Clinical trial NCT01950819
Conditions: End Stage Renal Disease (ESRD) Chronic Kidney Disease (CKD) Hemodialysis Renal Replacement Therapy Renal Transplantation
Keywords: kidney failure dialysis renal failure transplantation
Sponsor: Novartis Pharmaceuticals
Start date: 2013-12-03; Completion date: 2018-01-17
Enrollment: 2037 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2-year, randomized, multicenter, open-label, 2-arm study evaluating the graft function of everolimus and reduced CNI versus MPA and standard CNI in adult de novo renal transplant recipients.

Detailed description:

Arms: arm 1: Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus) arm 2: Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).
Interventions: intervention 1: Induction therapy intervention 2: Corticosteroids intervention 3: EVR+rCNI intervention 4: MPA+sCNI
Intervention descriptions: intervention 1: All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period. intervention 2: All subjects received maintenance therapy with corticosteroids throughout the 24 month study period. A minimum dose of 5 mg prednisone, or equivalent, per day was maintained. intervention 3: Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus) intervention 4: Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).

Protocol documents:
Prot_000.pdf: 
Clinical Development
RAD001A/everolimus
Protocol CRAD001A2433 / NCT01950819
A 24 month, multicenter, randomized, open-label safety and 
efficacy study of concentration-controlled everolimus with 
reduced calcineurin inhibitor vs mycophenolate with 
standard calcineurin inhibitor in de novo renal 
transplantation- Advancing renal TRANSplant eFficacy and 
safety Outcomes with an eveRolimus-based regiMen 
(TRANSFORM)
Authors:
 
Document type:
Amended Clinical Trial Protocol 
EUDRACT number:
2013-000322-66
Version number:
v01 Clean
Development phase:
IV
Release date:
14-Jul-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 03-Feb-2012


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 1 .............................................................................................................................9
Protocol synopsis...............................................................................................................11
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................17
2
Study objectives.................................................................................................................17
2.1
Primary objective...................................................................................................17
2.2
Secondary objectives .............................................................................................17
18
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale of study design.......................................................................................20
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....20
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................21
3.6
Risks and benefits..................................................................................................21
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................23
5
Treatment...........................................................................................................................24
5.1
Protocol requested treatment .................................................................................24
5.1.1
Investigational, control and concomitant drugs ....................................24
5.1.2
Additional study treatment....................................................................25
5.2
Treatment arms ......................................................................................................25
5.3
Treatment assignment, randomization...................................................................25
5.4
Treatment blinding.................................................................................................26
5.5
Treating the subject................................................................................................26
5.5.1
Subject numbering ................................................................................26
5.5.2
Dispensing the investigational treatment ..............................................26
5.5.3
Handling of study treatment..................................................................26
5.5.4
Instructions for prescribing and taking study treatment........................27


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........30
5.5.6
Rescue medication ................................................................................31
5.5.7
Concomitant Treatment.........................................................................32
5.5.8
Prohibited Treatment.............................................................................32
5.5.9
Discontinuation of study treatment and discontinuation from study ....33
5.5.10
Emergency breaking of treatment assignment ......................................34
5.5.11
Study completion and post-study treatment..........................................35
5.5.12
Early study termination.........................................................................35
6
Visit schedule and assessments .........................................................................................35
6.1
Information to be collected on screening failures..................................................38
6.2
Subject demographics/other baseline characteristics.............................................38
6.3
Treatment exposure and compliance .....................................................................39
6.4
Efficacy..................................................................................................................39
6.4.1
Appropriateness of efficacy assessments..............................................40
6.5
Safety.....................................................................................................................40
6.5.1
Physical examination ............................................................................40
6.5.2
Vital signs..............................................................................................41
6.5.3
Height and weight .................................................................................41
6.5.4
Laboratory evaluations..........................................................................41
6.5.5
Electrocardiogram (ECG) .....................................................................41
6.5.6
Pregnancy and assessments of fertility .................................................41
6.5.7
Appropriateness of safety measurements..............................................42
6.6
Other assessments..................................................................................................42
6.6.1
Resource utilization...............................................................................43
6.6.2
Health-related Quality of Life...............................................................43
6.6.3
Pharmacokinetics ..................................................................................43
6.6.4
Pharmacogenetics/pharmacogenomics .................................................43
6.6.5
Other biomarkers...................................................................................43
7
Safety monitoring ..............................................................................................................43
7.1
Adverse events.......................................................................................................43
7.2
Serious adverse event reporting.............................................................................45
7.3
Liver safety monitoring .........................................................................................46
7.4
Pregnancy reporting...............................................................................................46
7.5
Prospective suicidality assessment ........................................................................46
8
Data review and database management.............................................................................46
8.1
Site monitoring ......................................................................................................46
8.2
Data collection.......................................................................................................47


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8.3
Database management and quality control............................................................47
8.4
Data Monitoring Committee..................................................................................48
8.5
Adjudication Committee........................................................................................48
9
Data analysis......................................................................................................................48
9.1
Analysis sets ..........................................................................................................48
9.2
Subject demographics and other baseline characteristics......................................48
9.3
Treatments .............................................................................................................49
9.4
Analysis of the primary variable............................................................................49
9.4.1
Variable.................................................................................................49
9.4.2
Statistical model, hypothesis, and method of analysis..........................49
9.4.3
Handling of missing values/censoring/discontinuations.......................51
9.4.4
Supportive analyses...............................................................................51
9.5
Analysis of secondary variables ............................................................................53
9.5.1
Assessment of the key secondary endpoint of tBPAR, graft loss, or 
death ......................................................................................................53
9.5.2
Other secondary efficacy variables .......................................................54
9.5.3
Safety variables .....................................................................................55
9.5.4
Resource utilization...............................................................................57
9.5.5
Health-related Quality of Life...............................................................57
9.5.6
Pharmacokinetics ..................................................................................57
9.5.7
Pharmacogenetics/pharmacogenomics .................................................57
9.5.8
Biomarkers ............................................................................................58
9.5.9
PK/PD ...................................................................................................58
9.6
Interim analyses .....................................................................................................58
9.7
Sample size calculation..........................................................................................58
10 Ethical considerations........................................................................................................59
10.1
Regulatory and ethical compliance........................................................................59
10.2
Informed consent procedures.................................................................................59
10.3
Responsibilities of the investigator and IRB/IEC..................................................59
10.4
Publication of study protocol and results...............................................................60
11 Protocol adherence ............................................................................................................60
11.1
Protocol Amendments ...........................................................................................60
12 References (available upon request)..................................................................................60
13 Appendix 1: Clinically notable laboratory values .............................................................63
14 Appendix 2: Everolimus drug-drug interactions ...............................................................64
15 Appendix 3: Dose reduction guidance for MPA ...............................................................65
16 Appendix 4: Tacrolimus drug-drug interactions ...............................................................66


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17 Appendix 5 : Cyclosporine drug-drug interactions ...........................................................68
18 Appendix 6: Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and 
Implementation of Banff Working Groups 1.....................................................................71
List of tables
Table 5-1
CNI trough target level ranges ..............................................................29
Table 5-2
Guidelines for everolimus dose reduction/interruption.........................30
Table 5-3
Prohibited medications..........................................................................33
Table 6-1
Assessment schedule- Study Treatment to Month 24...........................36
Table 9-1
Power for non-inferiority and superiority testing:  Overall 
population and TAC alone population ..................................................58
List of figures
Figure 3-1
Study design- Primary Treatment to M12, Extension to M24..............19


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List of abbreviations
AE
Adverse event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical therapeutic chemical (classification)
b.i.d.
bis in die/twice a day
BPAR
Biopsy Proven Acute Rejection
BKV
BK virus
C-0h
Whole blood concentration before morning dose
CI
Confidence interval
CMV
Cytomegalovirus 
CKD
Chronic kidney disease
CNI
Calcineurin Inhibitor
CsA
Cyclosporine
CysC
Cystatin C
D
Death
DSE
Novartis Drug Safety & Epidemiology Department
eCRF
Electronic case report/record Form
ESRD
End stage renal disease
(e)GFR
(Estimated) Glomerular Filtration Rate
EVR
Everolimus
FAS
Full analysis set
FDA
US Food and Drug Administration
HbA1c
Glycosylated hemoglobin
HBV
Hepatitis B virus
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HDL
High density lipoprotein
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A 
ICH
International Conference on Harmonization


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IEC
Independent Ethics Committee
IN
Investigator notification
ITT
Intent-to-treat
i.v.
intravenous(ly)
IRB
Institutional Review Board
IRT
Interactive Response Technology 
KM
Kaplan Meier
LDL
Low density lipoprotein
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
MDRD4
Abbreviated MDRD formula (4 variables)
MMF
Mycophenolate mofetil
MNAR
Missing not at random
MPA
Mycophenolic acid (MP used here to denote MMF or mycophenolate sodium) 
mTORi
Mammalian target of rapamycin inhibitor
NG
Nasogastric
NI
Non inferiority
OC/RDC
Oracle clinical/remote data capture
p.o.
per os/by mouth/orally
PD
Pharmacodynamics
PPS
Per protocol set
RAD
40-O-2-hydroethyl-rapamycin, everolimus
RBC
Red blood cell
SAE
Serious adverse event
SAF
Safety set
SD
Standard deviation
TAC
Tacrolimus
tBPAR
treated Biopsy Proven Acute Rejection
TDM
Therapeutic drug monitoring
ULN
Upper limit of normal
WBC
White blood cell
WHO
World health organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Concentration controlled
Dosing regimen where the does is adjusted to achieve a given target level 
of drug in the blood
Control regimen
Drug regimen used post-randomization as a comparator to evaluate 
comparative effects of the investigational drug (i.e. the combination of MPA 
and a CNI- either tacrolimus or cyclosporine)
Enrollment
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Extension 
Study period from Month 12 visit to completion of Month 24 visit regardless 
of treatment status (i.e. can be on or off randomized regimen)
Investigational regimen
The investigational drug regimen tested in the study post-randomization  
(i.e. the combination of everolimus and a CNI- either tacrolimus or 
cyclosporine)
Lost to follow-up 
Those subjects whose status is unclear because they fail to appear for study 
visits without stating an intention to withdraw and cannot be contacted
Subject Number 
A number assigned to each subject who enrolls into the study 
Period
A distinct stage in the subjects’ participation in the study, each period 
serves a purpose in the study as a whole
Premature subject withdrawal
Point when the subject exits from the study prior to the planned completion 
of all assessments, synonymous with study discontinuation, not the same 
as treatment discontinuation
Primary Treatment Period
Study period from randomization to completion of Month 12 visit, 
regardless of treatment status (i.e. can be on or off randomized regimen) 
Screening period
Period from signing informed consent to successful completion of the 
transplant procedure
Study Completion
Point at which the subject came in for a final evaluation visit at Month 24 or 
complete discontinuation from the study if prior to Month 24
Study drug/ treatment
Any single drug or drug regimen administered to the subject as part of  the 
required study procedures in any study period, includes everolimus, 
tacrolimus, cyclosporine, basiliximab, MPA and corticosteroids
Treated biopsy proved acute 
rejection (tBPAR)
An acute rejection episode documented by histological evidence for which 
anti-rejection therapy (e.g. steroids, antibody or increase in study regimen 
immunosuppression) was given.
Treatment discontinuation
Point when subject permanently stops taking study/investigational or 
control treatment drug/regimen for any reason, not the same as study 
discontinuation/premature subject withdrawal
Study Discontinuation
Point when subject permanently stops taking part in the study, also termed 
premature subject withdrawal, not the same as treatment discontinuation
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points


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Amendment 1
Amendment rationale
In response to the French Health Authorities (HA) request, the protocol is updated with the 
recent notifications for use of mycophenolate based on EMA’s recommendation published on 
23 Oct 2015, and the Dear Health Care Professional Letter (DHCPL) for CellCept that was 
distributed by Roche by 10-Nov-2015.
Mycophenolate (mycophenolate mofetil or mycophenolic acid) is a confirmed teratogen 
associated with an increased rate of spontaneous abortion and congenital malformation 
compared with other immunosuppressants. Therefore, investigators should ensure that female 
and male patients taking mycophenolate understand the risk of harm to the baby, the need for 
effective contraception, and the need to immediately consult responsible investigator if there is 
a possibility of pregnancy or a suspected gap of contraception.
Recommendations for female patients:

Female patients sexually active should use two reliable methods of contraception 
simultaneously before starting and during therapy with mycophenolate, and for 6 weeks 
after stopping treatment following discontinuation of mycophenolate.

Female patients should not donate blood during therapy with mycophenolate and at least 6 
weeks following discontinuation of mycophenolate.
Recommendations for male patients:

Male patients sexually active should use condom for sex during therapy with 
mycophenolate and at least 90 days following discontinuation of mycophenolate. Condom 
use applies for both reproductively competent and vasectomized male patients (due to the 
risks associated with the transfer of seminal fluid). In addition, female partners of male 
patients treated with mycophenolate are recommended to use highly effective 
contraception during treatment and for a total of 90 days after the last dose of 
mycophenolate.

Male patients should not donate blood during therapy with mycophenolate and at least 6 
weeks following discontinuation of mycophenolate.

Male patients should not donate semen during therapy with mycophenolate and for 90 
days following discontinuation of mycophenolate.
Changes to the protocol
The recommendations described above are now reflected in the corresponding protocol section 
(6.5.6 -Pregnancy and assessments of fertility).
The changes do not influence the study population, design of the study, safety considerations 
nor the integrity of the data analysis.
First Patient First Visit has occurred on December 3rd, 2013. Last Patient First Treatment has 
been completed on January 26th, 2016. At the time of amendment 1 release, 2037 patients were
randomized.


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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Changes to the Inform Consent Form
 Novartis released on January 
18th, 2016 a revised CRAD001A2433 Informed Consent Form (ICF) in order to inform the 
patients about the new warnings regarding the pregnancy risks.
All participating sites were required to submit for approval the revised versions and re-
consented the patients.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and HA approval prior to 
implementation. 


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Protocol synopsis
Protocol number
CRAD001A2433
Title
A 24 month, multicenter, randomized, open-label safety and efficacy study 
of concentration-controlled everolimus with reduced calcineurin inhibitor 
vs mycophenolate with standard calcineurin inhibitor in de novo renal 
transplantation
Brief title
Advancing renal TRANSplant eFficacy and safety Outcomes with an 
eveRolimus-based regiMen (TRANSFORM)
Sponsor 
and 
Clinical 
Phase
Novartis, Phase IV
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study is designed to evaluate the impact of concentration-controlled 
everolimus with reduced exposure CNI, compared to mycophenolic acid 
(MPA) with standard exposure CNI, with respect to efficacy and safety in 
de novo renal transplant recipients. The primary endpoint combining 
efficacy (tBPAR) and graft function (eGFR) is consistent with recent 
Health Authority guidance on including an assessment of graft function as 
well as the traditional efficacy endpoints e.g. treated biopsy proven acute 
rejection, with or without clinical outcomes (i.e. Death and Graft loss). The 
endpoint represents an attempt to assess the clinical balance between 
having sufficient immunosuppression to prevent rejection while keeping 
CNI levels low enough to avoid nephrotoxicity. 
Primary Objective, Key 
Secondary Objective
Primary Objective- To evaluate the effect of everolimus with reduced 
exposure CNI versus MPA with standard exposure CNI on the binary 
composite of treated biopsy-proven acute rejection (tBPAR) or eGFR < 50 
mL/min/1.73m2 (estimated glomerular filtration rate by MDRD4 formula) at 
Month 12 post-transplantation.
Key Secondary Objectives
To evaluate everolimus with reduced exposure CNI compared to MPA 
plus standard exposure CNI at 12 months post-transplantation with 
respect to the composite efficacy failure rate of (treated biopsy proven 
acute rejection (tBPAR), graft loss or death).
To evaluate the binary composite endpoint of tBPAR or eGFR < 50 
mL/min/1.73m2 (MDRD4) Month 12 among compliant subjects.
Secondary Objectives
To evaluate, by treatment group;

The incidence of composite endpoint of tBPAR or eGFR < 50 
mL/min/1.73m2 (MDRD4) at Month 24.

The incidence of composite endpoint of tBPAR (excluding Banff 
grade 1A acute rejections) or eGFR < 50 mL/min/1.73m2
(MDRD4) at Month 24.

The incidence of composite endpoint of tBPAR or eGFR < 50 
mL/min/1.73m2 (MDRD4) at Month 12 by subgroup.

The incidence of composite endpoint of tBPAR, graft loss or 
death at Month 24. 


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
The incidence of composite endpoint of tBPAR, graft loss, 
death, or loss to follow-up at Months 12 and 24.

The incidence of composite endpoint of tBPAR, graft loss, 
death or eGFR < 50 mL/min/1.73m2 at Months 12 and  24. 

The incidence of composite endpoint of graft loss or death at 
Month 12 and 24. 

The incidence of individual endpoints of death, graft loss, 
tBPAR, BPAR, tAR, AR and humoral rejection at Months 12 
and 24.

The incidence of tBPAR by severity and time to event.

The incidence of tBPAR excluding Banff 1A grade acute 
rejections

The incidence of transplant recipients with eGFR < 50 
mL/min/1.73m2 at Months 12 and 24.                                          

Renal allograft function and change in renal allograft function 
from Month 1 (eGFR) at Months 12 and 24.

The evolution of renal function, as eGFR, over time by slope 
analysis.

Renal function by Cystatin C-based and other alternate 
formulae (e.g. CKD-EPI). 

The incidence of adverse events, serious adverse events and 
adverse events leading to study regimen discontinuation.

The incidence of CMV and BKV, new onset diabetes mellitus, 
chronic kidney disease with associated proteinuria and CNI 
associated adverse events.

Urinary protein and albumin excretion by treatment estimated 
by urinary protein/creatinine and urinary albumin/creatinine 
ratios.

The incidence of major cardiovascular events. 

The incidence of malignancies.
Study design
2-year, randomized, multicenter, open-label, 2-arm study evaluating the 
graft function of everolimus and reduced CNI versus MPA and standard 
CNI in adult de novo renal transplant recipients. Consented subjects 
(approximately 2040) meeting eligibility criteria will be randomized (1:1 
between the two treatment groups) into the 24-month treatment period. 
Randomization will be stratified by donor type and CNI usage. 
Population
Adult renal transplant recipients
Inclusion criteria (key)
1. Written informed consent obtained.
2. Male or female subject ≥ 18 years old
3. Subject randomized within 24 hr of completion of transplant 
surgery.
4. Recipient of a kidney with a cold ischemia time < 30 hr.
5. Recipient of a primary (or secondary, if first graft is not lost due to 
immunological reasons) renal transplant from a deceased 
heart beating, living unrelated, living related non-human 
leukocyte antigen identical or an expanded criteria donor. 
Exclusion criteria (key)
1.
Subject unable to tolerate oral medication at randomization.
2.
Use of other investigational drugs at the time of enrollment, or 
within 30 days or five half-lives of enrollment, whichever is 
longer.


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3.
History of hypersensitivity to any of the study drugs or to drugs 
of similar chemical classes.
4.
Subject is a multi-organ transplant recipient.
5.
Recipient of ABO incompatible allograft or CDC crossmatch 
positive transplant.
6.
Subject at high immunological risk for rejection as determined 
by local practice for assessment of anti-donor reactivity.
7.
Subject who is HIV positive.
8.
HBsAg and/or a HCV positive subject with evidence of elevated 
LFTs (ALT/AST levels ≥ 2.5 times ULN). Viral serology results 
obtained within 6 months prior to randomization are acceptable.
9.
Recipient of a kidney from a donor who tests positive for human 
immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg) or anti-hepatitis C virus (HCV).
10. Subject with a BMI greater than 35.
11. Subject with severe systemic infections, current or within the 
two weeks prior to randomization.
12. Subject requiring systemic anticoagulation that cannot be 
temporarily interrupted and  which would preclude renal biopsy.
13. History of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin), treated or untreated, within 
the past 5 years, regardless of whether there is evidence of 
local recurrence or metastases.
14. Subject with severe restrictive or obstructive pulmonary 
disorders.
15. Subject with severe hypercholesterolemia or 
hypertriglyceridemia that cannot be controlled.
16. Subject with white blood cell (WBC) count ≤ 2,000 /mm3 or with 
platelet count ≤ 50,000 /mm3.
17. Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until the 
termination of gestation, confirmed by a positive hCG laboratory 
test.
18. Women of child-bearing potential, unless they are using 
effective methods of contraception during dosing of study 
treatment.
Investigational 
and 
reference therapy
Investigational- everolimus plus reduced calcineurin inhibitor
Reference- mycophenolate plus standard calcineurin inhibitor
Efficacy assessments
Treated, biopsy proven acute rejection (tBPAR), death, graft loss
Safety assessments
Renal function, adverse events, infections
Other assessments
None 
Data analysis
The primary analysis will be performed on the Full Analysis Set following 
the intent-to-treat principle. The proportion of subjects with tBPAR or 
eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 will be compared for 
non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI using 
a 10% non-inferiority margin.  
The evaluation of non-inferiority for the key secondary endpoint, 
composite efficacy failure of tBPAR, graft loss, or death at Month 12, will 
only be assessed if EVR is shown to be non-inferior to MPA based on the 


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primary endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 at Month 12.  
The rates of tBPAR, graft loss, or death based on Kaplan-Meier estimates 
will be compared to assess non-inferiority using a 10% non-inferiority 
margin using the Full Analysis Set.
If non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI is 
achieved for both the primary and the key secondary endpoints, 
superiority of EVR plus reduced CNI to MPA plus standard CNI will be 
evaluated.
The above hierarchical fixed hypothesis testing procedure will not inflate 
overall Type I error rate.  Therefore, each hypothesis will be tested at the 
one-sided 0.025 significance level and no multiplicity adjustment is 
needed.
Key words
Transplantation, Kidney failure, renal failure, dialysis.


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1
Introduction
1.1
Background
Long-term graft survival in renal transplant recipients is dependent upon use of 
immunosuppressive agents. Despite improvements in current therapies, long-term 
transplantation outcomes have not significantly improved over the last decade. 
In renal transplant patients, chronic allograft nephropathy (interstitial fibrosis and tubular 
atrophy) is the main cause of graft failure. A number of factors have been implicated, including 
donor age, acute rejection, vascular remodeling and calcineurin-inhibitor (CNI)-induced 
nephrotoxicity. CNI’s represent the cornerstone of immunosuppressive therapy due to their 
efficacy in preventing acute rejection. However, CNIs have nephrotoxic side effects that can 
directly contribute to renal dysfunction and compromise long-term outcomes (Pascual 2009). 
Several studies have shown that kidney allograft function is an important predictor of graft 
failure and that renal function is the best candidate for predicting long-term renal allograft 
survival. Several reports have shown that improvements in graft half-life are related to 
conservation of renal function within the first-year post-transplantation (Park 2012, Kasiske 
2011, Wu 2010, Hariharan 2002). Therefore, treatment strategies that allow adequate 
immunosuppression to control rejection, avoid nephrotoxicity and improve long-term outcomes 
are sought. 
Everolimus (RAD001) is an inhibitor of the mammalian target of rapamycin (mTORi) that has 
been developed in combination with cyclosporine for the prevention of rejection episodes 
following kidney, liver and heart transplantation. Everolimus has been proven to be effective in 
preventing acute rejection. 
Initial phase III studies of fixed doses of everolimus versus mycophenolate mofetil (MMF) on 
combination with conventional exposure to cyclosporine have shown that everolimus is non-
inferior to MMF in preventing biopsy proven acute rejection and graft loss (Vitko 2004). In 
these studies, the everolimus regimen was associated with impaired renal function which was 
thought to result from potentiation of cyclosporine nephrotoxicity. 
Subsequently, 3 additional randomized studies demonstrated that de novo use of everolimus 
with concentration-controlled in combination with low exposure cyclosporine provided 
effective protection against rejection with good renal function (Nashan 2004, Vitko 2004, 
Tedesco 2010).
A recent analysis (Shihab 2012) from study CRAD001A2309 has shown that an exposure above 
3 ng/mL is adequate in reducing the risk of tBPAR. Moreover, lowest rates of renal dysfunction 
(defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound 
healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and 
hypertriglyceridemia were generally observed with everolimus trough concentration in the 
range 3–8 ng/mL and CsA levels of <100 ng/mL.
Two short-term studies conducted in the US have evaluated the de novo use of everolimus in 
combination with tacrolimus. CRAD001AUS01 was a pharmacokinetic study of tacrolimus and 
everolimus in 8 maintenance renal patients with renal insufficiency that suggested no 
pharmacokinetic interactions between everolimus and tacrolimus when given simultaneously. 
CRAD001AUS09 was a prospective, multicenter, open-label, randomized, 6-month study of 92 


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de novo renal transplant patients. This study also included PK assessments, which demonstrated 
no interaction between everolimus and tacrolimus. Patients received concentration-controlled 
everolimus, corticosteroids, and basiliximab with low exposure tacrolimus or standard exposure 
tacrolimus. Everolimus trough levels were to be maintained above 3ng/mL. Despite the 
reduction in tacrolimus exposure, the immunosuppressive regimen was associated with low 
BPAR rates in both study groups and an excellent graft function. The combination of 
everolimus and tacrolimus was found to be safe and well tolerated with no unanticipated safety 
issues.
Further evidence of the effectiveness of de novo everolimus in combination with tacrolimus 
was gained in the CRAD001A2426 (ASSET) study. ASSET was designed to determine whether 
concentration-controlled everolimus plus reduced exposure tacrolimus can preserve renal 
function in 199 de novo renal recipients. From the study, the authors concluded that use of EVR 
1.5mg bid in combination with low or very low TAC was associated with a low rate of tissue 
regeneration complications (lymphocele, wound complications, wound dehiscence or incisional 
hernia) in both groups. At Month 12, mean eGFR was higher in the tacrolimus 1.5–3 ng/ml 
group versus the 4–7 ng/ml group (57.1 ± 19.5 vs. 51.7 ± 20 ml/min/1.73 m2, respectively. 
Efficacy outcomes were similar in both study groups (Langer 2012).
Currently, study CRAD001AUS92 (EMPEROR) is ongoing. The study is set to compare the 
efficacy and safety of concentration-controlled de novo everolimus with reduced tacrolimus 
versus mycophenolate mofetil with standard dose tacrolimus. The study was recently completed 
and analysis is ongoing.
The additional benefits of a de novo everolimus based regimen, which could translate in a better 
long-term patient and graft survival, have also been evaluated. A pooled analysis of several 
everolimus based studies showed that there is a decreased incidence of CMV events compared 
to MPA based regimen (Nashan 2012, Brennan 2011, Havenith 2013). In addition, a post-hoc 
analysis has suggested that everolimus trough levels of > 8 ng/mL were associated with 
proteinuria, but not with everolimus trough levels of 3-8 ng/mL (Wiseman  2013, Loriga 2010). 
Other organ transplant indications beyond kidney provide additional evidence of the benefits of 
everolimus in transplantation. The anti-proliferative effects of everolimus, which may 
potentially support patient and graft survival, have been observed in the reduction of the risk 
for cardiac allograft vasculopathy (CAV) in heart transplant patients (Eisen 2003) and its use in 
drug-eluting stents (Grube 2004). 
Additionally, superior renal function from randomization to month 12 (difference 8.50 
mL/min/1.73 m2) in de novo liver transplant recipients treated with everolimus in combination 
with reduced tacrolimus vs. tacrolimus alone has recently been reported (De Simone 2012).
The de novo use of everolimus with CNI minimization provides an opportunity to manage the 
risk of acute allograft rejection, reduce exposure to CNI nephrotoxicity without compromising 
efficacy and potentially provide long-term benefits. To date, in the above-mentioned studies, a 
regimen with de novo everolimus and CNI minimization is at least as effective as standard CNI-
based regimens in terms of patient and allograft survival rates, with some improvements in renal 
function.
The present study builds on existing evidence and, with an innovative novel endpoint, 
combining renal function and allograft rejection, aims to demonstrate that de novo 


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concentration-controlled everolimus, plus very low levels of CNI, will lead to better overall 
graft outcomes, as compared to current standard of care, being MPA plus standard dose CNI. 
The study will aim to prospectively confirm the utility of this novel endpoint, which was 
developed in exploratory analyses of previous everolimus studies.
1.2
Purpose 
This study CRAD001A2433 is designed to evaluate the impact of concentration-controlled 
everolimus with reduced exposure CNI, compared to mycophenolic acid (MPA) with standard 
exposure CNI, with respect to efficacy and safety in de novo renal transplant recipients.
The primary endpoint combining efficacy (tBPAR) and graft function (eGFR) is consistent with 
recent Health Authority guidance on including an assessment of graft function as well as the 
traditional efficacy endpoints e.g. treated biopsy proven acute rejection, with or without clinical 
outcomes (i.e. Death and Graft loss). The endpoint represents an attempt to assess the clinical 
balance between having sufficient immunosuppression to prevent rejection while keeping CNI 
levels low enough to avoid nephrotoxicity. 
The data will be published in order to support the validity of this endpoint in renal 
transplantation and the benefit of everolimus in this population.
2
Study objectives
2.1
Primary objective
To evaluate the effect of everolimus with reduced exposure CNI versus MPA with standard 
exposure CNI on the binary composite of treated biopsy-proven acute rejection (tBPAR) or 
eGFR < 50 mL/min/1.73m2 (estimated glomerular filtration rate by MDRD4 formula) at Month 
12 post-transplantation.
2.2
Secondary objectives
Key Secondary Objectives

To evaluate everolimus with reduced exposure CNI compared to MPA plus standard 
exposure CNI at 12 months post-transplantation with respect to the composite efficacy 
failure rate of (treated biopsy proven acute rejection (tBPAR), graft loss or death).

To evaluate the binary composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2
(MDRD4) Month 12 among compliant subjects.
Other Secondary Objectives
To evaluate, by treatment group;

The incidence of composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2
(MDRD4) at Month 24.

The incidence of composite endpoint of tBPAR (excluding Banff grade 1A acute 
rejections) or eGFR < 50 mL/min/1.73m2 (MDRD4) at Month 24.

The incidence of composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2
(MDRD4) at Month 12 by subgroup (see Section 9.4.4).


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
The incidence of composite endpoint of tBPAR, graft loss or death at Month 24. 

The incidence of composite endpoint of tBPAR, graft loss, death, or loss to follow-up 
at Months 12 and 24.

The incidence of composite endpoint of tBPAR, graft loss, death or eGFR < 50 
mL/min/1.73m2 at Months 12 and  24. 

The incidence of composite endpoint of graft loss or death at Month 12 and 24. 

The incidence of individual endpoints of death, graft loss, tBPAR, BPAR, tAR, AR 
and humoral rejection at Months 12 and 24.

The incidence of tBPAR by severity and time to event.

The incidence of tBPAR excluding Banff 1A grade acute rejections

The incidence of transplant recipients with eGFR < 50 mL/min/1.73m2 at Months 12 
and 24.                                          

Renal allograft function and change in renal allograft function from Month 1 (eGFR) 
at Months 12 and 24.

The evolution of renal function, as eGFR, over time by slope analysis.

Renal function by Cystatin C-based and other alternate formulae (e.g. CKD-EPI). 

The incidence of adverse events, serious adverse events and adverse events leading to 
study regimen discontinuation.

The incidence of CMV and BKV, new onset diabetes mellitus, chronic kidney disease 
with associated proteinuria and CNI associated adverse events.

Urinary protein and albumin excretion by treatment estimated by urinary 
protein/creatinine and urinary albumin/creatinine ratios.

The incidence of major cardiovascular events. 

The incidence of malignancies.
3
Investigational plan
3.1
Study design
This is a 2-year, randomized, multicenter, open-label, 2-arm study evaluating graft function 
with everolimus and reduced CNI versus MPA and standard CNI in adult de novo renal 
transplant recipients (Figure 3-1). Consented subjects will enter the screening period and upon 


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meeting eligibility criteria, including successful transplantation, will enter the initial 12 Month 
treatment period then continue in the next treatment period to Month 24.
Figure 3-1
Study design- Primary Treatment to M12, Extension to M24 
Upon meeting eligibility criteria, approximately 2040 subjects (around 1020 per treatment arm) 
will be randomized (1:1) within 24 hr of transplantation, to the following treatment groups: 
Group 1: Everolimus plus Reduced CNI (see Table 5-1 for CNI target trough levels) 
Group 2: MPA plus Standard CNI (see Table 5-1 for CNI target trough levels)
Randomization will be stratified, within treatment groups, to balance; 1) recipients by donor 
type, living donors (LD), deceased standard criteria donors (SCD) and deceased expanded 
criteria donors ECD); 2) CNI usage, cyclosporine vs tacrolimus. The overall study population 
will contain no less than 50% recipients of living donor transplants and subjects taking 
cyclosporine will comprise no more than 20% of the population. 
Subjects will commence the randomized study regimen within 24 hr post-reperfusion of the 
allograft and should continue on the assigned open-label study regimen until the Month 24 visit. 
Induction therapy, with Basiliximab or rATG only, is mandatory for all subjects starting pre-or 
peri-operatively on the day of kidney transplant surgery (For details see Section 5.5.4). 
Corticosteroids are mandatory for all subjects through Month 24 and can be administered 
according to local practice but with a minimal daily dose of 5 mg prednisone, or equivalent. 
The study regimen/medication definition comprises either a) everolimus plus reduced CNI OR 
b) MPA plus standard CNI. Cyclosporine and tacrolimus dose adjustments will be made 
according to local trough values in order to maintain timely adherence to the protocol-specified 
ranges (See Table 5-1). Subjects are expected to remain on the original CNI (combined with 
everolimus or MPA) to which they were randomized until at least Month 24. However, if 
subjects discontinue either CNI due to AE/tolerability and can maintain everolimus or MPA 


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combined with the alternate CNI, within respective target levels as per protocol, they will not 
be considered to have discontinued study regimen/medication. 
The primary analysis of the trial is planned when the last subject has completed the Month 12 
visit. All subjects are expected to continue to Month 24 on the randomized study regimen. If 
subjects discontinue study medication (i.e. everolimus plus reduced CNI or MPA plus standard 
CNI) prior to Month 24 they should remain in study to Month 24 on standard of care 
immunosuppression.
It is planned that subjects completing the study to Month 24 on treatment may consent to 
participate in a separate three year observational study to Month 60 to allow validation of the 
composite endpoint with graft and subject outcomes up to 60 months post-transplant.
3.2
Rationale of study design
The controlled parallel group study design is well-established in de novo renal allograft 
recipients to evaluate an immunosuppressive drug regimen versus current standard treatment. 
As this trial uses three study drugs that need to be adjusted by therapeutic drug monitoring 
(TDM) to different target through levels, blinding is not possible due to the small therapeutic 
window and the burden of additional placebo drugs that subjects would need to take to finally 
ensure blinding of study drugs as well as the intention to have treatment arms close to clinical 
practice. 
The primary endpoint combining efficacy (tBPAR) and graft function (eGFR) is consistent with 
recent HA guidance (CHMP/EWP/263148/06, effective February 2009) and discussions (FDA 
Workshop, 2012: Endpoints in Clinical Trials of Kidney Transplantation) on including an 
assessment of graft function as well as the traditional efficacy endpoints e.g. treated biopsy 
proven acute rejection, with or without clinical outcomes (i.e. Death and Graft loss). The 
endpoint represents an attempt to assess the clinical balance between having sufficient 
immunosuppression to prevent rejection while keeping CNI levels low enough to avoid 
nephrotoxicity. 
The eGFR cutoff of 50 mL/min/1.73m2 represents a moderate level of renal dysfunction 
according to the CKD staging criteria. As such it provides a surrogate for graft function and is 
expected to be sensitive both to the effects of acute and chronic rejection and nephrotoxic side-
effects of immunosuppression. Analysis of previous renal transplant studies suggests that this 
cutoff, in combination with tBPAR, may provide a clinically meaningful approach to 
discriminate between immunosuppressive regimens in renal transplantation. 
Recent reports have shown that renal function over the first year post transplant is predictive of 
long-term renal graft survival. eGFR at 12 months has been associated strongly with subsequent 
long-term graft survival post-transplant (Park 2012, Kasiske 2011, Wu 2010). Thus, eGFR at 
one year post-transplant may represent a surrogate for long term graft survival and is therefore 
a relevant component in the composite.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
For everolimus the dosing will be as per the approved label for renal transplantation (including 
the target trough level of 3-8 ng/mL). The exposures of CNIs that are targeted will be lower 


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than the approved labels and will be designed to achieve significant reductions in CNI exposure 
compared to the control arm (see Table 5-1). The rationale is that this magnitude of reduction 
in CNI exposure can be achieved in combination with everolimus without impacting efficacy 
and with improved renal function since the CNI nephrotoxicity will be reduced. The inclusion 
of rabbit antithymocyte globulin (rATG) as an induction agent permits the inclusion of a broader 
range of centers and subjects and potentially higher risk subjects. rATG dose recommendations 
are based on practice according to a recent review but restricted in total dose in order to prevent 
over-immunosuppression (Deeks and Keating 2009). In addition, rATG may be used to provide 
immunological coverage for subjects with DGF. The assessment of efficacy and safety 
objectives at Month 12 post transplant with a longer term assessment at Month 24 are standard 
in the renal transplant indication. 
Several studies have indicated that the Month 12 renal function has a strong correlation with 
long term graft and subject survival (Park 2012, Kasiske 2011, Wu 2012). It is planned to 
examine the correlation between renal function at Month 12 with Month 24 and longer-term 
clinical outcomes, the longer term outcomes may be evaluated by a separate extension study.
3.4
Rationale for choice of comparator
Cyclosporine and tacrolimus, both known as calcineurin inhibitors (CNIs), are at present the
cornerstones in most of the immunosuppressive protocols used worldwide. In an effort to reflect 
current CNI usage as closely as possible, the ratio subjects receiving either tacrolimus or 
cyclosporine is anticipated to be approximately 4:1. MPA, cyclosporine, tacrolimus,
basiliximab and rATG have each been approved for the prevention of acute rejection after 
kidney transplantation by health authorities in each participating country.  The proposed 
standard target CNI levels are similar to those studied in previous clinical trials and are 
consistent with the updated prescribing information and reflect the current standard of care. 
3.5
Purpose and timing of interim analyses/design adaptations
There will be a futility analysis when approximately 30% of subjects have completed 6 months 
on study. The primary analysis will be performed when the last subject completes 12 months 
on study. There will be a second analysis when the last subject completes 24 months on study 
to evaluate longer term outcomes. 
3.6
Risks and benefits
In kidney transplantation there is a medical need for alternative immunosuppressive regimens 
which maintain the ability to prevent acute rejection while preserving renal function.  A regimen 
that will maintain efficacy while allowing reduced CNI exposure to minimize or avoid CNI-
associated adverse reactions (including nephrotoxicity) remains highly attractive. 
Early renal transplantation studies using everolimus fixed doses with standard CNIs (CsA) 
exposure were associated with progressive deterioration of kidney function. This risk was 
addressed successfully when concentration controlled everolimus (3-8 ng/mL) was used with 
basiliximab induction and reduced exposure to CsA (Study CRAD001A2309, Tedesco 2010). 
The recently completed liver transplantation study (CRAD001H2304) also demonstrated that 
everolimus, in combination with reduced tacrolimus exposure and corticosteroids, showed 


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comparable efficacy and superior renal function versus the approved standard exposure 
tacrolimus at 12 months post liver transplantation (DeSimone 2012).
Everolimus, like all immunosuppressants, is associated with side effects. These effects are 
predominantly class-specific and well described; they are usually dose-related and prior 
experience has supported the value of therapeutic drug monitoring (TDM) for managing 
everolimus, similar to CNIs.
Overall, the safety findings in study CRAD001A2309 were consistent with the known safety 
profile of both everolimus and cyclosporine;

Similar efficacy (tBPAR) compared to MPA plus standard cyclosporine control.

Similar subject and graft survival compared to MPA plus standard cyclosporine control.

Similar eGFR at Month 12 compared to MPA plus standard cyclosporine control.

Increased incidence (more than 5% difference vs control) of hyperlipidemia, peripheral 
edema, dyslipidemia and stomatitis/mouth ulcerations with everolimus, these events being 
generally manageable in clinical practice.
The side effect profile of everolimus in combination with tacrolimus has been characterized in 
study CRAD001AUS09 of 92 renal transplant recipients where the combinations of everolimus 
combined with tacrolimus maintained control of rejection while providing for preservation of 
graft function. There were no unanticipated safety issues and the  adverse events were  
consistent with everolimus and tacrolimus profiles. Currently,
analysis of study 
CRAD001AUS92 with everolimus and reduced tacrolimus versus an MPA+standard 
tacrolimus control arm is in progress. 
The benefits to subjects in this trial include potential improvement in renal function with 
preservation of graft survival, and increased medical monitoring and care. The risk to subjects 
in this trial will be minimized by compliance with the inclusion/exclusion criteria and particular 
compliance to the target levels for CNI and everolimus troughs (where non-compliance could 
cause over or under-immunosuppression). In addition to the site and CRA checking for 
compliance, the Novartis clinical team will also monitor compliance with the target levels and 
alert centers to correct out of range trough values.
4
Population
The study population will consist of male and female de novo renal transplant recipients. It is 
planned to randomize approximately 2040 subjects in around 200 centers worldwide. Since a 
20% screening failure rate is expected, approximately 2550 subjects will have to be screened.
The overall study population will contain no less than 50% recipients of living donor transplants 
and subjects taking cyclosporine will comprise no more than 20% of the population.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female subject ≥ 18 years old.
3. Subject randomized within 24 hr of completion of transplant surgery.


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4. Recipient of a kidney with a cold ischemia time < 30 hr.
5. Recipient of a primary (or secondary, if first graft is not lost due to immunological 
reasons) renal transplant from a deceased heart beating, living unrelated, living related 
non-human leukocyte antigen (HLA) identical or an expanded criteria donor (ECD, as 
defined below). 
ECD is defined as: 

Brain-dead donor > 60 years old OR

Donor age > 50 years old with two of the following criteria: 

History of hypertension 

Terminal serum creatinine ≥1.5 mg/dL 

Death resulting from cerebrovascular accident 
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
1. Subject unable to tolerate oral medication at time of randomization.
2. Use of other investigational drugs at the time of enrollment, or within 30 days or five half-
lives of enrollment, whichever is longer, except for dialysis related drugs which are not 
expected to interact with the study regimens.
3. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
4. Subject is a multi-organ transplant recipient.
5. Recipient of ABO incompatible allograft or complement-dependent lymphocytotoxic 
(CDC) crossmatch positive transplant (isolated positive B-cell crossmatches are not an 
exclusion criterion).
6. Subject at high immunological risk for rejection as determined by local practice for 
assessment of anti-donor reactivity e.g. high PRA, presence of pre-existing DSA.
7. Subject who is HIV positive.
8. HBsAg and/or a HCV positive subject with evidence of elevated LFTs (ALT/AST levels ≥ 
2.5 times ULN). Viral serology results obtained within 6 months prior to randomization are 
acceptable.
9. Recipient of a kidney from a donor who tests positive for human immunodeficiency virus 
(HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV).
10. Subject with a BMI greater than 35.
11. Subject with severe systemic infections, current or within the two weeks prior to 
randomization.
12. Subject requiring systemic anticoagulation that cannot be temporarily interrupted and  
which would preclude renal biopsy.
13. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases.


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14. Subject with severe restrictive or obstructive pulmonary disorders.
15. Subject with severe hypercholesterolemia or hypertriglyceridemia that cannot be 
controlled.
16. Subject with white blood cell (WBC) count ≤ 2,000 /mm3 or with platelet count ≤ 50,000 
/mm3.
17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment

Male sterilization (at least 6 m prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stabile on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment is she considered not of child bearing potential. 
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational, control and concomitant drugs
The following immunosuppressive drugs will be used in this study and will be administered in 
accordance with this protocol (see Section 5.5.4, Instructions for prescribing and taking study 


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treatment), not all dosage forms listed are available in each country, dependent on local approval 
status and regulations.
Investigational drug

Everolimus will be provided as 0.25, 0.5 and 0.75 and 1.0 mg tablets depending on locally 
approved dosage forms.
Control and concomitant drugs

Basiliximab as 20 mg lyophilized vial for intravenous administration following 
reconstitution with sterile water.

Rabbit anti-thymocyte globulin (rATG) will be provided locally as 25 mg lyophilized vial 
or as locally approved dosage form. 

MPA as either mycophenolic acid (sodium) 180 or 360mg enteric-coated tablets or 
mycophenolate mofetil 250 or 500 mg film coated tablets or 250mg capsules, depending 
on locally approved dosage forms. 

Cyclosporine as 10, 25, 50 and 100 mg capsules.

Tacrolimus as 0.5, 1.0 mg and 5.0 mg capsules. 
Corticosteroids for oral and i.v. administration will be supplied locally at the study centers.
5.1.2
Additional study treatment
No additional immunosuppressive agents may be used other than as per protocol. Concomitant 
therapies are as described below in Section 5.5.7.
5.2
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 1:1;

Everolimus plus reduced CNI (EVR+rCNI)

MPA plus standard CNI (MPA+sCNI)
5.3
Treatment assignment, randomization
At the Baseline Visit, within 24 hr of completion of transplant surgery, all eligible subjects will 
be randomized via Interactive Response Technology (IRT) to one of the treatment arms. 
Randomization will be stratified, within the treatment groups, by donor type (living donors (LD), 
deceased standard criteria donors (SCD) and deceased expanded criteria donors (ECD)) and 
CNI usage, cyclosporine vs tacrolimus. The investigator or his/her delegate will contact the IRT 
after confirming that the subject fulfills all the inclusion/exclusion criteria.  The IRT will assign 
the subject to a treatment arm and will specify the treatment to be dispensed to the subject. The 
randomization number will not be communicated to the caller. For subjects who are not eligible 
to be randomized post-transplantation the IRT must be informed that the subject is a screen 
failure and the screen failure recorded on the Screening disposition CRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject
randomization list will be produced by the IRT provider using a validated system that automates 


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the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms. 
The randomization scheme for subjects will be reviewed and approved by a member of the IIS 
Randomization Group.
5.4
Treatment blinding
Not applicable, this is an open label study.
5.5
Treating the subject
5.5.1
Subject numbering
Each subject is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
subject, the Subject Number will not be reused. 
Upon signing the informed consent form, the subject is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the subject to register them into the IRT. The site should select the 
CRF book with a matching Subject Number from the EDC system to enter data. 
If the subject fails screening and is not randomized for any reason, the IRT must be notified 
within 2 days that the subject was a screen failure/not randomized. The reason for not being 
randomized will be entered on the Screening  Disposition CRF.
5.5.2
Dispensing the investigational treatment
Each patient will be supplied by the study site with commercial drugs. Commercial Novartis 
drugs and/or 3rd party drugs used for this trial will be locally purchased and supplied either by 
the local CPO or by the clinical site per local regulations. In exceptional cases central supply 
may be carried out.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational treatment should be stored according to 
the instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the investigational treatment but no 
information about the subject. The investigator must maintain an accurate record of the 
shipment and dispensing of investigational treatment in a drug accountability log. Monitoring 
of drug accountability will be performed by the field monitor during site visits and at the 
completion of the trial. Subjects will be asked to bring all unused investigational treatment and 
empty packaging at each visit and at the end of the study or at the time of discontinuation of 
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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking study treatment
All dosages of everolimus, MPA, cyclosporine and tacrolimus and all dose changes during the 
study must be recorded, with reason for administration, on the corresponding Dosage 
Administration Record CRF. Dosages of basiliximab, rATG and steroids will be recorded on 
the Concomitant Medications CRF under the Immunosuppressive Mediations category.
Induction therapy, pre and post-transplant immunosuppression
CNI, MPA and/or steroids may be administered prior to transplant according to center practice 
but such practice must be applied consistently to all subjects at a given center. At randomization 
all subjects must follow the assigned regimen. Pre-transplant immunosuppression, including 
induction therapy and any CNI or MPA should be recorded on the Concomitant medication 
CRF under the immunosuppressive category.
Basiliximab induction
All subjects are to receive 2 x 20-mg doses of basiliximab administered intravenously. The first 
dose is to be given within 2 hr prior to transplant surgery, and the second dose should be 
administered on Day 4, or each dose can be according to local practice. The 20 mg vial should 
be reconstituted with 5 mL sterile water, the resultant solution is isotonic and may be injected 
as an i.v. bolus. Alternatively, the solution may be diluted to a volume of 50 mL with sterile 
saline and 5% dextrose and administered as an infusion over 30 minutes. If venous irritation 
occurs following bolus administration, the next dose (if appropriate) should be administered as 
a 30-minute infusion. Dosing of basiliximab will be recorded in the Concomitant Medications 
CRF under the immunosuppressive category.
Rabbit anti-thymocyte globulin induction therapy
Administration of rabbit anti-thymocyte globulin (rATG) induction therapy should be given at 
1.5 mg/kg/day and total dosage must not exceed 6 mg/kg. This dosing guidance is for 
Thymoglobulin®, where other rATG products are used usage should be consistent with local 
practice and approved labeling.  rATG induction therapy can be administered from the day of 
transplant. Close attention should be paid to hematological parameters (e.g. lymphocytes, WBC 
and platelets) when administering rATG. Refer to manufacturer’s product labeling for 
additional safety information. Dosing of rATG should be recorded on the Concomitant 
Medications CRF under the immunosuppressive category. 
Initiation of everolimus with CNI
Within 24 hr of successful transplantation the subject will be randomized to receive a regimen 
of either everolimus or MPA in combination with the CNI drug as per center practice. The first 
post-randomization dose of everolimus in combination with CNI must be given immediately 
after randomization, within 24 hr of transplantation. All everolimus doses and dose changes 
should be recorded on the everolimus dose administration record eCRF.


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Subjects will take everolimus twice daily in 12 hr intervals simultaneously with CNI, on a 
consistent schedule with regards to time of day and relation to meals.  No grapefruit or grapefruit 
juice should be taken at all throughout the study.
The starting dose will be different based on CNI usage due to differential PK interactions and 
the suggested starting dose tablet strengths below may be modified according to locally 
available dosage forms and investigators’ judgment to rapidly achieve a target trough level of 
3-8 ng/mL. All everolimus dosing will be recorded on the dose administration record for 
everolimus. 
For tacrolimus subjects the everolimus starting dose should be 3 mg/day as 1.5 mg bid: 1.5 mg 
everolimus in the morning, and 1.5 mg in the evening for all tacrolimus subjects. 
For cyclosporine subjects the everolimus starting dose should be 1.5 mg/day as 0.75 mg bid: 
0.75 mg everolimus in the morning, and 0.75 mg in the evening for all cyclosporine subjects. 
Everolimus medication will be provided in 0.25, 0.5, 0.75 and 1.0 mg tablet strengths, 
depending on locally approved dosage forms. 
The first everolimus trough level must be performed by Week 1, at the latest. If the everolimus 
trough level is below 3 ng/mL, the everolimus dose must be increased by at least 50%. 
Everolimus trough levels (C-0h) must be performed 5 days +/-2 days after any everolimus dose 
adjustment to confirm the levels are in the target range (3-8 ng/mL). The dose will be adjusted 
to maintain the everolimus levels in target (3-8 ng/mL), according to the local laboratory, for 
the duration of the study. The guidelines for everolimus dose reduction/interruption can be 
found in Table 5-2. The co-administration of drugs known to interfere with everolimus 
metabolism (see Appendix 2) should be avoided if possible. If these drugs are required, the 
investigator should carefully monitor everolimus and CNI trough levels.
In addition to the routine evaluations, everolimus trough blood levels must be monitored after 
each CNI dose reduction or after each CNI increase due to drug-drug interactions between these 
two compounds. Everolimus and CNI trough levels will be determined at the time points 
indicated in Table 6-1, for subjects in the investigational arm. 
Initiation of MPA with CNI
Within 24 hr of successful transplantation the subject will be randomized to receive a regimen 
of either everolimus or MPA in combination with the CNI drug as per center practice. The first 
post-randomization dose of MPA in combination with CNI must be given immediately after 
randomization, within 24 hr of transplantation.
Dosing of MPA will be as follows:

Enteric-coated mycophenolate sodium (Myfortic®) will be 2 tablets of 360 mg b.i.d. 
(1.44 g/day) for subjects randomized into the control group. 

Mycophenolate mofetil (MMF, Cellcept®) will be 2 tablets of 500 mg or 4 capsules of 
250 mg b.i.d (2 g/day) for subjects randomized into the control group. 
If a subject is treated with cyclosporine, the MPA dose should be maintained at these levels 
throughout the course of the study. If a subject is treated with tacrolimus, the MPA dose should 
be reduced after Week 2 to 1080 mg/day of Myfortic® or 1.5 g/day of MMF. The investigator 
is responsible for instructing the subjects regarding the exact dose and dosing schedule to be 


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followed. Dose adjustment/interruption guidance for MPA is provided in Appendix 3. All MPA 
doses and changes should be recorded on the MPA dose administration record eCRF.
Management of CNI targets
CNI should be adjusted to and maintained within the target ranges in Table 5-1.
Table 5-1
CNI trough target level ranges 
Study Visit
Tacrolimus Ranges
Cyclosporine Ranges
EVR arm
MPA arm
EVR arm
MPA arm
Day 1 ≤ Month 2
4-7 ng/mL
8-12 ng/mL
100-150 ng/mL
200-300 ng/mL
Month 2 ≤ Month 6
2-5 ng/mL
6-10 ng/mL
50-100 ng/mL
150-200 ng/mL
Month 6 ≤ Month 24
2-4 ng/mL
5-8 ng/mL
25-50 ng/mL
100-200 ng/mL
Tacrolimus administration
Tacrolimus will be administered as capsules p.o., b.i.d.. Tacrolimus should be initiated as soon 
as possible and no later than 24 h after reperfusion of the graft. The lowest permitted dosing of 
tacrolimus in this study is 0.5 mg b.i.d.  If tacrolimus is discontinued for more than 21 
consecutive days, switching to cyclosporine may be considered, otherwise the study regimen 
must be discontinued. Subjects who discontinue their study regimen are expected to remain in 
study on Standard of care to Month 24. Visits and assessments for such subjects are described 
in  Table 6-1.
Tacrolimus dosing will be modified by investigators as needed and recorded on the Tacrolimus 
Dosage Administration CRF at each visit. In the event of tacrolimus intolerance (e.g., 
nephrotoxicity, neurotoxicity) dose reduction of tacrolimus may be necessary. If it occurs that 
the tacrolimus trough level is outside the required target level, then the investigator will be 
asked to confirm the intended tacrolimus trough level, to record the start date and reason for 
dose reduction on the Tacrolimus Dosage Administration CRF.
The co-administration of drugs known to interfere with tacrolimus metabolism (see Appendix 
4) should be avoided if possible. If these drugs are required, the investigator should carefully 
monitor tacrolimus and/or everolimus trough levels.
Cyclosporine administration
Cyclosporine will be administered as capsules p.o., b.i.d., unless an oral solution or i.v. 
administration of cyclosporine cannot be avoided.  Cyclosporine should be initiated as soon as 
possible and no later than 24 h after reperfusion of the graft. The lowest permitted dosing of 
Cyclosporine in this study is 25 mg b.i.d.  If cyclosporine is discontinued for more than 21 
consecutive days, switching to tacrolimus may be considered, otherwise the study regimen must 
be discontinued. Subjects who discontinue their study regimen are expected to remain in study 
on Standard of care to Month 24. Visits and assessments for such subjects are described in  
Table 6-1.  
Cyclosporine dosing will be modified by investigators as needed and recorded on the 
Cyclosporine Dosage Administration CRF at each visit. In the event of cyclosporine intolerance 
(e.g., nephrotoxicity) dose reduction of cyclosporine may be necessary. If it occurs that the 
cyclosporine trough level is below the required target level, then the investigator will be asked 


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to confirm the intended cyclosporine trough level, to record the start date and reason for dose 
reduction on the Cyclosporine Dosage Administration eCRF
The co-administration of drugs known to interfere with cyclosporine metabolism (see Appendix 
5) should be avoided if possible.  If these drugs are required, the investigator should carefully 
monitor CNI and/or everolimus trough levels.
The investigator should promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject should be instructed to contact the investigator 
if he/she is unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment
For all everolimus subjects who are unable to tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to keep the subject on investigational drug. The 
following guidelines should be followed (Table 5-2), for management of lipid elevations refer 
to Section 5.5.7 for initial approach, prior to considering dose reduction. The everolimus dose 
should be decreased by at least 0.25 mg b.i.d if a dose reduction is necessary. If a temporary 
reduction in everolimus level is needed, the everolimus trough blood level should still be 
maintained no lower than 3 ng/mL. Everolimus should be discontinued if a trough level ≥3 
ng/mL cannot be maintained due to toxicity. Severe and unremitting changes may also lead to 
investigational drug discontinuation. 
For subjects having rATG administered, whether as  induction therapy, DGF or anti-rejection 
treatment the relative impact of all medications to reduced hematological parameters should be 
considered, thus everolimus dose reduction to these guidelines may not always be necessary 
under these circumstances.
Table 5-2
Guidelines for everolimus dose reduction/interruption
Platelet 
count
(/mm3)
Hemoglobin
(g/dL)
WBC count
(/mm3)
Cholesterol
(mmol/L)
Triglycerides
(mmol/L)
Dose reduction
75000
8
3000
> 9
> 8.5
Interruption
50000
6
≤ 2500
10
10.5
If everolimus is interrupted for safety reasons for longer than 21 consecutive days study regimen 
should be discontinued.  Everolimus may be interrupted during antibody treatment of rejection 
episodes. In case of any planned or emergency surgery during the study treatment period, 
everolimus can be interrupted and a compensatory increase in CNI may be considered. In 
elective cases, this may be done 5 days before surgery which would allow restart of everolimus 
by 21 days post-surgery, in these cases everolimus must be re-introduced at the latest by day 27 
after discontinuation. 
For MPA, dose adjustment or interruption should follow Appendix 3.  If MPA or either CNI is 
interrupted for more than 21 consecutive days the randomized study regimen must be 
discontinued. Subjects who discontinue their randomized study regimen are expected to remain 
in study with immunosuppression according to local practice until completing the treatment 
period at Month 24, visits and assessments for such subjects are described in  Table 6-1. All 
immunosuppressive therapy administered post discontinuation of study regimen (i.e. 


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MPA+CNI or EVR+CNI) should be recorded on the concomitant Medications CRF under the 
immunosuppressive category.
For subjects having rATG administered, whether as  induction therapy, DGF or anti-rejection 
treatment the relative impact of all medications to reduced hematological parameters should be 
considered, thus MPA dose reduction may not always be necessary under these circumstances.
All dose changes must be recorded on the everolimus or MPA Dosage Administration Record 
CRF as appropriate.
Treatment of Acute Rejection episodes
In all suspected acute rejection episodes, regardless of initiation of anti-rejection treatment, an 
allograft biopsy must be performed within 48 hr. All episodes of acute rejection must be entered 
on the corresponding CRF (e.g. Acute Rejection CRF, Kidney Allograft Biopsy CRF, etc.)
preferably within 24 hr.
Acute rejections should be treated with bolus methylprednisolone (other corticosteroids are 
acceptable at an equivalent dose) according to local practice.  Recommended treatment is with 
at least 3 boluses of i.v. methylprednisolone with a minimal dose of 250 mg/bolus or at least 2 
boluses of i.v. methylprednisolone with a minimal total dose of 750 mg. 
Other anti-rejection therapies (i.e. antibody therapy) should only be used in cases of steroid -
resistant rejections, vascular rejections or rejections with a Banff grade ≥ 2B.
All medications used for the treatment of suspected or confirmed acute rejections must be 
recorded on the Concomitant Medications CRF under the Immunosuppressive category.
Treatment of Delayed Graft Function (DGF)
In case of DGF, treatment will be according to local practice, but the randomized study regimen 
cannot be interrupted for more than 21 consecutive days. DGF treatments must maintain 
sufficient immunological coverage for the graft and may include maintaining, interrupting or 
reducing the dose of CNI and the use of anti-thymocyte globulin. In case of use of depleting 
antibody hematological parameters (e.g. lymphocytes, WBC and platelets) must be monitored 
carefully. Use of MPA and everolimus in subjects randomized to the other treatment arm (i.e. 
everolimus or MPA respectively) is prohibited during any interruption whether for DGF or 
other reasons. 
If a subject with DGF is not able to return to or maintain their randomized study regimen as per 
protocol after 21 consecutive days of interruption, the subject should be discontinued from the 
study. If a subject is placed on permanent dialysis (or retransplanted) the Graft Loss, and 
Adverse Event CRFs should be completed, as well as an SAE report of Graft Loss submitted. 
Dialysis treatments should be recorded on the Dialysis CRF.  Retransplantation should be 
recorded on the surgical and medical procedures CRF. 
5.5.6
Rescue medication
Not applicable.


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5.5.7
Concomitant Treatment
The investigator should instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study will be recorded on the Concomitant Medications 
CRF or the Surgical and Medical Procedures CRF respectively.
CMV prophylaxis
Cytomegalovirus (CMV) pre-emptive therapy and/or prophylaxis is recommended for all  donor 
CMV positive/recipient CMV negative cases and considered for all recipients who are CMV 
positive.  It is recommended that CMV prophylaxis be administered for a minimum of three
months after transplantation.  Prophylactic treatment with i.v. ganciclovir or oral valganciclovir 
is recommended and will be administered according to local practice, taking into account dose 
adjustments based on renal function. CMV prophylaxis is also recommended following 
antibody treatment of acute rejection episodes (see Section 5.5.5 above). Such prophylaxis 
should be recorded on the Concomitant Medications CRF. 
Pneumocystis jirovecii (Pneumocystis carinii) pneumonia prophylaxis
All subjects will be started on trimethoprim-sulfamethoxazole,  starting when oral medication 
can be tolerated and continuing until at least six months post-transplant.  After six months, 
subjects will be treated per local practice. Aerosolized pentamidine or dapsone may be 
administered to subjects who are unable to tolerate trimethoprim-sulfamethoxazole. 
These prophylactic treatments above must be applied consistently across the study population 
at each given center to avoid bias and confounding in the results.  Such prophylaxis should be 
recorded on the Concomitant Medications CRF. 
Treatment of hyperlipidemia
During the course of the study, the lipid profile will be monitored. Lipid lowering medications 
should be administered according to guidelines and local practice.
The combination of HMG-CoA reductase inhibitors concomitantly with fibrates should be 
avoided, due to the increased risk of myopathy and rhabdomyolysis in combination with 
cyclosporine. If combination therapy is needed, ezetimibe should be used in combination with 
statins. Lipid lowering therapy should be optimized before dosage reduction of study 
medication is considered.
Hepatitis B (HBV) prophylaxis
Prophylaxis for recurrent hepatitis B during the course of this study is allowed and will be 
administered at the discretion of the investigator.
5.5.8
Prohibited Treatment
Use of the treatments displayed in Table 5-3 is NOT allowed after informed consent up to the 
end of the 24 Month treatment period. If the use of any of these medications or other non-
protocol immunosuppressives is discovered prior to randomization subject must not be 
randomized and recorded as a screen failure. If discovered after randomization no further doses 


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are to be given and the subject should continue on the randomized treatment regimen, noting 
the protocol deviation.
Table 5-3
Prohibited medications
Medication
Action to be taken
Advagraf®
Discontinue Advagraf®, Subject to remain in 
study with protocol deviation.
Sirolimus
Discontinue sirolimus, Subject to remain in study 
with protocol deviation.
Belatacept
Discontinue belatacept, Subject to remain in 
study with protocol deviation.
Azathioprine
Discontinue azathioprine, Subject to remain in 
study with protocol deviation.
Induction therapy with Campath or other non-
protocol antibody agents 
Agent to be discontinued and subject to remain 
in study with protocol deviation.
5.5.9
Discontinuation of study treatment and discontinuation from study 
Discontinuation of study regimen 
The Dosage administration records for everolimus, MPA, tacrolimus and cyclosporine will be 
used to record if a subject has permanently discontinued study treatment and why.
Possible reasons for study treatment discontinuation are:

Adverse Event

Lack of Efficacy

Technical problems

Subject/Guardian Decision

Lost to follow-up

Death

Graft Loss
The investigator should discontinue a subject from their randomized treatment regimen if, on 
balance, he/she believes that continuation would be detrimental to the subject’s well-being.
If, at any time throughout the study, the randomized treatment regimen or any component of 
the regimen is interrupted for longer than 21 consecutive days, unless being held due to an 
elective surgical procedure then study regimen should be discontinued.
Subjects who become pregnant while taking study medication must be discontinued from study 
medication and from the study, such pregnancies should be reported as SAEs to Novartis DSE 
and entered as AEs in the CRF, the reason for discontinuation of study medication should be 
recorded as AE and reason for discontinuation from study is pregnancy (see next section below). 
Subjects who discontinue their randomized study regimen (any component whether everolimus, 
MPA or the CNI) should remain in the study, if possible, and receive standard of care 
immunosuppression, according to local practice, until completing the study at Month 24. Visits 
and assessments for such subjects are described in Table 6-1. All immunosuppressants after 


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discontinuation of study regimen must be recorded on the Concomitant Medication CRF under 
the Immunosuppressive category.
Subjects are expected to remain on the original CNI (combined with everolimus or MPA) to 
which they were randomized until at least Month 24. However, if subjects discontinue either 
CNI due to AE/tolerability and maintain everolimus or MPA combined with the alternate CNI, 
administered to respective target levels per protocol, they will not be considered to have 
discontinued study regimen/medication.
Discontinuation from Study and Study/Period completion
Subjects who discontinue their study treatment regimen should NOT be considered withdrawn 
from the study. Such subjects should remain in the study, if possible, and receive standard of 
care immunosuppression, according to local practice, until completing the study at Month 24. 
See Table 6-1 for the required assessments of these subjects after discontinuation of study 
regimen. 
The status of every randomized subject must be recorded on Month 12 and/or Month 24 Study 
Phase Completion CRFs as either completing or discontinuing from the respective study period, 
with reason for discontinuation. 
Possible reasons for discontinuation from the study are:

Technical problems

Subject/Guardian Decision

Lost to follow-up

Death

Graft Loss

Study terminated by sponsor

Pregnancy
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, 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 make every effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the Study Phase Completion CRF at Month 12 and/or Month 24 as 
applicable. 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator must 
show "due diligence" by documenting in the source documents steps taken to contact the s ubject, 
e.g. dates of telephone calls, registered letters, etc.
Subjects who are prematurely withdrawn from the study will not be replaced.
5.5.10
Emergency breaking of treatment assignment
Not applicable.


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5.5.11
Study completion and post-study treatment
Subject who successfully complete 24 months on treatment may be eligible to participate in a 
separate observational extension study for a further three years. Subjects who are prematurely 
withdrawn from the study should be treated according to local standard of care per investigator’s 
judgment. 
The study will be complete and ready for final analysis when the last active subject has 
completed their Month 24 visit.
5.5.12
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and treated as for a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are to be 
performed. “A” indicates assessments only to be performed for subjects maintaining the study 
regimen (i.e. EVR+CNI or MPA+CNI). Subjects should be seen for all visits on the designated 
day or as close to it as possible.
The day of randomization will be considered to be study Day 1.  Subjects will make scheduled 
study visits on Day 4, at the end of Weeks 1, 2 and 4 at the end of Months 2, 4, 6, 9, 12, 18 and 
24. All randomized subjects are expected to continue in the study up to Month 24 regardless of 
being on or off randomized treatment status. Subjects who discontinue their randomized study 
treatment regimen should be treated according to standard of care immunosuppression and 
return for the assessments indicated by X in Table 6-1. 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 to determine the subject and graft status.
At a minimum, subjects will be contacted for safety evaluations (SAEs) during the 30 days 
following the last study visit. Documentation of attempts to contact the subject should be 
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Table 6-1
Assessment schedule- Study Treatment to Month 24
Study Period
Screening1
Treatment to Month 12
Extension 
Treatment 
to Month 24
Visit
SCR
BL2
D4
W1
W2
W4
M2
M4
M6
M9
M12
M18
M2
4
Visit Number
1
99
101
102
103
104
105
106
107
108
199
201
299
Informed Consent 1
X
Demographics 
X
Inclusion/
Exclusion
X
X
Medical History
X
Kidney Transplant 
Background 
Recipient/Donor
X
Kidney Transplant 
Procedure
X
Viral serology3
Recipient/Donor
X
Pregnancy test4
X
X
X
X
X
IRT call
S
S
Screening 
Disposition1
X
Vital signs
X
X
A
A
A
A
A
A
X
X
X
X
X
Physical exam
S
S
S
Tacrolimus dose 
administration 
record5
X
A
A
A
A
A
A
A
A
A
A
Tacrolimus trough 
level6
X
X
X
X
X
X
X
X
X
X
Cyclosporine  
dose 
administration 
record5
X
A
A
A
A
A
A
A
A
A
A
Cyclosporine 
trough level6
X
X
X
X
X
X
X
X
X
X
Everolimus dose 
administration 
record5
X
A
A
A
A
A
A
A
A
A
A
Everolimus trough 
level6
A
A
A
A
A
A
A
A
A
A
MPA Dose 
administration 
record5
X
A
A
A
A
A
A
A
A
A
A
Central 
Laboratory7
X
A
A
A
A
A
X
X
X
X
X
Concomitant 
medication8
As Needed
Surgical and 
Medical 
Procedures
As Needed
Adverse events9
As Needed
CMV assessment
As Needed
BKV assessment
As Needed
Hospitalizations
As Needed
Allograft rejection
              As Needed


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Study Period
Screening1
Treatment to Month 12
Extension 
Treatment 
to Month 24
Visit
SCR
BL2
D4
W1
W2
W4
M2
M4
M6
M9
M12
M18
M2
4
Visit Number
1
99
101
102
103
104
105
106
107
108
199
201
299
Kidney allograft 
biopsy
              As Needed
Graft loss
As Needed
Dialysis log
As Needed
Death
As Needed
Withdrawal of 
Informed Consent
As Needed
Month 12 Period
Completion10
As Needed
X
Month 24 Period 
Completion10
As needed
X
X=assessment for all subjects in study regardless of on or off randomized study regimen, to be recorded in clinical data base
A=assessment ONLY for subjects maintaining their randomized study regimen, to be recorded on clinical data base
S=assessment to be recorded on source documentation
1.
Informed consent should be obtained prior to performing any study-related procedures. Screening may extend up to 4 
weeks prior to transplant e.g. for scheduled living donor transplants and ends when the subject is either randomized or 
becomes a screen failure. For every consented subject the Screening period disposition CRF must be completed to indicate 
whether they  were randomized or screening failures.
2.
The Baseline visit covers the transplant period from 24 hr prior to surgery until randomization or randomization failure. 
Randomization must occur within 24 hr of completion of transplant surgery and post-transplant criteria for randomization (e.g. 
ability to take oral medication) must be met. Day 1 is the day of first dose of study drug post-randomization and for 
subsequent visits one week is 7 days and one month is 30 days, thus the Week 1 visit is on the seventh day from Day 1. 
3.
Viral serology includes HCV, HIV, HBV surface antigen, CMV and EBV. Measurements made within the last 6 months 
will be accepted, otherwise these tests should be performed within one week of randomization. 
4.
Only for females of child bearing potential, serum pregnancy tests should be carried out according to local practice. Local 
result must be available and negative prior to randomization. 
5.
First dose of everolimus or MPA together with applicable CNI (tacrolimus or cyclosporine) must be given immediately 
following randomization and within 24 hr of transplantation. Pre-transplant immunosuppression, including induction therapy 
and any CNI or MPA should be recorded on the Concomitant medication CRF under the immunosuppressive category.
6.
Blood draws for everolimus, tacrolimus and cyclosporine (as applicable) trough concentrations should be performed 
locally as shown and additionally 5 days ± 2 days following each clinic visit in which tacrolimus, cyclosporine or everolimus
doses are changed. Subject clinical management should be based on these local trough levels. At certain centers, by 
agreement with the sponsor, central analysis of everolimus may be performed.
7.
Central laboratory tests  at each visit indicated include:  Biochemistry (sodium, potassium, chloride, calcium, Cystatin C, 
magnesium, inorganic phosphate, urea, creatinine, uric acid,  AST, ALT, alkaline phosphatase, total bilirubin, CPK, lipase 
and amylase); Hematology (platelets, hemoglobin, red blood cell (RBC), white blood cell (WBC) and differential count): 
Lipids: total cholesterol, HDL, LDL and triglycerides Urinalysis (protein, creatinine, albumin, glucose; proteinuria and 
albuminuria per 24hr period will be estimated from spot protein/creatinine and albumin/creatinine ratios).  For subjects who 
have discontinued study regimen who continue in the study to Month 24 all central laboratory assessments, including 
serum creatinine for renal function, should be performed, where no central laboratory serum creatinine is available local 
laboratory serum creatinine should be obtained. HbA1c and fasting plasma  glucose will also be carried out by the central 
laboratory at Week 4 and Months 4, 6, 9, 12 18 and 24. At certain centers, in agreement with the sponsor, central analysis of
everolimus levels may be performed.
8.
Induction therapy (basiliximab or rATG) should be recorded on the Concomitant Medications CRF under the 
Immunosuppressive Medications category. Pre-transplant CNI or MPA, if used, should be also recorded on the Concomitant 
medication CRF under the immunosuppressive category.
9.
All serious adverse events, serious infections and pregnancies must be reported from informed consent until 30 days 
after the last study visit post randomization (i.e. to the Month 12/24 visit or early discontinuation from study).
10. All subjects are expected to continue in the study to Month 24 regardless of whether they are on or off randomized study 
regimen, if subjects discontinue randomized study regimen they should continue on standard of care and attend study visits 
to M24. Any permanent discontinuation of the randomized study regimen should be recorded on the appropriate DAR(s) 
(everolimus MPA, tacrolimus or cyclosporine as needed). Post discontinuation of study regimen the immunosuppressive 


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Study Period
Screening1
Treatment to Month 12
Extension 
Treatment 
to Month 24
Visit
SCR
BL2
D4
W1
W2
W4
M2
M4
M6
M9
M12
M18
M2
4
Visit Number
1
99
101
102
103
104
105
106
107
108
199
201
299
regimen prescribed should be recorded on the Concomitant medication CRF under the immunosuppressive category and 
any CNI trough levels should be recorded on the appropriate local lab trough CRF.
For subjects who have discontinued randomized study regimen, visits need only be completed at Months 6, 9, 12, 18 and 24. 
For all subjects completing the study to Month 12 or discontinuing from the study prior to Month 12, the M12 Period completion 
form should be completed, regardless of on or off-treatment status. Similarly post-Month 12, for all subjects completing the 
study to Month 24 or discontinuing from the study prior to Month 24, the M24 Period completion form should be completed, 
regardless of on or off-treatment status.
 
6.1
Information to be collected on screening failures
All subjects who have signed informed consent but do not enter the next period (i.e. 
Randomized treatment to Month 12) will have the study completion CRF for the screening 
period, demographics (giving reason for screen failure), inclusion/exclusion and SAE data 
collected. Adverse events that are not SAEs will be followed by the investigator and collected 
only in the source data. All consented subjects must be entered in the interactive response 
technology (IRT) system at screening. For subjects who are not randomized the IRT and 
Screening Disposition CRF must both be updated to indicate screen failure.
Rescreening is only allowed for subjects who were screen failures on the initial Screening visit 
e.g. due to lab values out of range. Rescreened subjects should be recorded as screen failures 
under their original Subject ID number and assigned a new Subject ID number in the Database 
when consented for rescreening. 
All subjects who have signed informed consent and enter the next period of the study (i.e. are 
randomized to treatment) will have all adverse events occurring after informed consent is 
signed recorded on the Adverse Event CRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Subject demographics/other baseline characteristics
After informed consent has been signed and the subject’s eligibility to participate in the study 
has been determined, baseline subject information will be obtained in accordance with local 
regulations, including date of birth, age, sex (with child bearing status for females), race and 
ethnicity. In addition, relevant medical history (including CKD and ESRD history) and current 
medical conditions at screening, a full physical examination, vital signs and a pregnancy test 
(for females of child-bearing potential) will also be performed. 
At Baseline/Transplantation information on the renal transplant procedure, recipient and donor 
transplant background, recipient and donor viral serology and recipient/donor HLA testing 
results will be recorded. Post-transplant, when all Inclusion/Exclusion criteria are met, the 
subject may be randomized. For randomization of subjects the IRT must be contacted, CNI and 
Donor status provided and the IRT will assign the treatment group. For all subjects regardless 
of randomization status the IRT and Screening Disposition CRF must be completed to 


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document all consented subjects as either randomized or as screen failures and the reason for 
screen failure recorded in the CRF.
6.3
Treatment exposure and compliance
All pre-transplant immunosuppression administered, such as basiliximab, rATG and any other 
agents (CNI, MPA and/or corticosteroids) administered pre-randomization will be recorded on 
the Concomitant Medications CRF under the immunosuppressive category.
All post-randomization doses of everolimus, MPA, tacrolimus and cyclosporine administered 
during the course of the study will be recorded on the corresponding Dosage Administration 
Record CRF. 
For all these immunosuppressive drugs the start date, total dose, stop date and reason for dose 
administration or dose change are to be provided. If study drug is interrupted due to inability to 
tolerate oral medication and therapy via an NG tube is administered the non-study drug usage 
of the immunosuppressive should be recorded on the Concomitant Medications CRF under the 
immunosuppressive category.
Tacrolimus and cyclosporine trough levels will be determined locally and recorded on the 
relevant CRF. The local trough values will be used to adjust the tacrolimus and cyclosporine 
dosing. Post-discontinuation of study regimen, for subject remaining in study to Month 24, the 
CNI trough levels should be recorded on the appropriate local lab CRF.
Everolimus trough levels will be determined by the local Laboratory. However, for sponsor 
agreed centers where subject management is not possible using a local laboratory, the samples 
should be sent to the Designated Central laboratory. All local everolimus levels must be 
completed for all visits on the local everolimus CRF.
Other drugs administered prior to and continuing at start of study medication will be entered on 
the Concomitant medications CRF.
Compliance will be assessed by the investigator and/or study personnel at each visit and
information provided by the subject. This information should be captured in the source 
document at each visit.
6.4
Efficacy
Treated Biopsy Proven Acute Rejection (tBPAR)
A treated BPAR is any condition where the subject received anti-rejection treatment and was 
histologically diagnosed as acute rejection (according to the Banff 2009 criteria, Appendix 6). 
Renal biopsies will be collected for all cases of suspected acute rejection.
Kidney allograft biopsy
For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, an 
allograft biopsy must be performed within 48 hrs. Biopsies will be read by the local pathologist 
according to the updated Banff 2009 criteria (Appendix 6). The results of the biopsy read by 
the local pathologist will be listed on the Kidney Allograft Biopsy CRF. The results will be used 
for subject management for acute rejection. The local pathologist will remain blinded to 


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treatment. Any biopsies performed according to local practice (e.g. not for cause) should also 
be recorded.
Graft Loss
The allograft will be presumed to be lost on the day the subject starts dialysis and is not able to 
subsequently be removed from dialysis. If the subject undergoes allograft nephrectomy prior to 
starting permanent dialysis, then the day of nephrectomy is the day of graft loss. The reason for 
graft loss will be recorded on the Graft Loss CRF. This will be reported on the M12 or M24 
study completion CRF with Graft Loss as the reason for study discontinuation and on the 
appropriate Dosage Administration Record CRF(s) if death occurs while on randomized 
treatment. Graft loss is considered a Serious Adverse Event and should be reported on the 
Adverse Event CRF (as serious) and the SAE reported to the local Novartis Drug Safety and 
Epidemiology Department local Novartis Drug Safety and Epidemiology (DS&E) Department 
within 24 hr.
Death
In the event of subject death, the SAE leading to Death should be reported to Novartis DS&E 
within 24 hr. The events leading to the death should be entered on the Adverse Event CRF and 
the death should be indicated on the appropriate Dosage Administration Record CRF(s) (if 
death occurs while on randomized treatment) and on the Study Completion CRF.
6.4.1
Appropriateness of efficacy assessments 
The composite efficacy endpoint of treated BPAR and GFR< 50 mL/min/1.72 m 2 is novel in 
the kidney transplantation indication. This approach is consistent with recent HA guidance 
(CHMP/EWP/263148/06, effective February 2009) and discussions (FDA Workshop, 2012: 
Endpoints in Clinical Trials of Kidney Transplantation) on including an assessment of graft 
function as well as the traditional efficacy endpoints e.g. treated biopsy proven acute rejection 
with or without clinical outcomes (i.e. Death and Graft loss).  The endpoint represents an 
attempt to assess the clinical balance between having sufficient immunosuppression to prevent 
rejection while keeping CNI levels low enough to avoid nephrotoxicity. 
The composite of tBPAR, graft loss or death has been used as an endpoint in many previous 
studies in the kidney transplantation indication and has been widely accepted by Health 
Authorities for registration purposes in this indication.
6.5
Safety
Renal Function
Renal function by calculated eGFR using the MDRD4 formula (Coresh, 2003) from 
Randomization to Month 12 is a primary variable for assessment of renal function in this study. 
This will also be the primary method of assessment of renal function with respect to other renal 
endpoints.
6.5.1
Physical examination
A thorough physical assessment will be performed at Screening, Months 12 and 24 and the 
subject’s final study visit in case of study discontinuation prior to Month 24. 


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Information about the physical examination must be present in the source documentation at the 
study site. Significant findings that are present prior to the start of the study must be included 
in the Relevant Medical History/Current Medical Conditions CRF. Significant findings made 
after the start of study medication which meet the definition of an AE must be recorded in the 
AE CRF.
6.5.2
Vital signs
Vital signs (radial pulse rate and blood pressure) will be recorded as indicated in Table 6-1. 
Blood pressure and pulse rate will be assessed at the same arm each time of determination and 
after the subject has rested in the sitting position (may be supine if during hospitalization) for 
at least five minutes. Systolic and diastolic blood pressure will be measured three times using 
an automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat 
sitting measurements will be made at 1-2 minute intervals and the mean of the three 
measurements will be recorded on the Vital Signs CRF. In case the cuff sizes available are not 
large enough for the subject's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used. Clinically notable vital signs are defined in Appendix 1.
6.5.3
Height and weight
Height will be recorded at Screening only, weight will be recorded at Screening, Baseline and 
at each subsequent visit. Results will be recorded on the Vital Signs CRF.
6.5.4
Laboratory evaluations
A central laboratory will be used for clinical chemistry, hematology and urinalysis as indicated 
in Table 6-1. Details on the collection, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.
6.5.4.1
Hematology
Hematological parameters will be analyzed as described in Table 6-1. Clinically notable 
laboratory findings are defined in Appendix 1.
6.5.4.2
Clinical chemistry
Clinical chemistry parameters will be analyzed as described in Table 6-1. Clinically notable 
laboratory findings are defined in Appendix 1.
6.5.4.3
Urinalysis
Urinalysis will be performed as described in Table 6-1. 
6.5.5
Electrocardiogram (ECG)
Not applicable.
6.5.6
Pregnancy and assessments of fertility
Pregnancy testing (serum) must be carried out for all females of child-bearing potential as 
described in Table 6-1 or at premature discontinuation from the study.
Additional recommendations regarding pregnancy:


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Mycophenolate (mycophenolate mofetil or mycophenolic acid) is a confirmed teratogen 
associated with an increased rate of spontaneous abortion and congenital malformation 
compared with other immunosuppressants. Therefore, investigators should ensure that female 
and male patients taking mycophenolate understand the risk of harm to the baby, the need for 
effective contraception, and the need to immediately consult the responsible investigator if there 
is a possibility of pregnancy or a suspected gap of contraception.
Recommendations for female patients:

Female patients sexually active should use two reliable methods of contraception 
simultaneously before starting and during therapy with mycophenolate, and for 6 weeks
after stopping treatment following discontinuation of mycophenolate.

Female patients should not donate blood during therapy with mycophenolate and at least 6 
weeks following discontinuation of mycophenolate.
Recommendations for male patients:

Male patients sexually-active should use condom for sex during therapy with 
mycophenolate and at least 90 days following discontinuation of mycophenolate. Condom 
use applies for both reproductively competent and vasectomized male patients (due to the 
risks associated with the transfer of seminal fluid). In addition, female partners of male 
patients treated with mycophenolate are recommended to use highly effective 
contraception during treatment and for a total of 90 days after the last dose of 
mycophenolate.

Male patients should not donate blood during therapy with mycophenolate and at least 6 
weeks following discontinuation of mycophenolate.

Male patients should not donate semen during therapy with mycophenolate and for 90 
days following discontinuation of mycophenolate.
6.5.7
Appropriateness of safety measurements
The safety laboratory assessments (renal function, chemistry, hematology) selected are standard 
for the kidney transplant population. The blood levels of everolimus and CNIs are required for 
correct control of drug levels and dosing. The assessment of (serious) adverse events, including 
infections, graft loss, death, dialysis and details of certain viral infections (CMV and BKV) 
allow proper assessment safety related outcomes and side effects in this population. 


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6.6.1
Resource utilization
Resource utilization analysis may include hospitalization data, dialysis data and usage of 
Concomitant Medications, especially prophylaxis and with anti-CMV or anti-PCP agents.
6.6.2
Health-related Quality of Life
Not applicable.
6.6.3
Pharmacokinetics
Not applicable.
6.6.4
Pharmacogenetics/pharmacogenomics
Not applicable.
6.6.5
Other biomarkers
Not applicable.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. The occurrence of adverse events should be sought by non-
directive questioning of the subject at each visit during the study. Adverse events also may be 
detected when they are volunteered by the subject during or between visits or through physical 
examination, laboratory test, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information.

the severity grade

mild: usually transient in nature and generally not interfering with normal activities


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
moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

possibility of relationship to the study treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE), if so report date should be provided

action taken regarding study treatment 

whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria 

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:

Renal allograft biopsy

Acute rejection treatment 

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 signing the informed consent 

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 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
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 treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF. 


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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 treatment, 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 Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse event reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hr of learning of its occurrence. Any SAE experienced after the 30 day 
period should only be reported to Novartis if the investigator suspects a causal relationship to 
study treatment. 
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 hr 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.
Information about all SAEs (either initial or follow up information) is collected and recorded in 
English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the OC/RDC system (where available). The Investigator must assess the 
relationship to each specific component of the study treatment (if the study treatment consists 
of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hr of awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department.  
The telephone and fax number of the contact persons in the local department of Drug Safety 
and Epidemiology, specific to the site, are listed in the investigator folder provided to each site.  
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the case report form documentation at the study site. Follow-up information should be provided 
using a new paper SAE Report Form stating that this is a follow-up to a previously reported 
SAE  
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hr of awareness of the SAE or changes to an existing 
SAE. These data will automatically be submitted to Novartis Drug Safety & Epidemiology 
immediately after investigator signature or 24 hr after entry, whichever occurs first. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the subject


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continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same investigational 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
7.3
Liver safety monitoring
No additional testing other than in clinical chemistry as described in Table 6-1.
7.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must 
be reported to Novartis within 24 hr 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.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
7.5
Prospective suicidality assessment
Not applicable.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 


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information, laboratory data and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the subject's file. The investigator must 
also keep the original informed consent form(s) signed by the subject (a signed copy is given 
to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis staff will review the data entered into the CRFs by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff are required to respond to the query and confirm or correct the data.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
Randomization codes will be assigned using Interactive Response Technology (IRT). The IRT 
system will be supplied by a vendor, who will also manage the database. The database will be 
sent electronically to Novartis.
Protocol deviations will be identified, documented and communicated as required throughout 
the study. At the conclusion of the study, the occurrence of relevant 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 the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis Development management.


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8.4
Data Monitoring Committee
Not applicable.
8.5
Adjudication Committee
Not applicable.
9
Data analysis
Statistical analysis and report writing will be performed when the last subject has completed 12 
months on study. A second and final analysis will be performed when all subjects complete 24 
months of the study.
9.1
Analysis sets
The full analysis set (FAS) consists of all randomized and transplanted subjects. Subjects 
randomized but not transplanted will be excluded from the FAS. Subjects who are 
misrandomized due to documented (IVRS) administrative error (eligibility criteria) and have 
no study drug received are excluded from the FAS. Following the intention-to-treat (ITT) 
principle, subjects will be analyzed according to their randomized treatment assignment and 
according to the actual stratum they belong to. 
The per-protocol set (PPS) consists of all subjects in the FAS who complete the study without 
any major deviations from protocol procedures.  Major deviations include:

Subject had multiple transplants or has had previous transplants

Renal cold ischemia time  > 30 hr
Additional protocol deviations and final definition of the PPS will be made based on blinded 
examination of the data prior to the 12-month and 24-month database locks.
The safety set (SAF) consists of all subjects who received at least one dose of study drug. 
Subjects will be analyzed according to the treatment they actually received. 
All safety analyses will be performed on the SAF. Generally safety analyses will use treatment -
emergent data (on-treatment analysis by including data up to 2 days after the discontinuation of 
study drug). Selected variables will be analyzed using all available data including data assessed 
beyond study treatment discontinuation: AEs/infections and deaths. 
9.2
Subject demographics and other baseline characteristics
Demographic and background information for the FAS population will be summarized using 
frequency distribution (for categorical variables) and descriptive statistics of mean, median, 
maximum, minimum and standard deviation (for continuous variables). Background 
information includes prior medication taken before study entry, past/current medical conditions 
and transplant history.


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9.3
Treatments
Study medication
Duration of exposure to study regimen will be summarized in tables as follows. In addition to 
an overall summary of exposure duration for each study regimen, a separate summary will be 
made for CsA and TAC subgroups within a study regimen.

Number and percentage of subjects being exposed for prespecified time intervals (e.g. 1-7 
days, 8-14 days, 15-30 days, 31-60 days, etc) as well as cumulative exposure.

Summary statistics (n, mean, SD, median, Q1, Q3, minimum, maximum) for duration of 
exposure will also be provided.
Average daily doses and body weight-adjusted average daily doses (for CsA and TAC only) by 
visit window and treatment group will also be calculated. In calculating average daily doses, 
zero doses will be used for periods of temporary interruption of study medication, regardless of 
whether this was due to safety reasons or non-compliance.
The number and percentage of subjects of remaining on their randomized CNI or switching CNI 
at least once during the study will be summarized for each study CNI-specific study regimen.  
This will be provided for each study period (up to Month 12, Month 12 to 24, and cumulatively).
Concomitant medication
Average daily doses and body weight-adjusted average daily doses by visit window will be 
summarized for corticosteroids (expressed in doses equivalent to prednisone) for each treatment 
group for subjects who are on study medication.
Medications will be identified using the NovDTD including Anatomical Therapeutic Chemical 
(ATC) code. Concomitant medications other than immunosuppressants, as well as the use of 
immunosuppressants other than study medication will also be summarized as follows.

Medications will be presented in alphabetical order, by ATC codes and grouped by 
anatomical main group (the 1st level of the ATC codes). Tables will also show the overall 
number and percentage of subjects receiving at least one drug of a particular ATC code and 
at least one drug in a particular anatomical main group. 
9.4
Analysis of the primary variable
9.4.1
Variable
The primary efficacy variable is a binary composite endpoint of tBPAR or eGFR (MDRD4) < 
50 mL/min/1.73m2 at Month 12 post-transplantation. The component of eGFR (MDRD4) < 50 
mL/min/1.73m2 at Month 12 is defined as an incidence of eGFR (MDRD4) < 50 
mL/min/1.73m2 in the Month 12 visit window.
9.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will be performed on the Full Analysis Set following the intent -to-treat 
principle. The proportion of subjects meeting the primary endpoint of tBPAR or eGFR 
(MDRD4) < 50 mL/min/1.73m2 at Month 12 will be compared using a confidence interval 
approach.  


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Treatment by CNI interaction for the composite endpoint of  tBPAR or eGFR (MDRD4) < 50 
mL/min/1.73m2 will be assessed using a logistic regression model (see Section 9.4.4 for risk 
factor analysis).  If the interaction is not significant at the level of 0.10, i.e. the effects of 
treatment are similar for each CNI, then the primary analysis will be based on the pooled CNIs, 
i.e. everolimus plus reduced CNI (EVR+rCNI) vs. MPA plus standard CNI (MPA+sCNI). If 
this test shows significantly different event rates for tacrolimus vs. cyclosporine, then testing 
will be performed for the 2 CNIs separately, with the tacrolimus subgroup being considered 
primary 
 
Event rates will be compared between groups using the following hierarchical testing strategy:
a) Non-inferiority of EVR+rCNI vs. MPA+sCNI will be evaluated based on the primary 
endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 using a 10% 
non-inferiority margin (see Section 9.4.2.1).  
b) Non-inferiority of EVR+rCNI vs. MPA+sCNI will be evaluated with a 10% non-
inferiority margin for the key secondary endpoint of tBPAR, graft loss or death at Month 
12 (see Section 9.5.1). 
c) Superiority of  EVR+rCNI to MPA+sCNI will be evaluated based on the primary 
endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 (see Section 
9.4.2.2). 
The above hierarchical fixed hypothesis testing procedure will not inflate overall Type I error 
rate.  Therefore, each hypothesis will be tested at the one-sided 0.025 significance level and no 
multiplicity adjustment is needed. 
9.4.2.1
Non-inferiority of everolimus plus reduced CNI to MPA plus standard 
CNI
The null hypothesis:
H01:  REVR+rCNI - RMPA+sCNI ≥ 0.10 (non-inferiority margin): the difference in proportion of 
subjects experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is at least 10%.
The alternative hypothesis:
HA1: REVR+rCNI - RMPA+sCNI < 0.10 (non-inferiority margin): The difference in proportion of 
subjects experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is  less than 10%.
9.4.2.2
Superiority of everolimus plus reduced CNI to MPA plus standard CNI
The null hypothesis:
H03:  REVR+rCNI - RMPA+sCNI ≥ 0: the proportion of subjects experiencing tBPAR or eGFR 
(MDRD4) < 50 mL/min/1.73m2 at 12 months in the everolimus plus reduced CNI (REVR+rCNI) 
arm is greater than or equal to that in the MPA plus standard CNI arm (RMPA+sCNI) arm.
The alternative hypothesis:


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HA3: REVR+rCNI - RMPA+sCNI < 0: the proportion of subjects experiencing tBPAR or eGFR 
(MDRD4) < 50 mL/min/1.73m2 at 12 months in the everolimus plus reduced CNI (REVR+rCNI) 
arm is less than that in the MPA plus standard CNI arm (RMPA+sCNI) arm.
Both hypotheses H01 and H03 will be tested at the significance level of α = 0.025 (one-sided). A 
Z-test based 95% confidence interval will be constructed for the difference in proportion of 
subjects experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12  months between 
the everolimus plus reduced CNI arm (REVR+rCNI) and the MPA plus standard CNI arm 
(RMPA+sCNI). The everolimus plus reduced CNI arm will be claimed to have a non-inferior 
incidence of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 compared to the MPA plus 
standard CNI arm if the upper limit of the 95% CI is below 10%. The everolimus plus reduced 
CNI arm will be claimed to be superior to the MPA plus standard CNI arm with respect to 
composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months if the 
upper limit of the 95% CI is less than 0.
However, following the aforementioned hierarchical fixed hypothesis testing procedure, the 
hypothesis H03 for superiority of EVR plus reduced CNI to MPA plus standard CNI will be 
evaluated if non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI is achieved 
for the primary endpoint (rejecting the hypothesis H01) and the key secondary endpoint of 
tBPAR, graft loss or death at Month 12 (rejecting the hypothesis H02, see Section 9.5.1).
9.4.3
Handling of missing values/censoring/discontinuations
Since the subjects who have prematurely discontinued study regimen are followed on standard 
of care, renal function data (e.g. creatinine) and kidney allograft biopsy data will be collected 
post discontinuation of study regimen for these visits, it is expected that few subjects would be 
missing efficacy and/or renal function evaluation for the 12 month analysis. 
To define the primary variable – composite endpoint of tBPAR or eGFR (MDRD4) < 50 
mL/min/1.73m2, the following imputation method will be applied for subjects with missing 12-
month eGFR value. As allograft biopsy data will be collected on an as needed basis due to the 
nature of kidney transplant studies, no particular rule for missing biopsy will be applied.

Under the assumption of missing not at random (MNAR), subjects who lost their grafts will 
be assigned a value of zero for their 12-month eGFR;

Otherwise, under the assumption of missing at random (MAR), subjects who had missing 
values including those who died with a functioning graft will have a 12-month eGFR 
imputed using multiple imputation method based on the longitudinal eGFR (MDRD4) data 
at all available time points and covariates  of randomization strata (donor type and CNI), 
HLA mismatches (≤3 vs >3) and induction.
9.4.4
Supportive analyses 
The following analyses will serve as supportive analyses for the primary endpoint of tBPAR or 
eGFR (MDRD4)<50 mL/min/1.73m2 at Month 12.
The analysis outlined for the primary endpoint in Section 9.4.2 will be repeated using compliant 
subjects in the FAS population.


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Analysis on Per-Protocol Set
The analysis outlined for the primary endpoint in Section 9.4.2 will be repeated using the Per-
Protocol Set. 
Subgroup analysis
Subgroup analyses will be done for the primary composite endpoint of tBPAR or eGFR 
(MDRD4)<50 mL/min/1.73m2 at 12 months for the subgroups defined by:

recipient characteristics (recipient age group: <60 vs ≥60 yr, gender, race, region)

donor/transplant characteristics (donor age group: <60 vs ≥60 yr, gender, cold ischemia 
time: < 20 vs ≥20 hr, end stage disease leading to transplant, donor type; living donor, 
standard criteria deceased donor and expanded criteria deceased donor; HLA mismatches: 
<=3 vs >3)

CNI (tacrolimus vs. cyclosporine)

Induction (basiliximab vs. rATG)

Immunological risk (high vs. low)
Subgroup analyses will use the Z-test on event rates (proportions) and also present confidence 
intervals for the pairwise differences in proportions.
Risk factor analysis using a logistic regression model
To investigate prognostic variables that might have an impact on the primary efficacy endpoint, 
a logistic regression analysis will be performed to identify potential risk factors. For this 
analysis, the same variables to define the above subgroups as well as the interaction between 
treatment and CNI and the interaction between treatment and region will be used. In the model, 
recipient and donor age, cold ischemia time, and potentially HLA mismatches will be treated 
as continuous variables. 
Analyses with other imputations for missing eGFR (MDRD4) at Month 12
In addition to the imputation method described in Section 9.4.3, the following imputation 
method will be used to impute missing 12-month eGFR value to define the primary variable –
composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m 2. With these 
imputations, non-inferiority and superiority analyses described in Section 9.4.2 will be repeated.

Subjects who lost their grafts will be assigned a value of zero for their 12-month eGFR;

Otherwise, subject who had missing value including those who died with a functioning graft 
will have a 12-month eGFR imputed using the following imputation methods: 
a) The last non-missing observation carried forward (LOCF);
b) Penalty-adjusted imputation method: missing eGFR values will be imputed first 
under missing at random (MAR) assumption, then apply a multiplicative penalty 
factor to the imputed data for subjects who discontinued due to AE or death. For 
example, a penalty factor of 0.8 corresponds to a reduction of the MAR-imputed 
value by 20%. This penalty-adjusted imputation will be applied to both EVR + rCNI 
and MPA + sCNI arms. Penalty factors of 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 
0.1 and 0.0 will be used.


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c) Impute missing eGFR values in EVR + rCNI arm based on the data from the control 
arm (MPA + sCNI) as everolimus subjects would switch to control (standard care) 
or control-like medication after they discontinue everolimus. The missing eGFR 
values in the control arm will be imputed under MAR assumption.
The purpose of imputation (a) is to compare with historical trials as this imputation was the 
main imputation method used in the past. To verify the MAR assumption used in Section 9.4.3
for multiple imputation, imputation methods (b) and (c) will be applied under the assumption 
of missing not at random (MNAR). These two imputations will be based on the longitudinal 
eGFR (MDRD4) data using all available time points and randomization strata (donor type and 
CNI), HLA mismatches (≤3 vs >3), and induction as covariates.
9.5
Analysis of secondary variables
9.5.1
Assessment of the key secondary endpoint of tBPAR, graft loss, or 
death
For the key secondary objective regarding the composite efficacy failure of tBPAR, graft loss 
or death, to evaluate whether everolimus plus reduced CNI is non-inferior to MPA plus standard 
CNI at 12 months post-transplantation, the following hypotheses will be evaluated (α=0.025, 
one-sided) based on the Full Analysis Set:
The null hypothesis:
H03:  REVR+rCNI - RMPA+sCNI ≥ 0.10 (non-inferiority margin): the difference in Kaplan-Meier 
event rate of the composite efficacy failure of tBPAR, graft loss or death at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is at least 10%.
The alternative hypothesis:
HA3: REVR+rCNI - RMPA+sCNI < 0.10 (non-inferiority margin): the difference in Kaplan-Meier event 
rate of the composite efficacy failure of tBPAR, graft loss or death at 12 months between the 
everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) is  
less than 10%.
For this analysis, the event rate of the composite efficacy failure of tBPAR, graft loss or death 
will be estimated with Kaplan-Meier product-limit formula. Greenwood’s formula will be used 
to estimate variance of failure rates and to derive Z-test based confidence interval for the 
difference in failure rate between the everolimus plus reduced CNI and the MPA plus standard 
CNI arm.
Since the subjects who have prematurely discontinued study regimen are followed on standard 
of care, efficacy data including kidney allograft biopsies will be collected post-discontinuation 
of study regimen for these visits, it is expected that few subjects would be missing efficacy 
evaluation for the 12 months analysis. Subjects with missing efficacy evaluation for the 12 
month analysis will be censored at the latest day known to be free of the event.
As supportive analyses, this non-inferiority analysis will be repeated using the Per-Protocol Set, 
and Kaplan-Meier event rates of this key secondary endpoint will be summarized for the 
subgroups defined in Section 9.4.4.


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9.5.2
Other secondary efficacy variables 
Other secondary efficacy variables to be considered are as follows:
(1) Composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 24;
(2) Composite endpoint of tBPAR excluding grade IA rejections or eGFR (MDRD4) < 50 
mL/min/1.73m2 at Months 12 and 24
(3) Composite efficacy failure of tBPAR, graft loss, or death at Month  24;
(4) Composite efficacy failure of tBPAR, graft loss, death, or loss to follow-up at Month 12 
and 24;
(5) Components of composite efficacy failure as well as BPAR, AR, tAR at Month 12 and 
Month 24;
a) AR
b) tAR
c) BPAR;
d) tBPAR;
e) tBPAR excluding grade IA rejections;
f)
Humoral rejection
g) Graft loss;
h) Death.
(6) composite endpoint of tBPAR, graft loss, death or eGFR < 50 mL/min/1.73m2 at Months 
12 and  24;
(7) Composite endpoint of graft loss or death at Month 12 and Month 24;
(8) Composite endpoint of BPAR, graft loss or death at Month 12 and Month 24;
(9) eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 and Month 24;
(10) Renal function (eGFR by MDRD4, CKD-EPI and Cystatin C-based formulae) at Month 
12 and Month 24;
(11) Renal function change from Month 1 (Week 4) to Month 12 and Month 24;
(12) Evolution of renal function (eGFR by MDRD4) from Month 1 to Month 12 and Month 
24 (slope analyses).
The analyses on efficacy endpoints and renal function will be based on the Full Analysis Set. 
Selected parameters will be analyzed on the Per-Protocol Set as well. 
A Z-test based comparison will be performed for the following composite endpoints: tBPAR or 
eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 24, composite endpoint of tBPAR excluding 
grade IA rejections or eGFR (MDRD4) < 50 mL/min/1.73m2 at Months 12 and 24, endpoint of 
tBPAR, graft loss, death or eGFR < 50 mL/min/1.73m2 at Months 12 and 24, and endpoint of 
tBPAR, graft loss, death, or loss to follow-up at Months 12 and 24.


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For the composite efficacy failure (tBPAR, graft loss or death) at Month 24 and the composite 
endpoint of BPAR, graft loss or death at Month 12 and Month 24, Kaplan-Meier event rates 
will be estimated and compared between the everolimus plus reduced CNI and the MPA plus 
standard CNI arm. Similarly Kaplan-Meier event rates will be estimated and compared for AR, 
tAR, BPAR, tBPAR, humoral rejection, graft loss, death and the composite endpoint of graft 
loss or death. To assess time-to-event occurrence of efficacy endpoints, Kaplan-Meier plots will 
be produced and the log-rank test will be performed. A forest plot of KM event rate differences 
for efficacy endpoints will be produced.  Severity of tBPAR will be tabulated by treatment.
As a key component of the primary endpoint (tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m 2), 
the endpoint of eGFR (MDRD4) < 50 mL/min/1.73m2 will be summarized with raw incidence 
rates and compared. A Z-test based 95% confidence interval will be provided. 
For eGFR(MDRD4) at Month 12 and Month 24, analysis of covariance (ANCOVA) will be 
performed with treatment (everolimus vs MPA), CNI (CsA vs TAC), interaction of treatment 
and CNI, region, interaction of treatment and region, induction, donor type (living donor, 
deceased standard criteria donor and deceased expanded criteria donor), recipient gender and
donor gender as factors, and recipient age and BMI, donor age, cold ischemic time and 
eGFR(MDRD4) at Month 1 as covariates. The missing Month 12 or Month 24 values will be 
imputed using the same methods as described in Section 9.4.3 and Section 9.4.4 except LOCF 
approach for Month 24, for which a Month 24 eGFR value will be imputed using the last non-
missing observation carried forward (LOCF) from Month 6 onwards as subjects will be 
maintained in the same CNI target range since Month 6.
Renal function and change from Month 1 (Week 4) will be summarized by visit with descriptive 
statistics and graphically presented by visit. 
The evolution of renal function (eGFR by MDRD4) will be evaluated via a mixed effect model 
with intercept and subject as random effects and using with the same covariates/factors as used 
for the ANCOVA model.  Based on the mixed effect model, the treatment groups will be 
compared, and slope of renal function evolution for each treatment group will be assessed. 
9.5.3
Safety variables
Safety variables to be assessed include discontinuation from study, discontinuation from 
treatment, AE/infection, SAE, notable events, laboratory tests, and vital signs. All safety 
analyses will be done on the safety set. Generally safety analyses will use treatment -emergent 
data (on-treatment analysis by including data up to 2 days after the discontinuation of study 
drug). Selected variables will be analyzed using all available data including data assessed 
beyond study treatment discontinuation: AEs/infections and deaths. 
As subjects may not necessarily visit the clinics at the exact scheduled time, it may be 
misleading to lump all data with the same nominal visit number into the same visit in a by-visit 
analysis.  Thus, all data are to be “re-aligned” by referencing their visit date to the date of initial 
dose. Visit-based time windows will be defined for data analysis.
The Baseline value is represented by the last observation during the Baseline period.


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Assessment of premature study and study treatment discontinuation 
Incidence rate of subjects who prematurely discontinue study medication or study will be 
summarized by frequency tables.
AEs/infections
Generally, infection data are analyzed together with AE data.  In addition, infection data will 
be analyzed separately. Micro-organism will be additionally coded with NovORG dictionary.
The incidence of treatment-emergent AEs will be summarized by body system, severity and 
relationship to study drug.  The type (viral, bacterial, fungal, and others) and micro -organism 
of infections will be tabulated. In addition, AEs/infections will be summarized per SMQ narrow 
search.
 
 
All information pertaining to AEs noted during the study will be listed by subject, detailing AE 
(verbatim given by the investigator as well as the preferred term according to the MedDRA 
dictionary), body system, date starting and ending, causality, severity and drug-relatedness. 
Notable events
Notable events include death, non-fatal SAEs (including infections and rejections reported as 
SAE), AEs (including infections and rejections) leading to discontinuation from the study, and 
drop-outs due to notable events as reported on the Treatment/Study completion CRF): a) 
adverse event(s); b) abnormal laboratory result(s); c) abnormal test procedure result(s).
Vital signs
Vital signs variables include measurements of oral body temperature, systolic and diastolic 
blood pressures, pulse and body weight. Vital signs will be examined for abnormal values and 
change from baseline according to pre-specified clinically notable criteria.  Appropriate 
incidence rates of clinically notable abnormalities will be provided. Further, descriptive 
statistics of all vital signs variables as well as the changes from baseline will be presented by 
visit.  A by-subject listing of all vital signs (with clinically notable abnormalities being flagged) 
will be generated.
Laboratory data
Descriptive statistics (mean, standard deviation, minimum, median and maximum) of 
quantitative laboratory variables, including change from Baseline, will be generated by visit for 
laboratory parameters. Categorical levels of urinary protein/creatinine ratio (<30, 30 - <500, 
500 - <1000, 1000 - <3000, >=3000 mg/g) will additionally summarized by visit.
Abnormalities according to the clinical notable criteria (see Appendix 1) will be identified and 
tabulated for each applicable lab parameter. Lipids levels are categorized based on the following 
criteria per American Heart Association (Adult treatment panel III 2002). A by-subject listing 
of individual subject laboratory data will be generated; values outside of clinical notable will 
be flagged.  


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
Triglycerides
- Normal: < 150 mg/dL
- Borderline high: 150 – <200 mg/dL
- High: 200 – <500 mg/dL
- Very high: ≥ 500 mg/dL

Total cholesterol
- Normal: < 200 mg/dL
- Borderline high: 200 – <240 mg/dL
- High: ≥240 mg/dL

HDL cholesterol
- Low: < 40 mg/dL for men, <50 mg/dL for women 
- Normal: 40 – <60 mg/dL for men, 50 – <60 mg/dL for women
- Optimal: ≥60 mg/dL 

LDL cholesterol
- Optimal: < 100 mg/dL 
- Near or above optimal: 100 – <130 mg/dL 
- Borderline high: 130 – <160 mg/dL 
- High: 160 – <190 mg/dL 
- Very high: ≥ 190 mg/dL 
Total cholesterol /HDL ratio level is defined as
- Normal: <5
- High: >=5 but <=7
- Very High: >7
Tolerability
Tolerability of the regimens is assessed by summarizing the percentage of subjects requiring 
dose adjustment or interruption and premature treatment discontinuations due to adverse events 
by treatment group.
9.5.4
Resource utilization 
Data relating to resource utilization will be used for the purpose of economic evaluation, which 
will be carried out and reported as a separate activity.
9.5.5
Health-related Quality of Life 
Not applicable.
9.5.6
Pharmacokinetics 
Not applicable.
9.5.7
Pharmacogenetics/pharmacogenomics
Not applicable.


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9.5.8
Biomarkers
Not applicable.
9.5.9
PK/PD
Not applicable.
9.6
Interim analyses
A futility analysis will be performed when approximately 30% of subjects have completed 6 
months on study. The unblinded futility analysis results will be reviewed and considered 
together with other efficacy and safety data by an unblinded team. At their d iscretion, the 
unblinded team will make a recommendation regarding trial continuation/amendment/
termination. No stringent (binding) futility boundary is pre-specified. The details of the futility 
analysis will be provided in a separate document.
The primary analysis will be at Month 12 and the final analysis will be at Month 24.
9.7
Sample size calculation
The sample size for this study was chosen with the goals to (1) have high power to evaluate 
non-inferiority in both the overall population and the TAC alone population and (2) have 
adequate power to evaluate superiority in the both the overall population and the TAC alone 
population.  
As shown in Table 9-1, with a sample size of n=1020 randomized per arm (EVR, MPA), the 
study has at least 95% power to demonstrate non-inferiority (α=0.025, one-sided) in the overall 
and TAC alone populations at Month 12.  There are at least 73% and 63% power (α=0.025, 
one-sided) to demonstrate superiority of 7% or more in the overall and TAC alone populations,
respectively.
The calculations are based on the following assumptions:

80% of subjects are randomized to tacrolimus, 20% of subjects are randomized to 
cyclosporine

20% and 30% subjects are excluded from the PP population at Months 12 and 24 
respectively

For non-inferiority, the event rate in each arm is 50%, based on study results from 
RAD001A2309 and Ekberg 2007, and the non-inferiority margin for the primary 
composite endpoint is 10%.

For the evaluation of superiority, the event rate in the MPA + sCNI arm is 50%.
Table 9-1
Power for non-inferiority and superiority testing:  Overall population 
and TAC alone population
Population
Analysis 
Set
Time Point
(N evaluable per group)
Power:
Non-
inferiority
Power for
Superiority: difference from 
MPA + sCNI
-5%
-6%
-7%
-8%


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Overall
FAS
Month 12 or 24 
(N=1020)
>99
60
76
87
94
PPS
Month 12 (N=816)
98
50
66
79
89
Month 24 (N=714)
97
45
60
73
84
TAC
FAS
Month 12 or 24 (N=816)
98
50
66
79
89
PPS
Month 12 (N=653)
95
41
56
69
81
Month 24 (N=571)
92
37
50
63
75
All sample size calculations were performed using NQuery Advisor, Version 7.0 (modules 
PTE1b-1 and PTT1-1).
10
Ethical considerations
10.1
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 applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the subject. 
In cases where the subject’s representative gives consent, the subject should be informed about 
the study to the extent possible given his/her understanding. If the subject is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. 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 subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment 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 adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 


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Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her 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 Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, 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.
10.4
Publication of study protocol and results
Novartis 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.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as requests to approve deviations will not be granted.
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
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/IEC it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR.
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for subject safety may be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed within 10 working 
days or less, if required by local regulations.
12
References (available upon request)
Brennan DC, Legendre C, Patel D, Mange K, Wiland A, McCague K, Shihab FS (2011) 
Cytomegalovirus Incidence Between Everolimus Versus Mycophenolate in De Novo Renal 
Transplants: Pooled Analysis of Three Clinical Trials. Am J Transplant; 11(11):2453-62.


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CHMP guideline on clinical investigation of immunosuppressants in solid organ 
transplantation (2009) 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003593.pdf (accessed 7th June 2013)
Coresh J, Astor BC, Greene T, Garabed E, Levey AS (2003) Prevalence of chronic kidney 
disease and decreased kidney function in adult US population: Third national health and 
nutrition examination survey. Am J Kidney Dis; 41(1): 1-12.
De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F, Jonas S, Sudan 
D, Fung J, Fischer L, Duvoux C, Chavin KD, Koneru B, Huang MA, Chapman WC, Foltys D, 
Witte S, Jiang H, Hexham JM, Junge G; for the H2304 Study Group (2012) Everolimus With 
Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A 
Randomized Controlled Trial. Am J Transplant. 12:3008-3020.
Deeks ED and Keating GM (2009) Rabbit antithymocyte globulin: A review of its use in the 
prevention and treatment of acute renal allograft rejection. Drugs 69;1485-1512.
Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, 
Starling RC, Sørensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P; RAD B253 
Study Group (2003) Everolimus for the prevention of allograft rejection and vasculopathy in 
cardiac-transplant recipients. N Engl J Med; 349(9):847-58.
Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, Margreiter R, Hugo 
C, Grinyó JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study 
(2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med; 
357(25):2562-75. 
FDA Workshop, 2012: Endpoints in Clinical Trials of Kidney Transplantation. Transcript at 
http://www.fda.gov/Drugs/NewsEvents/ucm305308.htm
Grube E, Sonoda S, Ikeno F, Honda Y, Kar S, Chan C, Gerckens U, Lansky AJ, Fitzgerald PJ 
(2004) Six- and twelve-month results from first human experience using everolimus-eluting 
stents with bioabsorbable polymer. Circulation; 109(18):2168-71. 
Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP (2002) 
Post-transplant renal function in the first year predicts long-term kidney transplant survival. 
Kidney Int; 62(1):311-8.
Havenith SH, Yong SL, van Donselaar-van der Pant KA, van Lier RA, ten Berge IJ, 
Bemelman FJ (2013) Everolimus-treated renal transplant recipients have a more robust CMV-
specific CD8+ T-cell response compared with cyclosporine- or mycophenolate-treated 
patients. Transplantation; 95(1):184-91. 
Kasiske BL, Israni AK, Snyder JJ, Skeans MA; Patient Outcomes in Renal Transplantation 
(PORT) Investigators (2011) The relationship between kidney function and long-term graft 
survival after kidney transplant. Am J Kidney Dis; 57(3):466-75. 
Langer RM, Hené R, Vitko S, Christiaans M, Tedesco-Silva H Jr, Ciechanowski K, Cassuto 
E, Rostaing L, Vilatoba M, Machein U, Ulbricht B, Junge G, Dong G, Pascual J. (2012) 
Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, 
multicentre trial in renal transplantation. Transplant Int.  25:592-602.


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Loriga G, Ciccarese M, Pala PG, Satta RP, Fanelli V, Manca ML, Serra G, Dessole P, Cossu 
M (2010) De novo everolimus-based therapy in renal transplant recipients: effect on 
proteinuria and renal prognosis. Transplant Proc; 42(4):1297-302. 
Nashan B, Curtis J, Ponticelli C, Mourad G, Jaffe J, Haas T (2004) Everolimus and reduced-
exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, 
randomized, multicenter, open-label study. Transplantation, 78:1332-40.
Nashan B, Gaston R, Emery V, Saemann MD, Mueller NJ, Couzi L, Dantal J, Shihab F, 
Mulgaonkar S, Seun Kim Y, Brennan DC (2012) Review of cytomegalovirus infection 
findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in 
de novo renal transplant recipients. Transplantation; 93(11):1075-85. 
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of 
the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report 
(2002) Circulation. 106:3143–3421
Park WD,  Larson TS, Griffin MD, Stegall MD (2012) Identification and Characterization of 
Kidney Transplants With Good Glomerular Filtration Rate at 1 Year But Subsequent 
Progressive Loss of Renal Function. Transplantation 94:931-939
Pascual J (2009) The use of everolimus in renal-transplant patients. Int J Nephrol Renovasc 
Dis; 2: 9–21.
Shihab FS, Cibrik D, Chan L, Kim YS, Carmellini M, Walker R, Zibari G, Pattison J, Cornu-
Artis C, Wang Z, Tedesco-Silva Jr H (2012) Association of clinical events with everolimus 
exposure in kidney transplant patients receiving reduced cyclosporine. Clin Transplant. 2012. 
Tedesco Silva H Jr, Cibrik D, Johnston T, Lackova E, Mange K, Panis C, Walker R, Wang Z, 
Zibari G, Kim YS. (2010) Everolimus plus reduced-exposure CsA versus mycophenolic acid 
plus standard-exposure CsA in renal-transplant recipients. Am J Transplant. 10:1401-13. 
Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, Campbell S, Civati G, 
Bourbigot B, Alves Filho G, Leone J, Garcia VD, Rigotti P, Esmeraldo R, Cambi V, Haas T, 
Jappe A, Bernhardt P, Geissler J, Cretin N (2004) Everolimus with optimized cyclosporine 
dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized 
studies. Am J Transplant. 4:626-35. 
Wiseman AC, McCague K, Kim Y, Geissler F, Cooper M (2013) The effect of everolimus 
versus mycophenolate upon proteinuria following kidney transplant and relationship to graft 
outcomes. Am J Transplant; 13(2):442-9.
Wu J, Li H, Huang H, Wang R, Wang Y, He Q, Chen J (2010) Slope of changes in renal function 
in the first year post-transplantation and one-yr estimated glomerular filtration rate together 
predict long-term renal allograft survival. Clin Transplant; 24(6):862-8.


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Appendix 1: Clinically notable laboratory values
Laboratory variable
Standard units 
SI units
Liver function and related variables
SGOT (ASAT)
≥3 × ULN
≥3 × ULN
SGPT (ALAT)
≥3 × ULN
≥3 × ULN
Bilirubin
≥3 × ULN
≥3 × ULN
Renal function, metabolic and electrolyte variables
Urea 
5 ULN 
5 ULN
Creatinine 
After Wk4: ≥3 mg/dL
After Wk4: ≥265 μmol/L
OR
OR
>30% above value
>30% above value
from preceding visit
from preceding visit
Uric acid 
M ≥12 mg/dL
M ≥714 μmol/L
F ≥9 mg/dL
F ≥535 μmol/L
Glucose 
<45 mg/dL
<2.5 mmol/L
>250 mg/dL
>13.9 mmol/L
Cholesterol 
≥350 mg/dL
≥9.1 mmol/L
Triglycerides 
≥750 mg/dL
≥8.5 mmol/L
CK (MB) 
None
None
Potassium 
≤3.0 mEq/L
≤3 mmol/L
≥6.0 mEq/L
≥6 mmol/L
Calcium 
≤6 mg/dL
≤1.5 mmol/L
≥13 mg/dL
≥3.2 mmol/L
Hematology variables
Hemoglobin
<7 g/dL
<4.39 mmol/L
Platelets (thrombocytes)
<50 k/mm3
<50 × 109/L
≥700 k/mm3
≥700 × 109/L
Leukocytes (WBCs)
≤2.0 k/mm3
≤ 2.0 × 109/L
≥16 k/mm3
≥16 × 109/L
Hematology variables: differential
Granulocytes (poly, neutrophils)
≤1,000/mm3
≤1 x 109/L
Eosinophils 
≥12%
≥12%
Lymphocytes 
≤1,000/mm3
≤1× 109/L
Vital sign variables
Notable criteria
Systolic BP (mm/Hg)
Either an increase of 30 that results in 180 or >200(mm/Hg) OR
a decrease of 30 that results in 90 or <75 (mm/Hg)
Diastolic BP (mm/Hg)
Either an increase of 20 that results in 105 or >115 (mm/Hg) OR
a decrease of 20 that results in 50 or <40 (mm/Hg)


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Appendix 2: Everolimus drug-drug interactions
Drugs to be avoided:
Coadministration of everolimus with strong inhibitors and inducers of CYP3A4 is not 
recommended unless the benefit outweighs the risk.

Strong CYP3A4 inhibitors: ketoconazole, itraconazole, posaconazole, voriconazole, 
clarithromycin, telithromycin, ritonavir, atazanavir, saquinavir, darunavir

Strong CYP3A4 inducers: rifampicin, rifabutin

Foods: Grapefruit and grapefruit juice
Drugs to coadminister with caution:
In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially 
increasing the concentrations of medicinal products eliminated by these enzymes. Therefore, 
caution should be exercised when coadministering everolimus with 3A4- and 2D6 substrates 
with a narrow therapeutic index.

CYP3A4 substrates that may prolong QT interval: terfenadine, astemizole, cisapride

CYP2D6 substrates with narrow therapeutic index: quinidine, thioridazine
Perform everolimus therapeutic drug monitoring when initiating or discontinuing these 
drugs from the regimen:
Moderate inhibitors of CYP3A4 and P-glycoprotein may increase everolimus blood levels such 
as:

Antifungals: fluconazole

Macrolide antibiotics: erythromycin

Calcium channel blockers: verapamil, nicardipin, diltiazem

HIV protease inhibitors: nelfinavir, indinavir, amprenavir
Moderate inducers of CYP3A4 may increase the metabolism of everolimus and decrease 
everolimus blood levels such as:

Anticonvulsants: carbamazepine, phenobarbital, phenytoin

HIV protease inhibitors: efavirenz, nevirapine

Herbals: St. John’s wort (Hypericum perforatum)


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Appendix 3: Dose reduction guidance for MPA
Dose reduction or temporary interruption may be performed for MPA
Implementation of dose reduction will be based on thrombocytopenia, leukopenia, neutropenia, 
or other adverse events which are suspected to be related to study medication, and in the opinion 
of the investigator, are clinically warranted. The following guidelines should be used for both 
dose reduction and, once the event has resolved, restarting or increasing the dose of MPA back 
to original levels. 
Dose Reduction Guidelines
Platelets

platelet count < 100,000/mm³dose may be reduced at the discretion of the investigator

platelet count < 75,000/mm³ a second dose reduction should be considered

platelet count < 50,000/mm³ MANDATORY interruption of medication
WBC

WBC < 3500/mm³
dose may be reduced at the discretion of the investigator

WBC < 2500/mm³
a second dose reduction should be considered

WBC < 2000/mm³ MANDATORY interruption of medication
All these changes must be recorded on the MPA Dosage Administration Record CRF.


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Appendix 4: Tacrolimus drug-drug interactions
Please refer to most recent national prescribing information for current labeling 
recommendations.  
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 dysfunction. 
These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial 
clinical experience with the co-administration of tacrolimus and cyclosporine resulted in 
additive/synergistic nephrotoxicity.
Drugs that may alter tacrolimus concentrations
Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to 
inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as 
indicated by increased whole blood or plasma concentrations. Drugs known to induce these 
enzyme systems may result in an increased metabolism of tacrolimus or decreased 
bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of 
blood concentrations and appropriate dosage adjustments are essential when such drugs are 
used concomitantly.
*Drugs that may increase tacrolimus blood concentrations 
Calcium
Channel
Blockers
Antifungal
Agents 
Macrolide
Antibiotics
Gastrointestinal
Prokinetic
Agents
Other Drugs
diltiazem
nicardipine
nifedipine
verapamil
clotrimazole
fluconazole
itraconazole
ketoconazole**
voriconazole
clarithromycin
erythromycin
troleandomycin
cisapride
metoclopramide
bromocriptine
chloramphenicol
cimetidine
cyclosporine
danazol
ethinyl estradiol
methylprednisolone
lansoprazole***
omeprazole
protease inhibitors
nefazodone
magnesium-aluminum 
hydroxide
**In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 
30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral 
clearance of tacrolimus during ketoconazole administration was significantly decreased compared to 
tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was 
not significantly changed by ketoconazole co-administration, although it was highly variable between 
patients.
*** Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism 
of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in 
transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients 
who are efficient CYP2C19 metabolizers.


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*Drugs that may decrease tacrolimus blood concentrations
Anticonvulsants
Antimicrobials
Herbal Preparations
Other Drugs 
carbamazepine
phenobarbital
phenytoin
rifabutin
caspofungin
rifampin
St. John’s Wort
sirolimus §
* This table is not all inclusive.
§ Sirolimus is prohibited in this study.
St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since 
tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in 
patients receiving tacrolimus could result in reduced tacrolimus levels.
In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and 
magnesium-aluminum hydroxide resulted in a 21% increase in the mean tacrolimus AUC and 
a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone.
In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% 
vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there 
was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 
L/hr/kg) with concomitant rifampin administration.
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., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. 
Similarly, care should be exercised when HCV protease inhibitors (e.g. boceprevir and 
telaprevir), also metabolized by CYP3A, are administered concomitantly with tacrolimus.
Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their 
concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided 
(see Dosage Administration).
Other Drug Interactions
Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus, 
vaccination may be less effective. The use of live vaccines should be avoided; live vaccines 
may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and 
TY 21a typhoid.1
1Reference: Prograf™ package Insert, Revised August 2012.


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Appendix 5 : Cyclosporine drug-drug interactions
Please refer to most recent national prescribing information for current labeling 
recommendations.  All the individual drugs cited below are well substantiated to interact with 
cyclosporine. In addition, concomitant non-steroidal anti-inflammatory drugs, particularly in 
the setting of dehydration, may potentiate renal dysfunction. 
Drugs that may potentiate renal dysfunction
Antibiotics
Antifungals
Gastrointestinal Agents
gentamicin
tobramycin
vancomycin
trimethoprim with 
sulfamethoxazole
amphotericin B
ketoconazole
cimetidine
ranitidine
Antineoplastics
Anti-Inflammatory Drugs
Immunosuppressives
melphalan
azapropazone
diclofenac
naproxen
sulindac
colchicine
tacrolimus
Drugs that alter cyclosporine concentration
Compounds that decrease cyclosporine absorption such as orlistat should be avoided. 
Cyclosporine is extensively metabolized by cytochrome P-450 3-A. Substances that inhibit this 
enzyme could decrease metabolism and increase cyclosporine concentrations. Substances that 
are inducers of cytochrome P-450 activity could increase metabolism and decrease cyclosporine 
concentrations. Appropriate cyclosporine dosage adjustment to achieve the desired 
cyclosporine concentrations is essential when drugs that significantly alter cyclosporine 
concentrations are used concomitantly.
Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustments are 
essential when these drugs are used concomitantly.
Drugs that increase cyclosporine concentration
Calcium Channel Blockers
Antifungals
Antibiotics
diltiazem
nicardipine 
verapamil
ketoconazole 
fluconazole 
itraconazole
clarithromycin
erythromycin
quinupristin/
daldopristin
Glucocorticoids
Other Drugs
methylprednisolone
allopurinol
bromocriptine
danazol
metoclopramide
colchicine
amiodarone


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Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of CsA, thus 
should be avoided.
Prophylactic treatment with systemic antifungal agents (i.e., ketoconazole, itraconazole, and 
fluconazole) will not be allowed. If azoles are used during the study for the treatment of active 
infections, CsA levels should be carefully monitored and dose adjustments may be necessary.
Drugs that decrease cyclosporine concentration
Antibiotics
Anticonvulsants
Other Drugs
nafcillin
rifampin
carbamazepine
phenobarbital
phenytoin
octreotide
ticlopidine
orlistat
St. John’s Wort
There have been reports of serious drug interaction between cyclosporine and the herbal dietary 
supplement, St. John’s Wort. This interaction has been reported to produce a marked reduction 
in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of 
transplanted organs, and graft loss.
Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome 
P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care 
should be exercised when these two drugs are administered concomitantly.
Other drug-drug interactions
Pharmacodynamic interactions have been reported to occur between cyclosporine and both 
naproxen and sulindac, in that concomitant use is associated with additive decreases in renal 
function, as determined by 99 mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-
aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does 
not affect blood levels of cyclosporine, it has been associated with approximate doubling of 
diclofenac blood levels and occasional reports of reversible decreases in renal function. 
Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA 
reductase inhibitors (statins), aliskiren, repaglinide, NSAIDs, sirolimus, etoposide, and other 
drugs. Severe digitalis toxicity has been seen within days of starting cyclosporine in several 
patients taking digoxin. There are also reports on the potential of cyclosporine to enhance the 
toxic effects of colchicine such as myopathy and neuropathy, especially in patients with re nal 
dysfunction. If digoxin or colchicine are used concurrently with cyclosporine, close clinical 
observation is required in order to enable early detection of toxic manifestations of digoxin or 
colchicine, followed by reduction of dosage or its withdrawal. If digoxin is used concurrently 
with cyclosporine, serum digoxin concentrations should be monitored.
Literature and postmarketing cases of myotoxicity, including pain and weakness, myositis, and 
rhabdomyolysis, have been reported with concomitant administration of cyclosporine with 
lovastatin, simvastatin, atorvastatin, pravastatin, and, rarely fluvastatin. When concurrently 
administered with cyclosporine, the dosage of these statins should be reduced according to label 
recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients 
with signs and symptoms of myopathy or those with risk factors predisposing to severe renal 
injury, including renal failure, secondary to rhabdomyolysis.


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Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can 
occur.
During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines 
should be avoided. Frequent gingival hyperplasia with nifedipine, and convulsions with high 
dose methylprednisolone have been reported. The concomitant use of nifedipine should be 
avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine


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Appendix 6: Banff ’09 Meeting Report: Antibody Mediated 
Graft Deterioration and Implementation of Banff Working 
Groups 1
1. Normal
2. Antibody-mediated rejection – due to circulating anti-donor antibodies, C4d, and 
allograft pathology:
C4d deposition without morphologic evidence of acute rejection – C4d, anti-donor 
antibodies, no signs of acute or chronic rejection, no ATN-like minimal inflammation.
Acute antibody-mediated rejection – C4d, anti-donor antibodies, and acute tissue injury, 
such as: (“suspicious for” if antibody not demonstrated)

Type I – ATN-like minimal inflammation

Type II – Capillary involvement and/or thromboses

Type III – Arterial changes
3. Chronic antibody-mediated rejection – evidence of chronic tissue such as glomerular 
double contours, peritubular capillary basement membrane multilayering, interstitial 
fibrosis/tubular atrophy (IFTA), or fibrous intimal thickening in arteries. Borderline 
changes “suspicious” for acute T-cell-mediated cellular rejection. No intimal arteritis 
present, but there are foci of mild tubulitis with mild interstitial infiltration. Threshold 
for rejection diagnosis is not met.
4. T-cell mediated rejection

Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of 
moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 
tubular cells).

Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of 
severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular 
cells).

Type IIA - Mild to moderate intimal arteritis

Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area

Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid 
change and necrosis of medial smooth muscle cells (with accompanying 
lymphocytic inflammation)
5. Interstitial fibrosis and tubular atrophy**

Grade I - Mild interstitial fibrosis and tubular atrophy without (a) or with (b) specific 
changes suggesting chronic rejection

Grade II - Moderate interstitial fibrosis and tubular atrophy (a) or (b)

Grade E III - Severe interstitial fibrosis and tubular atrophy and tubular loss (a) or 
(b)
6. Other: Changes not considered to be due to rejection (e.g., post-transplant 
lymphoproliferative disorder, nonspecific changes, acute tubular necrosis, etc.), 
specifically:


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Amended Protocol Version v01 Clean
Protocol No. CRAD001A2433

Chronic hypertension - Arterial/fibrointimal thickening with reduplication of 
elastica, usually with small artery and arteriolar hyaline changes.

Calcineurin toxicity - Arteriolar hyalinosis with peripheral hyaline nodules and/or 
progressive increase in the absence of hypertension or diabetes. Tubular cell injury 
with isometric vacuolization.

Chronic obstruction - Marked tubular dilatation. Large Tamm-Horsfall protein casts 
with extravasation into interstitium, and/or lymphatics.

Acute bacterial pyelonephritis - Intratubular and peritubular neutrophils with 
destruction of the tubular epithelium.

Viral infection - Viral inclusions on histology and immunohistology and/or electron 
microscopy.
*The recommended format of report is a descriptive narrative signet followed by numerical 
codes (Banff ‘09) 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.
**Glomerular and vascular lesions help define type of chronic nephropathy; chronic/recurrent 
rejection can be diagnosed if typical vascular lesions are seen. Grades I, II and III may include 
nonspecific vascular and glomerular sclerosis, but severity is graded by tubulointerstitial 
features.
1 Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin W, 
Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, Einecke G, Gloor J, Glotz 
D, Kraus E, Legendre C, Liapis H, Mannon RB, Nankivell BJ, Nickeleit V, Papadimitriou JC, 
Randhawa P, Regele H, Renaudin K, Rodriguez ER, Seron D, Seshan S, Suthanthiran M, 
Wasowska BA, Zachary A, Zeevi (2008) A Banff 07 classification of renal allograft pathology: 
updates and future directions. Am. J. Transplant. 8:753-60.

SAP_001.pdf: 
Clinical Development 
RAD001A/everolimus 
CRAD001A2433 / NCT01950819 
A 24 month, multicenter, randomized, open-label safety and 
efficacy study of concentration-controlled everolimus with 
reduced calcineurin inhibitor vs mycophenolate with 
standard calcineurin inhibitor in de novo renal 
transplantation- Advancing renal TRANSplant eFficacy and 
safety Outcomes with an eveRolimus-based regiMen 
(TRANSFORM) 
RAP Module 3 – Detailed Statistical Methodology 
Amendment 5 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final 
Release date: 
February 27, 2018 
Number of pages: 
51 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to the previous version of RAP module 3 
Date 
Changes 
25-Jan-2016 
 For multiple renal function assessments within a visit window, 
guidelines given in section 1.1 were insisted to be followed, i.e., the 
closest value to the planned visit instead of the average will be taken 
for imputation. 
 Type of induction was identified as the first intake of rATG or 
basiliximab by Day 1 post-transplant. 
 
16-Feb-2016 
 Modified the 12-month analysis cut-off day: Month 12 Visit + 2 Weeks;  
 Modified the definition of NODM NMQ; The terms ‘pre-transplantation/ 
prior to or at randomization’ replaced with ‘prior to or at baseline’ and 
post-transplantation/ post-randomization to ‘post-baseline’ 
26-Feb-2016 
 Inserted PD IDs for major PDs 
10-Nov-2016 
 Re-organized the sections to match the new SAP template 
 The following analyses were removed: 
 
Risk analysis for the primary endpoint 
 
Subgroup analysis for other secondary efficacy endpoints, except 
for tBPAR and eGFR<50 at 12 months 
 
Per protocol analysis for secondary and other secondary points 
 
Imputation methods using LOCF and penalty-based adjustment 
 The following details were added: 
 
Compliance set population was added 
 
Analysis of “study treatment” 
 
Definition of MACE 
 
The population and imputation methods were added for different 
analysis 
 
Analysis method for imputed datasets 
 
SAS codes for multiple imputation, and back-to-control imputation 
were added 
 
Disposition summary, prior- and concomitant medication were 
added 
 
Definition of initial CNI stratum and CNI switch 
 
Definition of MPA compliance 
 The following revisions were made: 
 
Definition of on-treatment period for AE summary: to be consistent 
with the whole program, 7-days is used  
 
The list of (co)variates in different models was changed and 
harmonized 
 
The imputation of concomitant medication start day  
 
The visit window table 
 
 
 Changed the imputation rule for incomplete AE/CM start/end dates 
 Revised the definition of last contact day 
 Revised the covariates for the multiple imputation (removed M1 eGFR) 
 


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Date 
Changes 
 
 Clarified the definition of compliance 
 
 Revised the liver function criteria 
20-Feb-2017 
 Added that prednisone and equivalent was not used during study as 
major deviation for PP  
 Added the table of selection criteria for FAS and SAF 
 Specified HLA mismatch as categorical variable (<=3 or >3) in 
statistical models 
 Specified Kenward-Roger method for denominator degrees of freedom 
in mixed effect model. Used “Study Day” instead of “subject” in the 
random statement. 
 Added dummy code for mixed effect model  
 Defined treatment-emergent AE 
 Added program specific safety risk events 
 Added safety events for clinical trial safety disclosure 
 Added notable lab abnormalities in the list of newly occurring 
abnormality criteria 
 Updated the visit windows 
 Added details for multiple imputation and the control-based imputation 
 Changed Month 1 to Week 4. Changed “subject” to “patient” 
27-Feb-2018 
 Added discontinuation reasons hierarchy when several study drugs are 
affected 
 In laboratory assessments, for multiple observations in the same visit 
window, the worst case is selected 
 The last disposition date will be defined as the latest date in the 
database (across all visit dates itself, all visit related assessment 
dates, other assessment dates, event dates (start and end), 
medication dates). 
 


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Table of contents 
Table of contents ........................................................................................................................ 4 
1 
Introduction ......................................................................................................................... 7 
2 
Statistical Methods .............................................................................................................. 7 
2.1 
Data Analysis General Information ......................................................................... 7 
2.1.1 
General Definition ................................................................................... 8 
2.2 
Analysis Sets ............................................................................................................ 9 
2.2.1 
Subgroup of Interest .............................................................................. 10 
2.3 
Patient Disposition, Demographics and Baseline Characteristics ......................... 11 
2.3.1 
Patient Disposition ................................................................................ 11 
2.3.2 
Patient Demographics and Baseline Characteristics ............................. 12 
2.3.3 
Medical History ..................................................................................... 12 
2.4 
Treatments ............................................................................................................. 12 
2.4.1 
Study Treatment .................................................................................... 12 
2.4.2 
Compliance ........................................................................................... 13 
2.4.3 
Prior/Concomitant Medication .............................................................. 14 
2.5 
Analysis of Primary Objective............................................................................... 15 
2.5.1 
Primary Endpoint .................................................................................. 15 
2.5.2 
Statistical Model, Hypothesis, and Method of Analysis ....................... 15 
2.5.3 
Handling of Missing Values/Censoring/Discontinuations .................... 17 
2.5.4 
Supportive Analyses.............................................................................. 17 
2.6 
Analysis of Key Secondary Objective ................................................................... 18 
2.6.1 
Key Secondary Endpoints ..................................................................... 18 
2.6.2 
Statistical Model, Hypothesis, and Method of Analysis ....................... 18 
2.6.3 
Handling of Missing Values/Censoring/Discontinuations .................... 19 
2.6.4 
Supportive Analyses.............................................................................. 19 
2.7 
Analysis of Other Secondary Objective ................................................................ 19 
2.7.1 
Other Secondary Endpoints ................................................................... 19 
2.7.2 
Statistical Model, Hypothesis, and Method of Analysis ....................... 20 
2.7.3 
Analysis of Renal Function Endpoints .................................................. 21 
2.8 
Safety Evaluation ................................................................................................... 22 
2.8.1 
AEs Including Infections....................................................................... 22 
2.8.2 
Safety Events of Interest ....................................................................... 23 
2.8.3 
Program Specific Safety Risk Events ................................................... 24 
2.8.4 
Other Safety Events ............................................................................... 25 
2.8.5 
Safety Events for Clinical Trial Safety Disclosure ............................... 29 


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2.9 
Pharmacokinetic (PK)/Pharmacodynamic (PD)/PK-PD/Biomarkers 
Evaluations ............................................................................................................ 29 
 
 29 
 
 29 
 
 29 
 
 30 
2.12 
Interim Analyses .................................................................................................... 30 
2.12.1 
Futility Analysis .................................................................................... 30 
2.12.2 
Other Analyses ...................................................................................... 31 
2.12.3 
Calculation of Prediction Interval and Conditional Power ................... 33 
3 
Determination of Sample Size ........................................................................................... 35 
4 
Appendix ........................................................................................................................... 36 
4.1 
Visit-Windows ....................................................................................................... 36 
4.2 
Missing Data Handling .......................................................................................... 37 
4.2.1 
Missing GFR Data Imputation .............................................................. 37 
4.2.2 
CNI/EVR Trough Level Imputation ..................................................... 38 
4.2.3 
LOCF for Laboratory and Vital Sign Data ........................................... 40 
4.2.4 
Imputation of Incomplete Dates ............................................................ 41 
4.3 
Definition/Derivation of Efficacy Variables ......................................................... 43 
4.3.1 
Antibody-Mediated (Humoral) Rejection (AMR) ................................ 43 
4.3.2 
Acute Rejection (AR) ............................................................................ 44 
4.3.3 
Treated Acute Rejection (tAR) ............................................................. 44 
4.3.4 
Biopsy-Proven Acute Rejection (BPAR) .............................................. 44 
4.3.5 
Treated Biopsy-Proven Acute Rejection (tBPAR) ............................... 45 
4.3.6 
Antibody Treated Biopsy-Proven Acute Rejection ............................... 45 
4.3.7 
Death ..................................................................................................... 45 
4.3.8 
Graft Loss .............................................................................................. 45 
4.3.9 
Loss to Follow-Up................................................................................. 45 
4.3.10 
Composite Efficacy Failure................................................................... 46 
4.4 
Definition/Derivation of Safety Variables ............................................................. 46 
4.4.1 
MedDRA Preferred Terms or SMQs to Be Used to Define The 
Events of Interest................................................................................... 46 
4.5 
Renal Variables ...................................................................................................... 48 
4.5.1 
eGFR Using MDRD 4 ........................................................................... 48 
4.5.2 
eGFR Using Hoek Formula on Cystatin C ........................................... 48 
4.5.3 
eGFR Using CKD EPI Formula ............................................................ 48 


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4.6 
Clinically Notable Laboratory and Vital Signs Abnormality Criteria/Levels ....... 48 
4.6.1 
Clinically notable laboratory abnormality criteria/levels ...................... 48 
4.6.2 
Clinically notable vital signs abnormality criteria/levels ...................... 49 
4.7 
Statistical Models .................................................................................................. 49 
4.7.1 
Dummy Codes for Estimating Event Rate, Event Rate Difference 
and Respective 95% CI as Well as No-Difference Testing for The 
Composite Endpoint of BPAR or GFR<50 mL/min/1.73m2 ................ 49 
5 
References ......................................................................................................................... 50 
 


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1 
Introduction 
This document presents detailed Statistical Analysis Plan (SAP) of study CRAD001A2433 
entitled “A 24 month, multicenter, randomized, open-label safety and efficacy study of 
concentration-controlled everolimus with reduced calcineurin inhibitor vs mycophenolate with 
standard calcineurin inhibitor in de novo renal transplantation- Advancing renal TRANSplant 
eFficacy and safety Outcomes with an eveRolimus-based regiMen (TRANSFORM)”. This 
document covers futility, 12-month and 24-month analyses. Notable examples of analyses only 
to be performed at Month 12 (and not Month 24) include the non-inferiority analyses for the 
primary endpoint (tBPAR or eGFR(MDRD4) < 50 ml/min/1.73m2) and the key secondary 
endpoint (tBPAR, graft loss or death), the superiority analysis for the primary endpoint, and the 
analysis for compliant patients. 
2 
Statistical Methods  
Twelve-month and 24-month data will be analyzed by Novartis according to the data analysis 
section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR, unless 
otherwise indicated.  Important information is given in the following sections and details are 
provided. The futility analysis is described in Section 2.12.1, and will be performed by the CRO 
of Quanticate.  
All statistical analyses, tables and data listings will be produced using SAS® statistical 
software, Version 9.4 (or higher) for Unix. 
2.1 
Data Analysis General Information 
The cut-off day is defined as the latest study day before and up to which data will be used in 
the analysis on an individual patient level. The cut-off date for 12-month analysis will be the 
day of Month 12 Visit (specifically, Date of Discontinuation/Study Phase Completion as 
recorded on the Month 12 Disposition eCRF) + 2 Weeks, but no later than Day 450 (upper limit 
of Month 12 analysis window). For the 24-month analysis, there will be no cut-off day. All data 
in the clinical database will be used for the analyses. 
Data listings will include all data collected up to the cut-off date for the 12-month analysis, or 
all data recorded in the database for the 24-month analysis. 
For summary tables and figures, the following rules will be applied unless otherwise indicated: 
 Categorical data will be summarized by frequencies and percentages. Continuous data will 
be summarized by mean, median, standard deviation, minimum and maximum and the 
number of non-missing data points. 
 All AE/Infection, notable events, CMV information, EBV information and other events of 
interest will be summarized based on all collected events with onset on or after the first day 
of study medication up to the cut-off date or seven days after last dose of study medication. 
For SAE/infection and death, all events will be summarized. 
 All lab or vital sign tables will include data up to the cut-off date or two days after last dose 
of study medication (on-treatment analysis); 


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 Efficacy and renal function analyses will be primarily based on all available data including 
those after study medication discontinuation; as a sensitivity analysis they will include only 
data up to two days after last dose of study medication (on-treatment analysis). Patients will 
be censored for the time to event analyses if they do not have an event. For on-treatment 
analysis, the censoring day is two days after discontinuation of study medication or the last 
contact day, whichever is earlier; for analysis regardless of on-treatment or off-treatment, 
the censoring day is the last contact day. 
 For post-baseline continuous values, for a given patient, if multiple numeric measurements 
for a given variable are reported within the same visit window (see the definition for visit 
windows in Section 4.1), the following rule will be applied:  
 For quantitative measures including EVR/CsA/TAC trough levels, the closest value to 
the planned visit (baseline visit: date of transplant; other visits: midpoint of visit 
window) is taken (if tie, the last will be used).  
 For qualitative (categorical) assessment, the worst value of all records observed in the 
visit window will be used. An event defined on a quantitative measure is also a 
qualitative (categorical) assessment. For example, ALT >3x ULN; the highest (worst) 
value is compared to the ULN. 
Details about the definition of efficacy and safety events, data handling conventions including 
the ‘re-aligned’ visit windows, imputation of missing dates, and other details can be found in 
the Section 4.  
2.1.1 
General Definition  
2.1.1.1 
Study Day 
The date of randomization is defined as Day 1. 
A study day is defined as the number of days since the randomization and for a particular date 
it is calculated as follows: 
Study day = Assessment date – randomization date + 1. 
Day 1 is the reference point for separating pre- and post-randomization. For assessments 
performed before Day 1, the calculation is as follows: 
Study day = Assessment date – randomization date. 
2.1.1.2 
Date of Last Dose  
In general a study regimen stops if the combination is not given anymore, i.e. the date of last 
dose of study regimen is the earliest ‘date of last dose’ among the study drugs contained in the 
study regimen.  
However, for the investigational regimen containing everolimus, the date of last dose of study 
regimen is the date of the last intake of the investigational drug everolimus. This is a 
conservative approach in that any events occurring while still taking everolimus will be 
considered on-treatment events, even if the complete regimen is no longer being administered.  


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2.1.1.3 
Last Contact Day 
The last contact day for the 12-month analyses will be determined by screening the 12-month 
database and taking the maximum of any dates found post-randomization. If the maximum date 
is after the cut-off date for the 12-month analysis, use the cut-off day as the last contact day for 
the 12-month analysis. 
The last contact day for the 24 months analyses corresponds to the last recorded date in the 
database (across all visit dates itself, all visit related assessment dates, other assessment dates, 
event dates (start and end), medication dates). It should be prior to or on the day of study 
completion and therefore dates of events which occur after study completion will not be 
considered.  
2.1.1.4 
Baseline 
The baseline value is the last non-missing value prior to the randomization. 
The baseline body weight should be taken as the last non-missing weight prior to randomization. 
It is anticipated that in some cases, baseline body weight may be missing. In such cases, when 
used to derive other variable (i.e. dose per body weight), baseline body weight will be taken 
from the next available visit on the Vital signs form. However, in summary statistics of vital 
signs data, missing baseline body weights will be treated as missing. The exact algorithm to 
derive baseline body weight is as follows: it is the last assessment of any evaluations done up 
to the date of randomization; if there is no such assessment, it will be the first assessment taken 
after the date of randomization. 
The baseline height will be derived in a similar way as the baseline body weight. Subsequently, 
BMI will be calculated. 
2.1.1.5 
On-Treatment 
An on-treatment observation will be any assessment obtained on and after Day 1 but no later 
than two days after the discontinuation of randomized study medication. However, for 
AE/Infection, notable events, CMV information, EBV information and other events of interest, 
events occurring up to seven days (inclusive) after discontinuation of study medication are 
considered “on-treatment”. 
2.2 
Analysis Sets  
The full analysis set (FAS) consists of all randomized and transplanted patients. Patients 
randomized but not transplanted will be excluded from the FAS. Patients who are mis-
randomized due to documented (IVRS) administrative error (eligibility criteria) and have no 
study drug received are excluded from the FAS. Following the intention-to-treat (ITT) 
principle, patients will be analyzed according to their randomized treatment assignment and 
according to the actual stratum they initially belong to.  
The compliance set (CS) consists of all patients in the FAS who are compliant for both CNI 
and investigational drug (EVR/MPA). Compliance is defined in Section 2.4.2. 
The per-protocol set (PPS) consists of all patients in the FAS who complete the study without 
any major deviations from protocol procedures.  Major deviations include: 


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 Patient received multiple solid organ or tissue transplants (PD ID: EXCL04) 
 Renal cold ischemia time  > 30 hr (PD ID: INCL04) 
 Patient received kidney from a non-heart beating donor (PD ID: INCL06) 
 Patient Stratified incorrectly (PD ID: TRT08) 
 Patient randomized but did not receive study drug (EVR or MPA) (PD ID: TRT01) 
 Patient received treatment other than what they were randomized to (PD ID: TRT07) 
 Induction agent other than basiliximab or rATG used (PD ID: TRT05) 
 Patient did not receive any basiliximab or rATG for induction use (PD ID: TRT06) 
 Prohibited Concomitant Medication used (PD ID: COMD03) 
 Prednisone or equivalent was not used during the study (PD ID: TRT14) 
The safety set (SAF) consists of all patients who received at least one dose of study drug. 
Patients will be analyzed according to their actual treatment regimen and according to the actual 
stratum they initially belong to. All safety analyses will be performed on the SAF. 
Patients who did not sign the study main informed consent form will be excluded from any 
analysis sets (FAS, PPS, CS, and SAF). If a patient was mis-randomized due to documented 
(IVRS) administrative error (eligibility criteria), but received study drug, this patient will 
belong to both FAS and SAF. Table 2-1 illustrates the selection of patients for the FAS and 
SAF. 
Table 2-1 
Selection of patients for the full-analysis set and the safety set 
IC 
TX 
RND 
Mis-RND 
RX 
Dataset(s) 
No 
Y/N 
Y/N 
Y/N 
Y/N 
Exclusion 
Yes 
No 
No 
No 
No 
Screening failure 
Yes 
Yes 
No 
No 
No 
Randomization failure 
Yes 
Yes 
Yes 
No 
Y/N 
FAS 
Yes 
Yes 
Yes 
Yes 
Yes 
FAS 
Yes 
Y/N 
Y/N 
Y/N 
Yes 
SAF 
Yes 
No 
Yes 
Yes 
No 
Exclusion 
Yes 
Yes 
Yes 
Yes 
No 
Exclusion 
Yes 
No 
Yes 
No 
No 
Exclusion 
IC=informed consent, Tx=transplantation, RND=randomization, Rx=study treatment 
2.2.1 
Subgroup of Interest 
The following demographic/baseline characteristics are defined at the study level as subgroups 
for specified analyses:  
 Recipient characteristics: 
 Age group: <60 vs ≥60 yr 
 Gender 
 Race: Caucasian, Black, Asian and All other races   
 Region: US, EU, Asia, Australia, Latin America, and Middle East 


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 DGF (delayed graft function) 
 BMI <30 and ≥ 30 
 Donor/transplant characteristics: 
 Age group: <60 vs ≥60 yr 
 Gender 
 Cold ischemia time: < 20 vs ≥20 hr 
 End stage disease leading to transplant (Glomerular disease, Diabetes mellitus and All 
other diseases) 
 Donor type (living donor, standard criteria and expanded criteria deceased donor): 
donor type will be derived based on Kidney Donor Background Information eCRF, and 
not the randomization stratification from IRT. 
 HLA mismatches: <=3 vs >3 
 CNI (tacrolimus vs. cyclosporine) 
 Induction (basiliximab vs. rATG): 
 Basiliximab: preferred term: BASILIXIMAB; drug code/ID: 10892631 
 rATG: 
preferred 
term: 
ANTITHYMOCYTE 
IMMUNOGLOBULIN, 
or 
ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT); drug code/ID: 10878131 or 
10878151 
As early use of rATG can be for delayed graft function, type of induction will be identified 
as the first intake of rATG or basiliximab by Day 1 post-transplant. 
2.3 
Patient Disposition, Demographics and Baseline Characteristics 
2.3.1 
Patient Disposition 
Patient disposition will be summarized in terms of the number and percentage of patients who 
complete the screening, prematurely discontinued from study medication and from study (by 
primary reasons). When there are multiple reasons for discontinuation associated to study drugs 
and CNI that happened the same day, the primary reason will be the one related to, by order of 
priority, Everolimus, Tacrolimus, MPA and Cyclosporine. The number of patients in the 
different analysis sets, incidence of protocol deviations, and incidence of major protocol 
deviations and other deviation criteria leading to exclusion from per-protocol set will be 
summarized by treatment group. Listings of screen failure and study completion with primary 
reasons for premature discontinuation of the randomized study treatment will also be provided. 
In addition, the following listings will be presented: 
 Screen failure 
 Study completion status 
 Protocol Deviations (PDs) 
 Major protocol deviations and other deviation criteria leading to exclusion from per-
protocol set 
 Patients excluded from any analysis sets 


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2.3.2 
Patient Demographics and Baseline Characteristics 
Demographic and background information will be summarized based on the FAS population.  
Incidence rates of diabetes at baseline (see the definition in Section 2.8.3.3) and delayed graft 
function will be also summarized. 
Delayed graft function is defined when any of the following criteria are met within 21 days (end 
day of Week 2 visit window) after transplant: 
 AE eCRF page: MedDRA lower level term includes words: “graft dysfunction” or “graft 
function delayed”; verbatim contains “delayed graft function” or “DGF”. 
 Kidney Allograft Rejection eCRF page: “Primary reason rejection was suspected” = 
Delayed or slow recovery of graft function post-revascularization” or “Primary clinical 
diagnosis” = “delayed graft function”. 
2.3.3 
Medical History 
Relevant medical history/current medical conditions will be summarized by primary system 
organ class, preferred term, and treatment group. Frequencies and percentages of patients in the 
FAS in each treatment group will be presented. 
2.4 
Treatments 
The following descriptive analyses will be performed on the SAF by treatment group and total, 
unless otherwise stated. 
2.4.1 
Study Treatment 
Duration of Exposure 
Duration of exposure to study medication for SAF patients with a specified end date (date of 
last dose of study medication), i.e. for patients who permanently discontinued from study 
treatment or patients who completed the study: 
Duration of exposure = (Date of last dose of study medication – Date of first dose of study 
medication + 1) 
Duration of exposure to study medication for SAF patients without a specified end date: 
Duration of exposure = (Date of Month 12 study cut-off date – Date of first dose of study 
medication + 1) 
Note that duration of exposure includes periods of temporary interruption of study medication. 
Duration of exposure to study regimen will be summarized in tables as follows. In addition to 
an overall summary of exposure duration for each study regimen, a separate summary will be 
made for CsA and TAC strata within a study regimen. 
 Number and percentage of patients being exposed for prespecified time intervals (e.g. 1-7 
days, 8-14 days, 15-30 days, 31-60 days, etc) as well as cumulative exposure. 
 Summary statistics (n, mean, SD, median, Q1, Q3, minimum, maximum) for duration of 
exposure will also be provided. 


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Average Daily Doses and Body Weight-Adjusted Average Daily Doses 
Average daily doses and body weight-adjusted average daily doses (for CsA and TAC only) by 
visit window and treatment group will also be calculated. In calculating average daily doses, 
zero doses will be used for periods of temporary interruption of study medication, regardless of 
whether this was due to safety reasons or non-compliance. 
Dose Changes and Interruptions 
The number and percentage of patients with dose interruptions/adjustments will be summarized 
by reason for change and by the number of adjustments (any, one, two, three, more than three). 
Switching CNIs 
The number and percentage of patients of remaining on their initial CNI or switching CNI at 
least once during the study will be summarized for each study CNI-specific study regimen.  This 
will be provided for each study period (up to Month 12, Month 12 to 24, and cumulatively). 
Trough Levels of Study Drugs 
Everolimus, cyclosporine and tacrolimus trough levels (in ng/mL) will be summarized at each 
visit window using descriptive statistics, and the incidence rates of patients below, within or 
above the trough level target ranges at each visit will be presented for patients on treatment at 
that visit. The target ranges for CsA and TAC trough levels are provided in Table 2-1. The 
target range for everolimus trough levels is 3-8 ng/mL throughout the study. 
Box plots of everolimus, cyclosporine and tacrolimus trough levels will be presented by visit 
for each treatment group. The target trough level ranges will be shown in the plots.  
Table 2-2 
CNI trough level target ranges 
Study Visit 
Tacrolimus target ranges 
Cyclosporine target ranges 
 
EVR arm 
MPA arm 
EVR arm 
MPA arm 
Day 1 ≤ Month 2 
4-7 ng/mL 
8-12 ng/mL 
100-150 ng/mL 
200-300 ng/mL 
Month 3 ≤ Month 6 
2-5 ng/mL 
6-10 ng/mL 
50-100 ng/mL 
150-200 ng/mL 
Month 7 ≤ Month 24 
2-4 ng/mL 
5-8 ng/mL 
25-50 ng/mL 
100-200 ng/mL 
2.4.2 
Compliance 
2.4.2.1 
Compliance for MPA 
For each day, a patient is compliant to MPA as long as this patient takes MPA (non-compliant 
when MPA was off). If a patient is compliant for at least 70% of days on study, then this is a 
compliant patient. 
2.4.2.2 
Compliance for CNI/EVR: 
To evaluate patient compliance for CNI/EVR, CNI/EVR trough levels will be imputed (see 
Section 4.2.2 for details) for each day from the date of the first dose of the respective study drug 
(CNI/EVR) to the maximum study drug on-treatment date, which is defined as the minimum of 
(the date of the last study drug dose plus two days or the last contact day). For each day, patient 
compliance will be assessed by comparing the imputed trough level with the corresponding 


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target trough level range. If a patient was compliant for at least 70% of days on study, then this 
is a compliant patient. 
2.4.3 
Prior/Concomitant Medication 
Medications will be identified using the NovDTD including Anatomical Therapeutic Chemical 
(ATC) code. Prior medications are defined as drugs taken prior to the first dose of randomized 
study medication regardless of whether they continue thereafter. Any medication given at least 
once between the date of the first dose and the last dose of randomized study medication will 
be defined as concomitant medication, including those started before randomization and 
continued into the treatment period. Any medication started after the discontinuation of 
randomized study medication will not be considered as concomitant medication. Prior or 
concomitant medication will be identified based on recorded or imputed start and end dates. 
Rules for imputing incomplete (start and end) dates are described in Section 4.2.4. 
Prior and concomitant medications will be summarized by treatment group and total in separate 
tables for SAF. Medications will be presented in alphabetical order, by ATC codes and grouped 
by anatomical main group (the 1st level of the ATC codes). Tables will show the overall number 
and percentage of patients receiving at least one drug within a particular ATC code and at least 
one drug in a particular anatomical main group. 
2.4.3.1 
Steroids 
Steroids will be displayed using prednisone equivalent body weight adjusted doses. The doses 
displayed in the following table are considered equivalent. To determine prednisone equivalent 
doses, doses will be multiplied by the conversion factor shown in Table 2-2. To adjust the dose, 
the body weight measured closest to the start of a steroid dose will be used (from vital signs 
eCRF).  
Table 2-3 
Steroids conversion factors 
WHO drug code 
Preferred Term Corticosteroid 
Equivalent Dose [mg] 
Conversion Factor 
000447xx 
Prednisone  
5 
1 
000162xx 
Prednisolone 
5 
1 
000496xx  
Methylprednisolone 
4 
1.25 
012428xx 
Meprednisone 
4 
1.25 
001867xx 
Prednylidene 
40/7   
0.875 
000319xx 
Triamcinolone 
4 
1.25 
000146xx  
Cortisone  
25 
0.2 
000286xx 
Hydrocortisone 
20 
0.25 
002131xx 
Fludrocortisone 
2 
2.5 
000085xx 
Betamethasone 
0.75 
20/3 
000664xx  
Paramethasone 
2 
2.5 
000160xx  
Dexamethasone 
0.75 
20/3 
008827xx 
Deflazacort 
6 
5/6 
006445xx  
Cloprednol 
3 
5/3 


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Average daily doses and body weight-adjusted average daily doses by visit window will be 
summarized for corticosteroids (expressed in doses equivalent to prednisone) for each treatment 
group for patients who are on study medication. 
2.4.3.2 
Immunosuppressive Therapies 
All immunosuppressive medications will be summarized by ATC code, WHO preferred term 
and treatment group as follows: 
 Concomitant other than study medication (cyclosporine, everolimus, tacrolimus & MPA) 
 Taken after early discontinuation of randomized study medication  
2.4.3.3 
Lipid-Lowering Drugs 
Any medication with ATC code C10A will be considered lipid-lowering drugs. Lipid-lowering 
agents will be grouped by ATC code and summarized by WHO preferred terms. For any of 
these medications, the number of patients (and percentage) receiving at least one dose 
concomitantly with randomized study medication will be displayed; this will not include any 
drugs started after the discontinuation of study medication. 
2.5 
Analysis of Primary Objective 
2.5.1 
Primary Endpoint 
The primary efficacy variable is a binary composite endpoint of tBPAR or eGFR (MDRD4) < 
50 mL/min/1.73m2 at Month 12 post-transplantation. The component of eGFR (MDRD4) < 50 
mL/min/1.73m2 at Month 12 is defined as the incidence of eGFR (MDRD4) < 50 
mL/min/1.73m2 in the Month 12 visit window. 
2.5.2 
Statistical Model, Hypothesis, and Method of Analysis 
The primary analysis will be performed on the Full Analysis Set following the intent-to-treat 
principle.   
Testing of CNI effects: 
Based on FAS without imputation, treatment by CNI interaction for the composite endpoint of 
tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 will be assessed using a logistic regression 
model including covariates/factors for treatment, CNI, region, interaction of treatment and CNI, 
interaction of treatment and region, donor type, HLA mismatch (≤3 vs >3), induction therapy, 
recipient gender, recipient age, donor age, DGF, and eGFR (MDRD4) at Month 1. In the model, 
recipient and donor age will be treated as continuous variables. If the interaction is not 
significant at the level of 0.10, i.e. the effects of treatment are similar for each CNI, then the 
primary analysis will be based on the pooled CNIs, i.e. everolimus plus reduced CNI 
(EVR+rCNI) vs. MPA plus standard CNI (MPA+sCNI). If this test shows significantly different 
event rates for tacrolimus vs. cyclosporine, then testing will be performed for the 2 CNIs 
separately, with the tacrolimus subgroup being considered primary 
 
 
Testing strategy to control type I error: 


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Event rates will be compared between groups using the following hierarchical testing strategy: 
a. Non-inferiority of EVR+rCNI vs. MPA+sCNI will be evaluated based on the primary 
endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 using a 10% 
non-inferiority margin (see Section 2.5.2.1).   
b. Non-inferiority of EVR+rCNI vs. MPA+sCNI will be evaluated with a 10% non-
inferiority margin for the key secondary endpoint of tBPAR, graft loss or death at 
Month 12 (see Section 2.6.2).  
c. Superiority of EVR+rCNI to MPA+sCNI will be evaluated based on the primary 
endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 (see Section 
2.5.2.2).  
The above hierarchical fixed hypothesis testing procedure will not inflate overall Type I error 
rate.  Therefore, each hypothesis will be tested at the one-sided 0.025 significance level and no 
multiplicity adjustment is needed. For these statistical tests, one-sided p-values will be 
presented in the analysis outputs. 
2.5.2.1 
Non-Inferiority of Everolimus Plus Reduced CNI to MPA Plus Standard 
CNI 
The null hypothesis: 
H01:  REVR+rCNI - RMPA+sCNI ≥ 0.10 (non-inferiority margin): the difference in proportion of 
patients experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is at least 10%. 
The alternative hypothesis: 
HA1: REVR+rCNI - RMPA+sCNI < 0.10 (non-inferiority margin): The difference in proportion of 
patients experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is  less than 10%. 
The proportion of patients meeting the primary endpoint of tBPAR or eGFR (MDRD4) < 50 
mL/min/1.73m2 at Month 12 will be compared using a confidence interval approach.  
Multiple imputation will be used as the primary method for handling missing data (see Section 
2.5.3 and Section 4.2.1.1 for detail). The analysis first creates multiple (100) imputations of 
missing eGFR (MDRD4) values under a missing at random (MAR) assumption, resulting in 
multiple (100) imputed datasets. The imputation model assumes a multivariate normal model 
for the eGFR (MDRD4) measurements. This model will be estimated separately within each 
treatment stratum. Together with the tBPAR data, the binary composite endpoint of tBPAR or 
eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 post-transplantation will be derived. 
To the resulting 100 imputed datasets, the proportion of patients meeting the primary endpoint 
of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 will be estimated, yielding 
100 sets of parameter estimates and associated covariance matrices. The analysis results are 
then combined according to Rubin’s rules to derive overall estimates and confidence intervals 
that adequately reflect missing data uncertainty as well as associated p-values (see Section 4.7.1 
for sample analysis codes). The everolimus plus reduced CNI arm will be claimed to have a 


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non-inferior incidence of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 compared to the 
MPA plus standard CNI arm if the upper limit of the 95% CI is below 10%. 
2.5.2.2 
Superiority of Everolimus Plus Reduced CNI to MPA Plus Standard 
CNI 
The null hypothesis: 
H03:  REVR+rCNI - RMPA+sCNI ≥ 0: the proportion of patients experiencing tBPAR or eGFR 
(MDRD4) < 50 mL/min/1.73m2 at 12 months in the everolimus plus reduced CNI (REVR+rCNI) 
arm is greater than or equal to that in the MPA plus standard CNI arm (RMPA+sCNI) arm. 
The alternative hypothesis: 
HA3: REVR+rCNI - RMPA+sCNI < 0: the proportion of patients experiencing tBPAR or eGFR 
(MDRD4) < 50 mL/min/1.73m2 at 12 months in the everolimus plus reduced CNI (REVR+rCNI) 
arm is less than that in the MPA plus standard CNI arm (RMPA+sCNI) arm. 
Following the aforementioned hierarchical fixed hypothesis testing procedure, the hypothesis 
H03 for superiority of EVR plus reduced CNI to MPA plus standard CNI will be evaluated only 
if non-inferiority of EVR plus reduced CNI vs. MPA plus standard CNI is achieved for the 
primary endpoint (rejecting the hypothesis H01) and the key secondary endpoint of tBPAR, graft 
loss or death at Month 12 (rejecting the hypothesis H02, see Section 2.6.2). The everolimus plus 
reduced CNI arm will be claimed to be superior to the MPA plus standard CNI arm with respect 
to composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 12 months if the 
upper limit of the 95% CI estimated in Section 2.5.2.1 is less than 0. 
2.5.3 
Handling of Missing Values/Censoring/Discontinuations 
Since the patients who have prematurely discontinued study regimen are followed on standard 
of care, renal function data (e.g. creatinine) and kidney allograft biopsy data will be collected 
post discontinuation of study regimen for these visits, it is expected that few patients would be 
missing efficacy and/or renal function evaluation for the 12 month analysis.  
For the component of eGFR < 50 mL/min/1.73m2, a value for missing eGFR as a continuous 
variable will be imputed first (see Section 4.2.1.1 for the main imputation), then dichotomized 
it to derive this endpoint. As allograft biopsy data will be collected on an as needed basis due 
to the nature of kidney transplant studies, no particular rule for missing biopsy will be applied. 
2.5.4 
Supportive Analyses  
2.5.4.1 
Analysis on Treatment Compliant Patients 
The analysis outlined for the primary endpoint in Section 2.5.2 will be repeated using Compliant 
Set.  
2.5.4.2 
Analysis on Per-Protocol Set 
The analysis outlined for the primary endpoint in Section 2.5.2 will be repeated using the Per-
Protocol Set.  


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2.5.4.3 
Subgroup Analysis 
Subgroup analyses will be done for the primary composite endpoint of tBPAR or eGFR 
(MDRD4)<50 mL/min/1.73m2 at 12 months for the subgroups defined in Section 2.2.1. 
Subgroup analyses will use similar methods described in Section 2.5.2.1. 
2.5.4.4 
Analyses with Other Imputations for Missing eGFR (MDRD4) at Month 
12 
In addition to the main imputation, additional imputation method assuming missing not at 
random (MNAR) as provided in Section 4.2.1.2 will be used to impute missing 12-month eGFR 
value to define the primary variable – composite endpoint of tBPAR or eGFR (MDRD4) < 50 
mL/min/1.73m2. With these imputations, non-inferiority and superiority analyses described in 
Section 2.5.2 will be repeated. 
2.6 
Analysis of Key Secondary Objective 
2.6.1 
Key Secondary Endpoints 
The key secondary endpoint is the binary composite efficacy failure of tBPAR, graft loss or 
death at Month 12 post-transplantation.  
2.6.2 
Statistical Model, Hypothesis, and Method of Analysis 
For the key secondary objective regarding the composite efficacy failure of tBPAR, graft loss 
or death, the following hypotheses will be evaluated (α=0.025, one-sided) only if non-inferiority 
of EVR plus reduced CNI vs. MPA plus standard CNI is achieved for the primary endpoint 
(rejecting the hypothesis H01), and will be based on the Full Analysis Set:  
The null hypothesis: 
H02:  REVR+rCNI - RMPA+sCNI ≥ 0.10 (non-inferiority margin): the difference in Kaplan-Meier 
event rate of the composite efficacy failure of tBPAR, graft loss or death at 12 months between 
the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) 
is at least 10%. 
The alternative hypothesis: 
HA2: REVR+rCNI - RMPA+sCNI < 0.10 (non-inferiority margin): the difference in Kaplan-Meier event 
rate of the composite efficacy failure of tBPAR, graft loss or death at 12 months between the 
everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI arm (RMPA+sCNI) is  
less than 10%. 
For this analysis, the event rate of the composite efficacy failure of tBPAR, graft loss or death 
will be estimated with Kaplan-Meier product-limit formula. Greenwood’s formula will be used 
to estimate variance of failure rates and to derive Z-test based confidence interval for the 
difference in failure rate between the everolimus plus reduced CNI and the MPA plus standard 
CNI arm.  
A Kaplan-Meier table and plot will be produced. The differences between the two KM curves, 
corresponding to the two treatment arms, will be tested pair-wise using the log-rank test. In 


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these analyses, patients with event-free will be censored with the censoring time as defined as 
the Last Contact Day. 
2.6.3 
Handling of Missing Values/Censoring/Discontinuations 
Since the patients who have prematurely discontinued study regimen are followed on standard 
of care, efficacy data including kidney allograft biopsies will be collected post-discontinuation 
of study regimen for these visits, it is expected that few patients would be missing efficacy 
evaluation for the 12 months analysis. Patients with missing efficacy evaluation for the 12 
month analysis will be censored at the latest day known to be free of the event. 
2.6.4 
Supportive Analyses  
As supportive analyses, this non-inferiority analysis will be repeated using the Per-Protocol Set.  
Based on FAS, Kaplan-Meier event rates at Month 12 will be summarized for the subgroups 
defined in Section 2.2.1. 
2.7 
Analysis of Other Secondary Objective 
2.7.1 
Other Secondary Endpoints 
Other secondary efficacy variables to be considered are as follows: 
1. Composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 24 
2. Composite endpoint of tBPAR excluding grade IA rejections or eGFR (MDRD4) < 50 
mL/min/1.73m2 at Months 12 and 24 
3. Composite efficacy failure of tBPAR, graft loss, or death at Month  24 
4. Composite efficacy failure of tBPAR, graft loss, death, or loss to follow-up at Month 12 and 
24 
5. Components of composite efficacy failure as well as BPAR, AR, tAR at Month 12 and 
Month 24 
a. AR 
b. tAR 
c. BPAR 
d. tBPAR 
e. tBPAR excluding grade IA rejections; 
f. Humoral rejection 
g. Graft loss 
h. Death. 
6. Composite endpoint of tBPAR, graft loss, death or eGFR < 50 mL/min/1.73m2 at Months 
12 and  24 
7. Composite endpoint of graft loss or death at Month 12 and Month 24 
8. Composite endpoint of BPAR, graft loss or death at Month 12 and Month 24 
9. eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 and Month 24 


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10. Renal function (eGFR by MDRD4, CKD-EPI and Cystatin C-based formulae) at Month 12 
and Month 24 
11. Renal function change from Week 4 to Month 12 and Month 24 
12. Evolution of renal function (eGFR by MDRD4) from Week 4 to Month 12 and Month 24 
(slope analyses). 
2.7.2 
Statistical Model, Hypothesis, and Method of Analysis  
2.7.2.1 
Endpoints with eGFR (MDRD4) < 50 mL/min/1.73m2 as a Component  
Similar analysis method used for primary endpoint (Section 2.5.2.1) will be performed for the 
endpoint of eGFR (MDRD4) < 50 mL/min/1.73m2 and the composite endpoints with eGFR 
(MDRD4) < 50 mL/min/1.73m2 as a component based on the FAS. Difference between the 
event rates, and the corresponding 95% confidence interval and p-value for equality test will be 
provided. The multiple imputation presented in Section 4.2.1.1 will be applied for missing 
eGFR (MDRD4) values. 
 eGFR (MDRD4) < 50 mL/min/1.73m2  at Months 12 and 24 
 composite endpoint of  tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at Month  24 
 composite endpoint of tBPAR excluding grade IA rejections or eGFR (MDRD4) < 50 
mL/min/1.73m2 at Months 12 and 24  
 composite endpoint of tBPAR, graft loss, death or eGFR (MDRD4) < 50 
mL/min/1.73m2 at Months 12 and 24 
In addition, the composite endpoint of tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 
Month 24 will be analyzed in similar manner based on compliant set population. The endpoint 
of eGFR (MDRD4) < 50 mL/min/1.73m2 at Month 12 will be summarized on the FAS for the 
subgroups defined in Section 2.2.1. 
2.7.2.2 
Endpoints without eGFR (MDRD4) < 50 mL/min/1.73m2 as a 
Component 
Based on FAS, for the composite efficacy failure (tBPAR, graft loss or death) at Month 24 and 
the composite endpoint of BPAR, graft loss or death at Month 12 and Month 24, Kaplan-Meier 
event rates will be estimated and compared between the everolimus plus reduced CNI and the 
MPA plus standard CNI arm. Similarly Kaplan-Meier event rates will be estimated and 
compared for AR, tAR, BPAR, tBPAR, tBPAR excluding grade IA rejections, AMR, graft loss, 
death, the composite endpoint of graft loss or death, and composite endpoint of tBPAR, graft 
loss, death, or loss to follow-up at Months 12 and 24. Kaplan-Meier event rate difference, 95% 
confidence interval and p-value for equality test will be provided. To assess time-to-event 
occurrence, Kaplan-Meier tables and plots will be produced with a log-rank test p-value for the 
above variables. 
In addition, severity of tBPAR will be tabulated by treatment. The endpoint of tBPAR at Month 
12 will be summarized on the FAS for the subgroups defined in Section 2.2.1 
Forest plots of event rate differences for all efficacy endpoints specified in Section 2.7.2 will 
be produced on the FAS.  


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2.7.3 
Analysis of Renal Function Endpoints 
Formulas for computing GFR endpoints can be found in Section 4.5.  
2.7.3.1 
eGFR by CKD-EPI and Cystatin C-based Formulae 
The renal function (eGFR by CKD-EPI and Cystatin C-based formulae) analyses will be based 
on on-treatment analysis without imputation. Renal function and change from Week 4 will be 
summarized by visit with descriptive statistics. A two-sided t-test will be performed to compare 
the two treatment groups at each visit. A plot of mean and 95% CI of eGFR by visit will be 
provided.  
2.7.3.2 
eGFR by MDRD4 
The eGFR by MDRD4 analyses will be based on FAS with multiple imputation used as the 
primary method for the handling of missing data. Renal function and change from Week 4 will 
be summarized by visit with descriptive statistics. A two-sided t-test will be performed to 
compare the two treatment groups at each visit. A plot of mean and 95% CI of eGFR (MDRD4) 
by visit will be provided. These will be repeated for on-treatment renal function analyses. 
In addition, if different CNI effect is shown from the logistic regression, eGFR(MDRD4) and 
change in eGFR(MDRD4) from Week 4 by visit will be summarized for the subgroups of CNI 
(CsA and TAC). 
The proportion of patients by eGFR(MDRD4) range (<30, 30-<45, 45-<60, ≥60 
mL/min/1.73m2) will be summarized by visit.  
For eGFR(MDRD4) at Month 12 and Month 24, analysis of covariance (ANCOVA) will be 
performed with covariates/factors of treatment, CNI, region, interaction of treatment and CNI, 
interaction of treatment and region, donor type, HLA mismatch (≤3 vs >3), induction therapy, 
recipient gender, recipient age, donor age, DGF, and eGFR (MDRD4) at Month 1. In the model, 
recipient and donor age will be treated as continuous variables. The missing Month 12 or Month 
24 values will be imputed using the primary multiple imputation method.  
The evolution of renal function (eGFR by MDRD4) will be evaluated via a mixed effect model 
with intercept and study day as random effects and using covariates/factors treatment, study 
day, CNI, region, interaction of treatment and study day, interaction of treatment and CNI, 
interaction of treatment and region, donor type, HLA mismatch (≤3 vs >3), induction therapy, 
recipient gender, recipient age, donor age, DGF, and eGFR (MDRD4) at Month 1. In the model, 
study day, recipient and donor age, and eGFR (MDRD4) at Week 4 will be treated as continuous 
variables. Unstructured variance-covariance can be assumed, and the eGFR (MDRD4) data at 
Week 4 and onward will be used. The denominator degrees of freedom will be calculated using 
the Kenward-Roger method. No imputation will be applied for missing data. Based on the 
mixed effect model, the treatment groups will be compared, slope of renal function evolution 
for each treatment group will be assessed, and eGFR(MDRD4) value at Month 12/24 will be 
estimated.  
See dummy SAS codes below. 
   proc mixed method=ml; 
     class trt CNI region donor HLA induction gender_r DGF usubjid; 


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     model eGFR= trt day CNI region trt* day trt*CNI trt*region donor HLA 
induction gender_r age_d age_r DGF eGFR_1 / ddfm=kr; 
     random intercept day / patient=usubjid type=UN; 
   run; 
2.8 
Safety Evaluation 
Safety variables to be assessed include discontinuation from study, discontinuation from 
treatment, AE/infection, SAE, notable events, laboratory tests, and vital signs. All safety 
analyses will be done on the safety set.  
2.8.1 
AEs Including Infections 
Generally, infection data are analyzed together with AE data. In addition, infection data will be 
analyzed separately. Micro-organism will be additionally coded with NovORG dictionary. AEs 
and infections here refer to treatment-emergent events (on-treatment analysis by including data 
up to 7 days after the discontinuation of study drug). Treatment-emergent adverse events are 
defined as adverse events or infections that started after the first dose of randomized study 
medication or events present prior to the first dose of randomized study medication but that 
increased in severity. Selected variables will be analyzed using all available data including data 
assessed beyond study treatment discontinuation: SAEs and deaths. 
In all summaries about incidence rates of AEs/Infections, if a patient had multiple occurrences 
of an AE, the patient will be counted only once in the corresponding AE category. If a patient 
had multiple adverse events within a system organ class, he or she will be counted only once 
for that class. If a patient had multiple severity ratings for an AE, he or she will only be counted 
under the maximum rating. 
The following AEs/infections will be analyzed by system organ class and preferred term: 
 Any events (AEs/infections) 
 Frequent events (≥10% in any treatment group) 
 Events requiring study drug dose adjustment or temporary interruption 
 Events leading to premature discontination of study drug 
 Events suspected to be study drug related 
 Events requiring study drug dose adjustment or temporary interruption or leading to 
premature discontination of study drug 
 Events by maximum severity 
 Serious events (SAEs/serious infections) 
 Serious events suspected to be study drug related 
 Death 
Subgroup analyses will be done for AEs and SAEs including infections for the following 
subgroups: 
 CNI (tacrolimus vs. cyclosporine) 
 Region: US, EU, Asia, Australia, Latin America, and Middle East 


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Summaries by standard MedDRA query (SMQ) level (level 1 to 4, SMQ - narrow search) and 
preferred term will be produced for AEs and SAEs including infections, with relative risks and 
their 95% confidence intervals displayed.  
All information pertaining to AEs noted during the study will be listed by patient, detailing AE 
(verbatim given by the investigator as well as the preferred term according to the MedDRA 
dictionary), body system, date starting and ending, causality, severity and drug-relatedness.  
The MedDRA version used for reporting the study will be indicated as a footnote in the outputs. 
Infections 
The derivation of the infection type (viral, bacterial, fungal, and others) is based on the coded 
microorganism. Microorganisms are coded with NovORG (Novartis Organism Dictionary).   
The codes in NovORG are text strings of seven characters, L-abcde, where a,b,c,d, and e may 
be numbers or letters, e.g., L-1E601 (for enterococcus faecalis), L-24801 (for staphylococcus 
aureus) and L-43131 (for candida albicans). The 3rd character, a, will be used to determine 
infection type defined in Table 2-3. 
Table 2-4 
Novartis Organism Dictionary Categories for Infections 
NovORG Code 
Infection Type 
L-1bcde, L-2bcde 
Bacterial 
L-3bcde 
Viral 
L-4bcde 
Fungal 
L-xbcde, where x ≠ 1,2,3,4. 
Other 
Infections may not have been cultured or 
may have been recorded on the Adverse 
Events eCRF, for all such events the 
organism type is unknown 
Unknown 
In addition to summarizing infections together with AEs, the infections will be also tabulated 
by infection type (viral, bacterial, fungal, and others) and micro-organism of infections.  
2.8.2 
Safety Events of Interest 
Safety events of interest, such as risks defined in the Safety Profiling Plan, Risk Management 
Plan or events of interest regarding signal detection or routine analysis are defined in the 
Program Case Retrieval Sheet (CRS) that is stored in CREDI at the path Cabinets/CREDI 
Projects/R/RAD001A/Integrated Medical Safety. 
The following safety events of interest will be summarized with the number and percentage of 
patients experiencing the events, together with risk ratios (RRs) and 95% CIs. The version of 
the Case Retrieval Sheet used for the analyses will be described in a footnote. This includes 
MedDRA version and NMQ (Novartis MedDRA Queries) dictionary date. 
 Anemia: Haematopoietic erythropenia (SMQ, broad search) 


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 Gastrointestinal 
ulcers: 
Gastrointestinal 
ulceration 
(SMQ, 
narrow 
search) 
This is a sub-SMQ under "Gastrointestinal perforation, ulceration, haemorrhage or 
obstruction (SMQ – narrow search)" 
 Interstitial lung disease (CRS) 
 Hyperlipidemia (CRS) 
 Major cardiovascular events: Ischaemic heart disease and Cardiac failure (SMQ narrow 
search)  
 Malignancy (CRS) 
 NODM (See Section 2.8.3.3) 
 Peripheral edema (CRS) 
 Proteinuria (associated chronic kidney disease) (CRS) 
 Pleural effusion: MedDRA preferred term “Pleural effusion” 
 Renal failure, excluding proteinuria (CRS) 
 Stomatitis/mouth ulceration (CRS) 
 Thrombocytopenia: Haematopoietic  thrombocytopenia (SMQ, narrow search) 
 Thrombotic and thromboembolic events: Embolic and thrombotic events (SMQ) 
 Thrombotic microangiopathy (CRS) 
 Wound healing events/disorders or complications: See Section 4.4.1. 
2.8.3 
Program Specific Safety Risk Events  
The following program specific safety risk events as defined in the Program CRS will be 
summarized with the number and percentage of patients experiencing the events, together with 
risk ratios (RRs) and 95% CIs.  
 Angioedema 
 Chronic allograft nephropathy  
 Edema (including peripheral edema)   
 Everolimus and calcineurin inhibitor (CNI) induced renal dysfunction 
 Exposure in pregnancy/breast-feeding women 
 Hyperlipidemia 
 Impaired male fertility 
 Infections 
 Infections (Polyomavirus infection) 
 Interstitial lung disease 
 Leukopenia and pancytopenia 
 Malignancy 
 New onset diabetes mellitus (NODM) 
 Proteinuria (AE based definition) 
 Proteinuria (lab based definition) 
 Renal graft thrombosis 
 Stomatitis and Mouth ulceration 
 Teratogenicity 


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 Thrombotic microangiopathies (TMA) 
 Venous thrombosis 
 Wound-healing complications 
2.8.4 
Other Safety Events 
2.8.4.1 
CMV 
The incidence of CMV infection within each treatment group will be tabulated by donor versus 
recipient CMV serology pattern. Other CMV infection-related information including CMV 
syndrome, CMV disease with organ involvement will be tabulated by treatment group. 
Additionally, CMV infection, syndrome and disease will be analyzed by donor/recipient CMV 
serology status pre-transplantation and CMV prophylaxis. Within each CMV serology status, 
the Cochran Mantel Haenszel test will be used to examine differences between the treatment  
arms adjusting for the presence/absense of CMV prophylaxis. CMV prophylaxis is defined as 
the use of antiviral drugs specified in Table 2-4 within 14 days of transplantation that are taken 
consecutively for 30 days or more. 
Table 2-5 
CMV prophylaxis 
ATC code 
Drug code 
WHO preferred term 
J05AB 
00587301 
aciclovir 
J05AB 
00587302 
aciclovir sodium 
J05AB 
00784201 
ganciclovir 
J05AB 
00784202 
ganciclovir sodium 
J05AB 
01226201 
famciclovir 
J05AB 
01269701 
valaciclovir 
J05AB 
01269702 
valaciclovir hydrochloride 
J05AB 
01319501 
penciclovir 
J05AB 
01542201 
valganciclovir 
J05AB 
01542202 
valganciclovir hydrochloride 
J05AD 
00731301 
foscarnet 
J06BB 
00849701 
immunoglobulin cytomegalovirus 
2.8.4.2 
BKV 
The incidence of BKV infection will be tabulated for each treatment group:  
 Any BKV infection 
 BKV infection with a urinary or serological sign  
 Clinical or laboratory indicated BKV infection 
 BKV infection with an organ involvement (histological evidence) 


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2.8.4.3 
New Onset Diabetes 
A patient is identified as not having diabetes at baseline if all of the following conditions are 
met: 
 Diabetes was not reported as a medical history in Relevant medical history panel 
(MedDRA preferred term containing diabetic or diabetes); 
 No prior diabetic medication with ATC level 2 code “A10” taken prior to baseline. 
 Glucose (random) < 11 mmol/L (200 mg/dl), or fasting glucose measurements < 7 
mmol/L (126 mg/dl)  at the time of transplantation; 
For patients who do not have diabetes at baseline, new onset of diabetes will be identified if 
any of the following conditions are met: 
 Diabetes is reported as an adverse event (MedDRA preferred term containing diabetic 
or diabetes) with a date of onset (AE start date) post-baseline. 
 Any concomitant medication with ATC level 2 code “A10” used in diabetes, if 
administered for more than 2 consecutive weeks post-baseline. 
 Fasting glucose measurements ≥ 7 mmol/L (126 mg/dl) post-baseline on two separate 
occasions, or glucose (random) ≥ 11 mmol/l (200 mg/dl) on two separate occasions. 
The date of onset will be the earliest date when any of the above conditions is met. Depending 
on the onset date, a patient will be identified as having DM prior to baseline if the date is prior 
to or at baseline, and a patient will be identified as have DM post-baseline if the date is after 
baseline. 
In addition, new onset diabetes will be identified with a second definition below: 
New onset diabetes, defined in patients who were not diabetic at baseline, will be identified 
from the NODM NMQ in patients where diabetes is recorded as reason for a medication given 
post-baseline lasting for 30 days or more (Medications will be identified by searching ATC 
level 2 code of A10). 
Notes: The NODM NMQ includes all PTs with root ”diab” included in the NODM SMQ plus 
the PT “Hyperglycaemic hyperosmolar nonketotic syndrome” which includes the LLT 
“Diabetic hyperosmolar non-ketoacidosis”. In more descriptive terms, this would mean that the 
NODM NMQ  will include two sets of Preferred Terms (PTs) as follows: 
All PTs with root ”diab” included in the NODM  SMQ  
PTs of “Hyperglycaemic hyperosmolar nonketotic syndrome” with LLT as “Diabetic 
hyperosmolar non-ketoacidosis”. 
The expansions for the acronyms are as follows:  NODM= New-Onset Diabetes Mellitus, NMQ 
= Novartis MedDRA Queries, SMQ =Standard MedDRA query, LLT =Lowest Level Term, PT 
= Preferred Term. 
2.8.4.4 
Notable Events 
Notable events include death, non-fatal SAEs (including infections and rejections reported as 
SAE) and AEs (including infections and rejections) leading to discontinuation from the study 
treatment.  


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2.8.4.5 
Vital Signs 
Vital signs variables include measurements of oral body temperature, systolic and diastolic 
blood pressures, pulse and body weight. Vital signs will be examined for abnormal values and 
change from baseline according to pre-specified clinically notable criteria. Appropriate 
incidence rates of clinically notable abnormalities (see Section 4.6.2) will be provided. Further, 
descriptive statistics of all vital signs variables as well as the changes from baseline will be 
presented by visit. A by-patient listing of all vital signs (with clinically notable abnormalities 
being flagged) will be generated. 
2.8.4.6 
Laboratory Data 
Descriptive statistics (mean, standard deviation, minimum, median and maximum) of 
quantitative laboratory variables, including change from Baseline, will be generated by visit for 
laboratory parameters. Categorical levels of urinary protein/creatinine ratio (<30, 30 - <500, 
500 - <1000, 1000 - <3000, >=3000 mg/g) will additionally summarized by visit. When there 
will be multiple observations in the same visit, the worst case will be selected for this visit.  
Laboratory results recorded as >n or <n (above or below detection limit) will be either converted 
to n (if above detection limit) or set to one-half n (if below detection limit) for the purposes of 
summary statistics (e.g. if <0.2 was reported 0.1 will be used for the analyses). Original raw 
results will be listed. 
Abnormalities according to the clinical notable criteria (see Section 4.6.1) will be identified and 
tabulated for each applicable lab parameter. Lipids levels are categorized based on the following 
criteria per American Heart Association (Adult treatment panel III 2002). A by-patient listing 
of individual patient laboratory data will be generated; values outside of clinical notable will be 
flagged.   
 Triglycerides 
 Normal: < 150 mg/dL 
 Borderline high: 150 – <200 mg/dL 
 High: 200 – <500 mg/dL 
 Very high: ≥ 500 mg/dL 
 Total cholesterol 
 Normal: < 200 mg/dL 
 Borderline high: 200 – <240 mg/dL 
 High: ≥240 mg/dL 
 HDL cholesterol 
 Low: < 40 mg/dL for men, <50 mg/dL for women  
 Normal: 40 – <60 mg/dL for men, 50 – <60 mg/dL for women 
 Optimal: ≥60 mg/dL  
 LDL cholesterol 
 Optimal: < 100 mg/dL  
 Near or above optimal: 100 – <130 mg/dL  


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 Borderline high: 130 – <160 mg/dL  
 High: 160 – <190 mg/dL  
 Very high: ≥ 190 mg/dL  
 Total cholesterol /HDL ratio level is defined as 
 Normal: <5 
 High: >=5 but <=7 
 Very High: >7 
Newly occurring abnormalities since baseline will be summarized by treatment for the clinical 
notable laboratory abnormalities and the following abnormality criteria (AST or SGOT; ALT 
or SGPT; TBL: total bilirubin; ALP: serum alkaline phosphatase).  
 
ALT > 3× ULN 
 
ALT > 5× ULN 
 
ALT > 8× ULN 
 
ALT > 10× ULN 
 
ALT > 20× ULN 
 
ALT or AST  > 3× ULN 
 
ALT or AST  > 5× ULN 
 
ALT or AST  > 8× ULN 
 
ALT or AST  > 10× ULN 
 
ALT or AST  > 20× ULN 
 ALT or AST  > 3× ULN & TBL > 1.5× ULN  
 ALT or AST  > 3× ULN & TBL > 2× ULN     
 ALT or AST  > 5× ULN & TBL > 2× ULN     
 ALT or AST  > 8× ULN & TBL > 2× ULN     
 ALT or AST  > 10× ULN & TBL > 2× ULN    
 
ALT or AST  > 20× ULN & TBL > 2× ULN  
 
ALP > 1.5× ULN  
 
ALP > 2× ULN  
 
ALP > 3× ULN  
 
ALP > 5× ULN 
 
TBL > 1× ULN 
 
TBL > 1.5× ULN 
 
TBL > 2× ULN 
 
TBL > 3× ULN 
 ALP > 3× ULN & TBL > 2× ULN 
 ALT or AST  > 3× ULN & TBL > 2× ULN & ALP < 2× ULN 


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2.8.5 
Safety Events for Clinical Trial Safety Disclosure 
For the legal requirements of ClinicalTrials.gov and EudraCT, at the end of the study, two 
required tables on treatment emergent adverse events which are not serious adverse events with 
an incidence greater than 5% and on treatment emergent serious adverse events and SAE 
suspected to be related to study treatment will be provided by system organ class and preferred 
term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
 a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE;  
 more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
 The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT. 
2.9 
Pharmacokinetic (PK)/Pharmacodynamic (PD)/PK-PD/Biomarkers 
Evaluations  
Not applicable. 


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2.12 
Interim Analyses 
A futility analysis will be performed when approximately 30% of patients have completed 6 
months on the study. The futility analysis described in Section 1.4.1 will be based on the study 
target population, which consists of 6-month completers and remaining about 70% patients to 
be enrolled.  
The futility analysis outlined in this document is not designed to constitute a binding measure. 
All analyses will be provided by the CRO independent team to the Futility Review Board. This 
list of analyses can be amended at the request of the Futility Review Board. Details of the 
analyses will be specified in the futility analysis RAPs 
2.12.1 
Futility Analysis  
Although the primary study endpoint (the composite of tBPAR or eGFR (MDRD4) < 50 
ml/min/1.73m2) is at Month 12, the futility analysis will be based on the endpoint at 6 months. 
In kidney transplant trials, typically most tBPAR events (e.g. 80% in A2309 study) occur within 
the first 6 months, and eGFR at Months 6 and 12 are very similar (e.g. in A2309 study, the 
mean eGFR was 57.2 at Month 6 vs. 56.3 at Month 12 in the everolimus 1.5 mg group). 
Therefore, it is expected that the 6-month endpoint will be a good predictor of the 12-month 
endpoint. 
The futility of the non-inferiority for the primary endpoint will be assessed via conditional 
power together with 95% prediction interval. Conditional power is the probability of rejecting 
the following null hypothesis given the observed data from the futility analysis patients (6-
month completers) and assumptions on the data from future patients. In conjunction with the 
conditional power, a prediction interval will be calculated to estimate the potential treatment 
effect and its associated precision (See the calculations of the conditional power and prediction 
interval in Section 2.12.3). 
H01: REVR+rCNI - RMPA+sCNI  ≥ 0.10 (non-inferiority margin): the difference in proportion 
of patients experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 6 months 
between the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI 
arm (RMPA+sCNI) is at least 10%, vs. 
HA1: REVR+rCNI - RMPA+sCNI < 0.10 (non-inferiority margin): The difference in proportion 
of patients experiencing tBPAR or eGFR (MDRD4) < 50 mL/min/1.73m2 at 6 months 
between the everolimus plus reduced CNI (REVR+rCNI) and the MPA plus standard CNI 
arm (RMPA+sCNI) is less than 10%. 
For the futility analysis, the incidence rate of the composite endpoint of tBPAR or eGFR 
(MDRD4) < 50 ml/min/1.73m2 will be assessed for each arm for the 6-month completers. The 
6-month completers are defined as follows: 


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 ~30% of the total randomized patients who have reached Month 6 or discontinued from 
study early  (note: For those patients who were beyond Month 6 in the study, tBPAR 
up to Month 12 and eGFR (MDRD4) at Month 12 will be used instead if they are 
available at the time of the futility analysis).  
 Patients who have not reached Month 6 yet, but have experienced a tBPAR, graft loss 
or death event.  
For the 6-month completers, it is expected that there will be some patients who drop out from 
the study prior to Month 6 or miss Month 6 assessments. Missing Month 6 eGFR (MDRD4) 
will be imputed via the following approach, then the eGFR(MDRD4) value will be 
dichotomized to derive the component of eGFR (MDRD4) < 50 mL/min/1.73m2.  
 Under the assumption of missing not at random (MNAR), patients who lost their grafts 
will be assigned a value of zero. 
 Otherwise, under the assumption of missing at random (MAR), patients who had 
missing values including those who died with a functioning graft will have a Month 6 
eGFR imputed using multiple imputation method based on the longitudinal eGFR data 
at all available time points up to Month 6 and covariates of randomization strata (donor 
type and CNI), HLA mismatches (≤3 vs >3) and induction. 
For the remaining 70% of the patients, expected 6-month failure rates will be assumed using 
the following scenario: 
 Same incidence rates as observed from the 30% futility analysis patients (6-month 
completers) 
For completeness, an assessment of non-inferiority (with NI margin = 10%) for the key 
secondary endpoint of tBPAR, graft loss or death at Month 6, as well as superiority for the 
primary endpoint of tBPAR or eGFR (MDRD4) < 50 ml/min/1.73m2 at Month 6 will be 
provided using the same approach (i.e. conditional power together with prediction interval) and 
the assumption for the remaining 70% of patients.  
The futility analysis described above assumes the data from tacrolimus 
 
 The Independent Review Board may assess the poolability based on 
the unblinded futility analysis data and request additional analysis in the tacrolimus subgroup 
if this is indeed needed. 
Non-Binding Futility Stopping Rule 
Based on futility characteristics simulations, the futility stopping rule is developed, which is 
based on the conditional power for the non-inferiority of the composite endpoint of tBPAR or 
eGFR (MDRD4) < 50 ml/min/1.73m2. Recommendation to stop the trial due to futility can be 
considered if the calculated conditional power is ≤ 2% based on the scenario described in 
Section 2.12.1. 
2.12.2 
Other Analyses 
In addition to the futility analysis described in the previous section, the following analyses will 
be performed for the 6-month completers with data up to Month 6.  
Demographic and background information: 


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 Summary of demographics and transplant background information by treatment 
Disposition: 
 Summary table and listing of patient disposition at Month 6: ongoing study/study treatment, 
completed study/study treatment, and premature discontinuations of study/study treatment 
with reasons by treatment 
 Summary of patient disposition at Month 6 by treatment and randomization strata (CNI: 
CsA vs TAC, and donor type: living vs standard criteria vs expanded criteria deceased 
donor) 
 KM plot of premature discontinuation of study medication  
Study medication: 
 Summaries of average daily doses of study drug (everolimus and MPA) as well as CNI 
(cyclosporine and tacrolimus)  
 Summaries of number (percent) of patients with EVR/CNI trough levels within/below/ 
above target ranges 
 Box-plots of  EVR/CNI trough levels with target ranges displayed 
Efficacy (up to Month 6):  
 Summary of raw incidence rate (n and %) for the following events  by treatment as well as 
by treatment and randomization strata 
 composite of treated biopsy proven acute rejection (tBPAR) or GFR < 50   
mL/min/1.73m2 
 composite of tBPAR, graft loss, death or GFR < 50  mL/min/1.73m2 
 GFR < 50  mL/min/1.73m2 
 Summary of Kaplan-Meier incidence rate for the following events by treatment as well as 
by treatment and randomization strata: 
 composite of tBPAR, graft loss or death 
 composite of graft loss or death 
 individual endpoints of death, graft loss, tBPAR, BPAR, tAR, AR  
 Kaplan-Meier plot for: 
 Composite endpoint of tBPAR, graft loss or death 
 tBPAR 
 Graft loss/death  
 Forest plot of efficacy events 
Exceptions for Month 6 incidence rate: For those patients who were beyond Month 6 in the 
study, tBPAR up to Month 12 and eGFR (MDRD4) at Month 12 will be used instead if they 
are available at the time of the futility analysis. 
Renal function:  
 Summaries of estimated GFR (MDRD4) and serum creatinine by visit, as well as by visit 
and randomization strata 


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 Summaries of the changes from Week 4 for estimated GFR (MDRD4) and serum creatinine 
by visit 
 Plot of mean and 95% CI for estimated GFR (MDRD4) by visit  
 Incidence of patients with estimated GFR(MDRD4) in specified categories (<30; 30-<45; 
45-<60; 60-<90; >90 ; <50 mL/min/1.73m2) by visit (Week 4 and onward visits) 
AE/SAE 
Summary by primary SOC & PT for the followings: 
 Frequent events (≥10% in any treatment group) regardless of study drug relationship  
 Serious events regardless of study drug relationship by primary SOC & PT, and additionally 
by randomization strata 
 Infections regardless of study drug relationship by type of infection & specific micro-
organism  
 Events suspected to be related to study drug  
 Events leading to study drug discontinuation by primary SOC & PT, and additionally by 
randomization strata 
 Primary cause of death/graft loss 
Note: infections should be included as part of AEs. 
Laboratory 
 Summary of lipids (total cholesterol and triglycerides) by visit 
 Summary of Hematology (haemoglobin, platelets and total WBC) by visit 
The transplant background information, efficacy and GFR analyses will also be performed for 
the full analysis set with all data available at the time of the futility analysis (e.g. including data 
prior to Month 6 for patients recently enrolled or data beyond Month 6 for patients who have 
been in the study over 6 months). AEs/infections leading to study drug discontinuation and 
SAEs/serious infections will be analyzed for the safety analysis set with all data available at the 
time of the futility analysis. 
Listings for efficacy events and GFR will be provided for the full analysis set, and listings for 
everolimus and CNI trough levels and AEs will be provided for the safety analysis set. 
2.12.3 Calculation of Prediction Interval and Conditional Power 
2.12.3.1 Predicted Event and Event Rate 
Let N be planned sample size per treatment group (N=1020), ni be the number of patients for 
the futility analysis (6-month completers) for the treatment group i (e.g. i for EVR and MPA), 
xi be the observed events in the ni patients in the treatment i, and pf,i is assumed event rate in 
the future patients in the treatment i, the predicted (expected) events for the treatment i will be 
calculated as follows: 
 
ei = xi + (N - ni)pf,i 
The predicted event rate for the treatment i will be 
 
pi = ei/N 


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2.12.3.2 Prediction Interval 
Predicted difference in event rate between the two groups will be 
 
pEVR – pMPA = eEVR/N– eMPA/N 
Prediction interval for the difference will be (Evans, Li and Wei, 2007) 
 
(pEVR – pMPA) ± Z0.975 SEfull 
                   where  SEfull = SQRT[pEVR(1- pEVR)/N + pMPA(1- pMPA)/N] 
2.12.3.3 Conditional Power 
The predicted difference of pEVR – pMPA approximately follows a Normal distribution, test 
statistic Z can be constructed as 
 
Z = (pEVR – pMPA - δ) / SEfull 
 where δ is margin (δ = 0.10 corresponding to H01 and H03 for non-inferiority analyses, and δ = 
0 corresponding to H03 for superiority analysis). 
Assuming yi be number of events to be obtained in the future patients in the treatment i, let 
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)
(
[
)
(
,
,
,
,
975
.0
MPA
f
MPA
MPA
EVR
f
EVR
EVR
MPA
f
EVR
f
full
p
x
N
n
p
x
N
n
p
p
SE
Z
A










 
Then to reject the null hypothesis, we need 
A
N
p
y
n
N
N
p
y
n
N
MPA
f
MPA
MPA
EVR
f
EVR
EVR






)
)(
(
)
)(
(
,
,
 
Therefore, conditional power will be calculated as follows 


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











A
N
p
y
n
N
N
p
y
n
N
MPA
f
MPA
MPA
EVR
f
EVR
EVR
)
)(
(
)
)(
(
Pr
,
,
 
The variance of 
N
p
y
n
N
EVR
f
EVR
EVR
)
)(
(
,


is  
EVR
EVR
f
EVR
f
EVR
EVR
EVR
EVR
f
EVR
f
B
N
p
p
n
N
N
n
N
n
N
p
p













2
,
,
2
,
,
)
1(
)
(
)
1(
 
Similarly, the variance of 
N
p
y
n
N
MPA
f
MPA
MPA
)
)(
(
,


is 
 
 
The conditional power is 
           












A
N
p
y
n
N
N
p
y
n
N
MPA
f
MPA
MPA
EVR
f
EVR
EVR
)
)(
(
)
)(
(
Pr
,
,
           





















MPA
EVR
MPA
EVR
MPA
f
MPA
MPA
EVR
f
EVR
EVR
B
B
A
B
B
N
p
y
n
N
N
p
y
n
N
)
)(
(
)
)(
(
Pr
,
,
 











MPA
EVR
B
B
A
 
This calculation is adapted from (Chow and Chang, 2007). 
For this futility analysis, the predicted event rate and conditional power for the key secondary 
endpoint of tBPAR, graft loss or death will be calculated based on raw event rate rather than 
using KM method. 
3 
Determination of Sample Size 
The sample size for this study was chosen with the goals to (1) have high power to evaluate 
non-inferiority in both the overall population and the TAC alone population and (2) have 
adequate power to evaluate superiority in the both the overall population and the TAC alone 
population.   
With a sample size of n=1020 randomized per arm (EVR, MPA), the study has at least 95% 
power to demonstrate non-inferiority (α=0.025, one-sided) in the overall and TAC alone 
populations at Month 12.  There are at least 73% and 63% power (α=0.025, one-sided) to 
demonstrate superiority of 7% or more in the overall and TAC alone populations, respectively. 
The calculations are based on the following assumptions: 
 80% of patients are randomized to tacrolimus, 20% of patients are randomized to 
cyclosporine 
MPA
MPA
f
MPA
f
MPA
MPA
MPA
MPA
f
MPA
f
B
N
p
p
n
N
N
n
N
n
N
p
p











2
,
,
2
,
,
)
1(
)
(
)
1(


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 20% and 30% patients are excluded from the PP population at Months 12 and 24 
respectively 
 For non-inferiority, the event rate in each arm is 50%, based on study results from 
RAD001A2309 and Ekberg 2007, and the non-inferiority margin for the primary 
composite endpoint is 10%. 
 For the evaluation of superiority, the event rate in the MPA + sCNI arm is 50%. 
4 
Appendix  
4.1 
Visit-Windows 
Visit-windows will be used to summarize the data by visit and are defined in terms of weeks 
and months; these will be based on the study schedule of evaluation and comprised a set of days 
“around” the nominal visits. Visit-windows are non-overlapping; all together they cover the 
entire study period, e.g., the visit-window Month 2 comprises study days 45 to 90, i.e., it has 
the nominal visit Month 2 as “center” and includes the 15 days preceding study day 60 and 30 
days thereafter. Generally, visit-windows are not symmetrical around the nominal visit day. 
As patients do not necessarily have their examinations at the exact scheduled time, it might be 
misleading if all data with the same nominal visit number are lumped together for a by-visit 
analysis. Thus, all data (including reported unscheduled assessments) are “re-aligned” 
according to the window schema given below.  Note that the visit windows defined in the 
protocol are used to guide investigators whereas the ‘re-aligned’ visit windows in Table 4-1 
(simply called visit windows in the following) will be used for the analyses.   
Table 4-1 
Visit Windows 
Re-
aligned 
Visit 
Visit window 
Relative to randomization date 
Start  day of 
Visit window 
Midpoint 
End day of 
Visit window 
1 
Screening/Basel
ine 
Inform Consent 
 
randomization 
2 
Day 4 
1 (post-
randomization) 
4 
5 
3 
Week 1 
6 
7 
10 
4 
Week 2 
11 
14 
21 
5 
Week 4 
22 
28 
44 
6 
Month 2 
45 
60 
90 
7 
Month 4 
91 
120 
150 
8 
Month 6 
151 
180 
225 
9 
Month 9 
226 
270 
315 
10 
Month 12 
316 
360 
450 
11 
Month 18 
451 
540 
630 
12 
Month 24 
631 
720 
810 


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Re-
aligned 
Visit 
Visit window 
Relative to randomization date 
Start  day of 
Visit window 
Midpoint 
End day of 
Visit window 
13 
Month 12 
Treatment 
Endpoint (TEP) 
1 
 
450 
14 
Month 12 Study 
Endpoint (SEP) 
1 
 
450 
15 
Month 24 TEP 
1 
 
810 
16 
Month 24 SEP 
1 
 
810 
4.2 
Missing Data Handling 
4.2.1 
Missing GFR Data Imputation 
4.2.1.1 
Main Imputation 
The following is the main imputation method for handling missing eGFR data at Month 12. A 
similar imputation rule can be applied for missing eGFR at Month 24. These imputations will 
be applied to the primary analyses for the composite endpoint of tBPAR or eGFR < 50 
mL/min/1.73m2, as well as for eGFR alone. For the component of eGFR < 50 mL/min/1.73m2, 
a value for missing eGFR as a continuous variable will be imputed first, then it will be 
dichotomized in order to derive this endpoint. 
 Under the assumption of missing not at random (MNAR), patients who lost their grafts will 
be assigned a value of zero for their missing eGFR at the visits on and after graft loss; 
 Multiple imputation: Otherwise, under the assumption of missing at random (MAR), 
patients who had missing values including those who died with a functioning graft will have 
a 12-month eGFR imputed using multiple imputation method based on the 
covariates/factors CNI, region, donor type, HLA mismatch (≤3 vs >3), induction therapy, 
recipient gender, recipient age, donor age, and DGF, and all eGFR (MDRD4) data collected 
at the visit windows during the analysis period of interest. In the multiple imputation, 
recipient age, donor age and eGFR (MDRD4) data will be treated as continuous variables. 
To help preserve the relationship between outcome and covariates within each treatment, a 
separate model will be run for each treatment. This will also help ensure that the imputation 
model does not make stronger assumptions on data relations than the analysis model.  
To ensure that results can be replicated, the data should be sorted by patient number before 
running the model (the data should be in horizontal format with one row per patient). If there 
are multiple renal function assessments within a visit window, guidelines given in Section 2.1 
will be followed, i.e., the closest value to the planned visit (midpoint of visit window for post-
baseline visits) will be taken (if tie, the last will be used) for imputation. In addition, the seed 
used in the multiple imputation will be 2433. 
See dummy SAS codes below. 
proc mi data=DATAIN out=DATAOUT nimpute=100 seed=2433;  
   by treatment; 
   class CNI region donor HLA induction gender_r DGF; 


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   fcs reg (/details); 
   var CNI region donor HLA induction gender_r age_r age_d DGF GFR_vis1 
GFR_VIS2 … GFR_VISm;  
run; 
4.2.1.2 
Imputation for Sensitivity Analyses 
For sensitivity analyses for the composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 as 
well as for eGFR alone, the following imputation method will be used to impute missing eGFR 
values at Month 12. Similar imputation rules can be applied to missing GFR at Month 24. 
Patients who lost their grafts will be assigned a value of zero for their missing eGFR at the visits 
on and after graft loss. Otherwise, patient who had missing value including those who died with 
a functioning graft will have a 12-month eGFR imputed using the control-based imputation 
under the assumption of missing not at random (MNAR). Missing eGFR values in EVR + rCNI 
arm will be imputed based on the data from the control arm (MPA + sCNI) as everolimus 
patients would switch to control (standard care) or control-like medication after they 
discontinue everolimus.  
The imputation will be based on CNI, region, donor type, HLA mismatch (≤3 vs >3), induction 
therapy, recipient gender, recipient age, donor age, DGF, and eGFR (MDRD4) at Week 4 as 
covariates/factors, and all eGFR (MDRD4) data collected at the visit windows during the 
analysis period of interest. In the multiple imputation, recipient age, donor age and eGFR 
(MDRD4) data will be treated as continuous variables. 
See dummy SAS codes as below: 
proc mi data= seed=2433 nimpute=100 out=mi_out; 
class treatment CNI region donor HLA induction gender_r DGF; 
fcs reg (/details); 
mnar model (GFR_VIS1 GFR_VIS2 … GFR_VISm / modelobs = (treatment="MPA")); 
var CNI region donor HLA induction gender_r age_r age_d DGF GFR_VIS1 
GFR_VIS2 … GFR_VISm; 
Run; 
To ensure that results can be replicated, the data should be sorted by patient number before 
running the model (the data should be in horizontal format with one row per patient). patientIf 
there are multiple renal function assessments within a visit window, guidelines given in Section 
2.1 will be followed. In addition, the seed used in the multiple imputation will be 2433. 
4.2.2 
CNI/EVR Trough Level Imputation  
The exact time-varying trough concentration is not known. Imputation is required to estimate 
the time-varying concentration from the available trough concentration and dose records. The 
imputation method is essentially a backward imputation with a forward component (see 
illustration in Figure 4-1)   
1. For each patient, the maximum study drug on-treatment date will be created as the analysis 
cut-off date. 
2. Trough concentrations after the analysis cut-off date will be ignored. 
3. For patients without the study drug trough concentration at the cut-off date, the last 
observation will be carried forward to the cut-off date, so all patients will have study drug 
trough concentrations at the cut-off date (carry-forward imputation). 


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4. Assuming that a patient had concentration measurements on Days x and y (x<y), the 
concentration on Day x+1 to y-1 is assumed to be that of Day y. The first available trough 
level will be carried backward to the day of the first dose of respective study drug. Therefore 
each day from the day of the first dose of respective study drug to the cut-off date will have 
a trough concentration (carry-backward imputation). The rationale for this imputation is that 
a concentration measurement may trigger a change in dose, so a measured concentration is 
more representative of the past than of the future. 
Figure 4-1 
Imputation rule for concentration data: 2 hypothetical patients 
 
(a) Last contact day is after the last dose day + 2 days 
7         14         21        28         35        42        49         56        63    Day 
Last dose +2d 
Last contact 
concentration measurement 
Patient A with no trough measurement taken after day of last dose + 2 days 
Patient B with a trough measurement taken after day of last dose + 2 days 
 
Study drug concentration 
Ignored 
Analysis cut-off 


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(b) Last contact day is the same day as the last dose day (patient discontinued the study and 
the study drug on the same day) 
4.2.3 
LOCF for Laboratory and Vital Sign Data 
Summary statistics by visit window for laboratory (including renal) and vital sign variables 
using two different conventions of the last observation carried forward (LOCF) method.  
 LOCF using last on-treatment value (treatment endpoint = TEP) 
 LOCF using last available value (study endpoint = SEP) 
The month x treatment endpoint (of a certain variable, e.g., systolic blood pressure) is defined 
as the last available non-missing on-treatment observation (7-day rule) in the study period Day 
1 to Day z, where z is the last day of the Month x visit window (for the x Month analysis). For 
example, z = 195 is the last day of the Month 6 visit window. Therefore the Month 6 treatment 
endpoint for systolic blood pressure in a patient discontinuing study medication on Day 179 and 
reporting systolic blood pressures of 155, 190 and 165 mmHg on study Days 149, 180, and 189, 
respectively, would be 190 mmHg. This imputation is denoted as “TEP” in the visit window 
column of summary statistics tables. 
The month x study endpoint (of a certain variable, e.g., systolic blood pressure) is defined as the 
last available non-missing observation in the study period Day 1 to Day z, where z is the last 
day of the Month x visit window (for the x Month analysis). This imputation is denoted as “SEP” 
in the visit window column of summary statistics tables. 
In contrast to the Month x treatment endpoint, the Month x study endpoint may be an assessment 
obtained a long time after premature discontinuation of study treatment. 
7         14         21        28         35        42        49         56        63    Day 
Last dose +2d 
Last contact
concentration measurement 
Patient A with no trough measurement taken on the cut-off day 
Patient B with a trough measurement taken after on the cut-off day 
Study drug concentration 
Analysis cut-off 
d t
Last dose 


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The month x treatment endpoint and month x study endpoint will be defined for Month 12 and 
Month 24 and labeled as Month X TEP and Month X SEP (e.g. Month 12 TEP and Month 12 
SEP) in the analysis outputs. For the 24-month analysis, only Month 24 TEP and Month 24 SEP 
will be presented. 
4.2.4 
Imputation of Incomplete Dates 
Although not the rule, partially or completely missing dates occur. Known dates with this issue 
are the start date on the Medical History eCRF page, start and end dates on the Concomitant 
Medications eCRF page or Surgical and Medical Procedures eCRF page, and occasionally, start 
and end dates on the Adverse Event eCRF.  
Any date incompletely reported is split into its day, month, and year components. In SAS, a 
numeric date variable can only be defined if all three date components are known; incomplete 
dates are to be handled as text strings (character-type variables); as such, they could not be 
easily processed. An imputation rule for incomplete dates will be performed. 
4.2.4.1 
Incomplete Start Date for Adverse Events and Concomitant Medication  
This algorithm is expressed in the Variable Source Derivation column as #IMPUTAEV(event) 
where event is the partial start date of the adverse event. 
 The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
Note, if the imputed AE (or CM) start is after AE (or CM) end date, then set AE (or CM) start 
equal to AE (or CM) end date. 
 
Day 
Month 
Year 
Partial Adverse Event (or 
Concomitant Medication) 
Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
(TRTSDT) 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < 
TRTY 
 
( D ) 
 
( C ) 
 
( C ) 
 
( C ) 
 
YYYY = 
TRTY 
 
(B) 
 
( C ) 
 
(A) 
(A) 
 


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YYYY > 
TRTY 
 
(E) 
(A) 
(A) 
(A) 
 
The following table is the legend to the logic matrix. 
Relationship 
Before Treatment 
Start  
Partial date indicates AE (or CM) start date prior to Treatment Start 
Date 
After Treatment 
Start  
Partial date indicates AE (or CM) start date after Treatment Start 
Date 
Uncertain 
Partial date insufficient to determine relationship of AE (or CM) 
start date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
Uncertain 
No convention 
(A) After Treatment 
Start or Uncertain 
MAX( 01MONYYYY, TRTSDT+1 ) 
(B) Uncertain 
TRTSDT+1 
(C) Before 
Treatment Start 
15MONYYYY 
(D) Before 
Treatment Start 
01JULYYYY 
(E) After Treatment 
Start 
01JANYYYY 
4.2.4.2 
Incomplete End Date for Adverse Events  
Missing AE end dates will not be imputed. 
4.2.4.3 
Incomplete End Date for Concomitant Medication  
The following table explains the notation used in the logic matrix. Please note that missing end 
dates will not be imputed. 
 
 
Day 
Month 
Year 
Partial Conmed. end Date 
Not used 
MON 
YYYY 
Last Contact Date 
(LASTDT) 
Not used 
LSTM 
LSTY 
 
 
 
MON 
MISSING 
MON < LSTM 
MON = LSTM 
MON > LSTM 


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YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < LSTY 
 
(C) 
 
(A) 
 
(A) 
 
(A) 
 
YYYY = LSTY 
 
(B) 
 
(A) 
 
(B) 
(A) 
 
YYYY > LSTY 
 
(C) 
(A) 
(A) 
(A) 
 
 
Relationship 
Before Last contact 
date  
Partial date indicates CM end date prior to Last Contact Date 
After Last contact 
date 
Partial date indicates CM end date after Last Contact Date 
Uncertain 
Partial date insufficient to determine relationship of CM end 
date to Last Contact Date 
Imputation Calculation 
NC / Blank 
Uncertain 
No convention 
(A) Before/After 
Last contact date 
Last day MONYYYY 
(B) Uncertain 
LASTDT 
(C) Before/After 
Last contact date 
31DECYYYY 
 
At the Month-12 analysis, if the above logic is applied and the imputed end date is after the 
month 12 cut-off date, then the imputed end date is replaced with the month 12 cut-off date. 
4.2.4.4 
Medical History 
Start dates on the Medical History eCRF page are rather frequently incomplete. No dates will 
be imputed. Incomplete dates (if any) will be listed. 
4.3 
Definition/Derivation of Efficacy Variables 
All efficacy endpoints regarding biopsy described below will be identified from local 
pathologists’ evaluation of all biopsy readings. All acute rejections are recorded in the clinical 
database on the Kidney allograft rejection and Kidney allograft biopsy eCRFs.   
4.3.1 
Antibody-Mediated (Humoral) Rejection (AMR)  
A rejection is considered as an AMR if:  
 Acute antibody mediated rejection = “Yes” from kidney allograft biopsy eCRF page 


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Date of rejection will be “date rejection was first suspected” on the Kidney allograft rejection 
eCRF, or if missing, the first available date of the biopsy of the particular rejection episode on 
the Kidney allograft biopsy eCRF page.  
4.3.2 
Acute Rejection (AR)  
A rejection is considered an AR if:  
 Primary clinical diagnosis = “Acute rejection” or “Acute and chronic rejection” from 
Kidney allograft rejection eCRF page; OR 
 Antibody-mediated rejection  (see above); OR 
 Acute T-Cell mediated rejection = “Yes” from Kidney allograft biopsy eCRF page. 
Date of AR will be “date rejection was first suspected” on the Kidney allograft rejection eCRF, 
or if missing, the first available date of the biopsy of the particular rejection episode on the 
Kidney allograft biopsy eCRF page.  
4.3.3 
Treated Acute Rejection (tAR) 
A rejection is considered a tAR if:  
 Acute rejection  (see above); AND 
 Was anti-rejection therapy administered?  = “yes”   from  Kidney allograft rejection 
eCRF 
Date of tAR will be the date of the corresponding AR (note: tAR is a subset of AR). 
4.3.4 
Biopsy-Proven Acute Rejection (BPAR) 
A rejection is considered a BPAR if:  
 Primary clinical diagnosis = “Acute rejection” or “Acute and chronic rejection” from 
Kidney allograft rejection eCRF page; AND  
 Acute T-Cell mediated rejection = “Yes” or Acute antibody mediated rejection = “Yes” 
from Kidney allograft biopsy eCRF page. 
Date of BPAR will be “date rejection was first suspected” on the Kidney allograft rejection 
eCRF, or if missing, the first available date of the biopsy of the particular rejection episode on 
the Kidney allograft biopsy eCRF page (note: BPAR is a subset of AR). 
The BPAR episode can be classified into rejection types: t-cell mediated, antibody mediated, 
or any combination of those (see an illustration in Figure 4-2).  
Figure 4-2 
Example of a rejection episode 
 
Lab sample  
Bx: Banff IIa    
 
FU Bx: Banff IIb  
 
FU Bx: normal 
1 
 
3 
 
 
 
34 
 
 
 
65 
  
2 
 
4 
 
 
 
35 
 
 
 
       Day 
  
Suspicion 
steroid  
 
 
antibody 
 
  
of AR  
treatment 
 
 
treatment 


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4.3.5 
Treated Biopsy-Proven Acute Rejection (tBPAR) 
A rejection is considered a tBPAR if:  
 Biopsy-proven acute rejection (BPAR) (see above) and 
 Was anti-rejection therapy administered?  =  “yes” from Kidney allograft rejection 
eCRF page 
Date of tBPAR will be the date of the corresponding BPAR (note: tBPAR is a subset of BPAR, 
and it is also a subset of tAR). 
4.3.6 
Antibody Treated Biopsy-Proven Acute Rejection  
A rejection is considered an antibody treated BPAR if:  
 Biopsy-proven acute rejection (BPAR) (see above) and 
 Was antibody treatment administered?  =  “yes” from Kidney allograft rejection eCRF 
page 
Date of antibody treated BPAR will be the date of the corresponding BPAR (note: antibody 
treated is a subset of BPAR) 
4.3.7 
Death 
Death will be recorded at Death eCRF. The date of event will be recorded at this eCRF as well. 
4.3.8 
Graft Loss  
Graft loss will be recorded at Graft Loss eCRF. The date of graft loss will be recorded at this 
eCRF as well. 
4.3.9 
Loss to Follow-Up 
Patients lost to follow-up for the composite efficacy failure (tBPAR, graft loss or death) for the 
12-month analysis are defined as those who meet the following two conditions: 
 Last contact day is < Day 316 (start day of the Month 12 visit window); 
 Did not experience any efficacy event (of tBPAR, graft loss or death) up to the last 
contact day for the 12-month analysis.  
Patients lost to follow-up for the composite efficacy failure (tBPAR, graft loss or death) for the 
24-month analysis are defined as those who meet the following two conditions: 
 Last contact day is < Day 631 (start day of the Month 24 visit window); 
 Did not experience any efficacy event (of tBPAR, graft loss or death) up to the last 
contact day for the 24-month analysis 
The date of lost to follow-up is the date of last study contact for the respective analysis (12 or 
24-month analysis). 


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4.3.10 
Composite Efficacy Failure 
Several composite endpoints are defined as primary or secondary efficacy variables. The date 
of efficacy failure is calculated as the earliest available date among the individual components 
of the composite endpoint. 
For the composite endpoints and each individual endpoint, if the date of the event is not 
available, then the event will be included in listings and the simple proportion efficacy tables, 
but excluded from survival analysis. 
4.4 
Definition/Derivation of Safety Variables 
4.4.1 
MedDRA Preferred Terms or SMQs to Be Used to Define The Events of 
Interest 
The events of interest will be defined using MedDRA preferred terms or SMQs as follows. 
 Wound healing events/disorders or complications 
 
MedDRA Preferred term 
Abdominal wound dehiscence 
Culture wound positive 
Debridement 
Fungating wound 
Incision site abscess 
Incision site blister 
Incision site cellulitis 
Incision site complication 
Incision site erythema 
Incision site haematoma 
Incision site haemorrhage 
Incision site infection 
Incision site oedema 
Incision site pain 
Incision site pruritus 
Incisional drainage 
Inflammation of wound 
Post procedural cellulitis 
Post procedural infection 
Postoperative stitch sinus 


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Postoperative wound complication 
Postoperative wound infection 
Promotion of wound healing 
Stitch abscess 
Suture related complication 
Suture rupture 
Wound abscess 
Wound complication 
Wound contamination 
Wound decomposition 
Wound dehiscence 
Wound drainage 
Wound evisceration 
Wound haemorrhage 
Wound infection 
Wound infection bacterial 
Wound infection fungal 
Wound infection helminthic 
Wound infection pseudomonas 
Wound infection staphylococcal 
Wound infection viral 
Wound necrosis 
Wound secretion 
Wound sepsis 
Wound treatment 
High level term 
Healing abnormal NEC 
Following preferred terms under the high level term “Healing abnormal NEC” will also be 
searched:  
Excessive granulation tissue 
Impaired healing 


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4.5 
Renal Variables 
4.5.1 
eGFR Using MDRD 4 
Estimated GFR using the MDRD formula is bases on serum creatinine, age, race and gender. 
The MDRD formula is: 
eGFR-MDRD4 [mL/min/1.73m2] = 186.3*(C-1.154)*(A-0.203)*G*R;  
where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when 
gender is female or G=1 if gender is male, and R=1.21 when race is black or R=1 otherwise. 
4.5.2 
eGFR Using Hoek Formula on Cystatin C 
Estimated GFR using the Hoek formula bases on Cystatin C: 
eGFR-Hoek [mL/min/1.73m2] = - 4.32 + 80.35 * 1/C;  
where C = Cystatin C in mg/L. 
4.5.3 
eGFR Using CKD EPI Formula 
eGFR-CKDEPI [mL/min/1.73m2]   = 141 * min(C/κ,1)α * max(C/κ,1)-1.209 *0.993Age * 
1.018 [if female] * 1.159 [if black]; 
Where C is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 for 
females and –0.411 for males, min indicates the minimum of C/κ or 1, and max indicates the 
maximum of C/κ or 1. 
4.6 
Clinically Notable Laboratory and Vital Signs Abnormality 
Criteria/Levels 
4.6.1 
Clinically notable laboratory abnormality criteria/levels  
 
Laboratory variable 
 
 
 
Standard units  
SI units 
Liver function and related variables 
SGOT (ASAT)  
 
 
 
≥3 × ULN 
 
≥3 × ULN 
SGPT (ALAT)  
 
 
 
≥3 × ULN 
 
≥3 × ULN 
Bilirubin 
 
 
 
 
≥3 × ULN 
 
≥3 × ULN 
 
Renal function, metabolic and electrolyte variables 
Urea  
 
 
 
 
 
5  ULN  
 
5  ULN 
Uric acid  
 
 
 
 
M ≥12 mg/dL 
 
M ≥714 μmol/L 
 
 
 
 
 
 
 
F ≥9 mg/dL 
 
F ≥535 μmol/L 
Glucose  
 
 
 
 
<45 mg/dL 
 
<2.5 mmol/L 
 
 
 
 
 
 
 
>250 mg/dL 
 
>13.9 mmol/L 
CK (MB)  
 
 
 
 
None 
 
 
None 
Potassium  
 
 
 
 
≤3.0 mEq/L 
 
≤3 mmol/L 


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≥6.0 mEq/L 
 
≥6 mmol/L 
Calcium  
 
 
 
 
≤6 mg/dL 
 
≤1.5 mmol/L 
 
 
 
 
 
 
 
≥13 mg/dL 
 
≥3.2 mmol/L 
Hematology variables 
Hemoglobin 
 
 
 
 
<7 g/dL  
 
<4.39 mmol/L 
Platelets (thrombocytes) 
 
 
<50 k/mm3 
 
<50 × 109/L 
 
 
 
 
 
 
 
≥700 k/mm3 
 
≥700 × 109/L 
Leukocytes (WBCs) 
 
 
 
≤2.0 k/mm3 
 
≤ 2.0 × 109/L 
 
 
 
 
 
 
 
≥16 k/mm3 
 
≥16 × 109/L 
 
Hematology variables: differential 
Granulocytes (poly, neutrophils)  
 
≤1,000/mm3 
 
≤1 x 109/L 
Eosinophils  
 
 
 
 
≥12%  
 
≥12% 
Lymphocytes   
 
 
 
≤1,000/mm3  
 
≤1× 109/L 
4.6.2 
Clinically notable vital signs abnormality criteria/levels  
Vital sign variables 
 
Notable criteria 
Systolic BP (mm/Hg) 
 
 
Either an increase of 30 that results in 180 or >200(mm/Hg) OR 
 
 
a decrease of 30 that results in 90 or <75 (mm/Hg) 
Diastolic BP (mm/Hg) 
 
 
Either an increase of 20 that results in 105 or >115 (mm/Hg) OR 
  
 
a decrease of 20 that results in 50 or <40 (mm/Hg) 
4.7 
Statistical Models 
4.7.1 
Dummy Codes for Estimating Event Rate, Event Rate Difference and 
Respective 95% CI as Well as No-Difference Testing for The 
Composite Endpoint of BPAR or GFR<50 mL/min/1.73m2 
As described in Section 4.2.1, multiple imputation, and control-based imputation will be applied 
to the primary and sensitivity analyses for the composite endpoint of tBPAR or eGFR < 50 
mL/min/1.73m2. For the component of eGFR < 50 mL/min/1.73m2, a value for missing eGFR 
as a continuous variable will be imputed first, then dichotomized it to derive this endpoint. 
To estimate event rate, event rate difference and respective 95% CI as well as no-difference 
testing for tBPAR or eGFR < 50 mL/min/1.73m2, the following dummy SAS codes can be 
adapted: 
*** Use multiple imputation, or control-based imputation method to impute a value for 
missing eGFR as a continuous variable;  
*** Dichotomized imputed eGFR to derive the endpoint of eGFR < 50 mL/min/1.73m2; 
*** Derive the composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2; 
*** Assume the dataset imp_data contains the variable EVENT (event=1 if composite 
endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 occurred; =0 otherwise) for each of 
of the imputations; 
 
PROC sort data=imp_data; 
  by _imputation_; 


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run; 
 
ods output RiskDiffCol2=diff; 
proc freq data=imp_data; 
  by _imputation_; 
  tables trt*event/riskdiff;   
run; 
 
*** diff dataset contains the following: 
 
 Obs    _Imputation_    Row            Risk       ASE 
 
  1          1         Row 1          0.3623    0.0289 
  2          1         Row 2          0.4729    0.0300 
  3          1         Total          0.4177    0.0210 
  4          1         Difference    -0.1106    0.0417 
  5          2         Row 1          0.3732    0.0291 
  6          2         Row 2          0.4874    0.0300 
  7          2         Total          0.4304    0.0211 
  8          2         Difference    -0.1142    0.0418 
  … … 
 
*** Event rate and 95% CI in Treatment1; 
proc mianalyze data=diff(where=(row='Row 1')); 
      modeleffects risk; 
 
stderr ASE; 
run; 
 
*** Event rate and 95% CI in Treatment2; 
proc mianalyze data=diff(where=(row='Row 2')); 
      modeleffects risk; 
 
stderr ASE; 
run; 
 
*** Difference in event rate and 95% CI for ‘Treatment1 - 
Treatment2’; 
*** P-value for the no-difference test; 
proc mianalyze data=diff(where=(row='Difference')); 
      modeleffects risk; 
 
stderr ASE; 
run; 
5 
References 
1. Carpenter JR, Roger JH, Kenward MG. Analysis of Longitudinal Trials with Protocol 
Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Biopharm Stat. 2013;23(6):1352-71 
2. Chow SC, Chang M. Adaptive design methods in clinical trials. Chapman & Hall/CRC 2007 
3. Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, Margreiter R, 
Hugo C, Grinyó JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony 
Study (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J 
Med; 357(25):2562-75  
4. Evans S, Li L and Wei LJ. Data Monitoring in Clinical Trials Using Prediction. Drug 
Information Journal. 2007; 41: 733-742 


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5. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report 
of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, 
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) 
final report (2002) Circulation. 106:3143–3421 
6. Roger J, O’Kelly M. When and how to use reference based imputation for missing data. 
36th PSI annual conference presentation slides, 2013