A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease

Composite MACE endpoint was defined as: death due to any cause, non-fatal myocardial infarction or non-fatal stroke. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict first confirmed (adjudicated) occurrence of composite MACE over time. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

The 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. The results from the EQ-5D-5L questionnaire were converted into quality adjusted life year (QALY) units. The QALY is estimated by combining the value of life (utility value) and length of life. Quality adjusted life years are based on a principle assuming that a year of life lived in perfect health is worth 1 QALY and that a year of life lived in a state of less than perfect health is worth less than 1.

Time frame: Baseline to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

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, each item could be scored between 0 never to 4 always, maximum total score 32), avoidance (5 items, each item could be scored between 0 never to 4 always, maximum total score 20) and attention (5 items, each item could be scored between 0 never to 4 always, maximum total score 20). A higher score indicated greater cardiac anxiety and the total score range was between 0 and 72. Change from baseline in CAQ Global score and score per domain are presented.

Time frame: Baseline to Days 168 and 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

The DASI is a self-administered instrument developed to measure functional capacity in subjects with cardiovascular disease (CVD). 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 was 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 was calculated with a higher score indicating a higher functional capacity. The minimum score is 0 and the maximum score is 58.2 points. Change from baseline in DASI Global score is presented.

Time frame: Baseline to Days 168 and 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

Lower urinary tract symptoms were measured with the IPSS Version 1 (IPSS-1). The IPSS is a subject-administered questionnaire containing seven items to evaluate symptoms of urinary obstruction (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, nocturia) over the preceding week. Each urinary symptom question was assigned points from 0 to 5 indicating increasing severity of the particular symptom. The total IPSS-1 score was then calculated as summation over the responses for all 7 questions. The total IPSS-1 score was transformed to a scale from 0 (lowest score) to 100 (highest score). Higher scores reflect higher severity of symptoms. The IPSS-1 included an additional single question to assess a subject's QoL in relation to his urinary symptoms; response to this question was analyzed separately and was not included in the total IPSS score. The score was similarly scaled from 0 to 100. Change from baseline in IPSS Total and QoL scores are presented.

Time frame: Baseline to Days 168 and 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

Number of subjects shifting from normal value(s) in vital signs (pulse and blood pressure) at baseline to clinically significant abnormal value(s) at end-of-trial are presented. Note: Only subjects with appropriate baseline and post-baseline data are included in the evaluation.

Time frame: Baseline to Day 336 (end-of-trial)

Population: The safety analysis set consisted of all treated subjects (who received at least one dose of IMP) and was analyzed based on the actual treatment received. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

The intensity of AE was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.02) 5-point scale. AE were categorized as 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) and Grade 5 Death. Events with grades 3, 4 and 5 were categorized as severe.

Time frame: Start of IMP treatment until 3 months after last dosing of IMP

Population: The safety analysis set consisted of all treated subjects (who received at least one dose of IMP) and was analyzed based on the actual treatment received.

Adverse events were recorded from signed informed consent until end-of-trial. Adverse events with onset after start of IMP treatment, and within 3 months after (1 month=28 days) last dosing of IMP, were considered 'treatment-emergent' and are presented for the safety analysis set.

Time frame: Start of IMP treatment until 3 months after last dosing of IMP

Population: The safety analysis set consisted of all treated subjects (who received at least one dose of IMP) and was analyzed based on the actual treatment received.

Median levels and interquartile ranges for serum testosterone at Days 28, 168, and 336 are presented.

Time frame: Days 28, 168 and 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment. Subjects analyzed for this endpoint represent subjects who were evaluable for this outcome measure.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict confirmed (adjudicated) CV-related death. Percentage of observed subjects with outcome measure events during the trial are reported. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict death due to any cause. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Time to failure in PFS was defined as the time, measured in days, from randomization to the first occurrence of either death, radiographic disease progression, introduction of additional prostate cancer therapies for progression, or PSA failure. Subjects who discontinued treatment with IMP or withdrew from the trial were censored at the time of discontinuation/withdrawal. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict failure in PFS. Percentage of observed subjects with outcome measure events during the trial are reported.

Time frame: From randomization to end-of-trial for each subject (subjects not censored at Day 336)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict first confirmed (adjudicated) myocardial infarction. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict confirmed (adjudicated) occurrence of CV-related death, non-fatal myocardial infarction or non-fatal stroke. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict first confirmed (adjudicated) stroke. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict first confirmed (adjudicated) unstable angina requiring hospitalization. Percentage of observed subjects with outcome measure events during the trial are reported. Subjects were censored at the time a subject discontinued the trial, was lost to follow-up, discontinued treatment with IMP, initiated treatment with prohibited medication (including hormonal combination therapy), or at Day 336, whichever occurred first.

Time frame: Randomization to Day 336 (end-of-trial)

Population: The FAS consisted of all randomized and treated subjects (who received at least one dose of IMP) and was analyzed based on the planned (randomized) treatment.

The total number of CABG or PCI procedures observed for each subject over the duration of the trial

Time frame: First dose of IMP to Day 336 (end-of-trial)

CV-related ER visit events (that did not lead to hospitalization) was observed from the first exposure to IMP up until Day 336 for each subject.

Time frame: First dose of IMP to Day 336 (end-of-trial)

The total number of CV-related hospitalizations over the duration of the trial was defined as the number of hospitalizations due to CV-related adverse events, observed from the first exposure to IMP up until Day 336 for each subject.

Time frame: First dose of IMP to Day 336 (end-of-trial)