Conditions: Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 545
Healthy volunteers: no

Brief summary:
The purpose of this trial is to test if a marketed drug for advanced prostate cancer (FIRMAGON) can reduce the risk of cardiovascular complications as compared to another marketed drug for advanced prostate cancer (LUPRON DEPOT) in subjects with prostate cancer and cardiovascular disease.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Degarelix intervention 2: Leuprolide
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Protocol 
 
 
Title of trial:  
A Multi-Center, Randomized, Assessor-Blind, Controlled Trial Comparing the 
Occurrence of Major Adverse Cardiovascular Events (MACEs) in Patients 
with Prostate Cancer and Cardiovascular Disease Receiving Degarelix 
(GnRH Receptor Antagonist) or Leuprolide (GnRH Receptor Agonist) 
NCT number: 
NCT02663908 
Sponsor trial code: 
000108 
Date:  
26 Mar 2021  
 
 
 
 
 


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Clinical Trial Protocol 
 
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CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
 
 
A Multi-Center, Randomized, Assessor-Blind, Controlled Trial Comparing the Occurrence of 
Major Adverse Cardiovascular Events (MACEs) in Patients with Prostate Cancer and 
Cardiovascular Disease Receiving Degarelix (GnRH Receptor Antagonist) or Leuprolide 
(GnRH Receptor Agonist) 
 
000108 
 
 
 
EudraCT Number: 
2017-002495-20 
IND Number: 
051222 
Investigational Medicinal Product: 
Degarelix powder and solvent for solution for injection 
Leuprolide acetate 22.5 mg 3-month depot  
Indication: 
Prostate cancer 
Phase: 
3b 
Name and Address of Sponsor: 
Ferring Pharmaceuticals A/S 
Clinical R&D, Urology 
 
 
Denmark 
 
Tel. 
 
Version: 
7.0 (consolidated protocol; changes to protocol 6.0 
introduced with amendment #07 implemented) 
GCP Statement: 
This trial will be performed in compliance with GCP. 
 
 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. 


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SYNOPSIS 
TITLE OF TRIAL 
A Multi-Center, Randomized, Assessor-Blind, Controlled Trial Comparing the Occurrence of 
Major Adverse Cardiovascular Events (MACEs) in Patients with Prostate Cancer and 
Cardiovascular Disease Receiving Degarelix (GnRH Receptor Antagonist) or Leuprolide (GnRH 
Receptor Agonist) 
SIGNATORY INVESTIGATORS 
 Department of 
Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
 Division of Cardiology, Duke University 
Medical Center, Durham, NC, USA 
TRIAL SITES 
Approximately 70 trial sites will be opened in the USA and Canada. At the time of the interim 
analysis, or if the recruitment rate is lower than expected, additional sites in other countries may be 
opened. 
PLANNED TRIAL PERIOD 
First patient first visit (FPFV) expected Q1 2016 
Last patient last visit (LPLV) expected Q2 2021 
CLINICAL PHASE 
3b 
OBJECTIVES 
Primary Objective 
• The primary objective is to assess the effect of a gonadotropin-releasing hormone (GnRH) 
receptor antagonist (degarelix) on the risk of occurrence of major adverse cardiovascular 
events (MACEs) (a composite of death due to any cause, non-fatal myocardial infarction or 
non-fatal stroke) as compared to a GnRH receptor agonist (leuprolide) in patients with 
prostate cancer and concomitant cardiovascular disease (CVD) 
Secondary Objectives 
The secondary objectives are: 
CV- and Death-Related Objectives 
• To assess the rate of specific MACEs (individual components of the composite MACE 
endpoint), i.e. myocardial infarction (fatal, non-fatal) or stroke (fatal, non-fatal), in patients 
randomized to degarelix versus leuprolide 


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• To assess the rate of unstable angina requiring hospitalization (fatal, non-fatal) in patients 
randomized to degarelix versus leuprolide 
• To assess the risk of death due to any cause in patients randomized to degarelix versus 
leuprolide 
• To assess the rate of cardiovascular (CV)-related death in patients randomized to degarelix 
versus leuprolide 
Prostate Cancer-Related Objectives 
• To monitor testosterone levels at Days 28, 168, and 336 in the degarelix and leuprolide 
treatment groups 
• To evaluate the progression-free survival (PFS) failure rates (defined as either death, 
radiographic disease progressiona, introduction of additional therapy related to prostate 
cancerb or prostate-specific antigen [PSA] failurec, whichever is first) in the degarelix and 
leuprolide treatment groups 
a. 
One or more new metastatic skeletal lesions observed on bone scan; one or more new metastatic extra-
skeletal lesions at least 1.5 cm in greatest dimension visible on computed tomography (CT) or magnetic 
resonance imaging (MRI) scan as confirmed by the Investigator. 
b. Additional therapy includes radiation, anti-androgens (except for initial symptomatic flare protection) and 
second-line treatment 
c. 
PSA failure is defined as an increase in serum PSA of 50%, and at least 5 ng/mL, compared to nadir, 
measured on two consecutive occasions at least 2 weeks apart. 
• To compare the effects of degarelix with leuprolide with regards to local urinary tract and 
prostate cancer-related symptoms with the International Prostate Symptom Score (IPSS) 
questionnaire 
Health Economics and Patient Reported Outcome Objectives 
• To compare the effects of degarelix with leuprolide with regards to healthcare resource use 
• To compare the effects of degarelix with leuprolide with regards to health status through the 
EuroQol Group 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) 
• To compare the effects of degarelix with leuprolide with regards to functional capacity and 
Quality of Life (QoL) through the Duke Activity Status Index (DASI) 
• To compare the effects of degarelix with leuprolide with regards to heart-focused anxiety 
through the Cardiac Anxiety Questionnaire (CAQ) 
Safety Objective 
• To evaluate and compare the overall safety and tolerability of degarelix with leuprolide 
Exploratory Objectives 
The exploratory objectives are: 


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• To compare the effects of degarelix with leuprolide with regards to a second confirmed 
(adjudicated) occurrence of the composite MACE endpoint, in the subgroup of patients that 
survived the first CV event 
 
 
 
 
 
 
 
 
 
ENDPOINTS 
Primary Endpoint 
• Time from randomization to the first confirmed (adjudicated) occurrence of the composite 
MACE endpoint 
Secondary Endpoints 
Key Secondary Endpoints 
• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke 
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
Other CV and Death-Related Endpoints 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to the first confirmed (adjudicated) unstable angina requiring 
hospitalization 
• Time from randomization to death due to any cause 
Prostate Cancer-Related Endpoints 
• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment 
groups 
• Time from randomization to failure in PFS 
• Changes from baseline in IPSS Total and QoL scores 
 


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Health Economics and Patient Reported Outcomes Endpoints 
• Total number of CV-related hospitalization events over the duration of the trial 
• Total number of coronary artery by-pass grafting (CABG) or percutaneous coronary 
intervention (PCI) procedures over the duration of the trial 
• Total number of CV-related emergency room (ER) visit events over the duration of the trial 
• Change in utility, based on EQ-5D-5L 
• Changes from baseline in DASI Global score 
• Changes from baseline in CAQ Global score and score per domain 
Safety Endpoints 
• Incidence and intensity of adverse events 
• Changes in vital signs 
Exploratory Endpoints 
• Time from first adjudicated non-fatal MACE to a second confirmed (adjudicated) 
occurrence of the composite MACE endpoint in the subgroup of patients that survived the 
first CV event 
 
 
 
 
 
 
 
 
 
 
METHODOLOGY 
Trial Design 
This is a multi-center, randomized, assessor-blind, controlled trial to compare the occurrence of 
MACEs in patients with prostate cancer and concurrent CVD receiving either monthly treatment 
with degarelix or leuprolide 3-month depot for 1 year. Patients will be screened within 21 days 
prior to randomization for compliance with the inclusion and exclusion criteria. 
Patients will be randomized to one of the two treatments in a 1:1 ratio stratified by baseline age 
group and region. Patients should be evaluated by a CV specialist to ensure that their CVD 
treatment is according to standard-of-care before trial entry. Cardiovascular disease information and 
source medical documents will be requested by the Investigator from the patient’s CV specialist to 


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evaluate and document CVD history for eligibility, using a Medical / CV History Request Form. A 
process will be implemented for the collection and review of supporting source data (with the 
involvement of the contract research organization [CRO] and Duke Clinical Research Institute 
[DCRI]) to ensure the accuracy of patients’ medical records documentation for the CVD-related 
inclusion criteria. The Investigator should ensure that pre-existing CVD and any CVD that may be 
diagnosed during the trial is managed by a CV specialist according to standard clinical practice. 
After randomization, the management of CVD and prostate cancer is intended to reflect standard-
of-care. Monitoring for MACEs will occur throughout the trial applying a specific Clinical Events 
Classification (CEC) process ensuring blinding of the assessors. Adjudication of MACEs will be 
performed by an external independent blinded CEC Committee (see Trial Committees below). Trial 
visits are scheduled to occur monthly until trial end. 
Treatment 
Patients randomized to degarelix will receive a starting dose of 240 mg degarelix (two 
subcutaneous [s.c.] injections, each of 120 mg) followed by up to 11 single monthly (28-day 
intervals) s.c. injections of 80 mg degarelix, according to the approved dosing regimen. 
Patients randomized to leuprolide will receive one dose (22.5 mg leuprolide), administered 
intramuscularly (i.m.), every 3 months (84-day intervals) according to label recommendations, up 
to a total of 4 doses. 
In line with inclusion criterion No. 4 (see Criteria for Inclusion / Exclusion below), investigators 
and patients are encouraged to continue investigational medicinal product (IMP) treatment during 
the entire duration of the trial, unless clinical progression or medical status indicate otherwise at the 
discretion of the Investigator. 
Adverse Events, Cardiovascular-Related Recordings and other Safety Assessments 
Adverse events will be recorded from the time point of obtaining signed informed consent until the 
End-of-Trial visit. Adverse events that occur before administration of the first dose of IMP will be 
regarded as pre-treatment adverse events. 
The sources of adverse events cover: 
• The patient’s response to general questions about his health (a standard non-leading 
question such as “How have you been feeling since your last visit?” is asked at each visit) 
• Symptoms spontaneously reported by the patient 
• Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities 
• Other information relating to the patient’s health becoming known to the Investigator  
CV-related adverse events and any worsening in CV status will be collected from Visit 2 until the 
End-of-Trial visit. The sources of CV-related information cover: 
• Admission to hospital or ER since last visit 


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• Death 
• Admission for chest pain (ischemic) symptoms that could be an unstable angina or 
myocardial infarction event 
• Admission for new neurological symptoms that could be a cerebrovascular (stroke) event 
• Any drawn creatinine kinase (CK), creatine kinase-muscle brain (subunit) (CK-MBs) or 
troponin samples since last visit 
The information obtained should be entered in the electronic case report form (eCRF). In case pre-
defined items on the eCRF checklist are answered affirmatively, a specific clinical endpoint form in 
the eCRF relating to each of the questions that were answered “yes”, must be completed by the site 
personnel. 
In case of any suspected CV-related adverse events, further examination of CV status will be 
performed. Data on suspected CV-related adverse events and related medical documentation will be 
collected and delivered to the CEC Committee before the adjudication of MACEs takes place (see 
Trial Committees below). 
The Investigator should ascertain that patients are evaluated by a CV specialist and treated 
according to standard-of-care for their pre-existing CVD and any CVD that may be diagnosed 
during the trial. 
A physical examination will be performed at screening (Visit 1) and at the End-of-Trial visit. Vital 
signs (pulse and blood pressure) will be assessed at all visits. Blood samples for assessment of 
safety laboratory variables (clinical chemistry and hematology), as well as urine samples for 
urinalysis, will be collected at screening (Visit 1), at baseline (Visit 2) and at the End-of-Trial visit 
(Visit 14). In addition, blood samples for assessment of clinical chemistry will be collected at 
Visits 3 and 8 to allow for periodic safety monitoring for QT prolongation. 
 
 
 
 Data on suspected CV-related 
vital signs and laboratory findings will be delivered to the CEC Committee before the adjudication 
of MACEs takes place. 
A 12-led electrocardiogram (ECG) recording will be performed at baseline (Visit 2), Visits 3, 8 and 
at the End-of-Trial visit (Visit 14). In case of a CV event, additional ECG recordings may be 
performed at the discretion of the Investigator. Assessments of vital signs, baseline ECG recording, 
blood sampling, and urine collection must be performed prior to dosing. 
Concomitant medications will be recorded at all visits and drug accountability will be recorded 
from Visit 2 and throughout the trial. 
 


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Blood Samples for Serum Testosterone and Prostate-Specific Antigen 
Blood samples for monitoring of serum testosterone levels will be collected at screening (Visit 1), 
at Visits 3 and 8 and at the End-of-Trial visit (Visit 14). 
Blood samples for analysis of PSA, as part of the PFS endpoint, will be collected at screening 
(Visit 1), at baseline (Visit 2), and every 3 months until the End-of-Trial visit (Visit 14). 
Health Economics and Patient Reported Outcomes 
Health care resource use will be recorded by appointed trial personnel (e.g. trial nurse) at each visit 
from Visit 2 until the End-of-Trial visit (Visit 14). The patient reported outcome (PRO) 
questionnaires EQ-5D-5L, DASI and CAQ will be completed by the patient at baseline (Visit 2), at 
Visit 8 and at the End-of-Trial visit (Visit 14). The IPSS questionnaire will be completed by the 
patient at baseline (Visit 2) and at Visits 5, 8 and 11 and at the End-of-Trial visit (Visit 14). 
Trial Committees 
Three committees with specific roles and responsibilities will be established for the trial: 
• CEC Committee 
• Data and Safety Monitoring Board (DSMB) 
• Steering Committee 
An external independent CEC Committee will be established to provide an independent and blinded 
adjudication and classification of CV events throughout the trial. The CEC Committee will consist 
of 3 selected cardiology experts (including 1 chair), 1 neurology expert and 1 oncology expert not 
otherwise involved in the trial. In addition, 1 project leader and 1 coordinator at DCRI will support 
the CEC Committee activities. The complete adjudication process, including responsibilities and 
the composition of the CEC Committee, the schedule and format of the meetings, and the data to be 
evaluated are presented in a separate CEC charter. The adjudicated MACEs will be used for the 
primary endpoint analysis. Adjudicated MACE data will be transferred directly from the CEC 
Committee to the DSMB in order to keep those data blinded to the Sponsor. 
The independent DSMB will consist of 1 chair, 1 voting independent statistician, 1 cardiologist and 
1 urologist not otherwise involved in the trial. A non-voting statistician from the DSMB 
Independent Statistical Group (ISG) will attend DSMB meetings to present information and address 
questions related to the analyses. The major purpose of the DSMB is to periodically evaluate safety 
data throughout the trial period. An additional purpose of the DSMB is to perform a pre-planned 
unblinded interim analysis, assessing the treatment-related hazard ratio and event rates of the 
adjudicated MACEs. The responsibilities and the composition of the DSMB, the schedule and 
format of the meetings, the voting procedures, and the data to be evaluated are described in a 
separate charter document. 
The DSMB will perform one pre-planned and unblinded interim analysis of the primary endpoint 


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and will, based on pre-specified criteria, make recommendations to the Steering Committee 
whether to continue as is, to modify (increase the sample size) or to stop the trial due to futility 
according to predetermined criteria (outlined in the Statistical Analysis Plan [SAP] and the DSMB 
charter). 
The Steering Committee will consist of external experts (as a minimum a statistician, a cardiologist 
and a urologist) and a Sponsor representative who is not part of the trial team. The Steering 
Committee will be responsible for trial integrity and decisions related to the trial, such as protocol 
amendments, and decisions based on interim recommendations by the DSMB as to whether the trial 
is to be stopped, to be continued, or sample size is to be increased. 
Withdrawal and Follow-Up 
A patient who prematurely discontinues treatment with IMP should be called in for an end-of-
treatment visit as soon as possible (within 30 days) after a decision of treatment discontinuation has 
been taken. The reason for premature IMP discontinuation should be recorded in the eCRF. The 
patient should then be contacted by telephone each month throughout the trial period for collection 
of follow-up information on hospitalizations and potential CV events, and concomitant medication. 
At the end of the trial, i.e. after 336 days of participation in the trial, the patient should be called in 
for an end-of-trial visit. 
In case a patient is lost to follow-up, all attempts have to be made to obtain the vital and medical 
status of the patient at the planned end-of-trial for the patient. 
NUMBER OF PATIENTS 
Approximately 900 patients are planned to be randomized in a 1:1 ratio to treatment with either 
degarelix or leuprolide. The randomization will be stratified by baseline age group (<75 and 
≥75 years of age) and region (North America and Other regions). 
CRITERIA FOR INCLUSION / EXCLUSION 
Inclusion Criteria 
Each patient must meet the following inclusion criteria before entry into the trial: 
1. Signed informed consent obtained before any trial-related activity is performed. 
2. Histologically confirmed adenocarcinoma of the prostate. 
3. Clinical tumor staging (Tumor, Nodule and Metastasis [TNM]) available prior to 
treatment start; radiographic imaging (bone scan and/or CT scan and/or MRI) performed 
within 3 months prior to randomization. If no radiographic image is available at the time 
of screening, a bone scan should be performed. 
4. Investigator judgment to initiate continued androgen deprivation therapy (ADT) with an 
intended treatment duration of 12 months or longer including any of the following 
disease categories: 


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A. Patients with metastatic prostate cancer at the time of diagnosis. 
B. Patients with prostate cancer who develop metastases after local therapy. 
C. Patients with prostate cancer with very high-risk, high-risk or intermediate-risk 
disease with features of unfavourable prognosis who are going to be treated 
with definitive radiation therapy in combination with at least 12 months of 
neoadjuvant/adjuvant ADT. 
D. Patients with biochemical recurrence after local therapy who have a PSA 
doubling time <12 months. 
E. Patients previously treated with definitive local therapy (without ADT 
combination) who due to risk features such as positive margins, seminal 
vesicle invasion, extracapsular extension, or detectable PSA, will be treated 
with salvage radiation therapy in combination with neoadjuvant/adjuvant ADT 
that is planned for 12 months or longer. 
F. Patients with locally advanced prostate cancer who are not candidates (who are 
unsuited) for definitive therapy with surgery or radiation and will be treated 
with primary ADT. 
5. Patients must be treatment-naïve with regard to ADT at time of randomization (with the 
exception of prior history of neoadjuvant/adjuvant ADT to definitive therapy for which 
the last administration, e.g., injection of a depot ADT formulation was at least 
12 months prior to randomization). 
6. Patients must have a screening serum testosterone level above the lower limit of normal 
range, defined as >150 ng/dL (5.2 nmol/L), apart from those who had prior 
neoadjuvant/adjuvant ADT (>12 months prior to randomization) where non-castrate 
range (>50 ng/dL or ≥1.73 nmol/L) should be applied. 
7. Patients must have an Eastern Cooperative Oncology Group (ECOG) score of ≤2. 
8. Pre-existing CVD (confirmed diagnosis prior to randomization) with at least one of the 
following criteria documented with applicable medical source documents: 
A. Prior myocardial infarction ≥30 days before randomization. 
B. Prior revascularization procedure ≥30 days before randomization, specified as 
any of the following: 
− 
Coronary artery stent placement or coronary artery balloon angioplasty 
− 
Coronary artery bypass graft surgery  
− 
Stent placement or balloon angioplasty to a carotid, iliac, femoral, or 
popliteal artery 
− 
Carotid endarterectomy surgery 
− 
Vascular bypass surgery of the iliac, femoral, or popliteal arteries 
C. Results from an angiogram or CT angiogram of the coronary, carotid, iliac, 


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femoral, or popliteal arteries that documented at least one vascular stenosis 
≥50% at any time point before randomization. 
D. Carotid ultrasound results that documented a vascular stenosis ≥50% at any time 
point before randomization. 
E. Ankle-brachial pressure index (ABPI) <0.9 at any time point before 
randomization. 
Exclusion Criteria 
A patient who meets one or more of the following exclusion criteria cannot be included in this trial: 
1. Previous or current hormonal management of prostate cancer (surgical castration or 
other hormonal manipulation, including GnRH receptor agonists, GnRH receptor 
antagonists, anti-androgens, estrogens, megestrol acetate, ketoconazole, abiraterone and 
enzalutamide); except neoadjuvant/adjuvant ADT (in this case treatment has to be 
terminated at least 12 months prior to randomization). 
2. Hypersensitivity towards any component of the IMPs or excipients. 
3. Uncontrolled type 1 or type 2 diabetes mellitus (defined as hemoglobin A1c [HbA1c] 
>10%) at time of randomization. 
4. Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood 
pressure >110 mmHg) at time of randomization. 
5. A history of congenital Long QT Syndrome or risk factors for Torsade de Pointes 
ventricular arrhythmias (e.g. heart failure, hypokalemia, concomitant medication known 
to cause QT prolongation). 
6. Myocardial infarction within 30 days prior to randomization. 
7. Stroke (hemorrhagic or ischemic) within 30 days prior to randomization. 
8. Coronary, carotid, or peripheral artery revascularization within 30 days prior to 
randomization. 
9. Planned or scheduled cardiac surgery or PCI procedure that is known at the time of 
randomization. 
10. Other clinically significant disorder (other than prostate cancer and CVD) including, but 
not limited to, renal, hematological, gastrointestinal, endocrine, neurological, or 
psychiatric disease, and alcohol or drug abuse or any other condition, which may affect 
the patient’s health or the outcome of the trial as judged by the Investigator. 
11. Mental incapacity or language barrier precluding adequate understanding or co-
operation. 
12. Treatment with an investigational drug within the last month prior to randomization or 
longer if considered to possibly influence the outcome of the current trial or planned or 
concurrent participation in a clinical trial for any investigational drug or device. 


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INVESTIGATIONAL MEDICINAL PRODUCTS 
Degarelix (FIRMAGON) 
Degarelix (FIRMAGON) powder and solvent for solution for injection 1-month depot. 
Degarelix starting dose: Two s.c. depot injections containing 120 mg of degarelix each in 3.0 mL of 
sterile water (i.e. the starting dose will be 240 mg).  
Degarelix maintenance dose: A single s.c. depot injection containing 80 mg of degarelix in 4.0 mL 
of sterile water. The maintenance dose will be administered monthly (28-day intervals) for the rest 
of the trial period. A treatment window of ±7 days is allowed. 
Leuprolide acetate (LUPRON DEPOT 22.5 mg) 
Leuprolide acetate (LUPRON DEPOT 22.5 mg) lyophilized microspheres and diluent for 
suspension for intramuscular (i.m.) injection according to label recommendations, every 3 months 
(84-day intervals) throughout the trial. A treatment window of ±7 days is allowed. 
ADT will be restricted to degarelix and leuprolide to facilitate the comparison of CV risk in ADT-
naïve prostate cancer patients. Concomitant treatment with anti-androgens (e.g. bicalutamide 50 mg 
once a day) for a maximum period of up to 28 days is allowed in metastatic patients requiring initial 
symptomatic flare protection at the discretion of the Investigator. Other ADTs (e.g. abiraterone) are 
prohibited during the trial. 
DURATION OF TREATMENT 
Each patient will be treated for 1 year (336 days i.e. 12 treatment months of 28 days each). 
STATISTICAL METHODS 
Sample Size Calculations 
As suggested by a post-hoc analysis of degarelix safety data the 1-year event rates for a CV event 
or death due to any cause are 5.3% and 12.1% for degarelix and leuprolide, respectively, in the 
global patient population with prior CVD. This would correspond to an unadjusted hazard ratio of 
0.42 (in comparison, the adjusted hazard ratio is 0.39 [95 % confidence interval = [0.21; 0.71]]). 
Furthermore, based upon the re-assessment of the potential CV events captured in the degarelix 
safety data by an independent cardiologist, the 1-year event rates for CV event or death due to any 
cause are 4.8% and 9.3% for degarelix and leuprolide respectively. This corresponds to an 
unadjusted hazard ratio of 0.50 (in comparison, the adjusted hazard ratio is 0.48 [95% confidence 
interval = [0.23; 0.87]]). Accounting for the uncertainty in the post-hoc analysis of the global 
pooled data and the re-assessment of the potential CV events by a single independent cardiologist, 
the 1-year event rates for sample size calculations are set to 5.1% and 10.2% for degarelix and 
leuprolide, respectively. This corresponds to a hypothesized hazard ratio of 0.49. 
Trial Design 
One interim analysis is planned after 50% of the confirmed, adjudicated MACE endpoints have 


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been collected. The interim analysis will assess the hazard ratio, response rates of the adjudicated 
MACEs and reassess the sample size in the event that the stopping boundaries for futility are not 
crossed. The futility bound expressed in terms of the hazard ratio is 0.78. That is, if the observed 
hazard ratio is >0.78 the DSMB may suggest to stop the trial due to futility. The futility bounds are 
non-binding. Accounting for the possibility of stopping the trial early for futility, an alternative 
hypothesis of a hazard ratio of 0.49 and 80% power, 66 events are required at final analysis, 
corresponding to 876 patients, in order to reject the null hypothesis of equal hazards at the two-
sided 5% Type I error level. 
The trial will not be stopped early due to an overwhelming treatment benefit, but in order to 
implement the trial design, an alpha-spending function will be used with a close to zero spending of 
alpha at the interim analysis. 
Adjustments for Sample Size Re-Estimation 
The conditional power for different sample size increases will be evaluated at the interim using 
ADDPLAN™ 6. In case of a sample size increase, the final test statistics are adjusted by using the 
normal inverse method. This is done in order to protect the two-sided Type I error rate at 5%. 
The sample size calculations are performed with ADDPLAN™ 6, licensed by ADDPLAN, Inc., an 
Aptiv Solutions company and presented in Table S1. 
Table S1  Sample Size Calculations (Number of Events Rounded Upwards) 
Information 
Rate 
Accept H0 
Reject H0 
α spent 
Power 
Achieved 
Events 
Test 
Statistic 
Hazard 
Ratio 
Conditional 
Power 
Test 
Statistic 
 
 
50% 
0.7 
0.78 
8.5% 
 
<0.0001 
 
33 
100% 
1.96 
0.61 
 
1.96 
0.025 
80% 
66 
 
Statistical Analyses 
Primary Analysis 
The primary endpoint, the time from randomization to the first confirmed occurrence of the 
composite MACE endpoint in the two treatment groups, will be analyzed based on the Kaplan-
Meier estimator of the survival function and the log-rank test stratified for age group and region. 
The null hypothesis of equal hazard functions between the two treatment groups, will be rejected if 
the test statistics exceed the critical level for a two-sided hypothesis test with a Type I error level of 
5%. 
Conclusions on significance of the primary endpoint analysis will be based on the Full Analysis Set 
(FAS) censoring patients at the time of treatment discontinuation, initiation of prohibited therapies 
related to hormonal treatment, lost to follow-up/withdrawal from the trial or Day 336, whichever 
occurs first.  
Secondary Analyses 
If the primary analysis is significant at the two-sided Type I error-level of 5% the testing of the key 
secondary endpoints will proceed as described below. 


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CONFIDENTIAL 
Key Secondary Analyses 
The following analyses are included in the key secondary analyses: 
• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke 
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
The key secondary endpoints will be controlled for multiplicity (to ensure the family wise error rate 
is protected at a two-sided 5% Type I error-level) using a fixed-sequence testing method. The order 
of the testing sequence is as follows: 
1. Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke  
2. Time from randomization to confirmed (adjudicated) CV-related death 
3. Time from randomization to the first confirmed (adjudicated) myocardial infarction 
Other Secondary Analyses 
The remaining secondary endpoints will be tested outside the scope of the hierarchy; without 
adjustment for multiplicity. 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to the first confirmed (adjudicated) unstable angina requiring 
hospitalization 
• Time from randomization to death due to any cause 
• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment 
groups 
• Time from randomization to failure in PFS 
• Total number of CV-related hospitalization events over the duration of the trial 
• Total number of CABG or PCI procedures over the duration of the trial 
• Total number of CV-related ER visit events over the duration of the trial 
• Changes from baseline in Health-Related Quality of Life (HRQL) as measured by 
EQ-5D-5L, during the course of the treatment period 
• Changes from baseline in PRO instruments will be analyzed longitudinally across the 
treatment period (IPSS and EQ-5D-5L) and cross-sectionally (DASI and CAQ) 
Laboratory data, vital signs, and adverse events data will be presented as appropriate. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................. 2 
LIST OF TABLES ......................................................................................................................19 
LIST OF FIGURES.....................................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................20 
1 
INTRODUCTION .............................................................................................................22 
1.1 
Background.............................................................................................................22 
1.2 
Scientific Justification for Conducting the Trial ............................................................22 
1.3 
Benefit / Risk Aspects...............................................................................................24 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..........................................................................26 
2.1 
Objectives...............................................................................................................26 
2.1.1 
Primary Objective .........................................................................................26 
2.1.2 
Secondary Objectives ....................................................................................26 
2.1.3 
Exploratory Objectives ..................................................................................27 
2.2 
Endpoints ...............................................................................................................27 
2.2.1 
Primary Endpoint..........................................................................................27 
2.2.2 
Secondary Endpoints .....................................................................................27 
2.2.3 
Exploratory Endpoints ...................................................................................28 
3 
INVESTIGATIONAL PLAN..............................................................................................29 
3.1 
Overall Trial Design .................................................................................................29 
3.1.1 
Trial Design Diagram ....................................................................................29 
3.1.2 
Overall Design and Control Methods ...............................................................29 
3.1.3 
Trial Schedule ..............................................................................................30 
3.2 
Planned Number of Trial Sites and Patients ..................................................................30 
3.3 
Interim Analysis ......................................................................................................30 
3.4 
Trial Committees .....................................................................................................31 
3.4.1 
Clinical Events Classification Committee .........................................................31 
3.4.2 
Data and Safety Monitoring Board ..................................................................31 
3.4.3 
Steering Committee.......................................................................................31 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ...................................32 
3.5.1 
Trial Design .................................................................................................32 
3.5.2 
Selection of Endpoints ...................................................................................32 
3.5.3 
Blinding ......................................................................................................33 
3.5.4 
Selection of Doses in the Trial ........................................................................33 
3.5.5 
Selection and Timing of Dose for Each Patient ..................................................33 
3.5.6 
Selection of the Trial Population .....................................................................34 
3.5.7 
Withdrawal Criteria.......................................................................................34 
3.5.8 
Follow-up Procedures....................................................................................34 
4 
SELECTION OF TRIAL POPULATION ...........................................................................35 
4.1 
Trial Population .......................................................................................................35 
4.1.1 
Inclusion Criteria ..........................................................................................35 
4.1.2 
Exclusion Criteria .........................................................................................36 
4.2 
Method of Assigning Patients to Treatment Groups .......................................................37 
4.2.1 
Recruitment .................................................................................................37 


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4.2.2 
Randomization .............................................................................................38 
4.3 
Restrictions .............................................................................................................38 
4.3.1 
Prior and Concomitant Therapies ....................................................................38 
4.3.2 
Prohibited Therapy .......................................................................................38 
4.3.3 
Other Restrictions .........................................................................................39 
4.4 
Withdrawal Criteria ..................................................................................................39 
5 
TREATMENTS.................................................................................................................42 
5.1 
Treatments Administered ..........................................................................................42 
5.2 
Characteristics and Source of Supply ..........................................................................42 
5.3 
Packaging and Labelling ...........................................................................................43 
5.4 
Conditions for Storage and Use ..................................................................................43 
5.5 
Blinding / Unblinding ...............................................................................................43 
5.6 
Treatment Compliance ..............................................................................................43 
5.6.1 
Dispensing and Accountability........................................................................43 
5.6.2 
Assessment of Compliance.............................................................................44 
5.7 
Auxiliary Supplies ...................................................................................................44 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies .............................44 
6 
TRIAL PROCEDURES .....................................................................................................45 
6.1 
Trial Flow Chart ......................................................................................................45 
6.2 
Visit 1 (Screening) ...................................................................................................50 
6.3 
Visit 2 (Month 0) .....................................................................................................51 
6.4 
Visit 3 (Month 1) to Visit 13 (Month 11) .....................................................................52 
6.4.1 
Visit 3 (Month 1) to Visit 13 (Month 11) - All Visits ..........................................52 
6.4.2 
Visit 3 (Month 1) and Visit 8 (Month 6) ...........................................................52 
6.4.3 
Visit 3 (Month 1), Visit 4 (Month 2), Visit 5 (Month 3), Visit 8 (Month 6) and 
Visit 11 (Month 9) ........................................................................................52 
6.4.4 
Visit 5 (Month 3), Visit 8 (Month 6), and Visit 11 (Month 9)...............................52 
6.4.5 
Visit 8 (Month 6) ..........................................................................................53 
6.5 
End-of-Treatment Visit .............................................................................................53 
6.6 
End-of-Trial Visit / Visit 14 (Month 12) ......................................................................54 
6.7 
Unscheduled Visits...................................................................................................55 
7 
TRIAL ASSESSMENTS ....................................................................................................56 
7.1 
Assessment Related to Primary Endpoint and Key Secondary Endpoints ..........................56 
7.1.1 
Clinical Events Classification .........................................................................56 
7.2 
Assessments Related to Other Secondary Endpoints ......................................................56 
7.2.1 
Prostate Cancer-Related Assessments ..............................................................56 
7.2.1.1 Testosterone ....................................................................................56 
7.2.1.2 Progression-Free Survival .................................................................56 
7.2.1.3 International Prostate Symptom Score .................................................57 
7.2.2 
Health Economics .........................................................................................57 
7.2.2.1 Cardiovascular-Related Hospitalizations..............................................57 
7.2.2.2 Total Coronary Artery By-Pass Grafting and Percutaneous Coronary 
Intervention Procedures ....................................................................57 
7.2.2.3 Emergency Room Visit Events...........................................................57 
7.2.3 
Patient-Reported Outcomes ............................................................................58 
7.2.3.1 Duke Activity Status Index and Cardiac Anxiety Questionnaire ..............58 


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7.2.3.2 EQ-5D-5L ......................................................................................58 
7.2.4 
Safety Endpoints...........................................................................................59 
7.2.4.1 Adverse Events................................................................................59 
7.2.4.2 Vital Signs ......................................................................................59 
7.3 
Other Assessments ...................................................................................................60 
7.3.1 
Demographics ..............................................................................................60 
7.3.2 
Body Measurements ......................................................................................60 
7.3.3 
Medical History Including Cardiovascular Disease History .................................60 
7.3.4 
Histology, Treatment History (or Previous Therapy), Stage of Prostate Cancer 
and Eastern Cooperative Oncology Group (ECOG) Score ...................................60 
 
61 
7.3.6 
Electrocardiogram.........................................................................................61 
7.3.7 
Physical Examination ....................................................................................62 
7.3.8 
Concomitant Medications / Therapies ..............................................................62 
7.3.9 
Clinical Laboratory Variables .........................................................................62 
64 
7.4 
Handling, Storage and Destruction of Biological Samples ..............................................64 
8 
ADVERSE EVENTS..........................................................................................................65 
8.1 
Adverse Event Definition ..........................................................................................65 
8.2 
Collection and Recording of Adverse Events ................................................................65 
8.2.1 
Collection of Adverse Events..........................................................................65 
8.2.2 
Recording of Adverse Events..........................................................................65 
8.2.3 
Cardiovascular-Related Adverse Events ...........................................................69 
8.2.4 
Pregnancy and Pregnancy Outcome .................................................................70 
8.3 
Serious Adverse Events.............................................................................................71 
8.3.1 
Serious Adverse Event Definition....................................................................71 
8.3.2 
Collection, Recording and Reporting of Serious Adverse Events ..........................72 
8.3.2.1 Serious Adverse Event Reporting by the Investigator.............................72 
8.3.2.2 Protocol Specific Exceptions to Serious Adverse Event Reporting ...........72 
8.3.2.3 Expedited Reporting by the Sponsor ...................................................73 
8.4 
Follow-up of Adverse Events and Serious Adverse Events .............................................73 
8.4.1 
Follow-up of Adverse Events with Onset during the Trial ...................................73 
8.4.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit..................73 
9 
STATISTICAL METHODS ...............................................................................................74 
9.1 
Determination of Sample Size ....................................................................................74 
9.1.1 
Trial Design .................................................................................................74 
9.1.2 
Adjustments for Sample Size Re-Estimation .....................................................74 
9.2 
Patient Disposition ...................................................................................................75 
9.3 
Protocol Deviations ..................................................................................................75 
9.4 
Analysis Sets ...........................................................................................................75 
9.4.1 
Intention-to-Treat Analysis Set .......................................................................75 
9.4.2 
Full Analysis Set ..........................................................................................75 
9.4.3 
Safety Analysis Set .......................................................................................75 
9.5 
Trial Population .......................................................................................................75 
9.5.1 
Demographics and other Baseline Characteristics ..............................................75 
9.5.2 
Medical History and Concomitant Medication...................................................76 


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9.6 
Endpoint Assessments ..............................................................................................76 
9.6.1 
General Considerations ..................................................................................76 
9.6.2 
Primary Endpoint..........................................................................................76 
9.6.3 
Secondary Endpoints .....................................................................................77 
9.6.3.1 Time from Randomization to the First Confirmed (adjudicated) 
Occurrence of Cardiovascular-Related Death, Non-fatal Myocardial 
Infarction or Non-fatal Stroke ............................................................79 
9.6.3.2 Time from Randomization to the First (adjudicated) Occurrence of the 
Individual Components of the MACE Composite Endpoint ....................79 
9.6.3.3 Time from Randomization to Confirmed (adjudicated) Cardiovascular-
Related Death ..................................................................................80 
9.6.3.4 Time from Randomization to the First Confirmed (adjudicated) 
Unstable Angina Requiring Hospitalization..........................................80 
9.6.3.5 Time from Randomization to Death Due to Any Cause ..........................80 
9.6.3.6 Testosterone Levels at Days 28, 168 and 336 in the Degarelix and 
Leuprolide Treatment Groups ............................................................80 
9.6.3.7 Time from Randomization to Failure in Progression-Free Survival ..........80 
9.6.3.8 International Prostate Symptom Score - Total and QoL Scores ................81 
9.6.3.9 Total Number of Cardiovascular-Related Hospitalization Events Over 
the Duration of the Trial ....................................................................81 
9.6.3.10 Total Number of Coronary Artery By-Pass Grafting or Percutaneous 
Coronary Intervention Procedures Over the Duration of the Trial ............81 
9.6.3.11 Total Number of Cardiovascular-Related Emergency Room Visit 
Events Observed Over the Duration of the Trial ....................................82 
9.6.3.12 Duke Activity Status Index and Cardiac Anxiety Questionnaire Score......82 
9.6.3.13 Quality Adjusted Life Year................................................................82 
9.6.4 
Exploratory Endpoints ...................................................................................82 
9.7 
Extent of Exposure and Treatment Compliance.............................................................83 
9.8 
Safety.....................................................................................................................83 
9.8.1 
General Considerations ..................................................................................83 
9.8.2 
Adverse Events ............................................................................................83 
9.8.3 
Vital Signs ...................................................................................................85 
9.8.4 
Other Safety Variables...................................................................................85 
9.8.4.1 Body Measurements .........................................................................85 
9.8.4.2 Physical Examination Findings ..........................................................85 
9.8.4.3 Safety Laboratory Variables ..............................................................85 
9.8.4.4 Electrocardiogram ............................................................................85 
9.9 
Interim Analysis ......................................................................................................86 
10 
DATA HANDLING ...........................................................................................................87 
10.1 
Source Data and Source Documents............................................................................87 
10.2 
Electronic Case Report Form .....................................................................................88 
10.3 
Use of Patient Reported Outcome Measures Instruments ................................................89 
10.4 
Data Management ....................................................................................................89 
10.5 
Provision of Additional Information............................................................................89 
11 
MONITORING PROCEDURES ........................................................................................90 
11.1 
Periodic Monitoring .................................................................................................90 
11.2 
Risk-Based and Adaptive Monitoring..........................................................................90 


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11.3 
Centralized Monitoring .............................................................................................91 
11.4 
Audit and Inspection.................................................................................................91 
11.5 
Confidentiality of Patient Data ...................................................................................92 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ...............................................................93 
12.1 
Protocol Amendments...............................................................................................93 
12.2 
Deviations from the Protocol .....................................................................................93 
12.3 
Premature Trial Termination ......................................................................................93 
13 
REPORTING AND PUBLICATION ..................................................................................94 
13.1 
Clinical Trial Report.................................................................................................94 
13.2 
Confidentiality and Ownership of Trial Data ................................................................94 
13.3 
Publications and Public Disclosure .............................................................................94 
13.3.1 Publications Committee and Policies ...............................................................94 
13.3.2 Public Disclosure Policy ................................................................................95 
14 
ETHICAL AND REGULATORY ASPECTS.......................................................................96 
14.1 
Institutional Review Board / Research Ethics Board / Independent Ethics Committee .........96 
14.2 
Regulatory Authorities Authorization / Approval / Notification .......................................96 
14.3 
End-of-Trial and End-of-Trial Notification ..................................................................96 
14.4 
Ethical Conduct of the Trial .......................................................................................96 
14.5 
Patient Information and Consent.................................................................................96 
14.6 
Patient Information Card ...........................................................................................97 
14.7 
Compliance Reference Documents .............................................................................98 
15 
LIABILITIES AND INSURANCE ......................................................................................99 
15.1 
ICH-GCP Responsibilities .........................................................................................99 
15.2 
Liabilities and Insurance ...........................................................................................99 
16 
ARCHIVING .................................................................................................................. 100 
16.1 
Investigator File..................................................................................................... 100 
16.2 
Trial Master File .................................................................................................... 100 
17 
REFERENCES................................................................................................................ 101 
18 
APPENDIX 1   Cardiovascular Endpoint Definitions ......................................................... 104 
 
 
LIST OF TABLES  
Table 1 
Flow Chart of Assessments ...................................................................................... 46 
Table 2 
Treatment Flow Chart .............................................................................................. 49 
Table 3 
Clinical Laboratory Variables................................................................................... 63 
 
 64 
Table 5 
Sample Size Calculations (Number of Events Rounded Upwards) ............................. 75 
 
LIST OF FIGURES 
Figure 1 
Trial Design Diagram .............................................................................................. 29 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
ABPI 
Ankle-Brachial Pressure Index 
ADR 
Adverse Drug Reaction 
ADT 
Androgen Deprivation Therapy 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
AV 
Atrioventricular 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery by-pass Grafting 
CAQ 
Cardiac Anxiety Questionnaire 
CEC 
Clinical Events Classification 
CK 
Creatinine Kinase 
CK-MB 
Creatine Kinase-Muscle Brain (subunit) 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DASI 
Duke Activity Status Index 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
 Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ePRO 
Electronic Patient Reported Outcome 
EQ-5D-5L 
EuroQol Group 5 Dimensions 5 Levels Questionnaire 
EQ VAS 
EQ Visual Analogue Scale 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin-Releasing Hormone 
HbA1c 
Hemoglobin A1c 
HRQL 
Health-Related Quality of Life 
 
 
ICH 
International Conference on Harmonization 
ICMJE  
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
i.m. 
Intramuscular(ly) 


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IMP 
Investigational Medicinal Product 
IPSS 
International Prostate Symptom Score 
IRB 
Institutional Review Board 
ISG 
Independent Statistical Group 
ITT 
Intention-to-Treat 
LPLV 
Last Patient Last Visit 
LUTS 
Lower Urinary Tract Symptoms 
MACE 
Major Adverse Cardiovascular Event 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NLM 
National Library of Medicine 
 
 
PCI 
Percutaneous Coronary Intervention 
PDF 
Portable Document Format 
PFS 
Progression-Free Survival 
PRO 
Patient Reported Outcome 
PSA 
Prostate-Specific Antigen 
QALY 
Quality Adjusted Life Year 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
REB 
Research Ethics Board 
ROC 
Receiver Operating Characteristics 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous(ly) 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TNM 
Tumor, Nodule and Metastasis 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
Definition of Terms 
Investigator 
A Medical Doctor at the trial center responsible for the conduct of 
the clinical trial. 
Sponsor 
Ferring Pharmaceuticals A/S, Copenhagen, Denmark 
Month 
One treatment month is equal to 28 days/4 weeks 
Trial-related 
Activity 
Any procedure that would not have been performed during the 
normal management of the patient 
Screened 
Patient who has signed informed consent  
Randomization Patient is randomly assigned to a treatment group and given a unique 
patient number 


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1 
INTRODUCTION 
1.1 
Background 
The current management of advanced prostate cancer involves androgen deprivation therapy (ADT) 
(Medical Research Council Trial, 1997; Granfors, 1998; Messing, 1999). In general, suppression of 
the serum testosterone level to the desired therapeutic goal (≤0.5 ng/mL) can be achieved by 
surgical (bilateral orchiectomy) or medical castration including administration of gonadotropin-
releasing hormone (GnRH) receptor agonists or GnRH receptor antagonists.  
ADT is associated with a number of well-known side effects, such as sexual dysfunction, hot 
flashes, osteoporosis and metabolic changes that can lead to atherosclerosis (Nguyen, 2014; 
Allan, 2014). 
A number of large-scale epidemiological studies have in post-hoc analyses found that treatment 
with GnRH receptor agonists is associated with a long-term increased risk of cardiovascular disease 
(CVD) (Smith, 2008; Basaria, 2008; Saigal, 2007), however, this association appears to be lacking 
or less consistent for bilateral orchiectomy or anti-androgen treatment. In many cases, 
cardiovascular (CV) events develop early after treatment initiation (<12 months and as early as 
after 1-4 months of exposure), which could suggest a short-term treatment related risk for 
aggravation or destabilisation of existing atherosclerotic vascular disease (Smith, 2008; Basaria, 
2008; Tsai, 2007; Lester-Coll, 2013). This short-term risk raises concerns in patients with pre-
existing CVD where the potential mechanism could go beyond the medical castration related 
metabolic changes. In line with this, studies have consistently shown that history of major CV 
events is a strong risk factor for subsequent CV complications during ADT therapy (D'Amico, 
2007; Nanda, 2009). 
Degarelix is a GnRH receptor antagonist that competitively binds to GnRH receptors in the anterior 
pituitary gland. The qualitative difference in the mechanism of action between GnRH receptor 
antagonists and GnRH receptor agonists, including the effect on the follicle-stimulating hormone 
(FSH) as well as potentially functional GnRH receptors identified in peripheral tissues e.g. 
T-lymphocytes, raises the possibility that GnRH receptor agonists and GnRH receptor antagonists 
may have different profiles with respect to short-term CV safety in patients with established CVD 
(Albertsen, 2014; Smith, 2011). 
In the epidemiological studies which showed an increased risk of CV events, ADT was achieved 
with GnRH receptor agonists, and to a limited extent, anti-androgens. To-date, there is limited 
information as to whether GnRH receptor antagonists would carry similar CV risk. 
1.2 
Scientific Justification for Conducting the Trial 
The CV safety of degarelix was evaluated throughout the clinical development programme with 
1,836 prostate cancer patients exposed to degarelix. Of these, 775 patients were exposed to 
degarelix for more than one year. No general CV safety concerns were identified in the clinical trial 


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programme (Smith, 2011). More specifically, the potential effect of degarelix on prolongation of 
the QT interval was investigated in two controlled clinical trials. An analysis of data from the 
pivotal Phase 3 trial, FE 200486 CS21, demonstrated similar incidences of QT prolongation and 
arrhythmias for patients treated with degarelix or leuprolide (Smith, 2010). In addition, a Phase 1 
thorough QTc evaluation trial in healthy adult males (FE 200486 CS22) investigated the intrinsic 
effect of degarelix on the QT/QTc intervals (Clinical Trial Report FE 200486 CS22, 2012). This 
trial demonstrated that degarelix did not have any intrinsic effect on prolongation of the QTcF 
interval, heart rate, atrioventricular (AV) conduction, or cardiac repolarization. 
A non-comparative pooled analysis of CVD risk in 1,704 patients was performed to investigate 
associations of baseline CVD risk profile, dosing regimen and treatment duration with the incidence 
of CVD events during ADT with degarelix in patients with prostate cancer (Smith, 2011). Events 
were coded using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries 
(SMQs) terms and grouped into one of the four categories used for the collection of medical 
history: ischemic heart disease, cerebrovascular disorders, arterial thrombotic/embolic events, and 
claudication. This safety analysis demonstrated that the incidence of CV events was similar before 
and after degarelix treatment and events were largely confined to men with a history of CVD. 
In addition, a pooled analysis of data from six Phase 3/3b randomized, comparative trials 
(2,328 patients with prostate cancer treated with degarelix [n=1,491] and with GnRH receptor 
agonists [n=837]) was performed (Tombal, 2013; Albertsen, 2014). CV events were defined by any 
of the five MedDRA SMQs: myocardial infarction, ischaemic cerebrovascular conditions, 
haemorrhagic cerebrovascular conditions, embolic and thrombotic arterial events, and other 
ischaemic heart disease. 
In brief, the analysis showed that significantly fewer patients treated with degarelix experienced a 
CV event or death of any cause compared with those receiving a GnRH receptor agonist. In patients 
with a medical history of CVD at baseline, the risk of experiencing a CV event or death was 
approximately 50% lower in the degarelix group. Hence, these data suggest that men, especially 
those requiring ADT and with a history of CVD, may experience a significantly lower risk of CVD 
sequelae when treated with degarelix compared with a GnRH receptor agonist. 
The primary aim of the present safety trial is to prospectively evaluate short-term, drug-related CV 
risk by comparing the occurrence of major adverse cardiovascular events (MACEs) in patients with 
prostate cancer and concomitant CVD who receive degarelix or the GnRH receptor agonist 
leuprolide. In addition, a number of non-CV-related secondary endpoints will be studied with the 
purpose to further investigate the potential differences in the risk-benefit profile of degarelix versus 
GnRH receptor agonist. 
 
 
 
 Currently the most widely used biomarker in prostate 


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cancer is prostate-specific antigen (PSA), which is a glycoprotein that is found almost exclusively 
in normal and neoplastic prostate cells. Many but not all investigators have observed an association 
between a decline in PSA levels of 50% or greater and survival. However, PSA is not always 
optimal as a single biomarker for prostate cancer diagnosis or progression. Recent development in 
e.g. proteomics and immunology offer new approaches to evaluate progression. The methods are 
not fully developed and more evidence is needed in terms of validation in prostate cancer patients. 
 
 
 
1.3 
Benefit / Risk Aspects 
Treatment with degarelix or leuprolide is expected to be associated with benefits for the population 
of prostate cancer patients with concomitant CVD and in whom ADT is indicated, leading to 
delayed progression of prostate cancer or disease symptoms (Levine, 2010). 
Agonists initially stimulate the pituitary GnRH receptors, resulting in a rapid increase in 
testosterone levels (surge), which might stimulate prostate cancer cells and delay the onset of ADT 
(Klotz, 2014; Carter, 2014). This may lead to an exacerbation of clinical complications such as 
bladder outlet obstructions, spinal cord compression, and bone pain (clinical flare) in patients with 
advanced disease. Degarelix competitively binds to the GnRH receptor and promptly blocks 
testosterone production, resulting in a rapid (one to three days) and sustained suppression of 
testosterone to castrate levels (serum testosterone level ≤50 ng/dL), thereby avoiding testosterone 
surge and flare of clinical symptoms. 
Patients initiated with a GnRH receptor agonist regimen are on some occasions treated in 
combination with an anti-androgen during a limited period to avoid symptomatic flare associated 
with initial testosterone surge. Therefore, metastatic patients considered by the Investigator as 
requiring treatment with anti-androgen (e.g. bicalutamide 50 mg once a day) for a maximum period 
of up to 28 days in addition to leuprolide for symptomatic flare protection can be included and 
treated according to standard-of-care. 
The most common side effects of leuprolide are hot flashes, pain (especially joint pain and back 
pain), injection site pain and fatigue (LUPRON Prescribing Information, 2014). Leuprolide may 
also cause impotence. 
The risks of treatment with degarelix are likely to be associated with adverse reactions similar to 
those associated with other ADTs, such as hot flash/flushes, loss of libido, and impotence 
(Carter, 2014; FIRMAGON Prescribing Information, 2015). 
Mild, transient elevated values of hepatic transaminases have been observed in healthy volunteers 
as well as prostate cancer patients treated with degarelix (Carter, 2014; FIRMAGON Prescribing 
Information, 2015). The hepatic changes observed to date have been transient increases in 
transaminases without concomitant increases in bilirubin and with no obvious correlation to dose, 


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duration of treatment, or degarelix plasma concentrations. Similar changes in hepatic transaminases 
were also seen with the active comparator, leuprolide, in the pivotal Phase 3 trial 
(FE 200486 CS21) (Clinical Trial Report FE 200486 CS21, 2008; Klotz, 2008). Blood samples for 
analysis of hepatic transaminase (alanine aminotransferase [ALT]) and serum bilirubin will be 
collected at baseline and at the End-of-Trial visit. 
There is a risk of mild to moderate reactions at the injection site with degarelix. Injection site 
reaction adverse events were reported in 35% of patients treated with the 240/80 mg degarelix 
regimen in the CS21 trial (Clinical Trial Report FE 200486 CS21, 2008). The most commonly 
reported injection site reactions were pain (28%) and erythema (17%). These events occurred 
primarily after the starting dose of 240 mg degarelix. 
Overall, more than 3,600 prostate cancer patients have been exposed to degarelix in clinical trials 
and the administration of degarelix has not revealed any significant safety concerns specific to 
degarelix. The cumulative exposure from post-marketing exposure is 275,253 patients (as of 
17 August 2014) and no new important safety issues have been identified. It is considered that the 
benefit-risk profile for degarelix remains favorable. Patients included in the current trial will be 
monitored on a monthly basis during the entire course of the trial by central medical monitoring. 
An external Data and Safety Monitoring Board (DSMB) will on regular basis review safety data 
from the trial. 
Adverse events and any CV-related signs or symptoms will be closely monitored during the trial to 
safeguard the health and well-being of the patients. 
 


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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
• The primary objective is to assess the effect of a GnRH receptor antagonist (degarelix) on 
the risk of occurrence of MACEs (a composite of death due to any cause, non-fatal 
myocardial infarction or non-fatal stroke) as compared to a GnRH receptor agonist 
(leuprolide) in patients with prostate cancer and concomitant CVD 
2.1.2 
Secondary Objectives 
The secondary objectives are: 
CV- and Death-Related Objectives 
• To assess the rate of specific MACEs (individual components of the composite MACE 
endpoint), i.e. myocardial infarction (fatal, non-fatal) or stroke (fatal, non-fatal), in patients 
randomized to degarelix versus leuprolide 
• To assess the rate of unstable angina requiring hospitalization (fatal, non-fatal) in patients 
randomized to degarelix versus leuprolide 
• To assess the risk of death due to any cause in patients randomized to degarelix versus 
leuprolide 
• To assess the rate of CV-related death in patients randomized to degarelix versus leuprolide 
Prostate Cancer-Related Objectives 
• To monitor testosterone levels at Days 28, 168, and 336 in the degarelix and leuprolide 
treatment groups 
• To evaluate the progression-free survival (PFS) failure rates (defined as either death, 
radiographic disease progressiona, introduction of additional therapy related to prostate 
cancerb or PSA failurec, whichever is first) in the degarelix and leuprolide treatment groups 
a. 
One or more new metastatic skeletal lesions observed on bone scan; one or more new metastatic extra-
skeletal lesions at least 1.5 cm in greatest dimension visible on computed tomography (CT) or magnetic 
resonance imaging (MRI) scan as confirmed by the Investigator. 
b. 
Additional therapy includes radiation, anti-androgens (except for initial symptomatic flare protection) and 
second-line treatment. 
c. 
PSA failure is defined as an increase in serum PSA of 50%, and at least 5 ng/mL, compared to nadir, 
measured on two consecutive occasions at least 2 weeks apart. 
• To compare the effects of degarelix with leuprolide with regards to local urinary tract and 
prostate cancer-related symptoms with the International Prostate Symptom Score (IPSS) 
questionnaire 
Health Economics and Patient Reported Outcome Objectives 
• To compare the effects of degarelix with leuprolide with regards to healthcare resource use 


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• To compare the effects of degarelix with leuprolide with regards to health status through the 
EuroQol Group 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) 
• To compare the effects of degarelix with leuprolide with regards to functional capacity and 
Quality of Life (QoL) through the Duke Activity Status Index (DASI) 
• To compare the effects of degarelix with leuprolide with regards to heart-focused anxiety 
through the Cardiac Anxiety Questionnaire (CAQ) 
Safety Objective 
• To evaluate and compare the overall safety and tolerability of degarelix with leuprolide 
2.1.3 
Exploratory Objectives 
The exploratory objectives are: 
• To compare the effects of degarelix with leuprolide with regards to a second confirmed 
(adjudicated) occurrence of the composite MACE endpoint, in the subgroup of patients that 
survived the first CV event 
 
 
 
 
 
 
 
 
 
2.2 
Endpoints 
2.2.1 
Primary Endpoint 
• Time from randomization to the first confirmed (adjudicated) occurrence of the composite 
MACE endpoint 
2.2.2 
Secondary Endpoints 
Key Secondary Endpoints 
• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke 
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
Other CV and Death-Related Endpoints 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to the first confirmed (adjudicated) unstable angina requiring 
hospitalization 


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• Time from randomization to death due to any cause 
Prostate Cancer-Related Endpoints 
• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment 
groups 
• Time from randomization to failure in PFS 
• Changes from baseline in IPSS Total and QoL scores 
Health Economics and Patient Reported Outcomes Endpoints 
• Total number of CV-related hospitalization events over the duration of the trial 
• Total number of coronary artery by-pass grafting (CABG) or percutaneous coronary 
intervention (PCI) procedures over the duration of the trial 
• Total number of CV-related emergency room (ER) visit events over the duration of the trial 
• Change in utility, based on EQ-5D-5L 
• Changes from baseline in DASI Global score 
• Changes from baseline in CAQ Global score and score per domain 
Safety Endpoints 
• Incidence and intensity of adverse events 
• Changes in vital signs 
2.2.3 
Exploratory Endpoints 
• Time from first adjudicated non-fatal MACE to a second confirmed (adjudicated) 
occurrence of the composite MACE endpoint in the subgroup of patients that survived the 
first CV event 
 
 
 
 
 
 
 
 
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
 
Figure 1 
Trial Design Diagram 
 
3.1.2 
Overall Design and Control Methods 
Trial Design 
This is a multi-center, randomized, assessor-blind, controlled trial to compare the occurrence of 
MACEs in patients with prostate cancer and concurrent CVD receiving either monthly treatment 
with degarelix or leuprolide 3-month depot for 1 year. Patients will be screened within 21 days 
prior to randomization for compliance with the inclusion and exclusion criteria. A trial design 
diagram is provided in Figure 1. 
Patients will be randomized to one of the two treatments in a 1:1 ratio stratified by baseline age 
group and region, as detailed in Section 4.2.2. After randomization, the management of prostate 
cancer is intended to reflect standard-of-care. Monitoring for possible MACEs will occur 
throughout the trial applying a specific Clinical Events Classification (CEC) process ensuring 
blinding of the assessors as described in Section 7.1.1. 
Patients should be evaluated by a CV specialist to ensure that their CVD treatment is according to 
standard-of-care before trial entry. Cardiovascular disease information and source medical 
documents will be requested by the Investigator from the patient’s CV specialist to evaluate and 
document CVD history for eligibility, using a Medical / CV History Request Form. A process will 
be implemented for the collection and review of supporting source data (with the involvement of 
the contract research organization [CRO] and Duke Clinical Research Institute [DCRI]) to ensure 


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the accuracy of patients’ medical records documentation for the CVD-related inclusion criteria. The 
Investigator should ensure that pre-existing CVD and any CVD that may be diagnosed during the 
trial is managed by a CV specialist according to standard clinical practice. After randomization, the 
management of CVD and prostate cancer is intended to reflect standard-of-care. 
If a patient experiences a CV event during the course of the trial, the Investigator will be 
encouraged to let the patient continue in the trial if this is not considered to constitute a safety 
concern. Patients who prematurely withdraw from the trial or from treatment with investigational 
medicinal product (IMP) will be followed-up for potential CV events and hospitalizations 
throughout the trial period as described in Section 4.4. If a patient is lost to follow-up, all attempts 
have to be made to obtain the vital and medical status of the patient at the planned end-of-trial for 
the patient. 
Three committees with specific roles and responsibilities will be established for the trial; CEC 
Committee, DSMB, and Steering Committee. These committees are further specified in 
Section 3.4. 
3.1.3 
Trial Schedule 
First patient first visit (FPFV) is estimated for Q1 2016 and last patient last visit (LPLV) is 
expected in Q2 2021. The expected duration of the total trial (from FPFV to LPLV) will be 
approximately 64 months; 52 months (1 month=1 calendar month) for recruitment and additional 
12 months (1 month=28 days) for follow-up of last randomized patient. 
3.2 
Planned Number of Trial Sites and Patients 
A 15-20% screening failure rate is expected based on previous experience in degarelix trials. Based 
on the expected screening failure rate and the sample size requirements of at least 876 patients 
treated in the trial (438 patients randomized to degarelix treatment and 438 patients randomized to 
leuprolide treatment), between 1,008 and 1,052 patients will be screened for participation in the 
trial. The sample size calculation is detailed in Section 9.1. 
To achieve the requested number of patients within the given timelines, approximately 70 trial sites 
in the USA and Canada will be opened. Patient recruitment will be competitive between trial sites. 
At the time of the interim analysis, or if the recruitment rate is lower than expected, additional sites 
in other countries may be opened. 
3.3 
Interim Analysis 
A single interim analysis is planned for the trial and will be performed by the statistician on the 
external DSMB established for the trial. The interim analysis will assess the hazard ratio, response 
rates of the adjudicated MACEs and reassess the sample size in the event that the stopping 
boundaries for futility are not crossed. The timing of the interim analysis is planned to correspond 
with the positive adjudication of the first 33 (50%) MACEs. The exact timing of the interim 


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analysis will depend on the accrual rate, as well as the event rate in the two treatment groups. The 
actual recruitment period and sample size may need to be adapted accordingly.  
The interim analysis is further described in Section 9.9 and in the DSMB working procedure 
provided in a separate document. 
3.4 
Trial Committees 
3.4.1 
Clinical Events Classification Committee 
An external independent CEC Committee will be established to provide an independent and blinded 
adjudication and classification of CV events throughout the trial. The CEC Committee will consist 
of 3 selected cardiology experts (including 1 chair), 1 neurology expert and 1 oncology expert not 
otherwise involved in the trial. In addition, 1 project leader and 1 coordinator at DCRI will support 
the CEC Committee activities. The complete adjudication process, including responsibilities and 
the composition of the CEC Committee, the schedule and format of the meetings, and the data to be 
evaluated are presented in a separate CEC charter. 
The adjudicated MACEs will be used for the primary endpoint analysis (Section 7.1.1). 
Adjudicated MACE data will be transferred directly from the CEC Committee to the DSMB in 
order to keep those data blinded to the Sponsor. 
3.4.2 
Data and Safety Monitoring Board 
The independent DSMB will consist of 1 chair, 1 voting independent statistician, 1 cardiologist and 
1 urologist not otherwise involved in the trial. A non-voting statistician from the DSMB 
Independent Statistical Group (ISG) will attend DSMB meetings to present information and address 
questions related to the analyses. The major purpose of the DSMB is to periodically evaluate safety 
data throughout the trial period. An additional purpose of the DSMB is to perform a pre-planned 
unblinded interim analysis, assessing the treatment-related hazard ratio and event rates of the 
adjudicated MACEs. The responsibilities and the composition of the DSMB, the schedule and 
format of the meetings, the voting procedures, and the data to be evaluated are described in a 
separate charter document. 
The DSMB will perform one pre-planned and unblinded interim analysis of the primary endpoint 
(Section 9.9) and will, based on pre-specified criteria, make recommendations to the Steering 
Committee whether to continue as is or, to modify (increase the sample size) or, to stop the trial due 
to futility according to predetermined criteria (outlined in the Statistical Analysis Plan [SAP] and 
the DSMB charter). 
3.4.3 
Steering Committee 
The Steering Committee will consist of external experts (as a minimum a statistician, a cardiologist 
and a urologist) and a Sponsor representative who is not part of the trial team. The Steering 
Committee will be responsible for trial integrity and decisions related to the trial, such as protocol 
amendments and decisions based on interim recommendations by the DSMB as to whether the trial 


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is to be stopped, to be continued, or sample size is to be increased. The composition of the Steering 
Committee, the schedule and format of the meetings, and the voting procedures are presented in a 
separate Steering Committee charter. 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
The trial has a primary objective of assessing the effect of a GnRH receptor antagonist (degarelix) 
on the short-term CV risk as compared to a GnRH receptor agonist (leuprolide) in patients with 
prostate cancer and concomitant CVD. In addition, a number of non-CV-related secondary 
endpoints will be studied with the purpose to further investigate the potential differences in risk-
benefit profile of degarelix versus GnRH receptor agonists. 
In order to minimize the risk of imbalance between the treatment arms with respect to CVD 
prognostic risk factors the randomization will be stratified by baseline age group (<75 and 
≥75 years of age) and region (North America and Other regions). 
3.5.2 
Selection of Endpoints 
Androgen deprivation therapy has been reported to be associated with certain long-term metabolic 
effects, but also an increased risk of short-term major CV events. It has also been reported that 
history of CVD in prostate cancer patients is an increased risk factor for CV complications 
(Albertsen, 2014; Nguyen, 2014). 
A pooled analysis of data from clinical trials has shown that patients, especially those with a history 
of CVD, may experience a significantly lower risk of CVD sequelae when treated with degarelix 
compared with a GnRH receptor agonist (Section 1.2). The primary objective is to assess the effect 
of a GnRH receptor antagonist (degarelix) on the short-term risk of the occurrence of MACEs 
(defined as a composite of death due to any cause, non-fatal myocardial infarction or non-fatal 
stroke) as compared to a GnRH receptor agonist (leuprolide) in patients with prostate cancer and 
concomitant CVD. The CV endpoint definitions and methodology have been selected to conform to 
the Food and Drug Administration (FDA) guidance that is being developed on this topic 
(Hicks, 2015). The primary endpoint to compare CV risk between degarelix and leuprolide is 
defined as time from randomization to the first confirmed (adjudicated) occurrence of the MACE 
endpoint. Detailed descriptions of the methodology and CV endpoint definitions are given in a CEC 
charter provided in a separate document, as described in Section 3.4.1. The CV endpoint definitions 
are also provided in Appendix 1. 
The secondary endpoints consist of CV-related endpoints including the individual components of 
the MACE endpoint as well as non-CV-related measures. Such secondary endpoints will be studied 
with the purpose to further investigate the potential differences in risk-benefit profile of degarelix 
versus a GnRH receptor agonist and include prostate cancer-related endpoints, health economics, 
and evaluation of safety. Endpoints relating to patient reported outcomes (PROs) are included to 
allow capturing directly the patients’ perspective on the disease, and thus evaluating the impact of 


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its treatment on their emotional status and physical functioning.
 
 
 
3.5.3 
Blinding 
The feasibility process conducted by the Sponsor has demonstrated that a true double-blind design 
would be difficult to implement (due to different doses and treatment regimen and different 
incidence of injection-site reactions) and would be unlikely to fully maintain blinding through the 
randomized treatment administration period. Specific firewalls will be implemented between the 
sites, the Sponsor and the MACE assessors to minimize risk of bias. An external CEC Committee 
(Section 3.4.1) will be established for the trial to provide an independent and blinded adjudication 
of CV events. The CEC Committee will have coordinators who will work closely with the Sponsor 
team for the surveillance and query processes to identify all potential CV events from the clinical 
and safety databases and work collaboratively to redact information regarding the open-label trial 
treatment information for each endpoint. This team would assist with generating queries specific to 
each endpoint reported and would be fire-walled from the external CEC Committee physician 
reviewers that process the completed event packets for physician adjudication to ensure complete 
blinding of the adjudication team. The CEC classification and adjudication process are detailed in a 
separate CEC charter. 
3.5.4 
Selection of Doses in the Trial 
The regimen of a starting dose of 240 mg degarelix (40 mg/mL) followed by a maintenance dose of 
80 mg degarelix (20 mg/mL) at monthly intervals (240/80 mg dose regimen) has been approved for 
the treatment of advanced prostate cancer by the medicines agencies in the European Union, the 
USA, and Canada. 
The GnRH receptor agonist leuprolide (22.5 mg) will be administered intramuscularly (i.m.) every 
3 months over the trial period as per current national label recommendations. Leuprolide and its 3-
month depot formulation is selected as comparator, as being the most commonly used agent in this 
class of GnRH receptor agonists worldwide (IMS MIDAS report: www.imshealth.com). The 
Sponsor considers that the approved and standard-of-care dosing regimens specified above should 
be used in this trial. 
3.5.5 
Selection and Timing of Dose for Each Patient 
Patients randomized to degarelix will receive a starting dose (240 mg degarelix) at Visit 2 
(Month 0) followed by up to 11 maintenance doses (80 mg degarelix) at monthly (i.e. 28-day) 
intervals, according to the approved dosing regimen. 
Patients randomized to leuprolide will receive one dose (22.5 mg leuprolide) every 3 months (i.e. 
84 days), as per label recommendations, up to a total of 4 doses. 


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3.5.6 
Selection of the Trial Population 
Patients with hormone-dependent prostate cancer and pre-existing CVD considered at increased 
risk of adverse CV outcomes are to be included in the trial if the eligibility criteria in Section 4.1 
are met. Patients must be treatment-naïve with regard to ADT at the time of randomization with the 
exception of neoadjuvant/adjuvant ADT for which the last injection of a depot formulation was at 
least 12 months prior to randomization (Section 4.3). It is considered that patients in whom therapy 
with either GnRH receptor antagonist or GnRH receptor agonist for at least one year is thought to 
be indicated according inclusion criterion No. 4 (Section 4.1.1) are consistent with and representing 
the approved indications of the IMP. The prostate cancer population is to reflect clinical practice in 
relation to ADT in patients with pre-existing severe CVD. 
3.5.7 
Withdrawal Criteria 
In line with inclusion criterion No. 4 (Section 4.1.1), investigators and patients are encouraged to 
continue IMP treatment during the entire duration of the trial, unless clinical progression or medical 
status indicate otherwise at the discretion of the Investigator. 
Specific withdrawal criteria and processes for IMP treatment and/or trial discontinuation are 
described in Section 4.4. 
3.5.8 
Follow-up Procedures 
After the patient’s last visit, the Investigator must follow-up on any adverse events that occurred 
during the trial and are classified as serious or as related to the IMP until it is resolved or until the 
medical condition of the patient is stable. All such relevant follow-up information must be reported 
to the Sponsor. If the event is a chronic condition, the Investigator and the Sponsor may agree that 
further follow-up is not required. 
Following trial completion or premature IMP treatment and/or trial discontinuation, the Investigator 
may treat the patient according to normal practice. 
Follow-up procedures in case of premature IMP treatment and/or trial discontinuation are described 
in Section 4.4. 


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4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
4.1.1 
Inclusion Criteria 
Each patient must meet the following inclusion criteria before entry into the trial: 
1. Signed informed consent obtained before any trial-related activity is performed. 
2. Histologically confirmed adenocarcinoma of the prostate. 
3. Clinical tumor staging (Tumor, Nodule and Metastasis [TNM]) available prior to treatment 
start; radiographic imaging (bone scan and/or CT scan and/or MRI) performed within 
3 months prior to randomization. If no radiographic image is available at the time of 
screening, a bone scan should be performed. 
4. Investigator judgment to initiate continued ADT with an intended treatment duration of 
12 months or longer including any of the following disease categories: 
A. Patients with metastatic prostate cancer at the time of diagnosis. 
B. Patients with prostate cancer who develop metastases after local therapy. 
C. Patients with prostate cancer with very high-risk, high-risk or intermediate-risk 
disease with features of unfavourable prognosis who are going to be treated with 
definitive radiation therapy in combination with at least 12 months of 
neoadjuvant/adjuvant ADT. 
D. Patients with biochemical recurrence after local therapy who have a PSA doubling 
time <12 months. 
E. Patients previously treated with definitive local therapy (without ADT combination) 
who due to risk features such as positive margins, seminal vesicle invasion, 
extracapsular extension, or detectable PSA, will be treated with salvage radiation 
therapy in combination with neoadjuvant/adjuvant ADT that is planned for 12 
months or longer. 
F. Patients with locally advanced prostate cancer who are not candidates (who are 
unsuited) for definitive therapy with surgery or radiation and will be treated with 
primary ADT. 
5. Patients must be treatment-naïve with regard to ADT at time of randomization (with the 
exception of prior history of neoadjuvant/adjuvant ADT to definitive therapy for which the 
last administration, e.g., injection of a depot ADT formulation was at least 12 months prior 
to randomization). 
6. Patients must have a screening serum testosterone level above the lower limit of normal 
range, defined as >150 ng/dL (5.2 nmol/L), apart from those who had prior 
neoadjuvant/adjuvant ADT (>12 months prior to randomization) where non-castrate range 
(>50 ng/dL or ≥1.73 nmol/L) should be applied. 
7.  Patients must have an Eastern Cooperative Oncology Group (ECOG) score of ≤2. 


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8. Pre-existing CVD (confirmed diagnosis prior to randomization) with at least one of the 
following criteria documented with applicable medical source documents: 
A. Prior myocardial infarction ≥30 days before randomization. 
B. Prior revascularization procedure ≥30 days before randomization, specified as any of 
the following: 
− Coronary artery stent placement or coronary artery balloon angioplasty 
− Coronary artery bypass graft surgery  
− Stent placement or balloon angioplasty to a carotid, iliac, femoral, or popliteal 
artery 
− Carotid endarterectomy surgery 
− Vascular bypass surgery of the iliac, femoral, or popliteal arteries 
C. Results from an angiogram or CT angiogram of the coronary, carotid, iliac, femoral, 
or popliteal arteries that documented at least one vascular stenosis ≥50% at any time 
point before randomization. 
D. Carotid ultrasound results that documented a vascular stenosis ≥50% at any time 
point before randomization. 
E. Ankle-brachial pressure index (ABPI) <0.9 at any time point before randomization. 
4.1.2 
Exclusion Criteria 
A patient who meets one or more of the following exclusion criteria cannot be included in this trial: 
1. Previous or current hormonal management of prostate cancer (surgical castration or other 
hormonal manipulation, including GnRH receptor agonists, GnRH receptor antagonists, 
anti-androgens, estrogens, megestrol acetate, ketoconazole, abiraterone and enzalutamide); 
except neoadjuvant/adjuvant ADT (in this case treatment has to be terminated at least 
12 months prior to randomization). 
2. Hypersensitivity towards any component of the IMPs or excipients. 
3. Uncontrolled type 1 or type 2 diabetes mellitus (defined as hemoglobin A1c [HbA1c] >10%) 
at time of randomization. 
4. Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure 
>110 mmHg) at time of randomization. 
5. A history of congenital Long QT Syndrome or risk factors for Torsade de Pointes 
ventricular arrhythmias (e.g. heart failure, hypokalemia, concomitant medication known to 
cause QT prolongation). 
6. Myocardial infarction within 30 days prior to randomization. 
7. Stroke (hemorrhagic or ischemic) within 30 days prior to randomization. 
8. Coronary, carotid, or peripheral artery revascularization within 30 days prior to 
randomization. 


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9. Planned or scheduled cardiac surgery or PCI procedure that is known at the time of 
randomization. 
10. Other clinically significant disorder (other than prostate cancer and CVD) including, but not 
limited to, renal, hematological, gastrointestinal, endocrine, neurological, or psychiatric 
disease, and alcohol or drug abuse or any other condition, which may affect the patient’s 
health or the outcome of the trial as judged by the Investigator. 
11. Mental incapacity or language barrier precluding adequate understanding or co-operation. 
12. Treatment with an investigational drug within the last month prior to randomization or 
longer if considered to possibly influence the outcome of the current trial or planned or 
concurrent participation in a clinical trial for any investigational drug or device. 
4.2 
Method of Assigning Patients to Treatment Groups 
4.2.1 
Recruitment 
Approximately 70 trial sites in the USA and Canada will be opened. At the time of the interim 
analysis, or if the recruitment rate is lower than expected, additional sites in other countries may be 
opened. The participating patients will be recruited among the patients attending the clinics 
included in the trial. Advertisements may be used if approved by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Independent Ethics Committee (IEC) and regulatory 
authorities, as applicable according to local regulations. 
Each trial site will require potential participants to undergo a screening visit prior to randomization 
to a treatment group. Each patient who has given signed consent to participate in the trial will 
receive a unique screening number which must be entered in a screening log that must be 
maintained at each trial site. The screening number will be allocated sequentially in the order in 
which the patients are screened at the site, i.e. a patient must always be assigned to the lowest 
available screening number at each site. The results of each screening should be recorded in the 
screening log. The data for screened patients should also be entered in the electronic case report 
form (eCRF) with the reason for screening failure if the patient is not randomized to treatment. 
Under no circumstances will patients screened in the trial be permitted to be re-screened for a 
second time in this trial. 


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4.2.2 
Randomization 
Only patients who meet the eligibility criteria (Section 4.1) will be randomized to a treatment arm 
in this trial. The treatment arms will run in parallel. 
Computer-generated randomization lists will be prepared centrally by the Sponsor’s Department of 
Global Biometrics. Patients will be randomized to one of the two treatments in a 1:1 ratio stratified 
by baseline age group (<75 and ≥75 years of age) and region (North America and Other regions). 
The patients will be randomized and allocated to a treatment through the eCRF and thereby receive 
a unique randomization number. The randomization must be performed at Visit 2 (Month 0). 
4.3 
Restrictions 
4.3.1 
Prior and Concomitant Therapies 
Patients must be treatment-naïve with regard to ADT at time of randomization, except for 
neoadjuvant/adjuvant ADT given in combination with prostatectomy or radiotherapy with curative 
intent. This treatment should have been terminated at least 12 months prior to randomization. 
Concomitant treatment with anti-androgens (e.g. bicalutamide 50 mg once a day) for a maximum 
period of up to 28 days is allowed in metastatic patients requiring initial symptomatic flare 
protection at the discretion of the Investigator. Other hormonal management of prostate cancer is 
not allowed prior to or during the trial (Section 4.1). However, if a patient develops signs of disease 
progression, e.g. increased clinical signs and symptoms or rising PSA, additional secondary therapy 
can be added at the discretion of the Investigator to treat the prostate cancer. Patients on secondary 
treatments will be handled as described in Section 4.3.2. 
The Investigator will be encouraged to treat patients for their pre-existing CVD and any CVD that 
may be diagnosed during the trial according to standard-of-care. Other medication, which is 
considered necessary for the patient’s safety and well-being, may be given at the discretion of the 
Investigator. 
Details of all concomitant medications, and other therapies including surgical procedures, e.g. 
revascularizations including the main reason for their prescription must be recorded in the medical 
source data and the eCRF for all eligible patients at the Screening visit. This information should 
include name of the drug, route of administration, indication, and duration of treatment. It has to be 
clearly stated if the medication is given to treat progression of the prostate cancer. Any changes 
(including new therapies) must be recorded at each subsequent trial visit. 
4.3.2 
Prohibited Therapy 
Treatment with an investigational drug within the last month prior to randomization or longer is 
prohibited if considered to possibly influence the outcome of the trial.  
The following concomitant medications are prohibited from randomization until the End-of-Trial: 


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• Surgical castration or other hormonal manipulation in addition to the IMPs 
• Anti-androgens for combined androgen blockade (anti-androgen use for initial flare 
protection is allowed for a maximum period of up to 28 days) 
• Estrogens 
• Megestrol acetate 
• Ketoconazole 
• Abiraterone 
• Enzalutamide 
In case any additional hormonal therapy has been initiated as a combination treatment with the 
IMP, this is considered a change of ADT regimen and the patient should be called in for an end-of-
treatment visit and followed-up as described in Section 4.4. 
4.3.3 
Other Restrictions 
Patients planning to father a child should not participate in this trial since the risks associated with 
sperm exposure to degarelix have not been evaluated. 
4.4 
Withdrawal Criteria 
The patients have the right to withdraw from IMP treatment and/or the trial at any time for any 
reason without the need to justify their decision.  
Withdrawal of consent for treatment should be distinguished from withdrawal of consent for 
follow-up visits/telephone contacts and from withdrawal of consent for non-patient contact follow-
up, e.g., medical records checks. Therefore, when giving written consent for participation in the 
trial, patients will also be specifically asked to give written consent to safety follow-up procedures 
that will take place in case of withdrawal from IMP treatment, and/or in case a patient is lost to 
follow-up.  
Patients should be informed that not giving consent, or requesting withdrawal of consent for safety 
follow-up, will jeopardize the public health value of the trial. Withdrawal of consent for safety 
follow-up should be accompanied by documentation of the reason for withdrawal. 
Patients who withdraw from IMP treatment and/or the trial should be explicitly asked about the 
contribution of possible adverse events to their decision to withdraw consent, and any adverse event 
information elicited should be documented. 
Preferably the patient should withdraw consent in writing and, if the patient or the patient’s 
representative refuses or is physically unavailable, the trial site personnel should document and sign 
the reason for the patient’s failure to withdraw consent in writing. 


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A patient who prematurely discontinues treatment with IMP, or receives prohibited medication 
(Section 4.3.2), should be called in for an end-of-treatment visit (Section 6.5) as soon as possible 
(within 30 days) after a decision of treatment discontinuation has been taken. The reason for 
premature IMP discontinuation should be recorded in the eCRF. The patient should then be 
contacted by telephone each month throughout the trial period for collection of follow-up 
information on hospitalizations and potential CV events, and concomitant medication. At the 
telephone follow-ups, information will be collected using the standardized questions regarding 
hospitalizations and/or ER visits that may have occurred since the last telephone follow-up as 
described in Section 8.2.3. In case the patient has experienced a potential CV event, related event 
documentation will need to be collected for evaluation by the CEC Committee. After 336 days of 
participation in the trial, the patient should be called in for an end-of-trial visit (Section 6.6). 
In case a patient is lost to follow-up, despite every attempt (e.g., certified mail, telephone contact of 
patient or patient relatives) to get in contact, the vital and medical status of the patient should be 
investigated an additional last time at the end of the trial for that patient (i.e. 12 months after 
Visit 1), by accessing the patient’s hospital records, or publicly available sources such as national 
registries, newspaper obituaries and social networking websites. Attempts may also be made to 
contact the patient or his relatives to ascertain this information. However, the patients have the right 
to withdraw their consent for collection of this information at any time, without the need to justify 
their decision.a 
In case the patient has withdrawn his consent for participation in the trial, including any follow-up 
activities, no new data can be entered into the eCRF and data are recorded in the medical records 
only. Correction of previous data entries and/or entering of data related to visits/procedures done 
prior to but made available after withdrawal of consent (e.g. laboratory results) will be allowed 
unless the patient disapproves it. 
The Investigator also has the right to withdraw patients from the trial or from treatment with IMP. 
Since an excessive rate of trial withdrawals or IMP treatment withdrawals can render the trial 
devoid of meaning, the unnecessary withdrawal of patients should be strictly avoided and all 
necessary measures should be taken to prevent withdrawals/discontinuations from IMP treatment. 
In case of the occurrence of any CV event, the Investigator will be encouraged to let the patient 
continue in the trial as per protocol if this is not considered to constitute a safety concern. 
 
a Note: In the UK, the following paragraph is applicable instead: 
In case a patient is lost to follow-up, despite every attempt (e.g., certified mail, telephone contact of patient or patient 
relatives) to get in contact, the vital and medical status of the patient should be investigated an additional last time at 
the end of the trial for that patient (i.e. 12 months after Visit 1), by accessing the patient’s hospital records, or publicly 
available sources such as national registries and newspaper obituaries. Attempts may also be made to contact the 
patient or his relatives to ascertain this information. However, the patients have the right to withdraw their consent for 
collection of this information at any time, without the need to justify their decision. 


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Reasons for discontinuation from the trial or treatment with IMP include: 
• Significant non-compliance to trial protocol, as judged by the Investigator and/or the 
Sponsor 
• Other medical or safety reasons, as judged by the Investigator and/or the Sponsor 
Patients discontinued from the trial will not be replaced. 


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5 
TREATMENTS 
5.1 
Treatments Administered 
A treatment flow chart is provided in Table 2. 
Patients randomized to degarelix will receive: 
Start of treatment (Month 0): 
• A starting dose of 240 mg degarelix at a concentration of 40 mg/mL, administered as 
subcutaneous (s.c.) injections in the abdominal region via two equivalent injections of 
120 mg each. The volume of each injection is 3.0 mL. 
Month 1-11: 
• Eleven (11) maintenance doses of 80 mg degarelix at a concentration of 20 mg/mL, 
administered at monthly (28-day) intervals as s.c. injections in the abdominal region via one 
injection of 80 mg, i.e. the volume of each injection is 4.0 mL. 
Detailed administration guidelines for degarelix are given in the current national FIRMAGON 
label. 
Patients randomized to leuprolide will receive: 
Start of treatment (Month 0): 
• One dose of 22.5 mg leuprolide, administered as a single i.m. injection according to the 
directions for use in the manufacturer’s current national label. The volume of the injection is 
1.5 mL. 
Month 1-11: 
• Three (3) doses of 22.5 mg leuprolide, administered as i.m. injections every 3 months 
(Month 3, 6, and 9) according to the directions for use in the manufacturer’s current national 
label. The volume of each injection is 1.5 mL. 
5.2 
Characteristics and Source of Supply 
All IMPs are provided by the Sponsor and will be handled according to the principles of Good 
Manufacturing Practice (GMP). 
Degarelix 
Degarelix is provided as commercially available kits for Starting Dose and Maintenance Dose: 
• Starting Dose kit contains 2 sets of: 120 mg vial with powder for injection, prefilled syringe 
with 3 mL Sterile Water for Injection, vial adapter and administration needle (2 x 3.0 mL is 
withdrawn to deliver 240 mg degarelix at a concentration of 40 mg/mL) 


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• Maintenance Dose kit contains 1 vial with 80 mg powder for injection, prefilled syringe 
with 4.2 mL Sterile Water for Injection, vial adapter and administration needle (4.0 mL is 
withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL) 
Leuprolide 
Leuprolide acetate is provided as commercially available kits containing one prefilled dual chamber 
syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a 
suspension intended as an i.m. injection for 3-month administration (LUPRON DEPOT 22.5 mg). 
5.3 
Packaging and Labelling 
Packaging and labelling of the IMPs will be performed under the responsibility of the Sponsor’s 
IMP Department in accordance with GMP and national regulatory requirements. 
Country-specific labels of the IMPs will be used. The labels will contain a self-adhesive tear-off 
portion to be affixed to the drug dispensing log maintained at the trial site. All products will be 
uniquely numbered with IMP number. 
5.4 
Conditions for Storage and Use 
The Investigator will ensure that the IMP will be stored in appropriate conditions in a secure 
location with controlled access. The temperature in the storage compartment will be monitored 
regularly and the values shall be documented. Deviations in storage temperature must be reported 
without delay, and the IMP must not be used until further instructions from the Sponsor are 
received. 
The products must be stored and handled in accordance with the commercial product label 
information. 
5.5 
Blinding / Unblinding 
This is an assessor-blind trial. As described in Section 3.5.3, adjudication and classification of CV 
events for primary endpoint analysis will be performed by an external independent CEC Committee 
(Section 3.4.1) throughout the trial. Adjudicated MACE data for the pre-planned and unblinded 
interim analysis of the primary endpoint (Section 9.9) will be transferred directly from the CEC 
Committee to the DSMB (Section 3.4.2) in order to keep those data blinded to the Sponsor. 
5.6 
Treatment Compliance 
5.6.1 
Dispensing and Accountability 
The IMPs will only be dispensed to patients who meet the eligibility criteria and are randomized to 
a treatment group in the trial. The IMP will be administered to the patient by authorized dedicated 
trial drug administrators at the trial sites. 


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The allocation of the IMP kits will be done through an Interactive Response Technology system. 
The administration of IMP should be documented at the site in the subject dispensing log. This is to 
include IMP kit number, batch numbers, expiration date and date and time of administration. 
The dedicated monitor (a Sponsor representative) will verify the drug accountability during the 
trial. IMP carton kits (secondary packaging only) will be saved for drug accountability. 
5.6.2 
Assessment of Compliance 
The IMP will be administered to the patient by authorized trial staff at the trial sites. 
Overdoses and medication errors with and without clinical consequences must be reported as 
adverse events (Section 8.1). In presence of clinical reactions these must be reported as separate 
adverse events. In absence of clinical reactions this must be specified (Section 8.2.2). 
5.7 
Auxiliary Supplies 
The Sponsor will provide the trial sites with needles, and other auxiliaries needed for preparation 
and administration of the IMP. 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
All used IMP is to be destroyed at the trial site in accordance with local legislation after the drug 
accountability has been finalized and signed-off by the Investigator. If the IMP cannot be destroyed 
at the trial site it can be sent back to Warehouse/Sponsor after drug accountability has been 
finalized and signed-off by the Investigator. 
All unused IMP will be returned for destruction, as instructed by the IMP Department at the 
Sponsor and in accordance with local requirements, after the drug accountability has been finalized. 


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6 
TRIAL PROCEDURES 
6.1 
Trial Flow Chart 
All patients must receive verbal and written information about the trial before entering the trial. 
Trial-related procedures must not be performed on a patient before the informed consent has been 
signed. The Investigator is obliged to keep logs of all screened and randomized patients. A flow 
chart of trial procedures and assessments per visit is provided in Table 1 and a treatment flow chart 
is presented in Table 2. All trial assessments are detailed in Section 7. 
 


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Table 1 
Flow Chart of Assessments 
 
Screening 
Treatment / Follow-up Period 
End-of-
Treatment l 
End-of-
Trial 
Visit number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
14 
Month  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
Days from Visit 2 
Within 
21 days 
prior to 
Visit 2 
0 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
 
336 
 
Visit window (days) 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±7 
Signed informed consent a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CVD history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
History/stage/histology of prostate 
cancer/ECOG b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Radiographic imaging b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of IMP 
 
--- See separate treatment flow chart (Table 2)--- 
 
 
IPSS d 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PRO e 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Health economics f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Treatment / Follow-up Period 
End-of-
Treatment l 
End-of-
Trial 
Visit number  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
14 
Month  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
Days from Visit 2 
Within 
21 days 
prior to 
Visit 2 
0 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
 
336 
 
Visit window (days) 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±7 
12-lead ECG g 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital signs (pulse and blood pressure) g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling: g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Testosterone n 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X m 
- Clinical chemistry 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
- Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
- Glycemic evaluation h 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
- Metabolic evaluation i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
- PSA 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X m 
  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
Urine collection g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changes in concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events, including CV-related 
signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End-of-Trial form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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a) 
Signed informed consent must be obtained prior to any trial-related procedure. 
b) 
Stage of prostate cancer should be based on clinical assessment and radiographic imaging (e.g. bone scan, MRI or CT performed as per standard clinical practice at the discretion of the 
Investigator) and should have been done within 3 months prior to randomization. If no radiographic image is available at the time of screening, a bone scan should be performed as part of the 
screening procedures. These data must be available for trial documentation before randomization. 
c) 
The bone scan at the End-of-Trial visit (or End-of-Treatment visit) as part of the PFS endpoint follow-up can be performed up to 7 days before the actual visit.  
d) 
The IPSS questionnaire should be completed by the patient before the PRO questionnaires DASI, CAQ and EQ-5D-5L. 
e) 
PRO questionnaires: 1) DASI, 2) CAQ, and 3) EQ-5D-5L. The questionnaires should be completed in the given order. 
f) 
Health economics: CV-related hospitalization events, CABG/PCI procedures and ER visit events. 
g) 
ECG, vital signs, blood sampling, and urine collection must be performed prior to dosing. The results from the Screening visit must be available prior to randomization. 
h) 
Glycemic evaluation at the Screening visit: HbA1c in all patients (fasting not needed). Glycemic evaluation at Visit 2 and at the End-of-Trial visit: plasma glucose and serum insulin. The blood 
samples must be taken while the patient is in fasting state, i.e. minimum of 8 hours without caloric intake. 
i) 
Metabolic evaluation: total cholesterol, HDL-cholesterol, low density lipoprotein LDL-cholesterol, triglycerides and uric acid. The blood samples must be taken while the patient is in fasting 
state, i.e. minimum of 8 hours without caloric intake. 
 
 
 
 
l) 
Patients who prematurely discontinue treatment with IMP, or receive prohibited medication (Section 4.3.2), should be called in for an end-of-treatment visit as soon as possible (within 30 days) 
after a decision of treatment discontinuation has been taken. Following the End-of-Treatment visit, the patient will be followed-up as described in Section 4.4. 
m) Blood sampling for analysis of testosterone and PSA should not be done in patients who have discontinued treatment with IMP and have performed an end-of-treatment visit. 
n) 
Due to diurnal variations in testosterone level, patients with a screening serum testosterone level <150 ng/dL can be re-tested with laboratory results available prior to randomization, at the 
discretion of the Investigator. 
Abbreviations: CABG, Coronary Artery By-Pass Grafting; CAQ, Cardiac Anxiety Questionnaire; CT, Computed Tomography; CV, Cardiovascular; DASI, Duke Activity Status Index; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EQ-5D-5L, EuroQol Group 5 Dimensions 5 Levels Questionnaire; ER, emergency room; HbA1c, hemoglobin A1c (glycosylated 
hemoglobin); HDL, high density lipoprotein; 
 IMP, Investigational Medicinal Product; IPSS, International Prostate 
Symptom Score; LDL, low density lipoprotein; MRI, magnetic resonance imaging; 
 PCI, percutaneous coronary intervention; PFS, Progression-
Free Survival; PRO Patient Reported Outcome; PSA, Prostate-Specific Antigen. 
 


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Table 2 
Treatment Flow Chart 
 
Screening 
Treatment/Follow-up Period 
End-of-Trial 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Month 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Days from 
Visit 2 
Within 21 
days 
prior to 
Visit 2 
 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Treatment 
window 
 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Degarelix group 
Degarelix, s.c. a 
 
2x 
120 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
80 mg 
 
Leuprolide 
group 
Leuprolide, i.m. b 
 
22.5 mg 
 
 
22.5 mg 
 
 
22.5 mg 
 
 
22.5 mg 
 
 
 
a) 
Degarelix starting dose, Visit 2: two s.c. depot injections, each containing 120 mg of degarelix (i.e. the starting dose will be 240 mg). The volume of each injection is 3.0 mL.  
Degarelix maintenance doses, Visits 3-13: a single s.c. depot injection containing 80 mg of degarelix. The volume of each injection is 4.0 mL. 
b) 
Leuprolide patients: one leuprolide 22.5 mg 3-month depot injected i.m. according to label recommendations, every 3 months throughout the trial. The volume of each injection is 1.5 mL. 
Abbreviations: i.m., intramuscular; s.c., subcutaneous. 


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6.2 
Visit 1 (Screening) 
Patients will be screened within 21 days prior to randomization for compliance with the inclusion 
and exclusion criteria. 
The following must take place at Visit 1: 
• Signed and dated written informed consent, obtained prior to any trial-related procedures 
• Allocation of a screening number 
• Check of inclusion and exclusion criteria (those which are possible to check at screening) 
• Demographics (age, ethnicity, race) 
• Collection of the following data: 
– Medical history 
– CVD history using Medical / CV History Request Form 
• Vital signs (pulse and blood pressure) 
• Physical examination 
• History/stage/histology of prostate cancer should be based on clinical assessment and 
radiographic imaging. Bone scan (MRI or CT may be performed as per standard clinical 
practice at the discretion of the Investigator) should be performed within 3 months prior to 
randomization 
• Blood collection for central laboratory analysis of (Note: The result must be available prior 
to randomization.): 
– Testosterone (Due to diurnal variations in testosterone level, patients with a screening 
serum testosterone level <150 ng/dL may be re-tested prior to randomization, at the 
discretion of the Investigator.) 
– PSA 
– Clinical chemistry and hematology parameters  
– HbA1c  
 
 
 
• Urinalysis (dipstick) (Note: The result must be available prior to randomization.) 
• Recording of use of any concomitant medication (within the last 12 months prior to signed 
informed consent for participation in the trial) 
• Adverse events, including CV-related signs 
Patients considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit (Visit 2). 


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6.3 
Visit 2 (Month 0) 
The following must take place prior to randomization: 
• Ensure that the patient is still eligible for participation in the trial (including any changes in 
use of concomitant medications)  
• Check those inclusion and exclusion criteria that were not possible to fully check during 
screening 
Patients fulfilling all inclusion criteria and none of the exclusion criteria will proceed to 
randomization by an electronic system and thereby be allocated 1:1 (Section 4.2.2) to one of the 
two treatment groups. 
The following must take place after randomization, but before administration of the first dose 
of IMP (degarelix or leuprolide): 
• IPSS 
• PRO (DASI, CAQ and EQ-5D-5L) 
• Health economics (CV-related hospitalization events, CABG/PCI procedures and ER visit 
events) 
• Body measurements (body weight, waist and hip circumference, and height) 
 
 
• 12-lead electrocardiogram (ECG) 
• Vital signs (pulse and blood pressure) 
• Blood collection for central laboratory analysis of: 
– PSA 
– Clinical chemistry and hematology parameters  
– Glycemic and metabolic parameters (Note: The blood samples must be taken while 
the patient is in fasting state, i.e. minimum of 8 hours without caloric intake.) 
 
 
 
 
 
• Urinalysis (dipstick) 
Once the above has been completed, the following must be performed by the drug administrator: 
• Dispense and administer IMP (degarelix or leuprolide) according to randomization and 
treatment flow chart (Table 2) 
• Dispense anti-androgen therapy to metastatic patients randomized to receive leuprolide in 
cases where this is prescribed for flare protection, at the discretion of the Investigator. 


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Finally, the following must be recorded before the patient leaves the clinic: 
• Drug accountability 
• Adverse events, including CV-related signs 
6.4 
Visit 3 (Month 1) to Visit 13 (Month 11) 
6.4.1 
Visit 3 (Month 1) to Visit 13 (Month 11) - All Visits 
The procedures described in this section must take place at all visits (i.e. once monthly) from 
Visit 3 to Visit 13. 
The following must take place before administration of IMP: 
• Vital signs (pulse and blood pressure) 
• Health economics (CV-related hospitalization events, CABG/PCI procedures and ER visit 
events) 
Once the above has been completed, the following must be performed by the drug administrator: 
• Dispense and administer IMP (degarelix or leuprolide) according to randomization and 
treatment flow chart (Table 2) 
Finally, the following must be recorded before the patient leaves the clinic: 
• Drug accountability  
• Changes in use of concomitant medication 
• Adverse events, including CV-related signs 
6.4.2 
Visit 3 (Month 1) and Visit 8 (Month 6) 
• Blood collection (prior to dosing) for central laboratory analysis of: 
– Testosterone 
– Clinical chemistry parameters 
• 12-lead ECG 
6.4.3 
Visit 3 (Month 1), Visit 4 (Month 2), Visit 5 (Month 3), Visit 8 (Month 6) and 
Visit 11 (Month 9) 
 
 
 
6.4.4 
Visit 5 (Month 3), Visit 8 (Month 6), and Visit 11 (Month 9) 
The following additional procedure is recommended to be performed before any other 
assessments at Visits 5, 8 and 11: 
• IPSS 


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The following additional procedure must be performed before administration of IMP at 
Visits 5, 8 and 11: 
• Blood collection for central laboratory analysis of: 
– PSA 
6.4.5 
Visit 8 (Month 6) 
The following additional procedures are recommended to be performed before any other 
assessments at Visit 8: 
• PRO (DASI, CAQ and EQ-5D-5L) 
6.5 
End-of-Treatment Visit 
Patients who prematurely discontinue treatment with IMP, or receive prohibited medication 
(Section 4.3.2), should be called in for an end-of-treatment visit as soon as possible (within 
30 days) after a decision of treatment discontinuation has been taken. 
The following must take place at the End-of-Treatment visit: 
• IPSS 
• PRO (DASI, CAQ and EQ-5D-5L) 
• Health economics (CV-related hospitalization events, CABG/PCI procedures and ER visit 
events) 
• 12-lead ECG 
• Vital signs (pulse and blood pressure) 
• Blood collection for central laboratory analysis of: 
– Testosterone 
– PSA 
– Clinical chemistry and hematology parameters  
– Glycemic and metabolic parameters (Note: The blood samples must be taken while 
the patient is in fasting state, i.e. minimum of 8 hours without caloric intake.) 
• Urinalysis (dipstick) 
• Body weight, waist and hip circumference 
 
 
• Physical examination 
• Radiographic imaging (bone scan). (Imaging can be performed up to 7 days before the End-
of-Treatment visit.) 
• Drug accountability 
• Recording of any change in use of concomitant medication 


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• Recording of adverse events, including CV-related signs 
• Inform the patient about the planned follow-up and End-of-Trial visit 
Following the End-of-Treatment visit, the patient will be followed-up as described in Section 4.4. 
6.6 
End-of-Trial Visit / Visit 14 (Month 12) 
Patients should be called in for an end-of-trial visit after 336 days of participation in the trial. 
The following must take place at the End-of-Trial visit: 
• IPSS 
• PRO (DASI, CAQ and EQ-5D-5L) 
• Health economics (CV-related hospitalization events, CABG/PCI procedures and ER visit 
events) 
• 12-lead ECG 
• Vital signs (pulse and blood pressure) 
• Blood collection for central laboratory analysis of: 
– Testosterone (Note: Not in patients who have discontinued treatment with IMP and 
have performed an end-of-treatment visit.) 
– PSA (Note: Not in patients who have discontinued treatment with IMP and have 
performed an end-of-treatment visit.) 
– Clinical chemistry and hematology parameters  
– Glycemic and metabolic parameters (Note: The blood samples must be taken while 
the patient is in fasting state, i.e. minimum of 8 hours without caloric intake.) 
 
 
 
• Urinalysis (dipstick) 
• Body weight, waist and hip circumference 
 
 
• Physical examination 
• Radiographic imaging (bone scan). (Imaging can be performed up to 7 days before the End-
of-Trial visit.) 
• Drug accountability 
• Recording of any change in use of concomitant medication 
• Recording of adverse events, including CV-related signs 
• Completion of End-of-Trial form 


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6.7 
Unscheduled Visits 
The patient may be called in for additional unscheduled visits due to safety reason at the discretion 
of the Investigator or the Sponsor, unless the patient has withdrawn his consent. The patient may 
also contact the site due to safety reason for an unscheduled visit. The unscheduled visit may 
include additional collection of blood samples for safety reasons. The unscheduled visit may also 
include additional assessments deemed necessary by the Investigator such as laboratory samples, 
ECGs, or other procedures which were missed at a previous visit. All unscheduled visits should be 
described (including the reason for the visit) and documented in the medical/source record, and in 
the eCRF. 


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7 
TRIAL ASSESSMENTS 
7.1 
Assessment Related to Primary Endpoint and Key Secondary Endpoints 
7.1.1 
Clinical Events Classification 
Collection of CV-related adverse events will be performed from Visit 2 until the End-of-Trial visit 
as described in Section 8.2.3. An external CEC Committee will be established for the trial to 
provide an independent and blinded adjudication of CV events (see Section 3.4.1). A two-phase 
review process will be used and the adjudicated MACEs will be used for the primary endpoint 
analysis and the pre-planned interim analysis performed by the DSMB. The complete adjudication 
process and CV endpoint definitions are detailed in a CEC charter provided in a separate document. 
Cardiovascular endpoint definitions are also provided in Appendix 1. 
Final analysis of CV endpoint data is solely the responsibility of the trial statistician and will thus 
be independent of the CEC Committee, the Investigators and site personnel as well as the patients. 
7.2 
Assessments Related to Other Secondary Endpoints 
7.2.1 
Prostate Cancer-Related Assessments 
7.2.1.1 
Testosterone 
Blood samples for monitoring of serum testosterone levels will be collected at screening (Visit 1), 
at Visits 3 and 8 and at the End-of-Trial visit. The blood sampling must be performed prior to 
dosing. The analysis of testosterone will be performed by central laboratories. 
Due to diurnal variations in serum testosterone level, patients with a screening serum testosterone 
level <150 ng/dL may be re-tested for eligibility prior to randomization, at the discretion of the 
Investigator. 
Note: At the End-of-Trial visit, blood sampling for analysis of serum testosterone should not be 
performed in patients who have discontinued treatment with IMP and have performed an 
end-of-treatment visit where blood sampling for serum testosterone has been performed. 
7.2.1.2 
Progression-Free Survival 
Prostate-Specific Antigen 
Blood samples for analysis of PSA, as part of the PFS endpoint, will be collected at screening 
(Visit 1), at baseline (Visit 2), and every 3 months until the End-of-Trial visit (Visit 14). The blood 
sampling must be performed prior to dosing. The analysis of PSA will be performed by central 
laboratories. 
Note: At the End-of-Trial visit, blood sampling for analysis of PSA should not be performed in 
patients who have discontinued treatment with IMP and have performed an end-of–treatment visit 
where blood sampling for PSA has been performed. 


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Radiographic Imaging 
A bone scan follow-up will be performed in all patients at the End-of-Trial visit (or End-of-
Treatment visit) as part of the PFS endpoint. The bone scan can be performed up to 7 days before 
the actual visit. 
In addition, radiographic imaging (e.g. bone scan, MRI or CT performed as per standard clinical 
practice at the discretion of the Investigator) may be conducted in order to confirm suspected 
metastases as part of the PFS endpoint during the trial. 
7.2.1.3 
International Prostate Symptom Score 
The most common symptom of prostate cancer is urinary obstruction with lower urinary tract 
symptoms (LUTS). Lower urinary tract symptoms will be measured with the IPSS Version 1 
(standard version; IPSS-1) at baseline (Visit 2) and at Visits 5, 8 and 11 and at the End-of-Trial 
visit. At visits where PRO questionnaires also are to be completed the IPSS should be completed 
before the PRO questionnaires. 
The IPSS is a tool commonly used to assess severity of LUTS, and also to monitor progress of the 
disease process once therapy has been initiated. The patient will complete a questionnaire 
containing seven questions regarding incomplete emptying, frequency, intermittency, urgency, 
weak stream, straining, and nocturia. Each question will be assigned a score of 0 to 5. A score of 
“0” corresponds to a response of “not at all” for the first six symptoms and “none” for nocturia, and 
a score of 5 corresponds to a response of “almost always” for the first six symptoms and “5 times or 
more” for nocturia. The IPSS-1 includes an additional single question to assess a patient’s QoL in 
relation to his urinary symptoms; the response to this question is analyzed separately and is not 
included in the total IPSS score. 
7.2.2 
Health Economics 
7.2.2.1 
Cardiovascular-Related Hospitalizations 
Cardiovascular-related hospitalizations will be recorded at each visit from Visit 2 until the End-of-
Trial visit. 
7.2.2.2 
Total Coronary Artery By-Pass Grafting and Percutaneous Coronary 
Intervention Procedures 
Coronary artery by-pass grafting and PCI procedures will be recorded at each visit from Visit 2 
until the End-of-Trial visit. 
7.2.2.3 
Emergency Room Visit Events 
Emergency room visit events (that do not lead to hospitalizations) will be recorded at each visit 
from Visit 2 until the End-of-Trial visit. 


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7.2.3 
Patient-Reported Outcomes 
The PRO questionnaires are recommended to be completed before any other assessments are 
performed, by the patient in a quiet place without influence from trial personnel or accompanying 
family or friends. The trial personnel are not to help the patient choose an answer and must neither 
interpret nor rephrase questions which patients do not understand. 
At visits where the IPSS (Section 7.2.1.3) is to be completed, the IPSS should be completed before 
the PRO questionnaires. The PRO questionnaires should then be completed in the following order: 
1) DASI, 2) CAQ, and 3) EQ-5D-5L. 
After completion of the questionnaires, the trial personnel will review the document for 
completeness only and enter the data into the eCRF. The patient should be given the opportunity to 
complete the questionnaire if this was not done in the first place, before leaving the site.  
The questionnaires are validated for multinational use and will be provided in the local languages, 
as applicable. 
7.2.3.1 
Duke Activity Status Index and Cardiac Anxiety Questionnaire 
The DASI and CAQ will be assessed at baseline (Visit 2), at Visit 8 and at the End-of-Trial visit. 
The DASI is a self-administered instrument developed to measure functional capacity of CV 
patients. It contains 12 items referring to the present time assessing the ability to perform physical 
tasks in five domains: personal care (1 item), ambulation (4 items), household tasks (4 items), 
sexual function (1 item) and recreation (2 items). Each question is answered by one of four options: 
“yes with no difficulty” / “yes, but with some difficulty” / “no, I can’t do this” / “don’t do this for 
other reasons”. A global score is calculated with a higher score indicating a higher functional 
capacity. 
The CAQ is a self-administered questionnaire developed to measure heart-focused anxiety in 
persons with or without heart disease. It contains 18 items referring to the present time assessing 
cardiac anxiety in three domains: fear (8 items), avoidance (5 items) and attention (5 items). Each 
question is assigned a score between 0 “never” to 4 “always”. A global score and scores per domain 
are computed with higher score indicating greater cardiac anxiety. 
7.2.3.2 
EQ-5D-5L 
The EQ-5D-5L will be assessed at baseline (Visit 2), at Visit 8 and at the End-of-Trial visit. 
EQ-5D-5L is a standardized measure of health status developed in order to provide a simple, 
generic measure of health for clinical and economic appraisal (http://www.euroqol.org/home.html.). 
EQ-5D-5L essentially consists of 2 systems - the EQ-5D-5L descriptive system and the EQ visual 
analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the following 
5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ 
VAS is an overall estimation of the present health status. An EQ-5D-5L health status estimation 


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may be converted to a single summary index by applying a formula that essentially attaches 
weights to each of the levels in each dimension. This formula is based on the valuation of EQ-5D-
5L health status from general population samples in each country. Conversion from EQ-5D-5L into 
Quality Adjusted Life Year (QALY) units will create data for pharmacoeconomic evaluations of 
degarelix, as described in Section 9.6.3.13. 
7.2.4 
Safety Endpoints 
7.2.4.1 
Adverse Events 
Adverse events will be recorded from Visit 1 until the End-of-Trial visit. Adverse events that occur 
before the administration of the first dose of IMP at Visit 2 will be regarded as pre-treatment 
adverse events. For each adverse event the following parameters are recorded on the Adverse Event 
Log: description of event, date and time of onset, intensity, causal relation to IMP, action taken to 
IMP, other actions taken, seriousness of the adverse event, date and time of outcome, and outcome. 
Definitions are provided in Section 8.1. 
Data on suspected CV-related adverse events (except for pre-treatment events) will be delivered to 
the CEC Committee before the adjudication of MACE takes place (Sections 7.1.1 and 3.4.1). 
Potential CV-related adverse events will be closely followed. 
In case of IMP treatment discontinuation, the patient should be followed for the entire duration of 
the trial for recording of adverse CV events (Section 4.4). 
7.2.4.2 
Vital Signs 
Systolic and diastolic blood pressure (mmHg) and pulse (beats per minute) will be measured after 
resting for a minimum of 5 minutes in a sitting position at each visit throughout the trial. 
Assessments of vital signs must be performed prior to dosing if a dosing visit is scheduled. 
At Visit 2, the systolic and diastolic blood pressure must not exceed 180 mmHg or 110 mmHg, 
respectively. If the initial reading exceeds these values, a second reading may be taken two or more 
hours later; the patient may be included (if all other inclusion criteria are met) in the trial if the 
second reading demonstrates a systolic blood pressure ≤180 mmHg and the diastolic blood pressure 
is ≤110 mmHg. If the blood pressure is brought to 180 mmHg systolic or less and 110 mmHg 
diastolic or less by antihypertensive treatment, the patient can become eligible. 
Vital sign measurements outside normal ranges will be assessed as ‘abnormal, not clinically 
significant’, or ‘abnormal, clinically significant’ by the Investigator. ‘Abnormal, clinically 
significant’ measurements at the Screening visit will be recorded as medical history. ‘Abnormal, 
clinically significant’ changes in vital sign measurements will be reported as adverse events. 
The process of evaluating potential CV-related vital signs is described in the CEC Charter in a 
separate document. Data on suspected CV-related vital signs will be delivered to the CEC 
Committee before the adjudication of MACE takes place (Sections 7.1.1 and 3.4.1). Potential 
CV-related vital sign results will be closely followed. 


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7.3 
Other Assessments 
7.3.1 
Demographics 
Demographic data will be collected at the Screening visit and will include date of birth, ethnicity 
and race. 
7.3.2 
Body Measurements 
Body weight (without overcoat and shoes) will be measured at baseline (Visit 2) and at the End-of-
Trial visit. 
The patient’s height (without shoes) will be measured at baseline (Visit 2). 
 
 
 
 
 
Abnormal, clinically significant changes of body measurements will be reported as adverse events. 
Data on potential suspected CVD-related body measurements will be delivered to the CEC 
Committee before the adjudication of MACE takes place (Sections 3.4.1 and 7.1.1). 
7.3.3 
Medical History Including Cardiovascular Disease History 
Information on clinically significant previous and concomitant illnesses, other than prostate cancer, 
or any clinically significant signs or symptoms that are present before informed consent or findings 
from assessments and examinations done during screening will be recorded as medical history at 
the Screening visit. For planned procedures/hospitalizations during the trial, documentation should 
be completed at the time of the Screening visit. 
The patients’ CVD history will be collected by using a pre-specified Medical / CV History Request 
Form, which will be sent to the patients’ CV specialist. The patient’s eligibility will be based on the 
source documents received from the CV specialist. 
7.3.4 
Histology, Treatment History (or Previous Therapy), Stage of Prostate Cancer and 
Eastern Cooperative Oncology Group (ECOG) Score 
The date of diagnosis of prostate cancer, stage of prostate cancer, and information on previous 
prostate cancer therapy will be recorded in the eCRF at the Screening visit. Moreover, the ECOG 
performance status will be assessed for eligibility. 
Stage of the patient’s prostate cancer prior to randomization will be based on clinical assessment 
and radiographic imaging (e.g. bone scan, MRI or CT performed as per standard clinical practice at 


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the discretion of the Investigator). Radiographic imaging should be performed within 3 months 
prior to randomization, and will be classified according to the TNM classification. In case no 
radiographic image is available prior to screening, a bone scan will be performed as part of the 
screening procedures. The TNM staging data must be available for trial documentation before 
randomization. The TNM stage both at the time of prostate cancer diagnosis and at the time of the 
Screening visit of this trial will be recorded. 
For patients having undergone radical prostatectomy, pre-treatment TNM stage will be recorded.  
Histology of the prostate cancer will be reported using Gleason grading. An appropriate Gleason 
grade for each of the two most predominant patterns will be recorded. 
The ECOG performance status will be assessed according to the following scale (Oken, 1982): 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
 
 
 
 
7.3.6 
Electrocardiogram 
In this trial, 12-led ECG recordings will be performed at Visits 2, 3, 8, and at the End-of-Trial visit. 
The ECG must be performed after resting supine for 5 minutes and prior to dosing. The ECG 
measurements will include heartbeat, PR, QRS and QT intervals and T and U wave. 
All ECG recordings will be evaluated according to normal clinical practice without any central 
ECG reading. The clinical significance of the ECG recording will be evaluated as ‘Normal’, 
‘Abnormal, not clinically significant’, or ‘Abnormal, clinically significant’ by the Investigator or a 
cardiologist. 
Additional unscheduled ECG recordings may be performed if deemed necessary by the 
Investigator. All unscheduled ECG recordings should be described (including the reason for the 
ECG recording) and documented in the medical/source record, and in the eCRF. 


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In case of any CV event that is to be submitted to the CEC Committee for MACE adjudication 
(Sections 7.1.1 and 3.4.1), any unscheduled ECG recording that has been performed should be sent 
to the CEC Committee and the baseline ECG is to be attached as a reference of pre-event status for 
comparison. For patients without CV event during the course of the trial, no analysis on ECG 
changes will be done. 
Potential CV-related abnormal ECG results will be closely followed. 
7.3.7 
Physical Examination 
Physical examinations will be performed by the Investigator or a delegated Sub-Investigator (MD, 
Medical Doctor; DO, Doctor of Osteopathic Medicine; PA, Physician Assistant; NP, Nurse 
Practitioner) and must not be delegated to any other trial site personnel. The same individual should 
preferably perform all physical examinations for a patient during the course of the trial. 
A physical examination will be performed at the Screening visit and at the End-of-Trial visit for all 
patients. Abnormal, clinically significant findings at the Screening visit will be recorded as medical 
history. Abnormal, clinically significant changes in physical examination findings will be reported 
as adverse events. 
7.3.8 
Concomitant Medications / Therapies 
Information on concomitant medication therapies, including surgical procedures, will be collected 
at each visit throughout the trial. Concomitant medications are defined as any medication taken by 
the patient at entry or during the trial, other than the IMPs (Section 5.1). 
In case of IMP treatment discontinuation, the patient should be followed for the entire duration of 
the trial for recording of concomitant medications (Section 4.4). 
7.3.9 
Clinical Laboratory Variables 
Blood samples for clinical laboratory analyses will be collected at the time points indicated in  
Table 1. The clinical laboratory variables to be evaluated are presented in Table 3. The analyses of 
clinical laboratory variables will be performed at a central laboratory using appropriate and 
validated methods. 
Urine samples for urinalysis, will be collected at the Screening visit, at Visit 2 (prior to dosing), and 
at the End-of-Trial visit. The samples will be analyzed using a dipstick test at the clinic. 
Blood samples for assessment of safety laboratory variables (clinical chemistry and hematology) 
will be collected at the Screening visit, at Visit 2 (prior to dosing) and at the End-of-Trial visit. In 
addition, blood samples for assessment of clinical chemistry will be collected at Visits 3 and 8 to 
allow for periodic safety monitoring for QT prolongation. 
Blood samples for glycemic evaluations will be collected at the Screening visit, at Visit 2 and at the 
End-of-Trial visit. At the Screening visit, HbA1c (glycosylated hemoglobin) will be tested in all 


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patients to rule out uncontrolled diabetes (HbA1c>10%). Fasting plasma glucose and fasting serum 
insulin are to be measured at Visit 2 and at the End-of-Trial visit. 
Blood samples for metabolic evaluations will be collected at Visit 2 and at the End-of-Trial visit. 
The patients have to be in fasting state (minimum of 8 hours without caloric intake) prior to blood 
sampling for glycemic and metabolic evaluations at Visit 2 and at the End-of-Trial visit. 
The total amount of blood, including blood samples for exploratory analyses (Section 7.3.10), 
planned to be collected from each patient during the course of the trial is approximately 200 mL. In 
case a patient is performing an unscheduled visit, an additional amount of blood might be taken 
(approximately 20 mL per visit, if applicable). 
Table 3 
Clinical Laboratory Variables 
Glycaemia 
Metabolism 
Clinical Chemistry 
Hematology 
Urinalysis 
Hemoglobin 
A1c (HbA1c) 
Total cholesterol 
Albumin 
Hematocrit 
Blood 
Fasting plasma 
glucose 
High density 
lipoprotein (HDL)-
cholesterol 
Alkaline phosphatase 
(ALP) 
Hemoglobin 
Glucose 
Fasting serum 
insulin 
Low density 
lipoprotein (LDL)-
cholesterol 
Alanine 
aminotransferase (ALT) 
Mean cell hemoglobin  
concentration (MCHC) 
Ketones 
 
Triglycerides 
Calcium 
Mean cell volume (MCV) 
Leucocytes 
Uric acid 
Creatinine 
Platelet count 
pH 
 
Gamma-glutamyl 
transferase 
Reticulocytes 
Protein 
Potassium 
Red blood cell (RBC) count 
Nitrites 
Sodium 
White blood cell (WBC) count 
with differential count: 
o 
Neutrophils 
o 
Eosinophils 
o 
Basophils 
o 
Lymphocytes 
o 
Monocytes 
 
Total bilirubin 
Urea/BUN 
(blood/urea/nitrogen) 
 
 
The Investigator will review the laboratory results and evaluate and document whether the results 
are normal or abnormal and whether abnormal results are non-clinically or clinically significant. 
The Laboratory Report will be signed and dated by the Investigator. ‘Abnormal, clinically 
significant’ laboratory values will be reported as adverse events. 
In case of a CV event, data on suspected CV-related abnormal laboratory findings will be delivered 
to the CEC Committee before the adjudication of MACE takes place (Sections 3.4.1 and 7.1.1). 


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Potential CV-related laboratory results will be closely followed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 
Handling, Storage and Destruction of Biological Samples 
Blood samples will be handled in accordance with local regulations. 
Central laboratories will be used for analysis of all blood samples for clinical laboratory analyses in 
this trial (Section 7.3.9). Sampling tubes, material for shipment of the samples, and a laboratory 
manual detailing all sample collection and shipment procedures will be provided and distributed to 
the trial sites by the central safety laboratory. 
 
 
 
 
 
 
Urine samples will be analyzed at the clinic using a urine dipstick test (Section 7.3.9). 


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8 
ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient participating in a clinical trial. It 
includes: 
• Any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP. 
• Any laboratory abnormality, vital sign or finding from physical examination assessed as 
clinically significant by the investigator (findings from assessments and examinations done 
during Screening are not adverse events, but are recorded as medical history) 
• Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures. 
• Overdoses and medication errors with and without clinical consequences. 
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The Investigator must monitor the condition of the patient throughout the trial from the time of 
obtaining informed consent until the last visit. Adverse events will be recorded from the time point 
of obtaining signed informed consent until the End-of-Trial visit. Any concomitant illnesses, other 
than prostate cancer, or any clinically significant signs or symptoms that are present at the 
Screening visit (Visit 1) will be recorded as medical history (Section 7.3.3). Adverse events that 
occur before administration of the first dose of IMP at Visit 2 will be regarded as pre-treatment 
adverse events. 
The sources of adverse events cover: 
• 
The patient’s response to general questions about his health (a standard non-leading 
question such as “How have you been feeling since your last visit?” is asked at each visit) 
• 
Symptoms spontaneously reported by the patient 
• 
Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities 
• 
Other information relating to the patient’s health becoming known to the Investigator 
8.2.2 
Recording of Adverse Events 
The Investigator must record all adverse events in the Adverse Event Log provided in each 
patient’s eCRF with information about: 
• Adverse event 


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• Date and time of onset  
• Intensity 
• Causal relationship to IMP 
• Action taken to IMP 
• Other action taken 
• Date and time of outcome (time can be omitted, if applicable) 
• Outcome 
• Seriousness 
• Relation to prostate cancer progression 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
Adverse Event 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record. 
The patient may contact the trial site for an unscheduled visit due to safety reasons. The patient may 
also be contacted by the site for an unscheduled visit in case of an important safety signal (e.g. an 
abnormal laboratory value), unless he has withdrawn his consent. Any such unscheduled visits will 
be captured in the eCRF under unscheduled visits. Unscheduled visits are detailed in Section 6.7. 
If a patient suffers from the same adverse event more than once and the patient recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event should be applied.b 
Note the following: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalization is not an adverse event; the reason for hospitalization is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event). 
 
b  
Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse 
event) changes in intensity, this must be recorded as two separate events. The initial adverse event should be 
recorded with outcome “not yet recovered” and the date and time of outcome is when the intensity changed. 
The second adverse event should be recorded with date and time of onset when the intensity changed.  
 


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Date and Time of Onset 
The date and time of onset is the date and time when the first sign(s) or symptom(s) were first 
noted. If the adverse event is an abnormal clinically significant laboratory test or outcome of an 
examination, the onset date is the date the sample was taken or the examination was performed.  
Intensity / Common Terminology Criteria for Adverse Events Grading Scale 
The Investigator must grade each adverse event according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) (version 4.02). According to this 
guidance document all adverse events are rated on a 5-point scale corresponding to mild, moderate, 
severe, life-threatening or disabling and death. The guidance document will be provided to each 
trial site. 
Each adverse event must be graded according to the specific criteria for grading as described in the 
CTCAE. For events not described in the CTCAE the following criteria will be used: 
• Grade 1: Mild (minor; no specific medical intervention; asymptomatic laboratory findings 
only; marginal clinical relevance) 
• Grade 2: Moderate (minimal intervention: local intervention; non-invasive intervention) 
• Grade 3: Severe (significant symptoms, requiring hospitalization or invasive intervention; 
transfusion; elective interventional radiological procedure; therapeutic endoscopy or 
operation) 
• Grade 4: Life-threatening or disabling (complicated by acute, life-threatening metabolic or 
CV complications such as circulatory failure, hemorrhage, sepsis. Life-threatening 
physiologic consequences; need for intensive care or emergent invasive procedure; 
emergent interventional radiological procedure, therapeutic endoscopy or operation) 
• Grade 5: Death 
Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following: 
• Reasonable possibility:  
There is evidence or argument to suggest a causal relationship between the IMP and the 
adverse event. The adverse event may occur as part of the pharmacological action of the 
IMP or may be unpredictable in its occurrence. 
Examples:  
o 
Adverse events that are uncommon but are known to be strongly associated with IMP 
exposure. 
o 
Adverse events that are not commonly associated with IMP exposure, but the event 
occurs in association with other factors strongly suggesting causation, such as a strong 
temporal association or the event recurs on rechallenge. 


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• No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal relationship between the 
IMP and the adverse event. 
Examples: 
o 
Known consequences of the underlying disease or condition under investigation. 
o 
Adverse events common in the trial population, which are also anticipated to occur with 
some frequency during the course of the trial, regardless of IMP exposure. 
Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the 
following: 
• No change (medication schedule maintained or no action taken) 
• Withdrawn 
• Interrupted, e.g. in case of hospitalization 
Other Action Taken 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the patient. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log. 
Date and Time of Outcome 
The date and time the patient recovered or died. 
Outcome 
The outcome of an adverse event must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering 
• Not yet recovered 
• Fatal 


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8.2.3 
Cardiovascular-Related Adverse Events 
The objective and scope of the present trial is to investigate the short-term risk of CV events in 
patients with pre-existing CVD. Thus, CV- related adverse events and any worsening in CV status 
will be recorded from Visit 2 until the End-of-Trial visit and will be captured separately in the 
eCRF. 
At each monthly visit/contact with the patient, the Investigator must obtain information about: 
• Admission to hospital or ER since last visit 
• Death 
• Admission for chest pain (ischemic) symptoms that could be an unstable angina or 
myocardial infarction event 
• Admission for new neurological symptoms that could be a cerebrovascular (stroke) event 
• Any drawn creatinine kinase (CK), creatine kinase-muscle brain (subunit) (CK-MBs) or 
troponin samples since last visit 
The information obtained should be entered in the eCRF. In case pre-defined items on the eCRF 
checklist are answered affirmatively, a specific clinical endpoint form in the eCRF relating to each 
of the questions that were answered “yes”, must be completed by the site personnel. 
The following questions should be addressed directly to patients when reviewing this checklist at 
every monthly visit/contact: 
Were you admitted to the hospital or visited the emergency department since your last visit/contact 
with us? 
• If you were admitted to the hospital or visited the emergency department, was it due to 
symptoms such as chest pain (feeling of tightness, heavy pressure, squeezing or crushing 
pain), shortness of breath, nausea, fatigue, dizziness, or profuse sweating? These symptoms 
may have occurred at rest or during exercise. 
• If you were admitted to the hospital or visited the emergency department, was it due to 
symptoms such as sudden onset of weakness or difficulty in coordinating muscles needed to 
speak (slurred speech), difficulty swallowing, visual impairment (you could not see well), or 
numbness or weakness of legs or arms (you could not properly lift or move your arms or 
legs)? 
• If you were admitted to the hospital or visited the emergency department do you recall if the 
physician who treated you collected your blood to check if your heart muscle was damaged? 
Data on potential CV-related adverse events will be delivered to the CEC Committee before the 
adjudication of MACEs take place (Sections 3.4.1 and 7.1.1). Potential CV-related adverse events 
will be closely followed. 


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In case of premature discontinuation of treatment with IMP or premature trial discontinuation, the 
patient should be followed for recording of CV events as described in Section 4.4. 
8.2.4 
Pregnancy and Pregnancy Outcome 
In cases in which a foetus may have been exposed through transmission of the IMP via semen 
following paternal exposure, and the pregnancy results in an abnormal outcome (birth 
defect/congenital anomaly) this must be reported as a serious adverse event (SAE) to Global 
Pharmacovigilance (Section 8.3.2.1). 


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8.3 
Serious Adverse Events 
8.3.1 
Serious Adverse Event Definition 
Serious Adverse Events During the Trial 
An event is defined an SAE if 
it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a patient 
enrolled in a trial is per se not an event, but an outcome. 
is life-threatening 
The term life-threatening refers to an adverse event in which the patient was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe. 
requires in-patient hospitalization 
or prolongation of existing 
hospitalization 
The term hospitalization means that the patient was admitted to hospital or that 
existing hospitalization was extended as a result of an event. Hospitalization 
describes a period of at least 24 hours. Over-night stay for observation, stay at 
ER or treatment on an out-patient basis do not constitute a hospitalization. 
However, medical judgment must always be exercised and when in doubt the 
case should be considered serious (i.e. if case fulfils the criterion for a 
medically important event). Hospitalizations for administrative or social 
purposes do not constitute an SAE. Hospital admissions and/or surgical 
operations planned before trial inclusion are not considered adverse events, if 
the illness or disease existed before the patient was enrolled in the trial, 
provided that the condition did not deteriorate during the trial. 
results in persistent or significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgment by the investigator. 
is a congenital anomaly/birth 
defect 
Congenital anomaly/birth defect observed in any offspring of the patient 
conceived during treatment with the IMP. 
is an important medical event 
Important medical events are events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of important medical events include adverse 
events that suggest a significant hazard, contraindication or precaution, 
occurrence of malignancy or development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether 
events qualify as medically important. 
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product. Any organism virus or infectious particle (e.g. 
prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a patient exposed to a 
medicinal product. 


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8.3.2 
Collection, Recording and Reporting of Serious Adverse Events 
8.3.2.1 
Serious Adverse Event Reporting by the Investigator 
All SAEs, except potential non-fatal MACEs (Section 8.3.2.2), must be reported immediately to 
the Global Pharmacovigilance Department at the Sponsor as soon as it becomes known to the 
Investigator and not later than within 24 hours of their knowledge of the occurrence of an SAE. 
The Investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE. 
In this trial, the SAE form is part of the eCRF and will be submitted electronically. 
eCRF information regarding demographics, adverse events, medical history and concomitant 
medication is mandatory for initial reports and for follow-up reports if any changes have been 
made since the initial report. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the eCRF), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to the Global 
Pharmacovigilance Department at the Sponsor using the contact details below. In any case this 
information must be supplied by the Investigator upon request from the Sponsor. On any copies 
provided, such details such as patient’s name, address, and hospital ID number should be concealed 
and instead patient number should be provided. The Investigator will supply the Sponsor and the 
IRB/REB/IEC with any additional requested information such as results of post-mortem 
examinations and hospital records. 
In case the eCRF cannot be accessed and hence the SAE Report Form cannot be filled in within the 
eCRF system, a paper SAE Report Form should be used and sent to the Global Pharmacovigilance 
Department at the Sponsor using the contact details below. The information on the form must be 
transferred to the eCRF when the eCRF system has become accessible. 
Contact Details for Serious Adverse Event Reporting 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
Address:
 
E-mail: 
 
Fax: 
 
8.3.2.2 
Protocol Specific Exceptions to Serious Adverse Event Reporting 
Specified CV-related endpoint events in the trial will be recorded in their respective appropriate 
modules of the eCRF. For these events, all necessary information, including whether or not the 
event meets the definition of “serious”, will be collected in the eCRF. These events will NOT also 
require reporting as SAEs as described in Section 8.3.2.1. Specifically, the events covered in this 
exception are as follows: 


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• Myocardial infarction 
• Stroke 
• Unstable angina 
All events leading to death should be reported as an SAE. 
The DSMB will monitor suspected CV-related endpoint data and other safety data to ensure the 
safety of patients in the trial. 
8.3.2.3 
Expedited Reporting by the Sponsor 
The Sponsor will report all adverse events that are serious, unexpected and with a reasonable 
possible causality to the IMP as judged by either the Investigator or the Sponsor to all 
investigators and to IRB/REB/IEC (responsibility Clinical Research & Development, Ferring 
Pharmaceuticals A/S) and to regulatory authorities (responsibility Global Pharmacovigilance, 
Ferring Pharmaceuticals A/S) within the stipulated timelines. The expectedness is assessed by the 
Sponsor according to the Prescribing Information of the IMPs. 
In addition, adverse events identified by the Investigator or as potential CV-related signs will, 
regardless of causality, be provided by the Sponsor to the CEC Committee for adjudication 
(Sections 3.4.1 and 7.1.1). 
Serious adverse events will be considered reportable regardless of whether or not the IMP was used 
in accordance with the provisions in the trial protocol and labelling. 
8.4 
Follow-up of Adverse Events and Serious Adverse Events 
8.4.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the Investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the patient is stable. 
After the patient’s last visit, the Investigator must follow-up on adverse events that occurred during 
the trial and are classified as serious or as related to the IMP until it is resolved or until the medical 
condition of the patient is stable. All such relevant follow-up information must be reported to the 
Sponsor. If the event is a chronic condition, the Investigator and the Sponsor may agree that further 
follow-up is not required. 
In case a patient is lost to follow-up, the vital and medical status of the patient at the end of the trial 
should be investigated as described in Section 4.4. 
8.4.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit 
If the Investigator becomes aware of an SAE after the patient’s last trial visit, and he/she assesses 
the SAE to have a reasonable possible causality to the IMP, the case will have to be reported to the 
Sponsor, regardless how long after the end of the trial this takes place. 


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9 
STATISTICAL METHODS 
The Global Biometrics Department of the Sponsor will be responsible for the statistical analyses. 
All analyses will be detailed in a separate SAP. 
9.1 
Determination of Sample Size 
The primary objective is to assess the effect of degarelix on the risk of MACEs (a composite of 
death due to any cause, non-fatal myocardial infarction or non-fatal stroke) occurring during a 
1-year period as compared to treatment with a GnRH receptor agonist (leuprolide) in patients with 
prostate cancer and pre-existing CVD. 
As suggested by a post-hoc analysis of degarelix safety data the 1-year event rates for a CV event 
or death due to any cause are 5.3% and 12.1% for degarelix and leuprolide, respectively, in the 
global patient population with prior CVD. This would correspond to an unadjusted treatment-
related hazard ratio of 0.42. In comparison, the adjusted hazard ratio is 0.39 (95% confidence 
interval = [0.21; 0.71]). Furthermore, based upon the re-assessment of the potential CV events 
captured in the degarelix safety data by an independent cardiologist, the 1-year event rates for CV 
event or death due to any cause are 4.8% and 9.3% for degarelix and leuprolide respectively. This 
corresponds to an unadjusted hazard ratio of 0.50. In comparison, the adjusted hazard ratio is 0.48 
(95% confidence interval [0.23; 0.87]). Accounting for the uncertainty in the post-hoc analysis of 
the global pooled data and the re-assessment of the potential CV events by a single independent 
cardiologist, the 1-year event rates for sample size calculations are set to 5.1% and 10.2% for 
degarelix and leuprolide, respectively. This corresponds to a hypothesized hazard ratio of 0.49. 
9.1.1 
Trial Design 
One interim analysis (detailed in Section 9.9) is planned after 50% of the confirmed, adjudicated 
MACE endpoints has been collected. Due to the possibility of stopping the trial early for futility, an 
alternative hypothesis of a hazard ratio of 0.49 and 80% power, 66 events are required at final 
analysis, corresponding to 876 patients, in order to reject the null hypothesis of equal hazards at the 
two-sided 5% Type I error level. Note that the trial will not be stopped early due to an 
overwhelming treatment benefit. 
9.1.2 
Adjustments for Sample Size Re-Estimation 
The conditional power for different sample size increases will be evaluated at the interim using 
ADDPLAN™ 6. In case of a sample size increase, the final test statistic is adjusted by using the 
normal inverse method. This in order to protect the two-sided Type I error rate at 5%. 
The sample size calculations are performed with ADDPLAN™ 6, licensed by ADDPLAN, Inc., an 
Aptiv Solutions company and presented in Table 5. 


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Table 5 
Sample Size Calculations (Number of Events Rounded Upwards) 
Information 
Rate 
Accept H0 
Reject H0 
α spent 
Power 
Achieved 
Events 
Test 
Statistic 
Hazard 
Ratio 
Conditional 
Power 
Test 
Statistic 
 
 
50% 
0.7 
0.78 
8.5% 
 
<0.0001 
 
33 
100% 
1.96 
0.61 
 
1.96 
0.025 
80% 
66 
 
9.2 
Patient Disposition 
All patients screened and randomized will be accounted for. All post-randomization 
discontinuations will be summarized by time of, and reason for, discontinuation. The number of 
patients screened and not randomized will be presented with the reason(s) for screen failure. 
The number of patients screened and randomized will be provided. 
9.3 
Protocol Deviations 
Protocol deviations will be classified as either ‘important’ or ’non-important’. Important protocol 
deviations will be summarized by category and treatment group for the Full Analysis Set (FAS) to 
reflect general protocol adherence. No protocol deviations will lead to exclusion of data from the 
efficacy analyses. Individual important protocol deviations will be listed by patient.  
9.4 
Analysis Sets 
9.4.1 
Intention-to-Treat Analysis Set 
The Intention-to-Treat (ITT) analysis set consists of all randomized patients, and will be analyzed 
based on the planned (randomized) treatment. 
9.4.2 
Full Analysis Set 
The FAS consists of all randomized and treated patients (who received at least one dose of IMP), 
and will be analyzed based on the planned (randomized) treatment. 
9.4.3 
Safety Analysis Set 
The safety analysis set consists of all treated patients (who received at least one dose of IMP), and 
will be analyzed based on the actual treatment received. 
9.5 
Trial Population 
The trial population will be described for the FAS population. 
9.5.1 
Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics and medical history will be 
presented by treatment group for the FAS. In addition, summary of demographic and baseline 


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characteristics will be presented by trial site.
 
 
Abnormal baseline ECG results (Section 7.3.6) will be listed by patient and trial site. 
9.5.2 
Medical History and Concomitant Medication 
Medical history will be coded using MedDRA (version 17.1 or later) and tabulated by System 
Organ Class (SOC) and preferred term for the different analysis populations by treatment group. 
Concomitant medication will be coded using the Anatomical Therapeutic Chemical (ATC) 
classification system (World Health Organization [WHO] Drug Dictionary) and tabulated by the 1st 
level (Anatomic) and 2nd level (Therapeutic) for the same analyses sets. 
9.6 
Endpoint Assessments 
9.6.1 
General Considerations 
The analysis of efficacy will be performed for the FAS. Unless otherwise specified, time to event 
endpoints will be censored at the time of treatment discontinuation, initiation of prohibited 
therapies related to hormonal therapy, lost to follow-up/withdrawal from the trial or Day 336, 
whichever occurs first. In addition, all hypothesis tests will be two-sided at a significance level of 
5% and missing data will not be imputed. 95% confidence limits and the associated p-values will be 
presented for estimates of the treatment effect comparing degarelix to leuprolide for all regression 
analyses. P-values will be presented for all non-parametric tests, such as the log-rank test. 
All regression models analyzing the time to MACE or the time to components of the MACE 
composite endpoint will be adjusted for the following CV risk factors measured at baseline: waist 
circumference, body mass index (BMI), 
 blood pressure, diabetes 
status, cholesterol and triglyceride levels. All semi-parametric and non-parametric models will be 
stratified by baseline age group and region. 
9.6.2 
Primary Endpoint 
The primary endpoint, the time from randomization to the first confirmed occurrence of the 
composite MACE endpoint in the two treatment groups, will be analyzed based on the 
Kaplan-Meier estimator of the survival function and the log-rank test stratified for baseline age 
group and region.  
The null hypothesis of equal hazard functions between the two treatment groups will be rejected if 
the test statistic exceeds the critical level for a two-sided hypothesis test with a Type I error level of 
5%. 
All CV events identified by the CEC Committee as adjudicated MACEs will be summarized by 
visit and treatment group and results of statistical analyses will be tabulated as appropriate. 


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In order to examine the robustness of the primary endpoint, the following sensitivity analyses will 
be performed: 
• Time from randomization to the first confirmed (adjudicated) occurrence of non-fatal 
myocardial infarction, non-fatal stroke, non-fatal unstable angina requiring hospitalization, 
or all-cause death  
Time from randomization to the first confirmed (adjudicated) occurrence of non-fatal myocardial 
infarction, non-fatal stroke, non-fatal unstable angina requiring hospitalization, or all-cause death is 
defined similarly as the primary endpoint with the addition of the CV event unstable angina 
requiring hospitalization. Also, the endpoint will be analyzed as for the primary endpoint. 
• Time to first confirmed occurrence of a MACE-related adverse event (myocardial infarction 
SMQ (broad); Central nervous system hemorrhages and cerebrovascular conditions SMQ 
(broad); all-cause death) 
Time to first confirmed occurrence of a MACE-related adverse event is defined as for the primary 
endpoint with events being; any adverse event within the broad SMQ term ‘myocardial infarction’, 
any adverse event within the broad SMQ term ‘Central nervous system hemorrhages and 
cerebrovascular conditions’ or all-cause death. Also, the endpoint will be analyzed as for the 
primary endpoint. 
• Total occurrence of (adjudicated) myocardial infarction, stroke, and all-cause death 
Total occurrence of myocardial infarction, stroke and all cause death is defined as the total number 
of events (myocardial infarction, stroke or death) occurring over the duration of the trial. 
The endpoint will be compared between treatment groups using a negative binomial model. The 
estimated treatment difference with a 95% confidence interval will be presented.  
• Sensitivity analysis pertaining to treatment discontinuation or initiation of prohibited 
therapies related to hormonal therapy  
For the purposes of this sensitivity analysis, patients will NOT be censored at the time of treatment 
discontinuation or initiation of prohibited therapies related to hormonal therapy. Rather, 
information pertaining to all observed occurrences of the first adjudicated MACE in patients 
randomized in the trial will be used. Patients will be censored at lost to follow-up/withdrawal from 
the trial or Day 336, whichever occurs first. 
9.6.3 
Secondary Endpoints 
If, and only if the primary analysis is significant at the two-sided Type I error-level of 5% the 
testing of the secondary endpoints will proceed as described below. 


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Key Secondary Analyses 
The following analyses are included in the family of key secondary analyses: 
• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke 
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
The key secondary endpoints will be controlled for multiplicity (to ensure the family wise error rate 
is protected at a two-sided 5% Type I error-level) using a fixed-sequence testing method. The order 
of the testing sequence is as follows: 
1. Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke   
2. Time from randomization to confirmed (adjudicated) CV-related death 
3. Time from randomization to the first confirmed (adjudicated) myocardial infarction 
Other Secondary Analyses 
The remaining secondary endpoints will be tested outside the scope of the hierarchy; without 
adjustment for multiplicity. 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to the first confirmed (adjudicated) unstable angina requiring 
hospitalization 
• Time from randomization to death due to any cause 
• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment 
groups 
• Time from randomization to failure in PFS 
• Total number of CV-related hospitalization events over the duration of the trial 
• Total number of CABG or PCI procedures over the duration of the trial 
• Total number of CV-related ER visit events over the duration of the trial 
• Changes from baseline in Health-Related Quality of Life (HRQL) as measured by 
EQ-5D-5L, during the course of the treatment period 
• Changes from baseline in PRO instruments will be analyzed longitudinally across the 
treatment period (IPSS and EQ-5D-5L) and cross-sectionally (DASI and CAQ) 
Laboratory data, vital signs, and adverse events will be presented as appropriate. 
Patients’ functional capacity and heart-focused anxiety will be explored by describing DASI and 
CAQ scores at each visit and DASI and CAQ changes scores from baseline to each follow-up visit. 


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In addition, changes in scores over time will be explored and compared between patients treated 
with degarelix and patients treated by leuprolide using repeated measurement models. 
Analyses of outcomes on health economic and PRO instruments will be detailed in the SAP. 
All secondary endpoints will be summarized by visit and treatment group and results of statistical 
analyses will be tabulated as appropriate. Changes from baseline will be presented where 
appropriate. 
9.6.3.1 
Time from Randomization to the First Confirmed (adjudicated) Occurrence of 
Cardiovascular-Related Death, Non-fatal Myocardial Infarction or Non-fatal 
Stroke 
This endpoint is identical to the primary endpoint, only counting CV-related deaths, and not 
all-cause deaths as failures. Time, measured in days, from randomization to the first confirmed 
(adjudicated) occurrence of CV-related death, non-fatal myocardial infarction or non-fatal stroke, 
will be analyzed using the Kaplan-Meier estimator of the survival function and the log-rank test of 
the null hypothesis of equal hazard functions, stratified by age group and region. The p-value of the 
two-sided log-rank test with significance level of 5% will be presented along with plots of the 
estimated survival functions for the two treatment groups, stratified by age group and region. The 
treatment effect of degarelix will be further examined by fitting a stratified Cox regression model. 
The model will include treatment as a factor, be adjusted for the baseline CV risk factors and 
stratified by age-group and region. The 95% confidence limits and associated p-value for the hazard 
ratio comparing treatment with degarelix to leuprolide will be presented. 
9.6.3.2 
Time from Randomization to the First (adjudicated) Occurrence of the Individual 
Components of the MACE Composite Endpoint 
Time from randomization to the first adjudicated occurrence of the individual components of the 
MACE composite endpoint is defined as the number of days from randomization to the first 
adjudicated myocardial infarction / stroke. The occurrence of the components of the MACE 
composite endpoint will be adjudicated by the external independent CEC Committee. In order to 
correctly assess the treatment effect associated with degarelix with respect to the time to individual 
components of the MACE composite endpoint, it is necessary to account for the competing risk, 
death due to other causes. The above components of the MACE composite endpoint will be 
analyzed separately. The log-rank test stratified by age-group and region will be used to examine 
the null hypothesis of equal cumulative cause specific hazard functions. The p-value of the 
two-sided log rank test with significance level of 5% will be presented along with the plots of the 
estimated cumulative cause specific hazard functions for both treatments obtained from the 
Nelson-Aalen estimator, stratified by age group and region. 


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9.6.3.3 
Time from Randomization to Confirmed (adjudicated) Cardiovascular-Related 
Death 
Time from randomization to CV-related death is defined as the number of days from randomization 
to adjudicated CV-related death. Cause of death will be adjudicated by the external independent 
CEC Committee. Undetermined death will be presumed and analyzed as non-CV-related deaths on 
the secondary analysis. The time measured in days, from randomization to adjudicated CV-related 
death, will be analyzed as outlined in Section 9.6.3.2.  
9.6.3.4 
Time from Randomization to the First Confirmed (adjudicated) Unstable Angina 
Requiring Hospitalization  
Time, measured in days, from randomization to first adjudicated hospitalization for unstable angina 
will be analyzed as the individual components of the MACE primary endpoint, as outlined in 
Section 9.6.3.2. 
9.6.3.5 
Time from Randomization to Death Due to Any Cause 
Time from randomization to death due to any cause (overall survival) is defined as the number of 
days from randomization to death. The time measured in days, from randomization to death due to 
any cause, will be analyzed using the Kaplan-Meier estimator of the survival function and the 
log-rank test of the null hypothesis of equal hazard functions, stratified by age group and region. 
The p-value of the two-sided log-rank test with significance level of 5% will be presented along 
with plots of the estimated survival functions for the two treatment groups, stratified by age group 
and region. The treatment effect of degarelix will be further examined by fitting a stratified Cox 
regression model for the time to death from any cause. The model will include treatment as a factor, 
be adjusted for the baseline CVD risk factors as appropriate and stratified by age group and region. 
The 95% confidence limits and associated p-values for the hazard ratio comparing treatment with 
degarelix to leuprolide will be presented. 
9.6.3.6 
Testosterone Levels at Days 28, 168 and 336 in the Degarelix and Leuprolide 
Treatment Groups 
The proportion of patients with testosterone levels ≤0.5 ng/mL at each time point (Days 28, 168 and 
336), as well as the proportion of patients with testosterone levels ≤0.5 ng/mL between Days 28 and 
168 and Days 28 and 336, will be presented descriptively. 
9.6.3.7 
Time from Randomization to Failure in Progression-Free Survival 
Progression-free survival is a composite endpoint consisting of the following conditions: 
• Radiographic disease progression defined as one or more new metastatic skeletal lesions 
observed on bone scan; one or more new metastatic extra-skeletal lesions at least 1.5 cm in 
greatest dimension visible on CT or MRI scan as confirmed by the Investigator. 
• Introduction of additional therapy related to prostate cancer treatment including radiation, 
anti-androgens (except for initial flare protection) and second-line treatment. 


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• PSA failure defined as an increase in serum PSA of 50%, and at least 5 ng/mL, compared to 
nadir, measured on two consecutive occasions at least 2 weeks apart. 
• Death. 
Time to PFS failure is therefore defined as the time, measured in days, from randomization to the 
first occurrence of one of the above composite endpoint criteria. Time to PFS failure will be 
analyzed using the Kaplan-Meier estimator of the survival function and the log-rank test of the null 
hypothesis of equal hazard functions. The p-value of the two-sided log-rank test with significance 
level of 5% will be presented along with plots of the estimated survival functions for the two 
treatment groups. 
9.6.3.8 
International Prostate Symptom Score - Total and QoL Scores 
The severity of LUTS will be investigated by their IPSS-1 score. IPSS-1 is a questionnaire 
containing seven questions regarding incomplete emptying, frequency, intermittency, urgency, 
weak stream, straining and nocturia. Each question is assigned a total score on a scale from 0 to 5. 
The total IPSS-1 score is then calculated as the summation over the responses for all 7 questions. 
The total IPSS-1 score will be transformed to a scale from 0 (lowest score) to 100 (highest score). 
The final question in the IPSS-1 questionnaire regarding QoL in relation to urinary symptoms will 
similarly be scaled from 0 to 100. The change from baseline to Month 3, 6, 9 and 12 in IPSS-1 total 
and QoL score will be compared between treatments longitudinally using repeated measures 
analysis of covariance (ANCOVA). Based on the ANCOVA model the two-sided 95% confidence 
limits of the adjusted treatment contrasts and associated p-values will be provided. 
9.6.3.9 
Total Number of Cardiovascular-Related Hospitalization Events Over the 
Duration of the Trial 
The total number of CV-related hospitalization events over the duration of the trial is defined as the 
number of hospitalizations due to CV-related adverse events, observed during the 12 month 
follow-up period for each patient. The number of adjudicated CV-related hospitalizations, will be 
analyzed using a negative binomial model. The model will include a factor variable for treatment, 
the baseline count of CV-related hospitalizations as a covariate and the logarithm of the number of 
days of follow-up for each patient as an offset. The point estimate and 95% confidence limits of the 
rate ratio comparing the rate of CV-related hospitalizations among the degarelix and leuprolide 
treatment groups will be presented along with the associated p-value. 
9.6.3.10 
Total Number of Coronary Artery By-Pass Grafting or Percutaneous Coronary 
Intervention Procedures Over the Duration of the Trial 
The total number of CABG or PCI procedures observed during follow-up will be analyzed using a 
negative binomial model as outlined in Section 9.6.3.9. 


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9.6.3.11 
Total Number of Cardiovascular-Related Emergency Room Visit Events 
Observed Over the Duration of the Trial 
The total number of CV-related ER visit events observed during follow-up for each patient will be 
analyzed using a negative binomial model as outlined in Section 9.6.3.9. 
9.6.3.12 
Duke Activity Status Index and Cardiac Anxiety Questionnaire Score 
The DASI and CAQ will be assessed at baseline (Visit 2), Visit 8 and at the End-of-Trial visit. The 
change from baseline to Months 6 and 12 in DASI total score as well as CAQ total and domain 
scores will be compared between treatments both cross-sectionally using ANCOVA and 
longitudinally using repeated measures ANCOVA. Based on the ANCOVA models, the two-sided 
95% confidence limits of the adjusted treatment contrasts and associated p-values will be provided. 
9.6.3.13 
Quality Adjusted Life Year 
The EQ-5D-5L questionnaire can be used to estimate the QALY. The QALY is a measure of the 
value of health outcomes. Since health is a function of length of life and QoL, the QALY was 
developed as an attempt to combine the value of these attributes into a single index number. The 
basic idea underlying the QALY is simple: it assumes that a year of life lived in perfect health is 
worth 1 QALY (1 Year of Life × 1 Utility value = 1 QALY) and that a year of life lived in a state of 
less than this perfect health is worth less than 1. The QALY is derived as a cumulative measure for 
the treatment duration as the AUC of the time versus the index value. The AUC will be calculated 
using the trapezoidal rule for each of the visits values in relation to the baseline. 
The mean QALY at the end of the trial (12 months [1 month=28 days]) will be summarized by 
treatment arm and compared using an ANCOVA model, where the QALY is the dependent variable 
with treatment as the comparison factor, respectively. 
9.6.4 
Exploratory Endpoints 
The exploratory endpoint, time from the first non-fatal adjudicated MACE to a second confirmed 
(adjudicated) occurrence of the composite MACE endpoint, is aimed at further investigating the 
risk of CVD outcomes among prostate cancer patients treated with degarelix or GnRH receptor 
agonist. 
Only patients who have experienced one non-fatal MACE, will be considered at risk for a second 
MACE. The event time of interest will be the number of days from the first adjudicated non-fatal 
MACE until the second MACE. The endpoint will be analyzed via a Cox-type proportional 
intensity model. In essence the analysis is akin to the proposed conditional analysis of recurrent 
events (Prentice, 1981) with a modification made based on the definition of the composite MACE 
endpoint. The model will be adjusted for the CVD risk factors measured at baseline, e.g. 
 
 blood pressure, triglyceride levels, BMI, waist circumference, diabetes 
status, and age. Based on the Cox-type proportional intensity model, the two-sided 95% confidence 
limit of the adjusted relative rate for the treatment effect of degarelix compared to the GnRH 
receptor agonist will be provided alongside the associated p-value. Significant results will be 


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interpreted cautiously, as randomization will not provide protection against imbalance of potential 
baseline CVD risk factors not adjusted for in the model, among the two groups at risk for a second 
MACE. The treatment effect of degarelix compared to leuprolide with respect to the rate of MACEs 
will be further explored via an Andersen-Gill model. The risk set for the Andersen-Gill model 
includes all patients who are under observation and at-risk for a MACE, i.e. the Andersen-Gill 
model incorporates information from all observed MACEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7 
Extent of Exposure and Treatment Compliance 
Treatment compliance will be assessed on a by-patient basis by a listing of deviations from the 
doses to be administered per protocol and from the scheduled dosing intervals. 
The cumulated dose administered to each patient will be determined and summarized descriptively. 
9.8 
Safety 
9.8.1 
General Considerations 
Safety parameters will be evaluated for the safety analysis set (Section 9.4.3). 
9.8.2 
Adverse Events 
Adverse events will be tabulated by SOC and preferred term using MedDRA version 17.1 or later. 
The total number of patients reporting an adverse event, the percentage of patients (%) with an 
adverse event, and the number of events (E) reported will be presented. Adverse events will be 


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classified according to their intensity (using CTCAE version 4.02) and relationship to the IMP by 
the Investigator. 
Adverse events will be regarded as ‘pre-treatment’ if they occur between screening and the initial 
injections with IMP. Adverse events which occur in the time interval from initial dosing to 
3 months after (1 month=28 days) last dosing of IMP will be considered to be ‘treatment-
emergent’. Adverse events will be regarded as ‘post-treatment’ if they occur 3 months 
(1 month=28 days) or more after the last dosing of IMP. 
Written narratives will be issued for all serious adverse events and adverse events leading to 
withdrawal. Missing values will be treated as missing, except for causality of adverse events to trial 
drug. If causality is missing, the adverse event will be regarded as being reasonably possibly related 
to IMP. Related adverse events (judged as being reasonably possibly related to trial drug) will be 
termed adverse drug reactions (ADRs). 
An adverse event overview summary table will be prepared for the safety analysis set. It will 
display the number of patients reporting an adverse event, the percentage of patients (%) with an 
adverse event and the number of events reported for each treatment group. The following categories 
will be displayed: 
• All adverse events 
• Deaths 
• SAEs 
• Severe adverse events (CTCAE grade 3-5) 
• Adverse events leading to withdrawal 
• ADRs 
Summary tables will be prepared for the incidence of treatment-emergent adverse events by 
MedDRA SOC (alphabetically) and preferred term (in decreasing frequency of occurrence). The 
tables will display the total number (N) of patients exposed, and the percentage of patients (%) 
reporting treatment-emergent adverse events. Summary tables will be prepared for: 
• All adverse events 
• Common adverse events (at least 5% of patients) 
• Adverse events by causality (related/unrelated) 
• Adverse events by intensity 
• ADRs by intensity 
• SAEs 
• Adverse events leading to withdrawal 


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Supporting data listings will be provided for: 
• Adverse events sorted by trial site/Investigator/patient number 
• Adverse events sorted by MedDRA SOC and preferred term 
• SAEs 
• Adverse events leading to death 
• Adverse events leading to withdrawal 
• Adverse events adjudicated by the CEC Committee as MACE components 
9.8.3 
Vital Signs 
Mean change and mean percentage (%) change from baseline at End-of-Trial will be presented for 
each vital sign variable. Also, the actual values and changes from baseline in vital signs will be 
tabulated by visit. Incidence of markedly abnormal changes in vital signs values will be 
summarized and results adjudicated by the CEC Committee as MACE components will be listed. 
9.8.4 
Other Safety Variables 
9.8.4.1 
Body Measurements 
Mean change and mean percentage (%) change from baseline at End-of-Trial will be presented for 
body weight, BMI, waist circumference and waist-hip ratio. Incidence of markedly abnormal 
changes in body measurements will be summarized and results adjudicated by the CEC Committee 
as MACE components will be listed. 
9.8.4.2 
Physical Examination Findings 
A listing of patients with abnormal physical examination findings will be presented by body 
system. For all patients in this listing, both baseline and End-of-Trial data will be included for 
comparison. 
9.8.4.3 
Safety Laboratory Variables 
Mean change and mean percentage (%) change from baseline to the End-of-Trial will be presented 
for each laboratory variable. 
Incidence of changes in laboratory values relative to normal reference ranges will be summarized. 
Incidence of changes in urinalysis will be summarized. 
Laboratory results adjudicated by the CEC Committee as MACE components will be listed. 
9.8.4.4 
Electrocardiogram 
Abnormal ECG results (Section 7.3.6) will be listed by patient, visit and trial site. 


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9.9 
Interim Analysis 
One interim analysis is planned to be conducted based on the ITT analysis set when 50% of 
accumulated MACE information has been positively verified by the CEC Committee. Statistical 
information in this setting is proportional to the number of observed MACEs. The interim analysis 
is therefore planned to take place after the 33rd adjudicated MACE endpoint. The objective at the 
interim is to test whether there is any reason to stop early for futility. The futility bound expressed 
in terms of the hazard ratio is 0.78. That is, if the observed hazard ratio is >0.78 the DSMB may 
suggest to stop the trial due to futility. The futility bounds are non-binding. Due to the possibility of 
terminating the trial early based on futility the power is subsequently reduced, i.e. the risk of 
stopping a successful trial is inflated. To maintain the power at 80% the number of required events 
is inflated to 66 and the total number of patients to 876. 
The trial will not be stopped early due to an overwhelming treatment benefit, but in order to 
implement the trial design, an alpha-spending function will be used with a close to zero spending of 
alpha at the interim analysis. 
Based on the evaluation of the hazard ratio, the DSMB will have the option to recommend stopping 
the trial pre-maturely if any of the stopping boundaries are crossed. An O'Brien and Fleming type 
alpha spending function was used to compute the critical values for rejection, or acceptation of null 
hypothesis of equal hazards (Table 5). 
The interim and primary analyses are planned to be performed at the specified information rate 
levels, while the actual recruitment may not be uniform. Therefore, the actual recruitment and 
follow-up periods may have to be adjusted such that the necessary amount of events are observed. 
Increase of Sample Size 
In case the stopping boundaries are not crossed, the required sample size will be reassessed, in 
order to achieve a conditional power of 80% at final data stage, given the current data and the trend 
of hazard rates (i.e. the maximum likelihood estimates). The reassessment of the sample size based 
on conditional power will be calculated using the inverse normal method (Wassmer, 2006), 
implemented in ADDPLAN version 6.0.8 or higher. 
Details regarding the interim analysis are described separately in the SAP. 


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10 
DATA HANDLING 
10.1 
Source Data and Source Documents 
Source Data – International Conference on Harmonization Definition 
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). 
Source Documents - International Conference on Harmonization Definition 
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial). 
Electronic Source Data – FDA Guidance for Industry - Electronic Source Data in Clinical 
Investigations 
If a process is used, by which the subject uses a Data Collection Instrument or an ePRO system, 
which has no prior written or electronic record, to directly record and transmit protocol data to a 
technology service provider database, the service provider database is the source. 
Trial-specific Source Data Requirements – Sponsor 
For each patient allocated to treatment, the Investigator will indicate in the hospital/medical source 
records that the patient participates in this trial and the date of obtaining the informed consent. The 
records should document data on the condition of the patient at the time the patient is enrolled in 
the trial to enable verification of eligibility. Signed and dated informed consent will be stored and 
archived according to local requirements. In addition, the following information, at the minimum, 
will also be recorded in the hospital/medical source records for each patient: 
• Documentation of signed and dated Informed Consent 
• Patient’s name and date of birth 
• Screening/treatment allocation number 
• Trial identification 
• Eligibility of participation in the trial (inclusion/exclusion) 
• Body weight, height, waist and hip circumference 
• Dosing of IMP - dose and administration date 
• Documentation of endpoint questions addressed directly to the patient at each visit/contact 


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• Occurrence of any adverse events/SAEs (including description and duration) 
• Medical history 
• History, stage and histology of prostate cancer, and date of diagnosis 
• History of pre-existing CVD 
• Date of each visit 
• Any concomitant therapy 
• Status of the patient at the End-of-Trial 
• Reason for IMP treatment discontinuation/withdrawal, if applicable 
The following documents collected during the trial should be stored and archived together with the 
patient’s hospital/medical records or in the Investigator File as agreed upon prior to the trial start at 
each trial site: 
• Laboratory print-outs from central laboratory – evaluated, signed and dated by the 
Investigator 
• ECG print-outs/reports – evaluated, signed and dated by the Investigator 
• Patient dispensing logs of IMP 
• Any trial assessment performed 
• Any documentation obtained from other hospitals or medical centers regarding ER 
treatment or CV events 
Examples of data that may be recorded on a paper source not necessarily being hospital/medical 
source records include the following: 
• Evaluations of physical examinations 
• Evaluations of vital signs 
• Collection of laboratory samples 
• Demographics 
• 
 
10.2 
Electronic Case Report Form 
An eCRF system provided by an independent third-party CRO will be used for data capture. The 
system is validated and access at all levels to the system is granted/revoked following Sponsor and 
vendor procedures, in accordance with regulatory and system requirements. 
Data entry into the eCRF system should be done in a reasonable time, preferably within 3 working 
days after each trial visit. The Investigator will approve/authorize the eCRF entries for each patient 
with an electronic signature which is equivalent to a handwritten signature. 


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The eCRF system and the database will be hosted at the independent third party CRO. After the 
trial database is declared clean and released to the statistician, a final copy of the database will be 
stored at the Sponsor. An identical copy of the database will be transferred to the DCRI for 
independent validation of the trial results to support scientific presentations and publications. The 
site investigators will receive a copy of the trial site’s final and locked data (including audit trail, 
electronic signature and queries) as write-protected Portable Document Format (PDF) files 
produced by the independent third party CRO. The PDF-files will be stored on a CD and will be 
provided to the investigator before access to the eCRF is revoked. 
Errors occurring in the eCRF will be corrected electronically. Such corrections/modifications will 
be automatically tracked by an audit trail detailing the date and time of the correction, the reason 
for the correction and the name of the person making the correction. 
10.3 
Use of Patient Reported Outcome Measures Instruments 
An electronic PRO (ePRO) system provided by an independent third-party CRO will be used for 
collecting PRO measures. 
The IPSS, DASI, CAQ, and EQ-5D-5L questionnaires will be collected using an electronic trial 
slate device to be completed by the patient. 
In case of missing assessments, reasons should be recorded by trial personnel in the eCRF: 
questionnaire not given to the patient, patient refusal, lack of time from patient or functional 
limitation from patient to complete the questionnaire. 
Handling of missing assessments and missing data will be detailed in the SAP. 
10.4 
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
department at the Sponsor. The data management plan will be issued before data collection begins 
and will describe all functions, processes, and specifications for data collection, cleaning and 
validation. 
The data management plan will describe captured methods, who is authorized to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including 
timing of transfers), the origin and destination of the data and who will have access to the data at all 
times. 
10.5 
Provision of Additional Information 
On request, the Investigator will provide the Sponsor with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements. 


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11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will review the electronic data capture (EDC) remotely on an ongoing basis 
throughout the trial, will conduct remote monitoring via phone calls with the site on a regular basis 
and will also visit the site periodically. The monitor will contact and visit the Investigator 
periodically to ensure adherence to the protocol, International Conference on Harmonization-Good 
Clinical Practice (ICH-GCP), standard operating procedures and applicable regulatory 
requirements, maintenance of trial-related source records, completeness, accuracy and verifiability 
of eCRF entries compared to source data, verification of drug accountability and compliance to 
safety reporting instructions. 
The Investigator will permit the monitor direct access to all source data, including electronic 
medical records, and/or documents in order to facilitate data verification. The Investigator will co-
operate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
Investigator is expected to be able to meet the monitor during the on-site visits. When the first 
patient is randomized at the trial site a remote monitoring call visit will take place shortly 
afterwards to ensure adherence to the protocol. 
11.2 
Risk-Based and Adaptive Monitoring 
Risk-based monitoring will be applied to this trial. The frequency of the on-site monitoring visits 
will be adapted depending on the risk level of the site and workload. Site risk is based on multiple 
factors including, but not limited to, the quantity of data generated at site, quality of source 
documents, unreported adverse events or SAEs and number of protocol deviations. 
During on-site monitoring visits, the monitor will review medical records for suspected MACEs. 
The focus of on-site source review will be to detect any potential triggers including but not limited 
to: 
− signs and symptoms reported by the patient 
− changes in concomitant medication 
− visits to specialists other than the treating investigator and the assessments performed 
− the site’s adherence to follow-up of patients that discontinued treatment prematurely, and if 
extensive efforts have been given to follow-up with patients that were lost to follow-up as 
described in Section 4.4 
If an unreported adverse event is detected, additional source review will be performed for patient 
data not previously reviewed to minimize the risk of MACEs being missed. 
The risk-based and adaptive monitoring, the source data verification process, and definition of key 
variables to be monitored are described in detail in the Monitoring Plan for the trial. 


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11.3 
Centralized Monitoring 
Centralized monitoring will be in place for the trial with focus on critical variables. Monitoring of 
the patterns of suspected MACE endpoint reporting (triggers) across the participating sites will be 
performed by a statistical team at DCRI. The objective will be to ensure as complete endpoint 
ascertainment as possible by identifying sites with anomalous patterns of reporting suspected 
MACEs. This activity will include the initial development of one or more statistical models, with 
possible modifications of the model(s) as the amount of available data increases. Trigger 
monitoring reports will be generated every other month throughout the trial. These reports will be 
carefully reviewed and applicable measures will be installed if required. 
Additional approaches that will be implemented to ensure complete ascertainment of all potential 
MACEs are carefully delineated in the CEC Charter and include the implementation of structured 
questions that will trigger the reporting of potential MACE (when answered affirmatively) at every 
monthly patient visit, routine surveillance of the safety database to identify pre-selected MedDRA 
Preferred Terms related to the cardiovascular MACE endpoints studied to trigger the reporting of 
MACE endpoints (if not done already), and routine surveillance of the eCRF to query key data 
fields that could trigger the site to report a potential MACE. Details of this process are contained 
within Section 4.5 of the CEC Charter. 
11.4 
Audit and Inspection 
The Investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor mandated by the Sponsor, or to domestic/foreign regulatory inspectors or 
representatives from IRBs/REBs/IECs who may audit/inspect the trial. 
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki and all other relevant regulations. 
The plan is to audit at least 10 (ten) percent of the sites each year of the trial duration. The first site 
audits will be conducted at the first sites entering patients into the trial. Selection of additional sites 
for audit will be based on an ongoing risk assessment, including, but not limited to, parameters such 
as recruitment rate and quality/compliance issues encountered during monitoring and/or auditing. 
The patients must be informed by the Investigator and in the Patient Information/ Informed Consent 
Form that authorized personnel from the Sponsor and representatives from regulatory authorities 
and IRBs/REBs/IECs may wish to inspect their medical records. During audits/inspections the 
auditors/inspectors may copy relevant parts of the medical records. No personal identification apart 
from the screening/randomization number will appear on these copies. 
The Investigator should notify the Sponsor without any delay of any inspection by a regulatory 
authority or IRB/REB/IEC. 


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11.5 
Confidentiality of Patient Data 
The Investigator will ensure that the confidentiality of the patients’ data will be preserved. In the 
eCRF or any other documents submitted to the Sponsor, the patients will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to the Sponsor, e.g. the confidential patient identification 
code and the signed Informed Consent Documents, will be maintained by the Investigator in strict 
confidence. 


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12 
CHANGES IN THE CONDUCT OF THE TRIAL 
12.1 
Protocol Amendments 
Any change to this protocol will be documented in a protocol amendment, issued by the Sponsor, 
and agreed upon by the Co-Primary Investigators and the Sponsor prior to its implementation. 
Amendments may be submitted for consideration to the approving IRBs/REBs/IECs and regulatory 
authorities, in accordance with local regulations. An approval by the IRBs/REBs/IECs is required 
for a substantial amendment, e.g., one which could affect the safety of the patients, or which entails 
a change to the scope/design of the trial. 
Changes to the protocol to eliminate immediate hazard(s) to trial patients may be implemented prior 
to IRBs/REBs/IECs approval/favorable opinion. 
12.2 
Deviations from the Protocol 
Deviations from the Protocol should not occur. If deviations from the protocol occur, the 
Investigator must inform the monitor, and the implications of the deviation must be reviewed and 
discussed. Any deviation must be documented, either as answer to a query in the eCRF, in a 
protocol deviation report or a combination of both. A log of protocol deviation reports will be 
maintained by the Sponsor. Protocol deviation reports and supporting documentation must be kept 
in the Investigator’s File and in the Trial Master File. 
12.3 
Premature Trial Termination 
Both the Investigator (with regard to his/her participation) and the Sponsor reserve the right to 
terminate the trial at any time. Should this become necessary, the procedures will be agreed upon 
after consultation between the two parties. In terminating the trial, the Sponsor and the Investigator 
will ensure that adequate consideration is given to the protection of the best interests of the patients. 
Regulatory authorities and IRBs/REBs/IECs will be informed. 
In addition, the Sponsor reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter patients at an acceptable rate. 


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13 
REPORTING AND PUBLICATION 
13.1 
Clinical Trial Report 
The data and information collected during this trial will be reported in a clinical trial report 
prepared by the Sponsor and submitted for comments and signature to the signatory Investigators. 
13.2 
Confidentiality and Ownership of Trial Data 
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of the Sponsor. The Investigator and any other persons 
involved in the trial will protect the confidentiality of this proprietary information belonging to the 
Sponsor. 
13.3 
Publications and Public Disclosure 
13.3.1 
Publications Committee and Policies 
Prior to the end of the trial, a Publications Committee will be formed to include the trial Primary 
Investigators, other Steering Committee members, and Sponsor representatives. The Publication 
Committee will function as an independent body of scientific and medical experts acting to 
facilitate, encourage, and coordinate the complete and accurate presentation and publication of the 
trial results. The details regarding the processes that will govern the Publications Committee 
activities will be detailed in a separate Publications Committee Charter. 
The Publication Committee will be responsible for the primary multicenter publication, and will 
review and approve other analyses suggested by Steering Committee members, Sponsor 
representatives, or other investigators at participating institutions. The Publication Committee will 
consider each analysis proposal with due regard for the scientific merit of the proposed publication 
with the aim of promoting the dissemination of scientific and medical knowledge. 
Members of the Publication Committee, including Sponsor representatives, will read and 
constructively critique all abstracts and manuscripts prior to submission for presentation or 
publication. The Publication Committee will consider in good faith all comments provided by co-
authors and Sponsor representatives during that review period.  
The Sponsor will make all trial data available for independent statistical validation for the primary 
multicenter presentation and publication and for all other approved analyses.  
All manuscripts approved by the Publication Committee will conform to the Uniform Requirements 
for Manuscript Submitted to Biomedical Journals, including, but not limited to the standards for 
authorship. Authorship will based on the International Committee of Medical Journal Editors 
(ICMJE) criteria (see current official version: www.icmje.org/recommendations). 


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13.3.2 
Public Disclosure Policy 
International Committee of Medical Journal Editors member journals have adopted a trials-
registration policy as a condition for publication. This policy requires that all clinical trials be 
registered in a public, clinical trials registry. Thus, it is the responsibility of the Sponsor to register 
the trial in an appropriate public registry, i.e. www.ClinicalTrials.gov, which is a website 
maintained by the National Library of Medicine (NLM) at the U.S. NIH, and other public registries, 
as required. 


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14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Institutional Review Board / Research Ethics Board / Independent Ethics Committee 
An IRB/REB/IEC will review the protocol and any amendments and advertisements used for 
recruitment. The IRB/REB/IEC will review the Patient Information Sheet and the Informed 
Consent Form, their updates (if any), and any written materials given to the patients. A list of all 
IRBs/REBs/IECs to which the protocol has been submitted and the name of the committee 
chairmen will be included in the clinical trial report. 
14.2 
Regulatory Authorities Authorization / Approval / Notification 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a patient is 
exposed to any trial-related procedure, including screening tests for eligibility. 
14.3 
End-of-Trial and End-of-Trial Notification 
End-of-Trial is defined as the date the last patient performs the last visit in the trial. 
At the end of the trial, the regulatory authorities and IRBs/REBs/IECs will be notified about the 
trial completion according to national requirements. In addition, a summary of the clinical trial 
report, e.g. the synopsis, will be provided when available and within one year of trial completion 
(defined as LPLV). 
14.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), in 
compliance with the approved protocol, ICH-GCP and applicable regulatory requirements. 
14.5 
Patient Information and Consent 
The Investigator (or a medically qualified person delegated by the Investigator) will obtain a freely 
given written consent from each patient after an appropriate explanation of the aims, methods, 
anticipated benefits, potential hazards, and any other aspects of the trial which are relevant to the 
patient’s decision to participate. The trial patient must be given ample time to consider participation 
in the trial, before the consent is obtained. The Informed Consent Documents must be signed and 
dated by the patient and the Investigator who has provided information to the patient regarding the 
trial before the patient is exposed to any trial-related procedure, including screening tests for 
eligibility. 
The Investigator (or the person delegated by the Investigator) will explain that the patient is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for his further care and without the need to justify his decision. 


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Each patient will be asked to permit the Investigator to obtain CVD information and source medical 
documents from the patient’s CV specialist to evaluate and document CVD history for eligibility. 
Each patient will also be asked to permit the Investigator to obtain medical documentation from 
other hospitals or medical centers regarding ER treatment or CV events for the patient during the 
trial period. In addition, each patient will be asked to permit the Investigator to obtain health-related 
follow-up information, e.g. by contacting the patient or his relatives, or access hospital records or 
publicly available sources such as national registries, newspaper obituaries and social networking 
websites, for a period of not more than 12 months after the patient has entered the trial.c 
The patient will receive a copy of the Patient Information and his signed Informed Consent Form 
covering participation in the trial. 
If new information becomes available that may be relevant to the trial patient’s willingness to 
continue participation in the trial, a new Patient Information and Informed Consent Form will be 
forwarded to the IRBs/REBs/IECs (and regulatory authorities, if required). The trial patients will be 
informed about this new information and re-consent will be obtained. 
Each patient will be informed that the Sponsor, monitor(s), quality assurance auditor(s) and other 
representative(s) mandated by the Sponsor, IRB/REB/IEC or regulatory authority inspector(s), in 
accordance with applicable regulatory requirements, may review his source records and data. Data 
protection will be handled in compliance with national/local regulations. 
14.6 
Patient Information Card 
The patient will be provided with a Patient Information Card bearing the following information: 
• That he is participating in a clinical trial 
• That he is treated with GnRH receptor antagonist (degarelix) or GnRH receptor agonist 
(leuprolide) 
• Name and phone number of the Investigator 
• Trial code 
• Name and address of the Sponsor (if required by local regulations) 
The patient will be asked to return the Patient Information Card at the last trial visit, if applicable. 
 
c Note: In the UK, the following paragraph is applicable instead: 
Each patient will be asked to permit the Investigator to obtain CVD information and source medical documents from 
the patient’s CV specialist to evaluate and document CVD history for eligibility. Each patient will also be asked to 
permit the Investigator to obtain medical documentation from other hospitals or medical centers regarding ER 
treatment or CV events for the patient during the trial period. In addition, each patient will be asked to permit the 
Investigator to obtain health-related follow-up information, e.g. by contacting the patient or his relatives, or access 
hospital records or publicly available sources such as national registries and newspaper obituaries, for a period of not 
more than 12 months after the patient has entered the trial. 


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Each patient’s primary care physician and/or specialist will be notified of their participation in the 
trial by the Investigator, if the patient agrees. 
14.7 
Compliance Reference Documents 
The Helsinki Declaration, the consolidated ICH-GCP, and other national laws in the countries 
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct. 


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15 
LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of the Sponsor, the monitor and the Investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The Investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing the IMP in accordance with the approved protocol or an approved amendment, and 
for its secure storage and safe handling throughout the trial. 
15.2 
Liabilities and Insurance 
In case of any damage or injury occurring to a patient in association with the IMP or the 
participation in the trial, the Sponsor has contracted an insurance which covers the liability of the 
Sponsor, the Investigator and other persons involved in the trial in compliance with the laws in the 
countries involved. 


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16 
ARCHIVING 
16.1 
Investigator File 
The Investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the Investigator for at least 15 years (or longer if 
so required by local law) after the completion or discontinuation of the trial, if no further 
instructions are given by the Sponsor. 
The Investigator is responsible for the completion and maintenance of the confidential patient 
identification code which provides the sole link between named patient source records and 
anonymous eCRF and ePRO data. The Investigator must arrange for the retention of this Patient 
Identification Log and signed Informed Consent Documents for at least 15 years (or longer if so 
required by local law) after the completion or discontinuation of the trial. 
No trial site document may be destroyed without prior written agreement between the Investigator 
and the Sponsor. Should the Investigator elect to assign the trial documents to another party, or 
move them to another location, the Sponsor must be notified. Documents may be transferred to the 
Global Quality Assurance of the Sponsor, for example if the Investigator retires and the documents 
no longer can be archived by the site. The Sponsor may also arrange for archiving of the 
Investigator File at an external archive. 
16.2 
Trial Master File 
The Sponsor will archive the Trial Master File in accordance with ICH-GCP and applicable 
regulatory requirements. 


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Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance during 
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Tombal B, Albertsen P, de la Taille A, Malmberg A, Persson B, Olesen TK, Nilsson J. Lower risk 
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EAU March 2013. 
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18 
APPENDIX 1   
Cardiovascular Endpoint Definitions 
 
1 
ENDPOINTS / EVENT DEFINITIONS 
The cardiovascular endpoint definitions given below are based on the 2014 Definitions for 
Cardiovascular Endpoint Events in Clinical Trials1.  
1.1 
Death 
All deaths will be categorized as Cardiovascular, non-Cardiovascular or Undetermined. 
Cardiovascular Death: Cardiovascular Death is defined as death resulting from an acute 
myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death 
due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other 
cardiovascular causes. 
Non-cardiovascular Death: Non-cardiovascular death is defined as any death that is not thought to 
be due to a cardiovascular cause (e.g. cancer related death). Non-cardiovascular deaths will also be 
sub-classified as related to prostate cancer progression or to other causes. 
Undetermined Cause of Death: Undetermined cause of death refers to a death not attributable to 
one of the above categories of cardiovascular death or to a non-cardiovascular cause, due to 
absence of any information (e.g., the only available information is “patient died”). Undetermined 
death will be presumed and analyzed as non-cardiovascular deaths on the secondary analysis. 
1.2 
Myocardial Infarction 
The adjudication of myocardial infarction as a clinical endpoint will consider the occurrence 
relative to a percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). 
(It will also be consistent with the revised American College of Cardiology (ACC) / European 
Society of Cardiology (ESC) myocardial infarction definition document.) 
In the absence of a PCI or CABG, a spontaneous myocardial infarction is defined as: 
 
 
 
 
 


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CONFIDENTIAL 
For patients having a PCI, a myocardial infarction will be defined as: 
CK-MB (or troponin I/T or CK in the absence of CK-MB) >3 x ULN for samples obtained 
within 24 hours of the procedure if the baseline values were normal or at least a 50% increase 
over elevated baseline values that were stable or decreasing or development of new 
pathological Q waves (>0.04 seconds) in at least 2 contiguous leads in the absence of LBBB on 
the ECG. Symptoms of cardiac ischemia are not required. 
After CABG surgery, a myocardial infarction is defined as either: 
CK-MB (or CK in the absence of CK-MB) >5 x ULN for samples obtained within 24 hours of 
the procedure with development of new pathological Q waves in at least 2 contiguous leads in 
the absence of LBBB on the ECG. 
CK-MB (or CK in the absence of CK-MB) >10 x ULN for samples obtained within 24 hours of 
the procedure with or without development of new pathological Q waves in at least 2 
contiguous leads in the absence of LBBB on the ECG. 
Note: For institutions that report an 'intermediate' or 'equivocal' range for biomarker elevation that 
is not definitively associated with myocardial necrosis or infarction then the ULN should be the 
lower value for the necrosis or infarct range, not the 'equivocal' or 'intermediate' range lower 
value. 
1.3 
Unstable Angina Requiring Hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4 
Cerebrovascular Accident (Stroke) 
Stroke is defined as an acute focal neurological deficit of sudden onset that is not due to an 
identifiable non-vascular cause (i.e. brain tumor, trauma, brain procedures, metabolic condition) 
a) that is not reversible within 24 hours or results in death (in <24 hours) 
or  
b) that resolves in<24 hours and is accompanied by clear evidence of a new stroke on cerebral 
brain imaging studies (brain Computed tomography [CT] or Magnetic Resonance Imaging 
[MRI] scans) 
Classification: 
Ischemic Stroke: is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by central nervous system (CNS) infarction. 
Note: Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an 
ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. 
Hemorrhagic Stroke: is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
Note: Subdural hematomas without new neurologic symptoms are intracranial hemorrhagic events 
and not strokes. 
Undetermined Etiology: is defined as an acute episode of focal or global neurological dysfunction 
caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction but with insufficient information to allow categorization as either ischemic or 
hemorrhagic. 
 
 
 
 
 
1  Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular 
Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on C linical Data 
Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol 2015 Jul 28;66(4):403-69. 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Title of trial:  
A Multi-Center, Randomized, Assessor-Blind, Controlled Trial Comparing the 
Occurrence of Major Adverse Cardiovascular Events (MACEs) in Patients 
with Prostate Cancer and Cardiovascular Disease Receiving Degarelix 
(GnRH Receptor Antagonist) or Leuprolide (GnRH Receptor Agonist) 
NCT number: 
NCT02663908 
Sponsor trial code: 
000108  
Date:  
24 Feb 2021  
 
 
 
 
 


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Statistical Analysis Plan 
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CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
A Multi-Center, Randomized, Assessor-Blind, Controlled Trial Comparing the Occurrence of 
Major Adverse Cardiovascular Events (MACEs) in Patients with Prostate Cancer and 
Cardiovascular Disease Receiving Degarelix (GnRH antagonist) or Leuprolide (LHRH 
agonist) 
000108 
IND Number:  
 
 
  051222 
Investigational Medicinal Product : Degarelix powder and solvent for solution for injection 
  Leuprolide acetate 22.5 mg 3 month depot 
Indication: 
 Prostate cancer 
Phase: 
 3b 
Authors: 
 
 
Date of issue: 
24 February 2021 
Version: 
7.0 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group 


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Change log 
 
Version 
No. 
 
Effective 
Date 
 
Reason for the Change / Revision 
 
Supersedes 
  
1 
 
2 
 
 
3 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
        
 
 
Dec 16 – 2015 
 
Dec 18 – 2015 
 
 
 
 
 
 
 
Mar 28 - 2017 
 
 
 
 
 
 
 
 
Nov-18-2019 
 
 
 
 
 
 
 
 
 
 
  
 
 
Original SAP 
 
Format Change only.  No content was 
changed. 
 
The list of major protocol deviations in 
Section 5 was updated to reflect the changes 
to the clinical trial protocol introduced with 
clinical trial protocol amendment #01. 
 
To update the SAP in order to relect the 
revised eligibility criteria for the trial based 
on recommendations from the Steering 
Committee and changes made to the trial 
protocol in agreement with the US Food and 
Drug Administration (FDA) following review 
of the Clinical Trial Protocol Amendment 
number 01, dated 21 September 2016. 
 
The list of key secondary endpoints has been 
revised, and sensitivity endpoint “Time from 
randomization to the first confirmed 
(adjudicated) occurrence of cardiovascular 
death, non-fatal myocardial infarction or non-
fatal stroke” has been added to the list, and 
the testing strategy has been changed from 
Holm’s to a fixed. Also, PP analyses have 
been reduced to primary and exploratory 
endpoints. 
 
 
 
Not Applicable 
 
Version 1.0 
 
 
Version 2.0 
 
 
 
 
Version 3.0 
 
 
 
 
 
 
 
 
Version 4.0 
 


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       6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       7 
 
Sep 30 - 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Feb-24-2021 
 
 
 
 
Due to the trial being terminated early, the 
SAP was updated. The following changes has 
been made to the SAP: 
 
- Due to site errors in randomizations, the 
FAS will be used instead of ITT in order to 
present “correct” denominator  in tables. 
 
- Planned interim analyses have been 
cancelled. 
 
- Various changes to analyses no longer 
affected by the expected interim. 
 
- Sensitivity analyses of the primary endpoint 
including PP analyses have been cancelled. 
 
- Some analyses have been reduced (not 
removed) as deemed unnecessarily extensive, 
others have been slightly altered.  
 
- Analyses regarding markedly abnormal 
laboratory values have been cancelled as 
deem unnecessary by pharmacovigilance. 
 
Sensitivity analyses added to primary 
analysis.  
Slight rewording of some endpoints. 
Endpoint “Total number of emergency room 
(ER) visit events over the duration of the 
trial” changed to “Total number of CV-related 
emergency room (ER) visit events over the 
duration of the trial”. 
Treatment switch definition updated 
according to data collected. 
Important deviations to be summarized. 
General rewordings and clarifications added. 
 
 
Version 5.0 
 
 


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Signed Agreement on Statistical Analysis Plan 
 
 
Author: 
 Statistician, Global Biometrics 
 
The statistical analysis plan was reviewed by, 
 
 Urology, Global Clinical Development, Ferring Pharmaceuticals A/S 
 
 Urology, Global Clinical Development, Ferring 
Pharmaceuticals A/S 
 
 Statistician, Global Biometrics, Ferring Pharmaceuticals A/S 
 
 Statistical Programmer, Global Biometrics, Ferring Pharmaceuticals A/S 
 
 Clinical Trial Manager, Global Clinical Operations, Ferring Pharmaceuticals 
A/S 
 
 Pharmacovigilance physician, Global Pharmacovigilance, Ferring Pharmaceuticals 
A/S 
 
 Medical Writer, Global Medical Writing, Ferring Pharmaceuticals A/S 
 
 
 
The statistical analysis plan was reviewed and approved (signed electronically) by, 
 
 Global Biometrics, Ferring Pharmaceuticals A/S 


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TABLE OF CONTENTS 
1 
Introduction ...........................................................................................................................8 
1.1 
Abbreviations ..................................................................................................................8 
2 
Trial Objectives and Endpoints .............................................................................................. 10 
2.1 
Objectives..................................................................................................................... 10 
2.1.1 
Primary Objective ............................................................................................ 10 
2.1.2 
Secondary Objectives........................................................................................ 10 
2.1.3 
Exploratory Objectives...................................................................................... 11 
2.2 
Endpoints ..................................................................................................................... 11 
2.2.1 
Primary Endpoint ............................................................................................. 11 
2.2.2 
Secondary Endpoints ........................................................................................ 11 
2.2.3 
Exploratory Endpoints ...................................................................................... 12 
3 
Trial design .......................................................................................................................... 13 
The following section details the original trial design. However, the trial was terminated due to 
feasibility problems, with only 545 patients randomized and 14 of those with positively 
adjudicated events. Hence, many of these sections no longer apply. ....................................... 13 
3.1 
General Design Considerations ........................................................................................ 13 
3.2 
Determination of Sample Size .......................................................................................... 13 
3.2.1 
Fixed Trial Design............................................................................................ 14 
3.2.2 
Adjustments for Futility Analyses ....................................................................... 14 
3.2.3 
Adjustments for Sample Size Re-Estimation......................................................... 14 
4 
Patient Disposition ................................................................................................................ 16 
5 
Protocol Deviations ............................................................................................................... 17 
6 
Analysis Sets ......................................................................................................................... 18 
6.1 
Intention-To-Treat Analysis Set ....................................................................................... 18 
6.2 
Full Analysis Set............................................................................................................ 18 
6.3 
Safety Analysis Set ........................................................................................................ 18 
7 
Trial Population .................................................................................................................... 19 
7.1 
Demographics and Other Baseline Characteristics ............................................................... 19 
7.1.1 
Demographics.................................................................................................. 19 
7.1.2 
Vital Signs at Baseline ...................................................................................... 19 
7.1.3 
History and Stage of Prostate Cancer................................................................... 19 
7.1.4 
 20 
7.1.5 
Laboratory Efficacy / Pharmacodynamic Parameters at Baseline ............................. 20 
7.2 
 20 
7.2.1 
 20 
7.3 
 20 
7.4 
Physical Examination ..................................................................................................... 21 
8 
Exposure and Treatment Compliance ..................................................................................... 22 
8.1 
Extent of Exposure ......................................................................................................... 22 
8.2 
Treatment Compliance .................................................................................................... 22 
9 
Efficacy ................................................................................................................................ 23 
9.1 
General Considerations ................................................................................................... 23 


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9.2 
Primary Endpoint ........................................................................................................... 24 
9.2.1 
Primary Endpoint Analysis ................................................................................ 24 
9.2.2 
Sensitivity Analyses ......................................................................................... 25 
9.2.2.1 
Sensitivity Analysis: Time from randomization to the first confirmed 
(adjudicated) occurrence of non-fatal myocardial infarction, non-fatal 
stroke, non-fatal unstable angina requiring hospitalization, or all-
cause death ..................................................................................... 25 
9.2.2.2 
Sensitivity Analysis: Time to first confirmed occurrence of a MACE 
related adverse event (MI SMQ (broad); Central nervous system 
hemorrhages and cerebrovascular conditions SMQ (broad); all-cause 
death) ............................................................................................ 25 
9.2.2.3 
Sensitivity Analysis: Total occurrence of (adjudicated) myocardial 
infarction, stroke, and all-cause death ................................................. 25 
9.2.2.4 
Sensitivity Analysis pertaining to treatment discontinuation or 
initiation of prohibited therapies related to hormonal therapy.................. 25 
9.3 
Secondary Endpoints ...................................................................................................... 25 
9.3.1 
Time from randomization to the first confirmed (adjudicated) occurrence of 
cardiovascular-related death, non-fatal myocardial infarction or non-fatal stroke ........ 26 
9.3.2 
Time From Randomization to the first (adjudicated) occurrence of the individual 
components of the MACE composite endpoint...................................................... 27 
9.3.3 
Time from randomization to the first confirmed (adjudicated) unstable angina 
requiring hospitalization .................................................................................... 28 
9.3.4 
Time From Randomization to Death Due to Any Cause ......................................... 28 
9.3.5 
Time from Randomization to confirmed (adjudicated) Cardiovascular-Related 
Death ............................................................................................................. 28 
9.3.6 
Time from Randomization to Failure in Progression-Free Survival .......................... 29 
9.3.7 
Testosterone levels at day 28, 168 and 336 in patients treated with degarelix and 
leuprolide........................................................................................................ 30 
9.3.8 
Total number of Cardiovascular-Related Hospitalizations over the duration of the 
trial ................................................................................................................ 30 
9.3.9 
Total number of Coronary Artery By-Pass Grafting or Percutaneous Coronary 
Intervention Procedures over the duration of the trial ............................................. 30 
9.3.10 
Total number of Cardiovascular-Related Emergency Room Visit Events 
Observed over the duration of the trial ................................................................. 31 
9.3.11 
Difference in Quality Adjusted Life Year (QALY) During One Year of Treatment..... 31 
9.3.12 
Change from Baseline in Mean Total and QoL International Prostate Symptom 
Score during One Year of Treatment ................................................................... 32 
9.3.13 
Change from Baseline in the Mean Duke Activity Status Index and Cardiac 
Anxiety Questionnaire Score during One Year of Treatment ................................... 32 
9.4 
Exploratory Endpoints .................................................................................................... 33 
9.4.1 
Time from First Adjudicated MACE to Second Confirmed Adjudicated MACE......... 33 
9.4.2 
 34 
9.4.3 
 
 
 34 
10 Safety ................................................................................................................................... 35 
10.1 General Considerations ................................................................................................... 35 


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10.2 Adverse Events.............................................................................................................. 35 
10.2.1 
Overview of Treatment-Emergent Adverse Events ................................................ 35 
10.2.2 
Incidence of Adverse Events .............................................................................. 36 
10.3 Safety Laboratory Variables ............................................................................................ 37 
10.3.1 
Summary Statistics ........................................................................................... 37 
10.3.2 
Laboratory Variable Changes Relative to Normal Range ........................................ 38 
10.3.3 
Data Listings ................................................................................................... 38 
10.3.4 
Urinalysis ....................................................................................................... 39 
10.4 Vital Signs .................................................................................................................... 39 
10.4.1 
Vital Signs ...................................................................................................... 39 
10.4.1.1 
Summary Statistics .......................................................................... 39 
10.4.1.2 
Markedly Abnormal Changes ............................................................ 39 
10.4.1.3 
Data Listings .................................................................................. 39 
11 Interim Analysis.................................................................................................................... 40 
12 Deviations from Protocol Analysis .......................................................................................... 41 
13 References ............................................................................................................................ 42 
14 Tables, Listings and Figures................................................................................................... 43 
Appendix 1 
Markedly Abnormal Vital Signs and Electrocardiograms (ECGs) ...................... 44 
Appendix 2  
SMQs for AE Medical History of Special Interest.............................................. 45 
Appendix 3  
ATC codes and MedDRA terms for disease progression .................................... 46 
Appendix 4  
ATC codes and MedDRA terms for Prohibited Therapy.................................... 48 
Appendix 5 
Cardiovascular Endpoint Definitions ............................................................... 49 
 
 
LIST OF TABLES 
Table 1 
Sample Size Calculations (Number of Events Rounded Upwards).............................. 15 
Table 2 
Markedly abnormal Criteria for Vital Signs* .......................................................... 44 
Table 3 
Abnormal Criteria for Quantitative ECG Data......................................................... 44 
Table 4 
Cardiovascular Events......................................................................................... 45 
Table 5 
Diabetes Events ................................................................................................. 45 
Table 6 
ATC Codes for Antiandrogens ............................................................................. 46 
Table 7 
ATC codes for Additional Therapy ....................................................................... 46 
Table 8 
MedDRA Codes (preferred terms) for Radiation ..................................................... 47 
Table 9 
MedDRA Codes (preferred terms) for Second Line Treatment .................................. 47 
Table 10 
MedDRA Codes (preferred terms) for additional classification of investigators recording 
of disease progression ......................................................................................... 47 
Table 11 
ATC codes for prohibited concomitant medication .................................................. 48 
Table 12 
MedDRA code (preffered term) for prohibited therapy ............................................. 48 
          
LIST OF FIGURES 
Figure 1 
Trial Design Diagram ......................................................................................... 13 
 


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1 Introduction 
This document describes the planned statistical analyses for Trial 000108.  
1.1 
Abbreviations 
ADT 
Androgen Deprivation Therapy  
AIC 
Akaike Information Criterion 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
 
CABG 
Coronary Artery by-pass Grafting 
CAQ 
Cardiac Anxiety Questionnaire 
CDF 
Cumulative Distribution Function 
CEC 
Clinical Events Classification 
CI 
Confidence Interval 
 
 
 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DASI 
Duke Activity Status Index 
DSMB 
Data and Safety Monitoring Board 
  
ECG 
Electrocardiogram 
 
EQ-5D-5L 
EuroQol Group 5 Dimensions Questionnaire 
 
ER 
Emergency Room 
 
FAS 
Full Analysis Set 
FPR 
False Positive Rate 
 
 
GnRH 
Gonadotropin-Releasing Hormone 
HbA1c  
Hemoglobin A1c 
HRQL 
Health-Related Quality of Life 
 
 
 
 
IMP 
Investigational Medicinal Product 
 
IPCW                Inverse Probability of Censoring Weights 
IPSS 
International Prostate Symptom Score  
ITT 
Intention-to-Treat 
KMMI 
Kaplan-Meier Multiple Imputation 
LHRH 
Luteinizing Hormone Releasing Hormone  
LUTS 
Lower Urinary Tract Symptoms  
MACE 
Major Adverse Cardiovascular Event 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
 
 
 
PCA 
Prostate cancer 
PCI 
Percutaneous Coronary Intervention 
 
 
PFS 
Progression-Free Survival 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PSA 
Prostate-specific Antigen 
PT 
Preferred Term   
QALY 
Quality Adjusted Life Year 


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ROC 
 Receiver Operating Characteristics  
 
SOC 
System Organ Class 
TPR 
True Positive Rate 
WHO 
World Health Organization 
WLW                Wei – Lin – Weissfeld  
 
 
 
  
 
 
 
  
 
  
 


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2 Trial Objectives and Endpoints 
2.1 
Objectives 
2.1.1 Primary Objective 
• The primary objective is to assess the effect of a GnRH receptor antagonist (degarelix) on  
the risk of occurrence of  MACEs (a composite of death due to any cause, non-fatal 
myocardial infarction or non-fatal stroke) as compared to a GnRH receptor agonist 
(leuprolide) in patients with prostate cancer and concomitant CVD 
2.1.2 Secondary Objectives 
CV and Death Related Objectives 
• To assess the rate of specific MACEs (individual components of the composite MACE 
endpoint), i.e. myocardial infarction (fatal, non-fatal), stroke (fatal, non-fatal), in patients 
randomized to degarelix versus leuprolide 
• To assess the rate of unstable angina requiring hospitalization (fatal, non-fatal), in patients 
randomized to degarelix versus leuprolide  
• To assess the risk of death due to any cause in patients randomized to degarelix versus 
leuprolide 
• To assess the rate of cardiovascular (CV)-related death in patients randomized to degarelix 
versus leuprolide 
Prostate Cancer-Related Objectives 
• To monitor testosterone levels at Day 28, 168 and 336  in the degarelix and leuprolide 
treatment groups 
• To evaluate the progression-free survival (PFS) failure rates (defined as either death, 
radiographic disease progressiona, introduction of additional therapy related to prostate 
cancerb or prostate-specific antigen [PSA] failurec, whichever is first) in the degarelix and 
leuprolide treatment groups 
a. 
One or more new metastatic skeletal lesions observed on bone scan; one or more new metastatic extra-
skeletal lesions at least 1.5 cm in greatest dimension visible on computed tomography or magnetic 
resonance imaging (MRI) scan as confirmed by the Investigator. 
b. Additional therapy includes radiation, anti-androgens (except for initial symptomatic flare protection) and 
second-line treatment. 
c. 
PSA failure is defined as an increase in serum PSA of 50%, and at least 5 ng/mL, compared to nadir, 
measured on two consecutive occasions at least 2 weeks apart. 
• To compare the effects of degarelix with leuprolide with regards to local urinary tract and 
prostate cancer-related symptoms with the International Prostate Symptom Score (IPSS) 
questionnaire 
Health Economics and Patient Reported Outcome (PRO) Objectives 
• To compare the effects of degarelix with leuprolide with regards to healthcare resource use 


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• To compare the effects of degarelix with leuprolide with regards to health status through the 
EuroQol Group 5 Dimensions Questionnaire (EQ-5D-5L) 
• To compare the effects of degarelix with leuprolide with regards to functional capacity and 
Quality of Life (QoL) through the Duke Activity Status Index (DASI) 
• To compare the effects of degarelix with leuprolide with regards to heart-focused anxiety 
through the Cardiac Anxiety Questionnaire (CAQ) 
Safety Objective 
• To evaluate and compare the overall safety and tolerability of degarelix with leuprolide 
2.1.3 Exploratory Objectives 
• To compare the effects of degarelix with leuprolide with regards to a second confirmed 
(adjudicated) occurrence of the composite MACE endpoint, in the subgroup of patients that 
survived the first CV event 
 
 
 
 
 
 
 
 
  
2.2 
Endpoints 
2.2.1 Primary Endpoint 
• Time from randomization to the first confirmed (adjudicated) occurrence of the composite 
MACE endpoint 
2.2.2 Secondary Endpoints 
Key Secondary Endpoints 
• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke  
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
Other CV and Death-Related Endpoints 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to the first confirmed (adjudicated) unstable angina requiring 
hospitalization  
• Time from randomization to death due to any cause 
Prostate Cancer-related Endpoints 


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• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment groups  
• Time from randomization to failure in PFS 
• Changes from baseline in IPSS Total and Qol scores 
  
Health Economics and Patient-Reported Outcomes Endpoints 
• Total number of CV-related hospitalization events over the duration of the trial 
• Total number of coronary artery by-pass grafting (CABG) or percutaneous coronary 
intervention (PCI) procedures over the duration of the trial 
• Total number of CV-related emergency room (ER) visit events over the duration of the trial 
• Change in utility, based on EQ-5D-5L 
• Changes from baseline in DASI Global score 
• Changes from baseline in CAQ Global score and score per domain 
Safety Endpoints 
• Incidence and intensity of adverse events 
• Changes in vital signs 
2.2.3 Exploratory Endpoints 
• Time from first adjudicated non-fatal MACE to a second confirmed (adjudicated) 
occurrence of the composite MACE endpoint in the subgroup of patients that survived the 
first CV event 
 
 
 
 
 
 
 
 
 
 
 


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3 Trial design 
The following section details the original trial design. However, the trial was terminated due to 
feasibility problems, with only 545 patients randomized and 14 of those with positively adjudicated 
events. Hence, many of these sections no longer apply. 
3.1 
General Design Considerations 
This is a multi-center, randomized, assessor-blind, controlled trial to compare MACEs in patients 
with prostate cancer and concurrent CVD receiving either monthly treatment with degarelix or 
leuprolide 3-month depot for 1 year. Patients will be screened within 8 to 21 days prior to 
randomization for compliance with the inclusion and exclusion criteria. A trial design diagram is 
provided in Figure 1. 
 
Figure 1 
Trial Design Diagram 
Patients will be randomized to one of the two treatments in a 1:1 ratio stratified by age group 
(<75 and ≥75 years of age) and region (North America, other).  After randomization, the 
management of prostate cancer is intended to reflect standard-of-care. Monitoring for possible 
MACEs will occur throughout the trial applying a specific Clinical Events Classification (CEC) 
process ensuring blinding of the event assessors. 
3.2 
Determination of Sample Size 
The primary objective is to assess the effect of degarelix on the risk of MACEs (a composite of 
death due to any cause, non-fatal myocardial infarction or non-fatal stroke) occurring during a 1-
year period as compared to treatment with leuprolide in patients with prostate cancer and 
concomitant CVD. 
The observed one-year event rates for primary MACE endpoint are 5.3% and 12.1% for degarelix 
and LHRH agonist, respectively, in the global patient population with prior CVD were derived from 
a post-hoc analysis of degarelix safety data. This would correspond to an unadjusted treatment-
Screening Period
End of Trial
Treatment / Follow-up Period
21 to 8 days
prior to
randomization
Randomization
Day
0
Month
8
Month
9
Month
5
Month
7
Month
6
Month
1
Month
2
Month
3
Month
4
Month
10
Month
11
Month
12
80 mg
80 mg
80 mg
240 mg
80 mg
80 mg
80 mg
80 mg
80 mg
80 mg
80 mg
80 mg
22.5 mg
Leuprolide
i.m.
Degarelix
s.c.
22.5 mg
22.5 mg
22.5 mg


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related hazard ratio of 0.42. (In comparison, the adjusted hazard ratio is 0.39 (95% confidence 
interval [CI] = [0.21; 0.71]).) Furthermore, based upon the re-assessment of the potential CV events 
captured in the degarelix safety data by an independent cardiologist, the one-year event probability 
for CV event or death due to any cause are 4.8% and 9.3% for degarelix and leuprolide respectively. 
This corresponds to an unadjusted hazard ratio of 0.50 (in comparison, the adjusted hazard ratio is 
0.48 (95% confidence interval is [0.23,0.87]).  Accounting for the uncertainty in the post-hoc 
analysis of the global pooled data and the re-assessment of the potential CV events by a single 
independent cardiologist, the one-year event rates for sample size calculations are set to 5.1% and 
10.2% for degarelix and leuprolide, respectively. This corresponds to a hypothesized hazard ratio of 
0.49. 
3.2.1 Fixed Trial Design 
Given the alternative hypothesis, a power of 80% and a signficiance level of 5%,  the expected 
number of events required at the final analysis is 61. The sample size required for achieving this 
number of events assumes that all patients are followed-up for primary outcome (MACEs) for 12 
months (28 days each) after start of treatment and an annual drop-out rate of 5%. Assuming these 
characteristics a total sample size of 811 patients is required. 
3.2.2 Adjustments for Futility Analyses 
One interim analysis is planned after 50% of the confirmed, adjudicated MACE endpoints have 
been collected.  One of the objectives of the interim analysis is to test whether there is any reason to 
stop early for futility. The futility bound expressed in terms of the hazard ratio is 0.78. That is, if the 
observed hazard ratio is >0.78 the Data and Safety Monitoring Board (DSMB) may suggest to stop 
the trial due to futility. The futility bounds are non-binding. Due to the possibility to stop early for 
futility the power is deflated (risk of stopping a successful trial is inflated), and to reinstall the 
power at 80% the number of required events is inflated to 66 and the total number of patients to 
876. 
The trial will not be stopped early due to an overwhelming treatment benefit, but in order to 
implement the trial design, an alpha-spending function will be used with nearly zero spending of 
alpha at the interim analysis, α < 0.0001 (e.g. trial will not be stopped early for efficacy). 
3.2.3 Adjustments for Sample Size Re-Estimation 
The conditional power for different sample size increases will be evaluated at the interims using 
SAS. In case of a sample size increase, the final test statistic is adjusted by using the normal inverse 
method in order to protect the two-sided Type I error rate at 5%. 
The sample size calculations are performed with ADDPLAN™ 6, licensed by ADDPLAN, Inc., an 
Aptiv Solutions company and presented in Table 1. 


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Table 1 
Sample Size Calculations (Number of Events Rounded Upwards) 
Information 
Rate 
Stop for futility/No evidence reject H0 
Successful trial 
(Reject H0) 
α spent 
Power  
Events 
Test Statistic 
Hazard 
Ratio 
Conditional 
Power 
Test Statistic 
 
 
50% 
≤ 0.7 
≥ 0.78 
≤ 8.5% 
- 
< 0.0001 
- 
33 
100% 
≤ 1.96 
≥ 0.61 
- 
≥ 1.96 
0.025 
80% 
66 
 
• Assuming constant hazards, 𝜆𝑑𝑒𝑔𝑎𝑟𝑒𝑙𝑖𝑥= 0.0523/𝑦𝑒𝑎𝑟  𝜆𝑙𝑒𝑢𝑝𝑟𝑜𝑙𝑖𝑑𝑒= 0.1076/𝑦𝑒𝑎𝑟  
• 5% drop out rate in each arm 
• 1:1 randomization ratio 
When d, the number of events, has been observed, the approximate relationship between the 
standardized test statistic, Z, and the hazard ratio (HR) as given in (Jennison and Turnbull, 2000) is, 
𝒁≈𝒍𝒐𝒈(𝑯𝑹−𝟏)√𝒅/𝟒 
For reasons of interpretation, both Z and the hazard ratio are reported in design tables. 


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4 Patient Disposition 
All patients screened and randomized will be accounted for. All post-randomization 
discontinuations will be summarized by time of, and reason for, discontinuation. The number of 
patients screened and not randomized will be presented with the reason(s) for screen failure. 
Special attention should be paid to those patients who discontinue treatment with investigational 
medicinal product (IMP) and start an alternative treatment during the trial, including the dates 
corresponding to going off the randomized drug, i.e. the date of the last injection and the start of a 
new treatment, i.e. the date the new treatment was initiated.   
In addition, the breakdown of the overall disposition of patients by age group (<75 years of age, 
≥75 years of age) and region following the design (stratification) of the trial will be provided. Also, 
the number of patients screened and randomized, overall and by age group (<75 years of age, 
≥75 years of age) and region will be provided. 
1- Kaplan–Meier (1-KM) plots of the time to early discontinuation, as well as the time to treatment 
discontinuation or initiation of prohibited therapies related to hormonal therapy, will be displayed 
per treatment arm. In addition, time to early discontinuation by reason for discontinuation and 
treatment arm will be presented by cumulative incidence function curves. Differences in 
discontinuation rates and treatment discontinuation or initiation of prohibited therapies related to 
hormonal therapy rates between treatment groups will be tested using the Log Rank test (α=0.05, 
two-sided). 
 
 


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5 Protocol Deviations 
As no PP analyses are planned, there will be no classification of ‘minor’/’major’ events, reflecting 
potential impact on efficacy endpoints due to protocol violations. 
In order to reflect general (i.e. not specifically related to impact on efficacy) protocol adherence 
important deviations will be summarized by treatment group and category, and listed by subject for 
the Full Analysis Set. 


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6 Analysis Sets 
6.1 
Intention-To-Treat Analysis Set 
The Intention-to-Treat (ITT) analysis set consists of all randomized patients, and will be analysed 
based on the planned (randomized) treatment. 
6.2 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all randomized and treated patients (who received at least 
one dose of IMP), and will be analysed based on the planned (randomized) treatment. 
6.3 
Safety Analysis Set 
The Safety analysis set consists of all treated patients (who received at least one dose of IMP), and 
will be analysed based on the actual treatment received. 


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7 Trial Population 
All tables will be presented for the FAS. 
7.1 
Demographics and Other Baseline Characteristics 
Categorical data will be summarized using numbers and percentages. The percentages are based on 
the total number of patients with a corresponding assessment. Continuous data will be presented, for 
example, using the number of patients (N), mean and standard deviation, median, minimum and 
maximum. All baseline characteristics will be listed. 
7.1.1 Demographics 
 
 
 
 
7.1.2 Vital Signs at Baseline 
 
7.1.3 History and Stage of Prostate Cancer 
A summary table of history and stage of PCA will be presented, containing the following 
information: 
• Gleason score (as defined below) 
• Stage of prostate cancer (TNM classifications, as defined below) 
• ECOG performance score 
The following pathological stages will be recorded and summarized by treatment group, age (<75 
years and ≥75 years) and region: 
The Gleason score is calculated as the sum of the Gleason grade of the primary and secondary 
patterns. The following categories will be presented:  
• 2-4 
• 5-6 
• 7-10 
The stage of prostate cancer, based on the TNM classification, includes the following categories: 
• Localised: 
T½ & (NX or N0) & M0, 
• Locally Advanced: [T¾ & (NX or N0) & M0], or [N1 & M0], 
• Metastatic: 
M1 


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• Not classifiable: 
Results from T, N, and M categories that could not be resolved to  
 
Localised, Locally Advanced, or Metastatic 
 
 
 
 
 
 
 
 
7.1.5 Laboratory Efficacy / Pharmacodynamic Parameters at Baseline 
Baseline variables will be summarized by treatment, age (<75 years and ≥75 years) and region. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4 
Physical Examination 
Patients with abnormalities at any screening, baseline, or post-baseline visit will be listed with all 
physical examination evaluations.  


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8 Exposure and Treatment Compliance 
All tables will be presented for the FAS. 
8.1 
Extent of Exposure  
The cumulated dose administered to each patient will be determined and summarized descriptively. 
For patients discontinuing the trial early, are lost to follow-up or initiate treatment with an ADT 
other than Degarelix or Leuprolide,  their cumulated dose will be calculated up until the time of 
early discontinuation/lost to follow-up/treatment iniation.         
8.2 
Treatment Compliance  
Treatment compliance will be presented from data listings. Patients not receiving the scheduled 
dose will be listed by center, sorted by treatment group and patient number. 


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9 Efficacy 
The following sections detail the planned analyses in the protocol. Any changes to the planned 
analysis in the protocol are described in Section 12. 
9.1 
General Considerations 
The analysis of efficacy will be performed for the FAS (unless otherwise specified). For the purpose 
of this CV outcome study, patients prematurely discontinuing from treatment will be followed-up 
for the occurrence of MACE events based on monthly telephone interviews.  Unless otherwise 
stated, time to event endpoints will be censored at the time of treatment discontinuation, initiation 
of prohibited therapies related to hormonal therapy, lost to follow-up/withdrawal from the study or 
day 336, whichever occurs first. Initiation of prohibited therapy related to hormonal therapy 
includes the following: 
• Surgical castration or other hormonal manipulation in addition to the IMPs 
• Anti-androgens for combined androgen blockade (anti-androgen use for initial flare 
protection is allowed for a maximum period of up to 28 days after randomization) 
• Estrogens 
• Megestrol acetate 
• Ketoconazole 
• Abiraterone 
• Enzalutamide 
• Any additional hormonal therapy initiated as a combination therapy with the IMP 
The associated ATC and MedDRA codes for the above prohibited therapies are provided in Table 
11 and Table 12. Hypothesis tests will be two-sided at a significance level of 5% and missing data 
will not be imputed.  95% confidence limits and the associated p-values will be presented for 
estimates of the treatment effect comparing degarelix to leuprolide for all regression analyses. 
For the purposes of this trial, 
 
 
 
 
  
  
 
 
  
 
  
 
  
 


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9.2 
Primary Endpoint 
9.2.1 Primary Endpoint Analysis 
The primary endpoint, the time from randomization to the first adjudicated occurrence of the 
composite MACE endpoint in the two treatment groups, will be analyzed using the Kaplan-Meier 
estimator of the survival function and the log-rank test, stratified for age ( <75 and ≥75 years of 
age) and region and based on the FAS.  
 
Pseudo SAS code for Kaplan-Meier/log-rank test: 
 
PROC LIFETEST DATA=<DATA> PLOTS=SURVIVAL(); 
      TIME AVAL*CNSR(1); 
     STRATA  <STRAT1 STRAT2> /GROUP=ARMN  TEST=LOGRANK; 
RUN; 
 
The hazard ratio, comparing the hazard rate of the distribution of the time from randomization to 
the MACE composite endpoint between the degarelix and leuprolide arms, will be estimated based 
on the stratified Cox regression model, stratified by age-group and region and including treatment 
as a factor.  The variance estimate of the log hazard ratio will be obtained from the inverse of the 
observed information matrix for the partial likelihood. An approximate 95% CI for the hazard ratio 
will be calculated by exponentiation of the 95% CI for the log hazard ratio. Although,  the score test 
for this stratified Cox Regression model is equivalent to the stratified log-rank test, (Kalbfleisch and 
Prentice, 2002), the (Wald based) 95% CI may not be fully consistent with the stratfied log-rank 
test. The latter, however, defines the success of the trial. More precisely, the trial will be declared 
positive if a statistically significant (at two-sided 5% significance level) reduction in the hazard rate 
of the time from randomization to the composite MACE endpoint is demonstrated in the FAS based 
on the stratified log-rank test, for patients randomized to degarelix compared to leuprolide. 
 
TLF Figure: Primary Endpoint: Time to First Adjudicated MACE – FAS 
 


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9.2.2 Sensitivity Analyses 
9.2.2.1 Sensitivity Analysis: Time from randomization to the first confirmed (adjudicated) 
occurrence of non-fatal myocardial infarction, non-fatal stroke, non-fatal unstable 
angina requiring hospitalization, or all-cause death 
Time from randomization to the first confirmed (adjudicated) occurrence of non-fatal myocardial 
infarction, non-fatal stroke, non-fatal unstable angina requiring hospitalization, or all-cause death is 
defined similarly as the primary endpoint with the addition of cardiovascular events unstable angina 
requiring hospitalization. Also, the endpoint will be analyzed as for the primary endpoint. 
9.2.2.2 Sensitivity Analysis: Time to first confirmed occurrence of a MACE related adverse 
event (MI SMQ (broad); Central nervous system hemorrhages and cerebrovascular 
conditions SMQ (broad); all-cause death) 
Time to first confirmed occurrence of a MACE related adverse event is defined as for the primary 
endpoint with events being; any adverse event within the broad SMQ term ‘myocardial infarction’, 
any adverse event within broad SMQ term ‘Central nervous system hemorrhages and 
cerebrovascular conditions’ or all-cause death. Also, the endpoint will be analyzed as for the 
primary endpoint. 
9.2.2.3 Sensitivity Analysis: Total occurrence of (adjudicated) myocardial infarction, stroke, 
and all-cause death 
Total occurrence of myocardial infarction (MI), stroke and all-cause death is defined as the total 
number of events (MI, stroke or death) occurring over the duration of the trial. 
The endpoint will be compared between treatment groups using a negative binomial model. The 
estimated treatment difference with a 95% confidence interval will be presented.  
9.2.2.4 Sensitivity Analysis pertaining to treatment discontinuation or initiation of 
prohibited therapies related to hormonal therapy 
For the purposes of this sensitivity analysis, patients will NOT be censored at the time of treatment 
discontinuation or initiation of prohibited therapies related to hormonal therapy. Rather, information 
pertaining to all observed occurrences of the first adjudicated MACE event in patients randomized 
in the study will be used. Patients will be censored at lost to follow-up/withdrawal from study or 
day 336, whichever occurs first.      
9.3 
Secondary Endpoints 
If the primary analysis is significant at the two-sided Type I error-level of 5% the testing of the 
secondary endpoints will proceed as described below. 
Key Secondary Analyses 
The following analyses are included in the family of key secondary analyses: 


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• Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke  
• Time from randomization to confirmed (adjudicated) CV-related death 
• Time from randomization to the first confirmed (adjudicated) myocardial infarction 
The key secondary endpoints will be controlled for multiplicity (to ensure the family wise error rate 
is protected at a two-sided 5% Type I error-level) using a fixed-sequence testing method. The order 
of the testing sequence is as follows: 
1. Time from randomization to the first confirmed (adjudicated) occurrence of CV-related 
death, non-fatal myocardial infarction or non-fatal stroke  
2. Time from randomization to confirmed (adjudicated) CV-related death 
3. Time from randomization to the first confirmed (adjudicated) myocardial infarction 
The remaining secondary endpoints will be analyzed without controlling for multiplicity.  
Other Secondary Analyses 
• Time from randomization to the first confirmed (adjudicated) stroke  
• Time from randomization to first confirmed (adjudicated) unstable angina requiring 
hospitalization 
• Time from randomization to death due to any cause 
• Time from randomization to failure in PFS 
• Testosterone levels at Days 28, 168 and 336 in the degarelix and leuprolide treatment groups 
• Total number of CV-related hospitalizations over the duration of the trial 
• Total number of CABG or PCI procedures over the duration of the trial 
• Total number of CV-related ER visit events over the duration of the trial 
• Changes from baseline in Health-Related Quality of Life (HRQL) as measured by 
EQ-5D-5L, during the course of treatment period 
• The difference in QALY during one year of treatment with degarelix compared to leuprolide 
• The change from baseline in the mean DASI and CAQ score during one year of treatment 
with degarelix compared to leuprolide 
• The change from baseline in the mean total and QoL IPSS score during oneyear of treatment 
with degarelix compared to leuprolide 
9.3.1 Time from randomization to the first confirmed (adjudicated) occurrence of 
cardiovascular-related death, non-fatal myocardial infarction or non-fatal stroke 
This endpoint is identical to the primary endpoint, only counting CV-related deaths, and not all 
cause deaths as failures. The time measured in days, from randomization to first confirmed 
(adjudicated) occurrence of CV-related death, non-fatal myocardial infarction or non-fatal stroke, 


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will be analyzed using the Kaplan-Meier estimator of the survival function and the log-rank test of 
the null hypothesis of equal hazard functions, stratified by age group and region. The p-value of the 
two-sided log-rank test with significance level of 5% will be presented along with plots of the 
estimated survival functions for the two treatment groups, stratified by age group and region. The 
treatment effect of degarelix will be further examined by fitting a stratified Cox regression model. 
The model will include treatment as a factor, be adjusted for the baseline CV risk factors as 
appropriate and stratified by age-group and region. The 95% confidence limits and associated p-
value for the hazard ratio comparing treatment with degarelix to leuprolide will be presented. 
TLF Table: Secondary Endpoint: CV Death + MI + Stroke – FAS  
TLF Figure: Secondary Endpoint: CV Death + MI + Stroke – FAS 
 
9.3.2 Time From Randomization to the first (adjudicated) occurrence of the individual 
components of the MACE composite endpoint  
Time from randomization to the first adjudicated occurrence of the individual components of the 
MACE composite endpoint is defined as the number of days from randomization to the first 
adjudicated myocardial infarction / stroke. The occurrence of the components of the MACE 
composite endpoint will be adjudicated by the external independent CEC Committee. In order to 
correctly assess the treatment effect associated with degarelix with respect to the time to individual 
components of the MACE composite endpoint, it is necessary to account for the competing risk, 
death due to other causes. The above components of the MACE composite endpoint will be 
analyzed separately.  The log-rank test stratified by age-group and region will be used to examine 
the null hypothesis of equal cumulative cause specific hazard functions. The p-value of the two-
sided log rank test with significance level of 5% will be presented along with the plots of the 
estimated cumulative cause specific hazard functions for both treatments obtained from the Nelson-
Aalen estimator, stratified by age group and region.  
TLF Table: Secondary Endpoint: Time to First Adjudicated Myocardial Infarction – FAS  
TLF Figure: Cumulative Cause Specific Hazard Function for Time to First Adjudicated  
Myocardial Infarction – FAS  
TLF Table: Secondary Endpoint: Time to First Adjudicated Stroke – FAS   
TLF Figure: Cumulative Cause Specific Hazard Function for Time to First Adjudicated 
Stroke – FAS  


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9.3.3 Time from randomization to the first confirmed (adjudicated) unstable angina 
requiring hospitalization 
Time from randomization to the first adjudicated occurrence of unstable angina requiring 
hospitalization will be analyzed in the same manner as the individual components of the MACE 
primary endpoint, specified in Section 9.3.2. 
TLF Table: Secondary Endpoint: Time to First Adjudicated Unstable Angina Requiring 
Hospitalization – FAS  
TLF Figure: Cumulative Cause Specific Hazard Function for Time to First Adjudicated 
Unstable Angina Requiring Hospitalization – FAS  
9.3.4 Time From Randomization to Death Due to Any Cause 
Time from randomization to death due to any cause (overall survival, OS), is defined as the number 
of days from randomization to death. The time measured in days, from randomization to death due 
to any cause, will be analyzed using the Kaplan-Meier estimator of the survival function and the 
log-rank test of the null hypothesis of equal hazard functions, stratified by age group and region. 
The p-value of the two-sided log-rank test with significance level of 5% will be presented along 
with plots of the estimated survival functions for the two treatment groups, stratified by age group 
and region. The treatment effect of degarelix will be further examined by fitting a stratified Cox 
regression model for the time to death from any cause. The model will include treatment as a factor, 
be adjusted for the baseline CV risk factors as appropriate and stratified by age-group and region. 
The 95% confidence limits and associated p-value for the hazard ratio comparing treatment with 
degarelix to leuprolide will be presented. 
TLF Table: Secondary Endpoint: Time to Death Due to Any Cause – FAS  
TLF Figure: Survivor Function for Time to Death Due to Any Cause – FAS  
9.3.5 Time from Randomization to confirmed (adjudicated) Cardiovascular-Related Death 
Time from randomization to adjudicated CV-related death, is defined as the number of days from 
randomization to the date of the adjudicated CV-related death. The cause of death will be 
adjudicated by the external independent CEC Committee.   Undetermined deaths will be presumed 
and analyzed as non-cardiovascular deaths.  In order to correctly assess the treatment effect 
associated with degarelix with respect to the time to CV-related death, it is necessary to account for 
the competing risk, death due to other causes. The time measured in days, from randomization to 
the adjudicated CV-related death, will be analyzed using the Nelson-Aalen estimator of the 
cumulative cause specific hazard function and the log rank test of the null hypothesis of equal 
cumulative cause specific hazard functions, stratified by age group and region. The p-value of the 
two-sided log rank test with significance level of 5% will be presented along with plots of the 
cumulative cause specific hazard functions for the two treatment groups, stratified by age group and 
region. The treatment effect of degarelix will be further examined by fitting a stratified Cox-type 


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regression model for the cause specific hazard function associated with CV-related death. The 
model will include treatment as a factor, be adjusted for the baseline CV risk factors as appropriate 
and stratified by age-group and region. The 95% confidence limits and associated p-value for the 
cause specific hazard ratio comparing treatment with degarelix to leuprolide will be presented. 
TLF Table: Secondary Endpoint: Time to Adjudicated Cardiovascular-related Death – FAS  
TLF Figure: Cumulative Cause Specific Hazard Function for Time to Adjudicated 
Cardiovascular-related Death – FAS  
9.3.6 Time from Randomization to Failure in Progression-Free Survival 
Progression-free survival (PFS) is a composite endpoint consisting of the following conditions: 
• Death 
• Radiographic disease progression defined as one or more new metastatic skeletal lesions 
observed on bone scan; one or more new metastatic extra-skeletal lesions at least 1.5 cm in 
greatest dimension visible on computed tomography or magnetic resonance imaging scan as 
confirmed by the Investigator. 
• Introduction of additional therapy related to prostate cancer treatment including radiation, 
anti-androgens and second-line treatment.  (ATC and MedDRA codes for disease 
progression are included in Appendix 3) 
• PSA failure defined as the time from randomization to the second occasion (must be at least 
two weeks apart from the first and correspond to consecutive measurements) in which the 
PSA value fulfills the following criteria: 
I. 
An absolute increase of ≥ 5 ng/ml above nadir and  
II. 
An increase of ≥ 50 % of nadir 
Time to PFS failure is therefore defined as the time, measured in days, from randomization to the 
first occurrence of one of the above composite endpoint criteria. Patients discontinuing from 
treatment/withdrawn from the study will be censored at the time of discontinuation/withdrawal.  
Time to PFS failure will be analyzed using the Kaplan-Meier estimator of the survival function, the 
Cox regression model for the hazard rate and the log-rank test of the null hypothesis of equal hazard 
functions, stratified by age group and region. The p-value of the two-sided stratified log-rank test 
with significance level of 5% will be presented along with plots of the estimated survival functions 
for the two treatment groups, stratified by age group and region. The estimated hazard ratio and the 
associated 95% confidence interval and p-value comparing the treatment with Degarelix to 
Leuprolide will also be presented.   
TLF Table: Secondary Endpoint: Time to PFS Failure – FAS  
TLF Figure: Survivor Function for Time to PFS Failure – FAS  


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9.3.7 Testosterone levels at day 28, 168 and 336 in patients treated with degarelix and 
leuprolide 
The proportion of patients castrated at day 28, 168 and 336 will be presented by treatment group, 
along with the number of patients with testosterone measurements at each assessment. Castration is 
defined as testosterone levels ≤ 0.5 ng/mL. Further, the proportion of patients castrated at both day 
28 and 168, as well as at all three visits will be presented along with the number of patients with 
assessments at each of the corresponding times. For patients discontinuing treatment during the 
trial, any testosterone data collected after the date of discontinuation will be excluded from the 
analysis.   
TLF Table: Secondary Endpoint: Probability of testosterone levels remaining at castrate 
levels  – FAS  
9.3.8 Total number of Cardiovascular-Related Hospitalizations over the duration of the trial 
The total number of CV-related hospitalizations over the duration of the trial is defined as the 
number of hospitalizations due to CV-related adverse events, observed during the 12 month follow-
up period for each patient.  
The number of CV-related hospitalizations will be analyzed using a negative binomial model. The 
dependent variable will be the number of CV-related hospitalizations. The model will include a 
factor variable for treatment, the baseline count of CV-related hospitalizations (if available) as a 
covariate and will be further adjusted by including the logarithm of the number of days of follow-up 
for each patient as an offset. The inclusion of the offset term systematically adjusts the estimate of 
the treatment effect for potential differences in the duration of follow-up between patients. The 
model will further be adjusted for age-group and region. The estimated treatment difference with a 
95% confidence interval will be presented.  
TLF Table: Secondary Endpoint: Number of CV-related hospitalizations over the duration of 
the trial – FAS  
9.3.9 Total number of Coronary Artery By-Pass Grafting or Percutaneous Coronary 
Intervention Procedures over the duration of the trial 
The total number of CABG or PCI procedures observed over the duration of the trial will be 
analyzed in the same manner as the total number of CV-related hospitalizations, outlined in Section 
9.3.8. 
TLF Table: Secondary Endpoint: Number of CABG or PCI over the duration of the trial – 
FAS  
 


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9.3.10 Total number of Cardiovascular-Related Emergency Room Visit Events Observed 
over the duration of the trial 
The total number of CV-related ER visit events observed over the duration of the trial for each 
patient will be analyzed in the same manner as the total number of CV-related hospitalizations, 
outlined in Section 9.3.8. 
TLF Table: Secondary Endpoint: Number of Cardiovascular-related emergency room visits 
over the duration of the trial – FAS  
 
9.3.11 Difference in Quality Adjusted Life Year (QALY) During One Year of Treatment 
The EQ-5D-5L questionnaire can be used to estimate the QALY. The QALY is a measure of the 
value of health outcomes. Since health is a function of length of life and QoL, the QALY was 
developed as an attempt to combine the value of these attributes into a single index number. The 
basic idea underlying the QALY is simple: it assumes that a year of life lived in perfect health is 
worth 1 QALY (1 Year of Life × 1 Utility value = 1 QALY) and that a year of life lived in a state of 
less than this perfect health is worth less than 1. The QALY is derived as a cumulative measure for 
the treatment duration as the AUC of the time versus the index value. The AUC will be calculated 
using the trapezoidal rule for each of the visits values in relation to the baseline.  
A detailed derivation of the QALY:  
1) The EQ-5D-5L health state is converted into a single index value. The index values are 
country specific and we will use the value sets for the USA 
(http://www.euroqol.org/home.html.). 
2) The QALY at the end of the trial is derived as the cumulative AUC for the index value as a 
function of time during the 12 months of treatment. This will be calculated as: 
 
Where i=1, 2 and 3 for the corresponding visits at month 6, 11 and 12. The value, i=0, corresponds 
to baseline. 
Time is measured as the actual number of days from baseline date of EQ-5D to each of the post-
baseline EQ-5D Questionnaire completion dates during the 12 month trial. 
The QALY at Visit 13 will be calculated for any patients who have a non-missing baseline index 
value. That is, any patients who are missing the EQ5D index value at baseline will not have a 
QALY measurement. Last observation carried forward principle will be used for missing 
measurements at Visit 8 or Visit 13 using only post-baseline values. The EQ5D index value will be 
carried forward to the planned visit date in order to calculate the QALY at 12 months. For patients 
with missing index value at Visit 8, but with known index value either at Visit 13 or 14, the QALY 
will be calculated as the AUC from baseline up to the next known visit. 
𝐴𝑈𝐶=    
𝑖𝑛𝑑𝑒𝑥(𝑖−1) + 𝑖𝑛𝑑𝑒𝑥𝑖
2
   × 𝑇𝑖𝑚𝑒(𝑖−(𝑖−1)) 
𝑖
𝑖=1
 


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The mean QALY at the end of the trial (12 months [1 month=28 days]) will be summarized by 
treatment arm and compared using an analysis of covariance (ANCOVA) model, where the QALY 
is the dependent variable and adjusted for treatment, age-group and region respectively. 
9.3.12 Change from Baseline in Mean Total and QoL International Prostate Symptom Score 
during One Year of Treatment 
The severity of lower urinary tract symptoms (LUTS) will be investigated using the total IPSS 
score. IPSS is a questionnaire containing eight questions regarding incomplete emptying, frequency, 
intermittency, urgency, weak stream, straining and nocturia and one question relating to the quality 
of life. Each question is assigned a total score on a scale from 0 to 5. The total IPSS score is then 
calculated as the summation over the responses for question 1 to7.   
The eighth question regarding QoL is in relation to urinary symptoms denoted IPSS-QoL. The 
response to this question is analyzed separately and not included in the IPSS total score. 
Missing values will not be imputed for this endpoint. If responses are missing to one or more of 
questions 1-7, the IPSS total score is considered missing as well. Results will be presented based on 
the observed cases.   
Changes from baseline in the IPSS total score and QoL score will be compared between treatments 
longitudinally using repeated measures analysis of covariance (ANCOVA) with the change from 
baseline as the dependent variable and the baseline score as a covariate, treatment, age-group, 
region and visit as factors, including treatment by visit interaction term, assuming the working 
correlation matrix has the unstructured form implemented in SAS PROC MIXED.  Based on the 
repeated measures ANCOVA model, the two-sided 95% confidence limits of the adjusted treatment 
contrasts and associated p-values will be provided. 
TLF Table: Secondary Endpoint: IPSS – FAS  
9.3.13 Change from Baseline in the Mean Duke Activity Status Index and Cardiac Anxiety 
Questionnaire Score during One Year of Treatment 
The DASI and CAQ will be assessed at baseline (Visit 2), Visit 8, 14 and at the End-of-Trial visit. 
The change from baseline in DASI total score as well as CAQ total and domain scores will be 
compared between treatments longitudinally using repeated measures ANCOVA with the change 
from baseline as the dependent variable and the baseline score as a covariate, treatment, age-group,  
region and visit as factors, including treatment by visit interaction term, assuming the working 
correlation matrix has the unstructured form implemented in SAS PROC MIXED. Based on the 
ANCOVA model, the two-sided 95% confidence limits of the adjusted treatment contrasts and 
associated p-values will be provided. 
TLF Table: Secondary Endpoint: The change in the mean DASI Score during one-year of 
treatment- FAS  


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TLF Table: Secondary Endpoint: The change from baseline in the mean CAQ Score during 
one-year of treatment – FAS  
9.4 
Exploratory Endpoints 
9.4.1 Time from First Adjudicated MACE to Second Confirmed Adjudicated MACE 
The exploratory efficacy endpoint, time from the first adjudicated MACE to a second confirmed 
(adjudicated) occurrence of the composite MACE endpoint, is aimed at further investigating the risk 
of CVD outcomes among prostate cancer patients treated with degarelix or LHRH agonist. 
Only patients who have experienced one non-fatal MACE, will be considered at risk for a second 
MACE. The event time of interest will be the number of days from the first adjudicated non-fatal 
MACE until the second MACE. The endpoint will be analyzed via a Cox-type proportional 
intensity model. In essence the analysis is akin to the proposed conditional analysis of 
(Prentice, 1981) with a modification made based on the definition of the composite MACE 
endpoint. The model will include treatment as a factor, be
 
 
 , as well as stratified by age-group and region. Based on the 
Cox-type proportional intensity model, the two-sided 95% confidence limit of the adjusted relative 
rate for the treatment effect of degarelix compared to leuprolide will be provided alongside the 
associated p-value. Significant results will be interpreted cautiously, as randomization will not 
provide protection against imbalances between the two groups in potential confounders that are not 
explicitly adjusted for in the model. The treatment effect of degarelix compared to leuprolide with 
respect to the rate of MACEs will be further explored via an Andersen-Gill model (Andersen and 
Gill, 1982). The risk set for the Andersen-Gill model includes all patients who are under 
observation and at-risk for a MACE, i.e. the Andersen-Gill model incorporates information from all 
observed MACEs.  
 
 
Pseudo SAS code for implementing Andersen-Gill model 
PROC PHREG DATA=<DATA> COVS(AGGREGATE); 
      MODEL  (TSTART, TSTOP)*CNSR(1) = ARMN; 
    ID=USBJID; 
RUN; 
 
Note, in the above SAS code for the Andersen-Gill model, the robust standard errors are calculated 
by including the COVS(AGGREGATE) statement in the first line.  Alternatively, model based 
standard errors could be returned by replacing the COVS(AGGREGATE) option with COVM.   
TLF Table: Exploratory Endpoint: Time From First Non-Fatal adjudicated MACE to a 
Second Confirmed Occurrence of a MACE – FAS 


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10 Safety 
10.1 General Considerations 
Safety parameters will be evaluated for the safety dataset. 
10.2 Adverse Events 
Adverse events will be coded using MedDRA version 17.1 or later.  
For adverse events, missing values will be treated as missing, except for causality, intensity, 
seriousness, and outcome of adverse events. A worst-case approach will be used: if causality is 
missing, the adverse event will be regarded as related to the IMP; if the intensity of an adverse 
event is missing, the adverse event  will be regarded as severe; if seriousness is missing, the adverse 
event will be regarded as serious; if onset date is missing, it will be assumed to be the first day of 
dosing; if outcome is missing, and no date of outcome is present, the outcome is regarded as ‘Not 
Recovered’. 
An adverse event with the causal relationship to IMP judged as ‘No reasonable possibility’ is 
categorized as unrelated to IMP. An adverse event with the causal relationship to IMP judged as a 
‘reasonable possibility’ is categorized as related to IMP and as an adverse drug reaction. 
Treatment-emergent adverse events will be presented in summary tables and listings. The definition 
of a treatment-emergent adverse event is provided in Section 10.2.1. 
10.2.1 Overview of Treatment-Emergent Adverse Events 
Adverse events will be regarded as ‘pre-treatment’ if they occur between screening and the initial 
injections with IMP. Adverse events which occur in the time interval from initial dosing to 3 
months after (1 month=28 days) last dosing of IMP will be considered to be ‘treatment-emergent’. 
Adverse events will be regarded as ‘post-treatment’ if they occur 3 months (1 month=28 days) or 
more after the last dosing of IMP. 
An adverse event overview summary table will be prepared including the number of patients 
reporting an adverse event, the percentage of patients (%) with an adverse event, and the number of 
events (E) reported, for the following categories:  
• Treatment-emergent adverse events 
• Deaths  
• Serious adverse events  
• Adverse events leading to withdrawal  
• Severe and life threatening adverse events  
• Adverse drug reactions 
TLF Table: Overall summary of treatment-emergent adverse events – Safety 
 


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10.2.2 Incidence of Adverse Events 
Treatment-emergent adverse events will be summarized in a table by MedDRA SOC and Preferred 
Term (PT). The Table will display the total number of patients reporting an adverse event, the 
percentage of patients (%) with an adverse event, and the number of events (E) reported. Adverse 
events will be presented by SOC sorted alphabetically and PT sorted in decreasing frequency of 
occurrence. 
For each treatment the following counts are done: 
• For number of patients experiencing a particular event, counting will be done by patient and 
not by event. This is valid for both SOC and PT, i.e., a patient will only be counted once in 
each SOC and once within each PT. 
• For total number of events, counting will be done by event. This is valid for both SOC and 
PT, i.e., an event occurring more than once for the same patient will be counted for each 
occurrence. 
 
Summary tables will be prepared for: 
• All adverse events 
• Adverse events with an incidence [≥5%] of patients in any treatment group 
• Adverse events by causality (related/unrelated) 
• Adverse events leading to death 
• Adverse events by intensity  
• Serious adverse events  
• Adverse events leading to withdrawal 
Supporting data listings will be provided for: 
• All adverse events sorted by center and patient no. 
• All adverse events sorted by MedDRA PT 
• Serious adverse events  
• Adverse events leading to death 
• Adverse events leading to withdrawal.  
In addition, tables summarizing all the treatment-emergent adverse events by MedDRA SOC and 
PT displaying the total number of patients reporting an adverse event, the percentage of patients (%) 
with an adverse event, and the number of events (E) reported will be provided. 
TLF Table: Incidence of all adverse events by MedDRA System Organ Class and Preferred 
Term – Safety Analysis Set 
TLF Table : Incidence of treatment-emergent non-serious adverse events (>5% cut-off) by 
MedDRA System Organ Class and Preferred Term – Safety Analysis Set 


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TLF Table: Incidence of all adverse events by causality, MedDRA System Organ Class and 
Preferred Term – Safety Analysis Set 
TLF Table: Incidence of adverse events leading to death by MedDRA System Organ Class 
and Preferred Term – Safety Analysis Set 
TLF Table: Incidence of all adverse events by intensity, MedDRA System Organ Class and 
Preferred Term – Safety Analysis Set 
TLF Table: Incidence of serious adverse events by MedDRA System Organ Class and 
Preferred Term – Safety Analysis Set 
TLF Table: Incidence of adverse events leading to withdrawal by MedDRA System Organ 
Class and Preferred Term – Safety Analysis Set 
TLF Table: Incidence of treatment-emergent adverse events by MedDRA System Organ 
Class and Preferred Term – Safety Analysis Set 
TLF Table: Incidence of treatment-emergent adverse drug reactions by MedDRA System 
Organ Class and Preferred Term - Safety Analysis Set 
TLF Table: Incidence of treatment-emergent adverse events leading to discontinuations by 
MedDRA System Organ Class and Preferred Term - Safety Analysis Set 
TLF Table: Incidence of treatment-emergent serious adverse events by MedDRA System 
Organ Class and Preferred Term – Safety Analysis Set 
TLF Listing: Listings of all adverse events sorted by center and patient no. 
TLF Listing: Listings of all adverse events sorted by MedDRA Preferred Term 
TLF Listing: Listings of all serious adverse events 
TLF Listing: Listings of all adverse events leading to death 
TLF Listing: Listings of all adverse events leading to withdrawal 
10.3 Safety Laboratory Variables 
Baseline for all laboratory analyses will be the values obtained at the last assessment prior to the 
first dose of the IMP. Treatment-emergent laboratory data will include tests completed after the first 
dose of IMP through the residual time of drug effect. End of trial will include the last post-baseline 
observation during the trial.  
 
10.3.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline to the end of trial will be presented 
for each laboratory variable. In addition, descriptive statistics, i.e., the number of patients with data, 


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mean (standard deviation), median, minimum, and maximum values, will be presented for observed 
values and change from baseline at each time-point for each laboratory variable. 
 
 
 
10.3.2 Laboratory Variable Changes Relative to Normal Range 
Changes relative to normal ranges are presented with shift tables with total number of patients, and 
number and percent of patients who experienced a shift by treatment group and period. The 
following categories for shift tables are defined: 
• Low:   
Values which are below the lower reference range limit; 
• Normal:  
Values which are within the lower and upper reference range; 
• High:   
Values which are above the upper reference range limit. 
• Absent:  
No value for measured variable (for urinalysis only) 
• Present:  
Any value obtained for measured variable (for urinalysis only) 
For all hematology and clinical chemistry variables, shift tables will be prepared to compare 
baseline values to the worst in-treatment value. More specifically, for hematology and clinical 
chemistry, tables presenting the changes from Low or Normal to High and from High or Normal to 
Low will be provided. For urinalysis variables, shift tables will summarize the number (%) of 
patients who had “absent” values at baseline and “present” values during the treatment period.  
TLF Table: Incidence of hematology laboratory variable changes relative to normal range – 
Safety Analysis Set 
TLF Table: Incidence of chemistry laboratory variable changes relative to normal range – 
Safety Analysis Set 
TLF Table: Incidence of urinalysis variable changes relative to normal range – Safety 
Analysis Set 
 
10.3.3 Data Listings 
Data listings will be prepared by treatment group and center for all patients with any abnormal 
laboratory value at any time-point (including screening, baseline).  
TLF Listing: Patients with abnormal laboratory measurements  
 


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10.3.4 Urinalysis 
Incidence of changes in urinalysis will be summarized by treatment. A summary table with number 
of patients with change from Absent at baseline to Present during trial will be summarized.  
TLF Table: Incidence of changes from baseline in urinalysis measurements during the trial – 
Safety Analysis Set 
10.4 Vital Signs 
10.4.1 Vital Signs 
Baseline for all vital signs analyses will be the values obtained at the last assessment prior to the 
first dose of IMP. Treatment-emergent vital signs data will include tests completed after the first 
dose of IMP through the time of residual drug effect. End of trial will include the last post-baseline 
observation during the trial. 
10.4.1.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline at end of trial will be presented for 
each vital signs variable. In addition, descriptive statistics, i.e., the number of patients with data, 
mean (standard deviation), median, minimum, and maximum values, will be presented for observed 
values and change from baseline at each time-point for each vital signs variable.  
TLF Table: Summary of vital signs parameters by visit – Safety Analysis Set 
 
10.4.1.2 Markedly Abnormal Changes 
Summary tables will be prepared displaying the number and percentage of patients with normal 
baseline values who had one or more pre-specified markedly abnormal treatment-emergent value, 
as defined in Appendix 1. 
TLF Table: Incidence of Markedly abnormal vital signs measurements– Safety Analysis Set 
 
10.4.1.3 Data Listings 
Data listings will be prepared by center for all patients with any abnormal vital signs value at any 
time-point (including screening, baseline). 
TLF Listing: Patients with Markedly abnormal vital signs measurements 
 


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11 Interim Analysis 
As the trial was terminated early due to feasibility reasons, planned interims analyses have been 
cancelled. 


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12 Deviations from Protocol Analysis 
List of key secondary endpoints has been revised and testing procedure changed from Holm’s to 
fixed-sequence.   
Due to the trial being terminated early due to feasibility reasons, the statistical analysis plan has 
been reduced. See change log for details. 
 
 
 
    


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13 References 
ADDPLAN, Inc., an Aptiv Solutions Company (2011). ADDPLAN BASE version 6.0 User 
Manual, Rev. 2. Aptiv Solutions, Cologne, Germany. 
Lin, D.Y., Wei, L.J., and Ying, Z. (1993). Checking the Cox model with cumulative sums of 
martingale-based residuals. Biometrika 80, 557–572. 
Prentice RL, Williams BJ and Peterson AV. On the regression analysis of multivariate failure 
time data. Biometrika 1981;68:373-79. 
Wassmer G. Planning and Analyzing Adaptive Group Sequential Survival trials. Biom. J 2006 
Aug;48(4):714-29. 
Zhao et al., A Multiple Imputation Method for Sensitivity Analyses of Time-To-Event Data With 
Possibly Informative Censoring. J Biopharm Stat 2014 24(2) 229-253. 
Andersen P.K. and Gill, R.D. Cox’s Regression Model for Counting Processes: A Large Sample 
Study.  The Annals of Statistics 1982; 4: 1100-1120. 
Jennison, C. and Turnbull, B.W. (2000), Group Sequential Methods with Applications to Clinical 
Trials, New York: Chapman & Hall. 
Wei, L.J., Lin, D.Y. and Weissfeld, L. Regression Analysis of Multivariate Incomplete Failure 
Time Data by Modeling Marginal Distributions. JASA 1989; 408:1065-1073. 
Wu, L. and Cook, R.J. Misspecification of Cox regression models with composite endpoints. 
Stats In Med 2012; 31: 3545-3562.  
Blanche, P., Dartigues, J.F. and Jacqmin-Gadda, H.  Review and comparison of ROC curve 
estimators for a time-dependent outcome with marker-dependent censoring.  Biometrical J., 
55(2013) 5, 687-704. 
Hung, H. and Chiang, C. Optimal composite markers for time-dependent receiver operator 
characteristic curves with censored survival data.  Scandinavian Journal of Statistics (2010)37, 664-
679. 
Uno, H. Cai, T., Tian, L. and Wei, L. Evaluating prediction rules for t-year survivors with censored 
regression models. JAMA (2007)102, 527-537. 
Kalbfleisch, J.D. and Prentice, R.L.(2002) The Statistical Analysis of Failure Time Data, 2 nd 
Edition, New York: Wiley. 
Therneau, T.M. and Grambsch, P.M. (2000) Modeling Survival Data: Extending the Cox Model, 
New York: Springer-Verlag. 


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14 Tables, Listings and Figures 
An overview of the tables, listings and figures (TLFs) to be produced is provided in a separate 
document. 


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Appendix 1 
Markedly Abnormal Vital Signs and Electrocardiograms 
(ECGs) 
 
Table 2 
Markedly abnormal Criteria for Vital Signs* 
Variable 
Criterion Value 
Change from Baseline 
Systolic blood pressure 
 180 mmHg 
 90 mmHg 
Increase of  20 mmHg  
Decrease of  20 mmHg 
Diastolic blood pressure 
 105 mmHg  
 50 mmHg 
Increase of  15 mmHg  
Decrease of  15 mmHg 
Pulse rate 
 120 bpm 
 50 bpm 
Increase of  15 bpm 
Decrease of  15 bpm 
Body weight 
None 
 
Increase of  7% 
Decrease of  7% 
Body temperature 
> 38.3 C 
Increase to  39.4C 
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the specified 
change from baseline. 
 
Table 3 
Abnormal Criteria for Quantitative ECG Data 
Variable 
Baseline  
Abnormal Treatment-Emergent Value 
ECG heart rate 
Normal 
 50 bpm and decrease from baseline of  15 bpm 
 120 bpm and increase from baseline of  15 bpm 
Duration of PR interval 
Normal 
≥ 220 msec 
Duration of QRS interval 
Normal 
≥ 120 msec 
Duration of QTc interval 
Normal 
≥ 450 msec 
Duration of QTc interval 
Normal 
≥ 480 msec 
Duration of QTc interval 
Normal 
≥ 500 msec 
Duration of QTc interval 
Not applicable 
Increase from baseline of ≥ 30 msec 
Duration of QTc interval 
Not applicable 
Increase from baseline of ≥ 60 msec 
 


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Appendix 2  
SMQs for AE Medical History of Special Interest 
Table 4 
Cardiovascular Events 
SMQ  
SMQ code 
Myocardial infarction 
20000047 
Ischaemic central nervous system vascular conditions 
20000063 
Haemorrhagic central nervous system vascular conditions 
20000064 
Embolic and thrombotic events, arterial  
20000082 
Other ischaemic heart  disease  
20000168 
 
Table 5 
Diabetes Events 
SMQ  
SMQ code 
Hyperglycaemia/new onset diabetes mellitus 
20000041 
 


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Appendix 3  
ATC codes and MedDRA terms for disease progression 
A list of ATC codes for antiandrogens and additional therapies classified as disease progression are 
defined below. Please note that the list may be non-extensive. 
Table 6 
ATC Codes for Antiandrogens 
Level 5 codes 
L02BB01 Flutamide 
L02BB02 Nilutamide 
L02BB03 Bicalutamide 
L02BB04 Enzalutamide 
G03HA01 Cyproterone 
 
Table 7 
ATC codes for Additional Therapy 
Level 5 codes 
L01DB07 Mitoxantrone 
L01CD02 Docetaxel 
L01XX11 Estramustine 
L01CD01 Paclitaxel 
L02AA01 Diethylstilbestrol 
L02AA02 Polyestradiol phosphate 
L02AA03 Ethinylestradiol 
L02AA04 Fosfestrol 
L02AB01 Megestrol 
L02BG01 Aminoglutethimide 
L02BX03 Abiraterone  
G01AF11 Ketoconazole 
 
Investigators recording of disease progression are marked as a tick-box on the Adverse Event form 
in the eCRF. The MedDRA terms to be used for radiation and second line treatment are defined 
below.  
 


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Table 8 
MedDRA Codes (preferred terms) for Radiation 
10006089 
Brachytherapy to prostate 
PT 
10014442 
Electron radiation therapy to prostate 
PT 
10017683 
Gamma radiation therapy to prostate 
PT 
10034955 
Photon radiation therapy to prostate 
PT 
10061544 
Radiotherapy to prostate 
PT 
10048205 
X-ray therapy to prostate 
PT 
10014435 
Electron radiation therapy to bone 
PT 
10017675 
Gamma radiation therapy to bone 
PT 
10034947 
Photon radiation therapy to bone 
PT 
10062089 
Radiotherapy to bone 
PT 
10048197 
X-ray therapy to bone 
PT 
 
Table 9 
MedDRA Codes (preferred terms) for Second Line Treatment 
10061916 
Prostatectomy 
PT 
10050756 
Radical prostatectomy 
PT 
10038961 
Retro-pubic prostatectomy 
PT 
10042594 
Suprapubic prostatectomy 
PT 
10044445 
Transurethral prostatectomy 
PT 
 
The following terms are also to be classified as investigators recording of disease progression, in 
case the investigator did not check the tick-box, but only recorded the AE. 
Table 10 
MedDRA Codes (preferred terms) for additional classification of investigators 
recording of disease progression 
10010264 
Condition aggravated 
PT 
10061818 
Disease progression 
PT 
10061819 
Disease recurrence 
PT 
10048669 
Terminal state 
PT 
10051398 
Malignant neoplasm progression 
PT 
10027452 
Metastases to bone 
PT 
10027459 
Metastases to lymph nodes 
PT 
10027457 
Metastases to liver 
PT 
10027458 
Metastases to lung 
PT 
10027463 
Metastases to pleura 
PT 
10062194 
Metastasis 
PT 
 


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Appendix 4  
ATC codes and MedDRA terms for Prohibited Therapy 
A list of ATC codes for prohibited concomitant medication are defined below. Please note that the 
list may be non-extensive. 
Table 11 
ATC codes for prohibited concomitant medication 
Level 5 codes 
L02AB01 Megestrol acetate 
G01AF11 Ketoconazole        
L02BX03 Abiraterone  
L02BB04 Enzalutamide 
L02BB01 Flutamide 
L02BB02 Nilutamide 
L02BB03 Bicalutamide 
G03HA01 Cyproterone 
L02AA01 Diethylstilbestrol 
L02AA02 Polyestradiol phosphate 
L02AA03 Ethinylestradiol 
L02AA04 Fosfestrol 
 
Additionally all substances in the ATC G03 therapeutic subgroup are considered as prohibited 
concomitant medications.    
Table 12 
MedDRA code (preffered term) for prohibited therapy 
10049628 
Bilateral orchidectomy 
PT 
 
 
 
 
 
 
 
 


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Appendix 5 
Cardiovascular Endpoint Definitions 
Endpoints / Event definitions 
The cardiovascular endpoint definitions given below are based on the 2014 Definitions for 
Cardiovascular Endpoint Events in Clinical Trials1.  
1.1 
Death 
All deaths will be categorized as Cardiovascular, non-Cardiovascular or Undetermined. 
Cardiovascular Death: Cardiovascular Death is defined as death resulting from an acute 
myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death 
due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other 
cardiovascular causes. 
Non-cardiovascular Death: Non-cardiovascular death is defined as any death that is not thought to 
be due to a cardiovascular cause (e.g. cancer related death). Non-cardiovascular deaths will also be 
sub-classified as related to prostate cancer progression or to other causes. 
Undetermined Cause of Death: Undetermined cause of death refers to a death not attributable to 
one of the above categories of cardiovascular death or to a non-cardiovascular cause, due to absence 
of any information (e.g., the only available information is “patient died”). Undetermined death will 
be presumed and analyzed as non-cardiovascular deaths on the secondary analysis. 
1.2 
Myocardial Infarction 
The adjudication of myocardial infarction as a clinical endpoint will consider the occurrence 
relative to a percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). 
(It will also be consistent with the revised American College of Cardiology (ACC) / European 
Society of Cardiology (ESC) myocardial infarction definition document.) 
In the absence of a PCI or CABG, a spontaneous myocardial infarction is defined as: 
 
 
 
 
 
For patients having a PCI, a myocardial infarction will be defined as: 
CK-MB (or troponin I/T or CK in the absence of CK-MB) >3 x ULN for samples obtained 
within 24 hours of the procedure if the baseline values were normal or at least a 50% increase 


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over elevated baseline values that were stable or decreasing or development of new 
pathological Q waves (>0.04 seconds) in at least 2 contiguous leads in the absence of LBBB on 
the ECG. Symptoms of cardiac ischemia are not required. 
After CABG surgery, a myocardial infarction is defined as either: 
CK-MB (or CK in the absence of CK-MB) >5 x ULN for samples obtained within 24 hours of 
the procedure with development of new pathological Q waves in at least 2 contiguous leads in 
the absence of LBBB on the ECG. 
CK-MB (or CK in the absence of CK-MB) >10 x ULN for samples obtained within 24 hours of 
the procedure with or without development of new pathological Q waves in at least 2 
contiguous leads in the absence of LBBB on the ECG. 
Note: For institutions that report an 'intermediate' or 'equivocal' range for biomarker elevation that 
is not definitively associated with myocardial necrosis or infarction then the ULN should be the 
lower value for the necrosis or infarct range, not the 'equivocal' or 'intermediate' range lower 
value. 
1.3 
Unstable Angina Requiring Hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 
Cerebrovascular Accident (Stroke) 
Stroke is defined as an acute focal neurological deficit of sudden onset that is not due to an 
identifiable non-vascular cause (i.e. brain tumor, trauma, brain procedures, metabolic condition) 


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a) that is not reversible within 24 hours or results in death (in <24 hours) 
or  
b) that resolves in<24 hours and is accompanied by clear evidence of a new stroke on cerebral 
brain imaging studies (brain Computed tomography [CT] or Magnetic Resonance Imaging 
[MRI] scans) 
Classification: 
Ischemic Stroke: is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by central nervous system (CNS) infarction. 
Note: Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an 
ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. 
Hemorrhagic Stroke: is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
Note: Subdural hematomas without new neurologic symptoms are intracranial hemorrhagic events 
and not strokes. 
Undetermined Etiology: is defined as an acute episode of focal or global neurological dysfunction 
caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction but with insufficient information to allow categorization as either ischemic or 
hemorrhagic. 
 
 
 
1  Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular   
Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on C linical Data 
Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol 2015 Jul 28;66(4):403-69.