5, 6 or 7 Year Follow-up Control After the SCHEDULE Study (SCANDINAVIAN HEART TRANSPLANT EVEROLIMUS DE NOVO STUDY WITH EARLY CNI AVOIDANCE)
Phase: PHASE4
Conditions: Heart Transplantation
Sponsor: Novartis Pharmaceuticals

1 
1 
TITLE P 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
for 5,6 or 7 year follow-up control after the SCHEDULE study 
(SCANDINAVIAN HEART TRANSPLANT EVEROLIMUS DE NOVO STUDY WITH 
EARLY CNI AVOIDANCE) 
Study code:   
EudraCT number:  
Version number: 
 
Development phase: 
Release date: 
Document history:  
CRAD001ANO05 / NCT02864706 
2016-000404-28 
FINAL 2.0-DK 
IV 
07-Jul-2016
This version of the Clinical Study Protocol includes: 
• Substantial Amendment No.1, FINAL 1.0,
27-Jun-2016
• Updates to Section 4.5 as requested by the Danish
Health Authority during the assessment of the CTA
Title of original SCHEDULE study: 
A controlled randomized open-label multicentre study evaluating if early initiation of 
everolimus (Certican®) and early elimination of cyclosporine (Sandimmun Neoral®) in 
de novo heart transplant recipients can improve long-term renal function and slow 
down the progression of chronic allograft vasculopathy. 
Study code: 
CRAD001ANO02 
EudraCT number: 
2009-013074-41 
Coordinating Investigator: 
 
 
Sponsor Signatory: 
 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
2 
 
TABLE OF CONTENTS: 
 
Reason and rationale for the follow-up control 
 
 
 
 
3 
Protocol for the 5 to 7-year follow-up examination 
 
 
 
 
3 
 
1 
Introduction 
 
 
 
 
 
 
 
3 
 
 
1.1 
Background 
 
 
 
 
 
 
3 
 
 
1.2 
Study purpose 
 
 
 
 
 
4 
 
2 
Aims/Objectives 
 
 
 
 
 
 
4 
 
3 
Study design  
 
 
 
 
 
 
4 
 
4 
Material and methods  
 
 
 
 
 
5 
 
 
4.1 
Patients 
 
 
 
 
 
 
5 
 
 
4.2 
Treatments 
 
 
 
 
 
 
5 
 
 
4.3 
Efficacy assessments  
 
 
 
 
5 
 
 
 
4.3.1 Baseline Data for the Follow-up visit  
 
6 
 
 
 
4.3.2 Immunosuppressive Medication and 
 
 
 
 
Other Concomitant Medications 
 
 
7 
 
 
 
4.3.3 Renal Function 
 
 
 
 
7 
 
 
 
4.3.4 Intravascular Ultrasound and 
 
 
 
 
Cardiac Function 
 
 
 
 
7 
 
 
 
4.3.5 Vital Signs 
 
 
 
 
 
8 
 
 
 
4.3.6 Electrocardiogram 
 
 
 
 
8 
 
 
 
4.3.7 Cardiac rejections 
 
 
 
 
8 
 
 
 
4.3.8 Laboratory Evaluations 
 
 
 
8 
 
 
 
4.3.9 Health-related Quality of Life  
 
 
8 
 
 
4.4 
Statistics 
 
 
 
 
 
 
9 
 
 
4.5 
Adverse Events 
 
 
 
 
 
10 
4.5.1 Definitions 
 
 
 
 
 
10 
4.5.2 Occurrence of Selected Adverse Events (Including 
 
 
 
 
Serious Adverse Events) – Main Categories  
11 
 
 
 
4.5.3 Instructions for collecting/handling of Adverse 
 
 
 
 
Events and Serious Adverse Events  
 
13 
 
 
 
4.5.4 Pregnancy 
 
 
 
 
 
14 
 
5 
Site Monitoring 
 
 
 
 
 
 
14 
 
6. 
Ethics and Good Clinical Practice 
 
 
 
 
14 
 
7 
References 
 
 
 
 
 
 
 
15 
 
Signatures 
 
 
 
 
 
 
 
 
16 
 
 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
3 
 
 
REASON AND RATIONALE FOR THE FOLLOW-UP CONTROL 
This protocol is written to describe the procedures for a single 5, 6 or 7 year follow-up control visit 
of patients that participated in the 12-month SCHEDULE-study and the following 3-year follow-up 
examiniation/visit. The aim of this 5 to 7-year follow-up visit is to examine the effect of long term 
treatment, i.e. 5, 6 or 7 years, with early initiation of everolimus (Certican®) and early elimination 
of cyclosporine (CsA), compared to standard immunosuppressive regimen including CsA, on 
renal and heart function. During the time period of this follow-up examinations this visit will be 
performed as part of a routine annual visit 5, 6 or 7 years since transplantation (and inclusion in 
the original SCHEDULE study).  
PROTOCOL FOR THE 5 TO 7-YEAR FOLLOW-UP EXAMINATION 
1 
INTRODUCTION 
1.1 
Background 
The calcineurin inhibitors (CNIs) have contributed to low acute rejection rates and favourable 
short-term graft survival in heart transplantation (HTx) with 80-90% patients survival after 
12 months. However, the protective role of these and other immunosuppressive drugs in the 
development of cardiac allograft vasculopathy is uncertain; in fact CNIs and steroids have been 
implicated in the pathological development of this condition. In addition, new long term adverse 
effects have occurred including CNI-induced nephrotoxicity. Nearly 30% of HTx recipients 
demonstrate renal dysfunction already at 1 year post-HTx. Importantly, a glomerular filtration rate 
(GFR) <60 mL/min/1.73 m2 at this time point has been shown by our own group to be an 
independent risk factor for both all-cause and cardiac mortality (1). 
Everolimus, a proliferation signal inhibitor (PSI) is a potent, rapamycin-related 
immunosuppressive agent that exerts its immunosuppressive effect by blocking interleukin (IL-2 
and IL-5) driven proliferation of T and B cells. PSIs do not share the nephrotoxic properties of 
CNIs, but potential serious side effects such as exacerbation of proteinuria, impaired wound 
healing and pulmonary inflammation have been reported. 
As attention shifts towards improving long-term outcomes in thoracic transplant recipients, there 
is a growing emphasis on maintenance immunosuppressive regimens that minimize exposure to 
CNIs (2). CNI-related renal toxicity (3) is of particular concern in view of the high rate of chronic 
renal failure observed in heart and lung transplant recipients (4), but other CNI-related 
complications such as diabetes mellitus, hyperlipidemia, hypertension and infections can also 
adversely affect outcomes. Importantly, progressive renal disease, metabolic abnormalities and 
infections contribute to the risk of cardiac allograft vasculopathy (CAV) (5), the leading cause of 
death after the first year following HTx (6). Rapid progression of CAV in the first 5 years as well 
as in the first year after transplantation detected by intravascular ultrasound (IVUS) analysis is a 
powerful predictor for mortality, myocardial infarction, and the development of angiographic 
abnormalities (7, 8). 
The introduction of PSIs has created a novel opportunity to limit CNI exposure without loss of 
efficacy. 
Follow-up Examinations 
Extension phase of important studies are not uncommon, including in transplantation studies. 
Data of this kind have been published from other large outcome HTx studies (9, 10, 11). This 
form of studies allows a more complete evaluation of the effect of treatment as well as side 
effects. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
4 
 
The results from the SCHEDULE 3-year follow-up visit indicated that the beneficial effect of 
everolimus treatment with early CNI withdrawal on renal function in de novo heart transplant 
recipients seen at 12 months after transplantation (12) was maintained at 3 years after 
transplantation (13). The aim of this 5 to 7-year follow-up visit is therefore to further examine the 
long term effect (i.e. 5 to 7-years) of the combination of everolimus followed by early 
Cyclosporine A (CsA) withdrawal compared to standard immunosuppressive regimen including 
CsA, on renal function and progression of CAV. 
1.2 
Study Purpose 
To evaluate, in de novo heart transplant recipients, whether early initiation of everolimus and 
early elimination of CsA compared to standard immunosuppressive regimen including CsA can 
improve long-term renal function and slow down the progression of CAV. 
2 
AIMS/OBJECTIVES 
The major aim of this extension study is to evaluate the long-term (i.e. 5 to 7 years) effect of early 
initiation of everolimus and early elimination of CsA compared to standard immunosuppressive 
regimen including CsA on primary and secondary endpoints investigated in the SCHEDULE main 
study. The endpoints for this 5 to 7-year follow-up visit are: 
Primary endpoint: 
• 
Renal function as assessed by measured glomerular filtration rate (mGFR) 
Secondary endpoints: 
• 
Progression of CAV by IVUS analysis 
• 
Myocardial structure and function by echocardiography assessment 
• 
Quality of life by SF-36 (Minnesota Living with Heart Failure Questionnaire), Euro Quality 
of Life 5D (EQ 5D), and Beck Depression Inventory (BDI) form 
• 
Number of adverse events (AEs)/serious adverse events (SAEs) 
3 
STUDY DESIGN 
The 12-months SCHEDULE main study was a prospective, multi-center, randomized, controlled, 
parallel group, open label study in de novo heart transplant recipients. The study consisted of two 
study periods, period 1 (HTx to week 7-11) and period 2 (week 7-11 to Month 12). Patients 
fulfilling the inclusion and exclusion criteria were randomized to one of two treatment groups: 
(i) conventional treatment with CsA, mycophenolate mofetil (MMF), and corticosteroids 
(Group A), or (ii) low-dose CsA, everolimus, MMF, and corticosteroids (Group B). After period 1, 
CsA was discontinued in Group B (experimental set-up with off-label use of everolimus), while the 
standard triple-drug immunosuppressive regimen was maintained in Group A.  
In the 12-month SCHEDULE-study, 115 patients were randomized and treated. The main study 
was followed by a 3-year follow-up visit in which 102 of the 115 patients participated. 
This 5 to 7-year follow-up visit is a further longtime follow-up examination of the patients 
participating in the SCHEDULE main study and the 3-year follow-up visit. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
5 
 
4 
MATERIAL AND METHODS 
4.1 
Patients 
Inclusion criteria: 
• 
Patients who participated in the SCHEDULE 12-month main study, and who completed 
the 3 year follow-up visit, 
• 
Patients who are coming for a regular annual clinic visit 5 to 7 years after randomization in 
the main study 
• 
Obtaining of a separate signed patient informed consent will be required for participation 
in this follow-up examination. 
Exclusion criterium: 
• 
Patients with a retransplanted heart since the original SCHEDULE study 
 
The patients will be allocated the same patient number as in the main study. The patients were 
recruited from six transplant centers in Norway, Sweden and Denmark. Since this is a single visit 
control there are no withdrawal criteria. 
4.2 
Treatments 
After randomization in the main study patients in Group A received an immunosuppressive 
regimen consisting of CsA, MMF and corticosteroids in both study periods. Patients in Group B 
commenced on an immunosuppressive regimen consisting of low dose everolimus and CsA, 
MMF and corticosteroids in period 1. In period 2 the patients were subjected to abrupt and 
complete CNI withdrawal, to a CNI free immunosuppressive regimen consisting of everolimus, 
MMF and corticosteroids. 
After completion of the main study (12-months), most of the patients continued on the same 
immunosuppression. However, patients might have switched to alternative immunosuppressive 
drugs between Month 12 in the main study, the 3-year follow-up visit, and the 5 to 7-year follow-
up visit. 
4.3 
Efficacy assessments 
The assessments to be performed at the 5 to 7-year follow-up visit are presented in Table 1. The 
same clinical methods/investigations as used for the 12-month assessments (Visit 11) and the 
3-year follow-up visit will be used at the 5 to 7-year follow-up visit. Data from the main study and 
from the 3 year follow-up visit will also be used. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
6 
 
• 
Table 1 
Assessment Schedule 
Visit 
Follow-up 
Time after randomization 
5 to 7 years 
Informed consent 
X 
Baseline data  
X 
Concomitant therapy 
X 
Immunosuppressive therapy 
X 
12-led ECG 
X 
Vital signs 
X 
Echocardiography 
X 
Quality of life 
X 
IVUS1,2 
X 
Laboratory test hematology/biochemistry3 
X 
Laboratory test/lipid profile4 
X 
Urinalysis5 
X 
 
 
mGFR 
X 
Drug concentration trough levels: 
 
 
CsA 
X 
 
Tacrolimus 
X 
 
Everolimus 
X 
Drug daily doses: 
 
 
CsA 
X 
 
Tacrolimus 
X 
 
Everolimus 
X 
 
Corticosteroids 
X 
 
MMF 
X 
AEs 
X 
SAEs 
X 
ECG, electrocardiogram; IVUS, intravascular ultrasound; 
; mGFR, measured 
glomerular filtration rate; CsA, cyclosporine; MMF, mycophenolate mofetil; AEs, adverse events; SAEs, serious 
adverse events 
1. Measurements of microcirculation to be performed in connection with routine coronary angiography prior to IVUS 
examination (optional) 
2. If IVUS is not performed as part of the assessments made at the follow-up study visit 5 or 6 years after 
transplantation IVUS may be collected at the subsequent regular annual routine visit 
3. Hematology: hemoglobin, leukocytes, thrombocytes. Biochemistry: ASAT, ALAT, Urea, Creatinine, Uric acid, 
Sodium, Potassium, Albumin 
4. Laboratory tests/Lipid profile: Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, HbA1c, NT-proBNP, 
Troponin T, CRP 
5. Urinalysis: Albumin/creatinine ratio 
4.3.1 Baseline Data for the Follow-up Visit 
The following demographic/baseline data will be collected at the follow-up visit: 
• 
Patient number (randomization number in the main study) 
• 
Date of visit 
• 
Patient informed consent (date of obtained ICF) or the reason for not giving consent (i.e. 
death, patient unwilling to give consent, other reason) 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
7 
 
4.3.2 Immunosuppressive Medication and Other Concomitant Medications 
Present (at the time of the 5 to 7-year follow-up visit) immunosuppressive treatment (everolimus, 
CsA/tacrolimus, MMF, and corticosteroids [i.e. prednisolone]) including daily dose, information on 
start and/or stop of immunosuppressive treatment since the end of the original study and reasons 
for stopping/starting the immunosuppressive drugs will be collected. Present concomitant 
medications including indication and route of administration will also be collected. 
4.3.3 Renal Function 
Measured Glomerular Filtration Rate 
Renal function will be assessed by mGFR using the same method as used in the main study 
(chrome-Ethylenediaminetetraacetic acid [Cr-EDTA] clearance, technetium 
99m-Diethylenetriaminepentaacetic acid [99mTc-DTPA] clearance, or Iohexol clearance). 
 
Urine Spot Sample 
A spot sample (dipstick) will be used for determination of proteinuria (albumin/creatinine ratio). 
4.3.4 Intravascular Ultrasound and Cardiac Function 
Intravascular Ultrasound Measurements 
Intravascular ultrasound (IVUS) will only be performed on patients who have done IVUS 
examinations in the main study and at the 3-year follow-up visit. 
Note: If IVUS is not performed as part of the assessments made at the follow-up study visit 5 or 6 
years after transplantation IVUS may be collected at the subsequent regular annual routine visit. 
IVUS recordings will be performed in connection with a routine left sided heart catheterization 
using special catheters. Semi-automated contour detection of both the lumen and external elastic 
membrane (EEM) will be performed at intervals of 60 frames using dedicated software (QIVUS 
Clinical Edition, Medis Medical Imaging, Leiden, Netherlands). The longest possible segment 
between the most distal and proximal side branch visualized in the IVUS pullback will be 
analyzed for each patient. Following automatic contour detection, borders will be edited manually 
by two independent operators according to the guidelines for acquisition and analysis of IVUS 
images by the American College of Cardiology and European Society of Cardiology. 
The following parameters will be recorded for all patients using the mean result of all frames 
analyzed: 
• 
lumen cross-sectional area (CSA) 
• 
vessel CSA 
• 
intimal CSA 
• 
maximal intimal thickness (MIT) 
The CSA measurements will be utilized to calculate total atheroma volume using Simpson's 
method, as well as percent atheroma volume (PAV). The PAV value will be used for defining 
CAV. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
8 
 
Echocardiography 
Standard echocardiography assessment as done in the main study will be performed. 
Patients will be examined in the lateral recumbent position after 15 minutes of rest. The heart will 
be visualized by standard ultrasonic techniques and acoustic windows giving a total 
homodynamic and valvular assessment. 
Three heartbeats will be needed for this analysis. Analysis will be done blinded. Standard 
measurements including left ventricular end systolic dimension (LVESD) and left ventricular end 
diastolic dimension (LVEDD), , left ventricular performance assessed as fractional shortening 
(FF%), and left ventricular ejection fraction (LVEF) (Simpson’s method) will be performed. Local 
echocardiographic recordings will be recorded, echocardiographic recordings may also be read 
centrally. 
4.3.5 Vital Signs 
Body weight (kg), height (cm), systolic and diastolic blood pressure (mmHg; seated after at least 
20 minutes of rest), and heart rate (beats/min) will be recorded. 
4.3.6 Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed, and the following ECG 
parameters will be documented: type of rhythm, heart rate, PQ time, and QRS interval. 
4.3.7 Cardiac rejections 
Number and grading of biopsy proven and treated rejections and rejections with hemodynamic 
compromize since the 3 year follow-up visit will be collected. 
4.3.8 Laboratory Evaluations 
Hematology, Biochemistry and Urinalysis 
The following laboratory parameters will be analyzed: 
Hematology: hemoglobin, leukocytes, platelets. 
Biochemistry: serum creatinine, urea, uric acid, sodium, potassium, alanine aminotransferase 
(ALAT), aspartate aminotransferase (ASAT), albumin. 
Lipid profile/laboratory tests: total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, 
HbA1c, NT-proBNP, Troponin T, C-reactive protein (CRP). 
Urinalysis: albumin/creatinine ratio, see Section 4.3.3. 
Drug Concentration Trough Levels 
Whole blood levels (C-0 levels) will be measured for everolimus, CsA, and tacrolimus as part of 
the routine laboratory measurements. 
4.3.9 Health-related Quality of Life 
Quality of life will be examined using three validated questionnaires, i.e. the SF-36, EQ 5D, and 
the BDI form. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
9 
 
4.4 
Statistics 
The primary efficacy analysis will be based on the intention-to-treat (ITT) population. Statistical 
hypothesis testing will be performed, and confidence interval (CI) will be derived to estimate the 
effects. Two-sided tests will be performed on the 5% level of significance, and 95% two-sided CI 
for least square mean will be presented.  
The null hypothesis is that there is no difference in the mean of mGFR between the everolimus 
arm (µEverolimus) and the control arm (Control) (µControl) and the alternative hypothesis is that there is 
a difference between everolimus and control at the 5 to 7-years follow-up visit. 
H0: µEverolimus - µControl = 0 
H1: µEverolimus - µControl ≠ 0 
The above between-group comparisons will be performed using an ANCOVA with study 
treatment (Everolimus, Control) and randomization strata (mGFR above/below 60 mL/min and 
have/not have mechanical assist device) as classification variables. In addition, the mGFR values 
at baseline (Visit 6) will be used as covariate. 
In general data will be summarised by means of summary statistics. For continuous data, the 
following summary statistics will be presented: number of observations, mean value, standard 
deviation, minimum, first quartile, median, third quartile and maximum value. Categorical data will 
be presented as counts and percentages. Summary statistics will be presented by treatment 
group/total and assessment visit, as applicable. Individual patient data will be listed. 
The analyses of the data from the 5 to 7-year follow-up visit will be presented in a statistical 
analysis plan (SAP) prepared prior to database lock.  
Data sets to be analysed: 
The Safety Set will consist of patients who:  
• 
were included in the Safety Set in the Clinical Study Reports Addendum dated 
11 August 2015 for the 3 year follow-up visit 
• 
have at least one assessment at the 5 to 7-year follow-up visit 
 
The Intention-to-Treat (ITT) set will consist of patients who: 
• 
were included in the ITT in the Clinical Study Reports Addendum dated 11 August 2015 
for the 3 year follow-up visit 
• 
have at least assessment of the efficacy variable mGFR 
 at the 5 to 7-year follow-
up visit 
 
The Per Protocol Set (PPS) will consist of patients who: 
• 
were included in the PPS in the Clinical Study Reports Addendum dated 11 August 2015 
for the 3 year follow-up visit 
• 
have at least assessment of the efficacy variable mGFR 
 at the 5 to 7-year follow-
up visit 
• 
are on their randomized treatment i.e. Everolimus or Control (Control=Cyclosporine and/or 
Tacrolimus) at the 5 to 7-year follow-up visit 
• 
have no major protocol deviation at the 5 to 7-year follow-up visit. The final criteria for 
PPS, regarding which protocol deviations that warrant exclusions, will be determined 
when all data on protocol deviations are available and will be documented in a separate 
document before database lock 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
10 
 
The Extended PPS will consist of patients who: 
• 
were included in the ITT in the Clinical Study Reports Addendum dated 11 August 2015 
for the 3 year follow-up visit 
• 
have at least assessment of the efficacy variable mGFR 
 at the 5 to 7-year follow-
up visit 
• 
are on their randomized treatment i.e. Everolimus (Everolimus=Everolimus or Everolimus 
and Cyclosporine and/or Tacrolimus) or Control (Control=Cyclosporine and/or Tacrolimus 
[and not Everolimus]) at the 5 to 7-year follow-up visit 
• 
have no major protocol deviation at the 5 to 7-year follow-up visit. The final criteria for 
PPS, regarding which protocol deviations that warrant exclusions, will be determined 
when all data on protocol deviations are available and will be documented in a separate 
document before database lock 
4.5 
Adverse Events 
4.5.1 Definitions 
Adverse Event 
Any untoward medical occurrence in a patient or clinical trial patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
Comment: An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product (IMP), whether or not considered related to the IMP. 
Adverse Reaction 
All untoward and unintended responses to an IMP related to any dose administered. 
Comment: All AEs judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship. 
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator's Brochure for an unauthorized IMP or SmPC for an authorized 
product). 
Comments: When the outcome of an adverse reaction in this study is not consistent with the 
applicable product information, i.e. Section 4.8 of the SmPC, this adverse reaction should be 
considered as unexpected.  
Serious Adverse Event 
Any untoward medicinal occurrence or effect that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
Comments: Life-threatening in the definition of a serious adverse event (SAE) or serious adverse 
reaction refers to an event in which the patient was at risk of death at the time of event; it does 
not refer to an event which hypothetically might have caused death if it was more severe. 
Medical judgment should be exercised in deciding whether an AE/reaction is serious in other 
situations. Important AEs/reactions that are not immediately life-threatening or do not result in 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
11 
 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
 
4.5.2 Occurrence of Selected Adverse Events (Including Serious Adverse Events) – Main 
Categories 
AEs considered clinically relevant are listed in Table 2. Any of these AEs that have occurred 
during the time between the 3-year follow-up visit and the 5 to 7-year follow-up visit should be 
registered in the case report form (CRF). 
All SAEs should be reported to Novartis on specific SAE forms within 24 hours of learning of its 
occurrence to: 
Clinical Safety Desk Fax: 
 
 
 
 
 
 
To be answered: Has there been any occurrences of (clinically relevant) AEs since the 3-year 
follow-up visit i.e. from the 3-year follow-up visit to the 5 to 7-year follow-up visit.  
The total number of each AE/SAE should be recorded, i.e. one patient may have experienced 
several AEs. Further details regarding collection and handling of AEs/SAEs are provided in 
Appendix 1. 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
12 
 
• 
Table 2 
Selected Adverse Events – Main Categories 
 
Adverse Event 
3 years to 5/7 years 
 
AE 
SAE 
Infection 
      Pneumonia 
 
 
      Herpes Zoster 
 
 
      Herpes simplex 
 
 
      Sepsis 
 
 
Cancer 
     Squamous cell carcinoma 
 
 
     Basal cell carcinoma 
 
 
     Other skin cancer 
 
 
     PTLD 
 
 
     Solid tumor 
 
 
Bone marrow toxicity 
     Thrombocytopenia (<100000/µL) 
 
 
     Leucopenia (<3500/µL) 
 
 
     Anemia (<10 g/dL) 
 
 
Tromboembolic event 
     DVT 
 
 
     Pulmonary emboli 
 
 
     Stroke/TIA 
 
 
Gastrointestinal system 
     Diarrhea 
 
 
     Constipation 
 
 
      Pain 
 
 
Skin 
     Rash 
 
 
     Acne 
 
 
     Hirsutism 
 
 
Cardiac 
      Cellular rejection (grade) 
 
 
      Humoral rejection 
 
 
      LV dysfunction (EF<30%, or 25%↓) 
 
 
      Arrhythmias (clinically significant, requiring treatment) 
 
 
      PCI 
 
 
      Myocardial infarction 
 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
13 
 
Adverse Event 
3 years to 5/7 years 
 
AE 
SAE 
Renal 
      Proteinuria (albumin/creatinine >100) 
 
 
Hyperuricemia 
 
 
Peripheral oedema 
 
 
Gingival hyperplasia 
 
 
Other 
 
 
 
4.5.3 Instructions for collecting and reporting Adverse Events and Serious Adverse 
Events 
The purpose of this instruction is to guide how to collect and handle the side effects from a 
practical point of view. 
 
• 
When the patient comes to the clinic visit, ask him/her if there have been any adverse 
events (clinically relevant) since the 3-year follow-up visit (i.e. between the 3-year follow-
up visit and the 5 to 7-year follow-up visit). 
• 
Record serious and non-serious AEs and the total number of each event in the CRF (each 
patient might have experienced several events). 
• 
Check the adverse events/serious adverse events against medical records in order to 
source verify the events.  
• 
The serious adverse events must be reported to Novartis within 24 hours of learning of its 
occurrence. 
• 
State in the medical record for the study visit: 
- that the patient has been asked for clinically relevant adverse events 
- the events reported by the patient  
- refer to where in the medical record the different adverse events can be found (e.g. by 
date). 
• 
If the reported adverse events cannot be verified in medical record/any other source 
document the patient should be asked if he/she has been in contact with a doctor/hospital 
and/or received treatment due to the event and attempt to retrieve this information from 
the treating physician/hospital. It is important to make an effort to find the medical 
records/source documents and to document this for the study visit in the medical records. 
• 
As for the original study (CRAD001NO02, EudraCT number 2009-013074-41), everolimus 
(Certican®) is defined as the study drug. If the SAE is not previously documented in the IB 
or Package Insert for (new occurrence) and is thought to be related to the study drug a 
Drug Safety and Epidemiology Department associate may urgently require further 
information from the investigator for health authority reporting. Novartis may need to issue 
an Investigator Notification to inform all investigators involved in any study with the same 
study treatment that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
14 
 
4.5.4 Pregnancy 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 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 the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
 
5. 
SITE MONITORING 
Formal site monitoring will be performed as described in the Monitoring Plan for this study. 
Novartis designated CRO will assure compliance monitoring 
During the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the paper CRFs, the adherence to the protocol and to Good 
Clinical Practice and the progress of enrollment. 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 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 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 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. 
Access to source documents by auditors and regulatory inspectors will be granted. 
 
6. 
ETHICS AND GOOD CLINICAL PRACTICe 
This study was planned and shall be  performed according to the principles of Good Clinical 
Practice, the declaration of Helsinki, and national laws and regulations about clinical studies. The 
study will not start without written Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board approval and the written informed consent of the patient. 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
15 
 
7 
REFERENCES 
1 Arora S, Andreassen A, Simonsen S, Gude E, Dahl C, Skaardal R, et.al. Prognostic 
importance of renal function 1 year after heart transplantation for all-cause and cardiac 
mortality and development of allograft vasculopathy. Transplantation. 2007 Jul 27;84(2):149-
54. 
2 Zuckermann AO, Aliabadi AZ. Calcineurin-inhibitor minimization protocols in heart 
transplantation. Transplant Int 2009; 22(1): 78-89 
3 Keogh A. Calcineurin inhibitors in heart transplantation. J Heart Lung Transplant 2004; 23 (5 
Suppl): S202-206 
4 Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW et al. Chronic renal failure 
after transplantation of a nonrenal organ. N Eng J Med 2003; 349(10): 931-940 
5 Mehra MR. Contemporary concepts in prevention and treatment of cardiac allograft 
vasculopathy.  Am J Transplant 2006; 6(6): 1248-1256 
6 Taylor DO, Edwards LB, Aurora P, Christie JD, Dobbels F, Kirk R et al. Registry of the 
International Society for Heart and Lung Transplantation: twenty-fifth official adult heart 
transplant report – 2008. J Heart Lung Transplant 2008; 27(9): 943-956 
7 Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation 
study among heart transplantation recipients. Outcomes after five years. J Am Coll Cardiol 
2005;45:1532–7. 
8 Tuzcu M, Kapadia SR, Sachar R, et al. Intravascular ultrasound evidence of angiographically 
silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after 
cardiac transplantation. J Am Coll Cardiol 2005;45:1538–42. 
9 Kobashigawa JA, Patel J, Furukawa H, Moriguchi JD, Yeatman L, Takemoto S, et al. Five-
year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine 
in heart transplant patients. J Heart Lung Transplant. 2006 Apr;25(4):434-9. 
10 Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R, et al.; Mycophenolate 
Mofetil Cardiac Study Investigators. Three-year results of a randomized, double-blind, 
controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J 
Heart Lung Transplant. 2005 May;24(5):517-25. 
11 Eisen HJ. Long-term cardiovascular risk in transplantation--insights from the use of 
everolimus in heart transplantation Nephrol Dial Transplant. 2006 Jul;21 Suppl 3:iii9-13. 
12 Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, et al.; 
SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in 
heart transplant recipients: a randomized trial. Am J Transplant. 2014 Aug;14(8):1828-38. 
13 Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, et al.; 
SCHEDULE Investigators. Everolimus initiation with early calcineurin inhibitor withdrawal in 
de novo heart transplant recipients: Three-year results from the randomized SCHEDULE 
study.  Am J Transplant. 2015; XX, 1-10 (e-published) 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
16 
 
SIGNATURES 
This Clinical Study Protocol  is approved by: 
 
 
 
 
SPONSOR’S REPRESENTATIVE: 
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COORDINATING INVESTIGATOR:  
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol  
Sponsor: Novartis 
 
Study Code: CRAD001ANO05 
Version and Date: FINAL 2.0-DK, 07-Jul-2016 
EudraCT No.: 2016-000404-28 
 
17 
 
CLINICAL STUDY PROTOCOL AGREEMENT FORM 
I have read the Clinical Study Protocol, Final version 2.0-DK, dated 07-Jul-2016, and I agree to 
conduct the study according to this study protocol. 
 
Principal Investigator: 
 
Date: 
 
Signature: