known antidote for overdose with 
lulizumab pegol (BMS-931699).  
Lulizumab therapy will be discontinued in participants with persistent or worsening abnormalities in liver function tests 
despite discontinuation of tocilizumab (see Section 7.2.1). 
6.4 Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
1. Severe injection site reaction with the 1st dose 
2. Severe acute cellular rejection (Banff 1b or higher) (see Section 13.2, Participant Stopping Rules and Withdrawal 
Criteria) or any acute clinical or subclinical antibody mediated rejection 
3. Any diagnosis of malignancy other than basal cell carcinoma 
4. Any diagnosis of tuberculosis, or invasive fungal infection 
5. Grade 4 infection 
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. 


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6.5 Study Drug Access  
The investigational drug product, lulizumab pegol (BMS-931699), will be supplied by the product manufacturer through 
a clinical trial agreement between the drug manufacturer (Bristol-Meyers Squibb) and the study sponsor DAIT NIAID.  At 
the end of the study period, BMS will not continue to supply study drug.  The site investigator is responsible to ensure 
the subject receives appropriate standard of care or other appropriate treatment in the independent medical judgement 
of the investigator to treat the condition under study. 
 


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7. Immunosuppressive Regimen 
7.1 Induction Immunosuppression 
7.1.1 
Thymoglobulin 
Study participants will be administered four doses of rabbit anti-thymocyte globulin (Thymoglobulin), total dose 6 mg/kg 
given in divided doses on the day of transplantation and days 1-3.   
The first dose should be infused over at least 6 hours; doses on subsequent days should be infused over at least 4 hours. 
Premedication with methylprednisolone (see below), acetaminophen, and/or an antihistamine prior to each infusion is 
recommended. If the platelet count falls below 50,000 cells/mm3 after receiving Thymoglobulin, the subsequent dose 
will be delayed until the platelet count is >/= 50,000 cells/mm3.   
7.1.2 
Methylprednisolone 
All study participants will receive Methylprednisolone 500 mg IV on the day of transplantation, 250 mg IV on day 1, and 
125 mg IV on day 2 (prior to Thymoglobulin on days 1 and 2).     
7.2 Maintenance Immunosuppression 
7.2.1 
Actemra® (tocilizumab)  
7.2.1.1 Tocilizumab Formulation, Packaging, and Labeling 
Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the 
immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy 
chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra and inter-
molecularly by disulfide bonds.  Actemra® has a molecular weight of approximately 148 kDa. The antibody is produced in 
mammalian (Chinese hamster ovary) cells.  
Intravenous Infusion  
Actemra® injection is supplied as a sterile, preservative-free solution for further dilution prior to intravenous infusion at 
a concentration of 20 mg/mL. Actemra® is a clear, colorless to pale yellow liquid, with a pH of about 6.5.  Single-dose 
vials are available for intravenous administration containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of Actemra®. 
Injectable solutions of Actemra® are formulated in an aqueous solution containing disodium phosphate dodecahydrate 
and sodium dihydrogen phosphate dehydrate (as a 15 mmol per L phosphate buffer), polysorbate 80 (0.5 mg per mL), 
and sucrose (50 mg per mL).  
Subcutaneous Injection 
Actemra® injection is supplied as a sterile, clear, colorless to slightly yellowish, preservative free liquid solution for 
subcutaneous administration with a pH of approximately 6.0.  It is supplied in a 1 mL ready-to-use, single-use prefilled 
syringe (PFS) with a needle safety device.  Each prefilled syringe delivers 0.9 mL (162 mg) of Actemra®, in a histidine 
buffered solution composed of Actemra® (180 mg/mL), polysorbate 80, L-histidine and L-histidine monohydrochloride, 
L-arginine and L-arginine hydrochloride, L-methionine, and water for injection. 
7.2.1.2 Tocilizumab Dosage, Preparation, and Administration 
Package Insert Instructions for Intravenous Infusion  
Actemra® for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:  


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• 
Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.  
Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the Actemra® 
injection required for the patient’s dose from the infusion bag or bottle. 
Step 2. Withdraw the amount of ACTEMRA for intravenous infusion from the vial(s) and add slowly into the 0.9% or 
0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid 
foaming. 
• 
The fully diluted Actemra® solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 2° 
to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light.  
• 
The fully diluted Actemra® solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 2° 
to 8°C (36° to 46°F) for up to 24 hours or room temperature for up to 4 hours and should be protected from 
light.  
• 
Actemra® solutions do not contain preservatives; therefore, unused product remaining in the vials should not be 
used.   
• 
Allow the fully diluted Actemra® solution to reach room temperature prior to infusion.  
• 
The infusion should be administered over 60 minutes and must be administered with an infusion set. Do not 
administer as an intravenous push or bolus. 
• 
Actemra® should not be infused concomitantly in the same intravenous line with other drugs. No physical or 
biochemical compatibility studies have been conducted to evaluate the co-administration of Actemra® with 
other drugs.  
• 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. If particulates and discolorations are noted, the 
product should not be used.  
• 
Fully diluted Actemra® solutions are compatible with polypropylene, polyethylene and polyvinyl chloride 
infusion bags and polypropylene, polyethylene and glass infusion bottles. 
Package Instructions for Subcutaneous Injections 
Actemra® for subcutaneous injection is not intended for intravenous drip infusion.  
• 
Assess suitability of patient for SC home use and instruct patients to inform a healthcare professional before 
administering the next dose if they experience any symptoms of allergic reaction. Patients should seek 
immediate medical attention if they develop symptoms of serious allergic reactions. Actemra® subcutaneous 
injection is intended for use under the guidance of a healthcare practitioner. After proper training in 
subcutaneous injection technique, a patient may self-inject Actemra® or the patient’s caregiver may administer 
Actemra® if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be 
instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication 
administration.   
• 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration. Do not use Actemra® prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or 
discoloration. Actemra® for subcutaneous administration should be clear and colorless to pale yellow.  Do not 
use if any part of the PFS appears to be damaged.   
• 
Patients using Actemra® for subcutaneous administration should be instructed to inject the full amount in the 
syringe (0.9 mL), which provides 162 mg of Actemra®, according to the directions provided in the IFU.   


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• 
Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where 
the skin is tender, bruised, red, hard, or not intact. 
7.2.1.3 Tocilizumab Study Dosing 
Participants in CTOT-24 will receive 8 mg/kg of intravenous tocilizumab on day 2 after transplantation, then 162 mg 
subcutaneously every 2 weeks till day 168. 
 Actemra® is provided for study subjects enrolled in the trial.  Actemra® designated for the study will be maintained in 
the research pharmacy and accountability is expected as according to Section 6.2. 
7.2.1.4 Toxicity Prevention and Management for Tocilizumab 
Neutropenia 
As recommended by the manufacturer in the package insert, participants with ANC less than 2,000 per mm3 will be 
excluded from participation.  Neutrophil counts will be monitored weekly for 12 weeks after start of therapy and at least 
every 4 weeks thereafter until the end of therapy.. 
During the study, Actemra® dose will be maintained for participants with ANC >1000 /mm3, temporarily held for 
participants with ANC 250-1000/mm3 till the ANC recovers to >1000/mm3, and discontinued for participants with ANC 
<250/mm3.  
In addition, the following mitigation strategy (Table 3) for subjects with neutropenia will be followed: 
 
 


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Table 3. Neutropenia Mitigation Strategy 
ANC 
STRATEGY 
MEDICATION 
RECOMMENDED 
DOSE ADJUSTMENT 
MONITORING OF RESPONSE 
1500 to 
<2000/mm3 
Adjust dose 
of anti-
proliferative 
and stop 
concomitant 
medications 
that may be 
contributing 
to 
neutropenia 
Everolimus 
 
Reduce current dose by 
25-50% 
Weekly ANC 
 
When ANC improves to >2000/mm3, slowly 
increase dose of anti-proliferative agent   
MMF 
(or Myfortic) 
If on 1000 (720) mg bid: 
reduce to 500 (360) mg 
bid 
750 (540) mg bid: reduce 
to 500 (360) mg bid 
500 (360) mg bid: reduce 
to 250 (180) mg bid 
250 (180) mg bid: hold  
Valganciclovir 
Discontinue 
 
 
 
1000 to 
<1500/mm3 
Adjust dose 
of anti-
proliferative 
 
 
Everolimus 
 
Reduce current dose by 
50% 
Weekly ANC 
 
When ANC improves to  >1500/mm3, slowly 
resume anti-proliferative agent 
MMF 
(or Myfortic) 
If on 1000 (720) mg bid: 
reduce to 500 (360) mg 
bid 
If on 750 (540) mg bid: 
reduce to 250 (180) mg 
bid 
If on 500 (360) mg bid: 
reduce to 250 (180) mg 
bid 
If on 250 (180) mg bid 
:hold 
 
 
 
250 to 
<1000/mm3 
Hold anti-
proliferative 
 
AND 
 
Hold 
tocilizumab 
dosing until 
ANC 
improves 
Everolimus 
Hold 
Weekly ANC 
 
When ANC improves to  >1000/mm3, resume 
tocilizumab 
 
When ANC improves to >2000/mm3 for 2 
weeks after resuming tocilizumab, slowly 
resume anti-proliferative 
MMF 
(or Myfortic) 
Hold  
<250/mm3 
Adjust dose 
of anti-
proliferative 
 
AND 
 
Discontinue 
tocilizumab 
Everolimus 
Hold 
Weekly ANC 
 
When ANC improves to >500/mm3, resume 
MMF at 250 mg bid or Everolimus at 0.75 mg 
bid  
MMF (or 
Myfortic) 
Hold 
Thrombocytopenia 
As per directions from the package insert, participants with a platelet count <100,000/mm3 will be excluded from 
participation and platelet counts will be monitored at least every 4 to 8 weeks after start of therapy and at least every 3 
months thereafter for all subjects. 
 


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During the study, Actemra® dose will be maintained for participants with platelet count >100,000 /mm3, temporarily 
held for participants with platelet counts 50,000-100,000/mm3 till the count recovers to >100,000/mm3, and 
discontinued for participants with platelet counts <50,000/mm3. 
 
Elevated Liver Enzymes  
As per directions from the package insert, participants with transaminase levels > 1.5 times ULN will be excluded from 
participation in the study. ALT and AST levels will be monitored at least 4 to 8 weeks after start of therapy and at least 
every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin will be considered.  
During the study, Actemra® dose will be temporarily held for participants with AST or ALT 2-5 times ULN until the AST or 
ALT recover to <2 times ULN, and discontinued for participants with AST or ALT >5 times ULN. 
7.2.2 
Nulojix® (belatacept) 
Nulojix® is indicated for prophylaxis of organ rejection in adults receiving a kidney transplant.  As previously described, 
CTOT-24 participants will receive Nulojix®with Zortress®after induction with thymoglobulin and a 1-month corticosteroid 
taper.   
7.2.2.1 Nulojix® Study Dosing 
For CTOT-24 participants, Nulojix® (5mg/kg) will be administered every 4 weeks starting at day 84. Nulojix® will be 
started 1 week after the last study dose of lulizumab on day 77.  Nulojix® will be administered for 52 weeks during the 
study.  After 52 weeks, the site investigator will determine the best IS regimen for the subject.  
Nulojix® is provided for study subjects enrolled in the trial.  Nulojix® designated for the study will be maintained in the 
research pharmacy and accountability is expected as according to Section 6.2. 
7.2.3 
Zortress® (everolimus) 
Zortress® is indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving 
a kidney transplant.   
7.2.3.1 Zortress® Study Dosing 
Zortress®will be started at 0.75 mg BID 14 days after transplantation.  Zortress® will be titrated to target trough levels 3-
8 ng/mL.  Participants who do not tolerate everolimus will be switched to MMF.  Participants with rare hereditary 
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose mal absorption should not take 
everolimus as this may result in diarrhea and malabsorption; these participants should take MMF/MPA (Section7.2.5).  
Administration of medications known to interact with everolimus is allowed but trough levels should be carefully 
monitored and dosing titrated to maintain the target levels to minimize toxicity while maintaining efficacy.  Everolimus 
will be administered for 52 weeks during the study.  After 52 weeks, the site investigator will determine the best IS 
regimen for the subject. 
7.2.3.2 Zortress® Toxicity Prevention and Management 
In participants who develop any of the following conditions after initiation of Zortress® therapy, everolimus will be 
discontinued and mycophenolate mofetil will be started at 1000 mg twice daily. 
 
1. New onset or worsened proteinuria with urine pr/cr >1 g/g  
2. Severe hypercholesterolemia (LDL>190 mg/dL or triglycerides >500 mg/dL) not responsive to therapy with lipid 
lowering agents  
3. Severe edema or fluid accumulations such as pleural or pericardial effusions  


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4. Interstitial pneumonitis  
5. Severe mouth ulcers  
6. Severe cytopenia (WBC <1,000/mm3) (also see Table 3. Neutropenia Mitigation Strategy) 
7. Any condition which in the determination of the investigator requires discontinuation of Zortress® therapy such as 
planned surgery.  
7.2.4 
Maintenance Corticosteroids 
After the initial methylprednisolone doses, participants will commence a taper with oral prednisone:  60 mg on day 3, 30 
mg on days 4-10, 20 mg on days 11-17, 10 mg on days 18-24, and then taper to final maintenance dose of 5 mg daily by 
day 28. 
7.2.5 
Mycophenolate Mofetil (MMF)/Mycophenolic Acid (MPA) 
MMF/MPA will be started no later than one day after transplant at 1000/ 720 mg PO twice daily, provided the WBC 
count permits (see Table 3. Neutropenia Mitigation Strategy). Participants will stay on MMF/MPA till the everolimus 
level is within the therapeutic range.  Participants who do not tolerate everolimus can also stay on or switch back to 
mycophenolate mofetil 1000 mg twice daily or 720 mg twice daily of Myfortic (mycophenolic acid) and remain in the 
trial (see 7.2.3.2 Zortress Toxicity Prevention and Management).  As per standard of care, all Mycophenolate prescribers 
in the study will be required to enroll in the FDA mandated mycophenolate REMS (risk evaluation and mitigation 
strategy) program. 
7.3 Treatment of Rejection 
Study participants who develop mild acute cellular rejections (Banff type 1a) in this study will be treated with steroids 
and maintained on the study regimen. In participants with higher grades of acute cellular rejection (Banff type 1b and 
above) or any acute antibody mediated rejection, the study regimen will be discontinued and replaced with a 
tacrolimus-based regimen.  These participants will go into safety follow up.   
 
 


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8.  Other Medications 
8.1 Anti-Infective Prophylactic Medications 
All participants in the study will be required to receive CMV prophylaxis with valganciclovir for a minimum of 3 months, 
as tolerated.  Please refer to Table 3. Neutropenia Mitigation Strategy for management of medications known to 
contribute to neutropenia.  If valganciclovir is stopped to mitigate neutropenia, weekly CMV PCR monitoring will be 
performed until 12 weeks after transplant. 
Other anti-infective prophylaxis medications for the prevention of urinary tract infections, oral candidiasis and 
pneumocystis pneumonia will be administered per standard of care for kidney transplant recipients at each clinical 
center. 
8.2 Prohibited Medications/Products 
8.2.1 
Non-Leukoreduced Blood Products  
For participants requiring treatment, leukoreduced blood products should be used whenever possible. 
8.3.2 
Vaccinations 
The use of live vaccines will be proscribed during trial participation, as per standard of care for kidney transplant 
recipients. Examples include (but are not limited to) the following: intranasal influenza, measles, mumps, rubella, oral 
polio, BCG, yellow fever, live varicella, and TY21a typhoid vaccines. 
8.3.3 
Cytochrome P450 3A4 and P-gp  
Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with 
concomitant use of everolimus.  


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9.   Study Mandated Procedures 
9.1 Renal Transplant Biopsy 
Study participants will undergo biopsies at 6 months after transplantation.  Research tissue specimens will be collected 
during these procedures for mechanistic assays.  In the case of clinically indicated (“for-cause”) biopsies, unstained slides 
from FFPE kidney tissue will be sent to the central lab for mechanistic studies. In addition, digital images will be provided 
to the central pathologist in order to obtain a central read for all for-cause biopsies.  
9.2 Blood Draws 
Blood draws are necessary after kidney transplantation to monitor allograft function.  Whenever possible, study 
participants will have additional blood drawn for research purposes at time points when standard of care testing is 
already being done. Study participants will also have non-standard of care blood draws for research purposes.   
 


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10.  Study Visits 
10.1 
Enrollment 
The research study will be explained in lay terms to each potential research participant prior to transplantation.  The 
potential participant will sign an informed consent form before undergoing any study procedures.  Once the informed 
consent has been signed, the participant is considered enrolled in the study and will be assigned a unique participant 
number. 
10.2 
Donor Visit 
Donors will be asked to consent for one study visit where blood will be collected to allow for mechanistic assays.  See 
Appendix 1 for the donor schedule of events.  Minimal donor medical information will be collected (e.g. demographics, 
HLA typing, CMV serology status).  
10.3 
Screening/Baseline Visit 
The purpose of the screening period is to confirm eligibility to continue in the study.  
If not already available in the participant’s medical record (e.g. testing performed for transplant evaluation), testing 
should be performed according to the schedule of events (Appendix 2) to complement available results and confirm 
study eligibility.   
10.4 
Study Visits  
10.4.1 Medication Schedule 
Study participants will receive protocol directed medications on Day 0, 1, 2, 3 and 7 after transplant.  Thereafter, 
participants will return to the transplant clinic for study medications (i.e. lulizumab, belatacept, and tocilizumab) weekly 
until 12 weeks after transplant; biweekly until 26 weeks after transplant; and then monthly until study completion. See 
Appendix 3 Medication Schedule. 
10.4.2 Follow-Up Visits  
In addition to study medication administration, participants will have study assessments (i.e. physical exam, review of 
medical history and AE, laboratory testing and mechanistic blood collections) throughout the study (Appendix 2).  Study 
follow-up visits will be aligned with medication administration visits whenever possible.   
10.5 
 Unscheduled Visits/ Clinically Indicated Biopsies 
If creatinine increases or other concerns arise between scheduled study visits, participants will be instructed to return to 
the study site for an “unscheduled” visit.  Study assessments will be performed, and research specimens collected if a 
participant has a clinically indicated biopsy. Please see Appendix 2 for details. 
10.6 
Visit Windows 
Study visits should take place within the time limits specified in the schedule of events. 
 


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11. Mechanistic Assays 
The mechanistic goal of the study is to determine the impact of the proposed novel immunosuppression regimen on the 
alloimmune profile with a particular emphasis on mechanisms of tolerance.  Specific assays to be performed are 
described below. 
11.1 
Peripheral Blood Assays 
Peripheral blood samples will be collected from the donor and recipient pre-transplant and from the recipient at 1, 3, 6, 
9 and 12 months post-transplant to evaluate the impact on the allo-immune profile of the key components of the novel 
immunosuppression regimen. We are principally interested in comparing the effect of lulizumab pegol (BMS-931699) to 
belatacept. Comparisons will be made within the cohort across these time points.  
Time point 
Therapeutic agents 
1 and 3 months 
Lulizumab + tocilizumab 
6 months 
Belatacept + tocilizumab 
9 and 12 months 
Belatacept 
11.1.1 Multiparameter Flow Cytometry (MFC):  
Several panels of MFC will be used to profile potential changes in peripheral blood leukocyte subsets during the study.  
The panel design is shown in below in Table 4.  These panels will allow in-depth phenotyping of T cells, Tregs, and B cells 
along with profiling of monocytes and NK cells. 
Table 4. MFC Panel 
Panel name 
Markers 
Leukocyte subsets CD45, CD3, CD7, CD19, CD14, CD16, CD56, HLA-DR 
T cell phenotype 
CD45, CD3, CD4, CD8, CD28, CD2, CD45RO, CD57, PD-1, CCR7 
Treg 
CD45, CD3, CD4, CD127, CD25, FOXP3, HELIOS, CTLA-4, CD38, CD39 
B cell 
CD45, CD19, CD24, CD27, CD38, IgD, MTG 
11.1.2 Alloreactive T cell Frequency (ATF) assay 
This assay was developed in the UCSF Transplantation Laboratory by Q. Tang, PhD to measure the frequency of 
circulating donor-reactive CD4 conventional T cells, CD8 T cells and Tregs.  The Tang laboratory has used this assay to 
analyze 300+ samples collected from kidney, liver, lung, and islet transplants and maternal fetal pairs (see Figure 5).  


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Figure 5. 
ATF Assay. A. An example of ATF assay flow profile.  B. ATF results on transplant patients accumulated thus far n=265.   
This assay uses CD40L-stimulated donor B cells to stimulate CFSE-labeled recipient PBMC, with proliferation of T cell 
subsets determined on day 4 using flow cytometry.  Using this assay in kidney transplant recipients, the Tang Laboratory 
has found significantly higher donor-specific CD8 T cells in rejectors vs. non-rejectors in HIV+ kidney transplant 
recipients.  To determine the contribution of anergy, exhaustion, and deletion/terminal senescence, we will also add 
cytokines (IL-2, IL-7 and/or IL-15), antibodies to checkpoint molecules PD-1, LAG3, and TIM3, or both during stimulation 
with donor antigen presenting cells.  The rationale is that cytokines and checkpoint inhibitors will rescue anergic and 
exhausted cells, respectively whereas unresponsiveness due to deletion or terminal senescence cannot be rescued.  
Controls stimulated with antibodies to CD3 and CD28 will be included to determine if T cell dysfunction is donor specific. 
This will allow us to categorize each sample and each T cell subset as normal, anergic, exhausted, and deleted or 
terminally senescent.  We will then compare CD4 T conv, CD8 and Treg responses across time in the study. 
11.1.3 Donor Antigen Stimulated Gene Expression 
By analyzing gene expression in PBMC stimulated with donor antigen presenting cells, the Tang Laboratory has found 
that genes implicated in T cell checkpoint inhibition (CTLA-4, SFASL, NFATC1, NFATC2, LAG3 and HAVCR2) were 
expressed at higher level in a never-rejector vs. an early rejector among HIV+ liver transplant recipients (see Figure 6).  
In this assay, recipient PBMC are stimulated with donor antigen presenting cells (either activated B cells or monocyte-
derived dendritic cells), and the cells are collected on day 3 for gene expression analyses of a panel of 96 genes using 
qPCR.  This assay not only measures frequency of responders, but also the type of response induced by donor antigens.  
We will use this assay to determine if the different components of the novel regimen alter donor-specific responses to 
favor tolerance. 


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Figure 6. Donor-specific T cell response of HIV+ transplant patients. A. ATF comparison of rejector and non-rejector HIV+ kidney (n=8R, 8NR, top) 
and liver (n=6R, 9NR, bottom) transplant patients. B. Donor (D) and 3rd party (3rdP) sBc stimulated gene expression in pre-transplant PBMC of a 
liver transplant early rejector and a non-rejector. 
11.1.4 In Vitro Treg Suppression  
Donor-specific suppression activity of recipient Tregs will be measured by using irradiated donor PBMC as stimulators. 
General suppressive activity will be measured by stimulating Tregs with anti-CD3 and anti-CD28. Recipient PBMC will be 
collected and banked before transplant and at specified time points during therapy. PBMC collected before transplant 
will be used as standard responders so that changes observed in the amount of suppression can be attributed to the 
activity of Tregs collected at different points during the study. 
11.1.5 Kidney Solid Organ Response Test (KSORT) 
The Sarwal Laboratory has developed the kSORT blood QPCR assay as a noninvasive tool to detect high risk of acute 
rejection of renal transplants as early as 3 months prior to detection by the biopsy (Roedder S, 2014).  The KSORT gene 
signature comprises the following genes (CFLAR, DUSP1, ITGAX, RNF130, PSEN1, NKTR, RYBP, NAMPT, MAPK9, IFNGR1, 
CEACAM4, RHEB, GXMK, RARA, SLC25A37, EPOR, RXRA) developed into an assay called kSORT (kidney solid organ 
response test) (Table 5). kSORT provides an AR risk score where a score >0 indicates acute rejection and a score <0 
indicates no acute rejection. The SORT genes will be analyzed in our trial to define their association with inflammation 
and borderline rejection on kidney biopsies and to examine whether how they are modified in different phases of the 
study investigational regimen.  
 
 
 
 


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Gene ID 
Protein name 
Function 
DUSP1 
Dual specificity protein phosphatase-1 
Dephosphorylates MAP kinase to regulate cell cycle 
CFLAR 
CASP8 and FADD-like apoptosis 
inhibitor 
Cytosolic protein that inhibits tumor necrosis factor related apoptosis 
ITGAX 
Integrin alpha–X 
Membrane receptor for fibrinogen that mediates cell-cell interaction 
during inflammatory responses; important in monocyte adhesion and 
chemotaxis 
NAMPT 
Nicotinamide 
phosphoribosyltransferase 
Catalyzes formation of NAD; also exists as nonsecreted form that acts as 
cytokine and adipokine; plays a role in regulating circadian clock 
MAPK9 
Mitogen-activated protein kinase 9 
Activated by cytokines and/or stress response to promote cell 
proliferation, differentiation, migration, transformation and programmed 
cell death 
RNF130 
E3 ubiquitin-protein ligase RNF130 
Cytoplasmic zinc-binding protein 
IFNGR1 
Interferon-receptor gamma-1 
Membrane protein that binds interferon gamma; mutation causes 
Immunodeficiency 27A 
PSEN1 
Presenilin-1 
Stimulates cell-cell adhesion; may play role in signaling and apoptosis; 
mutations associated with familial early-onset Alzheimer’s 
RYBP 
RING1 and YY1-binding protein 
Nucleic and cytosolic protein that inhibits transcription, promotes 
apoptosis 
NKTR 
NK-tumor recognition protein 
Membrane protein that is a component of a putative tumor recognition 
complex on the surface of NK cells; binds cyclosporin A 
SLC25A37 
Mitoferrin-1 
Mitochondrial iron transporter that takes up iron for developing erythroid 
cells 
CEACAM4 
Carcinoembryonic antigen-related cell 
adhesion molecule 4 (CD66a) 
Surface protein found on lymphocytes for cell to cell adhesion 
RARA 
Retinoic acid receptor alpha 
Suppresses transcription when unbound, loss of suppression when bound, 
associated with spermatocyte survival when bound 
RXRA 
Rxra protein 
Nuclear protein that regulates transcription 
EPOR 
Erythropoietin receptor 
Promotes erythroblast proliferation and differentiation when bound by 
EPO 
GZMK 
Granzyme K 
Serine protease released by NK or T cells for killing of cancerous cells, 
viruses, or bacteria 
RHEB 
GTP-binding protein Rheb 
Promotes proliferation and inflammation through activation of mTOR 
complex 
Table 5.  kSORT genes 
 
11.1.6 HLA Antibody Testing for DSA 
HLA antibody testing will be conducted using singe antigen bead testing at 1, 3, 6 and 12 months post-transplant to track 
the development of any donor specific antibody. The testing will be done at the UCSF Immunogenetics Laboratory. 
11.2 
Biopsy Assays 
These assays will be performed on kidney tissue collected during protocol kidney biopsies at 6 months post-transplant 
and for any cause biopsies during the first year post-transplant.  


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11.2.1 Graft Histology 
Graft tissue will be obtained per study protocol at 6 months post-transplant. Histologic examination will be done at the 
University of California at San Francisco in the Laszik Laboratory. Biopsy results will be reported using the Banff ’07 
schema for acute rejection and chronic allograft injury.  The centers will send renal tissue (1 core in a formalin jar). 
For sites with clinically indicated biopsies performed at other times during the study, digital images of the local case (i.e. 
H&E, PAS, Trichrome) will be sent to the Laszik Laboratory for a central pathology read.  No extra cores will be collected 
specifically for the study at the time of clinically indicated biopsies, but available renal tissue will be sent to Laszik 
Laboratory for mechanistic assays.     
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.   Slide images will be stored for additional analysis, if 
needed. 
11.2.2 Multi-parameter Immunofluorescence and In Situ Hybridization 
The Laszik Laboratory has developed various sets of IF stains on FFPE kidney biopsies using a combination of 
inflammatory cell markers to measure inflammation (1) quantitatively and (2) qualitatively. The total inflammatory load 
is measured by using leukocyte common antigen (LCA) as a marker while the composition of the inflammation in kidney 
biopsies performed during the study.   
The Laszik Laboratory at UCSF has also adapted the RNAScope® in situ hybridization (ISH) platform to analyze FFPE 
biopsies for mRNA expression. This is a novel and highly sensitive ISH technology with very high specificity. To determine 
the cellular source of IL-6 mRNA expression, we have successfully applied multiplex IF stains to the same sections that 
the ISH was performed on. The quality of both the ISH and multiplex IF signals is sufficient to apply computer-assisted 
image analysis tools for quantitation of intragraft IL-6 levels.  
Renal tissue will be collected at 6 months post-transplant for these analyses. 
11.2.3 Gene Expression by Nanostring 
The Laszik Laboratory at UCSF has also developed a novel method of conducting gene expression analyses on FFPE-
embedded kidney biopsy tissue with the NanoString nCounter platform using a customized panel of 800 genes. 
Multivariate regression analysis was carried out to compare log2 transformed gene-expression levels in biopsies with 
acute cellular rejection and acute antibody mediated rejection compared to normal biopsies (12 biopsies in each group). 
They found that cases with ACR and AMR showed increased expression of IL6 compared to normal cases (see Table 6.) 
supporting a role for IL-6 blockade. This technology will be used in our study to measure the gene expression of IL-6 as 
well as other inflammatory cytokines in the IL6/Th17 and costimulation pathways. 
Table 6.  ACR and AMR mRNA Gene Expression 
mRNA 
Log2 fold change 
95% confidence limits 
corrected p-value 
IL6 (AMR vs. Normal) 
2.48 
1.51- 3.44 
<0.0005 
IL6 (ACR vs. Normal) 
2.00 
1.06- 2.94 
<0.0005 
 
 


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11.3 
Urinary Biomarkers of Graft Inflammation and Rejection  
11.3.1 Urine Cytokine Analysis 
The Sarwal Lab has analyzed whole genome expression profiles in 13 independent solid organ transplant cohorts and 
defined a 12-gene common rejection module (CRM) in biopsy tissue for the prediction of acute rejection (Khatri P, 
2013). They have now developed a non-invasive assay for mRNA analysis for the CRM genes in urine (uCRM) which will 
used in this study to assess the impact on graft inflammation of the novel immunosuppressive regimen used in this 
study.   In addition, we will also use urinary CXCL-9 which has been previously validated as a biomarker of immune 
mediated graft injury (Hricik, 2013). 
 


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12.  Biospecimen Storage 
Biological specimens 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 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 participant ID number that could be directly linked to the participant and the participant’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 participant or the participant’s 
medical record by any means. 
Study participants will be informed that they may be approached about additional clinical evaluations or studies that 
have received the full approval of the NIAID as new evaluations are identified.  If additional evaluations are determined 
to be desirable, this protocol (and other appropriate study documents, e.g., the informed consent and the statistical 
analysis plan) will be amended and submitted to the appropriate regulatory authorities, ethics committees, and IRBs for 
approval.  Each participant’s signature will be obtained on the revised informed consent form before additional 
evaluations are performed.  The specimens from these evaluations may be stored up to the end of the contract— 
approximately 5 years, or longer if the contract is extended. 
 


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13.  Criteria for Participant and Study Completion and Premature Study Termination 
13.1 
Participant Stopping Rules and 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” 3 months after the date of a missed study visit (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. 
5. CTCAE Grade 3 or higher injection site reaction for lulizumab pegol (BMS-931699).  
6. Development of delayed hypersensitivity reactions such as serum sickness. 
7. Development of cytokine release syndrome or systemic inflammatory response syndrome. 
8. Acute cellular rejection Banff Grade 2A or higher; acute clinical or subclinical antibody mediated rejection of any 
grade. 
9. TB or any invasive fungal infection. 
10. Development of acute diverticulitis or intestinal perforation 
11. Newly diagnosed malignancy, including PTLD.  A participant who develops completely resectable non-melanoma 
skin cancer can remain in the study. 
12. Development of PML. 
13. Development of COVID-19. 
13.2 
Participant Replacement 
Participants who receive at least 80% of the doses of lulizumab pegol (BMS-931699) and tocilizumab described in the 
study protocol will not be replaced and will be included in the per protocol analysis. Those who receive less than 80% of 
either agent will be analyzed in the intent-to-treat group.  Enrollment will continue until there are 10 subjects in the per 
protocol group.    
13.3 
Follow-up after Early Study Withdrawal 
Participants who are withdrawn from the study for any reason will undergo safety follow up till 1 year post-transplant 
(Appendix 4 Safety follow up schedule).  If a participant is withdrawn from the study and does not wish to follow up till 1 
year post-transplant, then he/she will be asked to complete a final visit.   
13.4 
Study Stopping Rules 
Any of these events will stop trial enrollment and require DSMB review (See Section 14.8.2).  Participants who have 
already received the first dose of the investigational agent will remain on study protocol directed therapy during the 
data review period.      
1. When 5 or more treated participants receive less than 80% of the expected total number of doses of either 
lulizumab pegol (BMS-931699) or tocilizumab  
2. Banff 2A or higher grade acute cellular rejections in any one of the first 5 participants in the first 6 months post-
transplant (Table 7) 


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3. Antibody-mediated rejection (of any grade) in any one of the first 5 participants in the first 6 months post-
transplant (Table 7) 
4. Any TB or invasive fungal infection  
5. Any diagnosis of PTLD or PML 
6. Any graft loss  
7. Any death  
8. Grade 4 infections in two participants 
Additionally, an expedited safety review will also be conducted by the DSMB if there are ≥2 episodes of acute rejection 
in 2 different subjects at any time during the study. During the process of data collection for the safety review and 
analysis by the DSMB, enrollment will be paused in the study, but others study operations can continue including the 
recruitment of potential participants, provision of study drug to previously enrolled participants. 
Table 7.  Rejection Episodes, Threshold of 25% 
Number of 
Subjects 
with Event 
Number of 
Enrolled Subjects 
Total 
Cumulative 
Incidence Rate 
(%) 
Lower 95% Exact 
Confidence Limit (%) 
2 
2 
100.00 
22.36 
3 
3 
100.00 
36.84 
2 
4 
50.00 
9.76 
3 
4 
75.00 
24.86 
3 
5 
60.00 
18.93 
4 
5 
80.00 
34.26 
3 
6 
50.00 
15.32 
4 
6 
66.67 
27.13 
4 
7 
57.14 
22.53 
5 
7 
71.43 
34.13 
4 
8 
50.00 
19.29 
5 
8 
62.50 
28.92 
4 
9 
44.44 
16.88 
5 
9 
55.56 
25.14 
5 
10 
50.00 
22.24 
6 
10 
60.00 
30.35 
*Highlighted and bolded rows meet the threshold for stopping the study; with a threshold of 25% the study would not be stopped 
until at least 3 subjects were enrolled. 
 
 


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14.  Safety Monitoring and Reporting 
14.1 
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 14.5, 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), 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 applies the 
standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5: http://ctep.cancer.gov/reporting/ctc.html. 
14.2 
Definitions 
14.2.1 Adverse Event (AE) 
Any untoward or unfavorable 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 )  
14.2.2 Suspected Adverse Reaction (SAR)  
Any adverse event for which there is a reasonable possibility that the investigational drug [or investigational study 
therapy regimen] 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)). 
14.2.3 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the Investigator Brochure 
or 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.  Please also 
see Section 14.5.2.2. 
“Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in the Investigator 
Brochure or 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)Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
Sponsor [add DAIT/NIAID or other Sponsor, if applicable], it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the 
investigator or Sponsor [add DAIT/NIAID or other Sponsor, if applicable], its occurrence places the subject at 


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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. 
14.2.4 Other Significant Adverse Events  
Overdose, potential drug-induced liver injury (DILI), or cancer must be reported as serious adverse events.   DILI is 
defined as:  
• 
ALT or AST elevation >3 times upper limit of normal (ULN) AND 
• 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) AND 
• 
No other immediately apparent possible causes of ALT or AST elevation and hyperbilirubinemia, including, but 
not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drugs(s) 
known to be hepatotoxic. 
In addition, any confirmed cases of COVID-19 infection of any grade in a study subject must be reported as a Serious 
Adverse Event. If no other serious criteria are met for DILI or COVID-19 infection, the event should be considered of 
medical importance. 
14.3 
Grading and Attribution of Adverse Events 
14.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects according to the criteria set 
forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 5.   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 study team and has been deemed appropriate for the subject population to be studied in this protocol.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE 
manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
Events grade 2 or higher will be recorded on the appropriate AE case eCRF for this study. 
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 


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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. 
14.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) will initially be 
determined by the site investigator and recorded on the appropriate AE 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 in Table 8.  
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 8.  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. 
Attribution assessment for the following study interventions and procedures will be made when a SAE is reported: 
Investigational Products: 
1. lulizumab pegol (BMS-931699) 
 
Immunosuppressive Regimen:  
1. Thymoglobulin 
2. Corticosteroids 
3. Tocilizumab 
4. Belatacept 
5. Everolimus  
6. Mycophenolate Mofetil/Mycophenolic Acid 
 
Study Mandated Procedures and Medications:  
1. Kidney biopsy  
2. Blood Draw  


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14.4 
Collection and Recording of Adverse Events 
14.4.1 Collection Period 
Adverse events will be collected from the time of first study procedure, until a participant completes study participation 
or until 30 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study.  
Donor adverse events occurring within 24 hours after study mandated blood draw will be collected if the AE meets 
serious criteria. 
14.4.2 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 14.3, Grading and Attribution of Adverse Events. 
14.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as described previously 
(Section 14.2, Definitions) on the appropriate AE/SAE eCRF regardless of the relationship to study therapy regimen or 
study procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 30 days after the subject prematurely withdraws (without withdrawing consent)/or is withdrawn 
from the study, whichever occurs first. 
14.5 
Reporting of Serious Adverse Events and Adverse Events 
14.5.1 Reporting of Serious Adverse Events to Sponsor 
This section describes the responsibilities of the site investigator to report serious adverse events to the sponsor via the 
AE/SAE eCRF.  Timely reporting of adverse events is required by 21 CFR and ICH E6 guidelines.  
Site investigators will report all serious adverse events (see Section 0, 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. 
14.5.2 Reporting to Health Authority 
After an adverse event requiring 24-hour reporting (per Section 14.5.1, 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: 
14.5.2.1 
Annual Reporting 
DAIT/NIAID will include in the annual study report to health authorities all adverse events classified as: 


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o Serious, expected, suspected adverse reactions (see Section 14.2.2, Suspected Adverse Reaction, and 
Section 14.2.3, Unexpected Adverse Event). 
o Serious and not a suspected adverse reaction (see Section 14.2.2, Suspected Adverse Reaction). 
o Pregnancies.  
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual IND Report. 
14.5.2.1.1 Frequent Infections in SOT Not Listed as “Expected’ in the Lulizumab IB 
Though infections are frequently observed in immunosuppressed kidney transplant recipients (Abbott, 2004) (Abbott K., 
2001) (Alangaden G. T., 2006) (Alangaden G. , 2007) (Karuthu, 2012) (Parasuraman, 2013) (Pelle, 2007) (Silva, 2010) 
(Veroux, 2008), the Reference Safety Information in BMS’ lulizumab IB (BMS-931699) does not list the occurrence of  
infections as expected SARs.  Given the high frequency of infections anticipated in the trial population, and the inability 
to identify infection causality (lulizumab vs other immunosuppressive drugs), the CTCAE v5.0 Grade 1 to 3 infections 
listed below of any etiology, (Table 9) will be reported in the IND Annual Report.   
Table 9: Frequent Infections in Solid Organ Transplant Recipients 
Most frequent infections in 
kidney transplant patients 
• 
Bacterial Urinary Tract Infection (UTI) 
• 
Bacterial Pneumonia 
• 
Bacteremia 
• 
Bacterial Sepsis 
Nosocomial and surgically 
related infections  
• 
Infection with antimicrobial-resistant species: methicillin-resistant Staphylococcus 
aureus, Vancomycin-resistant enterococci, Candida species (non-albicans) 
• 
Aspiration pneumonia 
• 
Catheter, stent infection 
• 
Wound infection 
• 
Anastomotic leaks, complications and ischemia 
• 
Clostridium difficile colitis 
Activation of Latent Infection 
(relapsed, residual, 
opportunistic) 
• 
Polyomavirus BK infection, nephropathy 
• 
Hepatitis C virus infection 
• 
Hepatitis B virus infection 
• 
Herpes virus infections: Herpes simplex virus, Cytomegalovirus, Varicella-zoster 
virus, Epstein-Barr virus  
Recipient-derived infections 
due to colonization 
• 
Pseudomonas 
Common Viral Respiratory 
Illnesses 
• 
Adenovirus infection 
• 
Rhinovirus infection 
• 
Influenza infection 
• 
Parainfluenza 
• 
RSV 
• 
SARS-CoV-2 infection 
Common Viral GI Illnesses 
• 
Norovirus 
• 
Enterovirus 
• 
Adenovirus 
• 
Rotavirus 
• 
Astrovirus 
• 
Sapovirus 
 
 


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14.5.2.2 
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 14.2.2, Suspected Adverse 
Reaction and Section 14.2.3, Unexpected Adverse Event and 21 CFR 312.32(c)(1)i).  
The sponsor shall report any suspected adverse reaction that is both serious and unexpected in an expedited manner.  
Expedited reporting of infections will comprise  only CTCAE v5.0 ≥ Grade 4 events.  All infections will be reported in the 
AR. 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 or other Sponsor] shall notify the FDA and all participating investigators of expedited Safety Reports within 
15 calendar days; unexpected fatal or immediately life-threatening suspected adverse reaction(s) shall be reported as 
soon as possible or within 7 calendar days.  
14.5.3 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 shall be distributed by 
DAIT/NIAID to all participating institutions for site IRB/IEC submission. 
14.6 
Pregnancy Reporting 
The investigator shall be informed immediately of any pregnancy in a study subject.  A pregnant subject shall be 
instructed to stop taking study medication. These subjects will revert to standard of care immunosuppression.  The 
investigator shall counsel the subject and discuss the risks of continuing with the pregnancy and the possible effects on 
the fetus. Monitoring of the pregnant subject shall continue until the conclusion of the pregnancy.    
The investigator shall report to the SACCC all pregnancies within 1 business day of becoming aware of the event using 
the Pregnancy eCRF.  All pregnancies identified during the study shall be followed to conclusion and the outcome of 
each must be reported.  The Pregnancy eCRF shall be updated and submitted to the SACCC when details about the 
outcome are available.  The SACCC will notify the sponsor and provide medical summaries of all pregnancy reports. 


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Information requested about the delivery shall include: 
o 
Gestational age at delivery 
o 
Birth weight, length, and head circumference 
o 
Gender 
o 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours 
after birth, if available 
o 
Any abnormalities. 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically indicated 
abortion - an SAE shall be submitted to the SACCC using the SAE reporting procedures described above.   
In addition, any pregnancy occurring during participation in CTOT-24 will be reported to the Mycophenolate, Actemra® 
and National Transplant pregnancy registries, as applicable.  
14.7 
Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB as well as the SACCC and sponsor when an “unanticipated problem 
involving risks to subjects or others” is identified, which is not otherwise reportable as an adverse event. 
14.8 
Review of Safety Information 
14.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive periodic reports from the SACCC compiling new and accumulating 
information on AEs, SAEs, and pregnancies recorded by the study site(s) 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.  
14.8.2 DSMB Review  
14.8.2.1 
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.   
14.8.2.2 
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 protocol chair or 
DAIT/NIAID. In addition, any of the events described under Study Stopping Rules (Section 13.4) will trigger an ad hoc 
comprehensive DSMB Safety Review. 
After review of the data, the DSMB will make recommendations regarding study conduct and/or continuation. 


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15.  Statistical Considerations and Analytical Plan 
15.1 
Overview  
This is a pilot, multi-center, single arm, prospective trial using the investigational product, lulizumab pegol (BMS-
931699), in the context of a novel immunosuppression regimen in primary living donor kidney transplant recipients at 
low immunologic risk. The scientific objective is to examine the safety and mechanisms of transplant immune regulation 
via pharmacologic modulation of Tregs. 10 participants will be enrolled and receive the study directed therapy for 1 
year. The primary safety endpoint (section 3.2) is the proportion (95% CI) of participants who remain free of biopsy-
proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria at 6 months after 
transplantation.   
The secondary safety endpoint (section 3.3) is the proportion (95% CI) of participants who remain free of biopsy-proven 
acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria at 12 months after transplantation.  
Mechanistic  endpoints include describing the frequency of circulating Tregs at 3, 6 and 12 months post-transplant,  Treg 
suppressive activity at 3, 6 and 12 months post-transplant using irradiated donor PBMC as stimulators and measuring 
cytokine production in response to anti-CD3 and anti-CD28, alloreactive T cell frequency at 3, 6 and 12 months post-
transplant, and the expression of T cell checkpoint inhibition related genes at 3, 6 and 12 months post-transplant.   
Study participants will continue to be followed for 24 months after transplantation to document safety events. 
15.2 
 Measures to Minimize Bias  
All biopsies will be read by a central pathologist and central reads will be used to assess all stopping rules and endpoint 
analyses.  Although the study is open-label, the mechanistic analyses of recipient specimens at the central laboratories 
will be blinded with respect to the status of the participant in the study. 
15.3 
Analysis Plan 
Statistical analyses of the safety and clinical outcomes will be descriptive for the analysis samples defined below in 
section 15.4.1., employing standard methods for the estimation of binomial proportions and their exact two-sided 95% 
confidence intervals. Statistical analyses of the mechanistic outcomes will be exploratory in nature. The plans for 
statistical analyses of study data will be described in more detail in a Statistical Analysis Plan (SAP). 
15.3.1 Analysis Populations. 
Intent-to-Treat (ITT) sample: all enrolled and transplanted participants. 
Safety sample: all participants that receive at least one dose of either lulizumab pegol (BMS-931699) or tocilizumab. 
Per Protocol (PP) sample: all participants that receive at least 80% of the doses of lulizumab pegol (BMS-931699) and 
tocilizumab as described in section 3.1.   
15.3.2 Analysis of Primary Endpoint   
The primary safety endpoint, defined in section 3.2, will be descriptively summarized with a point estimate and two-
sided, 95% exact binomial confidence interval.  The numerator will be the number of participants that meet the primary 
safety endpoint and will be analyzed using the safety sample.  A sensitivity analysis of the primary endpoint will also be 
performed using the per protocol (PP) sample.  
 


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15.3.3 Analysis of Secondary Endpoint 
The secondary safety endpoint, defined in section 3.3, will be descriptively summarized with a point estimate and two-
sided, 95% exact binomial confidence interval.  The numerator will be the number of participants that meet the 
secondary safety endpoint and will be analyzed using the safety sample.    
15.3.4 Analyses of Exploratory Endpoint(s)/Outcome(s) 
15.3.5 Descriptive Analyses  
Disposition of participants will be summarized in all participants that receive at least one dose of lulizumab pegol (BMS-
931699) or tocilizumab.  Standard descriptive statistics for continuous and categorical variables will be used to 
summarize the following on all participants: 
• 
baseline and demographic characteristics 
• 
use of concomitant medications 
• 
reasons for early termination 
• 
all reported AEs/SAEs 
15.4 
Interim Analyses  
No formal interim analyses of this study are planned. 
15.5 
Sample Size Considerations  
This pilot study is designed to evaluate 10 participants.  Therefore, no formal power and sample size analyses have been 
performed.  However, with 10 evaluable participants receiving at least 80% of the doses of lulizumab pegol (BMS-
931699) and tocilizumab as described in the study protocol, proportions of rejection-free participant and corresponding 
two-sided, 95% exact binomial confidence intervals are shown in Table 10.    
Table 10.  Proportions and Confidence Intervals for 10 Participants receiving at least 80% of the doses of lulizumab pegol (BMS-
931699) and tocilizumab 
Number of Participants Rejection-
Free at 6 Months 
Incidence Rate (%) 
95% Confidence Interval (%) 
0 
0 
(0.0, 30.85) 
1 
10 
(0.25, 44.50) 
2 
20 
(2.52, 55.61) 
3 
30 
(6.67, 65.25) 
4 
40 
(12.16, 73.76) 
5 
50 
(18.71, 81.29) 
6 
60 
(26.24, 87.84) 
7 
70 
(34.75, 93.33) 
8 
80 
(44.39, 97.48) 
9 
90 
(55.50, 99.75) 
10 
100 
(69.15, 100) 


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16.  Quality Assurance and Quality Control 
The sponsor will review site processes for quality management of the study 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. 
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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17. Identification and Access to Source Data 
17.1 
Source Data 
Source documents and source data are considered to be the original documentation where participant 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.  
17.2 
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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18.  Protocol Deviations 
18.1 
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 (Protocol Violation) - A Protocol Violation is a deviation from the IRB approved protocol that 
may affect the participant'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 participant 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 participant 
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 participant's rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
18.2 
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.  
Upon determination that a protocol deviation has occurred, the study staff will a) notify the site Principal Investigator, b) 
notify the NIAID Project Manager and c) will complete a Protocol Deviation form.  The SACCC will prepare and submit 
Protocol Deviation reports to the appropriate review bodies (i.e. DSMB, FDA).  The NIAID Medical Monitor will review 
and approve the action plan that will be implemented as a result of the Protocol Deviation.   


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19. Ethical Considerations and Compliance with Good Clinical Practice 
19.1 
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.  Any 
amendments to the protocol or to the consent materials will also be approved by the IRB before they are implemented. 
19.2 
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 investigator or physician designee listed on the FDA 
1572 will review the consent and answer questions.  The prospective participant will be told that being in the trial is 
voluntary and that he or she may withdraw from the study at any time, for any reason.  All participants (or their legally 
acceptable representative) 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.  
19.3 
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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20. Publication Policy 
The CTOT policy on the publication of study results will apply to this trial. 
 


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Shi, R. e. (2017). Pharmacokinetic, Pharmacodynamic, and Safety Profile of a Novel Anti-CD28 Domain Antibody 
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Treg Modulation with CD28 and IL-6 
         
         Version 5.0/ October 26, 2021 
Appendix 1.  Donor Schedule of Events  
 
 
 
Visit Number
D1
Visit Window
Donor Consent
x
Demographics (Age at Donation, Gender, Ethnicity)
x
Donor HLA Typing (retrospective chart review)
x
CMV IgG (retrospective chart review)
x
Coccidioidomycosis Serology (for subjects from endemic areas)
x
Alloreactive T Cell Frequency Assay (ATF)
Donor Antigen Stimulated Gene Expression (DAGE)
Study Assessments
Local Laboratory Assessments
Central Laboratory Assessments
x


 
Treg Modulation with CD28 and IL-6 
         
         Version 5.0/ October 26, 2021 
Appendix 2. Recipient Schedule of Events  
 


 
Treg Modulation with CD28 and IL-6 
         
         Version 5.0/ October 26, 2021 
Appendix 3.  Recipient Medication Schedule 
 


 
Treg Modulation with CD28 and IL-6 
         
         Version 5.0/ October 26, 2021 
Appendix 4.  Schedule of Events for Reduced Follow Up 
 
Mo 
1
Mo 
2
Mo 
3
Mo 
4
Mon 
5
Mo 
6
Mo 
9
Mo 
12
Wk 
4
Wk 
8
Wk 
12
Wk 
18
Wk 
22
Wk 
26
Wk 
42
Wk 
52
Day  Day  Day  Day  Day  Day  Day  Day  
28
56
84
126
154
182
294
364
Visit Number
RF1 RF2 RF3 RF4 RF5 RF6 RF7 RF8
Visit Window
± 4 
days
± 5 
days
Physical Examination/ Vital Signs
x
x
x
x
x
x
x
x
Review/Collect Concomitant Medications
→
→
→
→
→
→
→
→
Adverse Event/Serious Adverse Event Assessment 
→
→
→
→
→
→
→
→
CMV, EBV by PCR
x
x
x
x
BKV by PCR in serum 
x
x
x
x
x
x
x
CBC (with differential and platelets) 
x
x
x
x
x
x
x
x
T Cell Subsets (to include CD8+ and CD28- counts)
x
x
x
x
PT/INR
x
Basic Chemistry (Na, K, Cl, CO2, BUN, Glucose, Creatinine)
x
x
x
x
x
x
x
x
Liver Tests (ALT, AST, T Bilirubin, D Bilirubin) 
x
x
x
x
Everolimus Level
x
x
x
x
x
x
x
x
Fasting Lipid Panel
x
x
x
x
x
Urine Protein and Creatinine Ratio
x
x
x
x
x
x
x
Local Pathology Results - Graft Histology (When available with standard of care biopsy)
x
x
Multiparameter Flow Cytometry (MFC) - shared specimen 2 x 10 mL Green Top NaHep Tubes
Alloreactive T Cell Frequency (ATF) - shared specimen 2 x 10 mL Green Top NaHep Tubes
Donor Antigen Stimulated Gene Expression (DAGE) - 2 x 10 mL Green Top NaHep Tubes
x
x
In Vitro Treg Suppression (SUP)2 - 4 x 10 mL Green Top NaHep Tubes
x
x
Kidney Solid Organ Response Test by QPCR (KSORT) - 2.5 mL PAXgene Tube
x
x
Donor Specific Antibody (DSA) - 5 mL Red Top Tube  
x
x
Graft Histology (HIS) - Digital Images or Local Case
x
x1
Multi-Parameter Immunofluorescence/ In Situ Hybridization/ RNAScope (DII) - Tissue in Formalin (shared)
Gene Expression in Nanostring nCounter Platform (NANO) - Tissue in Formalin (shared)
Urine Supernatant for Archive (USP) - shared specimen 50-100 ml urine 
Urine Cytokine Analysis - Gene Expression Profiles (UPR) - shared specimen 50-100 ml urine 
1 Tissue should be collected from surveillance and/or for-cause biopsies for DII and NANO whenever available.  Slides should also be sent for central 
reading.  No extra passes specifcally for CTOT-24.
± 3 days
General Study Assessments
Local Laboratory Assessments
Central Laboratory Assessments
Blood Specimens
Renal Biopsy Specimens
Urine Specimens
x
x
x1
x
x
x
x