| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071119 |
| E.1.2 | Term | Hormone-dependent prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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) |
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| E.2.2 | Secondary objectives of the trial |
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
Prostate Cancer-Related Objectives:
To monitor testosterone levels at Days 28, 168, and 336 in the degarelix and leuprolide treatment groups
Health Economics and Patient Reported Outcome Objectives:
To compare the effects of degarelix with leuprolide with regards to healthcare resource use
Safety Objective:
To evaluate and compare the overall safety and tolerability of degarelix with leuprolide
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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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:
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, 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.
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| E.4 | Principal exclusion criteria |
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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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time from randomization to the first confirmed (adjudicated) occurrence of the MACE composite endpoint. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For each patient randomized into the study, the endpoint is evaluated from the time of randomization until the patient either completes or discontinues from the trial, whichever occurs first. |
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| E.5.2 | Secondary end point(s) |
1.Time from randomization to occurrence of the individual components of the MACE composite endpoint, i.e. myocardial infarction (fatal, non-fatal) or stroke (fatal, non-fatal).
2.Time from randomization to occurrence of unstable angina requiring hospitalization (fatal, non-fatal).
3.Time from randomization to death due to any cause.
4.Time from randomization to CV-related death.
5. Testosterone levels.
6. Time from randomization to PFS failure.
7.Change from baseline in IPSS Total and QoL scores.
8.Total number of CV-related hospitalization events over the duration of the trial.
9.Total number of coronary artery by-pass grafting (CABG) or percutaneous coronary intervention (PCI) procedures over the duration of the trial.
10.Total number of emergency room (ER) visit events over the duration of the trial.
11.Change in utility, based on EQ-5D-5L.
12.Change from baseline in DASI Global score.
13.Change from baseline in CAQ Global score and score per domain.
14.Incidence and intensity of adverse events
15.Changes in vital signs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4.For each patient(P) randomized into the study, the endpoint(EP) is evaluated from the time of randomiz until the (P) either completes or disc from the trial, whichever occurs first
5.Days 28,168and336
6.For each P rand into the study, the EP ev from the time of rand until the P either completes or disc from the trial, whichever occurs first
7,8.Days 0,84,168,252,336 and/or end of treatment(EoT)
9.For each P rand into the study, the EP is ev from the time of rand until the P either completes or disc from the trial, whichever occurs first
10.For each P rand into the study, the EP is ev from the time of rand until the P either completes or disc from the trial, whichever occurs first
11,13.Days 0,168 and 336 and/or EoT
14,15.Days 0,28,56,84, 112,140,168,196,224,252,280,308,336
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 72 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Slovakia |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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