Randomized Conversion of Calcineurin-Inhibitors(Tacrolimus to Sirolimus),6-24 Months Post Transplant Prednisone-Free Immunosuppression Regimen: Impact of Incidence of Acute Cellular Rejection,Renal Allograft Function & Lymphocytes Function
Phase: PHASE4
Conditions: Renal Transplant Rejection
Sponsor: Northwestern University

 
1
RANDOMIZED CONVERSION OF CALCINEURIN-INHIBITORS (TACROLIMUS 
TO SIROLIMUS) AT 6-24 MONTHS POST TRANSPLANT IN A PREDNISONE-
FREE IMMUNOSUPPRESSION REGIMEN: IMPACT ON INCIDENCE OF 
ACUTE CELLULAR REJECTION, RENAL ALLOGRAFT FUNCTION AND  
LYMPHOCYTES FUNCTION  
 
 
 
 
Prepared by 
Lorenzo Gallon, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2
 
Northwestern University 
Feinberg School of Medicine 
Division of Organ Transplantation 
 
RANDOMIZED CONVERSION OF CALCINEURIN-INHIBITORS (TACROLIMUS 
TO SIROLIMUS) AT 6-24 MONTHS POST TRANSPLANT IN A PREDNISONE-
FREE IMMUNOSUPPRESSION REGIMEN: IMPACT ON INCIDENCE OF 
ACUTE CELLULAR REJECTION, RENAL ALLOGRAFT FUNCTION AND  
LYMPHOCYTES FUNCTION  
 
 
 
 
 
Regulatory Sponsor: 
Lorenzo Gallon, MD 
Associate Professor of Medicine-Feinberg School of Medicine 
Division of Organ Transplantation 
676 N. St. Clair Street, Suite 1900 
Chicago, IL 60611 
(312) 695-4457 
Funding Sponsor: 
Northwestern Memorial Foundation 
676 Building, Room 2050 
Chicago, IL 60611                             
312 926-7788 
 
Pfizer Pharmaceuticals 
Study Product: 
Calcineurin Inhibitors, tacrolimus/Prograf®, 
sirolimus/Rapamune® and Cellcept®/mycophenolate 
mofetil/MMF 
 
 
 
 
 
Date: 
  11/01/2012 
Amendment # 
8 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the Division of Organ 
Transplantation- Feinberg School of Medicine.  No part of it may be transmitted, 
reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 

 
3
Background 
Immunosuppressive therapy with the calcineurin inhibitors (CI) 
Cyclosporine (CsA) and Prograf®/tacrolimus (Tac), have radically changed the 
field of organ transplantation. Ironically, although extensively and effectively used 
for kidney transplantation and other solid organ transplants, CsA and Tac cause 
important adverse renal side effects: acute and chronic renal dysfunction, 
hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular 
acidosis.  
Chronic nephrotoxicity from CI has been implicated as a principal cause of 
post-transplant renal dysfunction 1,2 and it is characterized by an irreversible and 
progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal 
arteries and arterioles 3-5. Early reports in cardiac transplant recipients by Myers 
et al. 6 clearly demonstrated the risk of chronic nephropathy with interstitial 
fibrosis in patients receiving CsA. Furthermore, reports by Goldstein et al. 7 and 
Hornerberger et al. 8 demonstrated that end-stage renal disease developed in 
4.3-6.5% of patients receiving heart transplants after 72-82 months of therapy 
with CsA. Similarly, liver transplant patients maintained on CI have been shown 
to develop chronic kidney disease.  
In a retrospective analysis, Fisher et al. showed a strong association of 
early (3 months post-transplant) kidney dysfunction and the risk of developing 
severe CFR post liver transplant 9. Gonwa et al. 10 reported an18% incidence of 
severe renal dysfunction at 13 years after orthotopic liver transplant and more 
important, the development of ESRD was associated with decreased patient 
survival. The increased mortality in patients with non-renal transplants with 
chronic renal failure was recently confirmed in a larger population-based cohort 
analysis 11.  In this study the incidence of chronic renal failure (CRF) in 69,321 
patients who received non-renal transplants was 16.5% and CRF was associated 
with an increase in mortality by a factor of more than four. Risks factors for 
developing renal failure included: older age, pre-transplant hepatitis C infection, 
hypertension, diabetes mellitus and chronic exposure to CI.  
In renal transplant recipients, complete avoidance of calcineurin inhibitors 
from the time of renal transplant surgery has been associated with increased 
incidence of acute cellular rejection. Conflicting data is available regarding the 
impact of CI avoidance on long term renal allograft function. 
We recently completed a retrospective analysis that evaluated renal 
transplant recipients in which calcineurin inhibitors have been substituted with 
sirolimus at 1 year post transplant and assessed the risk of rejection, patient and 
graft loss and renal allograft function. (Please see attached abstract submitted 
and accepted at the ATC 2007).  
 
From this analysis we concluded that, in a prednisone-free regimen, the 
conversion from calcineurin inhibitors to sirolimus at 1 yr. post-transplant was not 

 
4
associated with an increased risk of acute rejection or graft loss. A trend towards 
a better GFR was noted after conversion from calcineurin inhibitors to sirolimus. 
 
Little is known of the impact of immunosuppressive changes post renal 
transplant on  lymphocytes function.  
 
Research Objective  
The aim of the present study is to prospectively investigate the  
impact of CI conversion (tacrolimus→sirolimus) between 6 and 24 months post-
transplant on the incidence of acute cellular rejection, renal allograft function and 
lymphocytes function. 
 
Primary aim of the study is: 
to investigate the impact of CI conversion (tacrolimus→sirolimus) 
on the incidence of acute cellular rejection.  
 
Secondary aims of the study are: 
i) 
evaluate whether CI conversion (tacrolimus→sirolimus) 
contributes positively or negatively on the renal allograft 
function calculated with e-GFR and proteinuria; 
ii) 
patient and graft survival ; 
iii) 
evaluate if CI conversion impacts on lipid profile, incidence 
of hypertension, malignancies, and opportunistic infections 
and post-transplant DM; 
iv) 
evaluate possible modifications of lymphocytes function 
before and after conversion (tacrolimus→sirolimus) 
v) 
assess tubular toxicity by evaluating urinary biomarkers 
 
Methods  
Immediate Post Transplant Period 
Patients will receive immunosuppressive therapy as follows: 
Induction immunotherapy:  
1) Campath®/alemtuzumab (Anti CD52 humanized 
monoclonal antibody) (30mg IV), on the day of the kidney 
transplant,   
2) methylprednisolone (500 mg IV) on the day of transplant 
and on day 1 (250 mg IV) and 2 (125 mg IV) post-
transplant.  
No further steroid will be given post-transplant unless indicated by the 
following medical conditions: acute renal allograft rejection, renal disease that 
might require the use of steroids and other systemic diseases such as 
rheumatoid arthritis (RA), systemic lupus erthematosus (SLE), asthma. Patients 

 
5
will receive tacrolimus and Cellcept®/mycophenolate mofetil/MMF. The above 
medication regimen is our standard of care for renal transplant patients, and has 
been since 2000. 
 
Randomization 
For this research study, between 6 and 24 months post-transplant we plan 
to prospectively randomize 2:1 renal transplant patients to either: 
 
 
 
-Continue with tacrolimus and MMF or  
 
 
 
-Substitute tacrolimus with sirolimus and continue MMF 
 
A total of 400 pts. are expected to be screened for the randomization and we 
expect to be able to randomize 275 renal transplant patients into this protocol.   
 
Data Collection 
The following data will be collected at the time of randomization: 
 
Recipient demographics- such as age at transplantation, sex and race. 
 
Clinical history- Causes of end-stage renal disease, past medical history 
 
Transplant related information- donor age, cadaveric versus living kidney 
transplant, histocompatibility and cross match data, viral serology, history 
of acute rejection and delayed graft function, use of  induction therapy and 
immunosuppressants, use of  ACEI and/or ARB, level of renal allograft 
function- estimated GFR (e-GFR(12) using MDRD formula, proteinuria. 
 
Peripheral blood leukocytes will be obtained from renal transplant 
recipients for baseline (prior to randomization)  lymphocytes  functional 
activity and characterization of  lymphocytes subpopulations by flow 
cytometry analysis.  
 
Peripheral donor leukocytes (from living donor patients) will also be 
obtained at the time of randomization. These donor leukocytes will be 
used as stimulator cells to study the functional activity of the recipient’s  
lymphocytes function.  
 
 
Post randomization 
The recipients assigned to continue with tacrolimus and MMF will be 
routinely followed at our outpatient Transplant center with monthly labs. In 
addition to the baseline pre-randomization labs, at 6, 12 and 24 months post 
randomization, peripheral blood leukocytes will be obtained to study  
lymphocytes functional activity and to characterize  lymphocytes subpopulations 
by flow cytometry analysis. 

 
6
 
Post randomization, the recipients assigned to switch from tacrolimus to 
sirolimus and continue with MMF will be routinely followed at our Transplant 
center with monthly labs. Furthermore, during the period of conversion from 
tacrolimus to sirolimus, weekly labs will be obtained to monitor renal function and 
bone marrow function. In addition to the baseline pre-randomization labs, and 
labs collected at 6, 12,24, 36, and 48 months post randomization, peripheral 
blood leukocytes will be obtained to study  lymphocytes functional activity to 
characterize  lymphocytes subpopulations by flow cytometry analysis and urine 
will be collected to assess tubular toxicity by evaluating urinary biomarkers. 
 
Both groups of patients will be followed for 4 years post-randomization. In 
addition to monitoring renal allograft function, we will evaluate the incidence of 
acute rejection, patient and graft survival, the impact of CI conversion on the lipid 
profile, the incidence of hypertension, malignancies, opportunistic infections and 
post-transplant DM. 
 
Furthermore, with the peripheral leukocytes obtained at baseline prior to 
randomization and at 6, 12,24, 36, and 48 months post-randomization we will 
investigate possible modifications of lymphocytes function and of the  
lymphocytes subpopulations that might have occurred as a consequence of the 
switch from tacrolimus to sirolimus. 
 
Biopsy 
Chronic nephrotoxicity from calcineurin-inhibitors (CI) has been implicated 
as a principal cause of post-transplant renal dysfunction and it is characterized 
by an irreversible and progressive tubular atrophy, interstitial fibrosis, and focal 
hyalinosis of small renal arteries and arterioles. Furthermore, chronic 
nephrotoxicity from CI has been documented in all non-renal transplants and the 
chronic renal failure secondary to the use of CI has been associated with an 
increase in mortality by a factor of more than four. 
 
The present proposal is to identify those subjects already participating in 
this study who are willing to undergo a kidney biopsy with the aim of evaluating 
renal allograft pathology and renal allograft tissue gene expression profiles of the 
two groups of patients maintained on Tacrolimus/ MMF or switched to SRL/MMF. 
Performing kidney biopsies on the subjects who consent for the procedure will 
allow us to address the effect of immunosuppressive modifications on renal 
allograft pathology at 24 months post randomization.  We also plan to obtain 
renal allograft biopsies at 12 months post-transplant (standard of care) in order to 
establish a baseline parameter for to compare the 24 month sample.   An 
additional biopsy at 48 months will allow us to examine long term results of graft 
function.  We also plan to obtain renal allograft biopsies to be stored in RNA later 
to further extend our knowledge on the effect of CI free immunosuppression on 
gene expression profiles. 
 

 
7
Obtaining renal allograft tissue samples at 24 and 48 months post 
randomization can have potential important ramifications to help explain the 
mechanisms of fibrosis and tubular atrophy typically associated with CI and the 
role of CI elimination with the substitution of SRL. All data will then be analyzed 
comparing gene expression profiles of peripheral blood (Paxgene tubes are 
routinely collected at the different time points as part of the original 
study).  Based on power analysis, we will perform 24 and 48 months post 
randomization biopsies in 70% of the total subjects enrolled in the study 
(approximately 46 subjects from the tacrolimus/MMF group and approximately 93 
subjects from the sirolimus/MMF group). 
 
Donors 
Donor cells are essential in our study to evaluate the effect of different 
immunosuppressive agents alone or in combination on the process of allo-
recognition.  Donor cells from living donors have been being collected (there is a 
specific informed consent form for donors) and will continue to be collected when 
possible. Approximately 275 donors will be recruited for this study.  
 
While the process of obtaining donor cells from living donors is easy, 
recipients of a deceased donor kidney have, by definition, no living donor. 
Consequently, we cannot fully study their immune system. Instead, we would like 
to utilize already stored deceased donor cells to perform the experiments 
originally proposed in our ongoing project. We will use only donor cells from 
deceased donors whose families have consented to research. 
 
Primary Safety Endpoints 
The primary safety endpoints will be assessed on the adverse events 
(AEs) and serious adverse events (SAEs) that are observed throughout the trial. 
 
Treatment of Acute Renal Allograft Rejection 
Initial treatment for biopsy-confirmed acute rejection for all subjects will be 
pulse corticosteroids (methylprednisolone 500 mg IV x 3 days), tapered to a dose 
of 20 mg prednisone by day 7, unless the severity of the initial episode warrants 
use of anti-T-lymphocyte antibody (OKT3 or Thymoglobulin).  Recurrent rejection 
will be treated with anti-T-lymphocyte antibody (OKT3 or Thymoglobulin). 
 
Subject Selection and Withdrawal 
The study will be conducted at Northwestern Medical Faculty 
Foundation/Northwestern Memorial Hospital/ Northwestern University and 
subjects will be recruited from the patients seen in the Division of Solid Organ 
Transplantation.  A total of 400 recipient subjects will be screened and we expect 
that 275 recipients will be prospectively studied. The study will be conducted in 
recipients of living donor kidneys and deceased donor kidneys.  Patients who 
satisfy the following inclusion/exclusion criteria will be eligible for the study. 

 
8
 
Inclusion Criteria 
1) 
Subjects should be adults ≥ 18- ≤ 70 years of age 
2) 
Subjects can be either gender or of any ethnic background 
3) 
Subjects should be single organ recipients (kidney only) 
4) 
Subjects must be able to understand the protocol and provide informed 
consent. 
 
Exclusion Criteria 
1) 
Subjects with ESRD secondary to primary FSGS (focal segmental 
glomerulonephritis). 
2) 
Inability to comply with study procedures 
3) 
Inability to sign the informed consent 
4) 
Subjects with a significant or active infection 
5) 
Subjects who are pregnant or nursing females 
6) 
Subjects with a history of severe hyperlipidemia not controlled with statins,             
patients with at total cholesterol of > 400 mg/dl 
7)  
Subjects with a platelet count <100,000mm3   WBC< 2,000mm3 
8) 
Subjects with severe proteinuria at the time of randomization (>2gm/day) 
9)  
Subjects with more than 2 episodes of acute cellular rejection post 
transplantation will be excluded from this study 
10) 
An estimated GFR<40 cc/min (This will be calculated by MDRD or by 
Cockcroft-Gault formulas, which are both are commonly used formulas for 
estimated GFR.)  
11) 
A history of malignancy during the post-transplant period (other than 
treated basal cell cancer and/or squamous cell cancer) 
12) 
Subjects, who, due to the existence of a surgical, medical or psychiatric 
condition, other than the current transplant, which in the opinion of the 
investigator, precludes enrollment into this trial 
13)  
A history of ACR during the most recent previous 3 months prior to 
randomization 
**Other: prior to approaching any individual who has undergone desensitization 
procedures prior to transplant, we must first check with Dr. J. Friedewald 
 
Subject Recruitment and Screening 
The study will be conducted at Northwestern Medical Faculty 
Foundation/Northwestern Memorial Hospital/ Northwestern University and 
subjects will be recruited from the patients seen in the Division of Solid Organ 
Transplantation.  A total of 400 recipient subjects will be screened and we expect 
that 275 recipient patients to be prospectively studied.  

 
9
Early Withdrawal of Subjects 
When and How to Withdraw Subjects 
 
Subjects may withdraw from the clinical trial at any time for any reason 
with no prejudice to their medical care.  Subjects may also be stopped in the 
study without their consent if their medical care requires they be.  Also, the 
Institutional Review Board (IRB) may stop the study at any time and all subjects 
will be returned to taking tacrolimus and followed for safety.  Subjects will be 
informed of why they are being stopped. 
 
Subjects non-compliant with medications and clinic follow-ups will be 
withdrawn from the study. 
 
Subjects with post-transplant complications such as malignancy or 
infections that require modification or withdrawal of maintenance 
immunosuppression will be withdrawn from the study. 
Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be withdrawn prematurely from the study, an 
attempt will be made to collect at least survival data on such subjects throughout 
the protocol defined follow-up period. Such data is important to the integrity of the 
final study analysis, since early withdrawal could possibly be related to the safety 
profile of the study.  If a subject withdraws consent to participate in the study, 
attempts will be made to obtain permission to record at least survival data up to 
the protocol-described end of subject follow-up period. 
 
Study drugs 
Sirolimus (Rapamune) 
Sirolimus will initially be given at a dose of 2-4 mg orally (PO) daily. The 
dose will be modified to achieve 24 hours trough concentrations of 6-10 ng/ml by 
HPLC assay.  This medication will be given in an open label fashion. The first 
dose of sirolimus will be given at the time of randomization to those patients 
assigned to have tacrolimus switched to sirolimus. 
Mycophenolate Mofetil (Cellcept ) 
 
Cellcept® will be given at a dose of between 750 to 1000 mg PO twice 
daily.  The first dose will be given on Day 0 (day of kidney transplant surgery).  
This medication will be given in an open label fashion.  There will not be any 
change in the dose of Cellcept® at the time of randomization unless indicated by 
medical reasons (i.e. Neutropenia, GI side effects.)  
 
Tacrolimus (Prograf) 
Tacrolimus will be given 1-2 mg PO twice daily, beginning Day 1 (post-
operative Day 1).  The dose will be modified to achieve 12 hour trough 
concentrations of 6-10 ng/ml.  This medication will be given in an open label 
fashion. 

 
10
Alemtuzumab (Campath) 
The first dose of Campath® will be 30 mg given IV, and administered 
intra-operatively during renal transplantation.  This medication will be given in an 
open label fashion and will only be administered while the patient is in the 
hospital in the immediate post-transplant period. 
 
Corticosteroids (methylprednisolone) 
Time:  
 
 
 
Dose 
Preop (Intraop/Day 0) 
 
500 mg 
POD#1 (Day1) 
 
 
250 mg 
POD#2 (Day2) 
 
 
125mg 
POD#3(Day 3) 
 
 
0 mg 
  
Statistical Analysis  
Once the 2 groups of renal transplant patients are identified, two sample t 
tests will be used to compare differences in continuous variables between 
groups; chi square tests will be used to compare differences in discrete variables. 
Multivariable logistic regression analysis will be also performed to identify the 
combination of clinical variable that are significantly associated with the 
development of acute rejection and renal allograft function after conversion from 
tacrolimus →sirolimus. 
 
Safety and Adverse Events 
For the purpose of this clinical trial, the National Cancer Institute Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE), dated December 12, 
2003 will be used to grade all adverse events. 
 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study.  Intercurrent 
illnesses or injuries will be regarded as adverse events.  Abnormal results of 
diagnostic procedures are considered to be adverse events if the 
abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse 
event is any AE that is:  

 
11
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or 
abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is 
normally defined as the period from the initiation of any study procedures to the 
end of the study treatment follow-up.  For this study, the study treatment follow-
up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event will also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until 
the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.   
 
The investigator will notify the drug manufacturer, IRB, and FDA of any 
death or adverse event occurring at any time after a subject has discontinued or 

 
12
terminated study participation that may reasonably be related to this study.  The 
drug manufacturer, IRB, and FDA will also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse 
event if any one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged 
hospitalization should be documented and reported as a serious adverse event 
unless specifically instructed otherwise in this protocol. Any condition responsible 
for surgery should be documented as an adverse event if the condition meets the 
criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor 
surgery are reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery will not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target 
disease of the study, unless it is a worsening or increase in frequency of 
hospital admissions as judged by the clinical investigator. 
Recording of Adverse Events 
At each contact with the subject, the investigator/member of investigator’s 
team will seek information on adverse events by specific questioning and, as 
appropriate, by examination.  Information on all adverse events will be recorded 
in the source document, and also in the appropriate adverse event module of the 
case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though 
should be grouped under one diagnosis. 
 

 
13
All adverse events occurring during the study period must be recorded.  
The clinical course of each event should be followed until resolution, stabilization, 
or until it has been determined that the study treatment or participation is not the 
cause.  Serious adverse events that are still ongoing at the end of the study 
period must be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported 
immediately. 
IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) 
must be submitted to the IRB within 25 days of the investigator/sponsor’s 
knowledge of the event if this event meets UPIRSO criteria.  Copies of each 
report and documentation of IRB notification and receipt will be kept in the 
regulatory binder for the clinical trial.   
FDA Notification by Sponsor 
The principal investigator/sponsor shall notify the FDA and study drug 
manufacturer by telephone or by facsimile transmission of any unexpected fatal 
or life-threatening experience associated with the use of the drug within 24 hours 
of the investigator/sponsor’s knowledge of the event. 
If a previous adverse event that was not initially deemed reportable is later 
found to fit the criteria for reporting, the principal investigator/sponsor will submit 
the adverse event in a written report to the FDA and study drug manufacturer as 
soon as possible, but no later than 15 calendar days from the time the 
determination is made. 
Stopping Rules 
Subjects diagnosed with two acute renal allograft rejection episodes post 
conversion from tacrolimus to sirolimus will be stopped from participating in the 
study and will be switched back to tacrolimus.  
 
Subjects that develop significant side effects secondary to sirolimus (severe 
thrombocytopenia (platelets count <50, 000); severe hyperlipidemia not 
controlled by the use of statins or other cholesterol lowering agents; worsening 
proteinuria or severe de-novo proteinuria will have sirolimus stopped and patients 
will be switched back to tacrolimus 
 
Subjects developing post-transplant infections (i.e., UTI, CMV,HSV, EBV, 
HCV, HBV, HIV,PCP), that in the opinion of the investigator are detrimental to the 
subject and their participation in this research trial, will be stopped from 
participating in this study. 

 
14
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of 
the study. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 10 Study 
Monitoring, Auditing and Inspecting).  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
Internal Data and Safety Monitoring Plan 
An Internal Data and Safety Monitoring Plan, is based on the GCRC and 
some NIH guidelines for Data Safety Monitoring.  All physicians associated with 
the Solid Organ Transplant Department are listed as either the PI or Sub-I’s with 
this study.  The plan approved by the IRB would utilize the statistical analyst 
along with the current QA committee to review the research SAE’s and AE’s.  
 
Data Handling and Record Keeping 
 
Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject 
authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of 
their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts will be made to obtain permission to 
collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
 
Source Documents 
Source data is all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial.  Source data are contained in source documents   
Examples of these original documents, and data records include: hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or 

 
15
magnetic media, x-rays, biopsy slides, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial. 
 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument 
for the study.  All data requested on the CRF must be recorded.  All missing data 
must be explained.  If a space on the CRF is left blank because the procedure 
was not done or the question was not asked, “N/D” is placed in the space.  If the 
item is not applicable to the individual case, “N/A” is written in the space.  All 
entries should be printed legibly in black ink.  If any entry error has been made, 
forensic correction is made by drawing a single straight line through the incorrect 
entry and the correct data is entered above it.  All such changes must be initialed 
and dated.  Errors are not to be erased or covered with “white-out”.  For 
clarification of illegible or uncertain entries, the clarification is written above or 
next to the item, then initialed and dated.   
 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at 
least 2 years after the last approval of a marketing application in their country 
and until there are no pending or contemplated marketing applications in their 
country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  
 
Ethical Considerations 
This study is to be conducted according to US and international standards 
of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly 
constituted independent Institutional Review Board (IRB), (Northwestern 
University Institutional Review Board), in agreement with local legal prescriptions, 
for formal approval of the study conduct.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the investigator/sponsor before commencement of 
this study.  The investigator will place a list of IRB members and their affiliate in 
the regulatory binder for the clinical trial. 
 
All subjects for this study will be provided with a copy of the consent form 
describing this study and providing sufficient information for subjects to make an 
informed decision about their participation in this study. This consent form will be 
submitted with the protocol for review and approval by the IRB for the study.  The 
formal consent of a subject, using the IRB-approved consent form, will be 
obtained before the subject is submitted to any study procedures. This consent 

 
16
form will be signed by the subject and the investigator-designated research 
professional obtaining the consent.  The subject will be given a signed copy of 
the informed consent for their records. 
 
Study Finances 
This study is financed through Northwestern Memorial Foundation, divisional 
funding, and Pfizer Pharmaceuticals (as of March 2008). 
 
Conflict of Interest 
Any investigator who has a conflict of interest with the study (patent 
ownership, royalties, or financial gain greater than the minimum allowable by 
Northwestern University) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee- sanctioned conflict 
management plan prior to participation in this study.  All Northwestern University 
investigators will follow the University conflict of interest policy.  The investigators 
will sign conflict of interest document number ORSP-100, as per Northwestern 
University IRB guidelines. 
 
Subject Stipends or Payments 
All study related laboratory tests (flow cytometry analysis of peripheral 
lymphocyte and functional assays of  lymphocytes will be provided to the subject 
free of charge). Subjects will be provided with reimbursement for parking on 
study related visits. 
 
In addition, because most of the recipients’ donors do not usually need to 
return to this center’s transplant clinic beyond one-year post-transplant, a $25 
stipend will be paid to donors who come to this center solely to consent for this 
research study and allow the collection of the one-time blood sample necessary 
for the study. 
 
Publication Plan 
Findings from this study will be presented at scientific meetings as an 
abstract, a poster or oral presentation.  The findings may also be published in 
peer reviewed professional journals.  No subjects will be identified in any manner 
regardless of the way the results are presented to the scientific community and/or 
public. 
 
 

 
17
References 
 
1 
Bennett WM. Insights into chronic cyclosporine nephrotoxicity. Int J Clin 
Pharmacol Ther 1996, 34:515. 
2. 
Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic 
cyclosporine nephropathy: the Achilles' heel of immunosuppressive 
therapy. Kidney Int 1996, 50:1089. 
3. 
Myers BD: Cyclosporine nephrotoxicity. Kidney Int 1986, 30:964. 
4. 
Puschett JB, Greenberg A, Holley J, McCauley J. The spectrum of 
ciclosporin nephrotoxicity. Am J Nephrol 1990, 10:296. 
5. 
Young EW, Ellis CN, Messana JM, et al. A prospective study of renal 
structure and function in psoriasis patients treated with cyclosporin. 
Kidney Int 1994, 46:1216. 
6. 
Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporine-
associated chronic nephropathy. N Engl J Med 1984, 311:699. 
7. 
Goldstein DJ, Zuech N, Sehgal V, Weinberg AD, Drusin R, Cohen D. 
Cyclosporine-associated end-stage nephropathy after cardiac 
transplantation: incidence and progression. Transplantation 1997, 63:664. 
8. 
Hornberger J, Best J, Geppert J, McClellan M. Risks and costs of end-
stage renal disease after heart transplantation. Transplantation 1998, 
66:1763. 
9. 
Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. 
Chronic renal failure following liver transplantation: a retrospective 
analysis. Transplantation 1998, 66:59. 
10. 
Gonwa TA, Mai ML, Melton LB, et al. End-stage renal disease (ESRD) 
after orthotopic liver transplantation (OLTX) using calcineurin-based 
immunotherapy: risk of development and treatment. Transplantation 2001, 
72:1934. 
11. 
Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation 
of a nonrenal organ. N Engl J Med 2003, 349:931. 
12. 
Stoves J, Lindley EJ et al. MDRD equation estimates of glomerular 
filtration rate in potential living kidney donors and renal transplant 
recipients with impaired graft function. Nephrology Dialysis 
Transplantation 2002; 17:2037-2037