Conditions: Heart Transplantation
Keywords: Heart Transplantation Cardiac Transplantation CNI-sparing renal function CNI Cyclosporine A Everolimus mycophenolic acid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 162
Healthy volunteers: no

Brief summary:
This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

Detailed description:
This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

Arms:
arm 1: CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids arm 2: CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids

Interventions: intervention 1: Everolimus (EVR) intervention 2: cyclosporine A (CyA) intervention 3: tacrolimus (TAC) intervention 4: Enteric coated mycophenolate sodium (EC-MPS) intervention 5: mycophenolate mofetil (MMF) intervention 6: Corticosteroids
Intervention descriptions: intervention 1: Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL) intervention 2: 10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only intervention 3: 0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only intervention 4: 180 mg or 360 mg tablet dosed 1440-2280 mg per day intervention 5: 250 mg or 500 mg tablets with a dose of 1500-3000 mg per day intervention 6: according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent

Protocol document:
Prot_000.pdf: 
Everolimus 
CRAD001ADE14 / NCT00862979
A multi-center, randomized, open-label, parallel group 
study investigating the renal tolerability, efficacy and 
safety of a CNI-free regimen (Everolimus and MPA) versus 
a CNI-regimen with Everolimus in heart transplant 
recipients 
MANDELA – TRIAL 
Author(s) 
 
Document type 
Clinical Study Protocol  
EudraCT No. 
2007-002671-14 
Development phase 
IV 
Document status 
Version 5.0 (including Amendment 1 & 2 & 3 & 4) 
Release date 
 19 Jan 2016 
Number of Pages 
88 
Property of Novartis Pharma GmbH Nürnberg 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
List of Post-text supplements ................................................................................ 4 
List of tables .......................................................................................................... 4 
List of abbreviations .............................................................................................. 5 
Glossary of terms .................................................................................................. 7 
Signature Pages ................................................................................................... 8 
Protocol Synopsis ...................................................................................................... 13 
1 
Background ......................................................................................................... 18 
2 
Study purpose ..................................................................................................... 20 
3 
Objectives ........................................................................................................... 20 
4 
Study design ....................................................................................................... 21 
5 
Population ........................................................................................................... 22 
6 
Treatment ............................................................................................................ 25 
6.1 
Investigational and control drugs .............................................................. 25 
6.2 
Treatment groups ..................................................................................... 26 
6.3 
Treatment assignment .............................................................................. 27 
6.4 
Treatment blinding .................................................................................... 28 
6.5 
Treating the patient ................................................................................... 28 
6.5.1 
Study drug administration .......................................................... 28 
6.5.2 
Permitted study drug adjustments ............................................. 31 
6.5.3 
Rescue medication .................................................................... 34 
6.5.4 
Other concomitant treatment ..................................................... 36 
6.5.5 
Study drug discontinuation ........................................................ 37 
6.5.6 
Premature patient withdrawal from study treatment ................... 38 
6.5.7 
Emergency unblinding of treatment assignment ........................ 39 
7 
Visit schedule and assessments ......................................................................... 39 
7.1 
Follow-up of Patients after End of Study Treatment ................................. 44 
7.2 
Information to be collected on Screening failures ..................................... 45 
7.3 
Patient demographics/other baseline characteristics ................................ 45 
7.4 
Treatments ............................................................................................... 45 
7.5 
Efficacy ..................................................................................................... 46 
7.6 
Safety ....................................................................................................... 47 
7.7 
Tolerability ................................................................................................ 50 
7.8 
Resource utilization .................................................................................. 52 
7.9 
Health-related Quality of Life .................................................................... 52 
7.10 Pharmacokinetics ..................................................................................... 52 


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7.11 Pharmacogenetics/pharmacogenomics .................................................... 53 
7.12 Other biomarkers ...................................................................................... 53 
7.13 Additional Assessments ........................................................................... 53 
8 
Safety monitoring ................................................................................................ 53 
8.1 
Serious adverse event reporting ............................................................... 53 
8.2 
Pregnancies ............................................................................................. 54 
8.3 
Data Monitoring Board .............................................................................. 54 
9 
Data review and database management ............................................................. 54 
9.1 
Site monitoring .......................................................................................... 54 
9.2 
Data collection .......................................................................................... 55 
9.3 
Database management and quality control .............................................. 55 
10 Statistical methods .............................................................................................. 56 
10.1 Statistical methods ................................................................................... 56 
10.2 Populations for analysis ............................................................................ 57 
10.3 Background and demographic characteristics .......................................... 58 
10.4 Study treatments ...................................................................................... 58 
10.4.1 
Study medication ....................................................................... 58 
10.4.2 
Concomitant therapy .................................................................. 59 
10.5  Primary objective ...................................................................................... 59 
10.5.1 
Variable ..................................................................................... 59 
10.5.2 
Statistical hypothesis, model, and method of analysis ............... 60 
10.5.3 
Handling of missing values/censoring/discontinuations with 
respect to the primary outcome variable .................................... 60 
10.5.4 
Supportive analyses .................................................................. 60 
10.6 Secondary objectives ............................................................................... 61 
10.6.1 
Efficacy ...................................................................................... 61 
10.6.2 
Safety ........................................................................................ 62 
10.6.4 
Tolerability ................................................................................. 63 
10.6.5 
Resource utilization ................................................................... 64 
10.6.6 
Health-related Quality of Life ..................................................... 64 
10.6.7 
Pharmacokinetics ...................................................................... 64 
10.6.8 
Pharmacogenetics/pharmacogenomics ..................................... 65 
10.6.9 
Biomarkers................................................................................. 65 
10.7. Interim analysis ......................................................................................... 65 
10.8 Sample size calculation ............................................................................ 65 
11 Discussion and rationale for study design features ............................................. 66 


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12 References .......................................................................................................... 68 
Appendix 1:  Administrative procedures .................................................................... 70 
Appendix 2:  Clinically notable laboratory values and vital signs ............................... 72 
Appendix 3:  Possible Cyclosporin A drug interactions ............................................. 74 
Appendix 4:  Possible Tacrolimus Drug-Drug Interactions ........................................ 76 
Appendix 5:  Dose Reduction of Everolimus and MPA .............................................. 79 
Appendix 6: National Cholesterol Education Program Guidelines ............................. 84 
Appendix 7:  ISHLT Standardized Cardiac Biopsy Grading ...................................... 86 
List of Post-text supplements 
List of tables 
Table 4-1 
Study outline .............................................................................. 22 
Table 6-1 
Schematic diagram of medication administration ....................... 30 
Table 6-2 
Acute cellular rejection – diagnosis and treatment ..................... 34 
Table 7-1 
Assessment schedule ................................................................ 40 
 


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List of abbreviations 
 
 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase (Serum Glutamate Pyruvate Transaminase) 
AST (SGOT) 
Aspartate Aminotransferase (Serum Glutamatoxalacetate 
Transaminase) 
ATC 
Anatomical Therapeutic Chemical dictionary 
ATG 
Antithymocyte Globulin 
AUC 
Area Under the Curve 
Bid 
bis in diem/twice a day (12 hours apart) 
BPAR 
Biopsy-Proven Acute Rejection 
CAV 
Cardiac allograft valsculopahty 
CI 
Confidence Interval 
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 
CsA 
Cylcosporine A 
 
 
DSMB 
Drug Safety Monitoring Board 
EBV 
Epstein Barr virus 
ECG 
Electrocardiogram 
ENR 
Enrolled Patient Population 
EC-MPS 
Enteric Coated Mycophenolate Sodium 
FSH 
Follicle Stimulating Hormone 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-Density Lipoproteine Cholesterine 
HLA 
Human leukocyte antigen 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMPDH 
Inosine 5’-Monophosphate Dehydrogenase 
IRB 
Institutional Review Board 


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ITT 
Intention-to-Treat 
LAD 
Left Anterior Descending 
LDL 
Low-Density Lipoproteine Cholesterine 
LH 
Luteinizing Hormone 
LLN 
Lower limit of normal 
MACE 
Major Adverse Cardiac Events 
MDRD 
Modification of Diet in Renal Disease Study Group 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MIT 
Maximal Intimal Thickness 
mmHg 
Millimeters of Mercury 
MMF 
Mycophenolate Mofetil 
mTOR 
Mammalian Target of Rapamycin  
MPA 
Mycophenolic Acid 
NRP  
Non-Randomized Patient Group 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCP 
Pneumocystis carinii pneumonia 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PRA 
Panel reactive antibody 
RAD 
Everolimus 
RAN 
Randomized Patients Population (at Baseline Visit 2) 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SIMO 
Sandimmun® Optoral 
SL 
Serum Level 
SNOMED 
Systematized Nomenclature of Medicine 
SOP 
Standard Operating Procedures 
SRL 
Tac 
Sirolimus 
Tacrolimus 
TL 
Trough Level 
Tmax 
Time until Maximum Plasma Concentration 
TSH 
Thyroid-Stimulating Hormone 
Tx 
Transplantation 
ULN 
Upper Limit of Normal 
WBC 
White blood cells 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control; 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; this definition is consistent with US CFR 21 
Section 312.3 and is synonymous with 
“investigational new drug.” 
Randomization number 
A unique identifier on the label of each medication 
package in studies that dispense medication using an 
IVR system 
Patient number 
A unique identifier assigned to each patient who enrolls 
in the study 
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 
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 
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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Signature Pages 
Everolimus  
Protocol number: 
CRAD001ADE14 
Title: 
A multi-center, randomized, open-label, parallel group study 
investigating the renal tolerability, efficacy, and safety of a CNI-
free regimen (Everolimus and MPA) versus a CNI regimen with 
Everolimus in heart transplant recipients 
EudraCT-No.: 
2007-002671-14 
Approved by the following 
Signatures of Novartis Personnel: 
 
 
signature 
 
Date 
 
signature 
 
Date 
 
 
signature 
 
Date 
 
Signature of Co-ordinating Investigator: 
 
 
signature 
 
Date 
 


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Signature Page for Investigator 
 
Everolimus  
Protocol number: 
CRAD001ADE14 
Title: 
A multi-center, randomized, open-label, parallel group study 
investigating the renal tolerability, efficacy, and safety of a CNI-
free regimen (Everolimus and MPA) versus a CNI regimen with 
Everolimus in heart transplant recipients 
EudraCT-No.: 
2007-002671-14 
 
 
 
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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Amendment 2 
 
Amendment rationale 
 
The purpose of this amendment is to provide clarification with regard to protocol 
misunderstandings that were identified after an internal reassessment of the protocol. In 
particular, two exclusion criteria who were either missing in the synopsis (page 13) or 
protocol text (page 22) but mentioned in the corresponding part, were completed. 
Table 4-1 (Study Outline) was adapted to clearly indicate the timely application of 
medication. Additionally, the required time frames of SAE reporting have been clarified 
(section 7.1). 
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. 
This amended protocol will not be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities due to the non substantial nature. 
 
 
 


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Amendment 3 
Amendment rationale 
In response to German health authority’s request, the protocol was modified to implement 
most recent notifications for use of MPA based on the dear health care professional letter 
(DHCPL) that was sent out for CellCept® by Roche on 12-Dec-2014. In detail the study 
medication stopping rules were adopted to clearly follow the recommendations given in the 
DHCPL. This information was added to sections 6.5.1 (Study drug administration), 6.5.2 
(Permitted study drug adjustments), 6.5.6 (Premature patient withdrawal from study 
treatment) and to Appendix 5 (Dose Reduction of Everolimus and MPA). 
Further, two exclusion criteria were amended for enhanced study feasibility in line with 
clinical praxis and patients’ de facto condition as follows:  
Exclusion criterion 10 (enrollment) and exclusion criterion 4 (baseline) were modified 
to allow for inclusion of patients with leukocytes ≥3000/mm3 (see Protocol Synopsis 
and Section 5). 
Exclusion criterion 17 (enrollment) was removed. (see Protocol Synopsis and Section 
5). 
Corrections of typos were made for clarification of visit schedule (see Section 7, Table 
7.1). 
 
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. 
This amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities for approval. The changes described in this 
amended protocol require IEC approval prior to implementation. 
 
 
 
 
 
 
 


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Amendment 4 
Amendment rationale 
This amendment addresses the size of study population. In the study protocol 200 patients 
were intended to be randomized. Recruitment of study has been ongoing since 2009. Due to 
ongoing slow recruitment the planned sample size of 200 patients cannot be achieved in a 
considerable amount of time. Thus, enrollment will be terminated by 31st December 2015. At 
timepoint of preparation of this amendment 4 to protocol n = 160 patients have been 
randomized into this study.  
A comment was added to section 10.8. (Sample size calculation) 
Further, in response to German Health Authority’s request, the protocol was modified to 
implement most recent notifications for use of MPA based on the dear health care 
professional letter (DHCPL) that was sent out for CellCept® by Roche 10-Nov-2015.   
The novel safety informations were added to section 6.5.1. (Study drug administration). 
Additional pregnancy ß-HCG tests were implemented into section 7 (Visit schedule and 
assessments) and into the assessment schedule (Table 7-1) and are mandatory for all female 
patients of child bearing potential at screening, baseline, switch and every study visit.  
 
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. 
This amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities for approval. The changes described in this 
amended protocol require IEC approval prior to implementation. 
 


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Protocol Synopsis 
Title of study: 
A multi-center, randomized, open-label, parallel group study investigating the renal tolerability, 
efficacy, and safety of a CNI-free regimen (Everolimus and MPA) versus a CNI regimen with 
Everolimus in heart transplant recipients 
Study purpose: 
To assess whether a CNI-free regimen with Everolimus and MPA is associated with a better renal 
outcome as compared to the CNI regimen and Everolimus; while both treatments are expected to be 
comparable with respect to efficacy. 
Objectives: 
Primary 
 
Renal function assessed as glomerula filtration rate (GFR) – MDRD formula – 
18 months after heart transplantation 
Secondary 
 
To assess occurrence of treatment failures up to or at Month 18 post Tx, while  
  
treatment failure is defined as a composite endpoint of biopsy proven acute  
  
rejection of ISHLT 1990 grade ≥ 3A (ISHLT 2004 grade ≥ 2R), acute rejection  
  
episodes associated with hemodynamic compromise, graft loss / re-transplant, 
  
death, loss to follow-up (at least one condition must be present) 
 
To assess incidence of MACE and each of its components at Month 18 post 
Tx 
 
To assess renal function by GFR – Cockcroft-Gault method – at Month 12 and 
18 post Tx 
 
To assess renal function (serum creatinine) and evolution of renal function 
between Month 6 and Month 18 post Tx (creatinine slope) 
 
To assess safety and tolerability at Month 6, 9 and 18 post Tx (acc. to safety 
parameters specified in section 7.6) 
Population: 
The study population will consist of a representative group of 200 heart transplant patients (i.e. 200 
patients will be randomized at Month 6 post Tx to either the CNI-free or the CNI-based treatment 
group; 100 patients in each group). Enrollment will be continued until the required sample size will be 
achieved. 
The patients will be recruited from about 10 transplant centers in Germany. 
Inclusion/Exclusion criteria: 
 
To be fulfilled at Enrollment (Month 3 post Tx) 
Inclusion Criteria 
1. Males or females, aged 18 – 70 years 
2. Recipients of de novo cardiac transplants, 3 months prior to enrollment 
3. Patients with sufficient renal function, i.e. GFR >30 and <100 mL/min 
4. Patients who are willing and able to participate in the study and from whom written informed 
consent has been obtained. 
5. Women of childbearing potential should have a negative serum or urine pregnancy test within 7 
days prior to or at screening. Females are eligible if they are postmenopausal for at least 24 
months past last natural menses. Study medication should not be administered until a negative 


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pregnancy test report is obtained. Two or more acceptable methods of contraception should be 
started 1 month prior to beginning study drug unless abstinence is the chosen method, during 
therapy, and for 3 months after stopping the study. Abstinence is an allowed contraceptive method 
if in the judgment of the investigator the patient is reliably abstaining. Acceptable forms of birth 
control include any two or more of the following methods: surgical sterilization (e.g. bilateral tubal 
ligation, hysterectomy), hormonal contraception (implantable, patch, oral), IUD and barrier 
methods (male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic 
abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
 
Exclusion Criteria 
1. Multi-organ recipients, re-transplantation, or previous transplant with any other organ. 
2. Donor age: < 5 years or > 70 years 
3. Patients who are recipients of A-B-O incompatible transplants 
4. Calculated ischemia time > 6 hours (calculated ischemia time = total ischemia time MINUS time of 
the transplant in the OCS (Organ Care System) 
5. Patients with a historical or current peak PRA of > 25% at time of transplantation 
6. Patients with already existing antibodies against the HLA-type of the receiving transplant 
7. Patients with insufficient graft function, i.e. who suffered from severe rejection (i.e. more than 2 
episodes of ISHLT 1990 > Grade 2 resp. ISHLT 2004 > Grade 1R), recurrent acute rejection, or 
steroid resistant acute rejection during the first 3 months post Tx 
8. Patients with any known hypersensitivity to Everolimus, mycophenolic acid, Cyclosporin A, 
Tacrolimus, other drugs similar to Everolimus (e.g. macrolides), or other components of the 
formulations (e.g. lactose) 
9. Patients who have received an investigational drug within four weeks prior to study entry 
(Screening Visit - Month 3 post Tx) 
10. Patients with thrombocytopenia (platelets < 50,000/mm³), with an absolute neutrophil count of < 
1,500/mm³ or leucopenia (leucocytes < 3,000/mm³), or hemoglobin < 6 g/dL 
11. Patients with symptoms of significant somatic or mental illness. Inability to cooperate or 
communicate with the investigator, who are unlikely to comply with the study requirements, or who 
are unable to give informed consent 
12. Patients with a history of malignancy during the last five years, except squamous or basal cell 
carcinoma of the skin 
13. Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C (PCR+ only) 
virus positive. Laboratory results obtained within 6 months prior to study entry are acceptable. 
14. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C. 
15. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin 
> 3 times UNL) 
16. Presence of severe hypercholesterolemia (≥ 350 mg/dL; ≥ 9 mmol/L) or hypertriglyceridemia (≥ 
750 mg/dL; ≥ 8.5 mmol/L) 
17. Females of childbearing potential who are planning to become pregnant, who are pregnant or 
lactating, and/or who are unwilling to use effective means of contraception 
18. Presence of a clinically significant infection requiring continued therapy, severe diarrhea, active 
peptic ulcer disease, or uncontrolled diabetes mellitus that in the opinion of the investigator would 
interfere with the appropriate conduct of the study 
19. Evidence of drug or alcohol abuse 
20. Patients receiving drugs known to significantly interact with CsA and/or Everolimus according to 
the list provided in Appendix 3 to this protocol. Especially the administration of terfenadine, 
astemizole, or cisapride as well as strong inducers or inhibitors of cytochrome P450 3A4 will not 
be allowed. 
 


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To be fulfilled at Baseline (Month 6 post Tx - prior to randomization) 
In addition to the above criteria the following must be met at Baseline (Month 6 post Tx) prior to 
randomization. 
 
Inclusion Criteria 
1. Patients with sufficient renal function, i.e. GFR >30 mL/min 
 
Exclusion Criteria 
1. Graft loss / re-transplantation or death 
2. Changes to the immunosuppressive regimen prior to randomization due to immunologic reasons 
3. Patients who suffered from more than 2 severe rejections (more than ISHLT 1990 Grade 2 resp. 
ISHLT 2004 Grade 1R), recurrent acute rejection, or steroid resistant acute rejection 
4. Patients with thrombocytopenia (platelets < 50,000/mm³), with an absolute neutrophil count of < 
1,500/mm³ or leucopenia (leucocytes < 3,000/mm³), or hemoglobin < 6 g/dL 
5. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin 
> 3 times ULN) 
6. Patients with clinically significant infection requiring continued therapy which would interfere with 
the objectives of the study 
7. Presence of intractable immunosuppresant complications or side effects (e.g. severe 
gastrointestinal adverse events) at randomization visit (Month 6 post Tx) 
 
Investigational and reference therapy 
 
Investigational drug 
 Certican® 
 
Active ingredient: 
 
Everolimus (RAD001) 
 
Galenic form: 
 
tablets 
Dose: 
 
 
one tablet containing 0.25 mg, 0.75 mg, or 1.0 mg 
 
Dosing schedule: 
 
based on blood level (5 - 10 ng/mL) 
 
Packaging:  
 
blisters of 10 tablets 
 
 
 
Other components of the immunosuppressive regimen 
 
 Prograf® 
 
Active ingredient: 
 
Tacrolimus 
 
Galenic form: 
 
capsules 
 
Dose: 
 
 
one capsule containing 0.5 mg, 1.0 mg and 5.0 mg 
 
Dosing schedule: 
 
according to blood level  
Packaging:  
 
trade ware will be used 
 
 Sandimmun® Optoral 
 
Active ingredient: 
 
Cyclosporin A  
Galenic form: 
 
capsules 
 
Dose: 
 
 
one capsule containing 10 mg, 25 mg, 50 mg, or 100 mg  
Dosing schedule: 
 
according to blood level  
Packaging:  
 
trade ware will be used 
 
 Mycophenolic Acid (MPA) 
based on investigator’s decision, one of the following drugs will be used: 
 
 
 
Myfortic® 
Active ingredient: 
 
Enteric Coated Mycophenolate Sodium (EC-MPS) 
 
Galenic form: 
 
tablets  


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Dose: 
 
 
one tablet containing 180 mg or 360 mg  
Dosing schedule: 
 
1440 - 2880 mg/day 
Packaging:  
 
trade ware will be used 
 
 
CellCept® 
Active ingredient: 
 
Mycophenolate Mofetil (MMF) 
 
Galenic form: 
 
capsules / tablets 
 
Dose: 
 
 
one capsule containing 250 mg or one tablet containing 500 mg  
Dosing schedule: 
 
1500 - 3000 mg/day, if tolerated  
Packaging:  
 
trade ware will be used 
 
 Corticosteroids 
 
according to local standard. A dose of 0.05 - 0.3 mg/kg prednisolone or equivalent should be 
continued throughout the trial. 
Study design   
Prospective, multi-center, randomized, controlled, parallel group, open-label study in heart transplant 
recipients. 
During the first 3 months post Tx the patients will be treated outside this clinical study and according to 
center standards. 
Subjects who are fulfilling all inclusion criteria and none of the exclusion criteria will be enrolled into the 
trial 3 Months post transplantation. 
During a Run in phase (Month 3 - 6 month post transplantation), all patients will be treated with CNI 
(Tacrolimus or Cyclosporin A) + Everolimus or MPA + corticosteroids. 
At Baseline (Month 6 post Tx) all eligible patients (according to inclusion and exclusion criteria) will be 
randomized to one of the two treatment groups in a 1:1 ratio: 
 
Group 1: CNI-group 
Maintenance of immunosuppressive CNI-based regimen (CNI-
group) consisting of 
 
Tacrolimus (C0: 3 - 8 ng/mL) or Cyclosporin A (C0: 50 - 150 ng/mL) +  
Everolimus (C0: 5 - 10 ng/mL) +  
 
corticosteroids 
 
Group 2: CNI-free-group 
Switch immunosuppressive therapy to a CNI-free regimen 
consisting of 
MPA (MMF 1500 - 3000 mg/day OR EC-MPS 1440 - 2880 mg/day) + 
Everolimus (C0: 5 - 10 ng/mL) + 
corticosteroids 
 
INCLUDING during switch phase (months 6-9) (see table 4-1): 
Cyclosporin A ≤ 75 ng/mL (according to C0-level)  or Tacrolimus ≤ 5 
ng/mL (according to C0) 
The therapy switch will start the day after randomization 
(Month 6) and should be completed by Month 9 post Tx. 
 
The established treatment will be continued until Month 18 post Tx (final assessment). Control 
assessments will be performed at Month 10 and 12 after Tx. Renal function (GFR) as well as efficacy 
(BPAR, graft loss, death) will be assessed at every study visit. 


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Obligatory biopsies will be obtained at Month 6, 9, 12, 18. However, facultative biospsies may be 
obtained at every study visit. 
Assessments of renal tolerability  
 
Glomerular Filtration Rate (GFR), calculated according to MDRD-method (primary endpoint), and 
Cockcroft-Gault method 
 
Serum creatinine and slope of creatinine 
Efficacy assessments 
 
Death / graft loss / re-transplantation / acute rejection associated with hemodynamic compromise / 
biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R / treated 
acute rejection / loss to follow-up as well as treatment failure as a composite endpoint. 
 
Major Adverse Cardiac Events (MACE) 
 
Electrocardiogram (ECG) 
 
Echocardiogram 
Safety assessments   
 
Infections 
 
(Serious) Adverse Events 
 
Physical Examination 
 
Vital Signs 
 
(Safety) Laboratory evaluation 
Pharmakokinetic assessments 
 
Blood trough levels (C0-h) of Cyclosporin A, Tacrolimus, MPA and Everolimus 
Data analysis 
Statistical analysis and report writing will be performed when all patients have completed Month 18 
after Tx assessment. 
Change in glomerular filtration rate (MDRD method) will be used as the primary criterion in order to 
demonstrate the CNI-free regimen is superior to the CNI-based regimen regarding the prevention of 
renal failure. Primary analysis will be perfomed with the ITT population. 
Type I error probability is set to 0.05, two-sided.  
All other safety and efficacy variables will be presented by descriptive statistics and compared 
between both treatments using suitably chosen tests for unpaired or paired (laboratory data and vital 
signs) observations. Categorial variables will be analyzed with the chi2-test or Fisher’s exact test. 
Event data will be assessed by Kaplan-Meier statistics and compared between the two groups with the 
logrank test. In addition to the comparison of the two treatment groups, further comparisons will be 
made with the group of patients who were not eligible for randomization at Baseline visit 2. 
 
Sample size 
The probable difference between the CNI-free - and the CNI-group in the GFR is estimated as  = 8 
ml/min with  = 16 ml/min. With =.05 (two sided significance level) and 1- = 90% (power), n=86 
patients per group are required to demonstrate superior efficacy of the CNI-free regimen compared to 
the CNI-group in the GFR using the t-test 
. To compensate for 
some uncertainty of the assumptions for sample size calculation, the calculated sample size is 
increased by  15%. Therefore, a total number of N=200 patients (n=100 per treatment group) will be 
randomized and treated in both treatment arms after Baseline visit 2. 


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1 
Background 
The ultimate aim of immunosuppressive therapy in transplantation is to provide an 
efficacious regimen while minimizing (long-term) non-immune toxicities and without 
compromising safety. By combining synergistic drugs, it may be possible to reduce 
the exposure to individual agents and therefore avoid adverse effects whilst 
maintaining favorable clinical outcomes. 
Progress has been made in transplantation medicine with the introduction of 
calcineurin inhibitors (CNIs) such as Cyclosporin A (CsA) and Tacrolimus. Owing 
to the benefits of this drug class, the survival rates after heart transplantation 
markedly improved (Eisen H et al., 2005; Organ Procurement and Transplantation 
Network reports 1996-2001); however, with the increase in use, the side effects of 
this drug group became more evident (Keogh A, 2004; Eisen H et al., 2005; 
Schweiger M et al., 2005). Impairment of renal function was one of the major side 
effects associated with CNI-based immunosuppression (Lindenfeld JA et al., 2004). It 
is known that CNIs trigger arterial hypertension and, therefore, additional treatment is 
required to overcome this effect (Lindenfeld JA et al., 2004, Dalla Pozza R et al., 
2006). Furthermore, the incidence of tremor and cosmetic side effects (hirsutism and 
gingival hyperplasia) are common with CNI immunosuppression (Lindenfeld JA et al., 
2004). There has, therefore, been an increasing interest to explore combinations of 
treatment that allow for reduction in CNI exposure, as this may potentially enhance 
favorable long term outcomes. 
The immunosuppressant Everolimus is a proliferation signal inhibitor (PSI) with 
potent immunosuppressant activity that has been introduced since April 2005 in over 
60 countries for prophylaxis of organ rejection in adult renal and heart transplant 
recipients (Vitko S et al., 2004 and 2005; Krämer BK et al., 2005; Monaco AP et al., 
2005; Lober MI et al., 2005; Eisen HJ et al., 2003; Tendesco H, et al., in press). 
According to licensing, Everolimus should be administered with Cyclosporin A and 
steroids. 
Everolimus metabolism, via CYP3A4 in the liver, seems to cause less renal toxicity 
than calcineurin inhibitors. Promising data are available for 3- and 4-year treatment in 
renal transplant recipients (Vitko S et al., 2005; Lober MI et al., 2005; Tedesco H et 
al., 2006). 
First, CNI-free immunosuppression with a proliferation signal inhibitor was focused on 
the use of sirolimus (Rapamune), with studies demonstrating an improvement in 
renal function with sirolimus and mycophenolate mofetil (MMF) immunosuppression 
in heart transplant recipients (Lyster H et al., 2004; Groetzner J et al., 2004).  
Between June 2004 and July 2005 Lehmkuhl et al. (2007) conducted a single-center 
observational study with Everolimus in combination with low-dose Cyclosporin A in 
de novo heart transplant recipients. The findings demonstrated that use of 
Everolimus at a dose of 0.75 mg directly before engraftment allows for a pronounced 
reduction in CsA exposure post-transplant. Furthermore, this regimen preserves 


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renal function without loss of immunosuppressive efficacy and without a significant 
effect on post-transplant CK and cholesterol levels, suggesting that Everolimus and 
low-dose CsA may have an important role as part of the primary immunosuppressive 
strategy in de novo heart transplant recipients. 
The effects of CNI-free immunosuppression using Everolimus were investigated in a 
mulit-center trial including 60 maintenance heart transplant recipients (5.4  3.2 years 
post transplant) (Rothenburger et.al, 2007a). Reasons for switching to Everolimus 
were side effects associated with prior CNI immunosuppression. All patients 
underwent 
standardized 
switching 
protocols 
to 
reach 
the 
CNI-free 
immunosuppressive regimen consisting of Everolimus (target blood level: 4 – 8 
ng/mL), MMF (1000 mg twice daily), and prednisone (5 mg/day). All patients 
completed 6 months of follow-up. After switching to Everolimus, most patients 
recovered from the side effects associated with CNIs. Renal function improved 
significantly after 6 months (creatinine, 2.1  0.6 mg/dl vs. 1.5  0.9 mg/dL, p=0.001; 
creatinine clearance, 42.2  21.6 mL/[min * 1.73 m²] vs. 61.8  23.4 mL/[min * 1.73 
m²], p=0.018). Arterial hypertension improved after 3 months and remained 
decreased during the observation period. Tremor, peripheral edema, hirsutism, and 
gingival hyperplasia markedly improved. Adverse events occurred in 8 patients 
(13.3%), including interstitial pneumonia (n=2), skin disorders (n=2), reactive hepatitis 
B (n=1), and fever of unknown origin (n=3). Summarizing the preliminary data it was 
concluded that CNI-free immunosuppression using Everolimus may be safe, with 
excellent efficacy in maintenance heart transplant recipients.  
Since the publication of the results of the 2003 Certican consensus Meeting (Hummel 
M, 2005), clinical experience with the use of Everolimus has grown. An increasing 
number of patients treated outside of clinical studies have provided more information 
about the efficacy and safety of Everolimus. Based on these recent data, a second 
Certican Consensus Conference was held in January 2006 (Rothenburger et al., 
2007b). The main goal of the meeting was to discuss new areas for the application 
and indication of Everolimus in cardiac transplantation. The resulting report 
summarized the conclusions of the meeting and also brought fourth adaptations and 
changes in recommendations for the use of Everolimus: 
Key Considerations when using Everolimus (Rothenburger et al., 2007b, Table 1) 
CNI minimization: 
 Maintain target Everolimus trough blood levels 3 – 8 ng/mL 
 Monitor Everolimus trough blood levels after changes in dose 
 Avoid CYP3A4 inducers or inhibitors where possible 
 Statins should be given concomitantly with Everolimus and CsA 
 Target CsA C0 trough blood levels of 120 – 150 ng/mL after 3 months and 50 - 
100 ng/mL after 6 months 
 


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CNI-free: 
 Maintain target Everolimus trough blood levels 3 – 8 ng/mL 
 Do not eliminate before 6 months post-transplantation 
 Closely monitor rejection episodes especially within the first year post-
transplantation. 
However, further research is needed to address effectiveness of CNI-free 
immunosuppressive regimen based on Everolimus. The design chosen for the 
current study follows the abovementioned recommendations. A CNI-free regimen 
with Everolimus and MPA will be compared with a low-dose CNI regimen and 
Everolimus. It is expected, that the CNI-free regimen will result in superior renal 
function, when compared to the CNI-based regimen, while it is expected to be as 
efficacious and safe as the CNI-based regimen with regard to occurrence of biopsy 
proven acute rejection episodes, graft loss, and death. 
2 
Study purpose 
This phase IV study is designed to show that an early onset of a CNI-free regimen 
with MPA and Everolimus in heart transplant patients may be associated with better 
renal outcome, and similar efficacy as compared to a CNI-based regimen and 
Everolimus. 
3 
Objectives 
The primary objective of this trial is to demonstrate superiority of a CNI-free regimen 
with respect to the renal function at Month 18 post Tx assessed by glomerular 
filtration rate – MDRD method – as compared to the standard CNI-based regimen in 
heart transplant patients. 
Secondary objectives of this trial are: 
 to asses occurrence of treatment failures up to or at Month 18 post Tx, while 
treatment failure is defined as a composite endpoint of biopsy proven acute 
rejection of ISHLT 1990 grade ≥ 3A (ISHLT 2004 grade ≥ 2R), acute rejection 
episodes associated with hemodynamic compromise, graft loss / re-transplant, 
death, loss to follow up (at least one condition must be present) 
 to assess incidence of MACE and each of its components at Month 18 post Tx 
 to assess renal function by glomerular filtration rate - Cockcroft-Gault method - at 
Month 12 and 18 post Tx 
 to assess renal function (serum creatinine) and evolution of renal function between 
Month 6 and 18 post Tx (creatinine slope) 
 to assess safety and tolerability at Month 6, 9 and 18 post Tx (according to safety 
parameters specified in section 7.6) 


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4 
Study design 
This is a prospective, multi-center, randomized, controlled, parallel group, open label 
study in heart transplant recipients. A total of 200 patients fulfilling the inclusion and 
exclusion criteria at Baseline visit (Month 6 post Tx) will be randomized to the two 
treatment groups. Enrollment will be continued until the required sample size is 
achieved. 
Once consent is obtained, screening data will be collected to determine each 
patient’s eligibility for study participation. Screening assessment will be performed at 
Month 3 post Tx and relevant data from transplantation will be recorded 
retrospectively. 
During the first three months post Tx the patients may be treated according to center 
standards. Latest after study inclusion (Month 3 post Tx 2 weeks), the patients 
should receive an immunosuppressive regimen consisting of Cyclosporin A (based 
on C0-h level) or Tacrolimus (based on C0-h level) + Everolimus (target C0-h level: 
5 – 10 ng/mL) or MPA + corticosteroids. 
At Month 6 (1 week) post transplantation (Baseline), patients whose eligibility is 
confirmed by additional in- and exclusion criteria will be randomized and hence 
allocated to one of the two treatment groups in a 1:1 ratio. Patients will then either 
receive an immunosuppressive regimen consisting of a CNI (Tacrolimus or 
Cyclosporin A) with Everolimus with corticosteroids or be switched to the CNI-free 
regimen in the following way: 
Starting the day following the Month 6 assessment, Cyclosporin A will be reduced to 
≤75 ng/mL (according to C0 level) or Tacrolimus will be reduced to ≤5 ng/mL 
(according to C0 level) for 8 weeks and subsequently removed completely. 
Depending on the initial immunosuppression either MPA or Everolimus will be added 
to the patient´s immunosuppressive regimen. Consequently, patients receive a 
transitional immunosuppressive regimen of Cyclosporin A or Tacrolimus and 
Everolimus and MPA or MMF until complete switch to the CNI-free regimen is 
achieved at 9 months post Tx. 
Dose increase / adjustment of MPA should be performed based on the investigator’s 
experience and the given clinical conditions, adverse events, etc. The CNI-free 
regimen should be achieved after a maximum of 3 months and be stable by Month 9. 
During the therapy-switch a control assessment will be performed at Month 8. 
In all patients, further control assessments will be performed at Month 9, 10, 12 and 
18 (end of study and early discontinuation) post Tx. 
Corticosteroids must be added to the immunosuppressive regimen in all patients, 
according to local standard. A dose of 0.05 – 0.3 mg/kg prednisolone or equivalent 
should be continued throughout the whole study. 
Obligatory biopsies will be obtained at Month 6, 9, 12, 18. Facultatively biospsies 
may be obtained at every study visit. 


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Statistical analysis and report writing will be performed when all patients have 
completed Month 18 after Tx assessment. 
An external and independent Data Safety Monitoring Board (DSMB) will be instituted. 
The DSMB will review safety-related issues and will be entitled to make 
recommendations for changes in study conduct. Details on the function of the DSMB 
will be laid out in a separate DSMB Charter. 
 
 Table 4-1 
Study outline 
 
 
Patients should be seen for all visits on the designated day or as close to it as 
possible. 
Baseline visit assessments and randomization (Month 6 post Tx) may be performed 
within a time window of  1 week. 
5 
Population 
The study population will consist of 200 de novo heart transplant patients (100 
patients per treatment group) who are randomized to the two treatment groups at 
Baseline visit (Month 6 post Tx). The patients will be recruited from about 10 
transplant centers in Germany. 


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Inclusion / Exclusion criteria for Enrollment (Month 3 post Tx) 
The investigator must ensure that all patients who meet the following inclusion criteria 
and none of the exclusion criteria are offered enrollment in the study. No additional 
exclusions can be applied by the investigator, in order that the study population will 
be representative of all eligible patients. 
 
Inclusion Criteria 
The following inclusion criteria must be present at enrollment (Month 3 post Tx) 
1. Males or females, aged 18 – 70 years 
2. Recipients of de novo cardiac transplants, 3 months prior to enrollment 
3. Patients with sufficient renal function, i.e. GFR >30 and <100mL/min 
4. Patients who are willing and able to participate in the study and from whom written 
informed consent has been obtained. 
5. Women of childbearing potential should have a negative serum or urine 
pregnancy test within 7 days prior to or at screening. Females are eligible if they 
are postmenopausal for at least 24 months past last natural menses. Study 
medication should not be administered until a negative pregnancy test report is 
obtained. Two or more acceptable methods of contraception should be started 1 
month prior to beginning study drug unless abstinence is the chosen method, 
during therapy, and for 3 months after stopping the study. Abstinence is an 
allowed contraceptive method if in the judgment of the investigator the patient is 
reliably abstaining. Acceptable forms of birth control include any two or more of 
the following methods: surgical sterilization (e.g. bilateral tubal ligation, 
hysterectomy), hormonal contraception (implantable, patch, oral), IUD and barrier 
methods (male or female condom with spermicidal gel, diaphragm, sponge, 
cervical cap). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
Exclusion Criteria 
The following exclusion criteria must not be present at enrollment (Month 3 post Tx) 
1. Multi-organ recipients, re-transplantation, or previous transplant with any other 
organ. 
2. Donor age: < 5 years or > 70 years  
3. Patients who are recipients of A-B-O incompatible transplants 
4. Calculated ischemia time >6 hours (calculated ischemia time = total ischemia time 
MINUS time of the transplant in the OCS (Organ Care System) 
5. Patients with a historical or current peak PRA of > 25% at time of transplantation 
6. Patients with already existing antibodies against the HLA-type of the receiving 
transplant 
7. Patients with insufficient graft function, i.e. who suffered from severe rejection (i.e. 
more than 2 episodes of ISHLT 1990 > Grade 2 resp. ISHLT 2004 > Grade 1R), 


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recurrent acute rejection, or steroid resistant acute rejection during the first 3 
months post Tx 
8. Patients with any known hypersensitivity to Everolimus, mycophenolic acid, 
Tacrolimus, Cyclosporin A, other drugs similar to Everolimus (e.g. macrolides), or 
other components of the formulations (e.g. lactose) 
9. Patients who have received an investigational drug within four weeks prior to 
study entry (Screening Visit - Month 3 post Tx) 
10. Patients with thrombocytopenia (platelets < 50,000/mm³), with an absolute 
neutrophil count of < 1,500/mm³ or leucopenia (leucocytes < 3,000/mm³), or 
hemoglobin < 6 g/dL 
11. Patients with symptoms of significant somatic or mental illness. Inability to 
cooperate or communicate with the investigator, who are unlikely to comply with 
the study requirements, or who are unable to give informed consent 
12. Patients with a history of malignancy during the last five years, except squamous 
or basal cell carcinoma of the skin 
13. Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis 
C (PCR+ only) virus positive. Laboratory results obtained within 6 months prior to 
study entry are acceptable. 
14. Recipients of organs from donors who test positive for Hepatitis B surface antigen 
or Hepatitis C. 
15. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, 
ALT or total bilirubin > 3 times UNL) 
16. Presence of severe hypercholesterolemia (≥ 350 mg/dL; ≥9 mmol/L) or 
hypertriglyceridemia (≥ 750 mg/dL; ≥ 8.5 mmol/L) 
17. Females of childbearing potential who are planning to become pregnant, who are 
pregnant or lactating, and/or who are unwilling to use effective means of 
contraception 
18. Presence of a clinically significant infection requiring continued therapy, severe 
diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus that in the 
opinion of the investigator would interfere with the appropriate conduct of the 
study 
19. Evidence of drug or alcohol abuse 
20. Patients receiving drugs known to significantly interact with CsA and/or 
Everolimus according to the list provided in Appendix 3 to this protocol. Especially 
the administration of terfenadine, astemizole, or cisapride as well as strong 
inducers or inhibitors of cytochrome P450 3A4 will not be allowed. 
 
Inclusion / Exclusion criteria for Baseline (Month 6 post Tx – prior to 
randomization) 
Of all patients included into the study at Month 3 post Tx, those can continue into the 
randomized study period, in whom the following condition is observed at Baseline 
(Month 6 post Tx), prior to randomization. 
 


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Inclusion Criteria 
1. Patients with sufficient renal function, i.e. GFR > 30 and < 100 mL/min 
 
Exclusion Criteria 
Of all patients included into the study at Month 3 post Tx, those can not continue into 
the randomized study period, in whom one or more of the following criteria are met at 
Baseline (Month 6 post Tx), prior to randomization: 
1. Graft loss / re-transplantation or death 
2. Changes to the immunosuppressive regimen prior to randomization due to 
immunologic reasons 
3. Patients who suffered from more than 2 severe rejections (more than ISHLT 1990 
Grade 2 resp. ISHLT 2004 Grade 1R), recurrent acute rejection, or steroid 
resistant acute rejection 
4. Patients with thrombocytopenia (platelets < 50,000/mm³), with an absolute 
neutrophil count of < 1,500/mm³ or leucopenia (leucocytes < 3,000/mm³), or 
hemoglobin < 6 g/dL 
5. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, 
ALT or total bilirubin > 3 times ULN) 
6. Patients with clinically significant infection requiring continued therapy which 
would interfere with the objectives of the study 
7. Presence of intractable immunosuppressant complications or side effects (e.g. 
severe gastrointestinal adverse events) at randomization visit (Month 6 post Tx) 
 
6 
Treatment 
6.1 
Investigational and control drugs 
Investigational drug 
 Certican®  
Active ingredient:  
Everolimus (RAD001) 
 
Galenic form: 
 
tablets 
Dose: 
 
 
one tablet containing 0.25 mg, 0.75 mg or 1.0 mg 
Dosing schedule:  
based on drug level (5 – 10 ng/mL).  
 
Packaging: 
 
blisters of 10 tablets 
 
Other components of the immunosuppressive regimen 
 Prograf®  
Active ingredient:  
Tacrolimus 
 
Galenic form: 
 
capsules 
 


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Dose: 
 
 
one capsule containing 0.5 mg, 1.0 mg and 5.0 mg 
 
Dosing schedule:  
according to blood level 
 
Packaging: 
 
trade ware will be used 
 
 Sandimmun® Optoral  
Active ingredient:  
Cyclosporin A 
 
Galenic form: 
 
capsules 
 
Dose: 
 
 
one capsule containing 10 mg, 25 mg, 50 mg, or 100 mg 
Dosing schedule:  
according to blood levels (cf. Table 4-1 and section 6.5.2) 
Packaging: 
 
trade ware will be used 
 
 Mycophenolic Acid (MPA) 
 
based on investigator’s decision, one of the following drugs will be used: 
 
 
Myfortic®  
 
Active ingredient:  
Enteric Coated Mycophenolate Sodium (EC-MPS) 
 
Galenic form: 
 
tablets 
Dose: 
 
 
one tablet containing 180 mg or 360 mg  
Dosing schedule:  
1440 – 2880 mg/day, if tolerated  
Packaging: 
 
trade ware will be used 
 
 
CellCept®  
 
Active ingredient:  
Mycophenolate Mofetil (MMF) 
 
Galenic form: 
 
capsules / tablets 
 
Dose: 
 
 
one capsule containing 250 mg or  
 
  
 
 
 
one tablet containing 500 mg 
 
Dosing schedule:  
1500 – 3000 mg/day, if tolerated  
Packaging: 
 
trade ware will be used 
 
 Corticosteroids  
according to local standard. A dose of 0.05 – 0.3 mg/kg prednisolone or equivalent 
should be continued throughout the trial. 
 
6.2 
Treatment groups 
The day after Screening visit, during the run in phase, all patients will receive the 
following immunosuppressive therapy:  
Cyclosporin A (C0level: 100-200 ng/mL) or Tacrolimus (C0level: 5 - 10 ng/mL) and 
Everolimus (C0level: 5-10 ng/mL) or MPA and corticosteroids.  
At Baseline visit (Month 6 post Tx) patients will be assigned to one of the following 
two treatment groups in a ratio of 1:1: 


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 Maintenance of immunosuppressive CNI-based regimen (CNI group): 
Cyclosporin A (C0: 50 – 150 ng/mL) or Tacrolimus  (C0: 3 – 8 ng/mL)+ 
Everolimus (C0: 5 – 10 ng/mL) +  
Corticosteroids 
 Switch to CNI-free regimen (CNI-free group): 
MPA (MMF 1500 - 3000 mg/day OR EC-MPS 1440 - 2880 mg/day) + 
Everolimus (C0: 5 – 10 ng/mL) +  
Corticosteroids +  
Cyclosporin A ≤ 75 ng/mL (according to -evel) (months 6-9) or Tacrolimus ≤ 5 
ng/mL (according to C0) (months 6-9) 
 
6.3 
Treatment assignment 
A randomization list will be produced by or under the responsibility of Novartis 
Biometrics Department using a validated system that automates the random 
assignment of treatment groups to randomization numbers in the specified 1:1 ratio 
(CNI group, CNI-free group). The randomization scheme will be reviewed and locked 
after approval. According to the recommendations given in the ICH E9 Guideline 
“Statistical Principles for Clinical Trials” (CPMP, 1998), the used block length is 
specified in a separate document which is withhold from the study centers. The 
randomization list will be kept sealed in a secure location. 
At Enrollment (Screening Visit – Month 3 post Tx), patients will be assigned a unique 
patient identification number by the investigator. The patient identification number 
has two parts. The first part is the four-digit center number, which is assigned by 
Novartis. The second part will be assigned by the investigator starting with number 
“00001” in each study site. Once assigned to a patient, the patient identification 
number will not be reused. If the patient fails to be enrolled into the study for any 
reason, the patient’s identification number and the reason for not being enrolled will 
be entered on the Screening Failure Log. Note: The patient identification number is 
different from the randomization number. 
At Baseline visit (Month 6 post Tx), all eligible patients will be given a randomization 
number that assigns them to one of the treatment groups. The randomization 
numbers are sequentially allocated to the patients per center in the order of inclusion 
in the randomized treatment period. 
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 enrollment (Screening Visit – Month 3 post Tx):  
Study sites will inform the randomization department of the 
 
about each patient inclusion via fax. 


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2. 
Randomization (Baseline Visit – Month 6 post Tx): 
 
At day of randomization, the site will provide the information of eligible patient 
to 
 by fax. 
 
 randomization department 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. 
 
6.4 
Treatment blinding 
This is an open-label study. 
 
6.5 
Treating the patient 
6.5.1 
Study drug administration 
Everolimus is study drug from month 3 (visit 1). Before month 3 the patient will 
receive a prescription for Everolimus, the use of Everolimus before visit 1 is not 
excluded. Each study site will be supplied by Novartis with study drug (Everolimus). 
Study drug will be provided as tablets, packaged in boxes containing strips of blister 
packed tablets, and labeled as RAD001 Tablets. Study drug will be available in 0.25, 
0.75, and 1.0 mg strength. One component of the box consists of a 2-part label which 
includes an identifier of each single box of study medication. Before dispensing the 
study medication to an individual patient, investigator staff must enter the 4-digit 
patient number and the date of dispensing of the medication box on both parts of the 
label. The outer part of the label will be detached from the packaging and affixed to 
the source document (Drug Label Form in the CRF) containing that patient’s unique 
patient number. 
For the other immunosuppressive drugs (Cyclosporin A, Tacrolimus, MPA, 
corticosteroids) the patient will receive a prescription. 
The prescribed total daily dosage of the immunosuppressive drugs should be divided 
in two (equal) doses, applied 12 hours apart (i.e. 08:00 a.m. and 08:00 p.m.). 
The investigator should instruct the patient to take the study drug exactly as 
prescribed in order to promote compliance. All dosages prescribed and dispensed to 
the patient and all dose changes during the study must be recorded on the Dosage 
Administration Record CRF. 
In patients randomized to the CNI-free group, withdrawal of Cyclosporin A or 
Tacrolimus and commencement of MPA or Everolimus will be performed starting the 
day after randomization at Month 6 post Tx. 


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In a first step the Cyclosporin A should be decreased to a dose resulting in a C0 
blood level of ≤ 75 ng/mL for 8 weeks, and Tacrolimus should be decreased to a 
dose resulting in a level of ≤ 5 ng/mL. MPA or Everolimus should be introduced. 
Further increase / adjustment of MPA or Everolimus and removal of Cyclosporin A or 
Tacrolimus should be performed based on the investigator’s experience and the 
given clinical conditions, adverse events, etc. The CNI-free regimen should be 
achieved after a CNI reduction / elimination period of maximum of 3 months (starting 
from Month 6 post Tx and be stable by Month 9 post Tx). 
In cases of recurrent infections serum antibody concentration should be measured; if 
hypogammaglobulinemia presents as persistent and clinically significant, patients 
should be examined accurately and appropriate actions should be taken; dose 
reduction or change of immunosuppression should be taken into consideration. 
Patients with recurrent pulmonary disorders e.g. cough/dyspnea should as soon as 
possible be examined accurately for signs of bronchiectasis; dose reduction or 
change of immunosuppression should be taken into consideration. 
Corticosteroids must be added to the immunosuppressive regimen in all patients, 
according to local standard. A dose of 0.05 – 0.3 mg/kg prednisolone or equivalent 
should be continued throughout the whole study. 
 
Safety recommendations regarding the use of MPA: 
MPA is a powerful human teratogen, which increases the risk of spontaneous 
abortions and congenital malformations in case of exposure during pregnancy. 
Therefore following safety recommendations should be followed for all patients that 
are receiving MPA (f.ex. CellCept or myfortic).  
Investigators should ensure that women and men that are receiving MPA understand 
the risk of harm to the baby, the need for effective contraception, and the need to 
immediately consult responsible investigator if there is a possibility of pregnancy or a 
suspected gap of contraception. In addition, patients should not donate blood during 
therapy or for at least 6 weeks following discontinuation of MPA. 
 
Recommendations for female patients: 
Before starting treatment with MPA, women of child bearing potential must have 
undergone pregnancy testing, i.e. done at Screening, Baseline, Switch and following 
study visits (Assessment Schedule Table 7-1) in order to exclude unintended 
exposure of the embryo to mycophenolate. A pregnancy ß-HCG test is mandatory for 
all female patients in this trial at all indicated visits (Table 7-1). 
Pregnancy tests should be repeated as clinically required (e.g. after any gap in 
contraception is reported). Results of all pregnancy tests should be discussed with 
the patient. 


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Women of childbearing potential should use two reliable forms of contraception 
simultaneously before starting therapy, during therapy, and for six weeks after 
stopping treatment with MPA. 
 
Recommendations for male patients 
Sexually active men (including vasectomized men) are recommended to use 
condoms during treatment and for at least 90 days after cessation of treatment. In 
addition, female partners of male patients treated with MPA are recommended to use 
highly effective contraception during treatment and for a total of 90 days after the last 
dose. 
Men should not donate semen during therapy with MPA or for 90 days following 
discontinuation of MPA. 
 
Table 6-1 
Schematic diagram of medication administration 
Phase 
No Study 
Prephase 
Study Drug Treatment 
Period 
 
Run In 
BL 
Switch 
Maintenance 
Visit 
 
1 
2 
3 
4 
5 
6 
7 
Month post Tx 
0 - 3 
3 
6 
8 
9 
10 
12 
18 
Randomization 
 
 
X 
 
 
 
 
 
 
Treatments 
 
CNI group 
 
 
- Everolimus 
 
center 
practice 
C0-h level: 5 – 10 ng/mL 
- CNI 
(Cyclosporin A/ 
Tacrolimus)  
acc. to 
blood level *
acc. to blood level 
* 
acc. to blood level * 
- MPA 
center 
practice 
none 
None 
- Steroids 
0.05 – 0.3 
mg/kg 
0.05 – 0.3 mg/kg Prednisolone or equivalent
CNI-free group 
 
 
- Everolimus 
) 
center 
practice 
C0-h level: 5 – 10 ng/mL 
- CNI 
(Cyclosporin 
A/Tacrolimus)   
acc. to 
blood level *
CyA: C0 level of 
≤ 75 ng/mL for 8 
weeks, then 
removal 
Tac: C0 level of 
≤ 5 ng/mL for 8 
weeks, then 
removal 
None 


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- MPA 
center 
practice 
MMF 1.5 – 3 g/d 
OR 
EC-MPS 1440 – 
2880 mg/d 
MMF 1.5 – 3 g/d OR 
EC-MPS 1440 – 2880 
mg/d 
- Steroids 
0.05 – 0.3 
mg/kg 
0.05 – 0.3 mg/kg Prednisolone or equivalent
BL  
 
= Baseline visit: day of randomization – Month 6 post Tx 
 
 
CNI Group: 
treatment post randomization: Everolimus + Cyclosporin A/Tacrolimus + 
corticosteroids 
Cyclosporin A Dosage: Month 1 - 6: 
C0-h levels   100 – 200 ng/mL 
 
Month >6: 
C0-h levels     50 – 150 ng/mL  
 
 
 
(cf. section 6.5.2) 
Tacrolimus Dosage: 
Month 1 - 6: 
C0-h levels   5 - 10 ng/mL 
 
Month >6: 
C0-h levels   3 - 8 ng/mL 
 
 
CNI-free Group: 
treatment post randomization: Everolimus + MPA + corticosteroids 
 Cyclosporin A Dosage: Month 1 - 6: 
C0-h levels   100 – 200 ng/mL 
 
Month 6 - 9: 
C0-h levels     ≤75 ng/mL  
 
 
 
(cf. section 6.5.2) 
Tacrolimus Dosage: 
Month 1 - 6: 
C0-h levels   5-10 ng/mL 
 
Month 6 - 9: 
C0-h levels     ≤5 ng/mL  
 
 
6.5.2 
Permitted study drug adjustments 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. The 
recommendations described below should be followed as far as clinically feasible. 
All immunosuppressive medication, with single dose, unit, frequency, route of 
administration, indication, start and end dates will be recorded in the 
Immunosuppressive Therapies CRF. Only approved but no investigational drugs are 
permitted. 
Oral corticosteroids will be given at a dose of 0.03 – 0.5 mg/kg prednisolone or 
equivalent throughout the whole trial. If possible, it should remain stable during the 
entire course of the study. However, dose adjustments for medically indicated 
reasons will be possible. 
Everolimus 
Because Everolimus is the mainstay of immunosuppression, Everolimus dose should 
be continued on a stable level according to trough levels. Dose reductions should 
only be performed if the symptoms do not respond to other measures (e.g. reduction 
of MPA dose). 


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Target therapeutic ranges for Everolimus whole blood trough levels should be 5 - 10 
ng/mL. 
Dose adjustments may be performed if Everolimus whole blood trough levels outside 
the target range are measured. Dose adjustments of Everolimus should be monitored 
7 days later by a measurement of the Everolimus blood trough level. 
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 hyperlipidemias were common over the full 
exposure range, they 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 (< 100 
x 109/L) increased with Everolimus exposure; however, the incidence of clinically 
meaningful platelet reductions (< 75 x 109/L) was generally low. 
If Everolimus medication is interrupted for safety related considerations for more than 
2 weeks during the Run in phase (Month 3 to Month 6 post Tx) or 4 consecutive 
weeks within the 12 months study treatment (or cumulative for more than 8 weeks), 
discontinuation of the medication should be considered and the patient should be 
withdrawn from study treatment. Appropriate information needs to be recorded on the 
Dosage Administration CRF.  
 
Cyclosporin A 
Target therapeutic range for Cyclosporin A whole blood levels should be the 
following. 
Timepoint 
C0-h levels [ng/mL] 
Month 3 – 6 
100 – 200 
Month > 6 
50 – 150 
 
Dose adjustments may be performed if Cyclosporin A whole blood levels outside the 
target range are measured. In case of severe CsA toxicity, dose reductions below the 
target levels may be performed on the investigator’s discretion. 
In the CNI-free group the Cyclosporin A will be reduced to a dose resulting in a C0 
level of ≤ 75 ng/mL starting at Month 6 post Tx and finally (after 8 weeks of reduced 
dosage) removed completely. At the latest at Month 9, Cyclosporin A should be 
withdrawn completely from the immunosuppressive regimen in the CNI-free group. 
If Cyclosporin A medication is interrupted for safety related considerations for more 
than 4 consecutive weeks or more than 8 cumulative weeks after randomization, 
discontinuation of the medication should be considered and the patient should be 


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withdrawn from study treatment. Appropriate information needs to be recorded on the 
Dosage Administration CRF. 
 
Tacrolimus  
Target therapeutic range for Tacrolimus whole blood levels should be the following. 
Timepoint 
C0-h levels [ng/mL] 
Month 3 – 6 
5 – 10 
Month > 6 
3 – 8 
 
Tacrolimus dosing will be modified by investigators as needed and recorded on the 
Tacrolimus Dosage Administration CRF at each visit. In the event of Tacrolimus 
intolerance (e.g. nephrotoxicity, neurotoxicity) dose reduction of Tacrolimus may be 
necessary. If it occurs that the Tacrolimus trough level is below the required target 
level, then the investigator will be asked to confirm the intended Tacrolimus trough 
level, to record the start date and reason for dose reduction on the Tacrolimus 
Dosage Administration CRF. 
In the CNI-free group the Tacrolimus will be reduced to a dose resulting in a C0 level 
of ≤5 ng/mL starting at Month 6 post Tx and finally (after 8 weeks of reduced dosage) 
removed completely. At the latest at Month 9, Cyclosporin A or Tacrolimus should be 
withdrawn completely from the immunosuppressive regimen in the CNI-free group. 
 
If Tacrolimus medication is interrupted for safety related considerations for more than 
4 consecutive weeks or more than 8 cumulative weeks after randomization, 
discontinuation of the medication should be considered and the patient should be 
withdrawn from study treatment. Appropriate information needs to be recorded on the 
Dosage Administration CRF.  
 
The co-administration of drugs known to interfere with Tacrolimus metabolism should 
be avoided if possible. If these drugs are required, the investigator must monitor 
Tacrolimus and/or Everolimus trough levels (Appendices 3 and 4). 
 
Mycophenolic Acid (MPA) 
In patients randomized to the CNI-free group, treatment with MPA will be introduced 
starting the day after Baseline (Month 6 post Tx) assessment (see section 6.5.1). 
Either Mycophenolate Mofetil (MMF) or Enteric-Coated Mycophenolate Sodium (EC-
MPS) may be applied. 
In case of leukopenia (leukocyte count < 3,000/mm3), neutropenia (neutrophil count 
< 1,500/mm3), or anemia, MPA medication doses may be reduced at the discretion of 


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the investigator or eliminated completely until the event resolves. Furthermore, for 
any other moderate/severe AE which in the opinion of the investigator warrants a 
dose reduction or temporary interruption of the medication, this will be allowed. 
However, the MPA medication should be restarted once the AE has resolved or 
returned to an acceptable grading (see instructions given in Appendix 5). 
If MPA medication is interrupted for safety related considerations more than 2 weeks 
during the run in phase (Month 3 to Month 6 post Tx) or for more than 4 consecutive 
weeks or more than 8 cumulative weeks, discontinuation of the medication should be 
considered and the patient should be withdrawn from study treatment. Appropriate 
information needs to be recorded on the Dosage Administration CRF. 
The Month 18 assessments will be performed and documented for all patients who 
are withdrawn prematurely from the treatment at timepoint of discontinuation and 
again at month 18 after Tx. 
In cases of recurrent infections serum antibody concentration should be measured; if 
hypogammaglobulinemia presents as persistent and clinically significant, patients 
should be examined accurately and appropriate actions should be taken; dose 
reduction or change of immunosuppression should be taken into consideration. 
Patients with recurrent pulmonary disorders e.g. cough/dyspnea should as soon as 
possible be examined accurately for signs of bronchiectasis; dose reduction or 
change of immunosuppression should be taken into consideration. 
6.5.3 
Rescue medication 
Treatment for acute rejection episodes 
Patients with presumed acute rejection episodes must undergo endomyocardial 
biopsy within 48 h (regardless of initiation of anti-rejection treatment) and 
echocardiogram as needed. If the patient is not stable, the biopsy will be done within 
24 hours after the patient has been stabilized. The acute rejection is to be treated 
according to the following table, or according to local practice. The randomized 
immunosuppressive regimen should not be changed, unless a second Grade 3A 
rejection episode with or without hemodynamic compromise occurs or a second 
rejection episode associated with hemodynamic compromise occurs. If either 
situation occurs and the investigator chooses to change the randomized 
immunosuppressive regimen, the patient will be removed from study treatment. 
Table 6-2 
Acute cellular rejection – diagnosis and treatment 
ISHLT biopsy 
grade 1990 (2004 ) 
Hemodynamic compromise* 
Absent 
Present 
Grade 1A, 1B 
Mild 
(1R, mild) 
No treatment  
1-2 mg/kg oral corticosteroids for 3 - 5 days 
followed by 5 to 10 day taper or immediate 
return to baseline oral corticosteroids 
And/or 


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High dose IV corticosteroids with or without 
anti-lymphocyte antibody therapy 
Grade 2 
Focal 
Moderate 
(1R, mild) 
No treatment 
High dose corticosteroids for 3 days followed 
by taper or by immediate return to baseline 
oral corticosteroids 
And/or 
High dose IV corticosteroids with or without 
anti-lymphocyte antibody therapy 
Grade 3A, 3B 
Multifocal or diffuse 
(2R, moderate or 
3R, severe) 
1 - 4 mg/kg oral corticosteroids 
for 3-5 days followed by 5 to 10 
day taper or immediate return 
to baseline oral corticosteroids 
Or 
High dose IV corticosteroids for 
3 days followed by immediate 
return to baseline oral 
corticosteroids 
High dose corticosteroids for 3 days with or 
without 7 - 14 days of anti-lymphocyte 
antibody therapy followed by a taper or 
immediate return to baseline oral 
corticosteroids 
And/or 
High dose IV corticosteroids with or without 
anti-lymphocyte antibody therapy 
Grade 4 
Diffuse, polymorphous 
with or without edema, 
hemorrhage, vasculitis 
(3R, severe) 
High dose IV corticosteroids 
and anti-lymphocyte antibody 
therapy 
High dose IV corticosteroids with or without 
anti-lymphocyte antibody therapy 
* 
Hemodynamic compromise is considered to be present if one or more of the following 
conditions are met: 
 
Ejection fraction ≤ 30% or 25% lower than baseline or 
Fractional shortening ≤ 20% or 25% lower than baseline and/or Inotrope treatment 
Baseline is defined as Visit 1 
 
Treatment of CMV 
Treatment with gancyclovir, cytomegalovirus hyperimmune globulin, valgancyclovir or 
valcyclovir is permitted and will be at the investigator’s discretion per standard 
practice of the individual centers. Non-high risk patients will be treated according to 
local practice. CMV prophylaxis is also recommended following any antibody 
treatment of acute rejection episodes. 
Treatment of Pneumocystis carinii 
All patients should receive prophylactic treatment for Pneumocystis carinii 
Pneumonia (PcP) with trimethoprim/sulfamethoxazole (e.g. Bactrim® or Cotrim®) 
according to local practice. Duration and dosage depend on the discretion of the 
investigator. Aerosolized pentamidine or dapsone may be administered to patients 
unable to tolerate oral formulations. 


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Treatment of Candida 
Nystatin for oral thrush (Candida) will be used in a swish and swallow regimen. 
Routine use of systemic antifungal agents (i.e., ketoconazole, itraconazole, and 
fluconazole) will not be allowed unless patients are systemically infected. 
Administration of azoles may increase blood concentrations of Cyclosporin A, 
Tacrolimus and Everolimus; therefore their use should be minimized. Particular 
attention to side effects is required. If such agents are to be used, additional drug 
monitoring Cyclosporin A, Tacrolimus and Everolimus are recommended at start and 
end of treatment. 
Treatment of hyperlipidemia 
Lipid lowering medications (e.g. fluvastatin, Lescol®) are to be administered to all 
patients even if the patient does not have an elevated LDL-cholesterol or triglyceride 
levels at baseline. Initiation of treatment should follow the National Cholesterol 
Educating Program (NCEP) guidelines (Appendix 6).  
The daily starting dose should be the equivalent of 20 mg pravastatin, 5 mg 
simvastatin, 10 mg atorvastatin, or 20 mg fluvastatin, and may be increased to target 
and maintain a LDL level of < 130 mg/dL. In case of simvastatin, dose should not 
exeed 10 mg/day to account for the increased risk of myophathy/rhabdomyolysis, 
when combined with Cyclosporin A. 
When HMG-CoA reductase inhibitors are used concomitantly with gemfibrozil (and 
probably 
other 
fibrates), 
Cyclosporin 
A 
or 
erythromycin, 
myopathy 
and 
rhabdomyolysis have been reported. Therefore, the use of lovastatin will be 
prohibited in this study. 
Lipid lowering medications should be optimized prior to reduction of study 
medication. If the elevation of cholesterol and/or triglyceride levels persists, the 
dosing of study medication will be adjusted following the recommendations in 
Appendix 5. 
 
6.5.4 
Other concomitant treatment 
The investigator should instruct the patient to notify the study site about any new 
medications he/she takes after the start of the study drug. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug must be 
listed on the Prior-/Concomitant medications/Significant non-drug therapies CRF. If 
required for an AE, such concomitant medication should be cross-referenced on the 
AE CRF under “action taken”, appropriately coded for “concomitant medication 
taken”. 
Inducers of CYP3A4 (e.g. rifampin, carbamazepine, phenytoin, and barbiturates) 
have been shown or have the potential to decrease exposure to Everolimus. If these 
drugs are necessary, Everolimus doses may have to be increased. Potent inhibitors 
of CYP3A4 such as ketoconazole, itraconazole and fluconazole should be avoided 


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while the patient is on study medication. Everolimus has the potential to increase the 
exposure to terfenadine, astemizole and cisapride; hence these drugs should be 
avoided. In vitro data suggested that everolimus may have the potential to interact 
with quinidine, fluoxetine and paroxetine, and alternative medications should be 
considered. Since the potential for drug interaction with digoxin has not been 
evaluated, patients on digoxin should have periodic measurement of digoxin levels.  
The concomitant administration of nephrotoxic drugs (e.g. aminoglycosides, NSAIDs) 
and drugs known to interfere with Cyclosporin A and Tacrolimus pharmacokinetics 
(i.e., ketoconazole, erythromycin, phenytoin, barbiturates, carbamazepine, diltiazem, 
verapamil, rifampin) should be associated with a careful monitoring of renal function 
and Cyclosporin A / Tacrolimus blood trough levels. In addition, drugs known to 
interfere with Everolimus or MPA should be avoided (see Appendix 5 for possible 
drug interactions). 
 
6.5.5 
Study drug discontinuation 
In case of platelet count < 50,000/mm³, leukocyte count < 3,000/mm3 or neutrophil 
count < 1,500/mm3, at the discretion of the investigator, MPA medication dose may 
be reduced by half, or eliminated completely until the event resolves. In case of dose 
reduction, MPA should be reduced according to the guidelines given in Appendix 5. 
Everolimus should be continued on a stable dose level and reduced only if the 
symptoms do not respond to the reduction of the MPA dosage. 
In case of elevated cholesterol and/or triglyceride levels, lipid lowering medications 
should be maximized. If the elevation persists, the dosing of Everolimus should be 
adjusted following the recommendations given in Appendix 5. 
Dose reduction may be performed for those patients with other moderate/severe AEs 
according to the investigator’s judgment. Also in these cases, the medication doses 
can be reduced by half or interrupted completely until event resolves. 
If the MPA or Everolimus medication is interrupted for more than 2 weeks during the 
run in phase (Month 3 to Month 6 post Tx) or 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. 
Patients who discontinue study drug before completing the maintenance period at 
Month 18 post Tx should be scheduled for a visit as soon as possible, at which time 
all of the assessments listed for the final visit (Month 18) will be performed. Month 18 
assessments should be repeated at the initially planned timepoint, 18 months post 
transplantation.  
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 
following the last dose of study drug. 


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Patients who discontinue study drug should be considered withdrawn from the study 
only after the final visit assessments (month 18 post Tx) are performed or when it is 
clear that the patient will not return for these assessments. 
6.5.6 
Premature patient withdrawal from study treatment 
Patients may voluntarily withdraw from study treatment or study treatment may be 
discontinued at the discretion of the investigator at any time.Patients must be 
withdrawn prematurely from the study treatment if any of the following occur: 
 premature discontinuation of study drug (see section 6.5.5) 
 pregnancy 
 graft loss / re-transplantation 
 third severe rejection episode (ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade 
≥ 2R) with or without hemodynamic compromise or rejection episode requiring 
change in baseline immunosuppressive therapy according to this protocol or any 
rejection ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R within months 6 – 
9 (as assessed by per protocol biopsies) 
 occurrence or detection of severe medical disorder jeopardizing the life of the 
patient in the immediate future 
If such premature withdrawal from study treatment occurs, or if the patient fails to 
return for visits, the investigator must determine the primary reason for a patient’s 
premature withdrawal from the study and record this information on the Study / 
Treatment Completion CRF. 
Patients may be withdrawn from the study treatment prematurely at the investigator’s 
discretion for one of the following reasons:  
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. unsatisfactory therapeutic effect (e.g. severe rejecetion) 
5. protocol violation 
6. administrative problems 
7. patient’s condition no longer requires study treatment 
In cases of recurrent infections serum antibody concentration should be measured; if 
hypogammaglobulinemia presents as persistent and clinically significant, patients 
should be examined accurately and appropriate actions should be taken; MPA dose 
reduction or change of MPA-based immunosuppression should be taken into 
consideration. 
Patients with recurrent pulmonary disorders e.g. cough/dyspnea should as soon as 
possible be examined accurately for signs of bronchiectasis; MPA dose reduction or 
change of MPA-based immunosuppression should be taken into consideration. 


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For patients who are lost to follow-up, 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 discontinue participation in the trial for any reason will not be replaced. 
All patients who prematurely discontinue study treatment should still attend the final 
visit at Month 18 post transplantation to obtain follow up information on rejection 
episodes, allograft and patient survival, hospitalizations, malignancies and 
immunosuppressive medication. 
The CRFs Study Completion Page should be completed at month 18 or earlier if the 
patient can no longer be followed, e.g. due to death, withdrawal of consent, or loss to 
follow-up. 
 
6.5.7 Emergency unblinding of treatment assignment 
Not applicable, since this is an open-label trial. 
 
7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they 
are performed. All these obtained data must be supported in the patient’s source 
documentation. 


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Table 7-1 
Assessment schedule 
Phase 
Prephase 
Study Drug Treatment 
Period 
SCR 
BL 
Switch 
Maintenance 
Visit 
1 
2 
3 
4 
5 
6 
71/7.12
Month post Tx 
3 
6 
8 
9 
10 
12 
18 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/ exclusion 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
General medical history 
X 
 
 
 
 
 
 
Renal history (information on 
dialysis etc.) 
X 
 
 
 
 
 
 
Transplantation information 
X 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Endomyocardial biopsy 
 
X 
 
X 
 
X 
X 
ECG 
X 
X 
 
X 
 
X 
X 
Study medication check 
 
X 
X 
X 
X 
X 
X 
Laboratory test: 
 
 
 
 
 
 
 
- Hemat. / Biochemistry 
X 
X 
X 
X 
X 
X 
X 
- Viral Serology 
X 
X3 
X3 
X3 
X3 
X3 
X3 
- Pregnancy test4 (-HCG) 
X 
X 
X 
X 
X 
X 
X 
- Blood sampling for frozen 
   storage (2-5 mL EDTA blood) 
X 
X 
 
X 
 
 
X 
- Urinalysis (proteinuria) 
X 
X 
 
X 
 
 
X 
Drug concentration (C0-h) 
 
 
 
 
 
 
 
 
Tacrolimus/ Cyclosporin A5  
X 
X 
X 
X 
X 
X 
X 
 
Everolimus 
X 
X 
X 
X 
X 
X 
X 
Comments 
--- as necessary -- 
Echocardiogram 
--- as necessary -- 
Hospitalization6 
--- as necessary -- 
AEs 
--- as necessary -- 
SAEs 
--- as necessary -- 
Infections 
--- as necessary -- 
Concomitant therapy 
--- as necessary -- 
Positive inotropic effect or 
vasoactive treatment 
--- as necessary -- 
Immunosuppressive therapy 
--- as necessary -- 
Rejection episodes 
--- as necessary -- 
Hemodynamic compromise 
--- as necessary -- 
MACE 
--- as necessary -- 
End of study1/2 
 
 
 
 
X 
 
SCR: Screening visit: Month 3 post Tx 
 
BL: Baseline visit: day of randomization, Month 6 post Tx 


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1) At end of study (Month 18 post Tx) or at timepoint of discontinuation for patients with premature 
discontinuation of per protocol treatment  
2) At Month 18 post Tx: Only for patients who prematurely discontinued the per protocol treatment  
3) Only CMV-status (including pp65 Ag) 
4) Only in women of childbearing potential 
5) To be assessed only if Cyclosporin A or Tacrolimus is administered at that visit. C0-h levels have to be 
determined at all indicated timepoints. 
6) Hospitalization: see section 7.8, Resource utilization 
 
Patients should be seen for all visits on the designated day or as close to it as 
possible. However, timely intervals of  1 week will be regarded acceptable. 
 
Screening Visit - Visit 1 (Month 3 post Tx)  
This visit may be performed within a time window of  2 weeks. 
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 as well as renal history (especially information on 
dialysis) will be obtained and recorded. 
5. Transplantation information will be recorded (donor and recipient information, 
including viral serology; initiated immunosuppressive regimen, including induction 
therapy). 
6. A complete physical examination will be performed. 
7. Vital signs will be measured. 
8. A 12-lead ECG will be written. 
9. Venous blood will be drawn for measurement of hematology and biochemistry. 
10. Viral serology of CMV (including pp65 Ag), Hepatitis B (HbsAg), Hepatitis C, and 
HIV will be recorded. Results from ≤ 6 months prior Screening visit will be 
acceptable. 
11. Venous blood will be drawn for measurement of the C0-h levels of Cyclosporin A 
or Tacrolimus and Everolimus. 
12. Venous blood will be drawn for frozen storage until end of trial (2 EDTA-tubes, 2-5 
mL); only as a backup to repeat laboratory measurements if necessary). 
13. In woman of childbearing potential a pregnancy test will be performed (-HCG). 
14. Urinalysis 
for 
proteinuria 
will 
be 
performed 
(spot 
urine 
sample 
for 
protein/creatinine ratio may be used). 
15. Prior and concomitant medications / significant non-drug therapies will be 
recorded. 
16. Immunosuppressive medication taken at M3 post Tx and any dose adjustments 
that were performed within the five days preceding the Screening visit will be 
recorded. 


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17. Information on rejection episodes and MACE that occurred since transplantation 
will be recorded. 
 
Baseline Visit - Visit 2 (Month 6 post Tx) 
This visit may be performed within a time window of  1 week. 
1. Patient’s eligibility for the study according to in- and exclusion criteria will be 
checked 
2. The patient will be randomized to one of the two treatment arms. 
3. A complete physical examination will be performed. 
4. Vital signs will be measured. 
5. An endomyocardial biopsy will be performed. 
6. A 12-lead ECG will be written. 
7. Venous blood will be drawn for measurement of hematology and biochemistry. 
8. Venous blood will be drawn for measurement of viral serology (CMV status 
including pp65 Ag). 
9. Venous blood will be drawn for measurement of the C0-h levels of Cyclosporin A 
or Tacrolimus and Everolimus. 
10. Venous blood will be drawn for frozen storage until end of trial (2 EDTA-tubes, 2-5 
mL). 
11. In woman of childbearing potential a pregnancy test will be performed (-HCG). 
12. Urinalysis 
for 
proteinuria 
will 
be 
performed 
(spot 
urine 
sample 
for 
protein/creatinine ratio may be used). 
13. Changes in Concomitant medications / significant non-drug therapies will be 
recorded. 
14. (Changes in) immunosuppressive medication will be recorded. 
15. Information 
on 
rejection 
episodes, 
hemodynamic 
compromise, 
MACE, 
hospitalization, infections, and other (S)AEs that occurred since the last visit will 
be recorded. 
Switch of immunosuppressive regimen - Visit 3 (Month 8 post Tx) 
This visit may be performed within a time window of  1 week. 
1. Vital signs will be measured. 
2. Venous blood will be drawn for measurement of hematology and biochemistry. 
3. In woman of childbearing potential a pregnancy test will be performed (-HCG). 
4. Venous blood will be drawn for measurement of viral serology (CMV status 
including pp65 Ag) 
5. Venous blood will be drawn for measurement of 
 
- Everolimus C0-h level in all patients  
- Cyclosporin A C0-h level, only in patients of the CNI group 


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- Tacrolimus C0-h level, only in patients of the CNI group 
6. Changes in concomitant medications / significant non-drug therapies will be 
recorded. 
7. Changes in immunosuppressive medication (including study drug dosage) will be 
recorded. 
8. Information 
on 
rejection 
episodes, 
hemodynamic 
compromise, 
MACE, 
hospitalization, infections, and other (S)AEs that occurred since the last visit will 
be recorded. 
Maintenance Period - Visits 4, 5 and 6 (Month 9, 10, 12 post Tx) 
These visits may be performed within a time window of  1 week. 
1. Vital signs will be measured. 
2. An endomyocardial biopsy will be performed (only visits 4 and 6). 
3. A 12-lead ECG will be written (not at month 10, Visit 5). 
4. Venous blood will be drawn for measurement of hematology and biochemistry. 
5. Venous blood will be drawn for the measurement of viral serology (only CMV-
status including pp65 Ag). 
6. Venous blood will be drawn for measurement of 
 
- Everolimus C0-h level in all patients  
- Cyclosporin A C0-h level, only in patients of the CNI group 
- Tacrolimus C0-h level, only in patients of the CNI group 
7. In woman of childbearing potential a pregnancy test will be performed (-HCG). 
8. Changes in concomitant medications / significant non-drug therapies will be 
recorded. 
9. Changes in immunosuppressive medication (including study drug dosage) will be 
recorded. 
10. Information 
on 
rejection 
episodes, 
hemodynamic 
compromise, 
MACE, 
hospitalization, infections, and other (S)AEs that occurred since the last visit will 
be recorded. 
Only at Vist 4, Month 9 
11. A complete physical examination will be performed. 
12. Venous blood will be drawn for frozen storage until end of trial (2 EDTA-tubes, 2-5 
mL). 
13. Urinalysis 
for 
proteinuria 
will 
be 
performed 
(spot 
urine 
sample 
for 
protein/creatinine ratio may be used). 
 End of Study - Visit 7 (Month 18 and early discontinuation) 
In case of early discontinuation, Month 18 assessments need to be performed 
- as soon as possible after study drug discontinuation  
- additionally at the originally planned timepoint, i.e. 18 months after transplantation 


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1. A complete physical examination will be performed. 
2. Vital signs will be measured. 
3. An endomyocardial biopsy will be performed. 
4. A 12-lead ECG will be written. 
5. Venous blood will be drawn for measurement of hematology and biochemistry. 
6. In woman of childbearing potential a pregnancy test will be performed (-HCG). 
7. Venous blood will be drawn for measurement of viral serology (CMV-status 
including pp65 Ag). 
8. Venous blood will be drawn for measurement of 
 
- Everolimus C0-h level in all patients  
- Cyclosporin A C0-h level, only in patients of the CNI group  
- Tacrolimus C0-h level, only in patients of the CNI group 
9. Venous blood will be drawn for frozen storage until end of trial (2 EDTA-tubes). 
10. Urinalysis 
for 
proteinuria 
will 
be 
performed 
(spot 
urine 
sample 
for 
protein/creatinine ratio may be used). 
11. Changes in concomitant medications / significant non-drug therapies will be 
recorded (in case of early discontinuation until 30 days after last dose of study 
drug). 
12. Changes in immunosuppressive medication (including study drug dosage) will be 
recorded (in case of early discontinuation until 30 days after last dose of study 
drug). 
13. Information 
on 
rejection 
episodes, 
hemodynamic 
compromise, 
MACE, 
hospitalization, infections, and other (S)AEs that occurred since the last visit will 
be recorded  
14. End of Study / End of Treatment information will be obtained. 
 
7.1 
Follow-up of Patients after End of Study Treatment 
For all patients who were included into this trial, whether discontinued treatment 
prematurely or completed the entire study, the final examination will be performed 18 
months after transplantation (Visit 7 and / or visit 7.1, Month 18).  
At a minimum, all patients who discontinue from the study treatment prematurely will 
be contacted within 30 days following study treatment termination, to follow-up on 
any safety issues. Documentation of MACE, infections, immunosuppressive 
medication, and other concomitant medication should be continued for the period of 
30 days following the last dose of the per protocol immunosuppressive regimen. 
For all patients documentation of SAEs should be continued until 30 days after the 
patient has stopped study participation (visit 7 or 7.1, Month 18). 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. 


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Following discontinuation of the per protocol immunosuppressive regimen, the 
immunosuppressive therapy will be on the investigator’s discretion. 
 
7.2 
Information to be collected on Screening failures 
If a patient who signed informed consent fails to be enrolled into the trial at Month 3 
for any reason, the patient’s number and the reason for non-enrollment will be 
entered into the Screening Failure Log. 
 
7.3 
Patient demographics / other baseline characteristics 
The following demographic data and other baseline characteristics will be recorded: 
 Demography: date of birth, 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 of childbearing potential the serum pregnancy test (-HCG) will be 
performed locally within 7 days prior to Screening (Month 3 post Tx). Results must 
be available and negative prior to administration of medication and reported on the 
CRF. 
 Renal history 
 
Any 
significant 
prior 
and 
current 
renal 
diseases 
(e.g. 
presence 
of 
glomerulonephritis, nephrectomia, etc.) will be recorded with date of diagnosis and 
information whether it is an active problem). 
 Transplantation information:  
Donor information 
 
age, sex, race, viral serology on CMV, EBV, HepC, HbsAg, HIV  
Recipient information 
 
date of transplantation, duration of cold ischemia time, percentage of panel 
reactive antibodies (PRA) , viral serology on CMV, EBV, HepC, HbsAg, HIV, end 
stage disease leading to transplantation 
 
Initiated immunosuppressive regimen, including induction therapy 
 
7.4 
Treatments 
Records of all immunosuppressive drugs (Everolimus, Cyclosporin A, Tacrolimus, 
MPA, corticosteroids) used and dosages administered are to be kept during the 
whole study. Starting 5 days prior to the Screening visit, all changes to the 
medication dosing regimen should be recorded in the Dosage Administration Record 
CRF, along with the reason for change and dates. 


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The immunosuppressive regimen initiated after transplantation, including information 
whether and which induction therapy was applied, will be recorded. 
Drug accountability for Everolimus medication will be noted by the investigator 
and/or study personnel at each visit using pill counts. This information should be 
captured in the source document at each visit. 
 
7.5 
Efficacy 
The following efficacy variables will be obtained and recorded: 
 Endomyocardial biopsy  –  Rejection episodes / graft loss / re-transplant  
Per protocol biopsies will be performed at visits 2, 4, 6 and 7 and results of a 
biopsy that may have been performed at Month 1 post Tx will be recorded 
retrospectively. Additionally, a biopsy will be performed in any case of suspected 
rejection. Biopsies will be read and interpreted by local pathologists according to 
the ISHLT 1990 and/or 2004 diagnosis criteria (Stewart et al, 2005). A copy of the 
pathology report will be collected and filed in the investigator’s folder. The results 
will be recorded on the Endomyocardial Biopsy CRF at respective visit. 
All suspected rejection episodes must be recorded on the Endomyocardial Biopsy 
log / Suspected Rejection CRF, with the date rejection was first suspected, 
whether anti-rejection therapy was administered, whether the acute rejection was 
confirmed or with final clinical diagnosis specified, and final clinical outcome. 
Biopsy-proven acute rejection  
(ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R) 
The occurrence of a biopsy-proven acute rejection is diagnosed from per-protocol 
biopsies or from biopsies performed for suspected rejection episodes. Per protocol 
biopsies will be performed at Visits 2, 4, 6 and 7 / 7.1. 
In all suspected rejection episodes, a graft core biopsy and an echocardiography 
will be performed within 48 hours, regardless of the initiation of anti-rejection 
therapy. The results including date of occurrence of first symptoms will be 
recorded in the Endomyocardial Biopsy log / Suspected Rejection CRF and will be 
used for the efficacy analysis. 
Rejection episodes will be reported on the Endomyocardial Biopsy log / Suspected 
Rejection CRF only, and not on the AE CRF. An Endomyocardial Biopsy log / 
Suspected Rejection CRF will be completed each time a suspected or biopsy-
proven acute rejection has occurred. Rejection episodes occurring more than 10 
days after the start of the preceding one will be considered as a new rejection 
episode. 


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Rejection with hemodynamic compromise 
The occurrence of an acute rejection with hemodynamic compromise will be 
assessed using the Hemodynamic Compromise CRF. Positive inotrope therapy or 
vasoactive treatment will be recorded on the Prior-/Concomitant medications CRF. 
Graft loss / re-transplantation 
The allograft will be presumed to be lost on the day the patient is scheduled for re-
transplantation. This will be reported on the End of Treatment CRF if medication is 
discontinued prematurely and Study Completion CRF. Graft loss / re-
transplantation are considered a Serious Adverse Event and must be reported on 
the Serious Adverse Event Case Report Form, which must be faxed to Novartis. 
Major Adverse Cardiac Events (MACE) 
 
Major Adverse Cardiac Event will be defined as one of the following: 
 
  
- any death  
  
- myocardial infarction 
 
  
- coronary artery bypass grafting  
All major adverse cardiac events will be recorded on the CRF and are subject to 
expedited reporting as specified in section 8.1. 
 Echocardiogram 
 
Echocardiograms will be performed as needed for suspected rejection episodes. 
Results will be recorded on the Echocardiogram CRF. 
 Electrocardiograms (ECG) 
 
A 12-lead ECG will be written and documented in the CRF with ventricular rate, 
PQ interval, QRS duration and QT interval.  
Additionally, the investigator will assess the following: 
 
heart rate:  
normal, bradycard, tachycard,  
 
rhythm: 
 
eurhythmia, arrhythmia,  
 
block signs:  
S-A Block,   
 
 
 
AV-Block °I, °II (Wenckebach, Mobitz, Periodic), or °III, 
 
  
 
 
Interventricular Block (right bundle-branch, left bundle-branch) 
 
7.6 
Safety 
Safety assessments will consist of monitoring and recording all infections, AEs and 
SAEs, the regular monitoring of hematology, blood chemistry, and regular 
measurement of vital signs. 
Infections 
All infection episodes must be recorded on the Infection CRF (CMV infections on the 
CMV Infection CRF); they should not be collected on the AE CRF. Infections should 
be listed with severity, relationships, sample site, genus and species of 
microorganism specified, start and end dates, action taken. 


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CMV infection is defined as seroconversion of a negative patient or isolation of CMV 
from urine, saliva, blood or any other tissue. Symptomatic or clinically apparent CMV 
infection should be classified according to the criteria of the Paris CMV workshop 
(1993) into presumptive and proven CMV disease. Briefly, the diagnosis of 
presumptive CMV disease requires the demonstration of CMV viremia by any method 
in addition to fever > 38°C for at least 2 days in the absence of another clinical 
source, combined with one of the following findings: atypical lymphocytosis > 3%, 
WBC count < 4,000/mm3 or platelet count < 100,000/mm3. The diagnosis of proven 
CMV disease requires, apart from the presence of signs and/or symptoms of organ 
involvement, the detection of CMV in the affected organ. Particular attention will be 
given to clinically apparent CMV infections (presumptive and proven CMV disease). 
Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Study drug includes the investigational drug 
under evaluation and the comparator drug or placebo that is given during any phase 
of the trial. Medical conditions / diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse 
event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe)  
2. its relationship to the study drug (Everolimus) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken i.e: 
 
(a) no action taken;  
(b) study drug dosage adjusted/temporarily interrupted; 
 
(c) study drug permanently discontinued due to this adverse event;  
(d) concomitant medication taken; 
 
(e) non-drug therapy given; 
 
(f) hospitalization/prolonged hospitalization 
5. whether it is serious, where a serious adverse event (SAE) is defined as one 
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: 


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 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 MACE or a graft loss 
Unlike routine safety assessments, SAEs are monitored continuously and have 
special reporting requirements; see Section 8.1. 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an 
adverse event is detected, it should be followed until its resolution, 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 
study as needed. 
Physical examination 
Information about the physical examination must be present in the source 
documentation at the study site. Significant findings that are present prior to study 
enrollment must be included in the Relevant Medical History / Current Medical 
Conditions CRF. Significant findings made after the start of the study which meet the 
definition of an AE must be recorded on the AE CRF. 


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Vital signs 
Height will be recorded at Screening visit (Visit 1) only. Vital signs will be recorded at 
every study visit, and include body temperature, 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. 
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), red blood cell and platelet count  
  
 
 
hematokrit (HK) 
Blood chemistry:  
sodium, potassium, urea, creatinine, glucose (fasting)  
  
 
 
uric acid, ALAT, ASAT, albumin, total bilirubin, total cholesterol,  
  
 
 
HDL, LDL, triglycerides, CPK 
Viral Serology: 
CMV (including pp65 Ag) 
  
 
 
only at Screening (or up to 6 months prior screening): 
  
 
 
EBV, Hepatitis B (HbsAg), Hepatitis C, HIV 
Frozen Storage: 
2 tubes of EDTA blood 
Urinanlysis:   
protein 
  
 
 
GFR will be calculated according to the formula given below,  
  
 
 
Section 7.7 
For determination of the drug levels see Section 7.10. 
Viral serology  
All patients should be tested for EBV, Hepatitis B (HBsAg), Hepatitis C, CMV and HIV 
prior to study inclusion (earlier tests  6 months are acceptable). Any patients with a 
positive Hepatitis B surface antigen or Hepatitis C or HIV will be excluded from study 
participation. If results are not available at the Screening visit, the patient may be 
included. If results of a newly initiated assessment at the Screening visit will be 
positive, the patient will subsequently be dropped from the study and administered 
the standard care provided by the center. 
During the course of the trial, only CMV status (including pp65 Ag) will be assessed. 
7.7 
Tolerability 
Renal safety and tolerability will be the main objective of this trial. The following 
variables of renal safety and tolerability will be obtained and recorded: 


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 Glomerular Filtration Rate (GFR) 
 
The glomerular filtration rate (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 levels elevates linearly over 
time in a predictable manner.  
 
The GFR will be calculated via MDRD (primary endpoint) and Cockcroft-Gault-
Formula: 
Calculated value of GFR in ml / min - MDRD formula 
For men: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x 
                            (albumin0,318) 
For women: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x  
 
 
 
       (urea nitrogen -0,17) x (albumin0,318) x 0.762 
with urea nitrogen = urea / 2.144.  
Calculated value of GFR in ml/min - Cockcroft-Gault formula 
For men: GFR=




dl
mg
Creatinine
Serum
kg
Weight
Body
Age
/
72
)
140
(



 
For women: GFR=




dl
mg
Creatinine
Serum
kg
Weight
Body
Age
/
72
)
140
(
85
,0




 
units: [g/dl] for albumin, [mg/dl] for serum creatinine, [mg/dl] for serum urea 
 
Furthermore, 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. 
 
 Serum Creatinine 
 
For the analysis of serum creatinine, venous blood will be drawn and analyzed in 
the center’s local laboratory. 
 
Besides changes from baseline, the slope of the decline in reciprocal serum 
creatinine (1 divided by serum creatinine) versus time will be analyzed as an 
indicator of progressive renal disease (for the creatinine slope, see Gretz 1994; 
Lacour 1992; Kaplan et al., 2003; Kasiske et al., 2001). 
 


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7.8 
Resource utilization  
Approximately 95% of treatment costs of transplanted patients are related to 
hospitalization, immunosuppressants and concomitant medication. As information on 
immunosuppressants, concomitant medication and dialysis is collected traditionally in 
all transplant clinical studies, the focus of additional resource utilization data 
collection should be on hospitalization events. Thus, all relevant information about 
initial hospitalization due to transplantation and hospitalization after transplantation 
(in the transplant center and outside) will be recorded. The information collected this 
way includes reason for admission (including admission for adverse events, including 
infection, for dialysis post transplantation, and for treatment of acute rejection), the 
dates of admission and discharge, number of days on Intensive Care Units and 
number of days on a normal ward. 
7.9 
Health-related Quality of Life 
None 
 
7.10 
Pharmacokinetics 
The actual sample collection times, and the date and time of the previous drug dose 
(Everolimus, Tacrolimus or Cyclosporin A) will be recorded on CRF using a 24 hour 
clock. 
Cyclosporin/Tacrolimus A whole blood levels will be measured starting at Screening 
Visit. For patients of the CNI group Cyclosporin A/Tacrolimus blood level will be 
measured at every study visit, for patients of the CNI-free group Cyclosporin A/ 
Tacrolimus blood level will be measured until Cyclosporin A or Tacrolimus is removed 
from the immunosuppressive regimen (Month 6 or 8 post Tx). 
Everolimus blood levels will be measured in all patients starting at Screening Visit 
and at every study visit thereafter (if applicable). 
 Cyclosporin A (CsA) whole blood tests 
 
Analysis of the Cyclosporin A whole blood levels will be performed locally at the 
center. Whole blood level for CsA will be assessed within 5 minutes before the 
Cyclosporin A administration (C0-h level). 
 Tacrolimus (Tac) whole blood tests 
Analysis of the Tacrolimus whole blood levels will be performed locally at the 
center. Whole blood level for Tac will be assessed 5 minutes before the 
Tacrolimus administration (C0-h level). 
 
 Everolimus whole blood tests  
For the analysis of the Everolimus whole blood levels 2 ml of blood should be 


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drawn in EDTA tubes. The C-0h level will be obtained with blood sampling within 5 
minutes prior to medication intake. 
 
7.11 
Pharmacogenetics/pharmacogenomics 
None. 
 
7.12 
Other biomarkers 
None. 
 
7.13 
Additional Assessments 
None 
 
8 
Safety monitoring 
8.1 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has signed the informed consent form 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 within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise 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 local Novartis 
 
 
 
 
 
 
 


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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 newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by 
the investigator to the local Novartis
 
 
 
 
 
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 and will be entitled to 
make recommendations for changes in study conduct. Details on the function of the 
DSMB 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 trial 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 


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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 written or 
electronic 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 a copy of the signed informed consent form. 
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 efficacy 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 
subjects 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 required corrections or additions. The CRFs are forwarded to 
Data Management by field monitors or by the investigational site, one copy being 
retained at the investigational site and one copy being the working copy for the 
monitor. Once the CRFs have been received by Data Management, their receipt is 
recorded and forwarded for data entry and data management processes. If CRFs 
have been sent for data entry by the investigational site directly, Data Management 
staff has to review the CRFs upon receipt for any serious adverse event. 
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research 
Organization staff using double data entry with verification upon second entry. Text 
items (e.g. comments) are entered once and checked manually against the CRF. 
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, according the obvious 
correction document. 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 Data Management 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 


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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 made available for data 
analysis. Any changes to the database after that time can only be made by joint 
agreement between the Trial Statistician and the Clinical Trial Leader (both from the 
German CPO). 
 
10 
Statistical methods 
10.1 
Statistical methods  
 
 Analyses will be done when all patients have completed the 
trial at 18 months post Tx (or discontinued prematurely). The following periods will be 
considered for analyses: 
 The primary analysis of renal safety and tolerability concerns the period of 
randomized treatment between Month 6 (baseline) and Month 18 or the last 
assessment within this period in the event of a patient’s premature discontinuation 
from the study. If indicated, e.g. for analysis of renal function and type and 
frequency of adverse events, the period from Month 6 to Month 18 may be 
portioned into (a) the switch period between Month 6 and Month 9 and (b) the 
maintenance period between Months 9 and 18 after Tx. 
 As a separate study period, the first 6 months between transplantation and Month 
6 post Tx will be analyzed with regard to treatment, efficacy, and safety of the 
immunosuppressive regimen. 
 To allow conclusions about the total treatment period of the CNI-based versus the 
CNI-free treatment regimen including initial treatment and randomized therapy, 
the total period between transplantation and Month 18 will be analyzed and 
compared between the two treatment groups. In patients who discontinue 
prematurely from the study, both the last available information under study 
treatment as well as an additional assessment at Month 18 will be analyzed. 
The group of patients who were not randomized to one of the two treatment groups at 
Month 6 (Baseline visit) will be handled as a third patient group within exploratory 
analyses and described with respect to primary and secondary outcome variables 
and treatment variables for the same periods as described above. 
Adverse events will be analyzed separately for the initial 3 months period between 
Screening and Baseline visit and for the randomized treatment period between 
Baseline visit (Month 6) and Month 18, but also for the total treatment period. 


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Significant events like rejection episodes, hemodynamic compromise, and MACE will 
additionally be analyzed for the period between transplantation and Screening 
(Month 3 post Tx). 
Unless otherwise stated, all statistical tests will be two-sided and use the 0.05 level of 
statistical significance. All summary statistics will be presented by treatment group. 
Frequency distributions will be provided for categorical variables and the two 
treatment groups will be compared with chi2-tests. Descriptive statistics of mean, 
standard deviation, minimum, median and maximum will be presented for continuous 
variables, comparisons of the two treatment groups will be performed with suitable 
chosen 2-sample tests. Time to event data including rates of affected patients will be 
assessed by Kaplan-Meier statistics and compared between the two groups with the 
logrank test. 
Data from all centers that participate in this study will be combined. 
A detailed description of the statistical evaluation of this study will be provided in a 
Statistical Analysis Plan which will be finalized prior to closure of the study database. 
 
10.2 
Populations for analysis 
The enrolled patient population (ENR population) will include all patients who signed 
an informed consent regardless whether they received study treatment or not. 
The Safety Population (SAF population) will consist of all patients who signed an 
informed consent and who were treated with at least one dose of any 
immunosuppressive medication after the Screening visit. 
Note: The statement that a patient had no adverse events constitutes a safety 
assessment. 
The Randomized Population (RAN) is defined by all patients who were randomized at 
Baseline visit. This population will include patients who were randomized but not 
treated with the randomized medication. 
The ITT population will consist of all randomized patients who received at least one 
dose of any immunosuppressive therapy after Baseline Visit (Month 6) and have at 
least one post-baseline assessment of the primary outcome variable (renal function 
based on MDRD method). Randomized patients without data on the primary outcome 
variable will be excluded from this population; their data will be analyzed for the initial 
treatment period (up to Month 6) and within the RAN and SAF. 
Following the intent-to-treat principle, patients will be analyzed according to the 
treatment group they were assigned to at randomization. 
The Per-protocol Population will consist of all ITT patients who did not show major 
deviations from the protocol procedures that may have an impact on the study 
outcome and who have completed the treatment phase at Month 18 according to 
protocol. Criteria that are assumed to have such an impact will be defined before 
analysis during the Blind Review Meeting. 


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Besides the two patient groups who were eligible for randomization, a third patient 
group will be defined in whom a heart transplantation was performed but who did not 
qualify for randomization at Baseline visit (Month 6). This group will be addressed as 
“not randomized patients” (NRP) and described with respect to treatment and 
outcome variables. 
 
10.3 
Background and demographic characteristics 
Demographic and background information will be summarized for the ENR-, the 
SAF-, the ITT-, and the PP- Population, using frequency distributions for categorical 
variables and descriptive statistics of mean, standard deviation, minimum, median 
and maximum for continuous variables. Background information includes prior 
medication, past/current medical conditions and transplant history. 
Medical history will be coded using MedDRA and will be presented by system organ 
class, MedDRA preferred term and treatment group. Separate tables will be provided 
for past medical condition and current medical condition. Prior medication will be 
coded according to WHO Drug Reference List. 
In addition to these variables which were evaluated at Screening (Visit 1, Month 3 
post Tx), the course of renal function (GFR) as well as efficacy variables (treated 
acute rejection, biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 
2004 grade ≥ 2R, acute rejection associated with hemodynamic compromise, graft 
loss / re-transplantation, death) will be determined and properly described for the 
period between Transplantation and Baseline (Visits 2 - Month 6 post Tx). 
The two treatment groups will be compared descriptively with respect to these 
variables. Further, the NRP group will be described using the same variables. 
No formal statistical testing is planned for comparability purposes. 
 
10.4 
Study treatments  
10.4.1 
Study medication 
Study medication is Everolimus, RAD001); the other components of the 
immunosuppressive regimens are considered as concomitant medication. 
Duration (days) of Everolimus, study medication application will be summarized. 
Dosage averages will be calculated including and excluding zero doses for periods of 
temporary interruption of study medication regardless of whether this was due to 
safety reasons or patients’ non-compliance. Daily Everolimus, dose levels will be 
summarized with mean, standard deviation, minimum, median, and maximum by time 
interval. Frequency of dose reduction (including temporary dose interruption) for 
safety reasons as per protocol guidelines as well as average daily dose will be 
presented by visit. Reasons for dose adjustments (including temporary dose 


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interruption) will be presented by frequency distribution. Permanent treatment 
discontinuations will be analyzed by frequencies. 
These analyses will be performed per treatment group, for the ITT- and the PP 
population and related to the study phases (see section 10.1). 
10.4.2 
Concomitant therapy  
Daily Cyclosporin A and Tacrolimus doses adjusted by the patients’ visit-specific 
body weight, MPA doses, and steroids (expressed in doses equivalent to prednisone) 
will be summarized by visit and in the same way as the study medication. Data will be 
presented separately for each treatment group. Induction therapy (Basiliximab or 
ATG or no induction) received by patient will be summarized by treatment group, for 
the total (SAF) population, but also for the NRP group. 
Duration (days) of treatment with Cyclosporin A, Tacrolimus, MPA, and steroids as 
well as frequency of Cyclosporin A, Tacrolimus and MPA dose adjustments (including 
temporary dose interruption) for safety reasons as per protocol guidelines will be 
determined. Reasons for dose adjustments (including temporary dose interruption) 
will be presented by frequency distribution. Permanent treatment discontinuations will 
be analyzed using frequency distribution. All other immunosuppressive therapies will 
be summarized by ATC (Anatomical, Therapeutic, Chemical) classes. 
All analyses for concomitant medication will be presented per treatment group and 
study phase (see section 10.1). 
Corresponding data of the NRP group will be reported in a similar way. 
Medications other than those mentioned in this section taken concomitantly with the 
study medication will be summarized by treatment group and study period through 
frequency tables. Concomitant medication will be coded and summarized according 
to the ATC classification system. 
 
10.5  
Primary objective 
The primary aim of this study is to show superior renal function under the CNI-free 
regimen compared to the CNI-based regimen with respect to GFR as calculated by 
MDRD method. 
10.5.1 
Variable 
The primary variable for assessment of renal function is the 
 glomerular filtration rate (GFR) at Month 18, as assessed by the MDRD method 
(recalculated values, see section 7.5). 


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10.5.2 
Statistical hypothesis, model, and method of analysis 
According to the recommendation given in the Points to Consider document on 
“Adjustment for Baseline Covariates” (CPMP, 2003), the null hypothesis H0 of similar 
GFR level in both treatment groups 
H0: μCNI-free = μCNI-based 
will be tested against the two-sided alternative hypothesis of different efficacy 
(different GFR levels at month 18 after Tx) of the CNI-free regimen compared to the 
CNI-based regimen 
H1: μCNI-free ≠ μCNI-based 
with an analysis of covariance (ANCOVA) using “treatment” and “center” as factors 
and “baseline GFR value at Baseline visit 2 (Month 6)” as covariate. Type-I error 
probability will be set to a two-sided α=0.05. Adjusted means (=LS-means, LS: least 
square means) will be presented for the treatment contrast of GFR at Month 18 post 
Tx together with its confidence interval and a two-sided p-value. 
The ITT population will be used for the primary analysis. This analysis follows the 
intention-to-treat principle and thus reflects the actual performance of the 
investigational drug under practical conditions (“pragmatic approach”). 
10.5.3 
Handling of missing values/censoring/discontinuations with respect to 
the primary outcome variable 
If a patient discontinues from the study prematurely missing data with respect to the 
target parameter will be substituted by the last recorded value (last observation 
carried forward, LOCF). The LOCF method will only be applied if a patient has at 
least one assessment after Baseline, i.e. on Visits Months 8 to 18. Otherwise, the 
patient will be excluded from efficacy analysis within the ITT population (see section 
10.2). Under the assumption that the GFR will remain fairly stable or even worsen in 
the CNI group but will probably even improve in the CNI-free group, this strategy 
corresponds to a conservative estimate of the therapy effect within both treatment 
groups. 
Additionally, sensitivity analyses will be performed including the following imputation 
strategy: 
- 
Missing data for the primary outcome variable will be replaced by the mean 
of the non-missing values in the same treatment group. Further sensitivity 
analyses may be specified in the statistical analysis plan. 
10.5.4 
Supportive analyses 
The course of the GFR will be of special interest. Changes from Baseline to each 
post-baseline measure will be calculated by treatment group for each study visit. In 
addition, the GFR as recalculated by the Cockcroft-Gault method will be analyzed in 
the same manner (see secondary objectives). 


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In addition to quantitative analyses, the frequency distributions of patients with an 
improved GFR at study month 18 compared to BL (Month 6 post Tx) will be 
compared between the two regimens. 
If patients of the ITT population are switched from the CNI group to the CNI-free 
group during the study or during follow-up, they will be analyzed in their randomized 
group. If appropriate, a subgroup analysis will be performed comparing patients of 
the CNI group with and without switch to CNI-free treatment including a further 
analysis comparing both subgroups to the randomized CNI-free group. If treatment 
will be modified in the CNI-free group, they will be analyzed as randomized. 
It is planned to evaluate renal function and efficacy variables also at Month 18 in 
patients who discontinue prematurely (prior to Month 18) from the trial. An additional 
exploratory analysis will be conducted using the assessments at Month 18. 
Additionally to the analyses of data from the interval between BL (Month 6) and 
Month 18, the primary outcome variable will also be evaluated for the interval 
between Transplantation (prior to Tx) and Month 18. 
Results from these supportive analyses will be interpreted in an explorative manner. 
Corresponding data from the NRP group will be described in a similar manner. 
 
10.6 
Secondary objectives 
10.6.1 
Efficacy  
The following secondary efficacy variables will be analyzed in an explorative manner: 
 
Occurrence of treatment failure up to Month 18 defined as composite endpoint of 
biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade 
≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft 
loss / re-transplant, death, loss to follow up (at least one condition must be 
present).  
 
Occurrence of MACE and each of its components at Month 18 
Additionally to the analyses of data from the interval between BL (Month 6 post Tx) 
and Month 18, all secondary outcome criteria will also be evaluated for the interval 
between Month 0 (prior to Tx) and Month 18. 
Event data: 
Event rates will be estimated using the Kaplan-Meier method to handle patients who 
discontinue the treatment prior to suffering from an event adequately. The two groups 
will be compared using the logrank test. 
This procedure will be applied for the composite endpoint of treatment failure and 
each of its components, as well as MACE and each of its components. 
Narratives including relevant medical information will be provided for each biopsy 
proven acute rejection, CAV, graft loss, or death. 


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Corresponding data from the NRP group will be described in a similar manner. 
10.6.2 
Safety 
Safety variables will be analyzed separately for the period between a) Screening and 
Baseline, b) for the period between Baseline and Month 9, c) for the period between 
Baseline and final assessment (Month 18 or date of premature withdrawal from the 
study), d) as well as for the total treatment period (Screening to Month 18). For the 
randomized treatment period, analyses will be performed according to the treatment 
group into which the patients were randomized. 
All analyzes of safety parameters will be based on the safety population. 
Corresponding data from the NRP group will be described similarly for the period 
between Screening and Baseline visit. 
The key safety variables which will be analyzed will be as follows. 
 
Incidence and severity of infections, in particular clinically apparent CMV 
 
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events 
(SAEs) 
 
Incidence of AEs leading to discontinuation from the study 
 
Relative frequency of abnormal vital signs measurements and laboratory 
parameters 
The incidence rates for (serious) adverse events and infections will be analyzed by 
treatment group. 
AEs/Infections 
Generally, infections data are analyzed together with AE data. In addition, infection 
data will be analyzed separately. 
Data collected by AE CRFs and by Infection CRFs and CMV-CRFs are to be coded 
with the MedDRA dictionary that gives preferred term and body system information. 
The incidence of AEs will be summarized by body system, preferred term, severity, 
and relationship to study drug. All information pertaining to AEs noted during the 
study will be listed by treatment group and patient, detailing verbatim given by the 
investigator, the preferred term, the body system, start/end dates, severity and drug-
relatedness. The AE onset will also be shown relative (in number of days) to the day 
of initial dose per study period (within the first 3 months, after Baseline (Month 6)). 
In addition to being analyzed similarly as AEs, as described above, the relative 
frequency of infection by type and micro-organism will be tabulated. AEs occurring 7 
or more days after the discontinuation of study medication will not be included in 
AE/infection summary tables. 
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. Shift tables describing changes from status prior 
transplantation (Month 0) and Baseline based on the expanded normal limits will be 


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presented for treatment endpoints (study Month 6 and 18) and worst observations 
during the different study periods (up to Month 6 as well as between Month 6 and 
Month 18). 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 (e.g. the highest will be chosen for serum creatinine, the 
lowest for leukocytes). Further, descriptive statistics of change from baseline of all 
laboratory variables will be presented by visit. A by-patient listing of all laboratory 
data (with clinically notable abnormalities being flagged) will be generated. Only 
assessments obtained up to 2 days after the discontinuation of study medication will 
be considered “on-treatment” and analyzed with relationship to Everolimus. 
Vital signs 
Vital signs variables include measurements of oral body temperature, systolic and 
diastolic blood pressures, pulse and body weight. Vital signs will be examined for 
abnormal values and change from Baseline according to pre-specified clinically 
notable criteria (see Appendix 2). Appropriate incidence rates of clinically notable 
abnormalities for between-group differences will be provided. Further, descriptive 
statistics of change from baseline of all vital signs variables will be presented by visit. 
A by-patient listing of all vital signs (with clinically notable abnormalities being 
flagged) will be generated. Shift tables describing changes from baseline based on 
clinically notable criteria will be presented for treatment endpoint (Month 18) and 
worst on-treatment observations. Only assessments obtained up to 2 days after the 
discontinuation of study medication will be considered “on-treatment”. 
10.6.4 
Tolerability 
In addition to the analysis of the primary outcome variable of renal safety and 
tolerability, the following will be analyzed: 
 
Renal function as assessed by Cockcroft-Gault at moth 18 after Tx 
 
Serum creatinine and creatinine slope (1/serum creatinine versus time) including 
the treatment period between BL (Month 6) and Month 18 
Analyses of renal function as determined by other calculations (serum creatinine, 
glomerular filtration rate (GFR, Cockcroft-Gault)) will be evaluated in the same 
manner as described for the primary outcome measure. 
In addition to quantitative analyses, the frequency distributions of patients with an 
improved GFR at study Month 18 compared to BL (Month 6) will be compared 
between the two regimens. 
The creatinine slope (1 / serum creatinine versus time) will be determined from all 
assessments between Month 6 and Month 18 (both visits included) using a linear 
regression model. These slopes will be compared with a two-sided Wilcoxon rank-
sum test between the treatment groups. 
Additionally, tolerability of study medication will 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 


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results, adverse events, or toxicity. A number of reasons are pre-defined in 
section 7.7 of this protocol. The frequency distribution of these reasons will be 
presented with absolute and percent values. The most frequent reasons (total n  5) 
for discontinuation and/or conversion as well as the total number of patients who are 
affected by such intolerability of study medication will be compared between the two 
treatment groups using the exact Fisher test. 
10.6.5 
Resource utilization 
The treatment costs which arise from hospitalization, immunosuppressants, dialysis 
and concomitant medication will be performed separately by the Health Economics 
Department of Novartis. Results will be added in an Appendix to the Clinical Study 
Report. 
10.6.6 
Health-related Quality of Life 
No health-related Quality of Life assessments are planned to be performed in this 
study. 
10.6.7 
Pharmacokinetics 
Analysis of the Cyclosporin A, Tacrolimus and Everolimus blood levels will be done 
by treatment group and separately for the treatment phases (up to and after Month 
6), the NRP group will be analyzed. 
Everolimus 
Mean blood level values of Everolimus will be presented in tabular form for each 
timepoint (visit window) and as mean value over time. Trough values will be tried to 
be kept in a therapeutic window of 5 – 10 ng/mL during the whole study. The number 
of patients with deviations from the therapeutic window will be counted (separately for 
values “below” and “above” therapeutic range) and tabulated per visit and in total. 
Patients with any trough level value outside the therapeutic window will be described 
in detail by narratives reporting also Everolimus dose level and dose adjustments, if 
applicable. 
Cyclosporin A 
Mean blood level values of Cyclosporin A will be presented in tabular form for each 
timepoint and as mean value over time. Blood levels will be tried to be kept in 
therapeutic windows. The number of patients with deviations from the therapeutic 
window (see section 6.5.2) will be counted and tabulated per visit and in total. 
In the CNI-free group mean blood level values of cyclosporin A will be presented in 
tabular form for each assessment up to Month 8. 
Tacrolimus 
Mean blood level values of Cyclosporin A will be presented in tabular form for each 
timepoint and as mean value over time. Blood levels will be tried to be kept in 


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therapeutic windows. The number of patients with deviations from the therapeutic 
window (see section 6.5.2) will be counted and tabulated per visit and in total. 
In the CNI-free group mean blood level values of Tacrolimus will be presented in 
tabular form for each assessment up to Month 8. 
10.6.8 
Pharmacogenetics/pharmacogenomics 
No measurements of pharmacogenetics/pharmacogenomics will be done in this trial. 
10.6.9 
Biomarkers 
No biomarkers will be assessed in this trial. 
10.7. 
Interim analysis 
No interim analysis is planned. 
10.8 
Sample size calculation 
The probable difference between the CNI-free - and the CNI-group in the GFR is 
estimated as  = 8 ml/min with  = 16 ml/min. With =.05 (two sided significance 
level) and 1- = 90% (power), n=86 patients per group are required to demonstrate 
superior efficacy of the CNI-free regimen compared to the CNI-group in the GFR 
using the t-test 
. To compensate for some 
uncertainty of the assumptions for sample size calculation, the calculated sample 
size is increased by  15%. Therefore, a total number of N=200 patients (n=100 per 
treatment group) will be randomized and treated in both treatment arms after 
Baseline (Month 6 post Tx). 
In order to achieve the planned number of randomized patients as exactly as 
possible which may be hampered by the delay between inclusion (Screening – 
Month 3 post Tx) and randomization (Baseline - Month 6 post Tx), the rate of non-
randomized patients will be determined when 150 patients will be randomized, and 
extrapolated to a number of 200 randomized patients. Recruitment will be stopped, 
when 200 patients + 120% of the extrapolated rate of non-randomized patients will be 
included at Screening. The further 20% of non-randomized patients are considered 
as a safety margin to avoid underrecruitment of randomized patients. 
 
According to amendment 4, enrollment into this study will be terminated by 31st 
December 2015, by that time about 165 patients will have been recruited into this 
trial. Under the assumptions above, this would lead to a power of 82%. Since this 
sample size will contain also patients who discontinued the trial/medication early or 
who had other protocol deviations, the actual power will even be somewhat lower. 
 
Under the assumptions specified in the initial protocol, the study will still have 82% 
power with the now reduced sample size. That means that the scientific value will not 


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be compromised with 82% probability. However, even if the study should just fail to 
reach statistical significance, it will most likely still show the presence (or absence) of 
a non-significant trend, which would contribute to the body of evidence for this 
treatment option. 
 
 
11 
Discussion and rationale for study design features  
A parallel group design is the most appropriate model to show differences between 
two treatments. The design includes an initial phase of 3 months during which 
patients are treated according to center standard outside the trial and an additional 3- 
months Run in phase with a Cyclosporin A or Tacrolimus based immunosuppressive 
regimen which is required by clinical needs. 
Therapy switch from the CNI-based to the CNI-free regimen after randomization 
follows experiences from previous clinical trials as well as the recommendations of 
the second German-Austrian Certican Consensus Conference (Rothenburger et al., 
2007b, see section 1 of this protocol). 
Blinding of the two study treatments was not reasonable in this trial because dosing 
of Everolimus,, Tacrolimus and Cyclosporin A has to be based upon trough levels. 
Therefore the study has to be planned open-label. However, the endpoint of the 
study is GFR which is an objective outcome variable depending on laboratory 
measures. An influence of open-label treatment on this primary outcome variable is 
limited because dosing behavior will mainly be governed by drug trough levels but 
only in a few expected cases of renal toxicity by the creatinine level. 
The randomization visit at Month 6 was scheduled at a time-point after Tx when the 
adapation of the individual organism to the graft is considered stable, on average of 
all transplant patients. It is to be expected that the immunological risk at this timepoint 
is lower, and the benefit of CNI elimination will continue. For this purpose, a CNI-free 
regimen will be compared with a CNI based immunosuppressive regimen. It is 
expected, that the CNI-free regimen will result in a superior renal function when 
compared to the CNI -based regimen, while it is as safe and effective as the CNI-
based regimen with regard to occurrence of biopsy proven acute rejection episodes 
of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes 
associated with hemodymamic compromise, graft loss / re-transplant, death, and lost 
to follow up, as well as of treatment failure (composite endpoint). 
A maintenance treatment period of about 9 months under the two regimens, CNI-
based versus CNI-free, is considered sufficiently long to explore any differences 
between both groups in the glomerular filtration rate, which is the primary outcome 
measure. 
In summary, the present study design is adequate for investigating the influence of 
different immunosuppressive regimens with or without CNI on renal function. 


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12 
References 
1. Chapman TM, Perry CM, Everolimus. Drugs 2004;64:861-72. 
2. Dalla Pozza R, Kleinmann A, Bechtold S, Netz H. Hypertension in heart and 
heart-lung transplanted children: does impaired baroreceptor function play a role? 
Transplantation 2006;81:71-5. 
3. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft 
rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 
2003;349:847-58. 
4. Eisen H, Kobashigawa J, Starling RC, Valantine H, Mancini D. Improving 
outcomes in heart transplantation: the potential of proliferation signal inhibitors. 
Transplant Proc 2005;37:4S-178. 
5. Gretz NM. How to assess the rate of progression of chronic renal failure in 
children? Pediatr Nephrol. 1994;8:499-504. 
6. Groetzner J, Kaczmarek I, Meiser B, Muller M, Daebritz S, Reichart B. Sirolimus 
and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a 
cardiac transplant patient with chronic renal failure. J Heart Lung Transplant 
2004;23:770-3. 
7. Hummel M. Recommendations for use of Certican®(Everolimus) after heart 
transplantation: results from a German and Austrian Consensus Conference. J 
Heart Lung Transplant 2005;24(suppl):S196-200. 
8. Kaplan B, Schold J, Meier-Kriesche HU. Poor predictive value of serum creatinine 
for renal allograft loss. Am J Transplant. 2003;3:1560-1565. 
9. Kasiske BL, Andany MA, Hernandez D, Silkensen J, Rabb H, McClean J, Roel 
JP, Danielson B. Comparing methods for monitoring serum creatinine to predict 
late renal allograft failure. Am J Kidney Dis. 2001;38:1065-1073. 
10. Keogh A. Calcineurin inhibitors in heart transplantation. J Heart Lung Transplant 
2004;23:S202-6. 
11. Krämer BK, Neumayer HH, Stahl R, et al. Graft function, cardiovascular risk 
factors, 
and 
sex 
hormones 
in 
renal 
transplant 
recipients 
on 
an 
immunosuppressive regimen of Everolimus, reduced dose of Cyclosporin, and 
basiliximab. Transplant Proc. 2005;37:1601-4. 
12. Lacour B. Creatinine and renal function. Nephrologie (France). 1992;13:73-81. 
13. Lehmkuhl HB, Mai D, Dandel M, et al. Observational study with Everolimus 
(Certican) in combination with low-dose Cyclosporin A in de novo heart transplant 
recipients. J Heart Lung Transplant 2007 Jul; 26:700-4. 
14. Lindenfeld JA, Miller GG, Shaker SF, et al. Drug therapy in the heart transplant 
recipient: part II: immunosuppressive drugs. Circulation 2004;110:3858-65. 
15. Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate 
mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-
year randomized multicenter, Phase III study. Transplantation 2005;80:244-52. 


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16. Lyster H, Panicker G, Leaver N, Banner NR. Initial experience with sirolimus and 
mycophenolate mofetil for renal rescue from Cyclosporin A nephrotoxicity after 
heart transplantation. Trandplant Proc 2004;36:3167-70. 
17. Monaco AP, Morris PJ. Reduction in calcineurin inhibitor exposure and 
maintenance of effective immunosuppression: clinical experience with Everolimus 
(Certican). Transplantation 2005;79(suppl):S67-8. 
18. Organ Procurement and Transplantation network reports 1996-2001: Available at 
http://www.optn.org. 
19. Rothenburger M, Teerling E, Bruch C, et al. Calcineurin inhibitor-free 
immunosuppression using Everolimus (Certican) in maintenance heart transplant 
recipients: 6 months’ follow-up. J Heart Lung Transplant 2007a;26:250-7. 
20. Rothenburger M, Zuckermann A, Bara C, et al. Recommendations for the use of 
Everolimus (Certican®) in heart transplantation: results from the second German – 
Austrian Certican consensus conference. J Heart Lung Transplant 2007b;26:305-
11.  
21. Schweiger M, Wasler A, Prenner G, Tripolt M, Schwarz M, Tscheliessnigg KH. 
Late acute cardiac allograft rejection: new therapeutic options? Transplant Proc 
2005;37:4528-31. 
22. Stewart S, Winters G L, Fishbein M C, et al. Revision of the 1990 Working 
Formulation for the Standardization of Nomenclature in the Diagnosis of Heart 
Rejection. J Heart Lung Transplant 2005;24(11):1710-20. 
23. Tedesco H, Pascual J, Mage J, et al. 36 month analysis on efficacy and safety of 
2 doses of Everolimus combined with reduced dose Neoral in de novo kidney 
transplant recipients. Abstract 1281 of the World Transplant Congress, July 2006, 
Boston, MA. 
24. Tedesco H, Vitko S, Pascual J, et al. 12-month safety and efficacy of Everolimus 
with reduced exposure Cyclosporin A in de novo renal transplant recipients. 
Transplant Int (in press). 
25. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimized Cyclosporin A dosing 
in renal transplant recipients: 6-month safety and efficacy results of two 
randomized studies. Am J Transplant 2004;4:626-35. 
26. Vitko S, Margreiter R, Weimar W, et al. Three-year efficacy and safety results 
from a study of Everolimus versus mycophenolate mofetil in de novo renal 
transplant recipients. Am J Transplant 2005;5:2521-30. 


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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 2001/83/EC and US 
Code of Federal Regulations Title 21), 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. A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant 
data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, and regulatory authorities as 
required. 
Informed consent 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. Informed consent must be obtained before conducting 
any study-specific procedures (i.e., all of the procedures described in the protocol).  
The process of obtaining informed consent should be documented in the patient 
source documents. 
The informed consent form that complies with regulatory requirements and is 
considered appropriate for this study is provided separately. Any changes to the 
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 


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immediate action required for the safety of any patient included in this study, even if 
this action represents a deviation from the protocol. In such cases, Novartis 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, the study 
medication 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 the local language and comply with the legal 
requirements. They will include storage conditions for the drug and the randomization 
number but no information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of 
study drug in a drug accountability ledger. Drug accountability will be noted 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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Appendix 2:  Clinically notable laboratory values and vital signs 
 
Notable criteria 
Laboratory variable 
Standard units 
SI units 
Liver function and related variables 
SGOT (AST) 
3  ULN 
3  ULN 
SGPT (ALT) 
3  ULN 
3  ULN 
GGT 
3  ULN 
3  ULN 
Bilirubin 
2.0 mg/dL 
34.2 mol/L 
Alkaline phosphatase 
3  ULN 
3  ULN 
Albumin 
None 
None 
Total protein 
None 
None 
Renal function, metabolic and electrolyte variables 
Urea 
None 
None 
Creatinine 
>30% above baseline 
>30% above baseline 
Uric acid 
M 12 mg/dL 
F 9 mg/dL 
M 714 µmol/L 
F 535 µmol/L 
Glucose 
<45 mg/dL 
>250 mg/dL 
<2.5 mmol/L 
>13.9 mmol/L 
Cholesterol 
350 mg/dL 
9.1 mmol/L 
Triglycerides 
750 mg/dL 
8.5 mmol/L 
CPK (MB) 
None 
None 
Sodium 
None 
None 
Chloride 
None 
None 
Potassium 
3.0 mEq/L 
6.0 mEq/L 
3 mmol/L 
6 mmol/L 
Magnesium 
<0.97 mg/dL 
>3.65 mg/dL 
<0.4 mmol/L 
>1.5 mmol/L 
Calcium 
6 mg/dL 
13 mg/dL 
1.5 mmol/L 
3.2 mmol/L 
Phosphate 
None 
None 
Amylase 
2  ULN 
2  ULN 
Testosterone* 
None 
None 
LH 
None 
None 
FSH 
None 
None 
Lipase 
2  ULN 
2  ULN 
*male patients 
 
 


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Notable criteria 
Laboratory variable 
Standard units 
SI units 
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  
Urinalysis 
 
 
Albumin (mg/dL) 
None 
None 
Glucose (mg/dL) 
None 
None 
Erythrocytes 
None 
None 
Protein/creatinine 
<200 mg/g 
<22.7 mg/mmol 
 
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 
a decrease of ≥30 that results in ≤90  
or 
 <75 (mm/Hg) 
Diastolic BP (mm/Hg) 
Either an increase of ≥20 that results in ≥105  
or  
>115 (mm/Hg) 
or 
a decrease of ≥20 that results in ≤50  
or  
<40 (mm/Hg) 
Temperature (°C) 
None 
Weight (kg) 
None 
 


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Appendix 3:  Possible Cyclosporin A drug interactions 
All of the individual drugs cited below are well substantiated to interact with 
Cyclosporin A. In addition, concomitant non-steroidal anti-inflammatory drugs, 
particularly in the setting of dehydration, may potentiate renal dysfunction. 
A) 
Drugs that may potentiate renal dysfunction 
Antibiotics 
Antifungals 
Gastrointestinal agents 
Gentamicin 
Tobramycin 
Vancomycin 
Trimethoprim with-
sulfamethoxazole 
Amphotericin B 
Ketoconazole 
Cimetidine 
Ranitidine 
Antineoplastics 
Anti-inflammatory drugs 
Immunosuppressives 
Melphalan 
Azapropazon 
Diclofenac 
Naproxen 
Sulindac 
Tacrolimus 
B) 
Drugs that alter Cyclosporin A concentrations 
Cyclosporin A is extensively metabolized. Cyclosporin A concentrations may be 
influenced by drugs that affect microsomal enzymes, particularly cytochrome P-450 
-A. Substances that inhibit this enzyme could decrease metabolism and increase 
Cyclosporin A concentrations. Substances that are inducers of cytochrome P-450 
activity could increase metabolism and decrease Cyclosporin A concentrations. 
Monitoring of circulating Cyclosporin A concentrations and appropriate Cyclosporin 
A dosage adjustments are essential when these drugs are used concomitantly. 
Drugs that increase Cyclosporin A concentrations 
Calcium channel blockers 
Antifungals 
Antibiotics 
Diltiazem 
Nicardipine 
Verapamil 
Ketoconazole 
Fluconazole 
Itraconazole 
Clarithromycin 
Erythromycin 
Glucocorticoids 
Other drugs 
 
 
Bromocriptine 
Danazol 
 
Grapefruit and grapefruit juice affect Cyclosporin A metabolism, increasing blood 
concentrations of Cyclosporin A, thus should be avoided. Methylprednisolone, 
Metoclopramide, Allopurinol may have a small influence on Cyclosporin A 
metabolism, by slightly increasing blood concentrations of CsA. Thus, if patients are 
on methylprednisolone, metoclopramide, or allopurinol, the dose should be kept 
stable throughout the trial. 


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Drugs that decrease Cyclosporin A concentrations 
Antibiotics 
Anticonvulsants 
Other drugs 
Nafcillin 
Rifampin 
Phenobarbital 
Phenytoin 
Octreotide 
Rifabutin is known to increase the metabolism of other drugs metabolized by the 
cytochrome P-450 system. The interaction between rifabutin and Cyclosporin A has 
not been studied. Care should be exercised when these two drugs are administered 
concomitantly. Troglitazone, Carbamazepine and Ticlopidine may also decrease CsA 
concentrations, but to a lesser extent. Thus, if patients are on stable therapy with 
these drugs, the dose should be kept stable throughout the trial, and patients should 
be closely monitored throughout the study. 
 
Other drug interactions 
Reduced clearance of prednisolone, digoxin and lovastatin and simvastatin has been 
observed when these drugs are administered with Cyclosporin A. In addition, a 
decrease in the apparent volume of distribution of digoxin has been reported after 
Cyclosporin A administration. Severe digitalis toxicity has been seen within days of 
starting Cyclosporin A in several patients taking digoxin. Cyclosporin A should not be 
used with potassium-sparing diuretics because hyperkalemia can occur. 
During treatment with Cyclosporin A, vaccination may be less effective. The use of live 
vaccines should be avoided. Myositis has occurred with concomitant lovastatin and 
simvastatin, frequent gingival hyperplasia with nifedipine, and convulsions with high 
dose methylprednisolone. 
 
Population screen for co-medications influencing Everolimus 
Patients 
concomitantly 
receiving 
erythromycin 
antibiotics 
(erythromycin 
or 
azithromycin) had an average 20% lower Everolimus CL/F than those not receiving 
these co-medications. A single patient receiving intraconazole had a 3-fold lower 
Everolimus CL/F compares with the population average. These observations indicate 
that potent inhibitors of CYP3A can decrease the clearance of Everolimus and 
increase its blood levels. 
Additional drugs or drug classes explored in the population model for which no 
influence on Everolimus CL/F was detected were: atorvastatin (n=74 patients), 
pravastatin (n=41), simvastatin (n=18), gemfibrozil (n=10), quinolone antibiotics 
(n=124), Bactrim® (n=450), and various calcium-channel blockers (dihydropyridines, 
n=267, diltiazem, n=22 and verapamil, n=5). 
Inducers of CYP3A4 (e.g. rifampin, carbamazepine, phenytoin, and barbiturates have 
been shown or have the potential to decrease exposure to Everolimus, If these drugs 
are necessary, Everolimus, doses may have to be increased. Potent inhibitors of 


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CYP3A4 such as ketoconazole, itraconazole and fluconazole should be avoided 
while the patient is on study medication. Everolimus has the potential to increase the 
exposure to terfenadine, astemizole and cisapride; hence these drugs should be 
avoided. In vitro data suggested that Everolimus may have the potential to interact 
with quinidine, fluoxetine and paroxetine, and alternative medications should be 
considered. Since the potential for drug interaction with digoxin has not been 
evaluated, patients on digoxin should have periodic measurement of digoxin levels. 
 
Appendix 4:  Possible Tacrolimus Drug-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. Initial clinical experience with the co-administration of 
Tacrolimus and Cyclosporin A resulted in additive/synergistic nephrotoxicity. Patients 
switched from Cyclosporin A to Tacrolimus should receive the first Tacrolimus dose 
no sooner than 24 hours after the last Cyclosporin A dose. 
Dosing may be further delayed in the presence of elevated Cyclosporin A levels. 
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 
bromocriptine 
 


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Metoclopramide 
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). 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. 


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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 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. 
Other Drug Interactions  
Immunosuppressants may affect vaccination. Therefore, during treatment with 
Tacrolimus, vaccination may be less effective. The use of live vaccines should be 
avoided; live vaccines may include, but are not limited to measles, mumps, rubella, 
oral polio, BCG, yellow fever, and TY 21a typhoid.1 
Reference: Prograf package Insert, Revised April 2006. 


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Appendix 5:  Dose Reduction of Everolimus and MPA 
Dose reduction or temporary interruption may be performed for MPA or Everolimus. 
However, Everolimus should be continued on a stable dose level, if possible, and 
reduced or interrupted only if the symptoms do not respond to the reduction of the 
MPA dosage. 
Implementation of dose reduction will be based on thrombocytopenia, leukopenia, 
neutropenia, hypercholesterolemia, hypertriglyceridemia, or other adverse events 
which are suspected to be related to study medication, and in the opinion of the 
investigator, are clinically warranted. The following guidelines should be used for both 
dose reduction and restarting or increasing the dose of study medication back to 
original levels. 
In cases of recurrent infections serum antibody concentration should be measured; if 
hypogammaglobulinemia presents as persistent and clinically significant, patients 
should be examined accurately and appropriate actions should be taken; dose 
reduction or change of immunosuppression should be taken into consideration. 
Patients with recurrent pulmonary disorders e.g. cough/dyspnea should as soon as 
possible be examined accurately for signs of bronchiectasis; dose reduction or 
change of immunosuppression should be taken into consideration. 
 
Dose Reduction Guidelines 
Platelets 
 platelet count < 100,000/mm³ dose may be reduced at the discretion of the 
investigator 
 platelet count < 75,000/mm³ 
a second dose reduction should be considered 
 platelet count < 50,000/mm³ 
MANDATORY interruption of medication 
WBC 
 WBC < 2,500/mm³ 
dose may be reduced at the discretion of the investigator 
  
 
 
 
A second dose reduction may be implemented if the  
  
 
 
 
WBC continues to fall 
 
Dose Reduction 
EC-MPS 
MMF 
Maintenance dose 
3 tablets 360 mg b.i.d. 
3 capsules 500 mg b.i.d.
Initial dose reduction 
2 tablets 360 mg 
2 capsules 500 mg b.i.d.
Second dose reduction 
1 tablet 360 mg +  
1 tablet 180 mg b.i.d.. 
1 capsules 500 mg +  
1 capsule 250 mg b.i.d. 
 


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Increase or restart of study medication after a drop in platelets / 
WBC 
Increase dose of study medication following a single dose reduction 
After a single dose reduction, full dose of study medications must restart if: 
 platelet count > 100,000/mm³ (at least 3 days) 
 WBC > 3,500/mm³ 
 
(at least 3 days) 
Increase dose of study medication following a double dose reduction 
After a double dose reduction the mid dose of study medications may be restarted if: 
 platelet count > 75,000/mm³ 
(at least 3 days) 
 WBC > 3,500/mm³ (stable) 
(at least 3 days) 
the full dose of study medications must be restarted if 
 platelet count > 100,000/mm³ (at least 7 days) 
 WBC > 3,500/mm³ (stable) 
(at least 7 days) 
Restart of dose of study medication following an interruption 
After an interruption of study medications (due to a decrease in platelets/WBC) study 
medication may be restarted at the lowest dose if: 
 platelet count > 50,000/mm³ 
(at least 3 days) 
 WBC > 3,500/mm³ (stable) 
(at least 3 days) 
the mid dose of study medications may be restarted if: 
 platelet count > 75,000/mm³ 
(at least 3 days) 
 WBC > 3,500/mm³ (stable) 
(at least 3 days) 
the full dose of study medications must be restarted if 
 platelet count > 100,000/mm³ (at least 7 days) 
 WBC > 3,500/mm³ (stable) 
(at least 7 days) 
 


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Absolute neutrophil count cutoff levels 
A decrease in absolute neutrophil counts (ANC) to less than 1,000/mm³ should be 
avoided during the study. The investigator should use his/her discretion to reduce the 
dose of non-study medication known to be associated with neutropenia or leukopenia 
(e.g. ganciclovir, trimethoprim-sulfamethoxazole) before considering initiating a 
reduction in the dose of study medication. 
Recommendations for adjusting the dose of study medication in case of a decrease 
in absolute neutrophil counts are as follows: 
ANC < 1,500/mm³:  
 
Consider dose reduction  
  
 
 
 
 
(per investigator discretion) 
ANC < 1,000/mm³:  
 
Mandatory interruption of study medication 
Restart of study medication after a drop in ANC that required interruption of study 
medication 
ANC > 1,500/mm³ for 7 days: 
Restart full dose of study medication 
 
Lipid cutoff levels 
Evaluations of plasma cholesterol and/or triglyceride levels can result from a number 
of drugs commonly used in renal transplantation, including study medication, 
steroids, Cyclosporin A, and other drugs. 
If plasma cholesterol and/or triglyceride levels are found to be elevated, the dosing of 
all concomitant medication potentially affecting cholesterol and/or triglyceride levels 
should be re-considered and optimized as appropriate, in addition to providing dietary 
advice. 
If plasma cholesterol and/or triglyceride levels are still found to be elevated and the 
elevation is confirmed by a second measurement (performed within two weeks under 
fasting conditions [last meal  8 hours prior to sampling]) treatment based on the 
National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) 
guidelines (see Appendix 3) should be instituted. The patient’s CHD risk should be 
assessed as the NCEP ATP II guidelines are based on presence/absence of CHD 
and number of CHD risk factors. 
Treatment of elevated lipids should be maximized prior to dose reduction or 
interruption of study medication. 
Based on the National Cholesterol Education Program (NCEP) guidelines (Appendix 
3) the recommendations for treatment of hyperlipidemia prior to reduction/interruption 
of study medication are as follows: 
 
 


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If Total Cholesterol  250 mg/dL (6.5 mmol/L) and/or 
LDL-C  160 mg/dL (4.1 mmol/L): 
Review Concomitant Medication that may potentially contribute to lipid 
elevations and provide Dietary Instruction (Registered Dietitian) 
 
If Total Cholesterol still  250 mg/dL (6.5 mmol/L) and/or 
LDL-C still  160 mg/dL (4.1 mmol/L): 
Institute Statin (HMG CoA Reductase Inhibitor, e.g. Lescol®) Therapy Unless 
Contraindicated 
 
If Total Cholesterol still  250 mg/dL (6.5 mmol/L) and/or 
LDL-C still  160 mg/dL (4.1 mmol/L): 
Optimize Statin Therapy and/or Implement Other Lipid Lowering Therapy 
 
If Total Cholesterol still  250 mg/dL (6.5 mmol/L) and/or 
LDL-C still  160 mg/dL (4.1 mmol/L) and/or 
TG  600 mg/dL (6.9 mmol/L): 
Consider Fibrate Therapy for Treatment of Hypertriglyceridemia 
 
If Total Cholesterol still  250 mg/dL (6.5 mmol/L) and/or 
LDL-C still  160 mg/dL (4.1 mmol/L) and/or 
TG still  600 mg/dL (6.9 mmol/L): 
Consider Dose Reduction / Interruption 
 
Recommendations for adjusting the dose of study medication in case of 
hypercholesterolemia [Total Cholesterol  250 mg/dL (6.5 mmol/L) and/or LDL-
Cholesterol  160 mg/dL (4.1 mmol/L)] and / or hypertriglyceridemia [TG  600 mg/dL 
(6.9 mmol/L)], after treatment of elevated lipids had been maximized, are as follows: 


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Total Cholesterol and/or Triglycerides 
 
= 250 – 750 mg/dL 
= 600 – 1000 mg/dL 
Dose reduction should be considered 
= 6.5 – 19.4 mmol/L 
= 6.9 – 11.4 mmol/L 
 
>750 mg/dL 
> 1000 mg/dL 
Study medication should be  
> 19.4 mmol/L 
> 11.4 mmol/L 
Interrupted 
 
NB: If a patient is restarting the dose of study medication, the investigator my use 
his/her discretion with regard to the adjusted dose of study medication, i.e., they are 
not required to increase doses back to full dose regardless of the platelet or WBC 
levels, the ANC levels, and/or the cholesterol or triglyceride levels. 
 
Handling of Gastrointestinal Problems 
In case of gastrointestinal problems that are caused by the treatment with MPA or 
Everolimus the first step should be to divide the total daily dose in 3 to 4 single 
dosages. In case of persisting gastrointestinal complaints, the MPA dosage should 
be reduced in steps of 360 mg/day until the event resolves. 
In the event of gastrointestinal problems that are caused by any other reason (e.g. 
infections) the medication dosage of MPA and Everolimus should be maintained. 
Other appropriate actions should be taken based on the investigators’ experience 
and discretion. 
 


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Appendix 6: National Cholesterol Education Program Guidelines1 
 
Total cholesterol 
Under 200 mg/dL 
Desirable 
200 – 239 mg/dL 
Borderline-high 
240 mg/dL and over 
High 
HDL cholesterol 
Under 35 mg/dL 
Low 
Treatment based on LDL cholesterol 
Diet Therapy 
Initiation Level 
LDL Goal 
Without CHD and with 
fewer than 2 risk factors* 
160 mg/dL or over 
Under 160 mg/dL 
Without CHD and with 2 or 
more risk factors* 
130 mg/dL or over 
Under 130 mg/dL 
With CHD 
Over 100 mg/dl 
100 mg/dL or under 
Drug Treatment 
Initiation Level 
LDL Goal 
Without CHD and with 
fewer than 2 risk factors* 
190 mg/dL or over 
Under 160 mg/dL 
Without CHD and with 2 or 
more risk factors* 
160 mg/dL or over 
Under 130 mg/dL 
With CHD 
Over 130 mg/dl 
100 mg/dL or under 
*CHD Risk Factors: 
Positive 
- 
Age: Men  45 yrs 
 
 
  Women  55 yrs or premature menopause without estrogen replacement 
therapy 
- 
Family history of premature CHD (definite myocardial infarction or sudden death 
before 55 yrs of age in father or other male first-degree relative, of before 65 yrs 
of age in mother or other female first-degree relative) 
- 
Current cigarette smoking 
- 
Hypertension (Blood pressure  140/90 mmHg [confirmed by measurements on 
several occasions] or taking antihypertensive medication) 
- 
HDL Cholesterol < 35 mg/dL (0.6 mmol/L)   
(confirmed by measurements on several occasions) 
- 
Diabetes mellitus 
Negative: 
                                                 
1 Data from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Summary 
of the second report of the National Cholesterol in Adults [Adult Treatment Panel II] JAMA 269[23]:3015-3023, 
1993 


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- 
HDL Cholesterol  60 mg/dL (1.6 mmol/L)  
(confirmed by measurements on several occasions) 
 
 


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Appendix 7:  ISHLT Standardized Cardiac Biopsy Grading  
Acute Cellular Rejection 
2004 
 
1990 
 
Grade 0Ra 
No rejection 
Grade 0 
No rejection 
Grade 1R, mild 
Interstitial and/or 
perivascular infiltrate 
with up to 1 focus of 
myocyte damage 
Grade 1, mild 
 
 
A-Focal 
Focal perivascular 
and/or interstitial 
infiltrate without 
myocyte damage 
 
 
B-Diffuse 
Diffuse infiltrate 
without myocyte 
damage 
 
 
Grade 2, moderate 
(focal) 
One focus of infiltrate 
with associated 
myocyte damage 
Grade 2R, moderate 
Two or more foci of 
infiltrate with 
associated myocyte 
damage 
Grade 3, moderate 
 
 
 
A-Focal 
Multifocal infiltrate 
with myocyte 
damage 
Grade 3R, severe 
Diffuse infiltrate with 
multifocal myocyte 
damage  edema,  
hemorrhage  
vasculitis 
B-Diffuse 
Diffuse infiltrate with 
myocyte damage 
 
Grade 4, severe 
Diffuse 
polymorphous 
infiltrate with 
extensive myocyte 
damage  edema,  
hemorrhage + 
vasculitis 
a Where “R” denotes revised grade to avoid confusion with 1990 scheme. 
The presence or absence of acute antibody-mediated rejection (AMR) may be recorded as 
AMR 0 or AMR 1, as required (see below) 
 
 


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Nonrejection Biopsy Findings 
2004 
 
1990 
 
Ischemic injury 
Ischemic injury 
Early – up to 6 weeks post-transplant 
A = up to 3 weeks post-transplant 
Late – related to allograft coronary disease 
B = late ischemia 
Quilty effect 
Quilty effect 
 
A = no myocyte encroachment 
 
B = with myocyte encroachment 
Infection 
Infection 
Lymphoproliferative disorder 
Lymphoproliferative disorder 
 
Recommendations for Acute Antibody-Mediated Rejection (AMR) 
2004 
 
1990 
 
AMR 0 
Negative for acute antibody-
mediated rejection 
 
 
No histologic or 
immunopathologic features of 
AMR 
 
AMR 1 
Positive for AMR 
Humoral rejection (positive 
immunofluorescence, vasculitis or severe 
edema in absence of cellular infiltrate) 
recorded as additional required information 
 
Histologic features of AMR 
 
Positive immunofluorescence 
or immunoperoxidase staining 
for AMR (positive CD68, C4d) 
 
 
 
(Lit: Stewart S et al., 2005) 

SAP_001.pdf: 
Clinical Development 
RAD001/Everolimus/Certican® 
CRAD001ADE14 / NCT00862979
A multi-center, randomized, open-label, parallel group 
study investigating the renal tolerability, efficacy and 
safety of a CNI-free regimen (Everolimus and MPA) versus 
a CNI-regimen with Everolimus in heart transplant 
recipients 
Statistical Analysis Plan (SAP) 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
02-JUN-2017
Number of pages: 
25 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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CRAD001ADE14 / MANDELA 
 
Signature Page 
CRAD001ADE14 
 
 
 
 
_________________________ 
____________ 
Signature 
Date 
 
 
 
 
_________________________ 
____________ 
Signature 
Date 
 
 
 
 
_________________________ 
____________ 
Signature 
Date 
 
 
 
 
_________________________ 
____________ 
Signature 
Date 
 
 
 
 
_________________________ 
____________ 
Signature 
Date 
 
 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
02-Jun-2017 
Prior to 
DB lock 
Creation of 
final version 
N/A - First version 
NA 
 


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Table of contents 
Signature Page .......................................................................... Error! Bookmark not defined. 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design............................................................................................................. 9 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 13 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 14 
2.4.1 
Study treatment / compliance ................................................................ 14 
2.4.2 
Prior, concomitant and post therapies ................................................... 15 
2.5 
Analysis of the primary objective .......................................................................... 15 
2.5.1 
Primary endpoint ................................................................................... 15 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.5.4 
Supportive analyses ............................................................................... 16 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 16 
2.6.1 
Secondary endpoints ............................................................................. 16 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 17 
2.7 
Safety analyses ....................................................................................................... 17 
2.7.1 
Adverse events (AEs) ............................................................................ 17 
2.7.2 
Deaths .................................................................................................... 18 
2.7.3 
Laboratory data ..................................................................................... 18 
2.7.4 
Other safety data ................................................................................... 19 
2.8 
Pharmacokinetic endpoints .................................................................................... 19 
2.9 
PD and PK/PD analyses......................................................................................... 20 
2.10 
Patient-reported outcomes ..................................................................................... 20 
2.11 
Biomarkers ............................................................................................................. 20 


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2.12 
Other Exploratory analyses .................................................................................... 20 
2.13 
Interim analysis ...................................................................................................... 20 
3 
Sample size calculation ..................................................................................................... 20 
4 
Change to protocol specified analyses .............................................................................. 21 
5 
Appendix ........................................................................................................................... 21 
5.1 
Definitions ............................................................................................................. 21 
5.1.1 
Study periods ......................................................................................... 21 
5.1.2 
Calculated GFR ..................................................................................... 21 
5.1.3 
Objectives .............................................................................................. 22 
5.1.4 
Target therapeutic ranges ...................................................................... 24 
5.2 
Imputation rules ..................................................................................................... 24 
5.2.1 
Study drug ............................................................................................. 24 
5.2.2 
AE date imputation ............................................................................... 24 
5.2.3 
Concomitant medication date imputation ............................................. 24 
5.3 
AEs coding/grading ............................................................................................... 25 
5.4 
Laboratory parameters derivations ........................................................................ 25 
5.5 
Statistical models ................................................................................................... 25 
5.5.1 
Primary analysis .................................................................................... 25 
5.5.2 
Key secondary analysis ......................................................................... 25 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 25 
6 
Reference ........................................................................................................................... 25 


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List of abbreviations 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase (Serum Glutamate Pyruvate 
Transaminase) 
AST (SGOT) 
Aspartate Aminotransferase (Serum Glutamatoxalacetate 
Transaminase) 
ATC 
Anatomical Therapeutic Chemical dictionary 
ATG 
Antithymocyte Globulin 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day (12 hours apart) 
BPAR 
Biopsy-Proven Acute Rejection 
CAV 
Cardiac allograft valsculopahty 
CI 
Confidence Interval 
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 
CsA 
Cylcosporine A 
 
 
DSMB 
Drug Safety Monitoring Board 
EBV 
Epstein Barr virus 
ECG 
Electrocardiogram 
ENR 
Enrolled Patient Population 
EC-MPS 
Enteric Coated Mycophenolate Sodium (Myfortic®) 
FSH 
Follicle Stimulating Hormone 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 


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HDL 
High-Density Lipoproteine Cholesterine 
HLA 
Human leukocyte antigen 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMPDH 
Inosine 5’-Monophosphate Dehydrogenase 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
LAD 
Left Anterior Descending 
LDL 
Low-Density Lipoproteine Cholesterine 
LH 
Luteinizing Hormone 
LLN 
Lower limit of normal 
MACE 
Major Adverse Cardiac Events 
MDRD 
Modification of Diet in Renal Disease Study Group 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MIT 
Maximal Intimal Thickness 
mmHg 
Millimeters of Mercury 
MMF 
Mycophenolate Mofetil 
mTOR 
Mammalian Target of Rapamycin  
MPA 
Mycophenolic Acid 
NRP  
Non-Randomized Patient Group 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCP 
Pneumocystis carinii pneumonia 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PRA 
Panel reactive antibody 
RAD 
Everolimus, Certican 
RAN 
Randomized Patients Population (at Baseline Visit 2) 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SIMO 
Sandimmun® Optoral 
SL 
Serum Level 
SNOMED 
Systematized Nomenclature of Medicine 
SOP 
Standard Operating Procedures 
SRL 
Sirolimus 


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TL 
Trough Level 
tmax 
Time until Maximum Plasma Concentration 
TSH 
Thyroid-Stimulating Hormone 
Tx 
Transplantation 
ULN 
Upper Limit of Normal 
WBC 
White blood cells 
WHO 
World Health Organization 


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1 
Introduction 
This Statistical Analysis Plan describes the implementation of the statistical analysis planned 
in the protocol. 
1.1 
Study design 
This was a prospective, multi-center, randomized, controlled, parallel group, open label study 
in heart transplant recipients. Enrollment was terminated at 31st December 2015 with a 
protocol amendment. At that time 162 de novo heart transplant patients have been randomized 
to the two treatment groups at Baseline visit (Month 6 post Tx). The patients were recruited 
from 9 transplant centers in Germany. 
During the first three months post Tx the patients may have been treated according to center 
standards. Latest after study inclusion (Month 3 post Tx ±2 weeks), the patients received an 
immunosuppressive regimen consisting of Cyclosporin A (based on C0-h level) or Tacrolimus 
(based on C0-h level) + Everolimus (target C0-h level: 5 – 10 ng/mL) or MPA + 
corticosteroids. 
At Month 6 (±1 week) post transplantation (Baseline), patients whose eligibility was 
confirmed by additional in- and exclusion criteria were randomized and hence allocated to one 
of the two treatment groups in a 1:1 ratio in the following way: 
A randomization list was produced under the responsibility of Novartis Biometrics 
Department using a validated system that automates the random assignment of treatment 
groups to randomization numbers in the specified 1:1 ratio (CNI group, CNI-free group). The 
randomization scheme was reviewed and locked after approval. According to the 
recommendations given in the ICH E9 Guideline “Statistical Principles for Clinical Trials” 
(CPMP, 1998), the used block length was specified in a separate document which was 
withhold from the study centers. The randomization list was kept sealed in a secure location. 
At Baseline visit (Month 6 post Tx), all eligible patients were given a randomization number 
that assigns them to one of the treatment groups. The randomization numbers were 
sequentially allocated to the patients per center in the order of inclusion in the randomized 
treatment period. 
Randomization of individual patients was performed centrally by a CRO. Allocation of a 
patient to one of the two treatment groups was performed in the following steps. 
1. Information about patient enrollment (Screening Visit – Month 3 post Tx): Study sites 
informed the randomization department of the CRO about each patient inclusion via fax. 
2. Randomization (Baseline Visit – Month 6 post Tx): At day of randomization, the site 
provided the information of eligible patient to the CRO by fax. The CRO randomization 
department allocated the patient the next free consecutive randomization number allocated to 
the site. Randomization number and allocated treatment (according to the randomization list) 
were provided to the site by fax. 


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Patients then either received an immunosuppressive regimen consisting of a CNI (Tacrolimus 
or Cyclosporin A) with Everolimus with corticosteroids or were switched to the CNI-free 
regimen in the following way: 
Starting the day following the Month 6 assessment, Cyclosporin A was reduced to ≤75 ng/mL 
(according to C0 level) or Tacrolimus was reduced to ≤5 ng/mL (according to C0 level) for 8 
weeks and subsequently removed completely. Depending on the initial immunosuppression 
either MPA or Everolimus was added to the patient´s immunosuppressive regimen. 
Consequently, patients received a transitional immunosuppressive regimen of Cyclosporin A 
or Tacrolimus and Everolimus and MPA or MMF until complete switch to the CNI-free 
regimen was achieved at 9 months post Tx. 
Dose increase / adjustment of MPA was performed based on the investigator’s experience and 
the given clinical conditions, adverse events, etc. The CNI-free regimen was achieved after a 
maximum of 3 months and was stable by Month 9. During the therapy-switch a control 
assessment was performed at Month 8. 
In all patients, further control assessments were performed at Month 9, 10, 12 and 18 (end of 
study and early discontinuation) post Tx. 
Corticosteroids were added to the immunosuppressive regimen in all patients, according to 
local standard. A dose of 0.05 – 0.3 mg/kg prednisolone or equivalent were continued 
throughout the whole study. 
Obligatory biopsies were obtained at Month 6, 9, 12, 18. Facultatively biospsies may have 
been obtained at every study visit. 
Statistical analysis and report writing was performed when all patients had completed Month 
18 after Tx assessment. 
The primary analysis of renal safety and tolerability concerned the period of randomized 
treatment between Month 6 (baseline) and Month 18 or the last assessment within this period 
in the event of a patient’s premature discontinuation from the study. 
No interim analysis was conducted. 
1.2 
Study objectives and endpoints 
Objectives: 
Primary 
 Renal function assessed as glomerula filtration rate (GFR) – MDRD formula – 18 
months after heart transplantation 
Secondary 
 To assess occurrence of treatment failures up to or at Month 18 post Tx, while 
treatment failure is defined as a composite endpoint of biopsy proven acute rejection 
of ISHLT 1990 grade ≥ 3A (ISHLT 2004 grade ≥ 2R), acute rejection episodes 
associated with hemodynamic compromise, graft loss / re-transplant, death, loss to 
follow-up (at least one condition must be present) 


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 To assess incidence of MACE and each of its components at Month 18 post Tx 
 To assess renal function by GFR – Cockcroft-Gault method – at Month 12 and 18 post 
Tx 
 To assess renal function (serum creatinine) and evolution of renal function between 
Month 6 and Month 18 post Tx (creatinine slope) 
 To assess safety and tolerability at Month 6, 9 and 18 post Tx (acc. to safety 
parameters specified in section 7.6 of the protocol) 
2 
Statistical methods 
2.1 
Data analysis general information 
All statistical analyses were performed 
 
 Analysis was carried out using the SAS (Statistial 
Analysis System) software, version 9.2, 2009, SAS Institute Inc., Cary, North Carolina, USA. 
Analyses were done when all patients had completed the trial at 18 months post Tx (or 
discontinued prematurely). 
The following periods were considered for analyses: 
 The primary analysis of renal safety and tolerability concerns the period of randomized 
treatment between Month 6 (baseline) and Month 18 or the last assessment within this 
period in the event of a patient’s premature discontinuation from the study. If indicated, 
e.g. for analysis of renal function and type and frequency of adverse events, the period 
from Month 6 to Month 18 was portioned into (a) the switch period between Month 6 and 
Month 9 and (b) the maintenance period between Months 9 and 18 after Tx. 
 As a separate study period, the initial 3 months period between Screening and Baseline 
visit (run-in period) was analyzed with regard to treatment, efficacy, and safety of the 
immunosuppressive regimen.  
In patients who discontinued prematurely from the study, the last available information under 
study treatmentwas analyzed. 
Adverse events were analyzed separately for the initial 3 months period between Screening 
and Baseline visit (Run-in period) and for the randomized treatment period between Baseline 
visit (Month 6) and Month 18. 
Significant events like rejection episodes, hemodynamic compromise, and MACE were 
additionally analyzed for the period between transplantation and Screening (Month 3 post Tx) 
(Pre-screening period). 
Unless otherwise stated, all statistical tests were two-sided and used the 0.05 level of 
statistical significance. All summary statistics were presented by treatment group. Frequency 
distributions were provided for categorical variables. Descriptive statistics of mean, standard 
deviation, minimum, median and maximum were presented for continuous variables. Time to 
event data including rates of affected patients were assessed by Kaplan-Meier statistics and 
compared between the two groups with the logrank test. 


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Data from all centers that participated in this study were combined and the factor center was 
included in the analysis of the primary endpoint. 
2.1.1 
General definitions  
Study drug: 
The term “Study drug” refers to any drug administered to the patient as part of the required 
study procedures. 
Certican®/ Everolimus was investigationsal drug. Sandimmun®Optoral/Cyclosporin A, 
Prograf®/Tacrolimus and MPAs (Myfortic®/EC-MPS or CellCept®/MMF) were considered 
as study drug as well. Corticosteroids were handled in the same way as concomitant 
medication. 
 
Date of first administration of study drug: 
“Date of first administration of study drug” is defined as the first intake of study medication 
which should start within 5 days preceding the Screening visit and be documented on the 
Everolimus therapies CRF. 
 
Baseline: 
“Baseline” in the sense of “baseline value” means all values collected at Baseline visit at 
month 6 or, if not available, the corresponding value collected at Screening visit. 
 
Last contact: 
Last date a contact with the patient is documented, e.g. date of study visit, telephone call, 
letter, etc. 
 
2.2 
Analysis sets 
The Enrolled Patient Population (ENR) includes all patients who signed an informed 
consent regardless whether they received study treatment or not. 
The Safety Population (SAF) consists of all patients who signed an informed consent and 
who were treated with at least one dose of any immunosuppressive medication after the 
Screening visit. Note: The statement that a patient had no adverse events constitutes a safety 
assessment. 
The Randomized Population (RAN) is defined by all patients who were randomized at 
Baseline visit. This population will also include patients who were randomized but not treated 
with the randomized medication. 
The Full Analysis Set (FAS) consists of all randomized patients who received at least one 
dose of any immunosuppressive therapy after Baseline Visit (Month 6) and have at least one 


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post-baseline assessment of the primary outcome variable (renal function based on MDRD 
method). Randomized patients without data on the primary outcome variable will be excluded 
from this population; their data will be analyzed for the initial treatment period (up to Month 
6) and within the RAN and SAF. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment group they were assigned to at randomization. 
The Per-protocol Population (PP) consists of all FAS patients who did not show major 
deviations from the protocol procedures that may have an impact on the study outcome and 
who have completed the treatment period at Month 18 according to protocol. Criteria that are 
assumed to have such an impact were defined before analysis during the Blind Review 
Meeting and are documented in the Appendix, section 5.6 Rule of exclusion criteria of 
analysis sets. 
For the period before Baseline visit (Month 6) the enrolled patient population was divided by 
randomization status into randomized patients and not randomized patients. 
2.2.1 
Subgroup of interest 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and background information was summarized for the ENR-, the SAF- and the 
the FAS - Population, using frequency distributions for categorical variables and descriptive 
statistics of mean, standard deviation, minimum, median and maximum for continuous 
variables. Background information included prior medication, past/current medical conditions 
and transplant history. 
Medical history was coded using MedDRA and was presented by system organ class, 
MedDRA preferred term and treatment group. Separate tables were provided for past medical 
condition and current medical condition. Prior medication was coded according to WHO Drug 
Reference List. 
In addition to these variables which were evaluated at Screening (Visit 1, Month 3 post Tx), 
the course of renal function (GFR) as well as efficacy variables (treated acute rejection, 
biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute 
rejection associated with hemodynamic compromise, graft loss / re-transplantation, death) 
were determined and properly described for the run-in period between Screening (Visit 1, 
Month 3 post Tx) and Baseline (Visits 2, Month 6 post Tx). 
The two treatment groups were compared descriptively with respect to these variables.  
No formal statistical testing was conducted for comparability purposes. 
2.3.1 
Patient disposition 
Patient disposition was summarized for all patients by absolute 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 


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treatment for all patients (screening) resp. the Randomized Set (treatment and study). The 
number of patients per analysis set was summarized by treatment. 
Protocol violations were reported descriptively by treatment and a listing was generated for 
each treatment for all screened patients. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration (days) of Everolimus application were summarized. Dose interruptions, i.e. days 
with dose of 0 mg were considered for calculation of duration. Daily Everolimus dose levels 
were summarized with mean, standard deviation, minimum, median, and maximum by visit. 
Dosage averages were calculated including and excluding zero doses for periods of temporary 
interruption of study medication regardless of whether this was due to safety reasons or 
patients’ non-compliance. Assignment of the DAR records to the visits were calculated based 
on the visit dates. Reasons for dose adjustments (including temporary dose interruption) were 
presented by frequency distribution. These frequencies of dose reduction (including 
temporary dose interruption) for safety reasons as per protocol guidelines were presented by 
study period. Permanent treatment discontinuations were analyzed by frequencies. 
These analyses were performed per treatment group, for the SAF population and related to the 
study periods in the randomized treatment period (see section 2.1 Data analysis general 
information). For the run-in period, duration and mean daily dose were summarized for the 
ENR population displaying both, randomized versus not randomized patients as well as the 
inial treatment groups CNI+MPA versus CNI+ Everolimus 
Daily Cyclosporin A and Tacrolimus doses adjusted by the patients’ visit-specific body 
weight and MPA doses were summarized by visit and in the same way as Everolimus. Data 
were presented separately for each treatment group. Induction therapy (Basiliximab or ATG 
or no induction) received by patient was summarized by treatment group, for the SAF 
population. The distribution of the specific CNI medications was summarized by treatment 
group. 
Duration (days) of treatment with Cyclosporin A, Tacrolimus, MPA, and steroids as well as 
frequency of Cyclosporin A, Tacrolimus and MPA dose adjustments (including temporary 
dose interruption) for safety reasons as per protocol guidelines were determined. Reasons for 
dose adjustments (including temporary dose interruption) were presented by frequency 
distribution. Permanent treatment discontinuations were analyzed using frequency 
distribution. All other immunosuppressive therapies were summarized by ATC (Anatomical, 
Therapeutic, Chemical) classes. 
All analyses were presented per treatment group and study period (see 2.1 Data analysis 
general information). 
 


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2.4.2 
Prior, concomitant and post therapies 
Medications other than those mentioned in section 2.4.1 taken concomitantly with the study 
medication were summarized by treatment group and study period through frequency tables. 
Concomitant medication was coded and summarized according to the ATC classification 
system. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary aim of this study was to show superior renal function under the CNI-free 
regimen compared to the CNI-based regimen with respect to GFR as calculated by MDRD 
method (cGFR/MDRD). 
The primary variable for assessment of renal function was the  
 glomerular filtration rate (GFR) at Month 18, as assessed by the MDRD method 
(recalculated values, see Appendix, section 5.1.2 Calculated GFR. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The null hypothesis H0 of similar GFR level in both treatment groups 
H0: μCNI-free = μCNI-based 
was tested against the two-sided alternative hypothesis of different efficacy (different GFR 
levels at month 18 after Tx) of the CNI-free regimen compared to the CNI-based regimen 
H1: μCNI-free ≠ μCNI-based 
with an analysis of covariance (ANCOVA) using “treatment” and “center” as factors and 
“baseline GFR value at Baseline visit 2 (Month 6)” as covariate. Type-I error probability was 
set to a two-sided α=0.05. Adjusted means (=LS-means, LS: least square means) were 
presented for the treatment contrast of GFR at Month 18 post Tx together with its confidence 
interval and a two-sided p-value. 
The FAS population was used for the primary analysis. This analysis followed the intention-
to-treat principle and thus reflects the actual performance of the investigational drug under 
practical conditions (“pragmatic approach”). 
2.5.3 
Handling of missing values/censoring/discontinuations 
If a patient discontinued from the study prematurely missing data with respect to the target 
parameter were substituted by the last recorded value (last observation carried forward, 
LOCF). The LOCF method was only applied if a patient had at least one assessment after 
Baseline, i.e. on Visits Months 8 to 18. Otherwise, the patient was excluded from efficacy 
analysis within the FAS population. Prematurely performed month 18 visits were shifted to 
the closest visit following the date of last observation. 
Patients of the FAS population who switched from the CNI group to the CNI-free group 
during the study or during follow-up, were analyzed in their randomized group. 


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Additionally, sensitivity analysis was performed with a repeated measurement analysis. 
2.5.4 
Supportive analyses 
The primary analysis was once more performed with the PP set (as observerd analysis, AOA) 
The course of the GFR was of special interest. Changes from Baseline to each post-baseline 
measure were calculated by treatment group for each study visit. 
In addition to quantitative analyses, the frequency distributions of patients with an improved 
GFR at study month 18 compared to BL (Month 6 post Tx) was compared between the two 
regimens. For group comparison, a Fisher’s exact test was calculated. 
Additionally to the analyses of data from the interval between BL (Month 6) and Month 18, 
the primary outcome variable was also evaluated for the interval between Screening (Month 
3) and Baseline (Month 6). 
In addition to the LOCF method described above, missing values were handeled with an 
adapted LOCF method (LOCF-2), where the last recorded value under the initially given 
treatment after randomization was used for substitution of the missing data.  
Results from these supportive analyses were interpreted in an explorative manner. 
2.6 
Analysis of secondary efficacy objective(s) 
2.6.1 
Secondary endpoints 
The following secondary efficacy variables were analyzed in an explorative manner: 
 Occurrence of treatment failure up to Month 18 defined as composite endpoint of biopsy 
proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute 
rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, 
death, loss to follow up (at least one condition must be present). 
 Occurrence of MACE and each of its components at Month 18 
In addition to the analysis of the primary outcome variable of renal safety and tolerability, the 
following was analyzed: 
 Renal function as assessed by Cockcroft-Gault at month 12 and 18 after Tx 
 Serum creatinine and reciprocal creatinine slope (1/serum creatinine versus time) 
including the treatment period between BL (Month 6) and Month 18 
 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Event data: 
Event rates were estimated using the Kaplan-Meier method to handle patients who 
discontinue the treatment prior to suffering from an event adequately. Time to event was 
defined as the time from date of randomization to the first documented date of the event. The 
two groups were compared using the log-rank test. 


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This procedure was applied for the composite endpoint of treatment failure and each of its 
components, as well as MACE and each of its components. 
Narratives including relevant medical information were provided for each biopsy proven 
acute rejection, graft loss, or death. 
Tolerability: 
Analyses of renal function as determined by other calculations (serum creatinine, glomerular 
filtration rate (GFR, Cockcroft-Gault)) were evaluated in the same manner as described for 
the primary outcome measure. 
The creatinine slope (1 / serum creatinine versus time) was determined from all assessments 
between Month 6 and Month 18 (both visits included) using a linear regression model. These 
slopes were compared with a two-sided Wilcoxon ranksum test between the treatment groups. 
Additionally, tolerability of study medication was 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. The frequency distribution of these reasons was presented with absolute 
and percent values. The most frequent reasons (total n ≥ 5) for discontinuation and/or 
conversion as well as the total number of patients who are affected by such intolerability of 
study medication were compared between the two treatment groups using the exact Fisher 
test. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing values were imputed with the last observation carried forward (LOCF) method 
described at section 2.5.3. 
2.7 
Safety analyses 
 
2.7.1 
Adverse events (AEs) 
Safety variables were analyzed separately 
 for the period between Screening and Baseline (run-in period) 
 for the period between Baseline and Month 9 (switch period) 
 for the period between Month 9 and Month 18 (maintenance period)  
 for the period between Baseline and final assessment (Month 18 or date of premature 
withdrawal from the study) (randomized treatment period),.  
For the randomized treatment period, analyses of treatment emergent adverse events were 
performed according to the treatment group into which the patients were randomized. 
All analyses of safety parameters were based on the safety population. For the period between 
Screening and Baseline visit summaries of all adverse events were displayed for the ENR 
population by randomization status, i.e. randomized versus not randomized patients. 


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The key safety variables which were analyzed are as follows. 
 Incidence and severity of infections, in particular clinically apparent CMV 
 Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 Incidence of AEs leading to discontinuation from the study 
 Relative frequency of abnormal vital signs measurements and laboratory parameters 
The incidence rates for (serious) adverse events and infections were analyzed by treatment 
group. 
AEs/Infections: 
Generally, infections data were analyzed together with AE data. In addition, infection data 
were analyzed separately. 
Data collected by AE CRFs and by Infection CRFs and CMV-CRFs were coded with the 
MedDRA dictionary that gives preferred term and body system information. The incidence of 
AEs were summarized by body system, preferred term, severity, and relationship to study 
drug. All information pertaining to AEs noted during the study were listed by treatment group 
and patient, detailing verbatim given by the investigator, the preferred term, the body system, 
start/end dates, severity and drug relatedness. The AE onset was also shown relative (in 
number of days) to the day of initial dose per study period (within the first 3 months, after 
Baseline (Month 6)). 
In addition to being analyzed similarly as AEs, as described above, the relative frequency of 
infection by type and micro-organism was tabulated. AEs occurring 30 or more days after the 
discontinuation of study medication were not included in AE/infection summary tables. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
No adverse events of special interest were defined. 
2.7.2 
Deaths 
Treatment deaths were summarized together with serious treatment emergent adverse events 
and other significant treatment emergent advese events by treatment group for the Safety Set 
(SAF). 
Furthermore, deaths were analyzed as composite part of the secondary endpoints treatment 
failure and major adverse cardiac events for the Full Analysis Set (FAS). 
2.7.3 
Laboratory data 
Abnormalities according notable criteria (see Appendix 2 of study protocol) were identified. 
The proportions of patients with clinically notable abnormalities according to the notable 
criteria were summarized. Shift tables describing changes from status prior transplantation 
(Month 0) and Baseline based on the expanded normal limits were presented for treatment 
endpoints (study Month 6 and 18) and worst observations during the different study periods 
(up to Month 6 as well as between Month 6 and Month 18). The worst observation was 
defined as the highest or lowest measure during the different observations periods whereby 


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high or low were chosen according to the direction of abnormality (e.g. the highest will be 
chosen for serum creatinine, the lowest for leukocytes). Further, descriptive statistics of 
change from baseline of all laboratory variables were presented by visit. A by-patient listing 
of all laboratory data (with clinically notable abnormalities being flagged) was generated. 
Only assessments obtained up to 2 days after the discontinuation of study medication were 
considered “on-treatment” and analyzed with relationship to Everolimus. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
Any clinically significant abnormalities were presented as past/current medical condition. 
2.7.4.2 
Vital signs 
Vital signs variables included measurements of oral body temperature, systolic and diastolic 
blood pressures, pulse and body weight. Vital signs were examined for abnormal values and 
change from Baseline according to pre-specified clinically notable criteria (see Appendix 2 of 
study protocol). Appropriate incidence rates of clinically notable abnormalities for between-
group differences were provided. Further, descriptive statistics of change from baseline of all 
vital signs variables were presented by visit. A by-patient listing of all vital signs (with 
clinically notable abnormalities being flagged) was generated. Shift tables describing changes 
from baseline based on clinically notable criteria were presented for treatment endpoint 
(Month 18) and worst on-treatment observations. Only assessments obtained up to 2 days 
after the discontinuation of study medication were considered “on-treatment”. 
2.8 
Pharmacokinetic endpoints 
Analysis of the Cyclosporin A, Tacrolimus and Everolimus blood levels were done by 
treatment group and separately for the treatment periods (after Month 6). 
Everolimus: 
Mean blood level values of Everolimus were presented in tabular form for each timepoint 
(visit window) and as mean value over time. The number of patients with deviations from the 
therapeutic window (see section 5.1.4 Target therapeutic ranges) were counted (separately for 
values “below” and “above” therapeutic range) and tabulated per visit and in total. 
Patients with any trough level value outside the therapeutic window were described in detail 
by narratives reporting also Everolimus dose level and dose adjustments, if applicable. 
Cyclosporin A: 
Mean blood level values of Cyclosporin A were presented in tabular form for each timepoint 
and as mean value over time. Blood levels were tried to be kept in therapeutic windows. The 
number of patients with deviations from the therapeutic window (see section 5.1.4 Target 
therapeutic ranges) were counted and tabulated per visit and in total. 
In the CNI-free group mean blood level values of cyclosporin A were presented in tabular 
form for each assessment up to Month 8. 
Tacrolimus: 


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Mean blood level values of Tacrolimus were presented in tabular form for each timepoint and 
as mean value over time. Blood levels were tried to be kept in therapeutic windows. The 
number of patients with deviations from the therapeutic window (see section 5.1.4 Target 
therapeutic ranges) were counted and tabulated per visit and in total. 
In the CNI-free group mean blood level values of Tacrolimus were presented in tabular form 
for each assessment up to Month 8. 
 
2.9 
PD and PK/PD analyses 
Pharmacogenetics/pharmacogenomics were not assessed in this trial. 
2.10 
Patient-reported outcomes 
No health-related Quality of Life assessment was performed in this study. 
2.11 
Biomarkers 
No biomarkers were assessed in this trial. 
2.12 
Other Exploratory analyses 
No additional exploratory analyses were performed. 
2.13 
Interim analysis 
No interim analysis was conducted. 
3 
Sample size calculation 
The probable difference between the CNI-free - and the CNI-group in the GFR was estimated 
as δ = 8 ml/min with σ = 16 ml/min. With α=.05 (two sided significance level) and 1-β = 
90% (power), n=86 patients per group were required to demonstrate superior efficacy of the 
CNI-free regimen compared to the CNI-group in the GFR using the t-test 
 
. To compensate for some uncertainty of the assumptions for sample size 
calculation, the calculated sample size was increased by ≈ 15%. Therefore, a total number of 
N=200 patients (n=100 per treatment group) were initially planned to be randomized and 
treated in both treatment arms after Baseline (Month 6 post Tx). 
According to amendment 4, enrollment into this study was terminated by 31st December 2015, 
by that time about 165 patients had been recruited into this trial. Under the assumptions 
above, this would lead to a power of 82%. Since this sample size also contains patients who 
discontinued the trial/medication early or who had other protocol deviations, the actual power 
was even somewhat lower. 


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4 
Change to protocol specified analyses 
Missing data for the primary outcome variable were dealt with the LOCF method according to 
protocol, but instead of an additional replacement with the mean of the non-missing values, 
the LOCF2 method (as described in section 2.5.4) as well as repeated measures analysis (see 
section 2.5.3) were used. 
Not randomized patients were considered for the run-in period but not for the randomized 
treatment period. 
5 
Appendix 
5.1 
Definitions 
5.1.1 
Study periods 
The following study periods were used for analysis: 
 Pre-screening period: Tx – V1/M3/Screening 
 Run-in period: V1/M3/Screening – V2/M6/Baseline 
 Randomized treatment period: V2/M6/Baseline – V7/M18/EOS 
o Swith period: V2/M6/Baseline – V4/M9 
o Maintenance period: V4/M9 – V7/M18/EOS 
In the event of a patient’s premature discontinuation, the respective period was defined till the 
last assessment within this period. 
For patients who discontinue prematurely from the study, both, the last available information 
under study treatment was analyzed. 
5.1.2 
Calculated GFR 
MDRD formula 
𝑐𝐺𝐹𝑅 [𝑚𝑙/𝑚𝑖𝑛]
= 170 × 𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑒[𝑚𝑔/𝑑𝑙]−0.999 × 𝑎𝑔𝑒[𝑦𝑒𝑎𝑟𝑠]−0.176 
× 𝑢𝑟𝑒𝑎 𝑛𝑖𝑡𝑟𝑜𝑔𝑒𝑛[𝑚𝑔/𝑑𝑙]−0,17 × 𝑎𝑙𝑏𝑢𝑚𝑖𝑛[𝑔/𝑑𝑙]0.318 × 𝐶 
with C=1 for men and C=0.762 for women  
and urea nitrogen = urea/2.144 
 
Cockcroft-Gault formula 
𝑐𝐺𝐹𝑅 [𝑚𝑙/𝑚𝑖𝑛] = 𝐷 × (140 −𝑎𝑔𝑒[𝑦𝑒𝑎𝑟𝑠]) × 𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]
72 × 𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔/𝑑𝑙]
 
with D=1 for men and D=0.85 for women 
 


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Age[years]: calculated as (“Visit date” [days] – “Date of birth” [days]) / 365.25  
Age, Body Weight and all serum variables were taken from the respective visit. Missing 
values of Body Weigth were imputed by carrying forward the last known observation, if Body 
Weigth was missing at Screening (V1/M3), the first non-missing observation was carried 
backward. 
5.1.3 
Objectives 
Steroids 
 Source: Other Immunosuppressive Therapies 
 Occurrence: “Immunosuppressive therapy” WHO ATC codes H02 and L04 
 
Treatment failure 
Treatment failure was defined as a composite endpoint of biopsy proven acute rejection of 
ISHLT 1990 grade ≥3A (ISHLT 2004 grade ≥2R), acute rejection episodes associated with 
hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one 
condition must be present). 
Biopsy proven acute rejection 
 Source : Endomyocardial biopsy CRF at respective visit 
 Occurrence: “ISHLT grade / 1990” in (“Grade 3A”, “Grade 3B”, “Grade 4”) AND/OR 
“ISHLT grade / 2004” in (“Grade 2R moderate”, “Grade 3R severe”) 
 Date of event: “Date of biopsy” 
Acute rejection episodes associated with hemodynamic compromise 
 Source: Endomyocardial biopsy CRF at respective visit 
 Occurrence: “Is hemodynamic compromise present?” = 1 (“Yes”) 
 Date of event: “Date of biopsy” 
Graft loss 
 Source: Hospitalization CRF 
 Occurrence: “Primary reason for hospitalization” = 20 (“Graft loss”) 
 Date of event: “Date of admission” 
Loss to follow-up 
 Source: Study completion CRF 
 Occurrence: “Primary reason for premature discontinuation” = 8 (“Lost to follow-up”) 
 Date of event: “Last known date subject took study drug” 
 


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MACE 
Major Adverse Cardiac Evets (MACE) were defined as one of the following: any death, 
myocardial infarction, coronary artery bypass grafting 
Prior to Screening, MACE are documented on the Relevant medical history CRF, section 
“Major Adverse Cariac Events”. After start of study drug, MACE are documented on the 
Adverse Event CRF. 
 
Death 
 Source: Study completion CRF 
 Occurrence: “Primary reason for premature discontinuation” = 10 (“Death”) 
 Date of event: “Date of death” 
Myocardial infarction 
 Source: Adverse Events CRF 
 Occurrence: “Advese event” MedDRA PT in (10000891, 10028596, 10066592, 
10049768) AND/OR “Mark if AE meets definition of MACE”=1 (ticked) 
 Date of event: “Start date” 
Coronary artery bypass grafting 
 Source: Adverse Events CRF 
 Occurrence: “Advese event” MedDRA PT = 10011077 AND/OR “Mark if AE meets 
definition of MACE”=1 (ticked) 
 Date of event: “Start date” 
 
Specific adverse events 
Adverse Events leading to permanent discontinuation of study drug 
 Source: Adverse Events CRF / Infections CRF/CMV CRF 
 Occurrence: “Action taken” = 2 (“Study drug permanently discontinued due to this 
adverse event/infection”) 
 
Infections 
 Source: Adverse Events CRF / Infections CRF/CMV CRF 
 Occurence: Infections are all treatment emergent adverse events with MedDRA SOC 
= 10021881 (Infections and infestations) or events verified as infections after medical 
review (not necessarily coded as “Infections and infestations”). 
 


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5.1.4 
Target therapeutic ranges 
Everolimus 
Target therapeutic ranges for Everolimus whole blood trough levels should be 5 – 10 ng/mL. 
Cyclosphorin A 
Target therapeutic range for Cyclosporin A whole blood levels should be the following: 
From Month 3 up to Month 6: 100 – 200 ng/mL. After Month 6: 50 – 150 ng/mL. 
In the CNI-free group the Cyclosporin A will be reduced to a dose resulting in a C0 level of ≤ 
75 ng/mL starting at Month 6 post Tx and finally (after 8 weeks of reduced dosage) removed 
completely. At the latest at Month 9, Cyclosporin A should be withdrawn completely from the 
immunosuppressive regimen in the CNI-free group. 
Tacrolimus 
Target therapeutic range for Tacrolimus whole blood levels should be the following: 
From Month 3 up to Month 6: 5-10 ng/mL. After Month 6: 3-8 ng/mL. 
In the CNI-free group the Tacrolimus will be reduced to a dose resulting in a C0 level of ≤5 
ng/mL starting at Month 6 post Tx and finally (after 8 weeks of reduced dosage) removed 
completely. At the latest at Month 9, Cyclosporin A or Tacrolimus should be withdrawn 
completely from the immunosuppressive regimen in the CNI-free group. 
5.2 
Imputation rules 
5.2.1 
Study drug 
In case of missing or partial start date, the start date should be shifted to earliest possible date, 
but not earlier than the Screening visit. Missing or partial end dates should be shifted as far 
back as possible but not later than the last known date subject took study drug (from Study 
Completion CRF). 
 
5.2.2 
AE date imputation 
In case of missing or partial start date or end date of an AE, the start date should be shifted to 
the earliest possible date, but not earlier than the first intake of study drug while the end date 
should be shifted as far back as possible. 
5.2.3 
Concomitant medication date imputation 
In case of missing or partial start date or end date of a concomitant medication, the start date 
should be shifted to the earliest possible date, but not earlier than the first intake of study drug 
while the end date should be shifted as far back as possible. 
5.2.3.1 
Prior therapies date imputation 
In case of missing or partial start date or end date of a prior therapy, the dates should be 
shifted to the earliest possible date, but not earlier than the first intake of study. 


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5.2.3.2 
Post therapies date imputation 
In case of missing or partial start date or end date of a post therapy, the start date should be 
shifted to the earliest possible date, but not earlier than the first intake of study drug while the 
end date should be shifted as far back as possible. 
5.2.3.3 
Other imputations 
5.3 
AEs coding/grading 
5.4 
Laboratory parameters derivations 
Clinically notable laboratory values and vital signs are defined in chapter 12, Appendix 2 of 
the study protocol. 
5.5 
Statistical models 
5.5.1 
Primary analysis 
5.5.2 
Key secondary analysis 
5.6 
Rule of exclusion criteria of analysis sets  
The rules for subject classification in the analysis sets are defined in the VAP Module 3 
“CRAD001ADE14_Module 3_ Protocol Deviations_Final1.1_31-Mai-2017.doc” and the 
DRM protocol “Protocol_DRM_20170522.docx”. 
6 
Reference 
Not applicable