EVOLVD: Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients
Phase: PHASE3
Conditions: Cardiac Allograft Vasculopathy
Sponsor: Lars Gullestad

EVOLVD Protocol version 3.0 18th October, 2021 
Page 1 
 
EVOLVD: Cholesterol lowering 
with EVOLocumab to prevent 
cardiac allograft Vasculopathy in 
De-novo heart transplant 
recipients 
 
 
Protocol Identification Number: EVOLVD 3.0 
EudraCT Number: 2017-005097-19    
 
SPONSOR: 
Oslo University Hospital (OUS) 
Address: Postboks 4590 Nydalen 
0424 Oslo, Norway 
E-mail: post@oslo-universitetssykehus.no 
 
PRINCIPAL INVESTIGATOR: 
Professor Lars Gullestad 
Address: OUS-Rikshospitalet 
Postboks 4590 Nydalen 
0424 Oslo, Norway 
Tel: 23070000 
E-mail: lars.gullestad@medisin.uio.no 
 
PROTOCOL VERSION NO. 3.0 
18th October, 2021 
Kaspar Broch 
 
 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 2 
 
Contact details 
 
Sponsor: 
Oslo University Hospital (OUS) 
Address: Postboks 4590 Nydalen 
0424 Oslo, Norway 
E-mail: post@oslo-universitetssykehus.no 
 
Principal Investigator  
Professor Lars Gullestad 
Address: OUS-Rikshospitalet 
Postboks 4590 Nydalen 
0424 Oslo, Norway 
Tel: 23070000 
E-mail: lars.gullestad@medisin.uio.no 
 
National coordinating 
investigators  
Lars Gullestad 
E-mail: lars.gullestad@medisin.uio.no  
K. Karason 
E-mail: kristjan.karason@medfak.gu.se 
F. Gustafsson 
E-mail: finng@dadlnet.dk  
K. Lemström 
E-mail karl.lemstrom@helsinki.fi  
 
Participating Departments: 
Department of Cardiology, Oslo University 
Hospital, Rikshospitalet; Oslo,  
Department of Cardiology, Sahlgrenska 
University Hospital, Gothenburg, Sweden,  
The Clinic for Heart Failure and 
Valvular Disease, Skåne University Hospital 
and Lund University, Lund, Sweden, 
Department of Cardiology, Rigshospitalet, 
Copenhagen, Denmark,  
Department of Cardiology, Aarhus University 
Hospital, Skejby, Denmark  
Helsinki University Hospital Heart and Lung 
Center, Helsinki, Finland 
 
  
Monitor: 
Clinical Research Support  
Research Support Unit  
Oslo Hospital Services  
Oslo University Hospital  
 
 
 

EVOLVD Protocol version 3.0 18th October, 2021 
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Protocol Synopsis 
EVOLVD: Cholesterol lowering with EVOLocumab to prevent cardiac 
allograft Vasculopathy in De-novo heart transplant recipients 
 
 
Sponsor 
Oslo University Hospital 
Phase and study type 
Phase IIIB, interventional, randomised controlled trial 
Investigational Medical 
Product (including active 
comparator and placebo) :       
Evolocumab or matching placebo 
Centres: 
Oslo University Hospital, Rikshospitalet, Oslo, Norway 
Study Period: 
 
Estimated date of first patient enrolled (study start) November 1st, 2018 
Anticipated recruitment period: February 1st , 2019 – February 28th, 
2022 
Estimated date of last patient completed treatment: February 28th, 2023 
Estimated date of last patient completed (last patient, last visit: Study 
end): March 31st , 2023 
 
Treatment Duration: 
12 months 
Follow-up: 
13 months (including treatment period) 
Objectives  
The main goal of this study is to evaluate the effect of the PCSK9 
inhibitor Evolocumab on cardiac allograft vasculopathy in de novo heart 
transplant recipients.  
Secondary objectives are to assess the impact of treatment on: i) 
cholesterol levels, ii) renal function, iii) inflammation, iv) Quality of life, 
v) cardiac function as assessed by biomarkers and echocardiography, vi) 
the number of rejections, and (vii) safety and tolerability. As an 
exploratory outcome, we will assess the effect of treatment on clinical 
events (death, myocardial infarction, cerebral stroke, cancer, end stage 
renal disease) 
Endpoints: 
Primary endpoint: The primary endpoint will be the baseline-adjusted 
maximal intimal thickness as measured by coronary intravascular 
ultrasound (IVUS) after 12 months of treatment. 
 
Secondary endpoints:  
 
Percent atheroma volume  
 
Cardiac allograft vasculopathy (defined as mean a maximal 
intimal thickness ≥0.5 mm over the entire matched segment) 

EVOLVD Protocol version 3.0 18th October, 2021 
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 
LDL cholesterol 
 
Estimated glomerular filtration rate (eGFR) 
 
Quality of life as assessed by the SF36 and the EQ 5D 3L EuroQoL 
questionnaires, and the Beck’s Depression Inventory 
 
N-terminal pro-B-type natriuretic peptide (NT-proBNP) 
 
Cardiac troponin T (TnT) 
 
The number of rejections 
 
The number of adverse events 
 
The number of major clinical adverse events, defined as death, 
myocardial infarction, percutaneous coronary 
intervention/coronary bypass surgery, cerebral stroke, cancer, 
end stage renal disease (exploratory endpoint) 
 
Study Design: 
This is a multicentre, multinational, dual arm, double blind, randomised, 
placebo-controlled trial. 
Main Inclusion Criteria:    
De novo heart transplant recipient.  
Main Exclusion Criteria 
Contraindications to study medication. 
Inability to perform coronary angiography with IVUS 
Estimated glomerular filtration rate < 20 ml/min 
Failure to obtain written informed consent 
Sample Size: 
130 patients 
Efficacy Assessments: 
Coronary IVUS, echocardiography, clinical assessment, blood samples 
for the assessment of lipid levels and inflammatory markers 
Safety Assessments: 
Physical examination. In-hospital observation for during the first dose of 
study drug administration. A 24-hour contact number will be provided. 
Repeat assessment after 1, 2, 3, 6, 9, 12, and 13 months. 
 
 

EVOLVD Protocol version 3.0 18th October, 2021 
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List of abbreviations and definition of terms 
Abbreviation or special term 
Explanation 
AE 
Adverse event  
CAV 
Cardiac allograft vasculopathy 
CRF 
Case report form  
CRP 
C-reactive protein 
DMC 
Data monitoring committee 
eGFR 
Estimated glomerular filtration rate 
GCP 
Good clinical practice 
ICH 
International Conference on Harmonisation 
IVUS 
Intravascular ultrasound 
LDL 
Low density lipoprotein 
NT-proBNP 
N-terminal pro-B-type natriuretic peptide 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
SAE 
Serious adverse event   
SUSAR 
Suspected unexpected serious adverse reaction 
TnT 
Cardiac troponin T 
 
 
 

EVOLVD Protocol version 3.0 18th October, 2021 
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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 
Enrolment 
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 drugs 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.” 
Randomisation 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 enrols in the study. 
In the EVOLVD study, the patient number equals the randomisation 
number 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrolment, randomisation, 
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 
Randomisation number 
A unique identifier assigned to each randomised patient, 
corresponding to a specific treatment group assignment 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 7 
 
Table of contents 
Contact details 
2 
Protocol Synopsis 
3 
List of abbreviations and definition of terms 
5 
Table of contents 
7 
1 
Introduction 
10 
1.1 
Cardiac allograft vasculopathy 
10 
1.2 
Cholesterol lowering and PCSK9 inhibitors 
10 
1.3 
Pre-Clinical & Clinical Experience with evolocumab 
11 
1.4 
Known and potential risks and benefits 
11 
1.5 
Rationale for the study and purpose 
12 
1.6 
Rationale for study endpoint 
12 
2 
Study objectives and related endpoints 
13 
2.1 
Primary endpoint 
13 
2.2 
Secondary endpoints 
13 
4 
Study population 
14 
4.1 
Selection of study population 
14 
4.2 
Number of patients 
15 
4.3 
Inclusion criteria 
15 
4.4 
Exclusion criteria 
15 
5 
Treatment 
16 
5.1 
Drug identity, supply and storage 
16 
 
Supply, packaging, labelling, handling, storage and accountability 
16 
5.2 
Dosage and administration 
16 
5.3 
Duration of therapy 
16 
5.4 
Monitoring during drug administration 
16 
5.5 
Concomitant medication 
16 
 
Birth control 
17 
5.6 
Drug accountability 
17 
5.7 
Drug labelling 
17 
5.8 
Subject identification 
18 
5.9 
Study drug allocation 
18 
6 
Study procedures 
20 
6.1 
Flow chart 
20 
6.2 
By visit 
21 
 
Screening visit 
21 
 
Randomisation and Baseline Procedures (Day 1) 
22 
 
Visits one, two, three, six and nine months after start of treatment 
22 
 
End of treatment visit 
23 

EVOLVD Protocol version 3.0 18th October, 2021 
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13 months safety control 
24 
6.3 
Criteria for patient discontinuation 
24 
6.4 
Procedures for discontinuation 
24 
 
Study drug discontinuation 
24 
 
Patient discontinuation 
25 
 
Trial discontinuation 
25 
7 
Assessments 
25 
7.1 
Assessment of efficacy 
25 
 
Intravascular ultrasound (IVUS) 
25 
 
Echocardiography 
26 
 
Quality of life 
27 
 
Blood samples 
27 
 
Biobanking 
28 
 
Cardiac microcirculation 
28 
7.2 
Safety and tolerability assessments 
28 
8 
Safety monitoring and reporting 
28 
8.1 
Definitions 
28 
 
Adverse event (AE) 
28 
 
Adverse events of special interest (AESI) 
29 
 
Serious adverse event (SAE) 
29 
 
Suspected unexpected serious adverse reaction (SUSAR) 
29 
8.2 
Time period for reporting adverse events and serious adverse events 
29 
8.3 
Recording of adverse events 
30 
8.4 
Reporting procedure 
30 
 
Adverse events, adverse events of special interest and serious adverse events 
30 
 
Suspected unexpected serious adverse reactions 
30 
 
Annual safety report 
31 
 
Clinical study report 
31 
8.5 
Procedures in case of emergency 
31 
8.6 
Safety monitoring 
31 
9 
Data management and monitoring 
31 
9.1 
Electronic case report forms (eCRFs) 
32 
9.2 
Source data 
32 
9.3 
Study monitoring 
32 
9.4 
Confidentiality 
32 
9.5 
Database management 
32 
9.6 
Biobanking 
33 
10 
Statistical methods and data analysis 
33 
10.1 
Determination of sample size 
33 
10.2 
Randomisation 
33 

EVOLVD Protocol version 3.0 18th October, 2021 
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Allocation- sequence generation 
33 
 
Allocation- procedure to randomise a patient 
33 
 
Blinding and emergency un-blinding 
34 
10.3 
Population for Analysis 
34 
10.4 
Planned analyses 
34 
10.5 
Statistical analysis 
34 
11 
Study management 
35 
11.1 
Investigator delegation procedure 
35 
11.2 
Protocol adherence 
35 
11.3 
Study amendments 
35 
11.4 
Audit and inspections 
35 
12 
Ethical and regulatory requirements 
36 
12.1 
Ethics committee approval 
36 
12.2 
Other regulatory approvals 
36 
12.3 
Informed consent procedure 
36 
12.4 
Subject identification 
36 
13 
Trial sponsorship and financing 
36 
14 
Trial insurance 
37 
15 
Publication policy 
37 
16 
References 
38 
 
 
 
 

EVOLVD Protocol version 3.0 18th October, 2021 
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1 
Introduction 
Heart transplantation is the treatment of choice for selected patients with end-stage heart 
failure.1 World-wide, the median survival after transplantation is more than 11 years.2 However, the 
longevity of the allograft is significantly limited by cardiac allograft vasculopathy.3 This is a unique 
form of accelerated atherosclerosis that is characterised by a diffuse, progressive thickening of the 
arterial intima of the arteries in the allograft.4  
Pravastatin reduces cholesterol levels and mitigates cardiac allograft vasculopathy in heart 
transplant recipients,5, 6 and is recommended in the routine treatment of heart transplant recipients.7 
Despite the widespread use of statins, however, the prevalence of hyperlipidaemia reaches 88 % 5 
years after heart transplantation.2 Due to drug interactions,8 statin-associated myopathy is 
widespread in transplant recipients. The high prevalence of statin-related side effects limits our 
ability to achieve optimum lipid levels in heart transplant recipients with statin therapy alone. On the 
other hand, there have been no randomised controlled trials to show that second-line lipid lowering 
drugs improve outcomes in these patients.9 
Evolocumab is an inhibitor of the enzyme pro-protein convertase subtilisin–kexin type 9 (PCSK9). 
The PCSK9 inhibitors induce a massive reduction in low density lipoprotein (LDL) cholesterol.10 
Evolocumab lowers LDL cholesterol on top of statin therapy, and the additional reduction in LDL 
cholesterol translates to a reduced incidence of myocardial infarction and stroke in patients with 
coronary artery disease.11  
1.1 
Cardiac allograft vasculopathy 
Cardiac allograft vasculopathy is a major impediment to long-term survival in heart transplant 
recipients.12, 13 It is present in 48 % of heart transplant recipients within 10 years after 
transplantation,2 and accounts for 30% of deaths occurring beyond the first year.3 The 
pathophysiology of cardiac allograft vasculopathy is not fully elucidated. The aetiology is likely to be 
multifactorial. Classical risk factors for coronary artery disease are thought to contribute. Donor male 
gender, hypertension, and diabetes are risk factors for the development of vasculopathy in the 
allograft,14 suggesting that pre-existing atherosclerosis predisposes to vasculopathy. Animal models 
have shown that hyperlipidaemia accelerates allograft vasculopathy.15-17 In human heart transplant 
recipients, there is a clear link between cholesterol levels and the risk of developing allograft 
coronary artery disease.18-20 In addition to traditional risk factors for atherosclerotic disease, low 
grade inflammation and chronic, antibody-mediated rejection are thought to contribute to the 
disease process.12, 13  
Statin therapy reduces the prevalence of cardiac allograft vasculopathy in heart transplant 
recipients.6 Research performed at the Scandinavian transplant centres has shown that early 
conversion from a calcineurin-based immunosuppressive regimen to a regimen based on everolimus, 
an inhibitor of the mechanistic target of rapamycin, alleviates cardiac allograft vasculopathy in de 
novo heart transplant recipients.21 However, cardiac allograft vasculopathy remains a major obstacle 
in the effort to improve outcomes after heart transplantation.4 
1.2 
Cholesterol lowering and PCSK9 inhibitors 
Serum levels of low density lipoprotein (LDL) cholesterol levels are strong predictors of 
atherosclerotic coronary artery disease.22, 23 Inhibitors of the rate-limiting enzyme of human 
cholesterol synthesis, hydroxymethylglutaryl co-enzyme A (HMG CoA), called statins, were the first 
drugs to effectively lower serum cholesterol. Multiple trials have concluded that statin therapy 
significantly reduces the risk of myocardial infarction, stroke and mortality.24-28 
Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin–
kexin type 9 (PCSK9).29  Proprotein convertase subtilisin–kexin type 9 is an enzyme that binds to and 
degrades the low density lipoprotein (LDL) receptor and prohibits recycling of the LDL receptor to the 
cell surface. Evolocumab thus reduces circulating levels of LDL by increasing LDL clearance by 

EVOLVD Protocol version 3.0 18th October, 2021 
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receptor mediated endocytosis.10 Evolocumab lowers LDL cholesterol levels by approximately 60%. In 
the landmark FOURIER trial, 27,564 patients with atherosclerotic cardiovascular disease and LDL 
cholesterol levels of 1.8 mmol/l or higher despite statin therapy were randomly allocated to 
treatment with evolocumab or matching placebo. In the evolocumab arm, there was a highly 
significant reduction in LDL cholesterol, and fewer cardiovascular clinical events.11 To date, there 
have been no controlled trials to assess the effect of PCSK9-inhibitors on cardiac allograft 
vasculopathy. 
1.3 
Pre-Clinical & Clinical Experience with evolocumab  
According to the Summary of Product Characteristics (SPC), available at www.medicines.org.uk, 
studies in animals have not shown evolocumab to affect embryonic development, be carcinogenic, or 
cause infertility. The carcinogenic potential of evolocumab was evaluated in a lifetime study 
conducted in hamsters at exposures up to 38-fold the recommended human doses of 140 mg every 2 
weeks. The mutagenic potential of evolocumab has not been evaluated; however, monoclonal 
antibodies are not expected to alter DNA or chromosomes. There were no adverse effects on fertility 
at the highest dose in a fertility and early embryonic developmental toxicology study in exposed to 
30-fold the recommended human doses of 140 mg every 2 weeks. In addition, there were no adverse 
evolocumab-related effects on surrogate markers of fertility in sexually mature monkeys.  
There have been no trials to assess the safety of evolocumab in pregnancy, and according to the 
approved label, Repatha® should not be used during pregnancy unless the clinical condition of the 
woman requires treatment with evolocumab. The effect on breastfed infants has not been evaluated 
in controlled trials. Evolocumab has an effective half-life of 11- 17 days, and is eliminated through 
proteolysis in a non-saturable manner. Moderate renal dysfunction (estimated glomerular filtration 
rate [eGFR] > 30 ml/ min) is not associated with a significantly altered plasma half-life of evolocumab 
and is not a contraindication to treatment with Repatha®. Limited data are available in patients with 
severe renal impairment.  
Repatha® has marketing approval in The United States and the EU for the treatment of 
hypercholesterolaemia at the doses intended for use in the EVOLVD trial. There is considerable 
clinical experience with evolocumab, including the large, phase IV FOURIER trial,11 and the OSLER 1 
open-label extension study.30 The over-all favourable safety profile of evolocumab is evident from 
the low level of drug-related adverse events in these trials. 
1.4 
Known and potential risks and benefits 
For potential risks and benefits, we refer to the approved label for evolocumab. Surveillance 
reports, observational studies, and some small randomised trials31, 32 of statin therapy have 
suggested that statins (or the low levels of LDL cholesterol that result from their use) may be 
associated with impaired cognitive function. Also, there are well-known associations between statin 
use and myopathy, and between statin use and new-onset diabetes. The prevalence of statin-
induced rhabdomyolysis has been negligible in large, randomised clinical trials,27 but may be 
considerably higher in unselected populations, and particularly in patients who receive cyclosporine.8 
However, from the evidence so far, there is no reason to be concerned about neither cognitive 
function, nor myopathy with regard to treatment with evolocumab. In the FOURIER trial, no 
significant between-group differences were observed in the overall rates of adverse events, serious 
adverse events, or adverse events thought to be related to the study agent. The rates of muscle-
related events were evenly distributed between the treatment arms.11 In a separate study 
comprising 1204 of the patients enrolled in the FOURIER trial, neurocognitive function was assessed 
with the Cambridge Neuropsychological Test Automated Battery. There was no between-group 
difference in the change in neurocognitive function from baseline to the repeated assessment after a 
median of 19 months of treatment with evolocumab/ placebo.33 There does not seem to be an 
increased risk of new-onset diabetes mellitus in patients treated with evolocumab.34 Consistently, 
there has been a slightly increased incidence of injection-site reactions with evolocumab. In the 

EVOLVD Protocol version 3.0 18th October, 2021 
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FOURIER trial, this minor adverse event occurred in 2.1% of patients allocated to evolocumab, and in 
1.6% allocated to placebo.11  
The benefit of PCSK9 inhibition in heart transplant recipients is unknown. Circumstantial 
evidence suggests that intensive LDL cholesterol lowering can reduce the incidence of allograft 
vasculopathy in heart transplant recipients. Furthermore, there is reason to believe that a reduced 
burden of coronary disease will improve outcomes in this population. The EVOLVD trial is designed to 
assess the hypothesis that treatment with 420 mg evolocumab subcutaneously every month for one 
year leads to a lower burden of cardiac allograft vasculopathy in de novo heart transplant recipients.  
The main objective of the EVOLVD trial is to assess the effect of evolocumab on measures of 
cardiac allograft vasculopathy. While conventional coronary angiography is performed per current 
routine in our heart transplant recipient several weeks after heart transplantation and again one year 
after heart transplantation, in the EVOLVD trial, we plan to perform the first angiography up to eight 
weeks earlier, if there is no contraindication to coronary angiography at this time. In conjunction with 
the conventional exam, we will perform intravascular ultrasound and, in a subset of the patients, 
analyses of coronary physiology. The latter examination is more thoroughly described in Appendix B. 
We have no reason to believe that advancing the baseline angiography puts our patients at increased 
risk of complications. The addition of the IVUS and microcirculation measurements will add 
approximately 30 minutes to the procedure. The added measurements are associated with a minimal 
increase in risk on top of the conventional angiography.35      
1.5 
Rationale for the study and purpose 
Cardiac allograft vasculopathy is an important cause of morbidity and mortality in heart 
transplant recipients. Our own data show that, although clinical coronary artery disease often 
manifests years after heart transplantation, there are substantial changes in the coronary artery 
intima thickness over the first year after transplantation, suggesting that the adverse process starts 
shortly after transplantation.21 Moreover, our data suggest that, whereas early intervention can 
prevent long-term progression of cardiac allograft vasculopathy,36 the same intervention is less 
effective when administered late after heart transplantation.37 Thus, there seems to be a window of 
opportunity for preventive measures against cardiac allograft vasculopathy in de-novo transplant 
recipients.  
The strong association between cholesterol levels and coronary heart disease in the general 
population, the high cholesterol levels in heart transplant recipients, the high prevalence of 
vasculopathy in the cardiac allograft, and the association between cholesterol levels and cardiac 
allograft vasculopathy together provide a strong rationale for aggressive cholesterol lowering in 
heart transplant recipients. Statins improve outcomes in heart transplant recipients, but their limited 
effect on post-transplant cholesterol levels, adverse effects, and drug interactions contribute to their 
not providing sufficient prophylaxis against post-transplant atherosclerotic disease.  
Evolocumab is a well-tested drug with a favourable safety profile. It effectively reduces 
cholesterol levels on top of statin therapy in patients with coronary heart disease. We hypothesise 
that evolocumab on top of statin therapy will significantly lower LDL levels in de novo heart 
transplant recipients. We assume that this reduction in cholesterol levels will manifest as a reduced 
burden of cardiac allograft vasculopathy as measured by intracoronary ultrasound. Ultimately, we 
believe that a reduced burden of vasculopathy will translate to reduced morbidity and long-term 
mortality in heart transplant recipients. The EVOLVD trial is a randomised, placebo-controlled, double 
blind study designed to test the hypothesis that treatment with evolocumab can ameliorate cardiac 
allograft vasculopathy in heart transplant recipients. 
1.6 
Rationale for study endpoint 
The ultimate endpoint for risk-reducing drugs is all-cause mortality. Currently, the one-year 
survival in heart transplant recipients is almost 90 %. Thus, for adequate power, an outcome-driven 
trial would require hundreds, possibly thousands of patients to show a difference between treatment 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 13 
 
groups. With a mere 5000 patients receiving a cardiac allograft each year world-wide, designing a 
trial with coronary outcomes or mortality as primary endpoints simply is not feasible. Intima 
thickness as measured by IVUS is an established surrogate endpoint for coronary heart disease. Trials 
have shown that aggressive lipid-lowering treatment can alleviate, or even reverse, the 
atherosclerotic burden in patients with coronary heart disease.38-40 In these trials, the primary 
efficacy endpoint has been the percentage atheroma volume, defined as  
 
the area enclosed by the external elastic membrane− the luminal area
the area enclosed by the external elastic membrane
∗100.40  
 
On the other hand, in heart transplant recipients, it is the maximal coronary intima thickness that 
has been shown to be associated with outcome.41, 42 These measures are closely correlated. Our own 
data show that IVUS measurements are reproducible and that the repeated measure variability in 
intima thickness is low.21, 37 Furthermore, the measurement is not associated with significant risk on 
top of the risk associated with coronary angiography,35 which is performed on a regular basis in heart 
transplant recipients.   
2 
Study objectives and related endpoints 
The main goal of this study is to evaluate the effect of evolocumab administered subcutaneously 
every month for one year on the development of cardiac allograft vasculopathy in cardiac allograft 
recipients.  
Secondary objectives are to assess the impact of treatment on: i) cholesterol levels, ii) renal 
function, iii) inflammation, iv) cardiac function as assessed by biomarkers and echocardiography, v) 
quality of life, vi) the number of allograft rejections, and (vii) safety and tolerability. As an exploratory 
endpoint, we will assess the impact of treatment on the number of major clinical events (death, 
myocardial infarction, percutaneous coronary intervention/coronary bypass surgery, cerebral stroke, 
cancer, and end stage renal disease). 
2.1 
Primary endpoint  
The primary endpoint will be the baseline-adjusted maximal intimal thickness as measured by 
coronary intravascular ultrasound (IVUS) at end-of treatment, 12 months after randomisation. The 
maximal intima thickness is defined as the largest distance (in mm) from the intimal leading edge to 
the external elastic membrane.  
2.2 
Secondary endpoints 
Secondary endpoints measured at 1 year will be the baseline-adjusted: 
 
Percent atheroma volume as measured by IVUS 
 
Cardiac allograft vasculopathy (defined as mean a maximal intimal thickness ≥0.5 mm over the 
entire matched segment)  
 
LDL cholesterol 
 
Estimated GFR 
 
Quality of life as assessed by the SF-36 and 5D EuroQoL questionnaires, and the Beck’s 
Depression Inventory 
 
N-terminal pro-B-type natriuretic peptide (NT-proBNP) 
 
Cardiac troponin T (TnT) 
 
The number of allograft rejections 
 
The number of adverse events 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 14 
 
 
The number of major clinical adverse events, defined as death, myocardial infarction, 
percutaneous coronary intervention/coronary bypass surgery, cerebral stroke, cancer, end 
stage renal disease (exploratory endpoint)  
3 
Overall study design 
This is a phase 3, double blind, randomised, placebo-controlled trial. Participants will be 
randomised in a 1:1 fashion to receive subcutaneous injections of 420 mg evolocumab or matching 
placebo every month for one year. The study is designed to show superiority regarding the primary 
endpoint in patients assigned to active treatment versus patients allocated to the placebo arm. 
 
 
Study Period 
 
Estimated date of first patient enrolled (study start) November 1st, 2018 
Anticipated recruitment period: February 1st, 2019 – February 28th, 2022 
Estimated date of last patient completed treatment: February 28th, 2023 
Estimated date of last patient completed (last patient, last visit: Study end): 
March 31st, 2023 
Treatment Duration: 
12 months 
Follow-up: 
13 months 
4 
Study population 
4.1 
Selection of study population 
The EVOLVD trial will be performed at six Scandinavian centres; Oslo University Hospital, 
Rikshospitalet; Oslo, Sahlgrenska University Hospital, Gothenburg, Sweden, Skåne University 
Hospital, Lund Sweden, Rigshospitalet, Copenhagen, Denmark, Aarhus University Hospital, Skejby, 
Denmark, and Helsinki University Hospital Heart and Lung Center, Helsinki, Finland. Together, these 
centres perform approximately 130 heart transplantations each year. We will recruit de novo heart 
transplant recipient who fulfil eligibility criteria (below) who are willing to participate, and who give 
written, informed consent. Eligible subjects will be asked for consent to participate in the trial by 
study personnel who are not in a position that can be perceived to undermine the voluntariness of a 
participant’s consent to participate in research. The person who contacts the subject in the consent 
process should therefore be separate from the clinical team.  
Patients 
screened 
Evolocumab 
Efficacy and safety 
assessment 
Baseline 
assessment 
Efficacy and safety 
assessment 
Placebo  
Patients 
excluded 
Randomisation 

EVOLVD Protocol version 3.0 18th October, 2021 
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4.2 
Number of patients 
We aim to enrol 130 patients in this trial. 
4.3 
Inclusion criteria 
Patients will be screened for eligibility during routine follow-up 4 – 8 weeks after heart 
transplantation. 
All of the following conditions must apply prior to administering the investigational medicinal 
product: 
 
Heart transplant recipient within the last 4 – 8 weeks.  
 
Age between 18 and 70 years. 
 
Informed consent obtained and documented according to Good Clinical Practice (GCP), and 
national/regional regulations. 
 
No contraindications to coronary angiography with intravascular ultrasound 
 
Estimated glomerular filtration rate > 20 ml/min/1.73 m2 as assessed by the MDRD formula.43 
4.4 
Exclusion criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
 
Decompensated liver disease (Child-Pugh class C) 
 
Severe renal failure, i.e. eGFR < 20 ml/min/1.73 m2 or on renal replacement therapy 
 
Ongoing rejections or infections* 
 
Known sensitivity or intolerance to evolocumab or any of the excipients of Repatha® 
 
Prior use of PCSK9 inhibition treatment 
 
Indication for treatment with PCSK9 inhibitor 
 
Alcohol or drug abuse within 3 months of informed consent that would interfere with trial 
participation or any ongoing condition leading to decreased compliance with study 
procedures or study drug intake 
 
Participation in another clinical trial involving an investigational drug and/or follow-up within 
30 days prior to enrolment. 
 
Pregnancy.  
 
The subject is a nursing woman 
 
Female subject who has either (1) not used at least one highly effective method of birth 
control** for at least 1 month prior to screening or (2) is not willing to use such a method 
during treatment and for an additional 15 weeks after the end of treatment, unless the 
subject is sterilised or postmenopausal† 
 
 
                                                          
*Only rejections with haemodynamic compromise and infections with hemodynamic consequences or 
infections that contraindicate coronary angiography with IVUS are to be regarded as exclusion criteria 
**Highly effective methods of birth control include not having heterosexual intercourse or using birth 
control methods that work at least 99% of the time when used correctly, including combined (estrogen 
and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable or implantable); intrauterine device or intrauterine hormone-releasing system; 
bilateral tubal occlusion; and a vasectomised partner. Sexual abstinence is a reliable method of birth 
control in women who are highly unlikely to establish a sexual relationship to a new partner over the 
course of the trial only. The reliability of sexual abstinence needs to be re-evaluated over the duration of 
the trial and with due consideration to the preferred and usual lifestyle of the subject. 
† Menopause is defined as 12 months of spontaneous and continuous amenorrhea with a follicle 
stimulating hormone (FSH) level > 40 IU/L (or according to the definition of "postmenopausal range" for 
the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral 
oophorectomy 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 16 
 
5 
Treatment 
For this study, subcutaneous evolocumab (Repatha®) and matching placebo are defined as 
investigational medicinal products.  
5.1 
Drug identity, supply and storage 
Medication and comparator 
Active drug: Evolocumab for subcutaneous injection. 
Placebo: The placebo is presented in an identical prefilled autoinjector. It is supplied as a sterile, 
single use, preservative free solution for subcutaneous injection in a disposable, spring based 
prefilled autoinjector. The prefilled autoinjector contains a 1.0 mL deliverable volume of 1.1% (w/v) 
sodium carboxymethylcellulose, 250 mM proline, 10 mM acetate, and 0.01% (w/v) polysorbate 80, 
pH 5.0. 
 
Supply, packaging, labelling, handling, storage and accountability 
The manufacturer supplies study drugs to the investigators on site. It is labelled with information 
according to local regulation. The study medication will be stored in a locked refrigerator (2-8°C), 
protected from unintended use. All study medications supplied for this trial will be retained in a safe 
place at all times of the study. Only personnel authorised by the principal investigator should 
dispense the study medication, and the accountability is the responsibility of investigator. An up to 
date study medication inventory (dispensing records) will be maintained at all times. 
5.2 
Dosage and administration 
After the participant has provided informed consent, he or she will be randomised to receive 
subcutaneous evolocumab (Repatha®) or matching placebo. The randomisation process will be 
performed online via the commercially available electronic case report form (eCRF) system called 
Viedoc®. The investigational drug, evolocumab/placebo, will be administered subcutaneously once 
monthly in abdomen, thigh, or upper arm for the duration of the treatment period (one year). 420 
mg evolocumab/placebo will be administered by giving 3 injections consecutively within 30 minutes 
using the single-use prefilled autoinjector.  
5.3 
Duration of therapy 
The investigational medicinal products will be administered subcutaneously every month for one 
year. No other study-specific intervention will be provided.  
5.4 
Monitoring during drug administration 
The first dose(s) of study drug will be administered in a hospital setting. A study nurse will 
instruct the patients on how to self-administer the drug. The patients will self-administer the 
subcutaneous injections. 
5.5 
Concomitant medication 
All concomitant medication will be recorded in the patient’s file and CRF. Study participation 
does not preclude administration of drugs that are provided on clinical indication. On the contrary, 
study participants will receive standard-of-care treatment as recommended in prevailing guidelines.  
We routinely use induction therapy at the time of heart transplantation. We introduce 
maintenance immunosuppressive therapy consisting of a combination of a calcineurin inhibitor, 
mofetil mycophenolate and steroids on the first post-operative day with gradual tapering of the 
calcineurin inhibitor and steroid doses over the first year. In selected patients, we add everolimus 
with reduction of the calcineurin inhibitor dose or complete cessation of calcineurin inhibitor 
treatment. We perform regular bioptic controls as recommended by the International Society of 
Heart and Lung Transplantation (ISHLT). We administer trimethoprim-sulpha o.d. for the first 6 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 17 
 
months after heart transplantation according to current recommendations. In patients with blood 
pressure consistently above 140/90, we provide anti-hypertensive treatment.  
Pravastatin 40 mg o.d. is routinely introduced during the first five postoperative days and 
continued indefinitely unless there are contraindications to statin use, or there is a need to escalate 
treatment. To keep investigators blinded to treatment allocation, we will not perform measurements 
of blood lipids for the during the treatment phase.  
 
Birth control 
Female participants who are not postmenopausal or sterilised, must agree to use highly effective 
methods of birth control for at least 1 month prior to screening, during treatment with the 
investigational drug (evolocumab/placebo) and for an additional 15 weeks after the end of 
treatment. Highly effective methods of birth control include not having heterosexual intercourse or 
using birth control methods that work at least 99% of the time when used correctly, including 
combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable or implantable); intrauterine device or 
intrauterine hormone-releasing system; bilateral tubal occlusion; and a vasectomised partner, 
provided that the partner is the sole partner of the female trial participant and that the vasectomised 
partner has received medical assessment of the surgical success. Sexual abstinence is a reliable 
method of birth control in women who are highly unlikely to establish a sexual relationship to a new 
partner over the course of the trial only. The reliability of sexual abstinence needs to be re-evaluated 
over the duration of the trial and with due consideration to the preferred and usual lifestyle of the 
subject. 
5.6 
Drug accountability 
The responsible site personnel will confirm receipt of study drug and will use the study drug only 
within the framework of this clinical study and in accordance with this protocol. The manufacturer 
(AMGEN®) provides the active study drug and matching placebo. The first dose(s) of the study drug 
or matching placebo will be administered by trained hospital personnel. The patients will receive full 
information on how to administer the drug subcutaneously, and will administer the subsequent 
injections themselves. The manufacturer supplies study medication to the investigators on site. It will 
be labelled with information according to local regulation. The study medication will be stored in 
locked refrigerators (2-8°C), protected from unintended use. All study medications supplied for this 
study must be retained in a safe place at all times of the study. Only personnel authorised by the 
principal investigator should dispense the study medication, and the accountability is the 
responsibility of the investigators. A study medication inventory (dispensing records) for all 
medication dispensed must be maintained at all sites at all times and must always be kept up to date. 
Used study medication can be send to destruction before the monitor double-checks used study 
medication if two study nurses verify that the used study medication has been dispensed to the 
correct subject with the correct KIT number. The nurses have to sign the Master drug accountability 
log as well as the Subjects drug accountability log. Study medication must be destroyed as per local 
guidelines and documented in the Site file. Any abnormalities must be documented on both logs and 
filed in the Site file. 
5.7 
Drug labelling 
The investigational product will have a label permanently affixed to the outside and will be 
labelled according with ICH/GCP and national regulations, stating that the material is for clinical trial 
/ investigational use only and should be kept out of reach of children. The label will also specify batch 
number and expiry date. 
 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 18 
 
The boxes containing evolocumab/placebo will have an affixed label stating (in the local 
language) that box contains injection pens filled with 140 mg evolocumab (Repatha®) or placebo for 
clinical investigation in the EVOLVD trial, that the drug is meant for monthly subcutaneous injection, 
and that it should be stored refrigerated at 2° - 8°C in the original carton to protect from light and 
kept out of sight and reach of children. 
 
Label example (in Norwegian): 
 
Injeksjonsvæske, oppløsning 
Subkutan bruk 
Oppbevares i originalpakningen 
Følg den anbefalte doseringen eller se 
protokoll for bruksanvisning. 
Til klinisk utprøving 
Oppbevares utilgjengelig for barn 
Må ikke fryses 
Må ikke ristes 
Senteradresse: __________________ 
Senterets telefonnr.: _______________  
 
5.8 
Subject identification 
Each study participant is identified by a unique subject identification number that is assigned 
after the subject signs the informed consent form. A unique randomisation code is generated 
through the online randomisation process. Once assigned, the subject identification number and the 
randomisation code cannot be reused for any other subject. The same primary identifiers will be 
used throughout the study.  
 
5.9 
Study drug allocation 
Amgen will deliver study drugs to each site. A list identifying each kit number as active 
drug/placebo will be provided. Unblinded personnel not participating as study investigators or taking 
care of the study participants must sort the study drugs into containers containing active drug or 
placebo according to this list. The list must not be seen by blinded study personnel. The study drugs 
must be stored and handled according to the trial protocol and the Standard Operating Procedure 
(SOP) detailing study drug storage and accountability.  
 
Once randomisation has been performed in the eCRF, a randomisation number specific to that 
study participant is generated. This number must be presented to the unblinded study personnel 
who have access to the study drugs. The unblinded personnel will also be in the possession of a drug 
allocation list generated by the Research Support Services at Oslo University Hospital linking each 
randomisation number to active treatment or placebo. This list must not be seen by blinded study 
personnel. Based on the randomisation number, the unblinded personnel will pick a study drug box 
with the correct treatment (active drug or placebo), write down the corresponding kit number on the 
drug allocation list. The blinded study personnel must enter the kit number in the eCRF. There is an 
internal control procedure embedded in the eCRF that will generate an error message if the kit 
number selected does not correspond to the treatment to which the patient has been randomised. 
 
Each time the study participant needs more study drug, the blinded investigator or study nurse 
must present the randomisation number to the unblinded study personnel, who will dispense new 
boxes. All the corresponding kit numbers must be recorded on the drug allocation list (by the 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 19 
 
unblinded personnel) and in the eCRF. Several boxes can be dispensed at once, providing that the 
intended date of use does not exceed the drug expiry date.  
 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 20 
 
6 
Study procedures 
6.1 
Flow chart 
Study phases 
Pre-
treatment 
Treatment 
Follow-up 
 
Baseline 
1 month 
2 months 
3 months 
6 months 
9 months 
12 months 
13 months 
Eligibility 
x 
 
 
 
 
 
 
 
 
 
Consent 
x 
 
 
 
 
 
 
 
 
Vital signs 
x 
(x) 
x 
x 
x 
x 
x 
x 
 
Physical exam 
x 
(x) 
 
 
x 
 
 
x 
 
Study drug administration 
 
x 
x 
x 
x 
x 
x 
 
 
Coronary angiography with 
IVUS 
 
x 
 
 
 
 
 
x 
 
Echocardiography 
 
Randomisation 
x 
 
 
 
 
 
x 
 
Blood samples 
 
x 
x 
x 
x 
x 
x 
x 
 
Quality of life 
 
x 
 
 
 
 
 
x 
 
Clinical events 
 
x 
x 
x 
x 
x 
x 
x 
x 
Safety 
x 
(x) 
x 
x 
x 
x 
x 
x 
x 
Microcirculation (optional) 
 
 
x 
 
 
 
 
 
x 
 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 21 
 
6.2 
By visit 
Study participants will be recruited from the pool of recently transplanted cardiac allograft 
recipients who attend regular follow-up at the participating centres. Typically, the patients are still 
hospitalised or visit the participating hospital on a near-daily basis over the first 8 weeks after heart 
transplantation. Subsequent visits and study drug injections can be performed within ± 14 days of 
the optimal interval. If it is necessary to perform a visit or an injection more than one week before or 
after the optimal time, on should aim to adjust the preceding and following visits in order to avoid 
very short or very long intervals between injections. Regarding the 12 month visit (12 months after 
randomization), we recommend postponing the regular 1 year control for the 12 month visit and 
clinical visit to coincide. 
 
Screening visit 
Informed consent 
Voluntary, written informed consent (Appendix A) must have been obtained for each subject before 
any study specific procedure is initiated. At this time, the patient will be registered in the eCRF, and a 
unique identifier will be assigned.  
The following tests will be performed at screening: 
Physical examination 
A physical examination (including examination of heart, lungs, abdomen, neck and assessment of 
peripheral circulation and oedema) must be performed; vital signs (blood pressure, and heart rate); 
and height and weight must be recorded. 
Medical history 
A medical history must be obtained, and age; gender; NYHA functional status; risk factors 
(hypertension, smoking, and diabetes mellitus); reason for and time since heart transplantation; 
and concomitant disease must be recorded. The time from organ harvest to aortic clamp removal 
minus the time on a warm perfusion device should be registered at centres that employ the 
Transmedic OCS® warm perfusion (or an equivalent) transport device. However, the centres are 
asked to keep a record of total ischaemia time (i.e. from harvest to aortic clamp removal) in case 
this information is needed at a later time. 
 
 The investigators should use clinical common sense when selecting which co-morbidities to list.  
 
Co-morbidities that affect the prognosis in heart transplant recipients, such as diabetes, 
COPD, and renal insufficiency must be registered.  
 
Co-morbidities relevant to the development of cardiac allograft vasculopathy, such as overt 
hypercholesterolemia and hypertension must also be listed.  
 
Likewise, diseases that may be relevant to the development of complications, such as 
immunodeficiency or recurring infections, should be listed.  
 
Chronic diseases that require treatment or that are likely to affect the participants’ quality 
of life, such as thyroid disease, skin diseases like psoriasis, gastrointestinal diseases etc., 
should also be listed.  
 
On the other hand, diseases and conditions that are either resolved (cured cancer without 
remission over the last five years, corrected orthopaedic disorders, previous surgery, intercurrent 
diseases) or diseases unlikely to affect outcomes or quality of life (like refraction abnormalities, 
minor loss of hearing, minor skin conditions) need not be mentioned. 
Concomitant medication 
All concomitant medication used by the participant within 28 days of the start of treatment must be 
recorded in the CRF by generic name and dose. 
Laboratory analyses 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 22 
 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; ALT; 
bilirubin; albumin; INR; CK; CRP; NT-proBNP; total cholesterol; LDL cholesterol, high density 
lipoprotein cholesterol and triglycerides. Serum hCG must be measured in women of childbearing 
potential‡. These are to be considered safety and descriptive parameters: Efficacy-samples must be 
collected at randomisation.  
 
 Randomisation and Baseline Procedures (Day 1) 
After confirmation of eligibility, baseline efficacy measurements can be made, and the online 
randomisation process can be performed. If more than 72 hours have passed since the screening 
visit, the physical exam should be repeated, vital signs recorded anew, and safety blood samples 
should be repeated.  
Quality of life 
Self-reported, health-related quality of life will be gauged with the SF-36, the Beck’s depression 
inventory, and EQ 5D 3L questionnaires. We will allow subjects to complete the quality of life 
assessments before study procedures are performed. 
Coronary angiography with intravascular ultrasound 
Per routine, we perform coronary angiography approximately 12 weeks after heart transplantation 
to assess the allograft vessels. For the EVOLVD trial, we will ask the participants to have this 
“baseline” angiography within 4 to 8 weeks after heart transplant. The baseline IVUS, which is 
performed for study-specific purposes only, must be performed before study-specific treatment is 
started. We surmise that, to obtain the wanted effect on coronary artery intima thickness, aggressive 
cholesterol lowering treatment should start as soon as possible after heart transplantation. We 
therefore want to advance the baseline coronary angiography, so that it is performed shortly after 
enrolment. 
Measurements of cardiac microcirculation (optional: See Appendix B) 
In a subset of approximately 80 patients, we aim to assess cardiac microcirculation. For description of 
rationale and methods, see Appendix B. 
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed prior to study drug 
administration. A copy of this exam will be stored in the clinical imaging archive under the patient’s 
real name for reasons of safety. 
Blood samples 
Blood for efficacy analyses (specified later) must be collected, drawn and appropriately labelled and 
stored in a dedicated biobank for later analysis. 
Randomisation 
The randomisation code will be generated online on the eCRF (Viedoc®) platform 
Study drug injection 
The first study drug injection, starting on day 1, will be performed by a dedicated study nurse, who 
will also provide training for self-administration of the study drug. 
 
Visits one, two, three, six and nine months after start of treatment 
These visits are for assessing lipid levels and safety. At these visits, we will assess: 
Medical history 
A medical history must be obtained, and NYHA functional status; well-being; adverse events; and 
concomitant disease must be recorded.  
Concomitant medication 
                                                          
‡ A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 23 
 
All concomitant medication used by the participant since the last visit must be recorded in the CRF by 
generic name and dose. Routine changes in doses of immunosuppressants need not be recorded in 
the eCRF. If the dose has been changed in response to a perceived clinical or biochemical 
complication, this event should be recorded as an adverse event. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; ALT; 
bilirubin; albumin; INR; CK; CRP; TnT and NT-proBNP (safety). Trough levels of immunosuppressive 
drugs must be measured. Blood for efficacy analyses must be collected, appropriately labelled and 
stored in a dedicated biobank for later analysis. Serum hCG must be measured in women of 
childbearing potential who have stopped menstruating after randomisation. 
Safety assessment 
Any untoward medical event (i.e. any AE, SAE or SUSAR) since the last visit must be recorded in the 
eCRF and the patient medical record. 
Study drug dispensing 
The study drug should be injected by the participant under the supervision of a study nurse on the 
visits 1, 2, and 3 months after start of treatment. At 3 months, injection pens for the next two 
injections will be dispensed by the study nurse, and the patients will receive information on when 
and how to perform the next injections. At 6 and 9 months, supervised injections should be made, 
and again study drugs must be dispensed for the intervening months. 
 End of treatment visit 
This study visit 12 months after heart transplant is designed to assess efficacy and safety. 
Quality of life 
Self-reported, health-related quality of life will be gauged with the SF-36, the Beck’s depression 
inventory, and EQ 5D 3L questionnaires. We will allow subjects to complete the quality of life 
assessments before study procedures are performed. 
Medical history 
A medical history must be repeated, and NYHA functional status; any change in risk factors 
(hypertension, smoking, diabetes mellitus), and concomitant disease must be recorded. Any medical 
events since inclusion in trial must be evaluated. Current well-being, symptoms, potential side effects 
and physical capacity must be assessed. 
Physical examination 
A physical examination must be performed, and results (including examination of heart, lungs, 
abdomen, neck and assessment of peripheral circulation and oedema); vital signs (blood pressure, 
and heart rate); and height and weight must be recorded. 
Concomitant medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) 
used by the participant since the last visit must be recorded in the CRF by generic name and dose. 
Routine changes in doses of immunosuppressants need not be recorded in the eCRF. If the dose has 
been changed in response to a perceived clinical or biochemical complication, this event should be 
recorded as an adverse event. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; ALT; 
bilirubin; albumin; INR; CK; CRP; TnT and NT-proBNP; total cholesterol; LDL cholesterol, high density 
lipoprotein cholesterol and triglycerides(safety). Blood for efficacy analyses must be collected, 
appropriately labelled and stored in a dedicated biobank for later analysis. 
Coronary angiography with intravascular ultrasound 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 24 
 
Per routine, we perform coronary angiography approximately 12 months after heart transplantation. 
For the EVOLVD trial, we perform the main efficacy assessment, the 12-month IVUS, at the 12-month 
follow-up visit.  
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed at the end of 
treatment. A copy of this exam will be stored in the clinical imaging archive under the patient’s real 
name for reasons of safety. 
Safety assessment 
Any untoward medical event (i.e. any AE, SAE or SUSAR) since the last visit must be recorded in the 
eCRF and the patient medical record. 
Measurements of cardiac microcirculation (optional) 
In patients who have been had microcirculatory measurements at baseline, we wish to repeat this 
measurement after one year’s treatment  
 
 
13 months safety control 
At 13 months, we will perform a telephone interview to assess clinical events and safety:  
Medical history 
A medical history must be repeated, and NYHA functional status; any change in risk factors 
(hypertension, smoking, diabetes mellitus), and concomitant disease must be recorded. Any medical 
events since inclusion in trial must be evaluated. Current well-being, symptoms, potential side effects 
and physical capacity must be assessed. 
Safety assessment 
Any untoward medical event (i.e. any AE, SAE or SUSAR) since the last visit must be recorded in the 
eCRF and the patient medical record. 
Laboratory analyses 
Serum hCG must be measured in women of childbearing potential. 
 
6.3 
Criteria for patient discontinuation  
Patients may be discontinued from study treatment and assessments at any time. Specific 
reasons for discontinuing a patient for this study are: 
 
Voluntary discontinuation: participating patients are free to discontinue his/her participation 
in the study at any point in time, without prejudice to further treatment. 
 
Major protocol deviation 
 
Incorrect randomisation, i.e. the patient does not meet the required inclusion/exclusion 
criteria for the study 
 
Patient lost to follow-up 
 
Patient’s non-compliance to study treatment and/or procedures 
6.4 
Procedures for discontinuation 
 
Study drug discontinuation 
The study participants may discontinue study drug treatment at any time according to their 
preferences. The investigator may also advise study drug discontinuation in case of side effects, if 
adverse effects of the treatment are suspected, or if contraindications to the continued use of 
evolocumab arise. Study drug discontinuation and the reason why must be documented in the eCRF 
as well as in the hospital record. Efforts should be made to make ensure that adherence to the study 
protocol is kept up even though the patient no longer takes the study drug. All available data will be 
used in the intention to treat analysis, unless the patient specifically disagrees to let the investigator 
use his or her data. 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 25 
 
 
Patient discontinuation 
Patient withdrawal must be documented in the CRF as well as in hospital records. If possible, a 
final assessment should be obtained (end of study visit). The reason for discontinuation is recorded. 
The investigator is obliged to follow up any significant adverse events until the outcome either is 
recovered or resolved, recovering/resolving, not recovered/not resolved, recovered/resolved with 
sequelae, fatal or unknown. Patients who withdraw will be included in the intention-to treat analysis.  
 
Trial discontinuation 
The whole trial may be discontinued at the discretion of the primary investigator or the sponsor 
in the event of any of the following: 
 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
 
Medical or ethical reasons affecting the continued performance of the trial 
 
Difficulties in the recruitment of patients 
 
Cancellation of drug development  
The sponsor and principal investigator will inform all investigators, the relevant Competent 
Authorities and Ethics Committees of the termination of the trial along with the reasons for such 
action. If the study is terminated early on grounds of safety, the Competent Authorities and Ethics 
Committees will be informed within 15 days. 
7 
Assessments  
7.1 
Assessment of efficacy  
Efficacy will be evaluated through assessments of cardiac allograft vasculopathy; clinical events, 
blood tests of lipids, renal function, cardiac biomarkers, and inflammation; echocardiography; self-
assessed quality of life; and cognitive function. All efficacy assessments will be made prior to 
administration of the first study drug dose, and at the end-of-treatment visit after twelve months. 
The results will be reported as baseline-adjusted between-group differences. Efficacy samples for the 
determination of blood lipids, renal function, and clinical events will be collected at 1, 2, 3, 6, 9, and 
12 months, and analysed retrospectively. Cardiac biomarkers (NT-proBNP and TnT), will be analysed 
as safety parameters as well as efficacy parameters. 
 
Intravascular ultrasound (IVUS) 
Intravascular ultrasound examination of the same major epicardial coronary artery 
(preferentially the left-anterior descending coronary artery) will be performed during routine 
coronary angiography at 4 – 8 weeks after heart transplantation and at end-of-treatment one year 
after randomisation. In patients who have completed at least 6 months of study drug treatment, we 
will allow the second IVUS exam (used for assessment of the primary endpoint) to be performed at 
the time of study discontinuation for subjects who are unable to complete 12 months of treatment. 
All IVUS analysis will be conducted after trial closure by a core laboratory (Oslo University Hospital, 
Rikshospitalet, Oslo, Norway) by personnel blinded to patient treatment. Precise matching of the 
IVUS recordings at baseline and at 12 months will be performed and contour detection of both the 
lumen and external elastic membrane will be performed at approximately 1 mm intervals using 
validated software (QIVUS, v.3.0, Medis medical imaging systems, Leiden, the Netherlands). Borders 
will be reviewed 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.44  
The primary IVUS efficacy variable will be the mean change in the maximal intimal thickness between 
matched slices from baseline to 12 months as this parameter is an established predictor of all-cause 
mortality, myocardial infarction and angiographic abnormalities among HTx recipients.42 In 
accordance with established guidelines, the largest distance from the intimal leading edge to the 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 26 
 
EEM is defined as the maximal intimal thickness.44 Secondary IVUS variables are: (i) incidence of 
cardiac allograft vasculopathy (defined as mean a maximal intimal thickness ≥0.5 mm over the entire 
matched segment) and (ii) normalised total atheroma volume. 
 
Echocardiography 
Top specified cardiac ultrasound devices will be used for echocardiographic imaging. Patients are 
examined in the lateral recumbent position after > 5 minutes of rest at baseline, and after 12 
months. The heart is visualised by the standard ultrasonic techniques and imaging planes as 
recommended by the European society of echocardiography45 providing a comprehensive 
hemodynamic and valvular assessment. In addition to apical recordings of the left ventricle, 
parasternal short axis cine loops at the mid-papillary level are recorded. Tissue Doppler examinations 
are performed from the three apical planes by using colour coding, and single pulsed Doppler at the 
septal and lateral mitral ring. Two-dimensional imaging from the apical position should be performed 
in the three standard planes in two imaging depths: One encompassing the ventricle(s) and atria, and 
one with the sector encompassing the left ventricle only, ensuring that the mitral plane is within the 
imaging sector throughout the cardiac cycle. Two-dimensional images should be optimised for 
speckle tracking analysis by 1) ensuring that 200 msec is recorded before and after each cine loop 2) 
keeping the frame rate above 50 frames/s and 3) ensuring that the sector encompasses the full 
thickness of the myocardium. 
At least three heart beats (at least five in atrial fibrillation) are recorded with each registration. 
Recordings are performed before treatment and after 3 months, prior to study drug discontinuation. 
Blinded analysis of echocardiographic data will be performed off line using EchoPac (GE Vingmed). 
The following recordings should be obtained: 
 
Projection: 
 
Parameter: 
 
Parasternal long axis 
Cine loop 
Left ventricle 
Zoom LVOT (3 different recordings, only at 
baseline) 
 
 
M-mode 
Mid left ventricular 
 
Colour Doppler 
Left ventricular outflow tract 
Mitral valve 
Parasternal short axis 
Cine loop 
Left ventricle at the level of the papillary 
muscle 
Left ventricle at mid-ventricular level 
Aortic valve 
 
Colour Doppler 
Aortic valve and right ventricular outflow 
tract 
Apical 4chamber / 5 
chamber 
Cine loop 
Four-chamber including atria 
 
Four-chamber zoom left ventricle* 
Four-chamber zoom right ventricle 
 
Colour Doppler 
Mitral valve 
Aortic valve 
Tricuspid valve 
 
Doppler 
 
Mitral valve tip (pulsed wave)  
Mitral regurgitation jet (continuous wave) 
Pulmonary vein (pulsed wave) 
Left ventricular outflow tract (pulsed wave) 
Aortic flow velocity (continuous wave) 
Tricuspid regurgitation jet (continuous 
wave) 
 
Tissue Doppler 
Colour TVI left ventricle 

EVOLVD Protocol version 3.0 18th October, 2021 
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Colour TVI right ventricle 
TVI pulsed wave mitral annulus septum 
TVI pulsed wave mitral annulus 
anterolateral wall 
Apical 2 chamber 
Cine loop 
Two-chamber including left atrium 
Two-chamber zoom left ventricle* 
 
Tissue Doppler 
Colour TVI left ventricle 
Apical long axis 
Cine loop 
Apical long-axis including left atrium 
Apical long-axis zoom left ventricle* 
 
 
Colour Doppler 
Mitral valve 
Aortic valve 
 
 
 
*Settings ideal for speckle tracking: Patient in breath-hold for three consecutive heart beats. Frame rate above 
50 beats per min. The sector should include full thickness of ventricular wall. On the other hand, the left 
ventricle should fill entire sector (no “dead space”). Depth set so as to include mitral annulus at any time 
trough heart cycle. LVOT: Left ventricular outflow tract; TVI: Tissue velocity imaging. 
 
Quality of life 
Quality of life will be examined at baseline and at the end of treatment using three validated 
questionnaires; the SF36 (version 1)46, the Beck’s depression inventory, and the EQ 5D 3L EuroQoL 
questionnaires.47 The SF-36v2 is a 36-item general health-related quality of life instrument that has 
36 questions that contribute to 8 domains or scale scores of physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, and role-emotional and mental health.46 The 
EQ 5D 3L EuroQoL questionnaire consists of 2 pages, the EQ-5D descriptive system and the EQ visual 
analogue scale. The Beck depression inventory is a 21-question multiple-choice self-report inventory 
for measuring the severity of depression. The test is rated on a 4-point scale ranging from 0 to 3 
based on severity of each item. The maximum total score is 63. 
 
Blood samples 
We will collect fasting blood samples for biobanking at baseline, and at every subsequent visit. 
For biobanking, 18 ml blood should be collected in tubes containing EDTA, 6 ml in tubes with citrate 
and 6 ml in tubes without additives. The tubes with EDTA and citrate should be put on ice 
immediately and be centrifuged at 3700 rotations/min for 20 minutes. The tubes without additives 
should be left at room temperature for 1-2 hours prior to centrifugation at 3500 rotations/min for 15 
minutes. The tubes containing citrate as the anticoagulant should be put on ice immediately. The 
resulting plasma and serum, respectively, should be stored in multiple aliquots (at least four aliquots 
of serum and six aliquots of plasma per patient per visit), and labelled with the unique trial subject 
number, and the letter A signifying baseline, and the letter B signifying the 1-month visit etc. The 
samples should be stored at -80 degrees Celsius until analysis.  
Blood samples for safety will be collected at screening, and 1, 2, 3, 6, 9, and 12 months after 
randomisation. These blood samples will be collected and analysed at the study sites as per clinical 
routine. The glomerular filtration rate (in in ml/min/1.73 m2) will be estimated by the MDRD formula: 
175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x  1.212 [if black], where SCr is serum creatinine in 
mg/dl, and age is measured in years.43 C-reactive protein, NT-proBNP, and troponin T-values will be 
used for endpoint analyses. Blood lipids must be assessed after end-of treatment only, to avoid what 
will effectively amount to study drug allocation unblinding. To avoid bias, the investigators will be 
blinded to the lipid analyses. 
NT-proBNP will be assayed on a MODULAR platform (Roche Diagnostics, Basel, Switzerland). 
Plasma levels of CRP will be determined by a high-sensitivity particle-enhanced immunoturbidimetric 
assay (Tina-quant CRP [Latex] HS, Roche Diagnostic, Basel, Switzerland). TnT will be assessed using a 
high-sensitive immunoassay (Roche hs-TnT). 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 28 
 
 
Biobanking 
A dedicated biobank will be established at Oslo University Hospital, Rikshospitalet under the 
auspices of Professor Lars Gullestad. Blood samples for efficacy can be stored at each centre at -80 
degrees in dedicated freezers until analysis. Blood samples for tertiary/exploratory efficacy analyses, 
including vasoactive peptides, markers of endothelial function and inflammatory markers, must be 
shipped to the core laboratory at Oslo University Hospital for analysis. 
 
Cardiac microcirculation 
In selected patients, we will perform a substudy where we perform measurements of the cardiac 
microcirculation. See Appendix B. 
7.2 
Safety and tolerability assessments  
Safety will be monitored by the assessments described below as well as the collection of AEs at 
every visit. Significant findings that are present prior to the signing of informed consent must be 
included in the relevant medical history/ current medical condition page of the CRF. For details on AE 
collection and reporting, refer to Section 8.  
For the assessment schedule, refer to Flow chart in Section 6.1.  
Study-specific physical examinations will be performed at baseline and at 1, 2, 3, 6, and 12 
months. Vital signs including heart rate and blood pressure will be recorded.  
 
Blood samples for safety analyses will be drawn at baseline and after 1, 2, 3, 6, 9, and 12 months. 
Local laboratory cut-points for normal values will be used for safety analyses. Haemoglobin; white 
blood cell count, platelet count; serum potassium; serum sodium; glucose, glycosylated haemoglobin 
(HbA1c); creatinine; ALT; bilirubin; albumin; INR; CRP; TnT; and NT-proBNP. For the EVOLVD trial, we 
will not perform routine measurements of total cholesterol; LDL cholesterol, HDL cholesterol or 
other blood lipids for the duration of the treatment period. Instead, the biobank samples will be 
analysed regarding blood lipids retrospectively for efficacy and compliance assessments. 
8 
Safety monitoring and reporting 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an adverse event (AE) or serious adverse event (SAE). Each patient will be 
instructed to contact the investigator immediately should they manifest any signs or symptoms they 
perceive as serious. When judging whether an adverse event is unexpected or not, the Repatha® 
Summary of Product Characteristic (SPC) will be used as reference safety information. 
The methods for the collection of safety data are described below. 
8.1 
Definitions 
 
Adverse event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
If an abnormal laboratory value/vital sign are associated with clinical signs and symptoms, the 
sign/symptom should be reported as an AE and the associated laboratory result/vital sign should be 
considered additional information that must be collected on the relevant CRF. 

EVOLVD Protocol version 3.0 18th October, 2021 
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Adverse events of special interest (AESI) 
In general, AESIs are AEs that occur in categories of special interest with regard to determining 
the benefit/risk profile and overall safety of a drug. Whereas there have been no particular safety 
concern in the large, randomised, placebo-controlled trials involving evolocumab, the clinical 
experience with this drug outside of controlled trials is yet limited. In particular, we will monitor any 
pregnancy that may arise during the trial. However, pregnancies during the first year after heart 
transplantation are extremely rare, and we will demand that female participants of fertile potential 
use at least one highly effective method of birth control for the duration of the treatment phase. 
Immunosuppressants used after heart transplantation have a narrow therapeutic range and are 
sensitive to drug interactions. While there is no pharmacokinetic or pharmacodynamic reason to 
expect interactions with evolocumab, we will monitor levels of immunosuppressive drugs closely.  
 
Serious adverse event (SAE) 
Any untoward medical occurrence that:  
 
Results in death 
 
Is immediately life-threatening 
 
In itself requires hospitalisation or prolongation of existing hospitalisation  
 
Results in persistent or significant disability or incapacity 
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. 
Important medical events may not be immediately life-threatening or result in death or 
hospitalisation, but may jeopardise the subject or may require intervention to prevent one of the 
listed outcomes in the definitions above. In such situations, or in doubtful cases, the case should be 
considered as serious. Hospitalisation for administrative reason (for observation or social reasons) is 
allowed at the investigator’s discretion and will not qualify as serious unless there is an associated 
adverse event warranting hospitalisation. 
 
 
Suspected unexpected serious adverse reaction (SUSAR)  
Adverse Reaction: all untoward and unintended responses to an investigational medicinal 
product related to any dose administered;  
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information. 
Suspected Unexpected Serious Adverse Reaction: SAE (see section 8.1.2) that is unexpected as 
defined in section 8.2 and possibly related to the investigational medicinal products. When judging 
whether a possibly study drug related serious adverse event is unexpected or not, the Repatha® SPC 
will be used as reference safety information.   
8.2 
Time period for reporting adverse events and serious adverse events  
For each patient the he standard time period for collecting and recording AE and SAEs will begin 
at the start of study treatment and will continue for 30 day after end-of treatment (at which time 
approximately 30 days will have passed since the last study drug injection). We will proactively follow 
up all AEs and SAEs for each patient during the course of the study; events will be followed up to 
resolution, unless the event is considered to be unlikely to resolve due to the underlying disease. 
Every effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. Mandatory reporting of new AEs ends 30 days after the end-of-
treatment visit. 

EVOLVD Protocol version 3.0 18th October, 2021 
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8.3 
Recording of adverse events 
If the patient has experienced adverse event(s), the investigator will record the following 
information in the CRF: 
The nature of the event(s) will be described by the investigator in precise standard medical 
terminology (i.e. not necessarily the exact words used by the patient). 
The duration of the event will be described in terms of event onset date and event ended data. 
The intensity of the adverse event will be categorised as mild / moderate / severe / life-
threatening / death according to Common Terminology Criteria for Adverse Events version 4.0: 
 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated;  
 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily life;  
 
Severe: Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily life;  
 
Life-threatening consequences: urgent intervention indicated.  
The causal relationship of the event to the study medication will be assessed as one of the 
following: 
 
Unrelated: There is not a temporal relationship to investigational product administration (too 
early, or late, or investigational product not taken), or there is a reasonable causal relationship 
between non-investigational product, concurrent disease, or circumstance and the AE. 
 
Unlikely: There is a temporal relationship to investigational product administration, but there 
is not a reasonable causal relationship between the investigational product and the AE. 
 
Possible: There is reasonable causal relationship between the investigational product and the 
AE. Dechallenge information is lacking or unclear. 
 
Probable: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to dechallenge. Rechallenge is not required. 
Definite: There is a reasonable causal relationship between the investigational product and the 
AE. Action taken: Which investigations/medical procedures/treatments that are initiated as a result 
of the adverse event. 
The outcome of the adverse event – whether the event is resolved or still ongoing. 
 
It is important to distinguish between seriousness and severity of AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 8.1. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but is not an SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke, but would be an SAE. 
8.4 
Reporting procedure 
 
Adverse events, adverse events of special interest and serious adverse 
events 
All adverse events and serious adverse events that should be reported as defined in section 8.1.1 
will be recorded in the patient's CRF. SAEs must be reported by the investigator to the sponsor, Oslo 
University Hospital, within 24 hours after the site has gained knowledge of the SAE. The Serious 
Adverse Event Report Form must be completed, documented in the eCRF, signed and sent to Lars 
Gullestad. The initial report shall promptly be followed by detailed, written reports if necessary. The 
initial and follow-up reports shall identify the trial subjects by unique trial code numbers assigned to 
the latter. The sponsor keeps detailed records of all SAEs reported by the investigators and performs 
an evaluation with respect to seriousness, causality and expectedness 
 
Suspected unexpected serious adverse reactions 

EVOLVD Protocol version 3.0 18th October, 2021 
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SUSARs will be reported to the National Competent Authorities in each participating country and 
the local Ethics Committee according to national regulations. The following timelines should be 
followed: 
The sponsor will ensure that all relevant information about suspected serious unexpected 
adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible to 
the Norwegian Medicines Agency and the Regional Committee for Medical and Health Research 
Ethics in any case no later than seven (7) days after knowledge by the sponsor of such a case, and 
that relevant follow-up information is subsequently communicated within an additional eight (8) 
days. The sponsor shall ensure that suspected adverse reactions that are serious and unexpected are 
reported to the Norwegian Medicines Agency and the Regional Committee for Medical and Health 
Research Ethics within 15 days of the sponsor after knowledge of the event. The sponsor shall inform 
all investigators of the trial substance in question of suspected adverse reactions that are serious and 
unexpected. An account of any interruption in treatment or any breaking of the treatment code, the 
investigator’s assessment of the causal relationship, and consequences for further testing shall 
accompany the notification of suspected adverse reactions pursuant to the first and second 
paragraphs. SUSARs will be reported to the drug manufacturer, Amgen® at time of regulatory 
submission. 
The National Competent Authorities may require that individual reports of adverse events 
described in collective reports should also be submitted. The sponsor shall keep detailed records of 
all adverse events that are reported to him by the investigator. The records shall be submitted to the 
National Competent Authorities on request. Amgen® will receive annual safety reports and a Final 
(End of Study) Report, including unblinded data for blinded studies and reports of unauthorised use 
of a marketed product. 
 
Annual safety report 
Once a year throughout the clinical trial, the sponsor will provide the Norwegian Medicines 
Agency with an annual safety report. The format will comply with national requirements.  
 
Clinical study report 
The adverse events and serious adverse events occurring during the study will be discussed in 
the safety evaluation part of the Clinical Study Report. 
8.5 
Procedures in case of emergency 
The investigator is responsible for assuring that there are procedures and expertise available to 
cope with emergencies during the study (see also section 10.2.3). 
8.6 
Safety monitoring  
A data safety monitoring committee will be appointed to assess trial safety.  The committee 
consist of an independent clinician and a statistician. It will receive reports summarising patient 
recruitment and the number of AEs / SAEs after the first 20 patients have been randomised, and 
again after 50 % and 100 % of patient enrolment. The data safety monitoring committee will receive 
additional information on demand and can advise temporary or permanent stop in patient 
enrolment. The committee will have access to the randomisation code, and can, if they so choose, 
perform an interim analysis regarding the number of adverse events and serious adverse events. The 
data safety monitoring committee is independent from the sponsor and will be composed of 
individuals with no competing interest with regard to the study investigational products or study 
outcome. 
9 
Data management and monitoring 

EVOLVD Protocol version 3.0 18th October, 2021 
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9.1 
Electronic case report forms (eCRFs) 
The designated investigator staff will enter the data required by the protocol into the electronic 
Case report form (eCRF). The Principal Investigator is responsible for assuring that data entered into 
the eCRF are complete, accurate, and that entry is performed in a timely manner. If any assessments 
are omitted, the reason for such omissions will be noted in the eCRFs. Corrections, with the reason 
for the corrections will also be recorded. After database lock, the investigator will receive a digital 
copy of the subject data for archiving at the investigational site. An online eCRF will be used in this 
trial.  
9.2 
Source data  
Some data will be recorded directly into the eCRF, which, together with the patient medical 
record, is to be considered the source data. All data important for patient safety and continued care 
must be duplicated in the patient’s medical record as described below. Study-specific imaging data 
and blood analyses are independent source data.  
The medical records of each patient should clearly describe at least: 
 
That the patient is participating in the study 
 
The patient’s study identification number 
 
Date when the informed consent was obtained from the patient;  
 
Results of all assessments confirming a patient’s eligibility for the study; 
 
Diseases (past and current; both the disease studied and others, as relevant); 
 
Surgical history, as relevant; 
 
Treatments withdrawn/withheld due to participation in the study; 
 
Results of assessments performed during the study; 
 
Treatments provided, changes in treatments during the study and the time points for the 
changes;  
 
Visits to the clinic / telephone contacts during the study, including those for study purposes 
only; 
 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality 
assessments;  
 
Date of, and reason for, discontinuation from study treatment;  
 
Date of, and reason for, withdrawal from study; 
 
Date of death and cause of death, if available. 
9.3 
Study monitoring  
The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check 
that the study is conducted as approved by the Ethics committee and adheres to GCP guidelines. 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed 
access to source data for source data verification in which case a review of those parts of the hospital 
records relevant to the study may be required.  
9.4 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code 
list. Patient files shall be kept for the maximum period of time permitted by each hospital. The study 
documentation (CRFs, Site File etc.) shall be retained and stored during the study and for 15 years 
after study closure. All information concerning the study will be stored in a safe place inaccessible to 
unauthorised personnel. 
9.5 
Database management 
Data will be entered into the eCRF without delay and stored in the dedicated and secured online 
platform (Viedoc®). Data will be extracted from Viedoc for analysis, and the extracted data will be 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 33 
 
stored in dedicated, secure areas at the participating centres. Data will be stored in a de-identified 
manner, where each study participant is recognisable by his/her unique trial subject number. The 
data will be stored until Dec 31st, 2040 in compliance with local regulations, or until the patient 
requires that his/her data are deleted. Data in the eCRF will be handled according to GCP. Only the 
personnel authorised to enter and/or analyse data (i.e. investigators) will have access to the 
database.  
9.6 
Biobanking 
A biobank will be established at the Dept. of Cardiology, Oslo University Hospital, Rikshospitalet 
for the analysis of serum and plasma. The samples will be stored in multiple aliquots and labelled 
with the unique trial subject number, and the letter A signifying baseline, and the letter B signifying 
the visit at one month, C signifying 2 months etc. The samples will be stored at -80 degrees Celsius in 
a dedicated research freezer. The material is scheduled for destruction by Dec 31st, 2040. Professor 
Lars Gullestad at Oslo University Hospital, Rikshospitalet will be responsible for the biobank. 
Biochemical analyses may be performed at other participating centres, and the samples may be 
shipped between countries for storage and analyses. 
10 
Statistical methods and data analysis 
10.1 
Determination of sample size 
This trial is designed to assess the effect of evolocumab on intima thickness as measured by 
coronary IVUS. The sample size of the present study is based calculations relating to the primary 
outcome, the change in maximal intima thickness from baseline to one year. In the SCHEDULE trial, 
we observed an increase in the maximal intima thickness of 0.08 +/- 0.12 mm in the placebo group, 
whereas the corresponding increase was 0.03 +/- 0.06 mm in the everolimus arm.21 Intensive 
cholesterol reduction has been shown to actually reverse the atherosclerotic volume in previous 
trials. We therefore hope to achieve a 0.05 mm between-group difference in the change in the 
intima thickness in the EVOLVD trial. With an estimated 0.09 mm standard deviation, we will require 
51 patients in each arm with a power of 80%, at a two sided alpha level of 5%. To increase the 
chances of reaching the primary and secondary outcomes, and to compensate for uncertainties in 
this calculation, we will ensure that 120 patients complete the one-year follow-up. To allow for a 
dropout rate of 5 - 10% we aim to include 130 patients. 
 
In the SCHEDULE trial, the mean increase in the percent atheroma volume was 1.3 ± 2.3 
percentage points in the everolimus arm versus 4.2 ± 5.0 percentage points in the cyclosporine 
group. Provided that evolocumab can produce a similar reduction in the progression of the atheroma 
volume, with an estimated standard deviation of 3.7 percentage points, we will need just 26 patients 
in each arm to detect a between-group difference in the important secondary outcome, the change 
in percent atheroma volume, with an α of 5 % and a power of 0.8.   
10.2 
Randomisation  
 Allocation- sequence generation 
Balanced, permuted block randomisation (in a 1:1: ratio for the two study arms) will be 
performed online in Viedoc and stratified by centre. 
 Allocation- procedure to randomise a patient 

EVOLVD Protocol version 3.0 18th October, 2021 
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We will use a computerised randomisation procedure for treatment allocation. Random 
treatment allocation will be executed on the online, password-protected platform designed for study 
purposes (Viedoc™) once eligibility has been confirmed and the informed consent has been signed.  
 Blinding and emergency un-blinding 
The study participants (patients) and all study personnel, including investigators, personnel 
assessing outcomes, study nurses, data analysts and treating physicians and nurses, will be blinded to 
study drug allocation.  
Un-blinding will be performed in the event of AEs where knowledge of the type of drug might be 
of importance to the personnel treating the patients, and in the event of SUSARS.  Un-blinding will be 
performed by personnel with the designated role of performing unblinding, and the result will 
immediately be reported to the primary investigator, who will then take the required action(s). The 
eCRF is designed to handle emergency unblinding by allowing investigators to take on different roles, 
one of which is the role of emergency unblinder. When taking on this role, the investigator can 
unmask study drug assignment for a particular patient without further compromising the integrity of 
the randomisation list. Emergency unblinding is traceable in the eCRF system and will only be 
performed if requested by an investigator, and only if required to make important medical decisions 
for the patient in question. Two of the study personnel at the sponsor site only, will be given the 
emergency unblinding role. Their telephone numbers will be distributed among the study personnel. 
At least one of the designated emergency unblinders will be available at any time on a 24-hour basis. 
Unless unavoidable, other investigators and the personnel assessing outcomes, should not be made 
aware of treatment allocation. 
10.3 
Population for Analysis 
 The following populations will be considered for the analyses:  
 
Intention to treat (ITT) population: All randomised participants, regardless of protocol 
adherence. 
 
Safety population: All patients who have been enrolled in the trial, and who have received at 
least one dose of the investigational medicinal product (evolocumab or placebo).   
 
Per-protocol population (PP): Includes all subjects who have completed 12 months of 
treatment. 
10.4 
Planned analyses 
The main statistical analysis is planned when the last patient has completed the end-of-
treatment visit 12 months after randomisation. The number severity of adverse events will be 
assessed consecutively.  
Deviation from the original statistical plan will be described and justified in the Clinical Study 
Report. Amendments to plan can be done until the day of database lock. 
10.5 
Statistical analysis 
All statistical tests will be performed using a two-sided 5 % level of significance. Continuous 
efficacy variables will be analysed using baseline-adjusted ANCOVA for comparisons between the 
treatment arms. If necessary, values will be log-transformed to meet the assumptions of the tests. All 
analyses will primarily be analysed according to the intention-to-treat principle.  The number of 
major clinical events will be analysed using descriptive statistics. Between-group differences in 
ordinal categorical variables, such as NYHA class, will be analysed using ordinal logistic regression, 
whereas the count variables will be assessed by Poisson regression. Demographic, efficacy and safety 
data will be summarised by treatment group using means, minimums, medians, maximums, 
interquartile ranges and standard deviations for continuous variables and frequency counts and 
percentages for categorical variables. Per protocol analyses will be performed using the same 
methods as for the intention-to-treat analyses. 

EVOLVD Protocol version 3.0 18th October, 2021 
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The primary endpoint, the between-group difference in the baseline-adjusted intima thickness 
at 12 months, will be calculated by baseline-adjusted ANCOVA according to the intention-to-treat 
principle, the statistical null-hypothesis being that the intima thickness does not differ between the 
two treatment arms. Secondary analyses will be made according to the per-protocol-principle as 
baseline-adjusted absolute values after end-of-treatment. 
 
 
Key, secondary endpoints: 
The secondary endpoints “Percent atheroma volume as measured by IVUS” and “Cardiac 
allograft vasculopathy” will be tested, at a two-sided alpha level of 0.05, in a hierarchical fashion.The 
baseline-adjusted between-group difference in the atheroma volume, eGFR, quality of life, and 
biomarkers reflecting cardiac function, blood lipids, and inflammation will be calculated by ANCOVA 
according to the intention to treat principle. The statistical null-hypotheses are that the changes in 
these characteristics do not differ between patients allocated to evolocumab and patients allocated 
to placebo. 
Secondary per protocol analyses will be performed using the same methods as for the intention-
to-treat analyses. Exploratory analyses will be made for efficacy variables stratified by centre.  
Safety analyses will include tabulation of type and frequency of all adverse events. Any serious 
adverse events will be reported with comprehensive narratives. Any value of safety laboratory 
parameters outside normal ranges will be identified. 
Missing data will be omitted from analyses, i.e. there will be no imputation or estimation of 
missing values. However, a comparison of the baseline characteristics of those with an intima 
thickness measurement at 12 months and the baseline characteristics of those without a value will 
be performed to assess any bias introduced due to missing data. Statistical analyses will be 
performed in IBM SPSS Statistics version 21 or later. 
11 
Study management 
11.1 
Investigator delegation procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all 
the involved co-workers and their role in the project. He will ensure that appropriate training 
relevant to the study is given to all of these staff, and that any new information of relevance to the 
performance of this study is forwarded to the staff involved. 
11.2 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
11.3 
Study amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of 
the study protocol (Amended Protocol) must be notified to and approved by the Competent 
Authority and the Ethics Committee according to EU and national regulations. 
11.4 
Audit and inspections 
Authorised representatives of a Competent Authority and Ethics Committee may visit the centre 
to perform inspections, including source data verification. Likewise, the representatives from sponsor 
may visit the centre to perform an audit. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents to determine whether these 

EVOLVD Protocol version 3.0 18th October, 2021 
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activities were conducted, and data were recorded, analysed, and accurately reported according to 
the protocol, Good Clinical Practice (ICH/GCP), and any applicable regulatory requirements. The 
principal investigator will ensure that the inspectors and auditors will be provided with access to 
source data/documents. 
12 
Ethical and regulatory requirements 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory requirements. 
Registration of patient data will be carried out in accordance with national personal data laws. 
12.1 
Ethics committee approval 
The study protocol, including the patient information and informed consent form to be used, 
must be approved by the regional ethics committee in each participating country before enrolment 
begins in the particular country. 
The investigator is responsible for informing the regional ethics committee of any serious and 
unexpected adverse events and/or major amendments to the protocol as per national requirements. 
12.2 
Other regulatory approvals 
The protocol will be submitted and approved by the applicable, national competent authorities 
before commencement of the study. The protocol will also be registered on www.clinicaltrials.gov 
before inclusion of the first patient. 
12.3 
Informed consent procedure 
The investigator is responsible for giving the patients full and adequate verbal and written 
information about the nature, purpose, and potential risks and benefits of the study. Study 
participants will be informed as to the strict confidentiality of their patient data, but that their 
medical records may be reviewed for trial purposes by authorised individuals other than their 
treating physician.  
It will be emphasised that study participation is voluntary and that the patient is allowed to 
refuse further participation in the protocol whenever she/he wants. This will not prejudice the 
patient’s subsequent care. Written informed consent must be obtained for all study participants 
before enrolment in the study. This will be done in accordance with the national and local regulatory 
requirements. The investigator is responsible for obtaining signed informed consent. 
A copy of the patient information and consent form will be given to the patients. The signed and 
dated consent forms will be filed in the Investigator Site File binder. 
12.4 
Subject identification 
The investigator is responsible for keeping a list of all patients (who have received study 
treatment or undergone any study specific procedure) including patient’s date of birth and personal 
number, full names and last known addresses.  
The patients will be identified in the eCRFs by a study-specific, unique identification number. 
13 
Trial sponsorship and financing 
The EVOLVD trial is an investigator-sponsored (ISS) study which receives funding from Amgen®. 
Amgen has also provided the study drug. The funding sources have had no role in the design of the 
study; neither will they participate in the implementation of the trial, in the analyses of the results, or 

EVOLVD Protocol version 3.0 18th October, 2021 
Page 37 
 
in the decision to publish. The investigators take sole responsibility for the integrity of the data, the 
writing of the manuscript and the dissemination of the results. 
14 
Trial insurance 
The Principal investigator has insurance coverage for this study through membership of the Drug 
Liability Association.  
15 
Publication policy 
Upon study completion and finalisation of the study report the results of this study will either be 
submitted for publication and/or posted in a publicly assessable database of clinical study results. We 
will allow for a separate publication of baseline characteristics once all subjects have been enrolled. 
The results of this study will also be submitted to the Competent Authorities and the Regional  
Ethics Committees according to EU and national regulations. All personnel who have contributed 
significantly with the planning and performance of the study (Vancouver convention 1988) may be 
included in the list of authors. The funding sources have had no role in the conception of the study; 
neither will they participate in the implementation of the trial, in the analyses of the results, or in the 
decision to publish. 
 
 
 

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16 
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