Conditions: Delayed Graft Function
Keywords: kidney failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of this pilot study is to evaluate concentration-controlled everolimus with low dose tacrolimus compared to early conversion to CNI-free regimen and MMF/MPA with standard dose tacrolimus in de novo renal transplant recipients of ECD/DCD kidneys. Given tacrolimus and MMF/MPA is a widely prescribed immunosuppressive regimen in the United States, comparisons of tacrolimus and MMF/MPA regimens to investigational therapies and treatment regimens are needed. Also, considering the fact that ECD/DCD is a fast growing fraction of donors, evaluation of various regimens' effects on rather delicate ECD/DCD kidneys is necessary.

Detailed description:
The purpose of this pilot study is to evaluate concentration-controlled everolimus with low dose tacrolimus compared to early conversion to CNI-free regimen and MMF/MPA with standard dose tacrolimus in de novo renal transplant recipients of ECD/DCD kidneys. Given tacrolimus and MMF/MPA is a widely prescribed immunosuppressive regimen in the United States, comparisons of tacrolimus and MMF/MPA regimens to investigational therapies and treatment regimens are needed. Also, considering the fact that ECD/DCD is a fast growing fraction of donors, evaluation of various regimens' effects on rather delicate ECD/DCD kidneys is necessary.

The primary objective of this study is to evaluate concentration-controlled everolimus and low dose tacrolimus compared to MMF/MPA with standard dose tacrolimus at 24 months post-transplant with respect to the composite efficacy failure rates (treated biopsy proven acute rejection episodes (BPAR), graft loss, death, loss to follow-up) in de novo renal transplant recipients.

The key secondary objective is to compare renal function of the everolimus treatment arms to the MMF/MPA treatment arm at 12 and 24 months post-transplantation. Renal function will be measured by the calculated glomerular filtration rate (GFR), using the MDRD (Modification of Diet in Renal Disease) formula (20).

Arms:
arm 1: Concentration controlled everolimus(ERL) \& Low dose tacrolimus(TAC) + corticosteroid withdraw arm 2: Concentration controlled everolimus \& low dose tacrolimus --\> mycophenolate mofetil (MMF) at Month 3 + corticosteroid arm 3: Standard dose of tacrolimus + mycophenolate mofetil + corticosteroid withdraw

Interventions: intervention 1: Everolimus intervention 2: Tacrolimus intervention 3: Mycophenolate mofetil (MMF/MPA)
Intervention descriptions: intervention 1: One of the immunosuppressants currently being evaluated to replace CNIs in patients with CNI nephropathy is the mammalian Target of Rapamycin (mTOR) inhibitor, Sirolimus. Everolimus is a derivative of Sirolimus and belongs to this class of immunosuppressants, therefore, both drugs have similar side effect profile. The half-life of Everolimus is almost half of Sirolimus (Everolimus 30 hours vs Sirolimus 62 hours), which makes its dose adjustment easier although it would require more frequent dosing. In clinical trials, Everolimus has demonstrated its potential role as a safe alternative in minimizing and/or eliminating CNI such as Cyclosporin A and Tacrolimus . intervention 2: One of the immunosuppressants currently being evaluated to replace CNIs in patients with CNI nephropathy is the mammalian Target of Rapamycin (mTOR) inhibitor, Sirolimus. Everolimus is a derivative of Sirolimus and belongs to this class of immunosuppressants, therefore, both drugs have similar side effect profile. The half-life of Everolimus is almost half of Sirolimus (Everolimus 30 hours vs Sirolimus 62 hours), which makes its dose adjustment easier although it would require more frequent dosing. In clinical trials, Everolimus has demonstrated its potential role as a safe alternative in minimizing and/or eliminating CNI such as Cyclosporin A and Tacrolimus. intervention 3: Control Drug

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
A Pilot Study Comparing the Safety and Efficacy of Zortress 
(Everolimus) With Low Dose Tacrolimus to Early Conversion to 
Calcineurin Inhibitor-Free Regimen and Mycophenolic acid With 
Standard Dose Tacrolimus in Recipients of DCD and Elevated KDPI 
Kidneys 
 
 
 
Assessment of Zortress (EVErolimus) in Recipients of Elevated KDPI and DCD kidneys  
– EVERED trial 
 
 
 
 
 
 
 
 
 
Version number:  
03  
Release date:  
25-FEB-2015 
 
 
 
 
 
 


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Study Personnel/Contacts 
 
Principal Investigator 
Matthew Cooper, MD 
Director, Kidney and Pancreas Transplantation 
MedStar Georgetown Transplant Institute 
MedStar Georgetown University Hospital 
3800 Reservoir Road, NW 
2nd Floor, Main Building 
Washington, DC 20007-2113 
Tel: 202-444-6058 
Fax: 202-444-8193 
Email: Matthew.Cooper@gunet.georgetown.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ............................................................................................................. 3 
List of tables ..................................................................................................................... 5 
List of figures ................................................................................................................... 5 
List of abbreviations ......................................................................................................... 6 
Protocol synopsis.............................................................................................................. 8 
 
1 Background.................................................................................................................... 13 
 
2 Purpose and rationale ................................................................................................... 14 
 
3 Objectives ..................................................................................................................... 14 
3.1 Primary objective......................................................................................................... 14 
3.2 Secondary objectives ................................................................................................. 14 
 
4 Study design .................................................................................................................. 15 
 
5 Population....................................................................................................................... 17 
5.1 Inclusion criteria .......................................................................................................... 17 
5.2 Exclusion criteria ......................................................................................................... 18 
 
6 Treatment........................................................................................................................ 19 
6.1 Investigational and control drugs................................................................................. 19 
6.2 Treatment arms .......................................................................................................... 19 
6.3 Treatment assignment................................................................................................. 19 
6.4 Treatment blinding....................................................................................................... 20 
6.5 Treating the patient..................................................................................................... 20 
6.5.1 Patient numbering .................................................................................................... 20 
6.5.2 Dispensing the study drugs...................................................................................... 20 
6.5.3 Study drug supply, storage and tracking................................................................... 21 
6.5.4 Instructions for prescribing and taking the study drugs............................................ 21 
6.5.5 Permitted study drug dose adjustments and interruptions........................................ 22 
6.5.6 Rescue medication ................................................................................................... 24 
6.5.7 Other concomitant treatments .................................................................................. 25 
6.5.8 Study drug discontinuation and premature patient withdrawal.................................. 27 
6.5.9 Study completion and post-study treatment.............................................................. 28 
6.5.10 Early study termination............................................................................................ 28 
 
7 Visit schedule and assessments .................................................................................... 29 
7.1 Information to be collected on screening failures......................................................... 30 
7.2 Patient demographics/other baseline characteristics.................................................. 31 
7.3 Treatment exposure and compliance.......................................................................... 31 
7.4 Efficacy......................................................................................................................... 31 
7.4.1 Acute Rejection......................................................................................................... 31 
7.4.2 Treated Biopsy Proven Acute Rejection .................................................................. 32 


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7.4.3 Kidney Biopsy........................................................................................................... 32 
7.4.4 Graft Loss................................................................................................................. 32 
7.4.5 Death....................................................................................................................... 32 
7.4.6 Renal function .......................................................................................................... 32 
7.4.7 Premature study treatment discontinuation.............................................................. 33 
7.4.8 Premature study discontinuation............................................................................. 33 
7.4.9 Appropriateness of efficacy measurements ............................................................. 33 
7.5 Safety.......................................................................................................................... 33 
7.5.1 Physical examination............................................................................................... 33 
7.5.2 Vital signs / Weight................................................................................................... 33 
7.5.3 Adverse events........................................................................................................ 33 
7.5.4 Infections.................................................................................................................. 33 
7.5.5 Major Adverse Cardiac Events................................................................................ 34 
7.5.6 Laboratory evaluations............................................................................................. 34 
7.5.7 Hematology............................................................................................................... 34 
7.5.8 Clinical chemistry...................................................................................................... 34 
7.5.10 Urine measurements............................................................................................... 34 
7.5.11 Pregnancy and assessments of fertility................................................................. 35 
7.5.12 Viral serology including CMV and BKV .................................................................. 35 
7.5.13 Appropriateness of safety measurements.............................................................. 36 
7.6 Other assessments...................................................................................................... 36 
7.6.1 Resource utilization................................................................................................... 36 
7.6.2 Health-related Quality of Life..................................................................................... 36 
 
8 Safety monitoring........................................................................................................... 37 
8.1 Adverse events............................................................................................................ 37 
8.2 Serious adverse event reporting.................................................................................. 38 
8.3 Pregnancies ................................................................................................................ 39 
8.4 Data Monitoring Committee ………………………………………………………………...39 
 
9 Data review and database management........................................................................ 40 
9.1 Data Collection ............................................................................................................ 40 
9.2 Database management and quality 
control………….......................................................................................................... 
40 
 
10 Data analysis................................................................................................................ 40 
10.1 Populations for 
analysis ............................................................................................................... 
 
40 
10.2 Patient demographics/other baseline characteristics............................................... 41 
10.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)........................................................................................................................ 41 
10.4 Analysis of the primary objective(s)............................................................................ 41 
10.4.1 Variable .................................................................................................................. 42 
10.4.2 Statistical hypothesis, model, and method of analysis............................................ 42 
10.4.3 Handling of missing values/censoring/discontinuations.......................................... 42 
10.4.4 Supportive analyses................................................................................................ 42 


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10.5 Analysis of secondary objectives............................................................................... 43 
10.5.1 Efficacy (secondary)............................................................................................... 43 
10.5.2 Safety..................................................................................................................... 43 
10.5.3 Health-related Quality of Life.................................................................................. 44 
10.6 Sample size calculation............................................................................................. 44 
10.7 Power for analysis of critical secondary variables .................................................... 44 
10.8 Interim Analysis …………………………………………………………………………….45 
 
11 Ethical considerations................................................................................................... 45 
11.1 Regulatory and ethical compliance............................................................................ 45 
11.2 Informed consent procedures.................................................................................... 45 
11.3 Responsibilities of the investigator and IRB............................................................... 45
 
 
11.4 Publication of study protocol and results................................................................... 46 
 
12 Protocol adherence ...................................................................................................... 46 
12.1 Protocol Amendments............................................................................................... 46 
 
13  Key References .............................................................................................................46 
 
Appendix 1: Clinically notable laboratory values and vital signs....................................... 48 
Appendix 2: Banff 2007 Classification of renal allograft rejection..................................... 49 
Appendix 3: Guidelines for Everolimus and MMF/MPA dose reduction.......................... 50 
Appendix 4: Possible Everolimus drug-drug interactions................................................. 52 
Appendix 5: Possible Tacrolimus drug-drug interactions ................................................ 53 
Appendix 6: Possible MMF/MPA drug-drug interactions ................................................. 54 
 
List of tables 
 
Table 6-1 
Target therapeutic ranges for Tacrolimus C0-h levels in whole 
blood.................................................................................................................................. 25 
Table 7-1 
Evaluation schedule..................................................................................... 30 
Table 13-1 
Criteria for Notable Abnormalities ............................................................ 
48 
Table 13-2 
National cholesterol education program guidelines..................................... 51 
Table 13-3 
Treatment based on LDL cholesterol........................................................... 51 
Table 13-4 
Everolimus Drug Interactions ...................................................................... 52 
Table 13-5 
Drugs that may affect Tacrolimus blood concentrations.............................. 54 
Table 13-6 
Possible MMF/MPA Drug-Drug Interactions............................................... 54 
 
List of figures 
Figure 4-1 
Treatment Scheme........................................................................................ 17 
 
 
 
 
 


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List of abbreviations 
AE  
 
adverse event 
Alk Phos  
alkaline phosphatase 
ALT (SGPT)  alanine aminotransferase 
ANC   
absolute neutrophil count 
ANCOVA  
analysis of covariance 
AST (SGOT) aspartate aminotransferase 
ATG   
antithymocyte globulin 
BID 
 
twice a day 
BKV   
BK Virus: virus isolated from renal transplant patient, initials B.K. 
BPAR  
biopsy proven acute rejection 
CC  
 
creatinine clearance 
CDC   
complement dependent cytotoxicity 
CI  
 
confidence interval 
CIT  
 
cold ischemic time 
CKD   
chronic kidney disease 
CMV   
cytomegalovirus 
CNI   
calcineurin inhibitor 
CRF   
Case Report/Record Form 
CSR   
Clinical Study Report 
DGF   
delayed graft function 
DSA   
donor-specific antibodies 
EC  
 
Ethics Committee 
ECG   
Electrocardiogram 
CRF   
electronic Case Report/Record Form 
ELISA  
enzyme linked immunosorbent assay 
ERL  
Everolimus 
GFR   
glomerular filtration rate 
ICH   
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC   
Independent Ethics Committee 
IMS   
Integrated Medical Safety 
IN  
 
Investigator Notification 
i.v.  
 
intravenous(ly) 
IRB   
Institutional Review Board 
KDPI  
Kidney Donor Profile Index 
LLN   
lower limit of normal 
MDRD  
modification of diet in renal disease 
MMF   
Mycophenolate mofetil 
MPA  
Mycophenolic acid 
NG  
 
nasogastric 
OPTN/SRTR Organ Procurement and Transplantation Network/Scientific Registry of 
Tranplant Recipients 
PCR   
polymerase chain reaction 


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p.o.   
oral(ly) 
QD 
 
once a day 
REB   
Research Ethics Board 
SAE   
serious adverse event 
SF-36  
Medical Outcomes Trust Short Form 36 Health Survey 
SOC  
Standard of Care 
SUSAR  
Serious, unexpected, serious adverse reaction 
TAC  
Tacrolimus 
ULN   
upper limit of normal 
MGTI   
MedStar Georgetown Transplant Institute 
WBC   
white blood cells 
WHO   
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol synopsis 
Title of study: A Pilot Study Comparing the Safety and Efficacy of Zortress (Everolimus) 
With Low Dose Tacrolimus to Early Conversion to Calcineulin Inhibitor-Free Regimen and 
Mycophenolic acid With Standard Dose Tacrolimus in Recipients of  elevated KDPI and 
DCD Kidneys 
Purpose and rationale: The purpose of this pilot study is to evaluate the efficacy and 
safety of everolimus (1.5 mg/day) with standard therapy in recipients of DCD and kidneys 
from donors with Kidney Donor Profile Indices greater than 70 .  
 
Objectives: 
• The primary objective of the study is to evaluate efficacy of Everolimus treatment arms 
compared to Mycophenolate treatment arm with respect to the composite efficacy 
failure rate including treated Biopsy-Proven Acute Rejection (BPAR) episodes, delayed 
graft function, graft loss, and death or loss to follow-up.  The efficacy will be assessed at 
6, 12 and 24 months in recipients of  DCD and KDPI kidneys.  
 
• Secondary: To compare renal function (glomerular filtration rate calculated using the 
MDRD formula) of everolimus with low dose tacrolimus regimen to that of MMF/MPA 
with standard dose tacrolimus regimen at 24 months post-transplant. Other secondary 
objectives are: to compare the incidence of CMV and BKV, new onset diabetes mellitus, 
chronic kidney disease with associated proteinuria, adverse events, serious adverse 
events and tacrolimus associated adverse events. 
Population:  
The study population will consist of a representative group of male and female transplant 
recipients of  DCD and elevated KDPI kidneys, 18-65 years of age undergoing renal 
transplantation.  Approximately 50 patients are planned to be enrolled at MGTI. 
 
Inclusion/Exclusion criteria: 
 
Inclusion criteria 
• Male or female recipients 18-65 years of age undergoing primary or secondary 
kidney transplantation  
• Recipients of primary or secondary cadaveric,  DCD or elevated KDPI kidneys 
(defined as follows) 
• Donor whose heart has irreversibly stopped beating, previously referred to as 
non-heart-beating or asystolic donation 
• Donors whose KDPI is calculated at 70% or greater 
 
• Patients who have given written informed consent to participate in the study 


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Exclusion criteria 
• Cold ischemic time (CIT) > 30 hours 
• ABO incompatible transplants, or T, or B cell crossmatch positive transplant 
• Patients with a known hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes 
• Non-controlled DCD 
• Donor age >70 
• Patients with BMI >35 at baseline before surgery 
• Pregnant or lactating females 
• Females of childbearing potential unwilling to use an effective means of 
contraception or are planning to become pregnant 
• Patients with platelet count <100,000/mm at the evaluation before randomization. 
• Patients with an absolute neutrophil count of < 1,500/mm³ at baseline before surgery 
or white blood cell count of < 4,500/mm³ 
• Patients who are recipients of multiple solid organ transplants 
• Patients who have severe hypercholesterolemia (>350 mg/dL) or 
hypertriglyceridemia (>500 mg/dL). Patients with controlled hyperlipidemia are 
acceptable 
• Patients who have an abnormal liver profile such as ALT, AST, Alk Phos or total 
bilirubin >3 times the upper normal limit 
• Patients who are treated with drugs that are strong inducers or inhibitors of 
cytochrome P450 3A4, such as terfenadine, astemizole, cisapride, erythromycin, 
azithromycin, itraconazole, rifampin or lovastatin 
• Patients who received an investigational drug or who have been treated with a non-
protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to 
randomization  
• Patients with a history of malignancy of any organ system, treated or untreated, 
within the past 2 years whether or not there is evidence of local recurrence or 
metastases, with the exception of localized basal cell carcinoma of the skin  
• Patients who are HIV positive or Hepatitis C (PCR+ only) or Hepatitis B surface 
antigen positive  
• Recipients of organs from donors who test positive for Hepatitis B surface antigen or 
Hepatitis C (PCR+ only) 
• Patients with a history of severe diarrhea, active peptic ulcer disease, or 
uncontrolled diabetes mellitus (Hgb A1c <7.0 %) at baseline  
• Patients who have any surgical or medical condition, which in the opinion of the 
investigator, might significantly alter the absorption, distribution, metabolism and 
excretion of study medication, and/or the presence of severe diarrhea or active 
peptic ulcer 
• Patients who have cardiac failure (e.g. resting dyspnea, symptoms with less than 
ordinary activity, marked limitation of activity) at time of screening or any other 
severe cardiac disease as determined by the investigator 
• Patients with abnormal physical or laboratory findings of clinical significance within 3 
months of randomization which would interfere with the objectives of the study 


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• Patients with any history of coagulopathy or medical condition requiring long-term 
anticoagulation therapy after transplantation  (Low dose aspirin treatment is allowed) 
• Patients with known history of focal segmental glomerulosclerosis 
• Presence of psychiatric illness (i.e., schizophrenia, bipolar, major depression) that, in 
the opinion of the investigator, would interfere with study requirements 
 
Investigational and reference therapy: 
The following pharmaceutical agents will be utilized: 
 
Investigational drug: Everolimus will be provided by Novartis as 0.5 and 0.75 mg tablets.   
Control drug: Either MMF or MPA will be administered.  For this study, either MMF 1,000 
mg BID or MPA 720 mg BID will be allowed since MMF and MPA are considered to be 
therapeutically equivalent. 
 
Investigational or control drug will be administered as a dual immunosuppressive regimen 
with tacrolimus initially. 
 
All patients will receive induction therapy, Campath or Simulect.  Steroids will be 
administered and withdrawn according to our institutional practice. 
 
Study Design: 
After obtaining informed consents, patients will be screened for eligibility and randomized 
within 24h post-transplantation to receive either 1.5 mg of everolimus, 1.5 mg everolimus 
with CNI-free regimen conversion at month 3, or 1g/720mg of MMF/MPA (1:1:1) in 
combination with tacrolimus and corticosteroids. 
 
Antibody Induction Therapy: 
Campath (Alemtuzumab) 30 mg or Simulect (basiliximab) 20 mg will be administered at 
induction of anesthesia along with Solumedrol 500 mg intravenously.   
 
Everolimus treatment arm 1:  
Therapeutic drug monitoring of everolimus and tacrolimus is mandatory throughout the 
study.  From Day 5 on, the everolimus 0.75 mg BID dose will be increased if the trough 
level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL.  Tacrolimus will be initiated at 
0.1 mg/kg/day and adjusted according to our standard practice to achieve target trough 
levels.  From Day 3 on, a whole blood trough concentration will be targeted for 4 to 7 ng/mL. 
From Month 3, the target tacrolimus trough level will be 2 ng/mL to 5 ng/mL.   
 
Everolimus treatment arm 2:  
Therapeutic drug monitoring of everolimus and tacrolimus is mandatory throughout the 
study.  From Day 5 on, the everolimus 0.75 mg BID dose will be increased if the trough 
level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL.  Tacrolimus will be initiated at 
0.1 mg/kg/day and adjusted according to our standard practice to achieve target trough 
levels.  From Day 3 on, a whole blood trough concentration will be targeted for 4 to 7 ng/mL. 
From Month 3 (+/- 2 weeks), tacrolimus will be withdrawn and MMF/MPA will be initiated.   


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MMF/MPA treatment arm 3 (SOC):  
MMF/MPA dose will be initiated as 1 g BID (2 g/day)/720 mg BID (1,440 mg/day). 
Adjustments should be made for adverse events including but not limited to gastrointestinal 
intolerance and a decrease in WBC.  The tacrolimus will be initiated and adjusted to 
achieve a target whole blood trough concentration of 8 ng/mL to 12 ng/mL.  From Month 12 
on, the target tacrolimus trough level will be decreased to 6 ng/mL to 8 ng/mL.  Steroids will 
be administered according to our standard practice.  
 
Efficacy assessments: 
• Composite efficacy failure rate (treated BPAR, graft loss, death or loss to follow-up) 
• Incidence of graft loss, death, or loss to follow-up 
• Calculated GFR (eGFR) using the abbreviated MDRD formula 
 
Other assessments: 
• Laboratory evaluations of kidney function (including serum creatinine) 
• CMV and BKV events  
• Glucose intolerance 
• Everolimus trough blood levels 
• Tacrolimus trough blood levels 
• Association with proteinuria  
• Vital signs 
• Infections and Adverse events 
• Serious adverse events 
• SF-36 Health Survey questionnaires 
Statistical analysis:  
All data will be analyzed using the intent-to-treat approach as well as on-treatment based 
approach.  Comparisons between treatment groups experiencing composite efficacy failure 
and each component will be analyzed with Fisher’s exact test.  The Chi-square and/or one-
way analysis of variance (ANOVA) will be used for acute rejection episodes and creatinine 
levels respectively. 
 
Sample size justification: 
Since this is a pilot study, the sample size estimation method proposed by Julious was 
considered in order to minimize the sample size (14).  Julious proposes to employ sample 
size of 12 per group for a pilot study (14).  Assuming the drop out rate of 20% along with 
the ease of blocked randomization, we propose the sample size of 16 per arm, totaling 48 
patients.  The estimated effect size, α, and β corresponding to this sample size are 0.9, 
0.05 (two-sided), and 0.2 respectively (15).  A block size of 12 along with an allocation ratio 
of 1:1:1 will be employed as a randomization scheme. 
 
 
 
 


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Recruitment/Treatment Periods: 
 
The recruitment period is planned for 24 months. The treatment period is 24 months. A 
biopsy will be required at Month 3, 12 and 24.  Month 3 and 12 biopsies are done according 
to the institutional practice.  No follow-up period is planned.  Discontinued patients will be 
followed for renal function and incidence of efficacy failure at 3, 6, 12, and 24 months post-
randomization.  Serious adverse events will be recorded for 4 weeks after completing 
treatment. 
 
 
 


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1. Background 
Every year, as the waitlist for kidney transplants grows, the number of deaths among 
patients wait-listed also grows.  A serious shortage of this vital organ is reported to be 
responsible for the death of almost half of elderly patients on the waitlist (1).  One approach 
to meet this growing demand is to expand the criteria for kidney donors to ones that have 
been previously unacceptable.  The use of  elevated KDPI  and Donation after Cardiac 
Death (DCD) kidneys is increasing; 1,792 and 1,136 cases respectively, compared to 7,503 
standard kidneys in 2008 (2).  The number of available elevated KDPI kidneys rise every 
year; however, because of “less than ideal” (or delicate, problematic, etc) condition of these 
kidneys, and technical challenges it may impose, many centers do not accept these cases.  
MedStar Georgetown Transplant Institute (MGTI), like many other transplant programs 
nationwide, maintain renal transplant patients on double- maintenance therapy of 
calcineurin inhibitors (CNI), and Mycophenolic acid (MPA) with steroid withdrawal, as well 
as antibody induction therapy.  Although CNIs are one of the most common 
immunosuppressants prescribed, its nephrotoxicity and incidences with polyoma viral 
infection have been reported to be associated with less acute and subclinical rejection (12).  
Because of these side effects, a substantial number of clinical trials were and are being 
conducted to minimize and/or eliminate CNIs: However, no CNI-reduced/free standard 
therapy has been established so far.   
One of the immunosuppressants currently being evaluated to replace CNIs in patients with 
CNI nephropathy is the mammalian Target of Rapamycin (mTOR) inhibitor, Sirolimus.  
Everolimus is a derivative of Sirolimus and belongs to this class of immunosuppressants, 
therefore, both drugs have similar side effect profile (4, 5).  The half-life of Everolimus is 
almost half of Sirolimus (Everolimus 30 hours vs Sirolimus 62 hours), which makes its dose 
adjustment easier although it would require more frequent dosing.  In clinical trials, 
Everolimus has demonstrated its potential role as a safe alternative in minimizing and/or 
eliminating CNI such as Cyclosporin A and Tacrolimus (6-9, 18).   
Although the need for CNI-reduced/free therapy exists for all donor types, a growing 
recipient population of  DCD and elevated KDPI kidneys warrants greater protection from 
nephrotoxicity due to their suboptimal pathology.  In a pilot study conducted at University of 
British Columbia, CNI-free regimen using Sirolimus, MPA and steroids in  high KDPI 
recipients demonstrated significantly better renal function with comparable graft and patient 
survival after a 2-year follow-up, compared to CNI, MPA and steroid therapy (10,11).  So 
far, no study was conducted using Everolimus in  DCD and/or an elevated KDPI population 
(clinical trials.gov). 
Here, we propose to evaluate the efficacy and safety comparing Everolimus in combination 
with CNI-minimization regimen with standard therapy in recipients of / DCD and elevated 
KDPI kidneys.  This study will provide pivotal information on the use of Everolimus in 
growing population of kidney transplant recipients.   
 
 


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Objectives:  
The primary objective of the study is to evaluate efficacy of Everolimus treatment arms 
compared to MMF/MPA treatment arm with respect to primary efficacy failure rate, namely, 
the composite efficacy endpoint, treated BPAR episodes, delayed graft function, graft loss, 
death or loss to follow-up, at 24 months in recipients of  DCD or elevated KDPI kidneys.  
2. Purpose and rationale 
The purpose of this pilot study is to evaluate concentration-controlled everolimus with low 
dose tacrolimus compared to early conversion to CNI-free regimen and MMF/MPA with 
standard dose tacrolimus in de novo renal transplant recipients of / DCD and elevated 
KDPI kidneys.  Given tacrolimus and MMF/MPA is a widely prescribed immunosuppressive 
regimen in the United States, comparisons of tacrolimus and MMF/MPA regimens to 
investigational therapies and treatment regimens are needed.  Also, considering the fact 
that  DCD and elevated KDPI is a fast growing fraction of donors, evaluation of various 
regimens’ effects on rather delicate DCD and elevated KDPI kidneys is necessary. 
3.  Objective  
The objective of this study is to evaluate efficacy of concentration-controlled everolimus in 
combination with low dose tacrolimus and early conversion to CNI-free regimen in de novo 
renal transplant recipients of  DCD and elevated KDPI kidneys.  
3.1 
Primary objective 
The primary objective of this study is to evaluate concentration-controlled everolimus and 
low dose tacrolimus compared to MMF/MPA with standard dose tacrolimus at 24 months  
post-transplant with respect to the composite efficacy failure rates (treated biopsy proven 
acute rejection episodes (BPAR), graft loss, death, loss to follow-up) in de novo renal 
transplant recipients.   
3.2 
Secondary objectives 
The key secondary objective is to compare renal function of the everolimus treatment arms 
to the MMF/MPA treatment arm at 12 and 24 months post-transplantation.  Renal function 
will be measured by the calculated glomerular filtration rate (GFR), using the MDRD 
(Modification of Diet in Renal Disease) formula (20). 
Other secondary objectives include: 
• The incidence of treated BPAR at 12 months 
• The incidence of graft loss at 12 months 
• The incidence of death or loss to follow up at 12 months  
• Incidence of adverse events (AEs) 
• Incidence of serious adverse events (SAEs) 
• Incidence of new onset diabetes mellitus defined as non-diabetic patients before 
transplantation, who are receiving glucose lowering treatment for more than 30 days 


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post-transplant, or with a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with 2 
fasting plasma glucose values ≥ 126 mg/dL (7 mmol/L). 
• Incidence of CMV (viremia or viruria) and BKV (viremia or viruria) 
• Incidence of proteinuria by more than 3 fold or proteinuria reaching 1.5gm/day 
• The comparison of the health related quality of life for patients treated with everolimus 
plus low dose tacrolimus to CellCept plus standard dose tacrolimus 
 
4 
Study Design 
This is a 24 month, Single Center, Open-Label, Randomized, Parallel assignment, non-
inferiority pilot study of safety and efficacy, comparing Everolimus with low-dose Tacrolimus 
(2 arms; 1 arm will involve a conversion to MMF/MPA at month 3) and the standard of care 
(with standard dose Tacrolimus and MMF/MPA) in recipients of  DCD and elevated KDPI 
kidneys.  For this study, either MMF 1,000 mg BID or MPA 720 mg BID will be allowed 
since MMF and MPA are considered to be therapeutically equivalent. 
     All study patients must give a signed informed consent voluntarily prior to any study-related 
activities.  Once a signed consent is obtained, baseline assessment including laboratory 
testing will take place to determine patient’s eligibility to participate in the study.  Baseline 
assessments will occur in the time period starting 3 weeks pre-transplantation and ending 
at the time of transplantation.  Eligible patients will receive Campath or Simulect as an 
induction therapy according to the institutional practice.   
Randomization will occur within 24-hour of transplantation. Fifty patients who meet the 
inclusion/exclusion criteria will be randomized to receive their first dose of study drug (0.75 
mg Everolimus (2 arms) or 1,000/720 mg MMF/MPA)
 within 24 hours of transplantation 
(Figure 4-1).  The first dose of Tacrolimus will be given to all study participants according to 
our standard practice.  Patients will be assigned to either continuation on low-dose 
Tacrolimus (Arm 1), to conversion from low-dose Tacrolimus to Mycophenolate at month 3 
(Arm 2), or to standard therapy with Tacrolimus and Mycophenolate (Arm 3).   
Everolimus and Tacrolimus levels will be monitored throughout the study, and respective 
doses will be adjusted according to the desired trough levels.  Patients will be started on 
0.75mg BID.  Everolimus will be dosed to target trough levels of 3 to 8 ng/ml, starting on 
Day 7.   
Earlier increase in Everolimus level may decrease Tacrolimus exposure, which may lead to 
under-immunosuppression; increasing the risk of acute rejection (16).  Therefore, Day 7±1 
was chosen to initiate the first dose adjustment for Everolimus after careful consideration of 
the half-life of this drug and turnaround time of the trough level availability.  The target 
Everolimus trough level was determined based on the Novartis B201 and B251 studies 
(17).  
For Arms 1 and 2, the initial Tacrolimus dose of 0.03 mg/kg (based on ideal body weight) 
will be given within 24 hours of transplant.  Subsequently, the target Tacrolimus trough 
levels will be 4 to 7 ng/ml from Day 1 to Month 3, and 2 to 5 ng/ml from Month 3 until study 
completion.  For Arm 3, the initial dosing and adjustment will follow the institutional practice.  


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Patients on Arm 2 will be converted between weeks 12 and 14, after the protocol biopsy.  
Conversion of Tacrolimus to MMF/MPA (arm 2) will be done abruptly.  On the day of 
conversion, MMF/MPA 1,000/720 mg will be given twice a day while no Tacrolimus will be 
given.  In other words, there is no overlapping of Tacrolimus and MMF/MPA dosing.     
For Arm 2 (after Month 3) and arm 3, MMF/MPA will be initiated at 1,000/720 mg and 
administered according to our standard practice in corresponding arms.  Adjustment of 
doses may occur due to side effects, and in such cases, adjustment will follow the 
institutional standard practice.   
All groups will be treated with corticosteroids, and prednisone will be tapered off or 
withdrawn according to standard practice.      
For patients experiencing delayed graft function (DGF), Tacrolimus can be held up to 14 
days.  If this period is more than 14 consecutive days or more than two episodes of 7 days 
or longer, study drug discontinuation will be discussed among the study team including 
nephrologists.  In all suspected rejection episodes, biopsy will be performed, and all 
patients will be treated as per our standard practice based on biopsy findings.  
For patients on Arm 1 and 2 experiencing severe side effects such as complications due to 
delayed wound healing and mouth sores, Everolimus can be held up to 14 days.  Patients 
who will require a prolonged discontinuation of Everolimus longer than 14 days will be 
withdrawn, and will be monitored as a regular follow-up until 1 month after the 
discontinuation.  Then, patients will be monitored at a reduced follow-up schedule (Table 
1). 
During the 24 month study period, patients will be monitored according to the study visit 
schedule as listed in Table 1.  The assessment to address the primary objective will be 
performed at month 6, 12, and 24.  No interim analysis is planned.  All withdrawn patients 
will be monitored at a reduced follow-up schedule. 
 
 


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5 
Population 
 
Male and female renal transplantation patients, 18 to 65 years of age, receiving a 
cadaveric, or non-HLA identical living related donor kidney may enter the study. It is 
anticipated that MGTI will enroll approximately 50 patients.  Patients who discontinue the 
study prematurely will not be replaced. 
 
5.1 
Inclusion Criteria 
 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
• Male or female recipients 18-65 years of age undergoing primary or secondary 
kidney transplantation  
• Recipients of primary or secondary cadaveric,   DCD and elevated KDPI kidney 
(defined as follows) 
• Donor whose heart has irreversibly stopped beating, previously referred to as 
non-heart-beating or asystolic donation 
OR  
• Donor with a KDPI > 70 
 
24 mo* 
Arm 1 
ERL 0.75 
mg BID
ERL (tt 3-8 
ng/ml)
ERL (tt 5-8 
ng/ml)
Tac LD 
(tt 4-7 ng/ml) 
Figure 4-1. Treatment Scheme  
Tac  
(tt 8-12ng/ml) 
Tac  
(tt 6-8 ng/ml) 
Tac LD  
(tt 4-7 ng/ml) 
Tac  
(tt 2-5 ng/ml) 
ERL 0.75 
mg BID
ERL (tt 3-8 
ng/ml)
ERL (tt 5-8 
ng/ml)
MMF/MPA 
MMF/MPA 
Arm 2 
Arm 3 
SOC 
TXP 
12 mo* 
Day 7 
3 mo* 
*:     Biopsy       tt: Target Trough level 
LD:  0.1 mg/kg/day  SOC: Standard of Care 


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• Patients who have given written informed consent to participate in the study 
 
5.2 
Exclusion Criteria 
 
• Cold ischemic time (CIT) > 30 hours 
• Patients who are ABO incompatible, or T, or B cell crossmatch positive 
• Patients with a known hypersensitivity to any of the study drugs or to drugs of similar 
chemical class 
• Donor age >70 
• Patients with BMI >35 at baseline before surgery 
• Pregnant or lactating females 
• Females of childbearing potential unwilling to use an effective means of 
contraception or are planning to become pregnant 
• Patients with platelet count <100,000/mm3 at the evaluation before randomization. 
• Patients with an absolute neutrophil count of < 1,500/mm³ at baseline before surgery 
or white blood cell count of < 4,500/mm³ 
• Patients who are recipients of multiple solid organ transplants 
• Patients who have severe hypercholesterolemia (>350 mg/dL) or 
hypertriglyceridemia (>500 mg/dL). Patients with controlled hyperlipidemia are 
acceptable 
• Patients who have an abnormal liver profile such as ALT, AST, Alk Phos or total 
bilirubin >3 times the upper normal limit 
• Patients who are treated with drugs that are strong inducers or inhibitors of 
cytochrome P450 3A4, such as terfenadine, astemizole, cisapride, erythromycin, 
azithromycin, itraconazole, rifampin or lovastatin 
• Patients who received an investigational drug or who have been treated with a non-
protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to 
randomization  
• Patients with a history of malignancy of any organ system, treated or untreated, 
within the past 2 years whether or not there is evidence of local recurrence or 
metastases, with the exception of localized basal cell carcinoma of the skin  
• Patients who are HIV positive or Hepatitis C (PCR+ only) or Hepatitis B surface 
antigen positive  
• Recipients of organs from donors who test positive for Hepatitis B surface antigen or 
Hepatitis C (PCR+ only) 
• Patients with a history of severe diarrhea, active peptic ulcer disease, or 
uncontrolled diabetes mellitus (Hgb A1c <7.0 %) at baseline  
• Patients who have any surgical or medical condition, which in the opinion of the 
investigator, might significantly alter the absorption, distribution, metabolism and 
excretion of study medication, and/or the presence of severe diarrhea or active 
peptic ulcer 
• Patients who have cardiac failure (e.g. resting dyspnea, symptoms with less than 
ordinary activity, marked limitation of activity) at time of screening or any other 
severe cardiac disease as determined by the investigator 


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• Patients with abnormal physical or laboratory findings of clinical significance within 3 
months of randomization which would interfere with the objectives of the study 
• Patients with any history of coagulopathy or medical condition requiring long-term 
anticoagulation therapy after transplantation  (Low dose aspirin treatment is allowed) 
• Patients with known history of focal segmental glomeruloscrelosis 
• Presence of psychiatric illness (i.e., schizophrenia, bipolar, major depression) that, in 
the opinion of the investigator, would interfere with study requirements 
 
6 
Treatment 
The study is open label. Patients will receive either everolimus or MMF/MPA. 
 
6.1 
Investigational and Control Drugs 
• Investigational drug: Everolimus (ERL) will be provided as 0.75 mg tablets (10 
tablets/blister). Additionally, 0.5 mg tablets (10 tablets/blister) will be supplied for dose 
adjustments based on blood levels, tolerability, change in co-medications or clinical 
conditions.  Everolimus tablets are white to yellowish, marbled, round, flat with beveled 
edge.   
• Control drug: Mycophenolate Mofetil (MMF) 
Investigational or control drug will be administered in combination with tacrolimus (TAC).  
 
6.2 
Treatment Arms 
Within 24 hours after transplantation, after having met all inclusion/exclusion criteria, 
patients will be randomized to one of the following treatment groups in a ratio of 1:1:1.  All 
patients will receive Campath or Simulect as induction therapy as well as Solumedrol 
infusion.   
 
Investigational Drug 
 
Arm 1: 
Concentration controlled ERL + Low dose TAC + Corticosteroid withdraw 
 
Arm 2: 
Concentration controlled ERL + Low dose TAC -> MMF/MPA at Month 3 +  
Corticosteroid withdraw 
 
Control Drug 
 
Arm 3: 
Standard dose TAC + MMF/MPA + Corticosteroid withdraw 
 
 
6.3 
Treatment Assignment 
Once a potential study patient is identified and he/she fulfills the inclusion/exclusion criteria 
and the informed consent form is signed, the patient will be entered into the study.   
The patient will be assigned a patient identification number sequentially ( 001, 002 etc)  
Randomization will be performed by the Principal Investigator and/or the clinical research 


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coordinator using randomization envelopes which each have been randomly assigned a 
treatment group. A total of 16 patients will be randomized into each treatment group.  
.  
If a patient fulfills the conditions to be randomized, the study team will notify Research 
Pharmacy staff with the treatment arm  and a subject ID number.  The Research Pharmacy 
will then dispense the assigned drug accordingly. 
 
6.4 
Treatment Blinding 
This is an open-label study.  Therefore, after randomization, the investigator, pharmacist 
and patient will be aware of which treatment is administered to the patient.  The investigator 
should, however, withhold the treatment assignment from the local pathologist interpreting 
the biopsies. The local pathologist will provide the investigator their interpretation for clinical 
management of the patient. 
6.5 
Treating the patient 
6.5.1 Patient numbering 
Each patient is uniquely identified in the study by a patient number. The center number for 
this trial will be 01. Upon signing the informed consent form, the patient is assigned a 
patient number by the investigator.  The first patient is assigned patient number 001, and 
subsequent patients are assigned consecutive numbers (e.g. the second patient is 
assigned patient number 002, the third patient is assigned patient number 003).  Therefore, 
the first patient is identified as 01-001 (e.g. the second patient is identified as 01-002).  A 
patient number will not be reused. If the patient fails to be randomized for any reason, the 
reason for not being randomized will be entered on the Screening Log, and the 
Demography CRF should also be completed. 
6.5.2 Dispensing the study drug 
Novartis will supply packs of open-label study drug Everolimus. 
The study medication packaging has a 2-part label. A unique randomization number is 
printed on each part of this label which corresponds to the treatment arms, according to the 
confidential randomization list. The Research Pharmacy will identify the investigational drug 
to dispense to the patient using the randomization number on the label. Immediately before 
dispensing the investigational drug to the patient, the Research Pharmacy will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number. The randomization number must also be 
recorded on the Randomization Number CRF. 
6.5.3 Study drug supply, storage and tracking 
Study drugs must be received by the Research Pharmacy, handled and stored safely and 
properly, and kept in a secured location to which only the pharmacy staff and designated 
assistants have access. All study drugs should be stored according to the instructions 
specified on the drug labels upon receipt. Clinical supplies are to be dispensed only in 
accordance with the protocol. 


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Medication labels will be in English and comply with the legal requirements of the United 
States of America. They will include storage conditions for the drug. 
 
The Research Pharmacy will maintain an accurate record of the shipment and dispensing 
of study drug in a drug accountability ledger per their SOPs.  Patients will be asked to 
return all unused study drug and packaging at the end of the study or at the time of study 
drug discontinuation.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will destroy all used and unused study drug, packaging, drug labels, per 
research pharmacy policy and SOP and a copy of the completed drug accountability log will 
be retained with study files 
6.5.4 Instructions for prescribing and taking the study drug 
The investigator should instruct the patient to take the study drug exactly as prescribed. All 
dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Study Drug Administration Record CRF. 
Everolimus will be provided only as 0.5 mg or 0.75 mg tablets and will be packaged in 
boxes containing 12 strips of 10 blister packed tablets. The investigator will dispense the 
appropriate number of blister packed tablets to cover each visit and an additional 
medication in case of loss, breakage, or scheduling problems. 
The investigator/the study team is responsible for instructing the patients regarding the 
exact dose and dosing schedule to be followed.  
Medication labels will comply with the legal requirements of the United States of America 
and will be in English. The storage conditions for study drug will be described on the 
medication label. 
Investigational drug 
Patients will take ERL or MMF/MPA simultaneously with TAC twice daily in 12 hour 
intervals and on a consistent schedule with regards to time of day and relation to meals.  
For this study, either MMF 1,000 mg BID or MPA 720 mg BID will be allowed since MMF 
and MPA are considered to be therapeutically equivalent. 
No grapefruit or grapefruit juice should be taken throughout the study.   


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Arms 1 and 2 (Everolimus Groups) 
Initial dosing of ERL will be 1 tablet of 0.75 mg ERL BID (1.5 mg/day) for patients 
randomized into the either one of ERL groups. Additional medication for dose adjustments 
will be provided in 0.5 mg or 0.75 mg tablet strengths. The investigator is responsible for 
instructing the patients regarding the exact dose and dosing schedule to be followed.  At 
Day 7, ERL will be dosed to target trough levels of 3 to 8 ng/ml. At Month 3, ERL will be 
dosed to target levels of 5 to 8 ng/mL. The ERL trough level should remain less than 8 
ng/mL during the whole study duration.   
Patients may require dose adjustments based on tolerability, individual response, changes 
in co-medications, or clinical condition.  Dose adjustments can be made at 4-5 day 
intervals.  
Everolimus and tacrolimus should be taken at the same time and consistently either before, 
during or after meals.   
Arm 3 (MMF/MPA - Control group) 
Initial dosing of MMF/MPA will be 1000/720 mg BID (2/1.44 g/day) respectively for patients 
randomized into the MMF/MPA group.  The dose should be adjusted for gastrointestinal 
intolerance and/or a decrease in WBC.  For GI intolerance, the MMF/MPA dose should be 
reduced to 750 mg BID (1.5 g/day).  If the GI intolerance persists, the dose can be reduced 
to 500 mg BID (1 g/day).  MMF/MPA may be administered with antacids containing 
magnesium and aluminum hydroxides; however it is recommended that MMF/MPA and the 
antacid not be administered simultaneously.  If neutropenia develops, dosing with 
MMF/MPA should be interrupted or reduced and the patient managed appropriately.  The 
investigator is responsible for instructing the patients regarding the exact dose and dosing 
schedule to be followed. 
MMF/MPA and TAC should be taken at the same time and consistently either before, 
during or after meals.  
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
The investigator should promote compliance by instructing the patient to take the study 
drug exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the study drug as prescribed. 
6.5.5 Permitted study drug dose adjustments and interruptions 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and interruptions are permitted in order to keep the patient on study drug. The 
following guidelines should be followed:  
Therapeutic drug monitoring 
Blood for ERL trough levels will be obtained from all patients at the time points indicated in 
Table 7-1.  In the ERL group, therapeutic drug monitoring (TDM) will be mandatory 
throughout the study.  


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On Day 7 after initiation of Everolimus treatment 
For Arm 1 and Arm 2 (ERL groups), the 0.75 mg BID dose will be increased if the ERL 
trough level is < 3 ng/mL, and reduced if the ERL trough level is > 8 ng/mL until Month 3. 
Starting at Month 3, ERL will be dosed to target levels of 5 to 8 ng/mL.  The dose will be 
increased if the ERL trough level is < 5 ng/mL, and reduced if the ERL trough level is > 8 
ng/mL. 
Everolimus dose adjustments should be made on results of the trough levels from the 
hospital laboratory.  Tacrolimus dose adjustments should be made based on the results of 
the trough levels done at the local laboratory.  Tacrolimus trough levels will also be run at 
the hospital laboratory for purposes of the protocol.    
Follow-up ERL and TAC trough levels should be measured 5-7 days after any dose 
adjustment to ERL or TAC to ensure that the recommended troughs are achieved.   
Everolimus and MMF/MPA guidelines for dose reductions for safety reasons: 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. Reasons for study 
drug dose reductions may be for example, a decrease in the white blood cell count or 
platelet count, an increase in cholesterol or triglyceride level, gastrointestinal intolerance or 
other adverse events. Severe and unremitting changes may lead to study drug 
discontinuation.  If study medication (ERL or MMF/MPA) is interrupted for safety reasons 
for 2 episodes of ≥ 7 consecutive days, or more than 21 consecutive days, discontinuation 
of study medication should be discussed with the sponsor.   
During the course of the trial the study drugs will be administered on a BID regimen. Study 
medication will not be provided to patients after they have discontinued the study. 
• Everolimus 1.5 mg treatment groups 
• It is recommended to reduce the dosing from the standard 0.75 mg BID to 0.5 mg 
BID   The dosing should, however, always follow a BID schedule. 
• MMF/MPA 2,000/1,440 mg treatment group 
• MMF/MPA dose can be adjusted for gastrointestinal intolerance or a decrease in 
WBC.  If neutropenia develops (ANC < 1,300/mm3 ) dosing with MMF/MPA should 
be interrupted or reduced, appropriate diagnostic tests performed and the patient 
managed according to local practice.    
 
Additional information for dose adjustments based on laboratory values or other adverse 
events may be found in Appendix 3. 
All changes in dosing of the investigational and control drug must be recorded on the Study 
Drug Dosage Administration Record CRF with date and reason. 
The TAC dose must be adjusted to get C0-h value within the pre-specified target range:  for 
ERL Arm 1: 4 - 7 ng/mL from Day 1 until Month 3, and 2 - 5 ng/mL starting at the Month 3 
Visit; for ERL Arm 2: 4 – 7 ng/mL from Day 1 until Month 3, where the patient will be 
converted from TAC to MMF/MPA; for SOC arm 3: 8 - 12 ng/mL starting at Day 1 until 


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Month 12, and 6 – 8 ng/mL from Month 12 until study completion.   If TAC is held for > 14 
days, study drug should be discontinued and the patient discontinued from the study. 
These changes must be recorded on the Dosage Administration Record CRF. 
6.5.6 Rescue medication 
Treatment of acute rejection episodes 
In all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a 
graft core biopsy must be performed within 48 hours. Biopsies will be read by pathologists 
at MGTI according to the Banff criteria (Appendix 2). Determination of the need for 
treatment will be according to our pathologists’ findings and the overall clinical presentation 
of rejection. All episodes of acute rejection should be treated as per institutional standard 
practice, for example bolus steroids as first line and anti-T-cell antibody for steroid resistant 
rejections. 
The local pathologist will remain blinded to the patient treatment. The results of the biopsy 
read by the pathologists will be listed on the Kidney Allograft Biopsy CRF and will be used 
for patient management of acute rejection. A treated BPAR will be defined as a biopsy 
graded IA, IB, IIA, IIB, or III. The protocol treatment assignment should not be disclosed to 
the pathologists. 
Since patient management is based on local readings, for the analysis of the primary 
efficacy endpoint the pathologists’ biopsy readings will be used. For the analysis of 
secondary efficacy endpoints and for sensitivity analysis of the primary endpoint, the 
pathologists’ readings will be utilized. 
Treatment of patients unable to tolerate oral medication 
If a patient develops a short term intolerance of oral medication after the initial dose of 
study medication, study drug may be temporarily interrupted (Section 6.5.5), alternatively, 
administration of ERL suspension may be carried out via a nasogastric (NG) tube as 
described below. Such administration of study drug via NG tube will be recorded on the 
Immunosuppressive Therapy CRF.  If this period is more than 21 consecutive days or more 
than two episodes of 7 days or longer, study drug discontinuation will be discussed among 
the study team including the study nephrologists. Patients should be returned to oral 
medication as soon as possible after such an interruption of administration of study 
medication by mouth. 
Nasogastric administration of Everolimus (Patients randomized to everolimus) 
Everolimus may be administered via an NG tube until tablets can be tolerated. In order to 
guarantee adequate dosing the following handling instructions for the application of 
everolimus tablets via NG tube should be closely followed: 
• Do not use any special crushing equipment. 
• Pour the tablets into a small (plastic or glass) medicine beaker which contains 10 ml 
drinking water and wait about 10 minutes. 
• Then crush the tablets gently, using the back of a spoon until only small particles are 
visible. 


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• Stir the dispersion gently, pull the dispersion into a syringe and inject into the NG tube. 
• Rinse the beaker (and the spoon) 3 times with 5 ml drinking water and inject into the 
tube. 
• Finally flush the tube with 10 ml drinking water. 
6.5.7 Other concomitant treatments 
6.5.7.1 
Background immunosuppressive therapy 
 
Induction Therapy: 
 
Campath (Alemtuzumab) 30 mg or Simulect (basiliximab) 20 mg will be administered at 
induction of anesthesia along with Solumedrol 500 mg intravenously.  Basiliximab 20 mg 
will also be given intravenously on day 4 post-transplant. 
6.5.7.2 
Initiation and maintenance of Tacrolimus 
It is recommended that the initial dose of TAC be administered according to our standard of 
care practice within 24 hours after reperfusion of the graft.  If patients experience DGF, 
TAC can be held for up to and including 14 days.  However, TAC or study medication (ERL 
or MMF/MPA) must be started within 24 hours post-transplant.  Subsequently, ERL dosing 
will be adjusted according to trough level results from the reference laboratory.  Tacrolimus 
whole-blood trough concentrations will be determined on on all study visits.  Target TAC 
trough levels will be as follows in Table 6-1.  Target therapeutic ranges for TAC C0-h levels 
in whole blood will be assessed at the hospital laboratory for purposes of this protocol.    
If, for any time throughout the study, TAC is held for > 14 days, ERL should be 
discontinued and the patient discontinued from the study.  These patients should be 
followed throughout the remainder of the study to Month 24 on a follow-up schedule.  See 
Section 7.5, Safety assessments, Follow-up of prematurely discontinued patients. 
Table 6-1 
Target therapeutic ranges for Tacrolimus C0-h levels in whole blood 
Randomization Arm 
Time Post-transplant and Corresponding Levels  
 
0 – 3 months 
3 – 12 months 
12 – 24 months 
Arm 1 (Everolimus) 
4 - 7 ng/mL 
2 – 5 ng/mL 
2 - 5 ng/mL 
Arm 2 (Everolimus) 
4 - 7 ng/mL 
0 ng/mL 
0 ng/mL 
Arm 3 (MMF/MPA) 
8 - 12 ng/mL 
8 - 12 ng/mL 
6 - 8 ng/mL 
 
6.5.7.3 
Initiation and maintenance of steroids 
Intravenous and oral steroids will be administered and withdrawn according to the standard 
of practice at our institution.  For the cases that require maintenance steroid therapy, 5-10 
mg/day is allowed per our institutional practice. 
Dosing and changes of steroid dosing will be recorded in the Immunosuppressive 
Therapies CRF. 


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6.5.7.4 
Cytomegalovirus prophylaxis for viremia or viruria 
CMV prophylaxis with Valcyte for a minimum of 90 days is mandatory for all cases at our 
institution. Treatment with ganciclovir, cytomegalovirus hyperimmune globulin, acyclovir or 
valacyclovir will be administered according to our standard practice. All cases of CMV 
positive donors to CMV negative recipients will be treated with Valcyte for 6 months 
according to our standard practice. CMV prophylaxis may also be given following any 
antibody treatment of acute rejection episodes. 
6.5.7.5 
BK viremia or viruria  
Patients with BK viremia or viruria should be treated according to our institutional practice.  
Patients whose BKV treatment includes a reduction of immunosuppression can remain in 
the study if the ERL trough level remains between 3 ng/mL and 8 ng/mL or the MMF/MPA 
dose remains stable.  Patients treated with antiviral therapy can remain in the study.  
6.5.7.6 
Pneumocystis carinii pneumonia prophylaxis 
All patients will be started on trimethoprim-sulfamethoxazole, starting when oral medication 
can be tolerated and continuing for the 3 to 6 months post-transplant, in accordance with 
MGTI standard practice.  Aerosolized pentamidine or dapsone may be administered to 
patients unable to tolerate trimethoprim-sulfamethoxazole.  
6.5.7.7 
Treatment of oral Candida 
For oral thrush (Candida) Nystatin may be used in a swish and swallow regimen, 
alternatively clotrimazole (Mycelex) lozenges/troches may be used.  Routine use of 
systemic agents (i.e. itraconazole, voriconazole and fluconazole) will not be allowed unless 
patients are systemically infected. Administration of azoles may increase blood 
concentrations of everolimus; therefore their use should be minimized.  Particular attention 
to side effects is required (see Appendix 4). 
6.5.7.8 
Lipid lowering medications 
HMG CoA reductase inhibitors (e.g., fluvastatin) are to be administered according to our 
standard practice for the management of hyperlipidemia. Patients requiring treatment with 
this class of medication (especially lovastatin) should be monitored closely for signs of 
rhabdomyolysis, such as, dark-colored urine, fever, muscle cramps, pain, spasm, or 
stiffness, unusual tiredness or weakness. Lipid lowering therapy should be optimized 
before dosage reduction of study medication is considered (see Appendix 4). 
6.5.7.9 
Other medications 
The investigator and the study team will instruct the patient to notify the study site about 
any new medications he/she takes after the start of the study drug.  All medications (other 
than study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug must be listed 
on the Concomitant Medications/Significant Non-Drug Therapies after Start of Study Drug 
CRF. If administered for an adverse event (AE), it should be appropriately cross-referenced 
on the AE CRF. 


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All other immunosuppressive drugs other than those specified in the protocol are 
disallowed except those needed to treat rejection. 
6.5.8      Study drug discontinuation and premature patient withdrawal 
Study drug must be discontinued and the patient withdrawn from the trial if the investigator 
determines that continuing it would result in a significant safety risk for that patient. The 
following circumstances require study drug discontinuation: 
• Withdrawal of informed consent 
• Pregnancy 
• Use of immunosuppressive drugs other than those specified by protocol except those 
needed to treat acute rejection. 
• If the everolimus trough level is ≤ 3ng/mL and cannot be maintained. 
• If tacrolimus is held for more than 14 days. 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
If study drug (ERL or MMF/MPA) is interrupted for longer than 21 consecutive days or more 
than 2 episodes of 7 days or longer, discontinuation of study drug should be considered 
and discussed with the sponsor. 
For patients prematurely discontinuing ERL, a post-study follow-up contact will be made at 
Month 3, 6, 12, 18 and 24 after transplantation, except in patients who prematurely 
discontinue ERL due to death, lost to follow up or patient withdrew consent.  Information 
will be collected on serum creatinine levels, urea, rejection episodes, graft loss/ re-
transplant, 
malignancies, 
opportunistic 
infections, 
patient 
survival 
and 
current 
immunosuppressive therapy.  
Patients who prematurely discontinued ERL will be followed for any serious adverse event 
(SAE) occurring within 30 days following the last dose of ERL.  These SAEs should be 
reported to appropriate regulatory authorities.   
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, on balance, he thinks that continuation would 
be detrimental to the patient’s well-being. 
A Study Drug Discontinuation form should be completed, giving the date and primary 
reason for stopping the study drug. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  If premature withdrawal occurs for any 
reason, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the Study Completion CRF. 
Patients who discontinue study drug prior to the 24 month treatment period will be 
contacted at scheduled months 6, 12, 18 and 24 visits to obtain follow-up information and 
should not be considered withdrawn from the study. Information will be collected on vital 
signs, hospitalizations, rejection episodes, lab results (proteinuria and serum creatinine), 


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graft loss/re-transplant, SAEs, malignancies, opportunistic infections, patient survival, CMV 
infections and immunosuppressive therapy.  In addition, major adverse cardiac events 
(MACE) will be reported during the follow-up period as a Serious Adverse Event (SAE).  
These include acute myocardial infarction, congestive heart failure, percutaneous coronary 
intervention (PCI), automatic implanted cardiac defibrillator (AICD), coronary artery bypass 
graft surgery (CABG), cerebral vascular accident, and peripheral vascular disease. 
Biopsies will be obtained at 3, 12 and 24 months post-transplantation for all patients who 
agree to have this procedure done.  Biopsies will be obtained at 3 months and 1-year post-
transplantation biopsies are performed as a part of standard institutional protocol.  
If patients refuse to return for these visits or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to determine the 
information on survival status, graft loss/re-transplant, rejection episodes, malignancies, 
opportunistic infections and immunosuppressive therapies. Since patients will be followed 
even after discontinuation of study medication, the Study Completion CRF page should 
only be completed at Month 24 or earlier if the patient can no longer be followed, e.g, 
death, lost to follow-up, withdrawal of consent. 
No study drug will be provided for patients who discontinue study medication prior to study 
completion at 24 months. 
See Section 7 for the required assessments of these patients after study drug 
discontinuation. 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 
/the study team will show "due diligence" by documenting in the source documents steps 
taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients.   
6.5.9 Study completion and post-study treatment 
As study completion CRF page should be completed at Month 24.  The investigator/the 
study team also will provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or will refer them for appropriate ongoing care.  No drug will be 
provided after study completion at Month 24. 
6.5.10 Early study termination 
The study can be terminated at any time for any reason by the investigator.  Should this be 
necessary, the patient should be contacted and seen as soon as possible and treated as 
described in Section 7 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to assure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRB of the early termination of the trial. 


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7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “x” the visits when they are 
performed. 
Patients should be encouraged to attend all visits on the designated day.  However visit 
windows will be allowed of ± 1 day for Days 5 and 7, ± 3 days for Days 14, 21, and 28 
visits, ± 1 week for Months 2 – 12 visits, and ± 2 weeks for Months 15 – 24 visits. 
Patients who discontinue study drug before completing the study, and those who 
prematurely withdraw from the study for any reason, should be scheduled for a visit as 
soon as possible, at which time all of the assessments listed for the final visit will be 
performed.  
Patients who discontinue study drug should also return for the assessments indicated in 
Table 7-1, including a blood sample for serum creatinine.  If they refuse to return for these 
assessments or are unable to do so, every effort should be made to contact them or a 
knowledgeable informant by telephone when they refuse to return, and at 6, 12, and 24 
months to determine the information on survival status, graft loss/re-transplant, rejection 
episodes, malignancies, opportunistic infections and immunosuppressive therapies.  Since 
patients will be followed even after discontinuation of study medication, the Study 
Completion CRF page should only be completed at Month 24 or earlier if the patient can no 
longer be followed, e.g. death, lost to follow-up, or withdrawal of consent. 
All patients will be contacted 30 days after the last dose of study medication regarding 
Serious Adverse Event information.  Graft loss, death and malignancy are considered to be 
SAEs and should be entered on a SAE form and reported to the relevant regulatory 
authorities during the follow-up period (beyond 30 days after the last dose). Other Serious 
Adverse Events that are related to study medication as assessed by the investigator should 
also be entered on a SAE form and reported to the relevant regulatory authorities during 
the follow-up period. 
Patients who prematurely discontinue study medication due to death, lost to follow up or 
patient withdrew consent will not have any post-study follow up evaluations. 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last dose of study drug or last completed visit (whichever is later), including final contact 
at the 30-day point. Documentation of attempts to contact the patient should be recorded in 
the patient record. 
 
 
 
 
 
 
 
 
 
 
 


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Table 7-1 Evaluation schedule  
SCR 
OR
 
Day 
Month 
-21- 0 
0
 
1 
3 
5 
7 
14 21 28 
2 
3 
4 
6 
8 
10 12 15 18 21 24
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Background 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transplant information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology  
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Pregnancy test
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Laboratory tests
 
 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
Renal Biopsy
 
X1 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
X2 
 
 
 
X 
Study medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Campath dosage  
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Everolimus trough 
level 
 
 
 
 
 
x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
Tacrolimus trough 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
SF-36
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
Steroid 
Per hospital protocol 
Adverse events
 
As needed 
Allograft rejection  
As needed  
Graft loss record 
As needed 
Dialysis log 
As needed 
Infection log 
As needed 
End of treatment 
As needed 
Comments 
As needed 
Follow-up record 
Completed at 3, 6, 12, 18 and 24 months after the first dose of study medication for patients 
who prematurely discontinued study medication prior to Month 24.   
Renal Biopsies 
The study renal biopsy to be performed at 24 months.  If clinically indicated biopsies were 
done prior to the scheduled biopsies at month 3, 12 and 24, repeat biopsy may not be 
performed.    
OR: Day of transplant 
Windows:  Day 5, 7: ±1 day, Day 14, 21, 28: ±3 days, Month 2-12: ± 1 week, Month 15-24: ± 2 weeks 
Biopsy windows:  ± 4 weeks 
1. 
Pre-transplant biopsy  
2. 
3-month and 1-year post-transplantation biopsies are performed as part of standard institutional protocol. 
7.1 
Information to be collected on screening failures 
Patients discontinuing prior to randomization are considered screening failures.  If a patient 
discontinues before entering the treatment period, only the Demographic information and 


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Screening Log entry with the primary reason for discontinuation should be completed on 
the CRF. 
7.2 
Patient demographics/other baseline characteristics 
After informed consent has been signed and the patient’s eligibility to participate in the 
study has been determined, baseline patient information will be obtained, such as date of 
birth, age, sex, race, full relevant medical history/current medical conditions, information on 
renal transplantation background of recipient and donor and on transplantation procedure.   
Baseline assessments will occur in the time period starting 30 days pre-transplantation and 
ending at the time of transplant. Results of a physical examination at a baseline, include 
pregnancy test (within 48 hours prior to transplantation), vital signs, blood chemistry and 
hematology, urinalysis, including a quantitative protein/creatinine ratio. 
7.3 
Treatment exposure and compliance 
All doses of study medication administered during the course of the study will be recorded 
on the appropriate Study Drug Dosage Administration CRF.  Everolimus trough levels will 
be determined by the designated hospital laboratory.  
Tacrolimus dosing will be entered on a separate TAC Dosage Administration CRF. 
Tacrolimus trough levels will be locally determined and recorded on the relevant CRF.  
Dose adjustments will be made based on local assay results.  
Immunosuppressive therapies will be recorded on a separate Immunosuppressive 
Therapies CRF. Steroids will be recorded until steroid withdrawal occurs in accordance with 
MGTI’s standard practice. 
For all immunosuppressants, the start date, total dose, stop date and reason for 
administration or change are to be provided. If study drug is interrupted due to inability to 
tolerate oral medication and rescue therapy via an NG tube is administered the non-study 
drug immunosuppressive (i.e. crushed ERL suspension) should be recorded on the 
Immunosuppressive medications CRF.  For anti-hypertensive medications,  
Other drugs administered prior to and continuing at start of study medication will be entered 
on the ‘Concomitant medications’ CRF.  
Immunosuppressive drugs administered prior to and continuing at start of study medication 
will be entered on the ‘Immunosuppressive Medications’ CRF.  
Compliance will be assessed by the investigator and/or study personnel using pill counts 
(will be obtained from Investigational Drug Service pharmacy) and information provided by 
the patient. This information should be captured in the source document. 
7.4 
Efficacy 
7.4.1 Acute Rejection 
All suspected acute rejection episodes must be entered on the Kidney Allograft Rejection 
CRF. Suspected rejection episodes ultimately determined to be other conditions should 
also be entered on the Adverse Event CRF. 


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7.4.2 Treated Biopsy Proven Acute Rejection 
Renal biopsies will be collected for all cases of suspected acute rejection.  For all 
suspected rejection episodes, regardless of initiation of anti-rejection treatment, a graft core 
biopsy must be performed within 48 hours. Biopsies will be read by hospital pathologists in 
accordance with institutional practice. The results of the biopsy will be listed on the Kidney 
Allograft Biopsy CRF. The results will be used for patient management for acute rejection 
and for the efficacy analysis. A treated BPAR will be defined as a biopsy graded IA, IB, IIA, 
IIB, or III and which is treated with anti-rejection therapy. 
Reference to acute rejection reporting: 
Report any acute rejection episode on the Kidney Allograft Rejection CRF.  No SAE form 
will be completed.  However, if the episode is unusual in appearance or clinical course, 
and/or graft threatening, an Adverse Events CRF must be completed.  In this particular 
case, a SAE form will be completed when appropriate and submitted according to 
procedure outline in Section 8.2.  
7.4.3 Kidney Biopsy 
Baseline biopsies will be obtained on all patients. 3, 12, and 24 month biopsies will be 
obtained for all patients.  The Month 3 and Month 12 biopsies will be performed as a part of 
the standard of care.  In addition, biopsies should also be collected for any patients with 
suspected viral infection, renal dysfunction, or in all cases of suspected acute rejection.  
Any biopsy result should be recorded on the Kidney Allograft Biopsy CRF.   
7.4.4 Graft Loss 
The allograft will be presumed to be lost on the day the patient starts dialysis and is not 
able to subsequently be removed from dialysis. If the patient undergoes a graft 
nephrectomy, then the day of nephrectomy is the day of graft loss. This will be reported on 
the premature discontinuation of study medication CRF, if medication is discontinued 
prematurely. The reason for graft loss will be recorded on the Graft Loss CRF. If graft loss 
occurs after the patient has discontinued study medication, the appropriate Follow-Up CRF 
should be completed. Graft loss is considered a Serious Adverse Event and should be 
reported on the Serious Adverse Event CRF and the SAE form must be reported to the 
relevant regulatory authorities within 24 hours. 
7.4.5 Death 
In the event of patient death, an SAE form should be completed and reported to the 
relevant regulatory authorities within 24 hours. The events leading to the death should be 
entered on the Adverse Event CRF and the death should be indicated on the premature 
discontinuation of study medication CRF (if death occurs while on treatment) and the Study 
Completion CRF. 
7.4.6 Renal function 
Renal function will be assessed by measuring serum creatinine, by calculated GFR using 
the MDRD formula, and proteinuria as determined by a spot urine protein/creatinine ratio. 


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7.4.7 Premature study treatment discontinuation 
This will be captured on the Premature Discontinuation of Treatment CRF. Dates and 
reasons must be provided. 
7.4.8 Premature study discontinuation 
This will be captured on the Study Completion CRF.  Reason must be provided. 
7.4.9 Appropriateness of efficacy measurements 
The efficacy variables selected are standard for this indication/patient population. 
7.5 
Safety 
7.5.1 Physical examination 
A through physical examination will be performed during the baseline period and at the 
Month 12 and 24 visits.  
Information for all physical examinations must be included in the source documentation. 
Significant findings that are present prior to the start of study drug must be included in the 
Relevant Medical History/Current Medical Conditions screen on the patient’s CRF. 
Significant findings made after the start of study drug which meet the definition of an 
Adverse Event must be recorded on the Adverse Event screen of the patient’s CRF. 
7.5.2 Vital signs / Weight 
Vital signs (radial pulse rate, blood pressure and weight (to the nearest 0.1 kilogram [kg] in 
indoor clothing) will be recorded at baseline, prior to the first morning administration of 
study medication, and at each subsequent visit.  Systolic and diastolic blood pressure will 
be measured in accordance with MGTI’s standard practice. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
7.5.3 Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered 
to be related to study drug.  Medical conditions/diseases present before starting study drug 
are only considered adverse events if they worsen after starting study drug.  The 
occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study (See Section 8.1) 
7.5.4 Infections 
Infections should be recorded with the start and end date, type of infection, and 
medications used on infection log CRF. If medications are used to treat the infection, the 
name of the medication must be entered on the Concomitant Medications CRF. If the 
patient is hospitalized, an SAE form must be reported. 


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7.5.5 Major Adverse Cardiac Events 
Major Adverse Cardiac Events will be considered an SAE and will be entered in the 
adverse events CRF. These include acute myocardial infarction, congestive heart failure, 
percutaneous coronary intervention (PCI), automatic implanted cardiac defibrillator (AICD), 
coronary artery bypass graft surgery (CABG), cerebral vascular accident, and peripheral 
vascular disease 
7.5.6 Laboratory evaluations 
All laboratory tests will be done at the hospital affiliated laboratory.  Laboratory samples 
should be drawn prior to administration of the morning dose of both TAC and study 
medication. All samples will be drawn with the patient in the fasting state (more than eight 
hours after the last meal) if possible. Non-fasting blood samples will be clearly identified. 
Therapeutic drug monitoring (TDM) will be mandatory throughout the study. The transplant 
team will be alerted when ERL trough levels are < 3 ng/mL or > 8 ng/mL to adjust the dose 
of ERL.  All ERL dose adjustments will be made based on these results.   
Blood samples for TAC trough levels from the hospital affiliated laboratory will be used to 
obtain tacrolimus through levels.  Adjustments should be made for TAC using the trough 
levels from the laboratory. 
Extreme values will be reported to the investigator and/or the study team for immediate 
action as per standard of care.  The Investigator is asked to comment on these 
abnormalities if they are clinically significant in the CRF.  
 
7.5.7 Hematology  
Hematology will include platelets, hemoglobin, red blood cell count, white blood cell count, 
and absolute neutrophil count with differential to be measured at Baseline, on Day 1, 3, and 
5; Weeks 1, 2, and 4; Months 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24.  
7.5.8 Clinical chemistry 
Sodium, potassium, chloride, calcium, magnesium, inorganic phosphate, blood urea 
nitrogen, creatinine, glucose, uric acid, AST, ALT, alkaline phosphatase, total bilirubin, total 
cholesterol, HDL, LDL, triglycerides, CPK, lipase, and amylase will be assessed at hospital  
affiliated laboratory.  The blood chemistry will be measured at Baseline, on Day 1, 3, and 5; 
Weeks 1, 2, and 4; Months 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24.  LDL and HDL will be 
measured only at Baseline, Week 4, Months 6 and 12. 
Random or fasting plasma glucose values as needed to rule out or confirm suspected new 
onset of diabetes.  
If the CPK level is above the upper limit of normal, CK-MB fraction will be measured.   
If the total bilirubin concentration is greater than 1.5 times the upper limit of normal, total 
bilirubin should be differentiated into the direct and indirect reacting bilirubin.  


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7.5.9 Urine measurements  
Measurements will be taken for glucose, protein and quantitative protein/creatinine ratio by 
a mid-stream urine sample at Baseline, Day 1, 3, and 5; Weeks 1, 2, and 4; Months 2, 3, 4, 
6, 8, 10, 12, 15, 18, 21, and 24.  
7.5.10 Pregnancy and assessments of fertility 
Any pregnancy that occurs during study participation should be reported to the relevant 
regulatory authorities and the drug manufacturer. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects or congenital abnormalities.  
Any female patient that becomes pregnant after the start of study medication should be 
discontinued and the patient switched to standard treatment.  All pre-menopausal women 
who are not surgically sterile will have a serum pregnancy test at screening, and a urine 
pregnancy test if suspect, and at the end of study visit. Pre-menopausal women will also 
undergo pregnancy tests at 6 months, 12 months and the 24 months. A positive urine 
pregnancy test requires immediate interruption of study medication until a pregnancy is 
confirmed. If confirmed, the patient must be discontinued from the trial.   
7.5.11 Viral serology 
Viral serology will be assessed at screening and Months 3, 6, 12, 18, 24. All patients will be 
tested for hepatitis B surface antigen (HBsAg), Hepatitis C, CMV, BKV and HIV at baseline 
per standard of care.  Earlier tests  12 months, are acceptable. Any patients with a 
positive HBsAg, positive hepatitis C serology, or HIV will be excluded. If results are not 
available prior to randomization, the patient may be included. If results are later found to be 
positive, the patient will subsequently be dropped from the study and administered the 
standard care at MGTI. 
Premature discontinuation from study medication 
For those patients who prematurely discontinue study medication prior to Month 24, the 
Premature Discontinuation of Treatment CRF should be completed.  The date of last dose 
and reason for discontinuation of study medication should be clearly documented and all 
subsequent post-study follow-up evaluation forms should be completed at the appropriate 
time points.  Patients who prematurely discontinue study medication due to death, lost to 
follow up or patient withdrew consent will not have any post-study follow up evaluations. 
Premature study discontinuation and follow-up 
For all patients prematurely discontinuing study medication, a post-study follow-up contact 
will be made at 6, 12, and 24 months after transplantation, except in patients who 
prematurely discontinue study medication due to death, lost to follow up or patient withdrew 
consent.  Information on allograft and patient survival, malignancies, rejection episodes, 
and current immunosuppressive regimen will be collected.  A blood sample will also be 
collected for serum creatinine.  All patients will be contacted 30 days after the last dose of 
study medication regarding Serious Adverse Event information.  Graft loss, death and 
malignancy are Serious Adverse Events and should be entered on a SAE form and 


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reported to the relevant authorities during the follow-up period (beyond 30 days after the 
last dose). Other Serious Adverse Events that are related to study medication as assessed 
by the investigator should also be entered on a SAE form and reported to the IRB and other 
relevant authorities during the follow-up period. 
Clinically notable laboratory abnormalities present at the time of discontinuation will be 
followed until the abnormality is no longer considered clinically significant.  
This will be captured on the Study Completion CRF. Reason must be provided. 
7.5.12 Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
7.6 
Other assessments 
7.6.1 Resource utilization 
For resource utilization, all relevant information about initial hospitalization for initial 
transplantation and all follow-up hospitalizations post transplantation (in the transplant 
study center or all other centers, if any) will be recorded.  The hospitalization data will 
include the main reason for admission, duration of hospitalization and number of days by 
level of care.  All attempts should be made to collect RU variables in all patients throughout 
the duration of the study in order to avoid selection bias. There may also be circumstances 
when the collection of such data after completion of the study may be warranted.  These 
data will be collected in the Hospitalization CRF and will be presented in a separate report.   
7.6.2 Health-related Quality of Life  
The SF-36 is a widely used instrument to measure generic health status.  It is a 36-item 
questionnaire that yields an 8-scale health profile as well as summary measures of 
individual patients.  It has proven useful in monitoring generic and specific populations, 
comparing the relative burden of different diseases, differentiating the health benefits 
produced by different treatments, and in screening individual patients.  The purpose 
collecting SF-36 data in this study is to compare the final health status of those on the ERL 
and low dose TAC arm of the trial to those on the ERL and low dose TAC which converts to 
MMF/MPA arm and to those on the MMF/MPA and standard dose TAC arm of the trial.   
The eight profiles (scales) are: bodily pain, general health, vitality, mental health, physical 
functioning, role-physical, role-emotional and social functioning.  The two summary 
measures are physical health and mental health. 
Patients must complete the questionnaire before other clinical assessments at any given 
visit. The SF-36 can be administered in 5 to 10 minutes with a high degree of acceptability 
and quality.  An appropriate person should be designated to facilitate self-administration.  
The administrator should not influence but can answer questions and address concerns 
and ensure that the questionnaire is filled out correctly and completely. 
Completed questionnaires will be reviewed and examined by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. The 


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investigator should review not only the responses to the questions in the questionnaires but 
also for any unsolicited comments written by the patient. 
If the occurrence of AEs or SAEs is confirmed, the physician must record the events as per 
instructions given in Section 7.5.1 of the protocol. Investigators should not encourage the 
patients to change the responses reported. 
8 
Safety monitoring 
8.1 
Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered 
to be related to study drug. Study drug includes the investigational drug under evaluation 
and the comparator drug or placebo that is given during any phase of the study. Medical 
conditions/diseases present before starting study drug are only considered adverse events 
if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. All adverse events must be recorded on the Adverse 
Events CRF with the following information: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  


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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Protocol exempted events: Unusually severe rejection episodes 
Acute rejections are considered protocol exempted events.  They should not be reported 
simply because they result in hospitalization thus meeting the criteria for SAEs.  Acute 
rejection episodes will therefore not be routinely expedited to health authorities.  However, 
acute rejections should be reported as SAEs if they are unusual in appearance, clinical 
course and/or are graft threatening. 
Graft loss, death and malignancy are serious adverse events and should be entered on a 
SAE form for 30 days after last dose of study medication, including patients that 
prematurely discontinue from the study.   
Unlike routine safety assessments, SAEs are monitored continuously and have 
special reporting requirements; see Section 8.2. 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the adverse event should be recorded 
on the adverse event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can 
be found in the package inserts. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
8.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient begins taking study drug and until 30 days after the patient has stopped study 
participation must be reported to relevant regulatory authorities and IRB within 24 hours of 
learning of its occurrence.  Recurrent episodes, complications, or progression of the initial 
SAE must be reported as follow-up to the original episode, regardless of when the event 
occurs.  This report must be submitted within 24 hours of the investigator receiving the 
follow-up information.  An SAE that is considered completely unrelated to a previously 
reported one should be reported separately as a new event. 
The investigator must assess the relationship to study drug, complete and submit the SAE 
report forms. The original copy of the SAE reports and submission confirmation must be 
kept with the case report form documentation at the study site. 


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Follow-up information is sent to the same person to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether 
the blind was broken or not, and whether the patient continued or withdrew from study 
participation.  
 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
relevant regulatory authorities and drug manufacturers within 7 days of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications.  Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
8.4 
Data Monitoring Committee 
A data monitoring committee (DMC) will be instituted to review safety and efficacy.  The 
DMC will be comprised of at least 2 physicians, a pharmacist and a statistician not affiliated 
with the study.  They will be selected based on their scientific and clinical background and 
have expertise in kidney transplantation.   
The DMC will meet to review the available safety data after 12, 24, 36 and 48 patients 
enrollment to the study.  Following the completion of the enrollment, the DMC will meet bi-
annually and/or at the request of PI.  The DMC will review the clinical and laboratory safety 
data and make recommendations regarding the further conduct of the study with respect to 
safety.  If a safety concern is identified, the DMC will determine whether or not dosing 
should be continued or modified depending on the event and occurrence of other adverse 
events. 
Decisions based on the recommendations of the Board will take into account the potential 
risks and benefits associated with continuing enrollment of patients in the study.  The final 
decision with respect to the modification of the protocol will be made by the PI after having 
discussion with a selected group of experts.  In the event of study termination, all health 
authorities, IRB and DMC would be notified of the termination within one business day.  
9 
Data review and database management 
9.1 
Data collection 
The study staff will enter the study-related patient data required by the protocol into the 
study-specific electronic Case Report Forms (CRFs) that conforms to 21 CFR 312.62 
requirements.  Once the content of the electronic CRFs are reviewed for accuracy against 
the patient record, the data will be entered into a Georgetown University hosted HIPAA 
compliant electronic Web-based database (REDCap). 


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9.2 
Database management and quality control 
A designated study staff member will act as a data manager, will check for data 
discrepancies and, by generating appropriate queries, allow the data to be confirmed or 
corrected. The Investigator must certify that the data entered into the CRFs are complete 
and accurate.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.   
Laboratory samples will be processed at the hospital affiliated laboratory and the results will 
be available via the hospital and clinic information systems electronically.   
At the conclusion of the study, unused study drugs will be returned to Novartis and the 
occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis (Section 10).  Any changes to the database 
after that time can only be made by joint written agreement between the investigator and a 
contracted statistician. 
10 
Data analysis 
A contracted statistician at the Georgetown-Howard Center for Clinical and Translational 
Research will perform the statistical analysis.   
10.1 Populations for analysis 
Full Analysis Set (FAS; intent-to-treat) consists of all randomized patients who received at 
least one dose of study drug.  Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization. 
 
Safety Set (SS) consists of all patients who received at least one dose of study drug and 
had at least one post-baseline safety assessment.  Patients will be analyzed according to 
treatment received. Of note, the statement that a patient had no adverse events also 
constitutes a safety assessment. 
 
Per Protocol Set (PPS) consists of all FAS patients without a major protocol violation and/or 
deviation, and who have completed the study.  Analysis will be conducted in this set as 
well. 
 
Efficacy analysis will be performed on the FAS, as defined above, with patient data 
analyzed according to the treatment groups to which they were randomized.  It will also be 
done on the SS and PPS with patient assignment as treatment actually received.  


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10.2 Patient demographics/other baseline characteristics 
Demographic and other baseline characteristics will be recapitulated by treatment group.  
Unless otherwise specified, continuous variables will be summarized with the number of 
non-missing observations, mean, median, standard deviation, minimum and maximum.  
Discrete and categorical variables will be summarized by frequencies and percentages.   
10.3 Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
The average daily dose of ERL, MMF/MPA, and TAC will be recapitulated within the 
defined period by treatment group. 
On calculating dosage averages over a time period, zero doses will be used for periods of 
study medication interruption regardless of the reason (i.e. suspected drug toxicity, adverse 
events, non-compliance, etc). 
The reasons for ERL, MMF/MPA, or TAC dose adjustment will be assessed at certain 
periods and summarized by treatment group. 
 
The duration of exposure for ERL, MMF/MPA and TAC, measured in days since the first 
administration of the study medication, will be summarized. Note that duration of exposure 
includes periods of temporary interruption of respective medication. 
 
Summary statistics will be presented for total daily dose of corticosteroids, expressed in 
doses equivalent to prednisone. These calculations will include any steroids used for the 
treatment of rejection episodes.  
 
Other immunosuppressive therapies will be summarized by WHO drug names by treatment 
group. The tables will show the number of patients receiving these drugs at any time, and 
percentages. 
 
All non-immunosuppressive medications or non-drug therapies will be grouped into prior 
and concomitant medications and summarized separately by treatment group. 
All of the analysis will be performed on the SS. 
10.4 Analysis of the primary objective(s) 
Patients’ data will be summarized with respect to demography and baseline characteristics, 
including information on donor and recipient and on transplant procedures, for SS as 1 
group, for FAS and PPS by the randomized treatment groups. 
Efficacy will be analyzed on the pooled SS, and on FAS and PPS comparing the 3 
treatment groups. Efficacy variables include BPAR, graft loss, death and combinations 
thereof. 
Safety and tolerability will be assessed in terms of treatment-emergent adverse events, 
laboratory tests and vital signs measurements.  Safety analyses will be conducted on the 
SS, and on FAS comparing the 3 treatment groups. 


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10.4.1 Variable 
 
The primary efficacy variable is the composite efficacy failure rate (treated BPAR, graft loss, 
death or loss to follow-up) at 6, 12 and 24 months post-transplant.  The secondary variable 
is renal function assessed as eGFR during the first 24 months post-transplantation, 
determined by the MDRD formula.  Other secondary variables include the incidences of 
CMV and BKV, new onset diabetes mellitus, chronic kidney disease with associated 
proteinuria, adverse events, serious adverse events and tacrolimus associated adverse 
events. 
10.4.2 Statistical model, and method of analysis 
The primary analysis will be the comparison of ERL with TAC based on FAS using an 
analysis of variance (ANOVA) model. Stratification factors applied at randomization will be 
included as binary factors in the ANOVA model in addition to treatment group.  
10.4.3 Handling of missing values/censoring/discontinuations 
 
All efforts will be made to complete data except for cases of loss to follow-up, graft loss or 
death.  Loss to follow-up, graft loss or death is defined as one whose last day of contact is 
prior to Month 24 and who did not experience graft loss or death.  The missing data will be 
assumed to be missing at random except for above cases.  The sensitivity analysis based 
on a complete case analysis and a missing data analysis will be conducted if imputed data 
exceeds 5 % of total data.   
 
The modified last observation carried forward (LOCF) will be applied if eGFR has not been 
obtained at study visits.  Only in cases where the observed measurement was obtained 
within 6 weeks of the expected study visit, modified LOCF will be employed to impute 
missing data.  In other words, missing data will be replaced with data from out-of-window 
visit occur within 6 weeks of scheduled visit.  None of data will be carried forward beyond 6 
weeks, and will not be imputed by other methods.  For the FAS analysis, this will be done 
regardless of whether a patient discontinued study medication or not. For patients 
experiencing graft loss, the last value before dialysis or re-transplantation will be used.   
10.4.4 Supportive analyses 
Event rates will be compared between treatment groups using the Cochran-Mantel-
Haenszel test, stratified by induction therapy. 
 
A logistic regression analysis of the primary efficacy variable will be performed. The odds 
ratio for treatments, 95% confidence interval for the odds ratio, and p-values (if applicable) 
will be reported based on the fitted model. 
 
A Kaplan-Meier survival analysis will be performed where all treated BPARs, graft losses, 
deaths of losses to follow-up that occur up to month 24 will be considered efficacy failures. 
The incidence of the composite efficacy failure (treated BPAR, graft loss, death of loss to 
follow-up) within 24 months will be compared between the two treatment groups using 
Kaplan-Meier probability estimates of efficacy failure and the associated 95% CI obtained 


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using the standard error derived by applying Greenwood’s formula. The differences 
between the curves will be tested using the log-rank test. 
10.5 Analysis of secondary objectives 
10.5.1 Efficacy (secondary) 
 
Secondary efficacy variables include: 
• The incidence of treated BPAR at 24 months 
• The incidence of graft loss at 24 months 
• The incidence of death or loss to follow-up at 24 months 
 
The incidence of treated BPAR, graft loss, and death or loss to follow-up will be analyzed 
using a Cochran-Mantel-Haenszel test stratified by induction therapy. 
A Kaplan-Meier survival analysis will be performed for each time to treated BPAR, time to 
graft loss and time to death or loss to follow-up. The incidences will be compared among 
the three treatment groups using Kaplan-Meier probability estimates of efficacy failure and 
the associated 95 % CI obtained using the standard error derived by applying Greenwood’s 
formula.  The differences between the curves will be tested using the log-rank test. 
FAS will be used for analyses of the secondary efficacy variables. 
10.5.2 Safety 
 
Safety variables to be assessed include discontinuation from study, discontinuation from 
treatment, renal function, AE/infection, SAE, notable events, laboratory tests, and vital 
signs. 
 
Comparison of calculated GFR using an analysis of covariance (ANCOVA) with baseline 
(Month 1) GFR as a covariate, and treatment and induction therapy as main effects, will be 
performed.  Month 24 GFRs will be divided into three categories (<30, 30-60, >60) to 
classify chronic kidney disease.  The proportion of patients in certain categories will be 
compared between treatment groups using the Cochran-Mantel-Haenszel test controlling 
for the Month 1 category. 
 
Other safety variables include incidences of AEs, SAEs, new onset diabetes mellitus, CMV, 
BKV and proteinuria.  These incidences will be compared between treatment groups using 
a Cochran-Mantel-Haenszel test, stratified by induction therapy.  Urine protein/creatinine 
ratios will be compared between treatment groups using the Wilcoxon Rank-Sum test. 
 
Additional assessments of safety will be based on the frequency of adverse events and on 
the number of laboratory values that fall outside of pre-determined notable ranges. Other 
safety data (e.g. vital signs and special tests) will be considered as appropriate.  The data 
collected will be presented in listings, summary tables and graphs. All analyses will be 
performed on the SS. 
 


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Adverse events will be summarized by presenting, for each treatment group, the number 
and percentage of patients having any adverse event, having an adverse event in each 
body system and having each individual adverse event. The same type of summaries will 
be provided for serious adverse events and for events suspected to be related to the study 
medication. Any other information collected (e.g. severity or relatedness to study 
medication) will be listed as appropriate. 
 
Laboratory data will be summarized by presenting shift tables using notable ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw 
data and change from baseline values (means, medians, standard deviations, ranges) and 
by the flagging of notable values in data listings. 
 
Data from other tests (e.g. vital signs) will be listed, notable values will be flagged, and any 
other information collected will be listed as appropriate. Any statistical tests performed to 
explore the data will be used only to highlight any interesting comparisons that may warrant 
further consideration.  The data collected will be presented in listings, summary tables and 
graphs. All analyses will be performed on the SS. 
10.5.3 Health-related Quality of Life (HQOL) 
The SF-36 will be employed to assess HQOL in study subjects at Day 7, 28, Month 6, 12 
and 24 post-operation.  The mean scores of SF-36 will be summarized by visits according 
to treatment group.  The change from baseline in the summary scores will be compared 
using an ANOVA with treatment as a factor.  If the assumptions of the model are not met, 
the analysis will be done using Kruskal-Wallis tests. 
10.6 Sample size calculation 
Since this is a pilot study, the sample size estimation method proposed by Julious was 
considered in order to minimize the sample size (14).  Julious proposes to employ sample 
size of 12 per group for a pilot study (14).  Assuming the drop out rate of 20% along with 
the ease of blocked randomization, we propose the sample size of 16 per arm, totaling 48 
patients.  The estimated effect size, α, and β corresponding to this sample size are 0.9, 
0.05 (two-sided), and 0.2 respectively (15).  A block size of 12 along with an allocation ratio 
of 1:1:1 will be employed as a randomization scheme. 
10.7 Power for analysis of critical secondary variables 
Correlation between laboratories will be checked periodically throughout the study period.  
eGFR will be calculated using MDRD formula for each visit following the kidney 
transplantation.  All data will be analyzed using the intent-to-treat approach as well as on-
treatment based approach.  Comparisons between treatment groups experiencing 
composite efficacy failure and each component will be analyzed with Fisher’s exact test.  
The Chi-square and/or one-way analysis of variance (ANOVA) will be used for acute 
rejection episodes and creatinine levels respectively. 


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10.8 Interim analysis 
No interim analysis is planned. 
11 
Ethical considerations 
11.1 Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with US Code of 
Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of 
Helsinki. 
11.2 Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents.  
The investigator and the study team will prepare the informed consent form that complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for 
this study. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must avoid pregnancy for the duration of the 
study. If there is any question that the patient will not reliably comply, they should not be 
entered in the study. 
11.3 Responsibilities of the investigator and IRB 
The protocol and the proposed informed consent form must be reviewed and approved by 
IRB before study start. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to designated agents of Novartis, IRBs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made. 
11.4 Publication of study protocol and results 
The study team assures that the key design elements of this protocol will be posted in a 
publicly accessible database such as clinicaltrials.gov. In addition, upon study completion 
and finalization of the study report the results of this trial will be either submitted for 
publication and/or posted in a publicly accessible database of clinical trial results. 


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12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB it cannot be implemented. All major protocol deviations 
will be recorded and reported to the IRB. 
 
12.1 Protocol Amendment 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the IRB.  Notwithstanding the need for approval of formal 
protocol amendments, the investigator is expected to take any immediate action required 
for the safety of any patient included in this study, even if this action represents a deviation 
from the protocol. In such cases, Novartis and IRB should be notified of this action within 
10 working days. 
 
 
 
13.  Key References   
1. 
Schold J, Srinivas TR, Sehgal AR, Meier-Kreische HU.  Clin J Am Soc Nephrol 
2009; 4(7):1239-45. 
2. 
OPTN. Retrieved from http://optn.transplant.hrsa.gov/ 
3. 
Internal record 
4. 
Formica RN, Lorber KM, Friedman AL, Bia MJ, Lakkis F, Smith JD, Lorber MI.  
Transplant Proc 2004; 36(2S):495S-499S. 
5. 
Pascual J.  Nephrol Dial Transplant 2006; 21(3): iii18-iii23. 
6. 
Lorber MI, Ponticelli C, Mayer HW, Schmidlli H.  Am J Transplant 2002; 
2(S3):186. 
7. 
Kovarik JM, Kaplan B, Tedesco SH.  Transpantation 2002; 73:920-925. 
8. 
Curtis J, Nashan B, Ponticelli C.  Am J Transplant 2001; 1(S1):1335. 
9. 
Tedesco H, Ambuhl P, Lorber MI, Oyen O, Pirron U.  Am J Transplant 2002; 
2(S3):274. 
10. 
Luke PPW, Nguan CY, Horovitz D, Gregor L, Warren J, House AA.  Clin 
Transplant 2009; 23:9-15. 
11. 
House AA, Nguan CY, Luke PP.  Drugs 2008; 68(S1):41-49. 
12. 
Nankivell BJ, Chapman JR.  Transplant 2006; 81(5):643-654. 
13. 
Munivenkatappa RB, Schweitzer EJ, Papadimitriou JC, Drachenberg CB, Thom 
KA, Perencevich EN, Haririan A, Rasetto F, Cooper M, Campos L, Barth RN, 
Bartlett ST, Philosophe B.  Am J Transplant 2008; 8:2316-2324. 
14. 
Julious SA.  Pharm Statistics 2005; 4:287-291. 


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15. 
Hulley SB, Cummings SR, Browner WS, Grady GD, Newman TB.  Designing 
clinical research.  Lippincott Williams & Wilkins; 2007.   
16. 
Pascual J, Castillo DD, Cabello M, Pallardo L, Grinyo JM, Fernandez AM, Brunet 
M.  Transplantation 2010; 89(8):994-1000. 
17. 
Lorber MI, Ponticelli C, Whelchel J, Mayer HW, Kovarik J, Li Y, Schmidli H.  Clin 
Transplant 2005; 19:145-152. 
18. 
Pascual J.  Int J Neph Renovasc Dis 2009; 2:9-21. 
19. 
Holdaas H, Bentdal Ø, Pfeffer P, Mjørnstedt L, Solbu D, Midtvedt K.  Clin 
Transplant 2008; 22:366-371. 
20. 
Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone 
RD, Lau J, Eknoyan G.  Ann Intern Med 2003; 139:137-147. 
21. 
Anonymous. Randomization of subject assignment to a treatment group 
[Internet]. GraphPad.com; c2012 [cited 2012 Feb 17].  Available from GraphPad 
QuickCalcs Web site: http://graphpad.com/quickcalcs/randomize1.cfm   
22. 
Anonymous. CellCept (mycophenolate Mofetil) Drug Interactions [Internet]. 
Drugs.com; 
c2012 
[cited 
2012 
Feb 
26]. 
Available 
from 
Drugs.com; 
http://www.drugs.com/drug-interactions/mycophenolate-mofetil,cellcept-
index.html?filter=3 
23. 
Anonymus. Myfortic (mycophenolic Acid) Drug Interactions [Internet]. Drugs.com; 
c2012 
[cited 
2012 
Feb 
26]. 
Available 
from 
Drugs.com: 
http://www.drugs.com/drug-interactions/mycophenolic-acid,myfortic-
index.html?filter=3 
24. 
Friedman G, and Opper C.  Working copy of the Clinical Study Protocol 
CRAD001AUS92, 2nd ver.  c2012 [permission obtained from Novartis]. East 
Hanobor, NJ: Novartis, 2009.    
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1: Clinically notable laboratory values and vital signs 
Table 13-1 
Criteria for notable abnormalities 
Chemistry parameters 
Standard units 
SI units 
Liver function and related variables 
AST (SGOT) 
3  ULN 
3  ULN 
ALT (SGPT) 
3  ULN 
3  ULN 
Bilirubin 
3  ULN 
3  ULN 
Alkaline phosphatase 
3  ULN 
3  ULN 
Renal function, metabolic and electrolyte variables 
Urea 
None 
None 
Creatinine 
30% above baseline 
30% above baseline 
Uric acid 
M 12 mg/dL 
F 9 mg/dL 
M 714 µmol/L 
F 535 µmol/L 
Glucose 
<45 mg/dL or >250 mg/dL 
<2.5 mmol/L or >13.9 mmol/L 
Cholesterol 
350 mg/dL 
9.1 mmol/L 
Triglycerides 
750 mg/dL 
8.5 mmol/L 
CPK (MB) 
None 
None 
Potassium 
3.0 mEq/L 
6.0 mEq/L 
3 mmol/L 
6 mmol/L 
Magnesium 
<0.97 mg/dL or >3.65 mg/dL 
<0.4 mmol/L or >1.5 mmol/L 
Calcium 
6 mg/dL or 13 mg/dL 
1.5 mmol/L or 3.2 mmol/L 
Phosphate 
None 
None 
Amylase 
2  ULN 
2  ULN 
Lipase 
2  ULN 
2  ULN 
 
Hematology parameters 
Standard units 
SI units 
Hemoglobin 
<7 g/dL 
<4.39 mmol/L 
Platelets 
(thrombocytes) 
<50 k/mm3 
700 k/mm3 
<50  109/L 
700 109/L 
Leukocytes  (WBCs) 
2.0 k/mm3 or 16 k/mm3 
2.0  109/L or 16  109/L 
Granulocytes (neutrophils) 
1,000/mm3 
1  109/L 
Eosinophils 
12% 
12% 
Lymphocytes 
1,000/mm3 
1  109/L 
Urinalysis 
Protein/creatinine 
<200 mg/g 
<22.7 mg/mmol 
 
Vital sign variables 
Notable criteria 
Pulse (beats/min.) 
None 
Systolic BP (mm/Hg) 
Either an increase of 30 that results in 180 or >200(mm/Hg) 
or 
Either a decrease of 30 that results in 90 or <75 (mm/Hg) 


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Diastolic BP (mm/Hg) 
Either an increase of 20 that results in 105 or >115 (mm/Hg) 
or 
Either a decrease of 20 that results in 50 or <40 (mm/Hg) 
Appendix 2: Banff ’97 Classification of renal allograft rejection 
Banff ‘97 diagnostic categories for renal allograft biopsies1 
1. Normal 
2. Antibody-mediated rejection - Rejection demonstrated to be due, at least in part, to 
documented anti-donor antibody (“suspicious for” if antibody not demonstrated) 
• Type I – ATN – like – C4d+, minimal inflammation 
• Type II – Capillary–margination and/or thromboses, Ig and/or C4d+ 
• Type III – Arterial – v3, C4d+ 
3. Borderline changes (“suspicious” for acute cellular rejection). This category is used 
when no intimal arteritis is present, but there are foci of mild tubulitis (1 to 4 
mononuclear cells/tubular cross section) and at least i1. 
4. Acute/active rejection 
• TYPE IA - Cases with significant interstitial infiltration (> 25% of parenchyma 
affected) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section 
or group of 10 tubular cells). 
• TYPE IB - Cases with significant interstitial infiltration (> 25% of parenchyma 
affected) and foci of severe tabulitis (> 10 mononuclear cells/tubular cross section 
or group of 10 tubular cells). 
• TYPE IIA - Cases with mild to moderate intimal arteritis (v1). 
• TYPE IIB - Cases with severe intimal arteritis comprising > 25% of the luminal area 
(v2). 
• TYPE III - Cases with “transmural” arteritis and/or arterial fibrinoid change and 
necrosis of medial smooth muscle cells (v3 with accompanying lymphocytic 
inflammation). 
5. Chronic/sclerosing allograft nephropathy** 
• GRADE I (Mild)  
Mild interstitial fibrosis and tubular atrophy without (a) or with (b) 
specific changes suggesting chronic rejection. 
• GRADE II (Moderate) 
Moderate interstitial fibrosis and tubular atrophy (a) or 
(b). 
• GRADE III (Severe) 
Severe interstitial fibrosis and tubular atrophy and tubular 
loss (a) or (b). 
6. Other, specify (changes not considered to be due to rejection, i.e., post-transplant 
lymphoproliferative disorder, nonspecific changes, acute tubular necrosis, etc.) 
*The recommended format of report is a descriptive narrative signet followed by numerical 
codes (Banff 97) in parentheses. Categorization should in the first instance be based solely 
on pathologic changes, and then integrated with clinical data as a second step. More than 
one diagnostic category may be used if appropriate. 


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**Glomerular 
and 
vascular 
lesions 
help 
define 
type 
of 
chronic 
nephropathy; 
chronic/recurrent rejection can be diagnosed if typical vascular lesions are seen. 
1   Racusen LC, Colvin RB, Solez K, et al (2003) Antibody-mediated rejection criteria - an 
addition to the Banff ’97 classification of renal allograft rejection. American Journal of 
Transplantation; 3(6):708-714 
 
 
Appendix 3:  Guidelines for Everolimus and MMF/MPA dose reduction 
An investigator may interrupt temporarily or reduce, the dosage of study medication 
(Everolimus or MMF/MPA), if in his/her opinion this is clinically warranted, in response to 
any causally associated AE (e.g., neutropenia, thrombocytopenia, leukocytopenia, 
hyperlipidemia, hypertriglyceridemia or gastrointestinal intolerance).  The following 
guidelines should be followed: 
1- PLATELETS 
Platelet count < 75,000/mm3 
 
Step 1:  dose reduction should be considered and may be instituted at the discretion of the 
Investigator. 
Step 2:  if the platelet count remains below 75,000/mm3 despite the initial dose reduction, a 
further dose reduction may be implemented per the table below: 
Platelet count < 50,000/mm3 
Dose interruption should be considered. 
Platelet count < 30,000/mm3 
Dose interruption will be mandatory. 
If the platelet count returns to 30,000/mm3 for 3 days, study medications may be restarted 
at lowest reduced dose.  If the platelet count is stable at the reduced dose for 3 days, study 
medications may be increased to the next higher dose.  If the platelet count remains stable 
at greater than 75,000/mm3 for 7 days, the full dose of study medications may be restarted.  
2- WHITE BLOOD CELLS 
WBC < 3,000/mm3 or absolute neutrophil count < 1,300/mm3  
Step 1:  dose reduction should be considered and the first dose reduction may be instituted 
at the discretion of the Investigator. 
Step 2:  if the white count remains less than 3,000/mm3 despite the intial dose reduction, a 
further dose reduction may be implemented per the table  below:  
If the WBC is less than 2,000/mm3, dose interruption will be mandatory.  
Once WBC returns to 2,000/mm3 for 3 consecutive days, study medication may be 
restarted at the lowest level.  If the WBC is stable at the reduced dose for 3 days, study 
medication may be increased to the next higher dose level.  Once WBC returns to levels > 
3,000/mm3 for 7 days, study medication may be increased to the full dose. 
3- CHOLESTEROL 


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If cholesterol and/or triglycerides are found to be elevated, dosing should be reconsidered 
and optimized as appropriate, in addition to provided dietary advice. If the elevation is 
confirmed by a second measurement within 2 weeks under fasting conditions (last meal ≥ 8 
hours prior to sampling) the following guidelines are recommended.  
Cholesterol > 250 - 450 mg/dL or > 6.5 -11.6 mmol/L:   
Dietary instruction is strongly recommended and statin therapy, e.g. fluvastatin, should be 
considered (see Appendix 4) 
If the abnormality persists, the dosing of study medication will be adjusted as 
follows: 
Cholesterol ≥ 450 mg/dL or 11.6 mmol/L:  Dose reduction should be considered 
Cholesterol > 750 mg/dL or > 19.4 mmol/L:  Study medication should be interrupted 
4- TRIGLYCERIDES 
Triglycerides > 250 mg/dL or > 2.9 mmol/L:   
 
Dietary instruction is strongly recommended and statin therapy should be considered 
If the abnormality persists, the dosing of study medication will be adjusted as 
follows: 
Triglycerides ≥ 600 mg/dL or ≥ 6.9 mmol/L: Dose reduction should be considered 
Triglycerides > 1000 mg/dL or 11.4 mmol/L: Study medication should be interrupted 
 
 
 
 
 
 
 
 
Table 13-2 
National cholesterol education program guidelines 
Total cholesterol 
 
 
Under 200 mg/dL 
Desirable 
 
200-239 mg/dL 
Borderline-high 
 
240 and over 
 
High 
HDL cholesterol 
 
 
Under 35 mg/dL 
Low 


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Table 13-3 
Treatment based on LDL cholesterol 
Diet therapy 
Initiation level 
LDL goal 
Without CHD and without 
2 risk factors 
160 mg/dL or over 
Under 160 mg/dL 
Without CHD and with 2 or 
more risk factors 
Over 130 mg/dL 
Under 130 mg/dL 
With CHD 
Over 100 mg/dL 
100 mg/dL or under 
Drug treatment 
Initiation level 
LDL goal 
Without CHD and without 
2 risk factors 
190 mg/dL or over 
Under 160 mg/dL 
Without CHD and with 2 or 
more risk factors 
160 mg/dL or over 
Under 130 mg/dL 
With CHD 
130 mg/dL or over 
100 mg/dL or under 
(Data from Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol 
in Adults:  Summary of the second report of the National Cholesterol in Adults [Adult 
Treatment Panel II] JAMA 269[23]:3015-3023, 1993) 
 
 
 
 
 
 
 
 
Appendix 4: Possible Everolimus drug-drug interactions 
During treatment with immunosuppressive agents, such as everolimus, steroids and 
tacrolimus, vaccination may be less effective. The use of live vaccines should be avoided. 
Table 13-4 
Everolimus Drug Interactions 
Drugs not allowed Sirolimus 
Patients to be discontinued from everolimus 
if given 
Terfenadine 
Astemizole 
Cisapride 
Inhibitors of P-450 (CYP), in particular 
CYP3A (as everolimus) have the potential to 
increase the exposure of these drugs 
resulting in prolongation of QT intervals on 


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ECGs 
Ketoconazole* 
Clarithromycin 
Telithromycin 
Ritonavir 
Strong inhibitors of P-450 (CYP) have the 
potential to increase the exposure of 
everolimus 
Rifampicin 
Rifabutin 
Strong inducers of P-450 (CYP) have the 
potential to decrease the exposure of 
everolimus 
Drugs strongly 
discouraged 
Lovastatin** 
Simvastatin** 
Confirmed interaction between everolimus 
and this drug 
Cerivastatin** 
Rosuvastatin** 
Insufficient 
data 
available 
to 
make 
recommendations 
regarding 
concomitant 
use of the newer statins and everolimus 
Quinidine 
Fluoxetine 
Paroxetine 
Potential interaction of everolimus with CYP 
2D6 substrates 
Itraconazole* 
Voriconazole* 
Strong inhibitors of P-450 (CYP) have the 
potential to increase the exposure of 
everolimus 
Drugs 
necessitating 
close monitoring 
Digoxin 
Potential interaction with everolimus has not 
been evaluated, patients on digoxin should 
have periodic measurements of digoxin 
levels 
Fluconazole* 
 
Strong inhibitors of P-450 (CYP) have the 
potential to increase the exposure of 
everolimus 
* The concomitant administration of the antifungal agent ketoconazole, is prohibited in 
patients who are taking everolimus.  If ketoconazole must be administered, everolimus 
must be discontinued.  If –azole antifungal agents must be administered to patients, 
everolimus blood levels must be monitored closely. The investigator should anticipate the 
need to reduce or withhold the dose of everolimus.  Fluconazole may pose the smallest risk 
for drug-drug interactions.  
** Patients requiring treatment with this class of medication (especially lovastatin) should be 
monitored closely for signs of rhabdomyolysis, such as dark-colored urine, fever, muscle 
cramps, pain, spasm, or stiffness, unusual tiredness or weakness. 
Appendix 5: Possible tacrolimus drug-drug interactions  
Due to the potential for additive or synergistic impairment of renal function, care should be 
taken when administering tacrolimus with drugs that may be associated with renal 


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dysfunction.  These include, but are not limited to: aminoglycosides, amphotericin B and 
cisplatin.  Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, 
substances known to inhibit these enzymes may decrease the metabolism of tacrolimus 
with resultant increases in whole blood or plasma concentrations. Drugs known to induce 
these enzyme systems may result in an increased metabolism of tacrolimus and decreased 
whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate 
dosage adjustments are essential when such drugs are used concomitantly. 
Table 13-5 
Drugs that may affect Tacrolimus blood concentrations 
Calcium channel blockers 
Antifungal agents 
Gastrointestinal 
prokinetic agents 
Diltiazem 
Nicardipine 
Nifedipine 
Verapamil 
Clotrimazole 
Ketoconazole 
Fluconazole 
Itraconazole 
Cisapride 
Metoclopramide 
Macrolide antibiotics 
Other drugs 
Clarithromycin 
Erythromycin 
Troleandomycin 
Bromocriptine 
Cimetidine 
Cyclosporine 
Danazol 
Methylprednisolone 
Protease inhibitors 
Drugs that may decrease tacrolimus blood concentrations 
Anticonvulsants 
Antibiotics 
Carbamazepine 
Phenobarbital 
Phenytoin 
Rifabutin 
Rifampin 
Interaction studies with drugs used in HIV therapy have not been conducted.  However, 
care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are 
metabolized by CYP3A (e.g., ritonavir) are administered concomitantly with tacrolimus.  
Grapefruit juice affects CYP3A-mediated metabolism and should be avoided. 
Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus, 
vaccination may be less effective.  The use of live vaccines should be avoided. 
Appendix 6: Possible MMF/MPA drug-drug interactions  
The use of live attenuated vaccines should be avoided and patients should be advised that 
vaccinations may be less effective.  Influenza vaccinations may be of value. 


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Table 13-6 
Possible MMF/MPA Drug-Drug Interaction 
Drugs not allowed 
Cholestyramine 
Patients to be discontinued from 
CellCept, if given 
Drugs strongly 
discouraged or not 
to be administered 
simultaneously  
Acyclovir or prodrug- 
Valacyclovir 
Competition for tubular secretion 
may increase the concentration of 
CellCept 
Sevelamer 
CA2+free phosphate 
binders 
CA2+free phosphate binders to be 
given 2 hours after CellCept to 
minimize impact on absorption  
Norfloxin together with  
Metronidazole  
Not recommended to be given 
concomitantly with the combination 
of  both drugs  
Antacids with 
magnesium and 
aluminum hydroxides 
Do 
not 
take 
simultaneously, 
administer 
alone 
under 
fasting 
conditions 
Drugs necessitating 
close monitoring 
Ganciclovir or prodrug- 
Valganciclovir 
Competition for tubular secretion 
may increase the concentration of 
CellCept