Trial Outcomes & Findings for A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer (NCT NCT01946204)

NCT ID: NCT01946204

Last Updated: 2025-11-12

Results Overview

MFS was defined as the time from randomization to the time of first evidence of BICR-confirmed bone or soft tissue distant metastasis or death due to any cause, whichever occurred first. The MFS data for participants without metastasis or death were performed for US or ex-US regulatory purposes. Radiographic scans (bone scans and computerized tomography \[CT\] or magnetic resonance imaging \[MRI\] of the chest, abdomen, and pelvis) were performed for detection of metastasis throughout the study.

• Recruitment status: ACTIVE_NOT_RECRUITING
• Study phase: PHASE3
• Target enrollment: 1207 participants
• Primary outcome timeframe: Up to approximately 43 Months
• Results posted on: 2025-11-12

Participant Flow

Participant milestones

Measure	Placebo Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Overall Study STARTED	401	806
Overall Study Treated	398	803
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	401	806

Reasons for withdrawal

Measure	Placebo Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Overall Study Death	38	59
Overall Study Withdrawal by Subject	37	50
Overall Study Lost to Follow-up	3	7
Overall Study Ongoing	316	687
Overall Study Other	7	3

Baseline Characteristics

A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer

Baseline characteristics by cohort

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Total n=1207 Participants Total of all reporting groups
Age, Continuous	74.1 years STANDARD_DEVIATION 7.92 • n=10 Participants	73.7 years STANDARD_DEVIATION 8.07 • n=10 Participants	73.9 years STANDARD_DEVIATION 8.02 • n=20 Participants
Sex: Female, Male Female	0 Participants n=10 Participants	0 Participants n=10 Participants	0 Participants n=20 Participants
Sex: Female, Male Male	401 Participants n=10 Participants	806 Participants n=10 Participants	1207 Participants n=20 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=10 Participants	11 Participants n=10 Participants	16 Participants n=20 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	338 Participants n=10 Participants	659 Participants n=10 Participants	997 Participants n=20 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	58 Participants n=10 Participants	136 Participants n=10 Participants	194 Participants n=20 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=10 Participants	4 Participants n=10 Participants	4 Participants n=20 Participants
Race (NIH/OMB) Asian	47 Participants n=10 Participants	93 Participants n=10 Participants	140 Participants n=20 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=10 Participants	0 Participants n=10 Participants	0 Participants n=20 Participants
Race (NIH/OMB) Black or African American	20 Participants n=10 Participants	48 Participants n=10 Participants	68 Participants n=20 Participants
Race (NIH/OMB) White	276 Participants n=10 Participants	524 Participants n=10 Participants	800 Participants n=20 Participants
Race (NIH/OMB) More than one race	0 Participants n=10 Participants	1 Participants n=10 Participants	1 Participants n=20 Participants
Race (NIH/OMB) Unknown or Not Reported	58 Participants n=10 Participants	136 Participants n=10 Participants	194 Participants n=20 Participants
Region of Enrollment Australia	11 Participants n=10 Participants	30 Participants n=10 Participants	41 Participants n=20 Participants
Region of Enrollment Austria	2 Participants n=10 Participants	4 Participants n=10 Participants	6 Participants n=20 Participants
Region of Enrollment Belgium	3 Participants n=10 Participants	4 Participants n=10 Participants	7 Participants n=20 Participants
Region of Enrollment Canada	21 Participants n=10 Participants	61 Participants n=10 Participants	82 Participants n=20 Participants
Region of Enrollment Czech Republic	14 Participants n=10 Participants	20 Participants n=10 Participants	34 Participants n=20 Participants
Region of Enrollment Denmark	7 Participants n=10 Participants	14 Participants n=10 Participants	21 Participants n=20 Participants
Region of Enrollment Finland	5 Participants n=10 Participants	7 Participants n=10 Participants	12 Participants n=20 Participants
Region of Enrollment France	21 Participants n=10 Participants	39 Participants n=10 Participants	60 Participants n=20 Participants
Region of Enrollment Germany	20 Participants n=10 Participants	31 Participants n=10 Participants	51 Participants n=20 Participants
Region of Enrollment Hungary	1 Participants n=10 Participants	4 Participants n=10 Participants	5 Participants n=20 Participants
Region of Enrollment Israel	7 Participants n=10 Participants	7 Participants n=10 Participants	14 Participants n=20 Participants
Region of Enrollment Italy	12 Participants n=10 Participants	24 Participants n=10 Participants	36 Participants n=20 Participants
Region of Enrollment Japan	21 Participants n=10 Participants	34 Participants n=10 Participants	55 Participants n=20 Participants
Region of Enrollment Netherlands	11 Participants n=10 Participants	8 Participants n=10 Participants	19 Participants n=20 Participants
Region of Enrollment New Zealand	2 Participants n=10 Participants	6 Participants n=10 Participants	8 Participants n=20 Participants
Region of Enrollment Norway	3 Participants n=10 Participants	4 Participants n=10 Participants	7 Participants n=20 Participants
Region of Enrollment Poland	6 Participants n=10 Participants	28 Participants n=10 Participants	34 Participants n=20 Participants
Region of Enrollment Romania	5 Participants n=10 Participants	7 Participants n=10 Participants	12 Participants n=20 Participants
Region of Enrollment Russia	11 Participants n=10 Participants	24 Participants n=10 Participants	35 Participants n=20 Participants
Region of Enrollment Slovakia	6 Participants n=10 Participants	11 Participants n=10 Participants	17 Participants n=20 Participants
Region of Enrollment South Africa	17 Participants n=10 Participants	35 Participants n=10 Participants	52 Participants n=20 Participants
Region of Enrollment Spain	36 Participants n=10 Participants	95 Participants n=10 Participants	131 Participants n=20 Participants
Region of Enrollment Sweden	3 Participants n=10 Participants	10 Participants n=10 Participants	13 Participants n=20 Participants
Region of Enrollment Taiwan, Province Of China	5 Participants n=10 Participants	14 Participants n=10 Participants	19 Participants n=20 Participants
Region of Enrollment United Kingdom	38 Participants n=10 Participants	61 Participants n=10 Participants	99 Participants n=20 Participants
Region of Enrollment United States	113 Participants n=10 Participants	224 Participants n=10 Participants	337 Participants n=20 Participants

PRIMARY outcome

Timeframe: Up to approximately 43 Months

Population: Intent-to-Treat (ITT) population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

MFS was defined as the time from randomization to the time of first evidence of BICR-confirmed bone or soft tissue distant metastasis or death due to any cause, whichever occurred first. The MFS data for participants without metastasis or death were performed for US or ex-US regulatory purposes. Radiographic scans (bone scans and computerized tomography [CT] or magnetic resonance imaging [MRI] of the chest, abdomen, and pelvis) were performed for detection of metastasis throughout the study.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Metastasis-Free Survival (MFS) by Blinded Independent Central Review (BICR) Ex-US Regulatory	15.70 Months Interval 14.55 to 18.4	40.51 Months Interval 29.7 to 40.51
Metastasis-Free Survival (MFS) by Blinded Independent Central Review (BICR) US Regulatory	16.20 Months Interval 14.59 to 18.4	40.51 Months NA signifies: lower and upper limit of Confidence Interval(CI) was not estimable as lower, or upper, or both limits of CI for survivor function were above 0.5 using log(-log) transformation (default of Statistical Analysis System\[SAS\] Proc Lifetest).

SECONDARY outcome

Timeframe: Up to approximately 43 Months

Population: ITT population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

Time to metastasis (TTM) was defined as the time from randomization to the time of the scan that showed first evidence of BICR-confirmed radiographically detected bone or soft tissue distant metastasis. The TTM data for participants without metastasis were performed for US or ex-US regulatory purposes. Radiographic scans (bone scans and CT or MRI of the chest, abdomen, and pelvis) were performed for detection of metastasis throughout the study.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Time to Metastasis (TTM) US Regulatory	16.59 Months Interval 14.59 to 18.46	40.51 Months NA signifies: lower and upper limit of CI was not estimable (NA) as lower, or upper, or both limits of CI for survivor function were above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).
Time to Metastasis (TTM) EX-US Regulatory	15.70 Months Interval 14.55 to 18.4	40.51 Months Interval 31.15 to 40.51

SECONDARY outcome

Timeframe: Up to approximately 43 Months

Population: ITT population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

PFS defined as time from randomization to first documentation of BICR-confirmed radiographic progressive disease (PD) (development of distant/local/regional metastasis)/death due to any cause whichever occurred first. PFS data for participants without loco-regional disease were performed for US/ex-US regulatory purposes. Radiographic scans (bone scans and CT/MRI of chest,abdomen,pelvis) performed for detection of metastasis throughout study. PD based on RECIST v1.1; Subjects with one measurable lesion, At least 20% increase in sum of diameters of target lesions taking as reference smallest sum on study. In addition, sum must demonstrate an absolute increase of at least 5 millimeter(mm). Also, appearance of one/more new lesions was also considered PD. Subjects with non-measurable disease as per CT/MRI scans, unequivocal progression/appearance of one or more new lesions was considered PD. For new bone lesions detected on bone scans, second imaging (CT/MRI) was required to confirm PD.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Progression-free Survival (PFS) US Regulatory	14.72 Months Interval 14.49 to 18.37	40.51 Months NA signifies: lower and upper limit of CI was not estimable (NA) as lower, or upper, or both limits of CI for survivor function were above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).
Progression-free Survival (PFS) EX-US Regulatory	14.65 Months Interval 11.27 to 17.97	40.51 Months Interval 29.4 to 40.51

SECONDARY outcome

Timeframe: Up to approximately 43 Months

Population: ITT population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

Time to symptomatic progression was defined as the time from randomization to documentation in the CRF of any of the following (whichever occurred earlier): a) development of a skeletal-related event (pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to the bone); b) pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy; or c) development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Time to Symptomatic Progression	NA Months Interval 36.83 to NA signifies: median and upper limit of CI were NA. Median was NA as KM curve did not drop to 0.5 or below. Upper limit was NA as upper limit of CI for survivor function was above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).	NA Months The median was not estimable(NA) as Kaplan-Meier(KM) curve did not drop to 0.5 or below. The lower or upper limit was NA as lower or upper limit of CI for survivor function was above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).

SECONDARY outcome

Timeframe: Up to approximately 43 months

Population: ITT population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

Overall survival was defined as the time from randomization to the date of death due to any cause.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Overall Survival	39.03 Months Interval 39.03 to Here NA signifies that the upper limit of Confidence Interval (CI) was not estimable as upper limit of CI for the survivor function was above 0.5 using log(-log) transformation (the default of SAS Proc Lifetest).	NA Months The median was not estimable(NA) as Kaplan-Meier(KM) curve did not drop to 0.5 or below. The lower or upper limit was NA as lower or upper limit of CI for survivor function was above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).

SECONDARY outcome

Timeframe: Up to approximately 43 months

Population: ITT population included all participants who were randomized into the study, with study drug assignments designated according to initial randomization, regardless of whether participants received what was assigned.

Time to initiation of cytotoxic chemotherapy was defined as the time from randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.

Outcome measures

Measure	Placebo n=401 Participants Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=806 Participants Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Time to Initiation of Cytotoxic Chemotherapy	NA Months The median was not estimable (NA) as KM curve did not drop to 0.5 or below. The lower or upper limit was NA as lower or upper limit of CI for survivor function was above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).	NA Months The median was not estimable (NA) as KM curve did not drop to 0.5 or below. The lower or upper limit was NA as lower or upper limit of CI for survivor function was above 0.5 using log(-log) transformation (default of SAS Proc Lifetest).

Adverse Events

Placebo

Serious events: 92 serious events

Other events: 329 other events

Deaths: 1 deaths

Apalutamide

Serious events: 199 serious events

Other events: 716 other events

Deaths: 10 deaths

Serious adverse events

Measure	Placebo n=398 participants at risk Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=803 participants at risk Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Blood and lymphatic system disorders Anaemia	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Haemolytic Uraemic Syndrome	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Acute Coronary Syndrome	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Acute Myocardial Infarction	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Angina Pectoris	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Angina Unstable	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Aortic Valve Incompetence	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Atrial Fibrillation	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.87% 7/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Atrial Flutter	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Bradycardia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Cardiac Failure	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Cardiac Failure Acute	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Cardiac Failure Congestive	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.50% 4/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Cardiomyopathy	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Coronary Artery Disease	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Coronary Artery Occlusion	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Myocardial Infarction	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Myocardial Ischaemia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Right Ventricular Dysfunction	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Sinus Node Dysfunction	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Stress Cardiomyopathy	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Supraventricular Tachycardia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Cardiac disorders Ventricular Tachycardia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Congenital, familial and genetic disorders Hydrocele	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Ear and labyrinth disorders Vertigo	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Endocrine disorders Hypothyroidism	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Eye disorders Choroidal Haemorrhage	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Eye disorders Open Angle Glaucoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Eye disorders Retinal Detachment	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal Hernia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal Pain	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Chronic Gastritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Colitis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.62% 5/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Enteritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Erosive Duodenitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Gastrointestinal Haemorrhage	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Gingival Bleeding	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Ileus	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Incarcerated Umbilical Hernia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Inguinal Hernia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Inguinal Hernia Strangulated	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Intestinal Haemorrhage	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Intestinal Mass	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Large Intestine Polyp	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Lower Gastrointestinal Haemorrhage	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Melaena	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Mouth Ulceration	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Oesophageal Achalasia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis Acute	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Rectal Haemorrhage	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Small Intestinal Haemorrhage	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Small Intestinal Obstruction	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Umbilical Hernia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Asthenia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Chest Pain	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Dystrophic Calcification	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Gait Disturbance	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders General Physical Health Deterioration	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Hyperthermia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Multiple Organ Dysfunction Syndrome	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Non-Cardiac Chest Pain	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Oedema Peripheral	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Pain	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Pyrexia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.62% 5/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Soft Tissue Inflammation	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Hepatobiliary disorders Cholangitis Acute	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Hepatobiliary disorders Cholecystitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Hepatobiliary disorders Cholelithiasis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Neutropenia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Gastroenteritis Clostridial	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations H1n1 Influenza	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Influenza	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Necrotising Fasciitis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Osteomyelitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	1.1% 9/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Pneumonia Parainfluenzae Viral	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Prostatic Abscess	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Pulmonary Tuberculosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Sepsis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.87% 7/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Severe Fever with Thrombocytopenia Syndrome	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Skin Infection	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Staphylococcal Skin Infection	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Urinary Tract Infection	0.75% 3/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	1.2% 10/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Anal Abscess	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Appendiceal Abscess	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Appendicitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Bronchitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Cellulitis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Cellulitis Streptococcal	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Cellulitis of Male External Genital Organ	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Clostridium Difficile Infection	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Cystitis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Diverticulitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Erysipelas	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Subdural Haematoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Metabolic Alkalosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back Pain	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Gouty Arthritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Joint Swelling	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Lumbar Spinal Stenosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Muscular Weakness	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Ischaemic Stroke	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Lacunar Stroke	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Loss of Consciousness	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Paraparesis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Polyneuropathy	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Presyncope	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Seizure	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Spinal Cord Compression	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Syncope	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.62% 5/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Thrombotic Cerebral Infarction	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Transient Ischaemic Attack	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Product Issues Device Occlusion	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Alcoholism	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Anxiety	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Confusional State	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Delirium	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Major Depression	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Suicidal Ideation	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Acute Kidney Injury	1.0% 4/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.75% 6/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Azotaemia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Bladder Mass	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Bladder Neck Sclerosis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Urinary Tract Infection Bacterial	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Urosepsis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.62% 5/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Acetabulum Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Anastomotic Complication	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Ankle Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Avulsion Fracture	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Compression Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Craniocerebral Injury	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Facial Bones Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.75% 6/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Femoral Neck Fracture	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Femur Fracture	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Foot Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Rib Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Road Traffic Accident	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Seroma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Spinal Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Bladder Necrosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Calculus Urethral	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Calculus Urinary	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Cystitis Haemorrhagic	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Dysuria	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Haematuria	2.0% 8/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	1.6% 13/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Hydronephrosis	2.0% 8/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	1.00% 8/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Lower Urinary Tract Symptoms	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Micturition Disorder	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Pollakiuria	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Renal Failure	0.75% 3/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Renal Impairment	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Strangury	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Ureteric Obstruction	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Ureterolithiasis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urinary Bladder Haemorrhage	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urinary Retention	3.8% 15/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	1.2% 10/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urinary Tract Obstruction	1.0% 4/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Reproductive system and breast disorders Prostatic Mass	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Reproductive system and breast disorders Prostatitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Erythema Multiforme	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Granuloma Annulare	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Aortic Aneurysm	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Arterial Occlusive Disease	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Arteriosclerosis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Deep Vein Thrombosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Haematoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Hypertension	0.75% 3/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Hypertensive Crisis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Hypotension	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Peripheral Arterial Occlusive Disease	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Peripheral Ischaemia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Venous Aneurysm	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Venous Thrombosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urethral Stenosis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Gastrointestinal Stoma Complication	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Hip Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Humerus Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Joint Injury	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Ligament Sprain	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Lower Limb Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Lumbar Vertebral Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Perirenal Haematoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Pneumothorax Traumatic	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Procedural Pain	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Pubis Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Radius Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Thoracic Vertebral Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Toxicity to Various Agents	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Upper Limb Fracture	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Alanine Aminotransferase Increased	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Aspartate Aminotransferase Increased	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Blood Bilirubin Increased	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Blood Urine Present	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Eastern Cooperative Oncology Group Performance Status Worsened	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Weight Decreased	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Decreased Appetite	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Dehydration	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hyponatraemia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.62% 5/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in Extremity	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pathological Fracture	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Periarthritis	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Periostitis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Polyarthritis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Polymyalgia Rheumatica	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pseudarthrosis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Spinal Flattening	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Symphysiolysis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of Colon	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign Neoplasm of Bladder	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder Cancer	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Cancer	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Cancer Stage Ii	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric Cancer	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Neoplasm Malignant	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Melanoma	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Neoplasm of Renal Pelvis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Cancer Recurrent	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal Cancer	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal Cell Carcinoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous Cell Carcinoma of Lung	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional Cell Carcinoma	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Amnesia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Aphasia	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Balance Disorder	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Central Nervous System Lesion	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Cerebellar Infarction	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Cerebral Infarction	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Cerebrovascular Accident	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.37% 3/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Dizziness	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Haemorrhage Intracranial	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Haemorrhagic Stroke	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Headache	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic Respiratory Failure	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.00% 0/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Lung Disorder	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.25% 2/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pneumonia Aspiration	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	0.25% 1/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary Oedema	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	0.12% 1/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.

Other adverse events

Measure	Placebo n=398 participants at risk Participants received apalutamide matched placebo tablets orally on a continuous once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.	Apalutamide n=803 participants at risk Participants received apalutamide orally at a starting dose of 240 milligram (mg) (8 x 30 mg capsules then 4 x 60 mg tablets) in a continuous treatment cycles (each treatment cycle is of 28 days) once daily dosing regimen along with androgen deprivation therapy (ADT) until disease progression, withdrawal of consent or unacceptable toxicity or death.
Blood and lymphatic system disorders Anaemia	3.8% 15/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	6.4% 51/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Endocrine disorders Hypothyroidism	1.3% 5/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	6.0% 48/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal Discomfort	5.5% 22/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	4.6% 37/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal Pain	8.3% 33/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	8.0% 64/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal Pain Upper	8.0% 32/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.5% 44/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Constipation	13.1% 52/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	10.8% 87/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	15.1% 60/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	19.8% 159/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Dyspepsia	5.5% 22/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.2% 58/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	15.8% 63/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	18.1% 145/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	6.0% 24/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.4% 43/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Asthenia	8.3% 33/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	11.1% 89/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Fatigue	21.1% 84/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	30.4% 244/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
General disorders Oedema Peripheral	7.3% 29/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	8.5% 68/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	6.3% 25/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	9.7% 78/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Upper Respiratory Tract Infection	5.3% 21/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.5% 44/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Infections and infestations Urinary Tract Infection	9.3% 37/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.1% 57/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	8.8% 35/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	15.1% 121/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Investigations Weight Decreased	6.3% 25/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	15.9% 128/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Decreased Appetite	8.8% 35/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	12.3% 99/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hypercholesterolaemia	1.5% 6/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	6.1% 49/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Hyperglycaemia	3.8% 15/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.5% 44/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	7.5% 30/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	15.9% 128/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back Pain	14.8% 59/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	12.5% 100/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in Extremity	5.0% 20/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	9.1% 73/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Dizziness	6.3% 25/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	9.2% 74/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Dysgeusia	1.5% 6/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.1% 57/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Nervous system disorders Headache	6.3% 25/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	9.3% 75/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Psychiatric disorders Insomnia	5.3% 21/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	6.8% 55/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Dysuria	5.5% 22/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.1% 41/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Haematuria	8.5% 34/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.5% 60/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Nocturia	7.3% 29/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	4.9% 39/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Pollakiuria	8.5% 34/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.6% 45/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urinary Incontinence	3.8% 15/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.2% 42/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Renal and urinary disorders Urinary Retention	6.0% 24/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	3.5% 28/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	7.0% 28/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.2% 58/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.8% 15/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	7.8% 63/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	1.5% 6/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	6.2% 50/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Rash	3.3% 13/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	10.8% 87/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Rash Maculo-Papular	0.50% 2/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	5.4% 43/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Hot Flush	8.5% 34/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	14.1% 113/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.
Vascular disorders Hypertension	19.3% 77/398 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.	24.7% 198/803 • Up to approximately 43 months Safety population included all participants who received at least one dose of study drug.

Additional Information

Senior Medical Director, WC Clinical Oncology Department

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: ClinicalTrialDisclosure@its.jnj.com

Results disclosure agreements

• Principal investigator is a sponsor employee A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.
• Publication restrictions are in place

Restriction type: OTHER