Clinical trial NCT01551212
Conditions: Liver Transplantation
Keywords: Liver transplantation Everolimus Tacrolimus Renal function
Sponsor: Novartis Pharmaceuticals
Start date: 2012-05-24; Completion date: 2017-08-08
Enrollment: 339 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients.

Detailed description:

Arms: arm 1: Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: \< 5 ng/mL) arm 2: Tacrolimus (C0-h: 6-10 ng/ml)
Interventions: intervention 1: Everolimus intervention 2: Tacrolimus intervention 3: Corticosteroids
Intervention descriptions: intervention 1: tablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg intervention 2: capsule containing 0.5, 1.0, or 5.0mg intervention 3: For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator's discretion, but may not have been eliminated sooner than 6 months post-transplantation.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
RAD001 (Everolimus) 
CRAD001HDE13 / NCT01551212
A 12 month, multi-center, open-label, randomized, 
controlled study to evaluate efficacy/safety and evolution 
of renal function of everolimus in co-exposure with 
tacrolimus in de novo liver transplant recipients 
The Hephaistos Study 
Author(s): 
Document type: 
Clinical Study Protocol 
EUDRACT number : 
2011-003118-17 
Meets criteria for 
posting on 
clinicaltrials.gov 
Yes 
Development phase: 
III  
Version No. 
5.0 (including amendment 5) 
Release date: 
 19.08.2015 
Property of Novartis Pharma  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Signature Pages 
Everolimus 
CRAD001HDE13 
Approved by the following 
Signatures of Novartis Personnel: 
 
 
(Clinical Trial Leader)   
 
signature  
 
Date 
 
 
(Trial Statistician)   
 
signature  
 
Date 
 
 
 
 
signature  
 
Date 
 
  
 
 
 
signature  
 
Date 


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Signature of Principal Investigator: 
 
(Principal Investigator) 
 
signature  
 
Date 
 
 
Signature Page for Investigator 
Everolimus 
CRAD001HDE13 
 
I have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with the principles outlined in the 
Declaration of Helsinki. 
 
 
 
 
(Investigator) 
 
signature  
 
Date 
 
 


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Clinical Study Protocol (V5.0) 
 
Study No. CRAD001HDE13 
 
Table of contents 
Table of contents ........................................................................................................................ 4 
List of post-text supplements ...................................................................................................... 6 
List of figures ............................................................................................................................. 6 
List of abbreviations ................................................................................................................... 7 
Glossary of terms ........................................................................................................................ 9 
Amendment 2 ........................................................................................................................... 10 
Amendment 3 ........................................................................................................................... 11 
Amendment 4 ........................................................................................................................... 11 
Amendment 5 ........................................................................................................................... 11 
1 
Background ................................................................................................................... 12 
2 
Study purpose ............................................................................................................... 13 
3 
Objectives ..................................................................................................................... 13 
3.1 
Primary objective(s) ...................................................................................................... 13 
3.2 
Secondary objective(s) .................................................................................................. 13 
 
 15 
 
15 
 
 
 16 
 
 17 
 
 20 
 
 22 
 24 
4 
Study design .................................................................................................................. 24 
5 
Population ..................................................................................................................... 26 
5.1 
Inclusion/exclusion criteria ........................................................................................... 27 
5.2 
Premature patient withdrawal ....................................................................................... 29 
6 
Treatment ...................................................................................................................... 29 
6.1 
Patient numbering ......................................................................................................... 29 
6.2 
Investigational and control drugs .................................................................................. 30 


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6.3 
Treatment arms ............................................................................................................. 30 
6.4 
Treatment assignment ................................................................................................... 30 
6.5 
Treatment blinding ........................................................................................................ 31 
6.6 
Treating the patient ....................................................................................................... 31 
6.6.1 
Dispensing the study drug ..................................................................... 31 
6.6.2 
Instructions for use of study drug ......................................................... 31 
6.6.3 
Permitted study drug dose adjustments and interruptions .................... 32 
6.6.4 
Rescue medication ................................................................................ 34 
6.6.5 
Other concomitant treatment ................................................................. 34 
6.6.6 
Study drug discontinuation ................................................................... 35 
6.6.7 
Emergency unblinding of treatment assignment ................................... 36 
6.6.8 
Study completion and post-study treatment .......................................... 36 
7 
Visit schedule and assessments .................................................................................... 36 
7.1 
Information to be collected on screening failures ......................................................... 41 
7.2 
Patient demographics/other baseline characteristics .................................................... 41 
7.3 
Transplantation information ......................................................................................... 41 
7.4 
Immunosuppressive Drugs/Compliance ....................................................................... 41 
7.5 
Efficacy ......................................................................................................................... 42 
7.6 
Safety ............................................................................................................................ 44 
7.6.1 
Adverse events ...................................................................................... 44 
7.6.2 
Physical examination ............................................................................ 46 
7.6.3 
Vital signs ............................................................................................. 46 
7.6.4 
Laboratory evaluations .......................................................................... 46 
7.7 
Tolerability/acceptability .............................................................................................. 47 
7.8 
Resource utilization ...................................................................................................... 47 
7.9 
Health-related Quality of Life ...................................................................................... 47 
7.10 
Pharmacomonitoring ..................................................................................................... 47 
7.11 
Pharmacogenetics/pharmacogenomics ......................................................................... 48 
 
 48 
8 
Safety monitoring ......................................................................................................... 49 
8.1 
Serious adverse event reporting .................................................................................... 49 
8.2 
Pregnancies ................................................................................................................... 49 
8.3 
Data Monitoring Board ................................................................................................. 50 
9 
Data review and database management ........................................................................ 50 
9.1 
Site monitoring ............................................................................................................. 50 
9.2 
Data collection .............................................................................................................. 50 
9.3 
Database management and quality control ................................................................... 51 
10 
Data analysis ................................................................................................................. 51 
10.1 
Populations for analysis ................................................................................................ 51 
10.2 
Patient demographics/other baseline characteristics .................................................... 52 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, compliance)
 ...................................................................................................................................... 52 


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10.3.1 
Study medication ................................................................................... 52 
10.3.2 
Concomitant therapy ............................................................................. 53 
10.4 
Analysis of the primary objective(s) ............................................................................. 53 
10.4.1 
Variable ................................................................................................. 53 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 53 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 53 
10.4.4 
Supportive analyses ............................................................................... 54 
10.5 
Analysis of secondary objectives .................................................................................. 55 
10.5.1 
Efficacy (secondary) ............................................................................. 55 
10.5.2 
Safety .................................................................................................... 56 
10.5.3 
Tolerability ............................................................................................ 57 
10.5.4 
Resource utilization ............................................................................... 57 
10.5.5 
Health-related Quality of Life ............................................................... 57 
10.5.6 
Pharmacokinetics .................................................................................. 57 
10.5.7 
Pharmacogenetics/pharmacogenomics ................................................. 57 
10.5.8 
Biomarkers ............................................................................................ 57 
10.5.9 
PK/PD ................................................................................................... 57 
10.6 
Interim analysis ............................................................................................................. 58 
10.7 
Sample size calculation ................................................................................................. 58 
10.8 
Power for analysis of critical secondary variables ....................................................... 58 
11 
Discussion and rationale for study design features ....................................................... 58 
12 
References ..................................................................................................................... 59 
13 
Appendicies .................................................................................................................. 61 
13.1 
Appendix 1: Administrative procedures ....................................................................... 61 
13.2 
Appendix 2: Clinically notable laboratory values and vital signs ................................ 63 
13.3 
Appendix 3: Possible drug interactions ........................................................................ 64 
13.4 
Appendix 4: Tacrolimus drug interactions ................................................................... 66 
13.5 
Appendix 5: Guidelines for everolimus dose reduction ............................................... 69 
13.6 
Appendix 6:  Grading of acute liver allograft rejection ................................................ 71 
13.7 
Appendix 7: Definitions of CMV disease in solid organ transplant recipients ............ 73 
13.8 
Appendix 8: Milan Criteria ........................................................................................... 74 
13.9 
Appendix 9: Histological grading and staging of chronic hepatitis – Ishak-Knodell ... 75 
List of post-text supplements 
None 
List of figures 
None 


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List of abbreviations 
 
 
AE 
Adverse Event 
ALAT (SGPT) 
Alanine Aminotransferase (Serum Glutamate Pyruvate Transaminase) 
AP 
Alkaline Phosphatase 
ASAT (SGOT) 
Aspartate Aminotransferase (Serum Glutamatoxalacetate Transaminase) 
ATC 
Anatomical Therapeutic Chemical dictionary 
ATG 
Antithymocyte Globulin 
BPAR 
Biopsy-Proven Acute Rejection 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology collaboration 
Cmax 
Maximum Plasma Concentration 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
CPK 
Creatinine Phosphokinase 
CR 
Clinical Research 
CRF 
Case Report/Record Form 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
CS 
Corticosteroids 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein Barr Virus 
EDV 
EVR 
End diastolic velocity 
Everolimus, Certican 
eGFR 
Estimated GFR 
ENR 
Enrolled Patient Population 
EOS 
End Of Study 
ESRD 
End Stage Renal Disease 
GFR 
Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
GST 
Glutathione-S-Transferase 
HA 
Hepatic Artery 
HBsAg 
Hepatitis B Surface Antigen 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoproteine Cholesterine 


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HIV 
Human Immunodeficiency Virus 
HK 
Hematokrit 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IS 
Immunosuppression 
ITT 
Intention-to-Treat 
LCMS 
Liquid Chromatography - Mass Spectometry 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoproteine Cholesterine 
LTx 
Liver Transplantation 
MDRD 
Modification of Diet in Renal Disease Study Group 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model of End Stage Liver Disease 
MMF 
Mycophenolate mofetil 
mmHg 
Millimeters of Mercury 
MPA 
Mycophenolic Acid 
NODM 
New Onset Diabetes Mellitus 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCP 
Pneumocystis Carinii Pneumonia 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PSV 
Peak Systolic Velocity 
PV 
Portal vein 
RAD 
Everolimus, Certican 
RI 
Resistant Index 
RNA 
Ribonucleid acid 
RND 
Randomization 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
Scr 
Serum creatinine 
SMPC 
Summary of Product Characteristics 
SNOMED 
Systematized Nomenclature of Medicine 
SOP 
Standard Operating Procedures 
TAC 
Tacrolimus 
tmax 
Time until Maximum Plasma Concentration 
Tx 
Transplantation 


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ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WOCBP 
Women Of Child Bearing Potential 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug 
Enrollment 
Point/time of patient 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) 
Investigational drug 
The study drug whose properties are being tested in the study 
Patient number 
A number assigned to each patient who enrolls in the study; when 
combined with the center number, a unique identifier for each 
patient in the study is created. 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 
 
 
 
 
 
 
 


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Amendment 2 
Amendment rationale 
To allow more patients to be randomized into this study the following parameters of the in- 
and exclusion criteria were adapted (see next section). According to these adaptations the 
patient management was changed. 
In addition some editorial changes and changes regarding the statistical analysis were 
performed. 
At the time of the amendment 15 patients have been randomized to the study. 
Changes to the protocol 
The major changes that are made to the protocol are as follows: 
 Measurement of the Tacrolimus C-0h levels can now be performed as per local 
practice (section 4 and 6.3) 
 Inclusion criteria – randomization 2 was rephrased for a clearer understanding (section 
5.1). 
 Inclusion criteria – randomization 3: AST and ALT levels were raised to ≤5 times 
ULN, evaluation of gamma GT was deleted due to the fact that it does not reflect a 
prognostically important marker (section 5.1). 
 For a better understanding, exclusion criteria – randomization 2 was separated in 4 
independent criteria. Platelet, neutrophil and white blood cell count was reduced to 
50,000/mm3, 1,000/mm3 and 2,000/mm3 respectively (section 5.1). 
 Former inclusion criteria – randomization 2 (now 6): Calculation mistake of 
concentration of hypertriglyceridemia was corrected (section 5.1). 
 Graft loss was added as reason for premature patient withdrawal (section 5.2). 
 Dispensing of study drug and instruction for use of study drug are described in more 
detail to avoid misuse (section 6.6.1, 6.6.2).  
 According to the adaptation of in- and exclusion criteria, the permission of study drug 
adjustment and interruption in case of inability of tolerance of the protocol-specific 
dosing scheme is described in more detail (section 6.6.3 and appendix 5) 
 PCP prophylaxis and treatment of oral candida will be performed according to local 
practice (section 6.6.5) 
 It was added, that pregnancy outcomes must be collected for the female partners of 
any males who took study drug in this study (section 8.2) 
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.  
A copy of this CRAD001HDE13 Protocol Amendment will be sent to the EC for review. The 
changes described in this amendment require IRB/EC approval prior to implementation. 
In addition, a revised informed consent that takes into account the changes to the protocol 
described herein will be submitted to the IRB/EC for approval. 


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Amendment 3 
Amendment rationale and changes 
Details of five sub-studies which will be conducted in selected centers were added to the 
protocol in chapter 3.3 and in the assessment schedule in section 7.  
In addition some editorial changes were performed. 
A copy of this CRAD001HDE13 Protocol Amendment will be sent to the EC and HA for 
review. The changes described in this amendment require EC and HA approval prior to 
implementation. 
 
Amendment 4 
Amendment rationale and changes 
The protocol has been refined to clarify the mandatory usage of corticosteroids in this study. 
Additionally, Inclusion Criterion 3/Exclusion Criterion 11 has been adjusted to include total 
abstinence as acceptable contraception method. 
In addition some editorial changes were performed. 
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. 
A copy of this CRAD001HDE13 Protocol Amendment will be sent to the EC for review. The 
changes described in this amendment require IRB/EC approval prior to implementation. 
In addition, a revised informed consent that takes into account the changes to the protocol 
described herein will be submitted to the IRB/EC for approval. 
 
Amendment 5 
Amendment rationale and changes 
The purpose of this amendment is to adapt one exclusion criteria (Excl.Crit.N°5) to better 
align with given clinical praxis and patients’ condition post liver transplantation. 
Therefore Exclusion Criterion 5 (at randomization) has been adjusted to allow inclusion of 
patients with hemoglobin < 6.0 g/dL (transfusion of erythrocytes concentrate during or after 
transplantation are allowed according to investigator discretion.)  (see Section 5). 
In addition some smaller editorial changes were performed (correction of spelling errors). 
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. 
A copy of this CRAD001HDE13 Protocol Amendment will be sent to the EC and HA for 
review. The changes described in this amendment require IRB/EC and HA approval prior to 
implementation. 
 


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1 
Background 
 
The success rate of liver transplantation has drastically increased over the last 25 years. Data 
from the European Liver Transplant Registry have recently indicated that the current 5-year 
patient survival rate in Europe is 72% (Adam et al. 2003). Calcineurin inhibitors (CNI) have 
contributed largely to the improvement in patient and graft survival after liver transplantation. 
However long-term use of CNI, cyclosporine or tacrolimus, is associated with side-effects 
which are source of morbidity. Among long-term survivors population chronic renal 
dysfunction is a well-recognized cause of morbidity. 
In addition to CNI therapy pretransplantation renal impairment, post-operative acute renal 
failure, age of recipient, hepatitis C (HCV) infection, hypertension, diabetes mellitus, 
hyperlipidemia can contribute to development of chronic renal dysfunction after liver 
transplantation (Gonwa et al. 2001, Cohen et al., 2002, Velidedeoglu et al. 2002, Pawarode et 
al. 2003, Moreno et al. 2003, Ojo et al. 2003).  
Recently a population-based cohort analysis estimated the 5-year cumulative incidence of 
chronic renal failure defined as a glomerular filtration rate of 29 ml/min/1.73 m² of body-
surface area or less or the development of end-stage renal disease among 36 849 liver 
transplant patients to be 18% (Ojo et al. 2003). The prevalence of moderate chronic renal 
impairment would be several times higher (Pawarode et al. 2003, Moreno et al. 2003). 
Importantly, chronic renal failure as well as moderate chronic renal dysfunction has been 
associated with adverse outcome, namely increased mortality (Pawarode et al. 2003, Moreno 
et al. 2003, Ojo et al. 2003). Ultimately, a safe and effective therapeutic intervention which 
would reduce the incidence of chronic renal dysfunction is strongly recommended. 
As stated before, the major contributor to the level of renal function in a recipient of a liver 
allograft is the use and level of CNIs. Reducing or eliminating the exposure to tacrolimus 
early within the first several months post-transplant should result in improved renal function. 
Although MMF has been evaluated as a strategy to eliminate CNIs, the incidence of acute 
rejection after elimination of the CNIs of 19-40% is unacceptable to many clinicians and this 
approach has not been widely adopted. In contrast to MMF, data from the RAD001H2401 
study in 144 maintenance liver transplant recipients provides evidence to support that 
concentration controlled everolimus allows elimination of CNIs without increasing the risk 
for acute rejection compared to patients who remain on CNI-based therapy. 
The previous RAD001B158 study enrolled and randomized 119 de novo liver transplant 
patients to one of three fixed doses of everolimus (1, 2, or 4 mg/day) or to placebo in 
combination with standard Neoral trough drug blood levels. Overall, data from this Phase 2 
study supported that everolimus can be safely introduced into de novo recipients of liver 
allografts. Further, the results of pharmacokinetic modeling from this trial are consistent with 
the results from renal and cardiac transplant trials indicating that the trough level of 
everolimus in blood of less than 3 ng/mL is associated with the risk for acute rejection with 
loss of efficacy. Other recent trials substantiate that concentration controlled everolimus 
provides for the minimization of cyclosporine or for tacrolimus in de novo renal 
transplantation, as well as significant reduction of cyclosporine in cardiac transplantation 
without increasing the risk for acute rejection and preserving renal function.  


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Fibrosis of an allograft among recipients who are HCV positive is another important factor 
that contributes to the loss of the liver allograft. This group of recipients that may require 
antiviral therapy comprises at least 50% of the liver transplant population in many countries. 
However, there is at present no available therapeutic agent or regimen that has reliably 
demonstrated an effect on the development of fibrosis, or is well tolerated by HCV positive 
patients. Preclinical data suggest that there is an effect of proliferation signal inhibitors such 
as everolimus on processes that contribute to the development of liver fibrosis. Everolimus 
may directly or indirectly, by reducing or eliminating exposure to tacrolimus, reduce 
development or the rate of development of fibrosis in liver allografts (Verrill et al., 2002, Zhu 
et al., 1999, Frizell et al., 1994). 
Based on the experience that has accumulated in other solid transplant studies as well as in 
smaller liver transplant studies, introduction of everolimus may provide the opportunity to 
address the medical need of providing superior renal function by allowing for the reduction or 
for the elimination of tacrolimus early post-transplant, and possibly may impact the 
development or the rate of progression of fibrosis in HCV positive recipients. 
2 
Study purpose 
 
This study is designed to provide data on efficacy and safety of a post-transplantation regimen 
in liver allograft patients consisting of reduced tacrolimus in the presence of everolimus. 
3 
Objectives 
3.1 
Primary objective(s) 
To demonstrate that an immunosuppressive regimen based on everolimus (EVR) in co-
exposure with tacrolimus (TAC) has superior efficacy compared to tacrolimus alone on 
estimated glomerular filtration rate (MDRD-4 formula) at Month 12 in de novo liver 
transplant recipients. 
3.2 
Secondary objective(s) 
Key secondary objective: 
To evaluate the incidence of a composite of treated biopsy proven acute rejection (BPAR), 
graft loss or death at Month 12. 
Efficacy related objectives 
• 
To evaluate the incidence of a composite of treated BPAR, graft loss, death or loss to 
follow-up at months 6 and 12. 
• 
To evaluate the incidence of each component of the composite efficacy endpoint at 
month at months 6 and 12. 
• 
To evaluate the incidence of a composite of death or graft loss at months 6 and 12. 
• 
To evaluate treated BPAR by: (1) incidence, (2) time to event, (3) severity, (4) 
diagnosis leading to transplantation. 


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• 
To evaluate any acute rejection by: (1) incidence, (2) time to event, (3) severity. 
• 
To evaluate the incidence of: 
o Treated acute rejection. 
o BPAR. 
o Treated BPAR. 
Renal function-related objectives 
• 
To evaluate the evolution of post-randomization renal function over time assessed by 
the change in estimated GFR (MDRD-4), including to Months 6, and 12. 
• 
To evaluate renal function by eGFR using various methods (MDRD-4, Nankivell, 
Cockcroft-Gault, CKD-EPI and Hoek formulae). 
• 
To evaluate the incidence of patients experiencing a decline in eGFR (MDRD-4) of < 
10, 10<15, 15<20, 20<25, and ≥ 25 mL/min/1.73m2 from Screening, Week 2 post 
transplantation and randomization to Months 6, and 12. 
• 
To evaluate serum creatinine at various time points. 
• 
To evaluate renal function and change in eGFR from screening, randomization, and 
Week 2 post transplantation to Months 6 and 12 eGFR in following subgroups: age 
(< 60 and ≥ 60 years), gender, race, renal function strata (< 30, 30<45, 45<60, ≥ 60 
mL/min/1.73m2, below/above 45 mL/min/1.73m2, below/above 60 mL/min/1.73m2), 
HCV status, lab MELD score categories (≤14, 15-19, 20-24, 25-29, ≥ 30), and 
diagnosis leading to transplantation. 
• 
To evaluate urinary protein/creatinine ratio at various time points. 
• 
To evaluate the incidence of proteinuria of 0.5<1.0 g/day, 1.0<3.0 g/day and 
≥ 3.0 g/day at various time points. 
• 
To evaluate the incidence of and time to renal replacement therapy. 
Safety related objectives 
• 
To evaluate the incidence of Adverse Events (AEs)/Infections/Serious Adverse Events 
(SAEs). 
• 
To evaluate the incidence of treatment-related side effects, including incidence of new 
onset diabetes mellitus (NODM), evolution of metabolic parameters as subdivisions of 
serum/plasma lipid panel, neurotoxicity and hypertension. 
• 
To evaluate the incidence and reason (e.g. AE) of premature discontinuation of study 
medication and premature discontinuation from the study. 
• 
To evaluate the incidence and reason (e.g. AE) of interruption and dose adjustment of 
study medication. 


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Virus (HCV, CMV) and Hepatocellular Carcinoma (HCC) related objectives 
• 
To evaluate the incidence of HCV and HCV related fibrosis. 
• 
To evaluate rates of progression of HCV related allograft fibrosis. 
• 
To evaluate HCV viral load (HCV- messenger ribonucleic acid (mRNA) levels overall 
and by genotype). 
• 
To evaluate incidence of and response to HCV antiviral treatment. 
• 
To evaluate the rate of recurrence of HCC at 12 post-transplantation in patients with a 
diagnosis of HCC at the time of liver transplantation adjusting for various risk factors, 
such as number of tumor nodules, total tumor diameter, alpha fetoprotein level, etc. 
• 
To evaluate the incidence of de novo HCC malignancies. 
• 
Incidence and severity of CMV viral infections. 
 


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4 
Study design 
This is a 12-month, multi-center, open-label, randomized, controlled study to evaluate 
efficacy and safety and evolution of renal function of everolimus (EVR) in co-exposure with 
tacrolimus (TAC) in de novo liver transplant recipients. 
Patients will be consented and screened for eligibility prior to liver transplantation (LTx). The 
study treatment will start with a run-in period that ends on the day of randomization (RND), 
scheduled at 7-21 post- LTx. Patients after consent who have undergone successful LTx (with 
optional induction therapy) will be entered in this run in period (between 3 and 5 days post-
LTx) and may be initiated on an optional induction therapy, MMF, TAC at investigators’ 
discretion until at least day 7 or maximally until day 21 post LTx with mandatory CS therapy 
until at least Month 6 post Tx. 
Patients on MMF according to local practice must have the MMF administration discontinued 
by the time of RND. MMF is discontinued according to local practice. 
At day 7-21 post-transplantation the following information at minimum has to be obtained 
from a patient to be randomized into the study: 
 Abbreviated MDRD eGFR > 30 mL/min/1.73m2. Creatinine results obtained in local 
laboratory within 5 days prior to RND are acceptable. 


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All eligible patients (according to in-/exclusion criteria at RND) will be randomized in 
between 7 and 21 days post LTx to one of the two treatment groups in a 1:1 ratio: 
Arm 1: EVR/TAC group (Tacrolimus minimization arm) 
Everolimus should be initiated at the day of randomization. Therapeutic drug monitoring will 
be mandatory throughout the duration of the study. Whole blood trough levels should be 
obtained 5 ± 2 days after either everolimus or tacrolimus doses are changed.  
Everolimus dosing: Everolimus study drug will be started at the day of randomization at a 
dose of 1.0 mg b.i.d (2.0 mg daily dose). The everolimus whole blood trough (C-0h) levels 
should be targeted to be maintained between 3-8 ng/mL. The twice daily dose can be changed 
in order to maintain the 3-8 ng/mL C-0h levels through the remainder of the study. 
Tacrolimus dosing: After everolimus whole blood trough levels have been confirmed to be 
in the target range (3-8 ng/mL), tacrolimus tapering should begin, achieving a target 
tacrolimus C-0h levels of <5 ng/mL plus corticosteroids by three weeks after randomization 
and continuing through the remainder of the study. 
Arm 2: TAC group 
Tacrolimus dosing: Tacrolimus C-0h levels should be targeted to be maintained at 6-10 
ng/mL plus corticostroids. 
Control assessments will be performed at day 8 and 15 and at month 1, 3, 6, 9, and 12 after 
randomization. The final examination will be performed at Month 12 after randomization and 
at timepoint of early discontinuation from study treatment, if applicable. Drug dosage will be 
modified regarding to C-0h level measured as per local practice at standard visits (target C-0h 
levels: Certican® 3-8 ng/mL; TAC <5 ng/mL in Arm I and TAC 6-10 ng/mL in Arm II). The 
established treatment will be continued until Month 12 post RND (final assessment). Renal 
function (eGFR) as well as efficacy (treated BPAR, graft loss, and/or death) will be assessed 
at every study visit. 
Management of corticosteroids for all study arms 
For patients in all groups, corticosteroids will be initiated at or prior to the time of transplanta-
tion according to local practice. Corticosteroids may be used for the duration of the study 
according to the investigator`s discretion, but may not be eliminated sooner than 6 months 
post-transplantation. 
Peri-operative i.v. steroids may be used per local practice. Oral corticosteroids will be admi-
nistered according to local practice during the trial. However, after randomization, the mini-
mum dosage of corticosteroids must be equivalent to 5 mg prednisone/day. Corticosteroids 
may not be discontinued earlier than Month 6 post-transplantation. 
 
 
 
 
 


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Table 4-1 
Study outline 
 
Period 
Screening* 
Run in 
Period# 
Baseline 
RND 
Treatment  
EOS 
Visit 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
Days after 
Tx 
Before Tx 
7-21 
7-21 
 
 
 
 
 
 
 
Days of 
treatment 
 
 
1 
8 
15 
30 
90 
180 
270 
360 
Month of 
treatment 
 
 
 
 
 
1 
3 
6 
9 
12 
*day 21-day 1 (= day of transplantation) 
# day 1-day 7/21 after transplantation, end with randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*optionally center-specific  
 
 
EVR / TAC group (ARM I) 
 
EVR 
C0-h: 3-8 ng/mL 
TAC 
C0-h: <5 ng/mL 
CS 
prednisone equivalent at least until Month 6 
TAC group (ARM II) 
 
TAC 
6-10 ng/mL  
CS 
prednisone equivalent at least until Month 6  
5 
Population 
The study population will consist of de novo liver transplant recipients who will be enrolled 
prior to LTx and randomized 7 to 21 days post LTx in a 1:1 ratio to either everolimus (EVR) 


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in co-exposure with tacrolimus (TAC) at a reduced dose (< 5ng/ml) or TAC (6-10 ng/ml). 
330 evaluable patients (165 in each treatment group) will be recruited.  
The study will be conducted in 15 transplant centers in Germany. 
5.1 
Inclusion/exclusion criteria  
The investigator must ensure that all patients who meet the following inclusion and do not 
fulfill any of the exclusion criteria are offered enrollment in the study. No additional 
inclusion/exclusion parameters can be applied by the investigator, in order that the study 
population will be representative of all eligible patients. 
Inclusion Criteria 
1. Patients who are willing and able to participate in the study and from whom written 
informed consent has been obtained. 
2. Male or female recipients of a full-size liver allograft, aged 18 to 65 years. 
3. Females capable of becoming pregnant must have a negative pregnancy test prior to start 
of study and before randomization and are required to practice a medically approved 
method of birth control or live in total abstinence for the duration of the study. 
Exclusion Criteria 
1. HIV positive patients. 
2. Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have 
previously received an organ or tissue transplant. 
3. Patients with renal failure or CKD/ESRD who require renal replacement therapy for more 
than 2 weeks prior to transplantation. 
4. History of malignancy of any organ system within the past 5 years whether or not there is 
evidence of local recurrence or metastases, other than non-metastatic basal or squamous 
cell carcinoma of the skin or HCC (see next criteria). 
5. HCC that does not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3 nodules all ≤ 3 cm) at the 
time of transplantation. 
6. Patients with a known hypersensitivity to the drugs used on study or their class, or to any 
of the excipients. 
7. Patients receiving drugs known to significantly interact with any immunosuppressant used 
in the trial. 
8. Patients who are recipients of AB0 incompatible transplant grafts. 
9. Patients with a current systemic infection or sepsis requiring active use of IV antibiotics. 
10. Patients with symptoms of significant mental illness and with inability to cooperate or 
communicate with the investigator. Patients who are unlikely to comply with the study 
requirements, or who are unable to give informed consent. 
11. Women 
o who are pregnant or breast feeding (pregnancy defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/ml)). 


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o who are menstruating and capable of becoming pregnant* and not practicing a medically 
approved method of contraception (Pearl Index <1**) during and up to at least 4-8 
weeks after the end of treatment. A negative pregnancy test (serum) for all women 
entering menarche is required with sufficient lead time before inclusion. 
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 
months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post 
surgical bilateral oophorectomy with or without hysterectomy 
**examples of particularly reliable methods with Pearl Index (PI) <1, according to 
guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: 
• Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9) 
• Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.) 
• Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.) 
• Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14) 
• Progestin-containing contraceptives (Implanon®, PI=0-0.08) 
• Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) 
• Intra-uterine progestine device (Mirena®, PI=0.16) 
o Highly effective contraception methods include total abstincence (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. 
12. Patients, who have already been randomized into this study earlier must not be included a 
second time. 
13. Participation in another clinical trial. 
Inclusion Criteria - Randomization 
1. eGFR (MDRD4 formula) > 30 mL/min/1.73m2  at time of randomization. 
2. Absence of thrombosis via Doppler ultrasound of the major hepatic arteries, major hepatic 
veins, portal vein and inferior vena cava at time of randomization and prior to any 
initiation of treatment with everolimus. 
3. Allograft is functioning at an acceptable level by the time of randomization as defined by 
total bilirubin levels ≤3 times ULN and AlkP, AST, ALT levels ≤ 5 times ULN.  
Exclusion Criteria - Randomization 
1. Patients who are not able to take oral medication at time of randomization. 
2. Patients with platelet count <50,000/mm³)  
3. Patients with an absolute neutrophil count of <1,000/mm³  
4. Patients with a white blood cell count of <2,000/mm³)  
5. Patients with hemoglobin < 6.0 g/dL.(transfusion of erythrocytes concentrate during or 
after transplantation are allowed according to investigator discretion.)   
6. Patients 
with 
uncontrolled 
hypercholesterolemia 
(>350mg/dL; 
>9mmol/L) 
or 
hypertriglyceridemia (>750 mg/dL, >8.5 mmol/L). 
7. Patients with a protein/creatinine ratio indicating daily urinary protein excretion >1 g/24h 
at time of randomization. 
8. Patients with clinically significant or uncontrolled systemic infection requiring active use 
of IV antibiotics at the time of randomization. 


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9. Patients who have received an investigational drug within 30 days prior to randomization. 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study drug for any of the following reasons: 
 Withdrawal of informed consent (which leads also to study withdrawal) 
 Occurrence or detection of severe medical disorder jeopardizing the life of the patient in 
the immediate future 
 Occurrence of an episode of acute rejection that requires T-cell depleting therapy or 
occurrence of more than three steroid sensitive episodes of acute rejection. 
 Pregnancy  
 Graft loss 
Patients who discontinue study drug should NOT be considered withdrawn from the study. 
See Section 7 for the required assessments of these patients after study drug discontinuation. 
Patients also should be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason. Protocol violations may lead to patient withdrawal 
unless they indicate a significant risk to the patient’s safety. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason. 
If premature withdrawal of study drug occurs for any reason, the investigator must determine 
the primary reason for a patient’s premature withdrawal from the study medication and record 
this information on the Study Drug Completion CRF. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study drug will not be replaced by newly 
enrolled patients. 
6 
Treatment 
6.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g., the second patient is assigned patient 
number 2, the third patient is assigned patient number 3). Once assigned to a patient, a patient 
number will not be reused. If the patient fails to be randomized for any reason, the reason for 
not being randomized will be entered on the Screening Failure Log. 


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6.2 
Investigational and control drugs 
Investigational drug 
Certican®  
 
Active ingredient:  
everolimus (RAD001) 
Galenic form: 
 
tablets  
Dose: 
 
 
one tablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg 
 
Dosing schedule:  
twice daily, dose according to blood levels  
Packaging:  
 
blisters of 10 tablets 
Other immunosuppressive drugs 
 Tacrolimus 
Tacrolimus Hexal® 
 
Active ingredient:  
tacrolimus 
 
Galenic form: 
 
capsules 
 
Dose: 
 
 
one capsule containing 0.5, 1.0, or 5.0mg 
 
Dosing schedule:  
twice daily, dose according to blood levels  
Packaging:  
 
blisters of 10 capsules 
 
 Corticosteroids 
are mandatory within the first six months after TX. 
 
Further immunosuppressive agents are excluded. Everolimus and Tacrolimus Hexal® will be 
supplied by Novartis. 
6.3 
Treatment arms 
At Baseline (Visit 2) between 7 and 21 days post LTx patients will be assigned to one of the 
following two treatment groups in a ratio of 1:1.  
 EVR/TAC group (ARM I): 
Everolimus (C0-h: 3-8 ng/mL*) + tacrolimus (C0-h: < 5 ng/mL*)  
 TAC group (ARM II): 
Tacrolimus (C0-h: 6-10 ng/ml*)  
*Trough levels as per local practice, e.g. liquid chromatography coupled with mass 
spectrometry (LCMS). Values derived from enzyme based assays will be corrected (as 
described in the manufacturer’s instructions). 
6.4 
Treatment assignment 
At Baseline (Visit 2), which has to take place prior to randomization, all patients who meet 
the inclusion and do not fulfill any of the exclusion criteria will be given the lowest available 
number on the randomization list of the respective stratum. This number assigns them to one 
of the treatment arms. The investigator will enter the randomization number on the CRF. 
The randomization numbers will be generated using the following procedure to insure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A 


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randomization list will be produced under the responsibility of the Novartis Nürnberg GCP 
Officer using a validated system that automates the random assignment of treatment arms to 
randomization numbers in the specified ratio. Randomization will be stratified by HCV status 
(positive/negative) and lab MELD (Model of End Stage Liver Disease) score below/equal or 
above 30 at transplantation. 
Randomization of individual patients will be performed centrally by a CRO. Allocation of a 
patient to one of the two treatment groups will be performed in the following steps. 
1. 
Information about patient enrolment (Screening Visit): 
Study sites will inform the CRO about each patient inclusion via fax 
2. 
Randomization (Baseline Visit): 
At day of randomization, the site will provide the information of eligible patient to the 
CRO by fax.  
The CRO will allocate the patient the next free consecutive randomization number 
allocated to the site. Randomization number and allocated treatment (according to the 
randomization list) will be provided to the site by fax. 
The randomization number will be entered on the CRF of an individual patient.  
6.5 
Treatment blinding 
Not applicable, since this is an open-label study.  
6.6 
Treating the patient 
6.6.1 
Dispensing the study drug 
Each study site will be supplied by Novartis with Certican®and Tacrolimus Hexal®. Certican® 
will be provided as tablets in 0.25 mg, 0.5 mg, 0.75 mg and 1.0 mg strength, packaged in 
packages, and labeled according to the German legal requirements. Tacrolimus Hexal® will be 
provided as capsules in 0.5 mg, 1.0 mg and 5 mg strength.  
Immediately before dispensing study drug (Certican®) to the patient, investigator staff will 
detach the outer part of the label from the packaging and affix it to the source document (Drug 
Accounting Form) containing that patient’s unique patient number. Tacrolimus Hexal® 
dispensing will be also recorded on the Drug Accounting Form. 
6.6.2 
Instructions for use of study drug 
The starting dose will be 1 tablet of 1.0 mg everolimus in the morning, and 1 tablet of 1.0 mg 
in the evening for all patients. First dose of study drug has to be applied within 24h after 
randomization.  
Additional medication for dose adjustments will be provided in 0.25 mg, 0.5 mg and 0.75 mg 
tablet strengths. The dose will be adjusted to maintain the everolimus trough blood levels 
between 3-8 ng/mL. Five (5) days after randomization or any later, everolimus dose should be 
doubled if the trough level is below 3 ng/mL. The trough level should not exceed 8 ng/mL 
during the whole study duration.  
Target level of Certican® should be achieved within 14 days post randomization. Close 
monitoring of trough levels is required at least once monthly. 


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Patients in Arm 1 will take everolimus (C0-h: 3-8 ng/mL) twice daily in 12 hours intervals 
simultaneously with tacrolimus (C0-h: < 5 ng/mL), 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 investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
At each patient’s study visit, site personnel should count remaining study medication 
(everolimus, tacrolimus) to check compliance. 
All dosages dispensed to and returned by the patient during the study must be recorded on the 
Drug Accounting Form in the Investigator Folder. Patients randomized to a specific 
immunosuppressive regimen in Arm I or Arm II have to remain on this medication up to the 
end of the study – otherwise the patient will be discontinued form the study drug regimen. 
Patients may be seen by local general practitioner in between protocol defined visits. The 
main PI is responsible to give guidance to the local general practitioners for patient’s 
management. The PI is responsible to obtain all information about measured levels of 
immunosuppressive medications and changes of dosages throughout the study.  
6.6.3 
Permitted study drug dose adjustments and interruptions 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and interruptions are permitted in order to keep the patient on study drug. All 
changes must be recorded on the Dosage Administration Record CRF. 
The following guidelines should be followed as far as clinically feasible:  
Everolimus 
Because everolimus is the mainstay of the protocol in the investigational arm (Arm 1), 
everolimus dose should be continued on a stable level according to trough levels. Treatment 
interruptions and dose reduction will be allowed for those patients who do not tolerate the 
prescribed dose of everolimus indicated by the occurrence of adverse events. 
In both renal and heart transplantation, everolimus trough concentrations  3 ng/mL were 
associated with a significantly lower protection from acute rejection compared with trough 
levels > 3 ng/mL. Although hyperlipidemia was common over the full exposure range, it 
responded to corticosteroid dose reduction, dietary management, and lipid-lowering therapies, 
and were, therefore, not dose-limiting. The incidence of leukocytopenia did not show any 
exposure-response relationship to everolimus trough concentrations. The incidence of notable 
thrombocytopenia (< 100x109/L) increased with everolimus exposure; however, the incidence 
of clinically meaningful platelet reductions (< 75x109/L) was generally low. 
In severe hematologic adverse events (CTCAE 4.0) including leukocytopenia and 
thrombocytopenia everolimus should be interrupted until the condition has resolved. If a 
hemolytic uremic syndrome (hemolytic anemia, acute renal failure, uremia) occurs, 
everolimus has also to be permanently discontinued. 


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In case of a decrease of renal function all potential nephrotoxic medication other than the 
immunosuppressive agents should be discontinued first. If stadium 1 of acute kidney injury is 
met (an increase in SCr >or=0.3 mg/dl or 25µmol/l (Chertow, 2005) or an increase in SCr of 
50-100% from the initial value (Mehta, 2007)), everolimus and tacrolimus has to be reduced 
to the lowest trough levels according to the protocol (see above). If the acute kidney injury is 
not responsive to these measures, everolimus has to be discontinued. 
Target therapeutic ranges for everolimus whole blood trough levels should be 3-8 ng/mL. 
Dose should be adjusted if everolimus whole blood trough levels outside the target range are 
measured. Dose adjustments of everolimus should be monitored 5 ± 2 days later by a 
measurement of the everolimus blood trough level.  
 
For patients who are unable to tolerate the protocol-specified dosing scheme due to a decrease 
in the platelet count, a decrease in hemoglobin level, a decrease in white blood cell count, an 
increase in cholesterol level, an increase in triglyceride level, or other adverse events, dose 
adjustments are permitted in order to keep the patient on investigational drug. The respective 
guidelines are appended to the clinical trial protocol (see Appendix 5). 
 
The everolimus dose should be decreased by one dosing step (0.25mg 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. 
 
If everolimus is interrupted for longer than 4 consecutive weeks, or more than 8 cumulative 
weeks, discontinuation of study medication should be discussed with the sponsor. Study drug 
may be interrupted during antibody treatment of rejection episodes. During the course of the 
trial the study drugs will be administered on a b.i.d. regimen. Study medication will not be 
provided to patients after they have discontinued the study. 
If reduction of everolimus is necessary for the patient to remain in target trough range, 
everolimus dosing may be reduced by 0.25 mg intervals. 
Appropriate information needs to be recorded on the Dosage Administration CRF. 
The End of Treatment Visit will be performed and documented for all patients who are 
withdrawn prematurely from the treatment at time point of discontinuation. The Month 12 
assessments will be performed for all patients randomized in the study. 
Tacrolimus 
Dose should be adjusted if tacrolimus whole blood levels are outside the target range. Target 
therapeutic ranges for tacrolimus whole blood trough levels should be < 5 ng/mL in the 
investigational arm (Arm I) and 6-10 ng/ml in the control arm (Arm II). In case of severe 
tacrolimus toxicity, dose reductions below the target levels may be performed on the 
investigators’ discretion.  
If tacrolimus medication is interrupted for more than 4 consecutive weeks, or more than 
8 cumulative weeks, discontinuation of the tacrolimus should be considered. 


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Prednisone/Prednisolone 
Oral corticosteroids (prednisolone or equivalent) will be administered according to local prac-
tice during the trial. However, after randomization, the minimum dosage of corticosteroids 
must be equivalent to 5 mg prednisone/day. Corticosteroids may not be discontinued earlier 
than Month 6 post-transplantation. 
6.6.4 
Rescue medication 
Treatment for acute rejection episodes 
Treatment for biopsy proven acute rejection will commence at the clinician’s discretion or 
according to the center-specific protocol. An acute rejection episode will be considered to 
have been treated if a patient has received at least 3 days' treatment with a daily dose of 
15mg/kg (max.1000 mg) or more of i.v. methylprednisolone (or equivalent) and/or at least 3 
days of antilymphocyte therapy.  
Treatment of acute rejection or presumed acute rejection will be recorded on the appropriate 
CRF page.  
The biopsies will be read locally and the severity of acute rejection will be classified using the 
Rejection Activity Index (RAI) as defined by the World Gastroenterology Consensus 
Document (Banff, Hepatology 1997). In the event that a rejection episode is not confirmed by 
biopsy or a biopsy is not done, the clinician will score the severity of that rejection episode on 
the basis of clinical and functional criteria into severe (hospitalization, death) and non severe 
(all others). 
6.6.5 
Other concomitant treatment 
 
Cytomegalovirus prophylaxis 
Cytomegalovirus (CMV) prophylaxis or preemptive monitoring for CMV should be according 
to local practice and applied uniformly for all enrolled patients at the center. Treatment with 
valganciclovir, ganciclovir, cytomegalovirus hyperimmune globulin, acyclovir or valacyclovir 
is permitted and will be administered according to local practice. CMV prophylaxis is also 
recommended for CMV Donor positive, Recipient negative (D+/R-) patients and following 
any antibody treatment of acute rejection episodes. 
 
Pneumocystis carinii pneumonia prophylaxis 
Prophylactic treatment for pneumocystis carinii pneumonia (PCP) consisting Bactrim® or 
equivalent (trimethoprim / sulfamethoxazole), starting when oral medication can be tolerated 
will be used as per local practice. Aerolized pentamidine (300 mg/month) or dapsone (100 
mg/day) should be administered to patients unable to tolerate trimethoprim / sulfamethoxazole 
as per local practice.  
Treatment of oral Candida 
All patients will be treated according to local standard of care. The same prophylaxis strategy 
should be applied for all patients at a given site. Nystatin suspension in a swish and swallow 
regimen is recommended for the prophylaxis or treatment of oral thrush (Candida). 
Alternative clotrimazole lozenges/troches may be used. Routine use of systemic antifungal 
“azole” agents (i.e. ketoconazole, itraconazole, voriconazole and fluconazole) for oral 
candidiasis will not be allowed unless patients are systemically infected. Administration of 


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“azoles” may increase blood concentrations of both tacrolimus and everolimus; therefore their 
use should be minimized. Particular attention to side effects is required (see Appendix 3). 
 
 
Hepatitis B prophylaxis 
Prophylaxis for recurrent hepatitis B during the course of this study will be left to the 
investigator’s discretion. 
 
Treatment of HCV disease 
Treatment for HCV disease can be done but not preemptively. Investigators will be allowed to 
treat HCV only when recurrent HCV disease has been documented, based on histological 
evidence as determined by the local pathologist. Therapies used for post-transplantation HCV 
disease will be documented on the appropriate CRF section. HCV patients should not receive 
HCV therapy during the time of tacrolimus elimination. 
 
Recommended follow-up for HCC patients 
It is highly recommended to monitor and follow-up the HCC patients as per the best local 
practices. Patients may be evaluated every three months during the 12 months study duration. 
In addition to the routine laboratory monitoring/tests, tumor markers (AFP-alphaprotein) and 
hepatic ultrasound may be performed on a quarterly basis and computed tomography scans 
(CAT, CT) or MRI (especially Fe-MRI) twice a year. 
 
Other medication 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the investigational drug. All medications (other than 
investigational drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after patients screening visit must be listed on the Prior-
/Concomitant Medications/Significant Non-Drug Therapies pages in the CRF. If administered 
for an AE, it should be appropriately cross-referenced on the AE CRF. 
6.6.6 
Study drug discontinuation 
In case of elevated cholesterol and/or triglyceride levels, lipid lowering medications should be 
optimized.  HMG Co-A reductase inhibitors (e.g., fluvastatin) are to be administered 
according to local practice for the management of hyperlipidemia. The use of lovastatin is 
prohibited in this study. The starting dose of HMG Co-A reductase inhibitors will be 
equivalent to 20 mg pravastatin, 5 mg simvastatin or 20 mg fluvastatin, and may be increased 
to target and maintain a LDL level of < 130 mg/dL. Lipid lowering therapy should be 
optimized before dosage reduction of study medication is considered. If the elevation persists, 
the dosing of everolimus should be adjusted following the recommendations given in 
Appendix 5. 
Dose may be reduced for those patients with other moderate/severe AEs according to the 
investigators’ judgment. Also in these cases, the medication doses can be reduced by half or 
interrupted until event resolves. 
If the everolimus medication is interrupted for more than 4 consecutive weeks, or more than 
8 cumulative weeks within the 12 months study treatment, discontinuation of the respective 
medication should be considered and the patient withdrawn from study treatment. 


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Patients who discontinue study drug before completing the 12-months period should be 
scheduled for a visit as soon as possible, at which time all of the assessments listed for the 
final visit (EoT, Visit 9a) will be performed. The End of Study Assessment (Visit 9, Month 
12) should be repeated at the originally planned time point, i.e. on Month 12 post 
randomization.  
At a minimum, all patients who discontinue study drug, including those who refuse to return 
for a final visit, will be contacted for safety evaluations during the 30 days the last dose of 
study drug. 
Patients who discontinue study drug should be considered withdrawn from the study when it 
is clear that the patient will not return for the Month 12 assessments.  
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. 
Suspicion of thrombotic microangiopathy is raised when creatinine levels increase more than 
50% from previous level in combination with thrombocytopenia and signs of hemolysis. In 
these cases everolimus should be discontinued and clinical workout is required (e.g. blood 
smear, kidney biopsy, etc). 
6.6.7 
Emergency unblinding of treatment assignment 
Not applicable, since this is an open-label study. 
6.6.8 
Study completion and post-study treatment 
For all patients who were included into this study (i.e., who signed informed consent and are 
randomized), whether discontinued the study treatment prematurely or completed the study, 
the final examination 12 months after randomization (Visit 9) will be performed. 
The investigator also must provide follow-up medical care for all patients who are 
prematurely withdrawn from the study, or must refer them for appropriate routine care 
according to center practice.  
7 
Visit schedule and assessments 
Table 2 lists all of the assessments and indicates with an “X” the visits when they are 
performed.  
Patients should be seen for all visits on the designated day or as close to it as possible. During 
first month of treatment (until Visit 5) a time interval of  3 days and 14 days thereafter may 
be acceptable. For the final visit (Visit 9) a time interval of 30 days is acceptable. 
Patients who discontinue study drug before completing the study, and those who prematurely 
withdraw from the study for any reason, should be scheduled for a visit as soon as possible, at 
which all of the assessments listed for the EoT visit (visit 9a) will be performed.  
At a minimum, they will be contacted for safety evaluations during the 30 days following the 
last dose of study drug, including final contact at the 30-day point. Documentation of attempts 
to contact the patient should be recorded in the patient record.  


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All data obtained from the assessments listed in Table 2 and described in detail in the 
subsections below must be supported by the patient’s source documentation.  


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Table -2 
Assessment schedule 
Phase 
Screening1 Baseline2 
Treatment Phase 
EOT3 
EOS 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
9 
Days 
 
1 
8 
15 30 90 180 270 
 
360 
Month 
 
 
 
 
1 
3 
6 
9 
 
12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion  
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
General medical history  
X 
 
 
 
 
 
 
 
 
 
Transplantation 
information 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory test: 
- Hemat. / Biochemistry 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
GFR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
 
X 
 
 
X 
X 
X 
X 
X 
X 
Viral Serology 
X 
 
 
 
 
 
 
 
 
 
CMV Monitoring 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
HCV Monitoring  
 
 
 
 
 
 
 
 
 
 
     Viral load (RNA-level) 
X 
X4 
 
 
X4 
X4 
X4  X4 
X4 
X4 
     Genotype 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test5 (-HCG) 
X 
X 
 
 
 
 
 
 
 
X 
Liver Doppler 
Ultrasound6 
 
X 
 
 
 
 
 
 
 
 
Tacrolimus C0 level 
Everolimus C0 level 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rejection episodes 
 
 as necessary  
 
Biopsies8 
X7 
 as necessary  
X 
Infections 
 
 as necessary  
X 
AEs 
 
 as necessary  
X 
SAEs 
 
 as necessary  
X 
Comments 
 
 as necessary  
 
Concomitant therapy 
 
 as necessary  
 
Immunosuppressive 
therapy 
 
 as necessary  
 
End of treatment / End of 
study 
 
 
X 
X 
1) 
day 21-day of transplantation 
2) 
Visit 2 (Baseline) has to be performed prior to randomization, 7-21 days after Tx. 
3) 
End of Treatment Visit in case of premature study discontinuation 
4) 
Only in HCV positive Patients 
5) 
Only in women of childbearing potential 


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6) 
Liver Doppler Ultrasound of the hepatic artery, hepatic vein, portal vein, and inferior vena cava will be 
carried out up to 5 days prior to randomization. 
7) 
Intraoperatively 
8) 
For analysis of allograft fibrosis (only HCV positive patients) 
 
Screening Visit - Visit 1 (day -21 to Tx) 
1. Patient signs informed consent. 
2. Patient’s eligibility for the study according to in- and exclusion criteria will be checked. 
3. Demographic data will be recorded (sex, age, ethnic origin). 
4. Relevant medical history will be obtained and recorded until time point of randomization. 
5. Transplantation information will be recorded (donor and recipient information). 
6. A complete physical examination will be performed.  
7. Vital signs will be measured. 
8. Venous blood will be drawn for measurement of viral serology (HBsAg, HCV). 
9. Venous blood will be drawn for CMV monitoring (including pp65 Ag). 
10. Venous blood will be drawn for HCV monitoring: Viral load (RNA level), HCV genotype 
(only at screening) 
11. Menopausal status will be recorded and in all women of childbearing potential a 
pregnancy test will be performed (-HCG) (see also section 7.3). 
12. An intraoperative biopsy (preferably after reperfusion) will be performed for analysis of 
allograft fibrosis (only HCV positive patients). 
Baseline Visit - Visit 2 (day 1) 
The Baseline assessment has to be performed prior to randomization. 
1. Patient’s eligibility for the study according to in- and exclusion criteria will be checked. 
2. A complete physical examination will be performed.  
3. Vital signs will be measured. 
4. Urinalysis will be performed. 
5. Venous blood will be drawn for measurement of hematology and biochemistry.  
6. Glomerular Filtration Rate (GFR) will be calculated. 
7. Venous blood will be drawn for HCV monitoring: Viral load (RNA level), in HCV 
positive patients only. 
8. Venous blood will be drawn for measurement of the tacrolimus C0-h blood levels. 
9. Prior/Concomitant medications / significant non-drug therapies will be recorded. 
10. Patients eligible for the study will be randomized to one of the two treatment groups.  
11. Study drug intake will be performed within 24h. 
12. Information on rejection episodes biopsies, hospitalization, infections, and other (S)AEs 
that occurred since the last visit will be recorded. 


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Treatment phase – Visits 3, 4, 5, 6, 7, and 8 (Day 8, 15, Month 1, 3, 6, 9) 
1. A complete physical examination will be performed at each study visit. 
2. Vital signs will be measured at each study visit. 
3. Returned study medication (everolimus) and returned tacrolimus will be counted. Patient 
will be provided with new study medication (if necessary) and dosing instructions for drug 
intake until following visit. 
4. Venous blood will be drawn for measurement of hematology and biochemistry at each 
study visit.  
5. Venous blood will be drawn at Month 1, 3, 6, and 9 for CMV monitoring (including pp65 
Ag). 
6. Venous blood will be drawn at Month 1, 3, 6, and 9 for HCV monitoring in HCV positive 
patients only: Viral load (RNA level). 
7. Venous blood will be drawn for measurement of the tacrolimus and everolimus C0-h 
blood levels. 
8. Urinalysis will be performed at Month 1, 3, 6 and 9. 
9. Glomerular Filtration Rate (GFR) will be calculated at each study visit. 
10. Changes in Concomitant medications / significant non-drug therapies will be recorded at 
each study visit. 
11. (Changes in) Immunosuppressive medication will be recorded at each study visit. 
12. Information on rejection episodes, biopsies, hospitalization, infections, and other (S)AEs 
that occurred since the last visit will be recorded. 
End of Treatment/End of Study – Visit 9a and Visit 9 (Month 12)  
In case of early discontinuation of study drug treatment, Month 12 assessments need to be 
performed 
- 
as soon as possible after study drug discontinuation (Visit 9a). 
- 
additionally at the originally planned time point, i.e. 12 months post randomization 
(Visit 9). At Month 12 for patients who discontinued study drug prematurely, only the 
following numbers 1, 2, 4, 5, 6, 8, 9, and 13 are mandatory.  
1. A complete physical examination will be performed. 
2. Vital signs will be measured. 
3. Returned study medication (everolimus) and returned tacrolimus will be counted.  
4. Venous blood will be drawn for measurement of hematology and biochemistry. 
5. Venous blood will be drawn for CMV monitoring (including pp65 Ag). 
6. Venous blood will be drawn for HCV monitoring: Viral load (RNA level), in HCV 
positive patients only. 
7. Venous blood will be drawn for measurement of the tacrolimus and everolimus C0-h 
blood levels. 
8. Urinalysis will be performed.  
9. GFR will be calculated. 
10. A control biopsy will be performed for analysis of allograft fibrosis (only HCV positive 
patients). 


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11. End of Study / End of Treatment information will be obtained. 
12. Menopausal status will be recorded and in all women of childbearing potential a 
pregnancy test will be performed (-HCG) (see also section 7.3). 
For patients who prematurely discontinued study drug, information about rejection episodes, 
biopsies, opportunistic infections, malignancies and the current immunosuppression will be 
collected. SAEs will be collected until 30 days after the patient has stopped study 
participation (or longer in case of suspected relationship).  
7.1 
Information to be collected on screening failures 
Only demography data and the reason for failing (screening failure log) are collected for those 
patients who fail to enter the treatment phase. 
7.2 
Patient demographics/other baseline characteristics 
The following demographic data and other baseline characteristics will be recorded: 
 Demography: age, sex, and ethnic origin  
 Relevant medical history / current medical conditions:  
 
Relevant prior diseases and surgeries as well as concomitant diseases will be recorded with 
date of diagnosis / surgery and information on whether it is an active problem.  
For women, the menopausal status will be recorded. The pregnancy test (e.g. -HCG) will 
be performed locally within 7 days prior to visit 1, 2 and 9. Results must be available and 
negative prior to administration of study medication and reported on the CRF. 
7.3 
Transplantation information 
Donor information:  
Viral serology on CMV, EBV, HCV, HBsAg. 
Recipient information:  
Viral serology on CMV, EBV, HCV, HBsAg, underlying liver disease prior to transplantation 
7.4 
Immunosuppressive Drugs/Compliance 
Records of all immunosuppressive drugs (induction therapy, CS, MMF, everolimus, 
tacrolimus) used and dosages administered are to be kept during the study. All changes to the 
medication dosing regimen should be recorded in the Dosage Administration Record CRF, 
along with the reason for change and dates.  
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit.  
 
 
 


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7.5 
Efficacy  
The following efficacy variables will be obtained and recorded: 
Renal function 
Renal function will be assessed by measuring serum creatinine, serum cystatin C by Hoek’s 
formula, and estimated GFR (eGFR) by CKD EPI, by Cystatin C-based Hoek’s formula, 
MDRD-4, Nankivell and Cockcroft-Gault and proteinuria as determined by a spot urine 
protein/creatinine ratio. The evolution of renal function by chronic kidney disease strata 
(CKD) will be evaluated. The incidence of and time to renal replacement therapy will be 
assessed and the incidence of proteinuria at various timepoints will be evaluated. 
 Serum creatinine and serum cystatin C  
For the analysis of serum creatinine and serum cystatin C, venous blood will be drawn and 
analyzed in the center’s local laboratory.   
 Glomerular Filtration Rate (GFR) 
 
The GFR is the best clinical estimate of renal function in health and disease, and correlates 
well with the clinical severity of renal function disturbances. Several studies have shown 
that in patients with progressive renal disease, GFR declines or reciprocal serum creatinine 
and cystatin C levels respectively elevate linearly over time in a predictable manner. 
 
 
With the help of the serum creatinine and cystatin C values respectively, the GFR [ml/min] 
will be calculated via the following formulas: 
 
Nankivell formula 
cGFR will be estimated as 6.7/(SCr × 0.0884) + 0.25 × weight − 0.5 × urea −100/height2 + 
35(25 for women). 
Hoek’s formula 
cGFR will be estimated as -4.32+80.35/cystatin C [mg/L]. 
CKD EPI 
The CKD-EPI equation, expressed as a single equation, is GFR = 141 x min(Scr/ĸ, 1)α x 
max(Scr/ĸ, 1)1.209 x 0.993Age x1.018 [if female] x 1.159 [if black], where Scr is serum 
creatinine, ĸ 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 Scr/ĸ or 1, and max indicates the maximum of Scr/ĸ 
or 1 (Levey et al., 2009). 
Cockroft-Gault 
GFR [mL/min] =[(140-A)*weight/(72*C)]*(0,85 if female), where 
C is the serum concentration of creatinine [mg/dL] and A is age (years). 
MDRD-4 formula 
eGFR [mL/min/1.73m2] = eGFR= 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, otherwise G=1, 
R=1.21 when race is black, otherwise R=1. 
 


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Graft function: 
The incidence of acute rejection episodes, of CMV and HCV infections will be assessed. 
 Acute rejection episodes 
Acute rejection is defined as a clinically suspected acute rejection, whether biopsy-
proven or not, which has been treated and confirmed by the investigator according to 
the response to therapy. Each acute rejection must be recorded on the relevant CRF 
page with the clinical diagnosis specified, and, if a biopsy was performed, with the 
histological diagnosis. 
 Biopsy-proven acute rejection 
Biopsy-proven acute rejection (BPAR) is defined as a clinically suspected acute 
rejection confirmed by biopsy. For all clinically suspected rejection episodes a graft 
biopsy is performed at investigator’s discretion before or within a 24-hour period from 
the initiation of anti-rejection therapy. The local pathologist will grade biopsies. The 
results of the biopsy read by the local pathologist will be listed in the Allograft Biopsy 
CRF page. 
 Graft loss 
The allograft will be presumed to be lost if a patient has a liver retransplant or dies due 
to liver failure. 
The reason for graft loss will be recorded on the Graft Loss CRF page. If graft loss 
occurs after the patient has discontinued study medication prematurely, the graft loss 
will be entered on the Study Completion and Graft Loss CRF page. Graft loss is 
considered a Serious Adverse Event and must be reported. 
 Death 
In the event of patient death, a SAE form including the event leading to death must be 
completed and faxed to Novartis CS&E within 24 hours. The events leading to the 
death must be entered on the AE CRF page and the death must be indicated on the 
Premature Discontinuation and on the Study Completion CRF pages. 
 HCV infection 
The evolution of Hepatitis C (HCV) and the rate of progression of HCV related 
allograft fibrosis will be evaluated. The HCV viral load, the incidence of and response 
to HCV antiviral treatment and the incidence of de novo hepatocellular carcinoma 
(HCC) malignancies and the rate of recurrence of HCC will be assessed. Biopsies will 
be obtained in all patients who are listed as HCV positive by serology testing, at time 
of transplantation and at Month 12. The biopsies will be read by the local pathologist 
(who will remain blinded to patient treatment) according to the Ishak-Knodell scores 
(Ishak 1995) (see Appendix 9).  


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7.6 
Safety 
7.6.1 
Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after start of study drug even if the event is not considered to be 
related to study drug. Medical conditions/diseases present before obtaining informed consent 
have to be documented as medical history and are only considered adverse events if they 
worsen after study start. Abnormal laboratory values or test results constitute adverse events 
only if they induce clinical signs or symptoms, require study drug discontinuation or require 
therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. All adverse events must be recorded on the Adverse Events CRF with the 
following information: 
1. the severity grade (mild, moderate, severe)  
2. its relationship to the study drug (everolimus) and tacrolimus (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 treatment of acute rejection; acute rejections are considered to be a protocol exempted 
event. They should not be reported simply because they result in a hospitalization and 
thus meet the criteria for an SAE. Acute rejections should be reported as SAEs only if 
they are unusual in appearance, clinical course and/or are graft threatening 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 is a graft loss 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 8.1.  


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All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e., further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged, Other immunosuppressant taken/adjusted, concomitant medication 
stopped. The action taken to treat the adverse event should be recorded on the Adverse Event 
CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the informed consent process and the 
study as needed. 
Unusually severe rejection episodes 
Allograft rejection is an expected event in all forms of transplantation and will not be 
considered an SAE even though it may require prolonged hospitalization and medical therapy. 
These events will be reported in the Rejection CRF and no SAE form has to be completed. 
However, if in the opinion of an investigator a rejection episode is unusually severe and 
warrants specific notification, then an SAE form must be completed and submitted according 
to SAE reporting procedures outlined in Section 8.1. In this particular case, information needs 
also to be reported in the Adverse Event CRF. 
Infections 
All infection episodes must be recorded on the Infection CRF; they should not be collected on 
the AE CRF. Infections should be listed with severity, relationship, sample site, genus and 
species of microorganism specified, start and end dates, action taken.  
CMV infection: Information will be captured on laboratory-defined CMV (antigenemia-
positive, PCR positive), CMV syndrome (fever for the last 2 days, neutropenia, leukopenia, 
viral syndrome) and CMV-disease (organ involvement), on the CMV-specific CRF. CMV and 
HCV viral load (HCV positive patients only) will be measured locally at baseline, month 1, 3, 
6, 12, for evaluation of incidence and severity. Suspected CMV infections will be recorded on 
the Infection CRF and on the CMV-specific CRF-field during visits. CMV infections will be 
also assessed by donor/recipient constellation (D+R+ / D-R- / D+R- / D-R+). 
HCV infection: HCV information will be recorded on the Infection CRF. HCV viral load 
(HCV positive patients only) will be measured locally at baseline, month 1, 3, 6, 12, for 
evaluation of incidence and severity. HCV genotype will be assessed locally at baseline (HCV 
positive patients only).  
 


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7.6.2 
Physical examination 
Information about the physical examination must be present in the source documentation at 
the study site. 
Any clinically significant conditions that are present prior to the start of study drug intake 
must be recorded on the Relevant Medical History/Current Medical Conditions pages of the 
CRF. 
All new conditions found after start of the study drug intake which meet the definition of an 
Adverse Event must be recorded on the Adverse Event part in the CRF. 
7.6.3 
Vital signs 
Height will be recorded at Screening visit (Visit 1) only. Vital signs will be recorded at every 
study visit, and include radial pulse rate, systolic and diastolic blood pressure and weight (kg). 
Blood pressure and pulse rate will be assessed after the patient has rested in the sitting 
position for at least five minutes; blood pressure should be assessed at the same arm each time 
of determination. 
7.6.4 
Laboratory evaluations 
The center’s local laboratory will be used to analyze the clinical laboratory data during the 
study.  
The following variables will be examined: 
Hematology:  
 hemoglobin, leukocytes (including differential blood count and 
absolute neutrophil count), platelet count, hematokrit (HK) 
Blood chemistry:  
creatinine, urea/BUN, sodium, potassium, calcium, ALAT, ASAT,  
 protein, AP, albumin, CRP, phosphate, magnesium, CPK, total 
bilirubin, glucose (fasting), cystatin C, Hb1c, LDH 
Lipid profile:  
total cholesterol, HDL, LDL, triglycerides 
Viral serology: 
Hepatitis B (HBsAg¸ only at Screening), HCV,  
 
 
 
 
 
CMV (including pp65 Ag) 
Urinalysis:  
 
creatinine, protein, albumin  
 
Viral serology  
All patients will be tested for Hepatitis B (HBsAg), HCV, CMV at Screening, earlier tests  6 
months are acceptable. Any HIV positive patients will be excluded. If results are not available 
at Baseline, the patient may be included. However, an assessment has to be performed 
immediately. If results of a newly initiated assessment will be positive, the patient will 
subsequently be dropped from the study and administered the standard care provided by the 
center. 
New onset diabetes mellitus (NODM) 
The incidence of NODM will be assessed from Day 30 post-transplantation. NODM post-
transplantation, in patients without diabetic history, is defined by any of the following: 


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 Two consecutive fasting plasma glucose levels ≥ 126 mg/dL (7.0 mmol/L) post-
transplantation (> 30 days). 
 HbA1c ≥ 6.5 % from Day 75 onward. 
 Diabetes mellitus (DM) reported as an adverse event that is prevalent after Day 30. 
 Any concomitant medication with ATC level 2 code “A10” drugs used in diabetes, if 
prevalent after Day 30 and used for more than 30 days. 
Non-diabetic patients, identified at the time of transplantation by all the following: 
 DM or diabetic related terms were not included in medical history. 
 Glucose (random) < 11 mmol/L at the time of transplantation. 
 HbA1c < 6.5 % at the time of transplantation. 
In addition, incidence of patients that are pre-diabetic will be assessed using an HbA1c range 
of 5.7 to 6.4%. 
Pregnancy and assessments of fertility 
All women of childbearing potential will have a urine or serum pregnancy test (β-HCG) 
during pre-study/baseline/EOS evaluations and during the course of the study only, if 
clinically indicated. 
Additional blood samples 
Additional blood samples (unscheduled visits) can be scheduled for everolimus and 
tacrolimus trough levels determination at investigator’s discretion. 
 
7.7 
Tolerability/acceptability 
Tolerability of study medication can be assessed from the rate of patients who withdraw 
prematurely from study medication or in whom study medication had to be converted to 
another immunosuppressive regimen due to abnormal laboratory results, adverse events, or 
toxicity.  
 
All changes to the immunosuppressive medication dosing regimen will be recorded on the 
Dosage Administration Record CRF, along with the reason for change.  
7.8 
Resource utilization  
Not applicable 
7.9 
Health-related Quality of Life 
None 
7.10 
Pharmacomonitoring 
Everolimus C0-h whole blood levels will be measured only in patients included into ARM I 
(=investigational arm), tacrolimus C0-h whole blood levels will be measured in all patients 
included into ARM I (=investigational arm) and Arm II (control arm).  


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 Everolimus whole blood tests 
Analysis of the everolimus whole blood levels will be performed locally at the center 
during all visits throughout the study, starting on day 1 (Visit 2). Whole blood level for 
everolimus will be assessed as per local practice on blood taken within 5 minutes prior to 
everolimus administration (C-0h level). 
 Tacrolimus whole blood tests 
Analysis of the tacrolimus whole blood levels will be performed locally at the center 
during all visits throughout the study, starting on day 1 (Visit 2). Whole blood level for 
tacrolimus will be assessed by liquid chromatography coupled with mass spectrometry 
(LCMS). Values derived from enzyme based assays will be corrected (as described in the 
manufacturer’s instructions). 
7.11 
Pharmacogenetics/pharmacogenomics 
None.  


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8 
Safety monitoring 
8.1 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation must be reported to Novartis within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the German 
Novartis Drug Safety & Epidemiology Department. The telephone and telefax number of the 
contact persons in the local department of Drug Safety & Epidemiology, 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 is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.  
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 Novartis study drug, a Drug Safety & 
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 drug that this 
SAE has been reported. 
8.2 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours 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 
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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the German Novartis Drug Safety & Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
drug in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
8.3 
Data Monitoring Board 
An external and independent Data Safety Monitoring Board (DSMB) will be instituted before 
study start. The DSMB will review safety-related issues in a meeting and will be entitled to 
make recommendations for changes in study conduct. Details on the function of the DSMB 
and the frequency of the DSMB meetings will be laid out in a separate DSMB Charter.  
9 
Data review and database management 
9.1 
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 patient 
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 drug 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs, which will be documented as being the source 
data. The investigator must also keep the original informed consent form signed by the patient 
(a signed copy or a second original is given to the patient). 
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 the recording of data that will be used for all primary and safety 
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 patients will be disclosed. 
9.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 3-part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 


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required corrections or additions. The CRFs are forwarded to Data Management by field 
monitors, one copy being retained at the investigational site. Once the CRFs are received by 
Data Management, their receipt is recorded and they are reviewed prior to data entry.  
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research Organization 
staff following their own internal standard operating procedures that have been reviewed and 
approved by Novartis. Subsequently, the entered data are systematically checked by Data 
Management staff, using error messages printed from validation programs and database 
listings. Obvious errors are corrected by Data Management personnel. Other errors or 
omissions are entered on Data Query Forms, which are returned to the investigational site for 
resolution. The signed original and resolved Data Query Forms are kept with the CRFs at the 
investigator site, and a copy is sent to Novartis so the resolutions can be entered into the 
database. Quality control audits of all key safety and efficacy data in the database are made 
prior to locking the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
At the conclusion of the study the occurrence of any protocol violations 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 by joint 
written agreement between the Trial Statistician and Statistical Reporting and the Clinical 
Trial Leader. 
10 
Data analysis 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator(s) should be submitted to Novartis before 
publication or presentation. The final analysis will be done when all patients have completed 
their Visit 9 (Month 12) assessment or discontinued prematurely. It is planned that the data 
from all centers that participate in this protocol will be used, so that an adequate number of 
patients will be available for analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and pharmacokinetic 
measurements. All summary statistics will be presented by treatment group. Categorical 
variables will be summarized by absolute and relative frequencies. Continuous variables will 
be summarized by descriptive statistics of the number of valid and missing observations, 
mean, standard deviation, minimum, median and maximum. Time-to-event data including 
rates of affected patients will be assessed by Kaplan-Meier statistics. Group comparisons will 
be performed using appropriate two-sided statistical tests. 
10.1 
Populations for analysis 
The Full Analysis Set (FAS) will consist of all patients as randomized that received at least 
one dose of study drug and have a valid baseline assessment of the primary efficacy variable. 


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Following the intent-to-treat principle, patients will be analyzed according to the treatment 
they were assigned to at randomization. 
The Per-protocol Set (PP) will consist of a subset of patients of the FAS who did not show 
major deviations from the protocol procedures that may have an impact on the study outcome. 
Reasons for exclusion of the Per-protocol Set may be (but are not limited to): deviations from 
entry criteria, errors in treatment assignment, use of excluded/forbidden/un-allowed 
medication, premature discontinuation of randomized treatment or study, poor compliance, 
loss to follow-up, missing data in the primary efficacy variable. Criteria that are assumed to 
have such an impact will be defined in the Protocol Deviations Module of the Validation and 
Planning (VAP) documentation, and assessed before database lock during the data review 
meeting. 
The Safety Set will consist of all patients that received at least one dose of study drug and had 
at least one post-baseline safety assessment. Patients will be analyzed according to treatment 
received. Of note, the statement that a patient had no adverse events also constitutes a safety 
assessment. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline characteristics will be summarized for the full analysis set 
(FAS) by treatment group. Baseline characteristics include prior medication, past/current 
medical conditions and transplant history. 
Medical history will be coded using MedDRA and will be presented by MedDRA system 
organ class, preferred term and treatment group. Separate tables will be provided for past 
medical conditions and current medical conditions. Prior medication will be coded according 
to the WHO Drug Reference List and summarized by ATC class, preferred term and treatment 
group. 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
10.3.1 
Study medication 
Duration (days) of drug exposure to each individual component of the immunosuppressive 
treatment regimen will be summarized using descriptive statistics. Duration of drug exposure 
will be calculated as the difference between the last and first day of drug application +1. 
Dosage averages will be calculated including and excluding zero doses for periods of 
temporary interruption of treatment regardless of whether this was due to safety reasons or 
patients’ non-compliance. Daily dose levels will be summarized descriptively. Frequencies of 
the number of patients with any dose reduction (including temporary dose interruption) as 
well as the number of dose reductions by reason will be given. These analyses will be 
performed by treatment group for the safety set. 
Frequency tables displaying cumulative frequencies of ‘crude rates’ will be presented for the 
number of patients with trough levels below/within/above the defined therapeutic windows 
drug and by visit. If appropriate, treatment groups will be compared exploratory using the 
Pearson’s Chi-Square test (where all expected numbers are at least 1), otherwise Fisher’s 
exact test will be used (Campbell 2007). Furthermore, frequency tables for the number of 


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patients with trough levels below/within/above the defined therapeutic windows drug and by 
period. 
10.3.2 
Concomitant therapy  
Prior and concomitant medications and non-drug therapies will be coded according to WHO-
DRL. Concomitant medications taken through the study will be summarized by preferred 
term, ATC class and treatment group for the safety set. Dosages of corticosteroids will be 
converted to prednisolone dose equivalents and summarized as described above. 
10.4 
Analysis of the primary objective(s) 
The primary objective of the trial is to demonstrate that an immunosuppressive regimen based 
on everolimus (EVR) in co-exposure with tacrolimus (TAC) has superior efficacy compared 
to tacrolimus alone on estimated glomerular filtration rate (MDRD-4 formula) at 12 months 
after transplantation in de novo liver transplant recipients. 
10.4.1 
Variable 
The primary efficacy variable of this trial is the renal function at Month 12 after baseline 
assessed by estimated GFR based on recalculated values according to the MDRD-4 formula: 
eGFR [mL/min/1.73m2] = eGFR= 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, 
therwise G=1, R=1.21 when race is black, otherwise R=1. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The trial tests the null hypothesis that the treatment difference (investigational minus control) 
in mean eGFR at Month 12 after baseline is zero versus the alternative hypothesis that the 
treatment difference is different from zero. 
The hypotheses will be tested with an analysis of covariance (ANCOVA) with treatment , 
center, HCV-Class (positive, negative) and MELD (<=30 vs >30) as factors, and eGFR at 
Visit 1 (Baseline) as covariate. Raw as well as adjusted means (= LS-means, LS: least square 
means) will be presented for the treatment contrast together with a two-sided p value and the 
appropriate confidence interval, respectively. The significance level will be 5% (two-sided). 
There are no multiplicity issues to be addressed since only the hypothesis of superior efficacy 
of the investigational vs. the control regimen will be tested confirmatority. 
The Full Analysis Set will be used for the primary analysis. If patients of the FAS are 
switched from the reference to the investigational group during the study, they will be 
analyzed in their randomized group. If appropriate, a subgroup analysis will be performed 
comparing patients of the reference group with and without switch to the investigational 
group including a further analysis comparing the subgroups to the randomized investigational 
group. If treatment will be modified in the investigational group, they will be analyzed as 
randomized. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Missing values in cGFR will be imputed with the last valid observed value from that patient 
(LOCF). Under the assumption that the eGFR will remain fairly stable in the control group 
but will probably improve in the investigational group, this strategy corresponds to a 


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conservative estimate of the treatment effect. Alternative missing value procedures may be 
performed additionally as sensitivity analyses (see below).dealt with by multiple imputation 
(Molenberghs & Kenward 2007; White, Royston & Wood 2010). The multiple imputation 
procedure will be presented in detail (e.g. seed value, method for imputation) in the statistical 
analysis plan to be finalized before database lock. 
10.4.4 
Supportive analyses 
For sensitivity, the following analyses will be performed: 
The primary analysis will be repeated with the Per-protocol Set using the same 
ANCOVA model as described above. 
As a further supportive analysis, a Mixed Model for Repeated Measures (MMRM) will be 
fitted using treatment group, visit (as a categorical time variable) and subject as categorical 
variables (Molenberghs & Kenward 2007). Assuming that the time profile is not the same in 
the two treatment groups, a full visit-by-treatment interaction will be used. If a baseline is to 
be included in the model, the baseline-by-time interaction will be included in the model, 
otherwise strange and unrealistic restrictions on the implied covariance structure would be 
made in this case. An unstructured covariance matrix will be used. Since there are sufficient 
data, using a different covariance matrix in each treatment group might be considered: 
 
proc mixed; 
class subject visit treatment; 
model gfr = baseline treatment visit baseline*visit treatment*visit / s ddfm=kr; 
repeated time / subject = subject type = un group=treatment; 
run; 
The estimated adjusted treatment effect as well as the treatment contrast will be presented for 
the Month 12 visit together with appropriate two-sided 95% confidence intervals. The model 
will be fitted for both, the FAS as well as the PP set. 
Only in case of substantial drop-out (>20%) or if relevant differences in the drop-out-patterns 
between the two treatment groups are observed, a multiple imputation of missing values 
(Molenberghs & Kenward 2007; White, Royston & Wood 2010) will be performed as an 
alternative to account for missing values. The necessity of this procedure will be decided 
during the data review meeting, computational details (e.g. seed value, method for imputation)  
will be described in the statistical analysis plan to be finalized before database lock. 
 
The course of eGFR will be summarized descriptively by visit and treatment group for the 
FAS. Only observed cases will be used (no data imputed by multiple imputation, since 
multiple imputation implies the creation of more than one imputed value per patient). 
Absolute and percent changes from baseline to each post-baseline measure will be calculated 
by treatment group for each study visit as post-baseline minus baseline value. Between-group 
as well as within-group comparisons will be performed exploratory using suitable parametric 
(t-test/paired t-test) and nonparametric (Wilcoxon rank-sum test/Wilcoxon signed-rank test) 
statistical tests for paired and two-sample data, respectively. 


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10.5 
Analysis of secondary objectives 
10.5.1 
Efficacy (secondary) 
The following secondary efficacy variables will be analyzed in an explorative manner for the 
full analysis set (FAS): 
 efficacy-related endpoints, such as acute rejection, treated biopsy proven acute 
rejection (BPAR), graft loss, death and loss to follow-up (as composites or individual 
endpoints) 
 endpoints related to renal function: eGFR using various methods (MDRD-4, 
Nankivell, Cockcroft-Gault, CKD EPI and Hoek formulae 
Efficacy-related objectives 
The incidence of efficacy-related endpoints will be estimated using the Kaplan-Meier method. 
The number of events as well as the number of censored observations will be presented. 
Kaplan-Meier estimates will be presented by visit up to Month 12. Percentiles (25%, median, 
75%) of the event time distribution will be presented together with their two-sided 95% 
confidence interval. The two groups will be compared using the log-rank test. Kaplan-Meier 
curves will be displayed graphically. For rejections, Kaplan-Meier analyses may be stratified 
by severity grade. 
The following endpoints will be analyzed: 
 Incidence of a composite of treated biopsy proven acute rejection (BPAR), graft loss 
or death at Month 12. 
 Incidence of a composite of treated BPAR, graft loss, death or loss to follow-up. 
 Incidence of a composite of death or graft loss. 
 Incidence of acute rejection, treated acute rejection, BPAR, treated BPAR, graft loss, 
or death 
Renal function-related objectives 
Renal function as assessed by cGFR calculated according to the CKD-EPI, Cockcroft-Gault, 
Nankivell, MDRD-4, and Hoek formulas (see Section 7.5) will be analyzed using the 
ANCOVA model specified for the primary analysis. Raw as well as adjusted means will be 
presented for the treatment contrast together with its confidence interval and two-sided 
exploratory p values separately for each time point. Missing values will be dealt with in the 
ANCOVA analysis by multiple imputation. Additionally to the analysis at Month 12, an 
analysis at Month 6 will be performed. 
Descriptive statistics for observed values and changes from baseline as well as within-group 
and between-group comparisons using suitable parametric and non-parametric statistical tests 
will be displayed by visit and treatment group. Additionally, descriptive statistics will be 
presented for the following subgroups: 
 age: <60 vs. ≥60 years 
 gender: male vs. female 
 renal function at baseline: 30 – <45, 45 – <60, ≥60 mL/min/1.73m²; <45 vs 
≥45 mL/min/1.73m², <60 vs. ≥60 mL/min/1.73m² 
 HCV status at baseline: positive vs. negative 


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 lab MELD score at baseline: ≤14, 15 – 19, 20 – 24, 25 – 29, ≥30 
Serum creatinine as well as the urinary protein/creatinine ratio will be summarized using 
descriptive statistics for observed values and changes from baseline. Within-group and 
between-group comparisons will be performed using suitable parametric and non-parametric 
statistical tests and will be displayed by visit and treatment group. 
The incidence of patients experiencing a decline in eGFR of <10, 10 –  <15, 15 – <20, 20 – 
<25, and ≥25 mL/min/1.73m2 from baseline will be analyzed using frequency tables by visit 
and treatment group. Treatment groups will be compared exploratory using the Pearson’s 
Chi-Square test (where all expected numbers are at least 1), otherwise Fisher’s exact test will 
be used. 
The incidence of proteinuria of 0.5 – <1.0 g/day, 1.0 – <3.0 g/day and ≥3.0 g/day will be 
analyzed using frequency tables by visit and treatment group. Treatment groups will be 
compared exploratory using the Pearson’s Chi-Square test (where all expected numbers are at 
least 1), otherwise Fisher’s exact test will be used. 
10.5.2 
Safety 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) will be considered as appropriate. Adverse 
events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in each body system 
and having each individual adverse event. Any other information collected (e.g. severity 
(CTCAE) or relatedness to study medication) will be listed as appropriate. 
Adverse events/infections 
Data collected by AE CRFs and by Infection CRFs will be coded using MedDRA. The 
number of AE/patients with AE will be summarized by MedDRA system organ class and 
preferred term. Additionally, AE will be summarized by maximum severity, and for AE with 
suspected drug relation, serious AE (SAE), and AE leading to permanent discontinuation of 
study drug. In addition to being analyzed together with AE data, the incidence of bacterial, 
viral and fungal infections will be tabulated separately for all infections, by maximum 
severity, for infections with suspected drug relation, serious infections and infections leading 
to premature discontinuation of study drug. These summary tables will include adverse events 
of special interest, such as New Onset of Diabetes Mellitus (NODM, for definition see Section 
7.6.4), de novo HCC malignancies, HCV- and HCC-related fibrosis. 
All information pertaining to AE noted during the study will be listed by treatment group and 
patient, detailing the verbatim term given by the investigator, MedDRA preferred term and 
system organ class, start/end dates, severity, seriousness, relationship to study drug and action 
taken. The AE onset will also be shown relative (in number of days) to the date of initial dose. 
AE starting before, or 28 or more days after the discontinuation of study medication, will not 
be considered as treatment-emergent and will not be included in AE/infection summary tables 
but listed only. 


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Laboratory data 
Abnormalities according notable criteria (see Appendix 2) will be identified. The proportions 
of patients with clinically notable abnormalities according to the notable criteria will be 
summarized. Shifts from baseline value to worst post-baseline value based on the normal 
ranges will be presented graphically (Amit et al., 2008). The worst observation is defined as 
the highest or lowest measure during the different observations periods whereby high or low 
are chosen according to the direction of abnormality. Descriptive statistics of absolute values 
as well as change from baseline of all laboratory variables will be presented by visit and 
treatment group. A by-patient listing of all clinically notable abnormal laboratory data will be 
generated. Only assessments obtained up to 28 days after the discontinuation of study 
medication will be considered “on-treatment” and analyzed with relationship to 
immunosuppressive therapy. 
10.5.3 
Tolerability 
Tolerability of the study drug will be assessed from the rate of patients who withdraw 
prematurely from study drug or in whom study drug had to be converted to another 
immunosuppressive regimen due to abnormal laboratory results or adverse events. The 
frequency distribution of these reasons will be presented and compared between the 
treatments. 
10.5.4 
Resource utilization 
Not applicable. No resource utilization data will be generated. 
10.5.5 
Health-related Quality of Life 
Not applicable. No health-related quality of life data will be generated. 
10.5.6 
Pharmacokinetics 
Everolimus C0-h whole blood levels will be summarized by visit using descriptive statistics. 
Tacrolimus C0-h whole blood levels will be summarized by visit and treatment group using 
descriptive statistics. 
10.5.7 
Pharmacogenetics/pharmacogenomics 
Not applicable. No pharmacogenetic/pharmacogenomic data will be generated. 
10.5.8 
Biomarkers  
HCV viral load (HCV-ribonucleic acid (RNA) levels overall and by genotype) will be 
summarized descriptively by visit and treatment group. 
 
The number of patients with deviations from the therapeutic window will be counted and 
tabulated separately by visit and in total. 
10.5.9 
PK/PD 
Not applicable. No PK/PD data will be generated. 


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10.6 
Interim analysis 
Not applicable. No interim analysis is planned for this trial. 
10.7 
Sample size calculation 
The trial tests the null hypothesis that there is no difference in renal function, estimated by 
cGFR according to the MDRD-4 formula, at 12 months after randomization between the 
everolimus-based tacrolimus-minimization regimen and the tacrolimus-based control regimen 
versus the alternative hypothesis that the difference is 7.0 ml/min/1.73m2. A sample size of 
105 in each group will have 80% power to detect a difference in means of 7.0 ml/min/1.73m2 
assuming that the common standard deviation is 18.0 ml/min/1.73m2  with a 5% two-sided 
significance level. (One will decide in favor of H1 when the difference in means would be 
5.1 ml/min/1.73m2  or greater in favor of the everolimus-based group.) To adjust the sample 
size for a common drop-out rate (DOR) of 20% (using the fomula Nadj=N/(1-DOR)²), 165 
patients need to be randomized per group. Sample sizes were estimated using NQuery 
(Version 6.1) procedure “Two-group t-test for equal means (equal n’s)”. 
10.8 
Power for analysis of critical secondary variables 
Not applicable. Power for the analysis of critical secondary variables was not investigated. 
11 
Discussion and rationale for study design features 
The evaluation of the efficacy and safety of an immunosuppressive regimen in liver transplant 
recipients is best investigated using a randomized control trial, as opposed to observational 
studies where confounding by indication cannot be fully accounted for by  adjusting by 
multivariate procedures for differences in confounders that are imbalanced at the time of 
transplantation. This protocol will not utilize procedures to blind investigators or subjects to 
treatment assignment. The duration of experience of liver transplant physicians with 
tacrolimus indicates that optimizing the safety of this medication requires the physician to be 
aware of the use of tacrolimus and to the trough levels. This open label study, however, does 
include prospective collection of assessments that relate to potential issues that may be 
impacted by an open label design, e.g. management of tacrolimus levels above or below target 
ranges. Importantly, the occurrence of the primary endpoints of this study are objectively 
measured – renal function by laboratory data, and death or graft survival. 
The choice of the control arm for this study is based upon the predominance of tacrolimus use 
in liver transplantation worldwide in combination with corticosteroids, which are eliminated 
sometime after the first several months post-transplantation. As opposed to renal 
transplantation where triple or quadruple therapy is standard, adjunctive therapy with MMF is 
not pervasive and tends to be used short-term to allow a slow increase in the tacrolimus level 
while renal function recovers. The present study requires the discontinuation of MMF prior to 
randomization so that the control group is reflective of a regimen that has an approved liver 
transplant indication. 
 


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12 
References  
1. Adam R, Mc Master P, O’Grady JG et al. Evolution of liver transplantation in Europe: 
Report of the European liver transplant registry. Liver Transplantation 2003; 9:1231-43. 
2. Amit O, Heiberger RM, Lane PW: Graphical approaches to the analysis of safety data 
from clinical trials. Pharmaceut Statist (2008); 7: 20 – 35 
3. Banff Schema for Grading Liver Allograft Rejection: An International Consensus 
Document. Hepatology 1997;25(3):658-63. 
4. Bland JM, Altman DG: Statistical methods for assessing agreement between two methods 
of clinical measurement. Lancet. (1986); 8;1(8476):307 – 310. 
5. Chertow, Burdick E, Honour M, Bonventre JV,Bates DW. Acute kidney injury, mortality, 
length of stay and costs in hospitalized patients (2005), J Am Soc Nephrol. (2005);16 
(11):3365-3370. 
6. Cohen AJ, Stegall MD, Rosen CB et al. Chronic renal dysfunction late after liver 
transplantation. Liver Tranplantation 2002; 8:916-21. 
7. Frizell E, Abraham A, Doolittle M et al. FK506 enhances fibrogenesis in in vitro and in 
vivo models of liver fibrosis in rats.. Gastroenterology; 107(2):492-8. 
8. Gonwa TA, Mai ML, Melton LB et al. End-stage renal disease (ESRD) after orthotopic 
liver transplantation (OLTx) using calcineurin-based immunotherapy. Transplantation 
2001; 72:1934-39. 
9. Hoek FJ, Kemperman FAW and Krediet R: A comparison between cystatin C, plasma 
creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration 
rate. Nephrol Dial Transplant (2003) 18: 2024 – 2031. 
10. Humar et al., Reactivation of viruses in solid organ transplant patients receiving 
cytomegalovirus prophylaxis. American Journal of Transplantation (2006); 6: 262–274 
11. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration). A New Equation to Estimate Glomerular Filtration Rate. 
Ann Intern Med (2009) 150(9):604-12. 
12. Mehta, Kellum,Shah,Molitoris, Ronco,Warnock,Levin and the Acute Kidney Injury 
Network (2007) 11(2):1-8 
13. Molenberghs G, Kenward MG: Missing data in clinical studies. (2007) Chichester: John 
Wiley. 
14. Moreno JM, Cuervas-Mons V, Rubio E et al. Chronic renal dysfunction after liver 
transplantation in adult patients: prevalence, risk factors, and impact on mortality. 
Transplantation Proceedings 2003;35:1907-8. 
15. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after transplantation of a nonrenal 
organ. New England Journal of Medicine 2003;349:931-40. 
16. Pawarode A, Fine DM and Thuluwath PJ. Independent risk factors and natural history of 
renal dysfunction in liver transplant recipients. Liver Transplantation 2003;9:741-7. 


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17. Rothenburger M, Teerling E, Bruch C, Lehmkuhl H, Suwelack B, Bara C, Wichter T, 
Hinder F, Schmid C, Stypmann J. Calcineurin inhibitor-free immunosuppression using 
everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up. J 
Heart Lung Transplant. (2007); 26 (3):250-257. 
18. Velidedeoglu E, Crawford MD, Desai NM et al. Predictors of late kidney dysfunction 
post-liver transplantation. Transplantation Proceedings 2002;34:3315-16. 
19. Verrill C, Davies J, Millward-Sadler H et al. Organotypic liver culture in a fluid-air 
interface using slices of neonatal rat and adult human tissue – a model of fibrosis in vitro. 
J Pharmacol Toxicol Methods (2002); 48(2):103-10. 
20. Zhu J, Wu J, Frizell E et al. Rapamycin inhibits hepatic stellate cell proliferation in vitro 
and limits fibrogenesis in an in vivo model of liver fibrosis. Gastroenterology (1999); 
117(5):1198-204. 
21. Campbell I: Chi-squared and Fisher–Irwin tests of two-by-two tables with small sample 
recommendations. Statist. Med. 2007 (26): 3661-3675 
22. White IR, Royston P, Wood AM: Multiple imputation using chained equations: Issues and 
guidance for practice. Statist. Med. 2011 (30): 377-399 
 


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13 
Appendicies 
13.1 
Appendix 1: Administrative procedures 
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.  
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Approval letters concerning protocol and 
informed consent will be filed by Novartis. 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/REBs, 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. 
Informed consent   
Eligible patients may only be included in the study after providing written, IRB/IEC/REB-
approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents.   
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/REB, and a 
copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval. 
Amendments to the protocol 
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/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB 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 patient included in this study, even if this action represents a deviation from the 


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protocol.  In such cases, Novartis should be notified of this action and the IRB/IEC/REB at 
the study site should be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical trial agreement. 
Study drug supply and resupply, storage, and tracking 
Study drugs 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 
designated assistants have access. Upon receipt, all study drugs should be stored according to 
the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. 
Medication labels will be in and comply with the legal requirements of Germany. They will 
include storage conditions for the drug, but no information about the patient except for the 
randomization number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the field monitor during site visits and at the completion of the trial. Patients will be asked to 
return all unused study drug and packaging at the end of the study or at the time of study drug 
discontinuation.  
At the conclusion of the study and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.2 
Appendix 2: Clinically notable laboratory values and vital signs 
 
Laboratory variable 
Standard units 
SI units 
Liver function and related variables 
SGOT (AST) 
3  ULN 
3  ULN 
SGPT (ALT) 
3  ULN 
3  ULN 
Bilirubin 
3  ULN 
3  ULN 
Renal function, metabolic and electrolyte variables 
Urea 
None 
None 
Creatinine 
Day 8 or after: 
>30% above value from 
preceding visit 
or 
Day 8 to Wk 4:  4 mg/dL, 
After Wk 4:       3 mg/dL 
Day 8 or after: 
>30% above value from preceding 
visit 
or 
Day 8 to Wk 4:  354 µmol/L, 
After Wk 4:       265 µmol/L 
Uric acid 
M 12 mg/dL 
F 9 mg/dL 
M 714 µmol/L 
F 535 µmol/L 
Glucose 
<45 mg/dL 
>250 mg/dL 
<2.5 mmol/L 
>13.9 mmol/L 
Cholesterol 
350 mg/dL 
9.1 mmol/L 
Triglycerides 
750mg/dL 
8.5 mmol/L 
CPK (MB) 
None 
None 
Potassium 
3.0 mEq/L 
6.0 mEq/L 
3 mmol/L 
6 mmol/L 
Calcium 
6mg/dL 
13mg/dL 
1.5mmol/L 
3.2mmol/L 
Hematology variables 
Hemoglobin 
<7 g/dL 
<4.39 mmol/L 
Platelets 
(thrombocytes) 
<50 k/mm3 
700 k/mm3 
<50  109/L 
700 109/L 
Leukocytes 
(WBCs) 
2.0 k/mm3 
16 k/mm3 
2.0  109/L 
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  
 
Harmonized notable vital signs (and weight) 
Vital sign variables 
Notable criteria 
Pulse (beats/min.) 
None 
Systolic BP (mm/Hg) 
Either an increase of 30 that results in 180 or >200(mm/Hg) 
or 
Either a decrease of 30 that results in 90 or <75 (mm/Hg) 
Diastolic BP (mm/Hg) 
Either an increase of 20 that results in 105 or >115 (mm/Hg) 
or 
Either a decrease of 20 that results in 50 or <40 (mm/Hg) 
Weight (Kg) 
None 


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13.3 
Appendix 3: Possible drug interactions 
During treatment with immunosuppressive agents such as everolimus and tacrolimus 
vaccination may be less effective. The use of live vaccines should be avoided. 
 
Possible Everolimus Drug Interactions 
Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal 
wall and is a substrate for the multi-drug efflux pump, P-glycoprotein. Therefore, absorption 
and subsequent elimination of systemically absorbed everolimus may be influenced by 
medicinal products that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with 
strong 3A4-inhibitors and inducers is not recommended. See also drugs known to interact 
with tacrolimus (see Appendix 4). Grapefruit and grapefruit juice have the potential to affect 
the metabolism of drugs metabolized by CYP450 enzymes. Caution should be used in patients 
being administered everolimus. 
 
Drugs not allowed 
 
Sirolimus 
Patients to be discontinued from 
everolimus if these immunosuppressive 
drugs are given 
Terfenadine 
Astemizole 
Cisapride 
 
Inhibitors of P-450 (CYP), in particular 
CYP3A (as everolimus) have the 
potential to increase the exposure to 
these drugs, resulting in prolongation of 
QT intervals on ECGs 
Rifampicin 
Rifabutin 
Strong inducers of P-450 (CYP) have the 
potential to decrease the exposure of 
everolimus 
Clarithromycin 
Telithromycin 
Ritonavir 
Strong inhibitors of P-450 (CYP) have 
the potential to increase the exposure of 
everolimus 
 
Itraconazole** 
Voriconazole** 
Fluconazole** 
Ketoconazole** 
Strong inhibitors of P-450 (CYP) have 
the potential to increase the exposure of 
everolimus 
Cerivastatin 
Rosuvastatin 
Insufficient data available to make 
recommendations regarding concomitant 
use of the newer statins and everolimus 
Lovastatin* 
Simvastatin* 
Confirmed interaction between these 
drugs and drugs which are CYP3A 
substrates and/or inhibitors 
Drugs strongly discouraged 
 
Quinidine 
Fluoxetine 
Paroxetine 
Potential interaction of everolimus with 
CYP 2D6 substrates 
 
Drugs necessitating close 
monitoring 
 
Digoxin 
Potential interaction with everolimus has 
not been evaluated, patients on digoxin 
should have periodic measurements of 
digoxin levels 
*Patients requiring treatment with this class of medication should be monitored closely for 
signs of rhabdomyolysis, such as, dark-colored urine, fever, muscle cramps, pain, spasm, or 
stiffness, unusual tiredness or weakness. 


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**Concomitant administration of everolimus and these drugs necessitates close monitoring of 
everolimus levels. Fluconazole may pose the smallest risk for drug drug-interaction. 
 


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13.4 
Appendix 4: Tacrolimus drug interactions 
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. 
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 
 
Diltiazem 
nicardipine 
nifedipine 
verapamil 
clotrimazole 
fluconazole 
itraconazole 
ketoconazole** 
voriconazole 
clarithromycin 
erythromycin 
troleandomycin 
Gastrointestinal Prokinetic 
Agents 
Other Drugs 
 
Cisapride 
metoclopramide 
bromocriptine 
chloramphenicol 
cimetidine 
Cyclosporin A 
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). 


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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.  
*Drugs that may decrease Tacrolimus blood concentrations  
Anticonvulsants 
Antimicrobials  
 
carbamazepine  
phenobarbital  
phenytoin 
rifabutin  
caspofungin  
rifampin  
 
 
Herbal Preparations 
Other Drugs  
 
St. John’s Wort 
sirolimus  
 
*This table is not all inclusive.  
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. Based 
on a clinical study of 5 liver transplant recipients, co-administration of Tacrolimus with 
nelfinavir increased blood concentrations of Tacrolimus significantly and, as a result, a 
reduction in the Tacrolimus dose by an average of 16-fold was needed to maintain mean 
trough Tacrolimus blood concentrations of 9.7 ng/mL. Thus, frequent monitoring of 
Tacrolimus blood concentrations and appropriate dosage adjustments are essential when 


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nelfinavir is used concomitantly. 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).  
Following co-administration of Tacrolimus and sirolimus (2 or 5 mg/day) in stable renal 
transplant patients, mean Tacrolimus AUC0-12 and Cmin decreased approximately by 30% 
relative to Tacrolimus alone. Mean Tacrolimus AUC0-12 and Cmin following co-
administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively. 
The safety and efficacy of Tacrolimus used in combination with sirolimus for the prevention 
of graft rejection has not been established and is not recommended.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.5 
Appendix 5: Guidelines for everolimus dose reduction 
 
An investigator may interrupt temporarily or reduce the dosage of everolimus, if in his/her 
opinion this is clinically warranted, in response to any causally associated AE (e.g., 
neutropenia, thrombocytopenia, leukocytopenia, hyperlipidemia, hypertriglyceridemia). The 
following guidelines should be followed: 
 
1- PLATELETS 
 
Platelet count < 75,000/mm3 
 
Step 1: dose reduction should be considered and the first dose reduction may be instituted at 
the discretion of the Investigator. 
 
Step 2: if the platelet count remains below 75,000/mm3 despite the initial dose reduction, a 
further dose reduction may be implemented per the table below. 
 
Platelet count < 50,000/mm3 Dose interruption should be considered. 
Platelet count < 30,000/mm3 Dose interruption will be mandatory. 
 
If the platelet count returns to 50,000/mm3 for 3 days, everolimus may be restarted at lowest 
reduced dose. If the platelet count is stable at the reduced dose for 3 days, everolimus may be 
increased to the next higher dose. If the platelet count remains stable at greater than 
75,000/mm3 for 7 days, the full dose of everolimus may be restarted. 
 
2- HEMOGLOBIN 
 
Hemoglobin < 8 g/dL 
 
Step 1: dose reduction should be considered and the first dose reduction may be instituted at 
the discretion of the Investigator. 
 
Step 2: if the hemoglobin remains below 8 g/dL despite the initial dose reduction, a 
further dose reduction may be implemented per the table below. 
 
Hemoglobin < 6 mg/dL: dose interruption will be mandatory. 
Once hemoglobin returns to > 6 mg/dL for 3 days, everolimus may be restarted at the lowest 
(one 
tablet b.i.d) level. If the hemoglobin is stable at the reduced dose for 3 days, everolimus may 
be increased to the next higher dose. Once hemoglobin returns to levels > 8 mg/dL for 7 days, 
everolimus may be increased to the full dose. 
 
 
3- WHITE BLOOD CELLS 
WBC < 3,000/mm3 
Step 1: dose reduction should be considered and the first dose reduction may be instituted at 
the discretion of the Investigator. 


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Step 2: if the white count remains below 3,000/mm3 despite the initial dose reduction, a 
further dose reduction may be implemented per the table below. 
 
WBC < 1,500/mm3: dose interruption will be mandatory. 
Once WBC returns to 1,500/mm3 for 3 days, everolimus may be restarted at the lowest (one 
tablet b.i.d) level. If the WBC is stable at the reduced dose for 3 days, everolimus may be 
increased to the next higher dose. Once WBC returns to levels > 3,000/mm3 for 7 days, 
everolimus may be increased to the full dose. 
 
4- CHOLESTEROL 
 
Cholesterol > 300 mg/dL or > 8 mmol/L: 
Dietary instruction is strongly recommended and statin therapy, e.g. fluvastatin, should be 
considered. 
 
If the abnormality persists, the dosing of everolimus will be adjusted as follows: 
 
Cholesterol > 300 mg/dL or > 8 mmol/L: Dose reduction should be considered. 
Cholesterol > 350 mg/dL or > 9 mmol/L: Everolimus should be interrupted. 
 
5- TRIGLYCERIDES 
Triglycerides > 575 mg/dL or > 6.5 mmol/L: Dietary instruction is strongly recommended and 
statin therapy should be considered. 
 
If the abnormality persists, the dosing of everolimus will be adjusted as follows: 
 
Triglycerides > 575 mg/dL or > 6.5 mmol/L: Dose reduction should be considered. 
Triglycerides > 750 mg/dL or > 8.5 mmol/L: everolimus should be interrupted.  
Everolimus dose reduction 
 
Platelet count 
(/mm3) 
Hemoglobin 
(g/dL) 
WBC count 
(/mm3) 
Cholesterol 
(mmol/L) 
Triglycerides 
(mmol/L) 
Dose reduction 
<75,000 
<8 
<3000 
> 8 
>6.5 
Interruption 
<30,000 
<6 
<1500 
>9 
>8.5 
 
An investigator may interrupt temporarily or reduce, the dosage of the investigational drug 
(everolimus), if in his/her opinion this is clinically warranted. 
 
Dose reduction steps 
It is recommended to reduce the dosing from by one dosing step e.g. from 0.75 mg bid to 0.5 
mg bid . The dosing should, however, always follow a bid schedule. 


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13.6 
Appendix 6:  Grading of acute liver allograft rejection 
 
Rejection Activity Index (RAI) 
Criteria which can be used to score liver allograft biopsies with acute rejection, as defined by 
the World Gastroenterology Consensus Document. 
Category 
Criteria 
Score 
Portal 
inflammation 
Mostly lymphocytic inflammation involving, but not 
noticeably expanding, a minority of the triads 
1 
Expansion of most or all of the triads, by a mixed infiltrate 
containing lymphocytes with occasional blasts, neutrophils 
and eosinophils 
2 
Marked expansion of most or all of the triads by a mixed 
infiltrate containing numerous blast and eosinophils with 
inflammatory spillover into the periportal parenchyma 
3 
Bile duct 
inflammation / 
damage 
A minority of the ducts are cuffed and infiltrated by 
inflammatory cells and show only mild reactive changes 
such as increased nuclear: cytoplasmic ratio of the epithelial 
cells 
1 
Most or all of the ducts infiltrated by inflammatory cells.  
More than an occasional duct shows degenerative changes 
such as nuclear pleomorphism, disordered polarity and 
cytoplasmic vacuolization of the epithelium 
2 
As above for 2, with most or all of the duct showing 
degenerative changes or focal lumenal disruption 
3 
Venous endothelial 
inflammation 
Subendothelial lymphocytic infiltration involving some, but 
not a majority of the portal and/or hepatic venules 
1 
Subendothelial infiltration involving most or all of the portal 
and/or hepatic venules 
2 
As above for 2, with moderate or severe perivenular 
inflammation that extends into the perivenular parenchyma 
and is associated with perivenular hepatocyte necrosis 
3 
Total RAI Score =  /9 
Reference: Banff Schema for Grading Liver Allograft Rejection: An International Consensus 
Document. Hepatology 1997;25(3):658-63. 
 
 
 
 
 
 
 
 


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 Grading of acute liver allograft rejection 
Global assessment of rejection grade made on a review of the biopsy and after the diagnosis 
of rejection has been established 
Global assessment* 
Criteria 
Indeterminate 
Portal inflammatory infiltrate that fails to meet the criteria for the 
diagnosis of acute rejection (see reference below) 
Mild 
Rejection infiltrate in a minority of the triads that is generally mild 
and confined within the portal spaces 
Moderate 
Rejection infiltrate expanding most or all of the triads 
Severe 
As above for moderate with spillover into periportal areas and 
moderate to severe perivenular inflammation that extends into the 
hepatic parenchyma and is associated with perivenular hepatocyte 
necrosis 
*Verbal description of mild, moderate or severe acute rejection could also be labeled as Grade 
1, 11, and 111, respectively. 
Reference: Banff Schema for Grading Liver Allograft Rejection: An International Consensus 
Document. Hepatology 1997;25(3):658-63. 
 


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13.7 
Appendix 7: Definitions of CMV disease in solid organ transplant 
recipients 
 
 
 
Humar et al.,2006 
 


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13.8 
Appendix 8: Milan Criteria 
 
The United Network of Organ Sharing (UNOS) decided to prioritize allocation of organs to 
those HCC patients who met the tumor criteria recognized in the Milan experience to have the 
best outcomes (TNM = T2N0). The Milan criteria are based on tumor burden and limit 
prioritization for OLT to those who have either a single tumor under 5 cm or those with 3 or 
less tumors each under 3 cm, without evidence of metastatic disease or vascular invasion. The 
Milan criteria provide a simple means of selecting patients with HCC for transplantation who 
are at low risk (˜10%) for recurrence. 
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. (1996) Liver 
transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. 
N Engl J Med;334:693–699. 
Shetty K, Timmins K, Brensinger C, Furth EE, Rattan S, Sun W, Rosen M, Soulen M, Shaked 
A, Reddy KR, Olthoff KM. (2004) Liver transplantation for hepatocellular carcinoma 
validation of present selection criteria in predicting outcome. Liver Transpl;10(7):919-21. 
 
 
 


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13.9 
Appendix 9: Histological grading and staging of chronic hepatitis 
– Ishak-Knodell  
 
 
 


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SAP_001.pdf: 
Clinical Development 
RAD001 (Everolimus) 
CRAD001HDE13 / NCT01551212
A 12 month, multi-center, open-label, randomized, 
controlled study to evaluate efficacy/safety and evolution 
of renal function of everolimus in co-exposure with 
tacrolimus in de novo liver transplant recipients 
The Hephaistos Study 
Statistical Analysis Plan (SAP) 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
06NOV2017 
Number of pages: 
24 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
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SAP, Final version 1.0 
 
CRAD001HDE13 
 
Signature Page 
CRAD001HDE13 
 
 
 
 
_________________________ 
____________ 
(Clinical Trial Leader)  
Signature 
 
 
 
Date 
 
 
  
 
_________________________ 
____________ 
(Trial Statistican) 
 
Signature 
 
 
 
Date 
 
 
   
 
_________________________ 
____________ 
(CRO Statistican) 
 
Signature 
 
 
 
Date 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and 
title impacted 
(Current) 
06NOV2017 Pior 
to 
DB lock 
- 
N/A - First version 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP, Final version 1.0 
 
CRAD001HDE13 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets ............................................................................................................ 7 
2.2.1 
Subgroup of interest ................................................................................ 7 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 10 
2.3.1 
Patient disposition ................................................................................. 10 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 11 
2.4.1 
Study treatment / compliance ................................................................ 11 
2.4.2 
Prior, concomitant and post therapies ................................................... 11 
2.5 
Analysis of the primary objective .......................................................................... 11 
2.5.1 
Primary endpoint ................................................................................... 11 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.5.4 
Supportive analyses ............................................................................... 12 
2.6 
Analysis of the key secondary objective ............................................................... 13 
2.6.1 
Key secondary endpoint ........................................................................ 13 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 13 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 13 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 13 
2.7.1 
Secondary endpoints ............................................................................. 13 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.8 
Safety analyses....................................................................................................... 14 
2.8.1 
Adverse events (AEs) ............................................................................ 14 
2.8.2 
Deaths .................................................................................................... 15 
2.8.3 
Laboratory data ..................................................................................... 15 
2.8.4 
Other safety data ................................................................................... 16 
2.9 
Pharmacokinetic endpoints .................................................................................... 16 


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2.10 
PD and PK/PD analyses ........................................................................................ 16 
2.11 
Patient-reported outcomes ..................................................................................... 16 
2.12 
Biomarkers ............................................................................................................. 16 
2.13 
Other Exploratory analyses.................................................................................... 17 
2.14 
Interim analysis ...................................................................................................... 17 
3 
Sample size calculation ..................................................................................................... 17 
4 
Change to protocol specified analyses .............................................................................. 17 
5 
Appendix ........................................................................................................................... 17 
5.1 
Imputation rules ..................................................................................................... 19 
5.1.1 
Study drug ............................................................................................. 19 
5.1.2 
AE date imputation ............................................................................... 19 
5.1.3 
Concomitant medication date imputation ............................................. 19 
5.2 
AEs coding/grading ............................................................................................... 20 
5.3 
Laboratory parameters derivations ........................................................................ 20 
5.4 
Statistical models ................................................................................................... 20 
5.4.1 
Primary analysis .................................................................................... 20 
5.4.2 
Key secondary analysis ......................................................................... 20 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 24 
6 
Reference ........................................................................................................................... 24 


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List of abbreviations 
AE 
Adverse event 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Transaminase 
BPAR 
Biopsy Proven Acute Rejection 
CKD-EPI 
Chronic Kidney Disease – Epidemiology Collaboration 
CMV 
Cytomegalovirus 
CRO 
Contract Research Organizsation 
DSMB 
Data Safety Monitoring Board 
DOR 
Drop-Out Rate 
FAS 
Full Analysis Set 
eGFR 
Estimated Glomerular Filtration Rate 
EVR 
Everolimus 
gamma GT 
Gamma Glutamyltransferase 
GFR 
Glomerular Filtration Rate 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
LCMS 
Liquid Chromatography coupled with Mass Spectrometry 
LTx 
Liver Transplantation 
LOCF 
Last Observation Carried Forward 
MDRD-4 
Modification of Diet in Renal Disease, 4-variable version 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MELD 
Model of End Stage Liver Disease 
MMRM 
Mixed Model for Repeated Measures 
PCP 
Pneumocystis Carinii Pneumonia 
PPS 
Per-Protocol Set 
RAP 
Report and Analysis Process 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TAC 
Tacrilimus 
TFLs 
Tables, Figures, Listings 
ULN 
Uper Limit Normal Range 
VAP 
Vaöidation Analysis Plan 
WHO 
World Health Organization 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. 
 
1.1 
Study design 
This study was designed to provide data on efficacy and safety of a post-transplantation 
regimen in liver allograft patients consisting of reduced tacrolimus in the presence of 
everolimus. 
This is a 12-month, multi-center, open-label, randomized, controlled study to evaluate 
efficacy and safety and evolution of renal function of everolimus (EVR) in co-exposure with 
tacrolimus (TAC) in de novo liver transplant recipients. 
The trial tests the null hypothesis that there was no difference in renal function, estimated by 
eGFR according to the MDRD-4 formula, at 12 months after randomization between the 
everolimus-based tacrolimus-minimization regimen and the tacrolimus-based control regimen 
versus the alternative hypothesis that the difference is 7.0 ml/min/1.73m2. A sample size of 
105 in each group has 80% power to detect a difference in means of 7.0 ml/min/1.73m2 
assuming that the common standard deviation was 18.0 ml/min/1.73m2 with a 5% two-sided 
significance level. (One will decide in favor of H1 when the difference in means would be 5.1 
ml/min/1.73m2 or greater in favor of the everolimus-based group.) To adjust the sample size 
for a common drop-out rate (DOR) of 20% (using the fomula Nadj=N/(1-DOR)²), 165 
patients need to be randomized per group. Sample sizes were estimated using NQuery 
(Version 6.1) procedure “Two-group t-test for equal means (equal n’s)”. 
At Baseline (Visit 2) between 7 and 21 days post LTx patients were assigned to one of the 
following two treatment groups in a ratio of 1:1. 
 EVR/TAC group (ARM I): 
Everolimus (C0-h: 3-8 ng/mL*) + tacrolimus (C0-h: < 5 ng/mL*) 
 TAC group (ARM II):  
Tacrolimus (C0-h: 6-10 ng/ml*) 
*Trough levels as per local practice, e.g. liquid chromatography coupled with mass 
spectrometry (LCMS). Values derived from enzyme based assays were corrected (as 
described in the manufacturer’s instructions). 
No interim analysis was planned and performed. 
An independent Data Safety Monitoring Board (DSMB) was instituted before study start. The 
DSMB reviewed safety-related issues in a meeting and were entitled to make 
recommendations for changes in study conduct. Details on the function of the DSMB and the 
frequency of the DSMB meetings was laid out in a separate DSMB Charter. 


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1.2 
Analysis sets 
The Full Analysis Set (FAS) consists of all patients as randomized that received at least one 
dose of study drug. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
they were assigned to at randomization. 
The Per-protocol Set (PPS) consist of a subset of patients of the FAS who did not show 
major deviations from the protocol procedures that may have an impact on the study outcome. 
Reasons for exclusion of the Per-protocol Set may be (but are not limited to): deviations from 
entry criteria, errors in treatment assignment, use of excluded/forbidden/un-allowed 
medication, premature discontinuation of randomized treatment or study, poor compliance, 
loss to follow-up, missing data in the primary efficacy variable. Criteria that are assumed to 
have such an impact will be defined in the Protocol Deviations Module of the Validation and 
Planning (VAP) documentation, and assessed before database lock during the data review 
meeting. 
The Safety Set will consist of all patients that received at least one dose of study drug and had 
at least one post-baseline safety assessment. Patients will be analyzed according to treatment 
received. Of note, the statement that a patient had no adverse events also constitutes a safety 
assessment. 
1.3 
Study objectives and endpoints 
The primary objective was toTo demonstrate that an immunosuppressive regimen based on 
everolimus (EVR) in co-exposure with tacrolimus (TAC) has superior efficacy compared to 
tacrolimus alone on estimated glomerular filtration rate (MDRD-4 formula) at Month 12 in de 
novo liver transplant recipients. 
The key secondary objective was to evaluate the incidence of a composite of treated biopsy 
proven acute rejection (BPAR), graft loss or death until Month 12. 
Other efficacy related secondary objectives were 
 To evaluate the incidence of a composite of treated BPAR, graft loss, death or loss to 
follow-up at months 6 and 12. 
 To evaluate the incidence of each component of the composite efficacy endpoint at 
month at months 6 and 12. 
 To evaluate the incidence of a composite of death or graft loss at months 6 and 12. 
 To evaluate treated BPAR by: (1) incidence, (2) time to event, (3) severity, (4) final 
clinical diagnosis and outcome. 
 To evaluate any acute rejection by: (1) incidence, (2) time to event, (3) severity(4) 
final clinical outcome outcome. 
 To evaluate the incidence of: 
• 
Treated acute rejection. 
• 
BPAR. 


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• 
Treated BPAR 
Other renal function related related secondary objectives were 
 To evaluate the evolution of post-randomization renal function over time assessed by 
the change in estimated GFR (MDRD-4), including to Months 6, and 12. 
 To evaluate renal function by eGFR using various methods (MDRD-4, Nankivell, 
Cockcroft-Gault, CKD-EPI and Hoek formulae). 
 To evaluate the incidence of patients experiencing a decline in eGFR (MDRD-4) of < 
10, 10<15, 15<20, 20<25, and ≥ 25 mL/min/1.73m2 from Screening, Week 2 post 
transplantation (Day 15) and randomization to Months 6, and 12. 
 To evaluate serum creatinine at various time points. 
 To evaluate renal function and change in eGFR from screening, randomization, and 
Week 2 post transplantation (Day 15) to Months 6 and 12 eGFR in following 
subgroups: age (< 60 and ≥ 60 years), gender, race, renal function strata (< 30, 30<45, 
45<60, ≥ 60 mL/min/1.73m2, below/above 45 mL/min/1.73m2, below/above 60 
mL/min/1.73m2), HCV status, lab MELD score categories (≤14, 15-19, 20-24, 25-29, 
≥ 30), and diagnosis leading to transplantation. 
 To evaluate urinary protein/creatinine ratio at various time points. 
 To evaluate the incidence of proteinuria. as adverse event of special interest. 
 To evaluate the incidence of and time to renal replacement therapy as concomitant 
therapy of special interest. 
Safety related secondary objectives were 
 To evaluate the incidence of Adverse Events (AEs)/Infections/Serious Adverse Events 
(SAEs). 
 To evaluate the incidence of treatment-related side effects, including incidence of new 
onset diabetes mellitus (NODM), evolution of metabolic parameters as subdivisions of 
serum/plasma lipid panel, neurotoxicity and hypertension. 
 To evaluate the incidence and reason (e.g. AE) of premature discontinuation of study 
medication and premature discontinuation from the study. 
 To evaluate the incidence and reason (e.g. AE) of interruption and dose adjustment of 
study medication. 
Virus (HCV, CMV) and Hepatocellular Carcinoma (HCC) related secondary objectives were 
 To evaluate the incidence of HCV and HCV related fibrosis. 
 To evaluate HCV viral load (HCV- messenger ribonucleic acid (mRNA) levels overall 
and by genotype). 
 To evaluate incidence of and response to HCV antiviral treatment. 


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 To evaluate the rate of recurrence of HCC at 12 post-transplantation in patients with a 
diagnosis of HCC at the time of liver transplantation adjusting for various risk factors, 
such as number of tumor nodules, total tumor size and tumor metastasis. 
 To evaluate the incidence of de novo HCC malignancies. (adverse event of special 
interest) 
 • Incidence and severity of CMV viral infections. 
1.3.1 
Subgroup of interest 
For the analysis of the primary anylsis the following fixed factors were included in model: 
• 
HCV-(IgG), measured at screening in viral serology: positive vs. negative  
• 
Lab MELD, measured at screening: <=30 vs >30 
Descriptive statistitics for  
Descriptive statistics for the primary efficacy variable were presented for the following 
subgroups: 
 •age: <60 vs. ≥60 years 
 •gender: male vs. female 
 •renal function at baseline: 30 – <45, 45 – <60, ≥60 mL/min/1.73m²;  
 •renal function at baseline: <45 vs ≥45 mL/min/1.73m², 
 •renal function at baseline <60 vs. ≥60 mL/min/1.73m² 
 HCV status at baseline: positive vs. negative 
 lab MELD score at baseline: ≤14, 15 – 19, 20 – 24, 25 – 29, ≥30 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The data were analyzed by 
. Any data analysis carried out 
independently by the investigator(s) was submitted to Novartis before publication or 
presentation. The final analysis was done when all patients have completed their Visit 9 
(Month 12) assessment or discontinued prematurely. The data from all centers that participate 
in this protocol was used, so that an adequate number of patients will be available for analysis. 
Data were summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and pharmacokinetic 
measurements. All summary statistics were presented by treatment group. Categorical 
variables were summarized by absolute and relative frequencies. Continuous variables were 
summarized by descriptive statistics of the number of valid observations, mean, standard 
deviation, minimum, median and maximum. Time-to-event data including rates of affected 


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patients were assessed by Kaplan-Meier statistics. Group comparisons were performed using 
appropriate two-sided statistical tests. 
Analysis was carried out using the SAS (Statistial Analysis System) software, version 9.2, 
2009, SAS Institute Inc., Cary, North Carolina, USA. 
2.1.1 
General definitions  
Study treatment: 
 EVR/TAC  
 TAC  
Date of randomization: Date of Visit 2 (Baseline) 
Date of first treatment: max (date of randomization, min (start date of dosage administration*)) 
Date of last treatment: Max (max(end date of dosage administration*), Last known date 
subject took study treatment~) 
*: documented on Dosage Administration Record form 
~: documented on End of Treatment form 
 
2.2 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline characteristics were summarized for the full analysis set 
(FAS) by treatment group. Baseline characteristics include prior medication, past/current 
medical conditions and transplant history. 
Medical history was coded using MedDRA and was presented by MedDRA system organ 
class, preferred term and treatment group. Separate tables were provided for past medical 
conditions and current medical conditions. Prior medication was coded according to the WHO 
Drug Reference List and summarized by ATC class, preferred term and treatment group. 
2.2.1 
Patient disposition 
Patient disposition was summarized for all patients by absolut and relative frequencies of 
patients completing the study phases screening, randomization,treatment and study 
completion. Reasons for discontinuation of screening, treatment and study were shown by 
treatment for all patients (screening) resp  and the randomized set (treatment and study).  
The number of patients per analysis set was summarized by treatment. 
Protocol violations were reported descriptively by treatment.  
 


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2.3 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.3.1 
Study treatment / compliance 
Duration (days) of drug exposure to each individual component of the immunosuppressive 
treatment regimen was summarized using descriptive statistics. Duration of drug exposure 
was calculated as the difference between the last and first day of drug application +1. Dosage 
averages were calculated including and excluding zero doses for periods of temporary 
interruption of treatment regardless of whether this was due to safety reasons or patients’ non-
compliance. Daily dose levels were summarized descriptively. Frequencies of the number of 
patients with any dose reduction (including temporary dose interruption) as well as the 
number of dose reductions by reason were given. These analyses were performed by treatment 
group for the safety set. 
Frequency tables displaying cumulative frequencies of ‘crude rates’ will be presented for the 
number of patients with trough levels below/within/above the defined therapeutic windows 
drug and by visit.  
2.3.2 
Prior, concomitant and post therapies 
Prior and concomitant medications and non-drug therapies were coded according to WHO-
DRL. Concomitant medications taken through the study were summarized by preferred term, 
ATC class and treatment group for the safety set. Prior medication are defined as medication, 
which started 1 or more days before randomization. Concomitant medication are mediation, 
which were treated on at least one in the time interval randomization and last day of study 
treatement 
Corticosteroids will be displayed using prednisone equivalent body weighted adjusted doses. 
Analysis of the primary objective 
2.3.3 
Primary endpoint 
The primary objective of the trial was to demonstrate that an immunosuppressive regimen 
based on everolimus (EVR) in co-exposure with tacrolimus (TAC) has superior efficacy 
compared to tacrolimus alone on estimated glomerular filtration rate (MDRD-4 formula) at 12 
months after transplantation in de novo liver transplant recipients. 
The primary efficacy variable of this trial is the renal function at Month 12 after baseline 
assessed by estimated GFR based on recalculated values according to the MDRD-4 formula: 
eGFR [mL/min/1.73m2] = eGFR= 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, therwise G=1, R=1.21 when race is black, otherwise R=1. 
 
 


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2.3.4 
Statistical hypothesis, model, and method of analysis 
 
The trial tests the null hypothesis that the treatment difference (investigational minus control) in 
mean eGFR at Month 12 after baseline is zero versus the alternative hypothesis that the treatment 
difference was different from zero.  
The hypotheses was tested with an analysis of covariance (ANCOVA) with treatment , center, 
HCV-Class (positive, negative) and lab MELD (<=30 vs >30) as factors, and eGFR at Visit 2 
(Baseline) as covariate. Raw as well as adjusted means (= LS-means, LS: least square means) 
were presented for the treatment contrast together with a two-sided p value and the appropriate 
confidence interval, respectively. The significance level was 5% (two-sided). There are no 
multiplicity issues to be addressed since only the hypothesis of superior efficacy of the 
investigational vs. the control regimen was tested confirmatoritly.  
The Full Analysis Set was used for the primary analysis. Patients will be analyzed in their 
randomized group. 
2.3.5 
Handling of missing values/censoring/discontinuations 
Missing values in eGFR will be imputed with the last valid observed value from that patient 
(LOCF). Under the assumption that the eGFR will remain fairly stable in the control group 
but will probably improve in the investigational group, this strategy corresponds to a 
conservative estimate of the treatment effect.  
As sensitivity analyses a multiple imputation (Molenberghs & Kenward 2007; White, Royston 
& Wood 2010) will be performed. The specification for the multiple imputation procedure are 
presented in appendix 5.5.2. 
2.3.6 
Supportive analyses 
For sensitivity, the following analyses will be performed: 
The primary analysis will be repeated with the Per-protocol Set using the same ANCOVA 
model as described above. 
As a further supportive analysis, a Mixed Model for Repeated Measures (MMRM) will be 
fitted using treatment group, visit (as a categorical time variable) and subject as categorical 
variables (Molenberghs & Kenward 2007). Assuming that the time profile is not the same in 
the two treatment groups, a full visit-by-treatment interaction will be used. Baseline and the 
baseline-by-time interaction will be included in the model. An unstructured covariance matrix 
will be used. 
The estimated adjusted treatment effect as well as the treatment contrast will be presented for 
the Month 12 visit together with appropriate two-sided 95% confidence intervals. The model 
will be fitted for the FAS. 
Because there are less than 20 % study discontinuations in the study no multiple imputation of 
missing values (Molenberghs & Kenward 2007; White, Royston & Wood 2010) was 
performed as an alternative to account for missing values.  
The course of eGFR was  summarized descriptively by visit and treatment group for the FAS. 
Absolute and percent changes from baseline to each post-baseline measure were calculated by 


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treatment group for each study visit as post-baseline minus baseline value. Between-group as 
well as within-group comparisons will be performed exploratory using suitable parametric (t-
test/paired t-test). 
2.4 
Analysis of the key secondary objective 
2.4.1 
Key secondary endpoint 
The key secondary endpoint was the composite of treated biopsy proven acute rejection 
(BPAR), graft loss or death at Month 12. 
2.4.2 
Statistical hypothesis, model, and method of analysis 
The incidence of the composite of treated biopsy proven acute rejection (BPAR), graft loss or 
death until Month 12 was estimated using the Kaplan-Meier method. 
The number of events as well as the number of censored observations will be presented. 
Kaplan-Meier estimates will be presented by quarter up to Month 12. Percentiles (25%, 
median, 75%) of the event time distribution will be presented together with their two-sided 95% 
confidence interval. The two groups were compared using the log-rank test. Kaplan-Meier 
curve was displayed graphically.  
2.4.3 
Handling of missing values/censoring/discontinuations 
If no event occurred until Month 12 or End of Study the observation period will be censored 
at Month 12 (day 360 or at end of study) 
2.5 
Analysis of secondary efficacy objective(s) 
2.5.1 
Secondary endpoints 
The following secondary efficacy variables were analyzed in an explorative manner for the 
full analysis set (FAS): 
 efficacy-related endpoints, such as acute rejection, treated biopsy proven acute 
rejection (BPAR), graft loss, death and loss to follow-up (as composites or individual 
endpoints) 
 endpoints related to renal function: eGFR using various methods (Nankivell, 
Cockcroft-Gault, CKD EPI and Hoek formulae 
Efficacy-related objectives 
The following endpoints until Month 12 were analyzed: 
 acute rejection,  
 treated acute rejection,  
 BPAR,  
 treated BPAR,  
 graft loss, 


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 death 
 composite of treated biopsy proven acute rejection (BPAR), graft loss or death.  
 composite of treated BPAR, graft loss, death or loss to follow-up 
 composite of graft loss or death. 
Renal function-related objectives 
Renal function as assessed by eGFR calculated according to the CKD-EPI, Cockcroft-Gault, 
Nankivell, and Hoek formulas were the futher renal function-related secondary paramerter. 
Further parameter was the proteinuria. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Efficacy-related objectives 
The incidence of efficacy-related endpoints was estimated using the Kaplan-Meier method. 
The number of events as well as the number of censored observations was presented. Kaplan-
Meier estimates were presented by quarter up to Month 12. Percentiles (25%, median, 75%) 
of the event time distribution were presented together with their two-sided 95% confidence 
interval. The two groups will be compared using the log-rank test. Kaplan-Meier curves were 
displayed graphically 
The number of max. severity by patient was reported by frequency tables. 
Renal function-related objectives 
Renal function were analyzed using the ANCOVA model specified for the primary analysis. 
Raw as well as adjusted means were presented for the treatment contrast together with its 
confidence interval and two-sided exploratory p values separately for each time point.  
Additionally to the analysis at Month 12, an analysis at Month 6 (included eGFR calculated 
by MDRD-4 formula) was performed. 
The incidence of proteinuria was analyzed using frequency tables by treatment group as 
adverse of special interest.  
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing values will be dealt with in the ANCOVA analysis by LOCF-method.  
2.6 
Safety analyses 
The assessment of safety was based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data were 
considered as appropriate. 
2.6.1 
Adverse events (AEs) 
Treatment emergent events are defined as all adverse events started at baseline or later. 
Treatment emergent adverse events were summarized by presenting, for each treatment group, 
the number and percentage of patients having any adverse event, having an adverse event in 


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each body system and having each individual adverse event. Any other information collected 
(e.g. severity or relatedness to study medication) were listed as appropriate. 
Data collected by AE CRFs and by Infection CRFs were coded using MedDRA. The number 
of AE/patients with AE was summarized by MedDRA system organ class and preferred term. 
Additionally, AE will be summarized  
 by maximum severity,  
 for AE with suspected drug relation,  
 for serious AE (SAE), and  
 for AE leading to permanent discontinuation of study drug.  
In addition to being analyzed together with AE data, the incidence of bacterial, viral and 
fungal infections will be tabulated separately for all infections  
 by maximum severity,  
 for infections with suspected drug relation,  
 for serious infections and  
 for infections leading to premature discontinuation of study drug. 
Infections were defined as adverse events as adverse events in primary system organ class 
“Infections and infestations”. 
2.6.1.1 
Adverse events of special interest / grouping of AEs 
Adverse of special interst were 
 New onset of diabetes mellitus,  
 de novo HCC malignancies,  
 HCV- and HCV-related fibrosis 
 Proteinuria 
 CMV viral infections     
For the subgroup of patients with HbA1c baseline range of 5.7 to 6.4%, the onset of diabetes 
will be calculated additional. 
2.6.2 
Deaths 
Adverse events leading to death will be listed by treatment group. 
2.6.3 
Laboratory data 
Abnormalities according notable criteria (see Appendix 2 of the study prototocol) were 
identified. The proportions of patients with clinically notable abnormalities according to the 
notable criteria were summarized. Descriptive statistics of absolute values as well as change 
from baseline of all laboratory variables were presented by visit and treatment group. A by-


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patient listing of all clinically notable abnormal laboratory data was generated. Only 
assessments obtained up to 28 days after the discontinuation of study medication will be 
considered “on-treatment” and analyzed with relationship to immunosuppressive therapy. 
2.6.4 
Other safety data 
2.6.4.1 
ECG and cardiac imaging data 
Not applicable 
2.6.4.2 
Vital signs 
Vital signs were recorded at every study visit, and included  
• 
Radial pulse rate (bpm) 
• 
Systolic blood pressure (mmHg) 
• 
Diastolic blood pressure (mmHg) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
Abnormalities according notable criteria (see Appendix 2 of the study protocol) were 
identified. The proportions of patients with clinically notable abnormalities according to the 
notable criteria were summarized. Descriptive statistics of absolute values as well as change 
from baseline of all vital signs variables were presented by visit and treatment group. Only 
assessments obtained up to 28 days after the discontinuation of study medication was 
considered “on-treatment” and analyzed with relationship to immunosuppressive therapy. 
2.7 
Pharmacokinetic endpoints   
Everolimus C0-h whole blood levels were summarized by visit using descriptive statistics. 
Tacrolimus C0-h whole blood levels were summarized by visit and treatment group using 
descriptive statistics.  
Trough levels of everolimus and tacrolimus, respectively, were summarized descriptively by 
visit. The number of patients with deviations from the therapeutic window (see Section 4 of 
the protocol) were counted and tabulated separately by visit and in total. 
2.8 
PD and PK/PD analyses 
Not applicable 
2.9 
Patient-reported outcomes 
Not applicable 
2.10 
Biomarkers 
HCV viral load (HCV-ribonucleic acid (RNA) levels overall and by genotype) was 
summarized descriptively by visit and treatment group. 


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2.11 
Other Exploratory analyses 
Not applicable  
2.12 
Interim analysis 
An external and independent Data Safety Monitoring Board (DSMB) was instituted before study 
start. The DSMB reviewed safety-related issues in a meeting and was entitled to make 
recommendations for changes in study conduct. 
3 
Sample size calculation 
The trial tests the null hypothesis that there was no difference in renal function, estimated by 
eGFR according to the MDRD-4 formula, at 12 months after randomization between the 
everolimus-based tacrolimus-minimization regimen and the tacrolimus-based control regimen 
versus the alternative hypothesis that the difference is 7.0 ml/min/1.73m2. A sample size of 
105 in each group will have 80% power to detect a difference in means of 7.0 ml/min/1.73m2 
assuming that the common standard deviation was 18.0 ml/min/1.73m2 with a 5% two-sided 
significance level. (One will decide in favor of H1 when the difference in means would be 5.1 
ml/min/1.73m2 or greater in favor of the everolimus-based group.) To adjust the sample size 
for a common drop-out rate (DOR) of 20% (using the fomula Nadj=N/(1-DOR)²), 165 
patients need to be randomized per group. Sample sizes were estimated using NQuery 
(Version 6.1) procedure “Two-group t-test for equal means (equal n’s)”. 
Power for the analysis of secondary variables was not investigated. 
4 
Change to protocol specified analyses 
The study protocol was amended 5 times, the original protocol and all amendments are 
provided in Appendix 16.1.1. Previous sections of this report describe the study conduct as 
amended. The key features of each amendment are given below: 
Amendment 1 (20-Jan2012), before generation of CRF and inclusion of first, introduced the 
following changes: 
 Assesment schedule: Laboratory and GFR were shifted from Screening visit to baseline 
visit 
 Additional assessment in Screening visit: Menopausal status and in all women of 
childbearing potential a pregnancy test 
Amendment 2 (26-Sep-2012), 15 patient had been randomized to the study. The major 
changes that were made to the protocol were as follows: 
 Measurement of the Tacrolimus C-0h levels can now be performed as per local practice. 
 Inclusion criteria – randomization 2 was rephrased for a clearer understanding. 


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 Inclusion criteria – randomization 3: AST and ALT levels were raised to ≤5 times ULN, 
evaluation of gamma GT was deleted due to the fact that it does not reflect a 
prognostically important mark. 
 For a better understanding, exclusion criteria – randomization 2 was separated in 4 
independent criteria. Platelet, neutrophil and white blood cell count was reduced to 
50,000/mm3, 1,000/mm3 and 2,000/mm3 respectively 
 Former inclusion criteria – randomization 2 (now 6): Calculation mistake of concentration 
of hypertriglyceridemia was corrected. 
 Graft loss was added as reason for premature patient withdrawal. 
 Dispensing of study drug and instruction for use of study drug are described in more detail 
to avoid misuse. 
 According to the adaptation of in- and exclusion criteria, the permission of study drug 
adjustment and interruption in case of inability of tolerance of the protocol-specific dosing 
scheme is described in more detail. 
 PCP prophylaxis and treatment of oral candida will be performed according to local 
practice.  
 It was added, that pregnancy outcomes must be collected for the female partners of any 
males who took study drug in this study 
These amendments were not considered to have affected the interpretation of study results as 
they were minor. 
 
Amendment 3 (14-JUN2013): 57 patients had been randomized to the study: 
Five sub-studies which will be conducted in selected centers were added to the protocol. 
In addition some editorial changes were performed. 
 
Amendment 4 (19-NOV-2014): 186 patients had been randomized to the study: 
The protocol had been refined to clarify the mandatory usage of corticosteroids in this study. 
Additionally, Inclusion Criterion 3/Exclusion Criterion 11 had been adjusted to include total 
abstinence as acceptable contraception method. 
 
Amendment 5 (19-AUG-2015): 259 patients had been randomized to the study: 
The purpose of this amendment was to adapt one exclusion criteria (Excl.Crit.N°5) to better 
align with given clinical praxis and patients’ condition post liver transplantation. 
Therefore Exclusion Criterion 5 (at randomization) had been adjusted to allow inclusion of 
patients with hemoglobin < 6.0 g/dL (transfusion of erythrocytes concentrate during or after 
transplantation are allowed according to investigator discretion). 
 
Changes in statistical methods in compoarison to the protocol: 
The Virus (HCV, CMV) and Hepatocellular Carcinoma (HCC) related secondary objective “•
 
To evaluate rates of progression of HCV related allograft fibrosis 
are deleted. Reason is, that the in case from HCV the biopsies were not performed adequately. 
 


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The incidence of proteinuria of 0.5 – <1.0 g/day, 1.0 – <3.0 g/day and ≥3.0 g/day could not 
analysed, because in urine analysis protein is measures in g/l und not in g/day. Therefore, 
proteinuria could be only documented as adverse event. Therefore proteinuria is defined as 
further adverse event of special interest. 
 
CNV viral infection were defined as further adverse event of special interest. 
 
Treatment emergent events were defined as all adverse  started at baseline or later. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
According to Novartis-Germany guidelines missing values in dates will be imputed by a 
simple way: 
Missind day replacement by 15 
Missing month  replacement by 7 
Everolimus and Tacrolimus are studymedication. After treatment discontinuation this 
treatment are documented as “Immunosuppressive Medications”. For the anlsysis of 
Everolimus and Tacrolimus this treatment have to shifted from “Immunosuppressive 
Medications” to Study medication. If WHO-DD-preferred-name are EVEROLIMUS or 
TACROLIMUS, TACROLIMUS MONOHYDRATE in “Immunosuppressive Medications”, 
the record will be shifted to to “Study medication”. If the end-date of the medication is later 
than the last visit (e.g. Month 12)  or the medication is “contuing after study”, the end-date 
will be set to date of last visit. This adaption is necessary to calculate the treatment duration 
and the mean dose over thestudy for everolimus and tacrolimus. 
Duration  of exposure will be calculated until end of study. That means , that the period after 
end of treatment will also included. 
5.1.2 
AE date imputation 
According to Novartis-Germany guidelines missing values in dates will be imputed by a 
simple way: 
Missind day replacement by 15 
Missing month  replacement by 7 
5.1.3 
Concomitant medication date imputation 
According to Novartis-Germany guidelines missing values in dates will be imputed by a 
simple way: 
Missing day replacement by 15 


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Missing month  replacement by 7 
In the analysis of Immunosuppressive Medications, the medication tacrolimus and everolimus 
will be excluded. 
5.2 
Analysis of the primary objective 
Missing values in eGFR will be imputed with the last valid observed value from that patient 
(LOCF). That means the eGFR values will be carried forward in case of missing. For that 
procedure the visits will be ordered by date of visit. If the treatment are discontinued, the visit 
9a (End-oftreatment visit) will be performed. This additional visit will also be ordered after te 
last performed visit under treatment. 
According to this procedure, the last present eGFR values until Month 12 is used as primary 
endpoint for all patients. Please note, that in case of treatment discontinuations, the last value 
is not under treatment. 
5.3 
AEs coding/grading 
Adverse events were anaysed by MedDRA, version 20.0. 
5.4 
Laboratory parameters derivations 
The values from the local values are documented in digfferent units per parameter. The values 
were converted to standard units. The statistical analysis will be done by the converted values. 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The primary analysis is an analysis of covariance (ANCOVA) with treatment , center, HCV-
Class (positive, negative) and lab MELD (<=30 vs >30) as factors, and eGFR at Visit 2 
(Baseline) as covariate: 
ods output LSMeans=LSMeans;  *** LsMeans+CL for effects ***; 
ods output Estimates=Estimates; *Estimates+CL for contrasts; 
proc glm data= &data; 
   class tgp1c ctr1n; 
   model egfr = baseline tgp1c HCV_class lab_MELD_class / ss3; 
   lsmeans tgp1c / stderr ; 
   estimate "mean difference" tgp1c 1 -1;  
run; 
quit; 
HCV-Claasification: If in screening or baseline one HCV serology assessement (HCV or 
HCV-IgG) in recipient is positive, the patient is classified as positive, otherwise as negative 
5.5.2 
Key secondary analysis 
Multiple imputation (Molenberghs & Kenward 2007; White, Royston & Wood 2010) 
Alternative to LOCF, additionally as sensitivity analyses a multiple imputation (Molenberghs 
& Kenward 2007; White, Royston & Wood 2010) is planned:  
* Impute values via MCMC to obtain a monotone missing pattern*; 


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proc mi data=&data out=gfr_mono nimpute=20 seed=579415 NOPRINT  
  by tgp1c; 
  mcmc chain=multiple impute=monotone; 
  var v:; 
run; 
 
** Impute values via predictive mean matching *; 
proc mi data=gfr_mono out=gfr_imp nimpute=1 seed=579214 NOPRINT; 
  by tgp1c _imputation_; 
  monotone regpmm; 
  var v:; 
run; 
 
ods output LSMeans=LSMeans;  *** LsMeans+CL for effects ***; 
ods output Estimates=gfr_imp; *LsMeans+CL for contrasts; 
proc glm data= gfr_imp; 
   by _imputation_; 
   class tgp1c ctr1n; 
   model egfr_im = baseline tgp1c HCV_class lab_MELD_class / ss3; 
   lsmeans tgp1c / stderr ; 
   estimate "mean difference" tgp1c 1 -1;  
run; 
quit; 
 
*lsmeans; 
proc sort data=LSMeans; 
    by tgp1c; 
run; 
 
ods listing  close; 
ods rtf  exclude all; 
ods output ParameterEstimates=LSMeanMI; 
proc mianalyze data=LSMeans; 
   by tgp1c; 
          modeleffects lsmean; 
          stderr stderr; 
run; 
*lsmean difference; 
proc sort data=LSMeanDiff; 
    by parameter; 
run; 
 
ods output ParameterEstimates=LSMeanDiffMI; 
proc mianalyze data=LSMeanDiff; 
  by parameter; 
        modeleffects estimate; 
        stderr stderr; 
run; 
 
Mixed Model for Repeated Measures (MMRM) 
As a further supportive analysis, a Mixed Model for Repeated Measures (MMRM) will be 
fitted using treatment group, visit (as a categorical time variable) and subject as categorical 


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variables (Molenberghs & Kenward 2007). Assuming that the time profile is not the same in 
the two treatment groups, a full visit-by-treatment interaction will be used. Baseline and the 
baseline-by-time interaction will be included in the model. An unstructured covariance matrix 
will be used: 
 
proc mixed; 
 class subject visit treatment; 
 model gfr = baseline tgp1c HCV_class lab_MELD_class visit 
baseline*visit tgp1c*visit / s ddfm=kr; 
repeated time / subject = subject type = un group=treatment; 
run; 
 
Efficacy-related objectives 
For the efficacy related events only the events between Visit 2 (Baseline) and Day 360 
relavant. That means, that all events outside before Baseseline and after 360 are excluded 
from this analysis. 
Death: All Cases documented on the following pages   
 End of treatment 
 Study completion 
Date of event = Date of Death – Date of Baseline + 1 
Graft loss:  All cases documented on page Graft Loss 
Date of event = Date of Graft loss – Date of Baseline + 1 
Acute rejection: All rejections documented on page Liver Allograft Rejection with final 
clinical diagnosis “Acute rejection diagnosed by biopsy”,  Acute rejection diagnosed without 
biopsy” or “Acute and chronic rejection”. 
Date of event = Date rejection was first suspected– Date of Baseline + 1 
Treated ccute rejection: All rejections documented on page Liver Allograft Rejection with 
[final clinical diagnosis “Acute rejection diagnosed by biopsy”,  Acute rejection diagnosed 
without biopsy” or “Acute and chronic rejection”] and anti-rejection therapy. 
Date of event = Date rejection was first suspected– Date of Baseline + 1 
Biopsy proven acute rejection: All rejections documented on page Liver Allograft Rejection 
with final clinical diagnosis “Acute rejection diagnosed by biopsy. 
Date of event = Date rejection was first suspected– Date of Baseline + 1 
Treated Biopsy proven acute rejection: All rejections documented on page Liver Allograft 
Rejection with final clinical diagnosis “Acute rejection diagnosed by biopsy and anti-rejection 
therapy. 
Date of event = Date rejection was first suspected– Date of Baseline + 1 
For Kaplan-Meier anaylsis the first occurred event will be used. If no event is treated the 
time will be censored at min (day of visit Month 12, 360). If visit Month was not performed, 
the last visit until Month 12 will be used.  


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Day of vist = Visit Date – Date of Baseline + 1 
Adverse of special interest were defined as followed: 
AE of special interest 
Identification 
HCV (Hepatitis C Virus) 
PT „HEPATITIS C“  
OR “HEPATITIS C VIRUS TEST POSITIVE”  
OR “CHRONIC HEPATITIS C”  
OR “ACUTE HEPATITIS C”  
OR “HEPATITIS C ANTIBODY”  
“HEPATITIS C ANTIBODY POSITIVE“ 
“HEPATITIS C CORE ANTIBODY POSITIVE” 
PT contains “HEPATITIS C RNA“  
“HEPATITIS C VIRUS TEST“ 
“HEPATITIS C VIRUS TEST POSITIVE“  
HCV related fibrosis 
PT “HEPATIC FIBROSIS” (Query: HCV related?) 
CMV 
HLT “CYTOMEGALOVIRAL INFECTIONS” 
Proteinuria 
SMQ “PROTINURIA” 
New onset diabetes mellitus 
PT contains “Diabetes Mellitus” as Adverse event,  
but no PT containing “Diabetes Mellitus” as medical 
history 
Hepatocellular Carcinoma (HCC) 
HLT “HEPATIC NEOPLASMS MALIGNANT” OR  
“HEPATOBILIARY NEOPLASMS MALIGNANT 
UNSPECIFIED” 
De novo HCC malignancies 
HLT “HEPATIC NEOPLASMS MALIGNANT” OR  
“HEPATOBILIARY NEOPLASMS MALIGNANT 
UNSPECIFIED”  
as adverse event, but no HLT “HEPATIC 
NEOPLASMS MALIGNANT” OR 
“HEPATOBILIARY NEOPLASMS MALIGNANT 
UNSPECIFIED” as medical history 
Concomitant therapy of special interest were defined as followed. 
Concomitant therapy of special interest 
Identification 
Renal replacement therapy 
PT „NON-DRUG THERPY: DIALYSIS“ or  
ATC CODE  “B05Z (HEMODIALYTICS AND 
HEMOFILTRATES” 
 
Corticosteroids 
The doses displayed in the following table are considered equivalent. To determine 
prednisone equivalent doses, doses will be multiplied by conversion factor shown in the table 
above. To adjust the dose by weight measured closest to start of a steroid be used (from vital 
signs) 
 


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WHO-dug Code 
Preferred Term 
Corticosteroid 
Eqiuivalent Dose 
(mg) 
Conversion Factor 
000477xx 
Prednisone 
5 
1 
000162xx 
Prednisolone 
5 
1 
000496xx 
Methyprednisolone 
4 
1,25 
012428xx 
Meprednisone 
4 
1.25 
001867xx 
Prednylidene 
5 5/7=40/7 
0.875 
000319xx 
Triamcinolone 
4 
1.25 
000146xx 
Cortisone 
25 
0.2 
00286xx 
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 
Deflaxacort 
6 
5/6 
5.6 
Rule of exclusion criteria of analysis sets  
The rules for denition were planned in VAP, Module 3. The decisions were docuumted in the 
Minutes to the Data review Meeting 
6 
Reference 
Not applicable