A Study to Assess the Benefit of Treatment Beyond Progression With Enzalutamide in Men Who Are Starting Treatment With Docetaxel After Worsening of Their Prostate Cancer When Taking Enzalutamide Alone (PRESIDE)

• ClinicalTrials.gov Identifier: NCT02288247
• Recruitment Status: Completed
• First Posted: November 11, 2014
• Results First Posted: December 15, 2021
• Last Update Posted: April 5, 2024
• Sponsor: Astellas Pharma Europe Ltd.
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Europe Ltd. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Castration Resistant Prostate Cancer
• Interventions: Drug: Enzalutamide; Drug: Docetaxel; Drug: Prednisolone; Drug: Placebo
• Enrollment: 688

Participant Flow

Recruitment Details	Male participants with metastatic Castration-Resistant Prostate Cancer (mCRPC) who had progressed while on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or after receiving a bilateral orchiectomy and had not yet received chemotherapy were enrolled in the study.
Pre-assignment Details	Following Screening, participants received open-label (OL) treatment with enzalutamide in period 1 followed by period 2 randomized double-blind (DB) treatment with continued enzalutamide or placebo, adding with docetaxel and prednisolone. Participants were stratified by disease progression in Period 1 (evidence of radiographic progression or not).

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description	Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 milligrams per square meter (mg/m^2) in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Period Title: Period 1: OL Treatment (Max: 315 Weeks)
Started	688	0
Treated	687	0
Completed [1]	41	0
Not Completed	647	0
Reason Not Completed
Adverse Event	52	0
Death	35	0
Lost to Follow-up	1	0
Progressive Disease	392	0
Protocol Violation	9	0
Withdrawal by Subject	52	0
Other	106	0
[1] Completed participants are those who did not have a treatment discontinuation.
Period Title: Period 2: DB Treatment (Max: 180 Weeks)
Started	137 [1]	136 [2]
Treated	136	135
Completed [3]	1	1
Not Completed	136	135
Reason Not Completed
Adverse Event	10	8
Death	8	4
Lost to Follow-up	1	0
Progressive Disease	87	94
Protocol Violation	2	1
Withdrawal by Subject	7	7
Other	20	21
Randomized but not treated	1	0
[1] 137 participants from period 1 were randomized to period 2.; [2] 136 participants from period 1 were randomized to period 2.; [3] Completed participants are those who did not have a treatment discontinuation. Not completed participants discontinued treatment but are still ongoing the study.

Baseline Characteristics

Arm/Group Title		Enzalutamide
Arm/Group Description		Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules/placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Baseline Participants		687
Baseline Analysis Population Description		Safety Analysis Set 1 included all participants who received at least one dose of investigational medicinal product (IMP) in period 1.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	687 participants
		71.0 (7.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	687 participants
	Female	0 0.0%
	Male	687 100.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	687 participants
	White	681 99.1%
	Black Or African American	5 0.7%
	Other	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.
Time Frame	From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all participants who were randomized and received at least one dose of IMP.

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	136	135
Median (95% Confidence Interval); Unit of Measure: months
	9.53; (8.25 to 10.87)	8.28; (6.28 to 8.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.027
	Comments	From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
	Method	Cox proportional hazards model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.96
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Time to Prostate-specific Antigen (PSA) Progression
Description	Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later.
Time Frame	From date of randomization to the first PSA value (median duration: 35 weeks)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	136	135
Median (95% Confidence Interval); Unit of Measure: months
	8.44; (8.18 to 9.00)	6.24; (5.42 to 8.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
	Method	Cox proportional hazards model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.82
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Prostate-specific Antigen (PSA) Response
Description	PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported.
Time Frame	Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	136	135
Measure Type: Number; Unit of Measure: percentage of participants
Week 13	44.9	25.2
Any time after randomization (median of 35 weeks)	55.9	37.0

4. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. ORR was reported as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
Time Frame	From date of randomization up to median duration of 35 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	136	135
Measure Type: Number; Unit of Measure: percentage of participants
	31.6	25.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.142
	Comments	From the Cochran-Mantel-Haenszel test stratified by disease progression (radiographic, non-radiographic) in Period 1.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

5. Secondary Outcome

Title	Time to Pain Progression
Description	The time to an increase of >=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3, 4, 5, 6) at two consecutive evaluations >=3 weeks apart without decrease in analgesic score according to the World health Organization (WHO). Only participants with an average pain intensity item score >=4 were considered. The BPI-SF was an instrument to document pain-related functional impairment and contains 7 questions which included pain intensity [(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)] and pain interference ](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)]. The BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items of pain intensity.
Time Frame	From date of randomization up to median duration of 35 weeks

Outcome Measure Data

Analysis Population Description

Data was not estimable as none of the participants met the criteria for pain progression

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

6. Secondary Outcome

Title	Time to Opiate Use for Cancer-related Pain
Description	Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia [parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks].
Time Frame	From date of randomization up to median duration of 35 weeks

Outcome Measure Data

Analysis Population Description

Data was not estimable as none of the participants had cancer-related pain.

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

7. Secondary Outcome

Title	Time to First Skeletal-related Event (SRE)
Description	Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
Time Frame	From date of randomization up to median duration of 35 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first
Overall Number of Participants Analyzed	136	135
Median (95% Confidence Interval); Unit of Measure: months
	21.98 [1]; (15.18 to NA)	17.35 [1]; (17.35 to NA)

[1]

Upper limit of 95% confidence interval was not estimable due to insufficient number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.994
	Comments	From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
	Method	Cox proportional hazards model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.47 to 2.13
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)
Description	FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains rated on 0 to 4 Likert-type scale: physical well-being (PWB) (7 items; 0 [worst] to 4 [better], score range 0-28), social/family well-being (SWB) (7 items; 0 [worst] to 4 [better], score range 0-28), emotional well-being (EWB) (6 items; 0 [worst] to 4 [better], score range 0-24), and functional well-being (FWB) (7 items; 0 [worst] to 4 [better], score range 0-28), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale [PCS] 12 items rated on Likert-type scale 0 [worst] to 4 [better], score range 0-48). The total domain scores and PCS subscale score are then combined to a global quality of life score ranging between 0 to 156; higher scores representing better quality of life.
Time Frame	Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181

Outcome Measure Data

Analysis Population Description

Participants in the FAS population with available data were analyzed.

Arm/Group Title		Enzalutamide	Placebo
Arm/Group Description:		Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed		124	133
Mean (Standard Deviation); Unit of Measure: score on a scale
EWB: Baseline	Number Analyzed	122 participants	132 participants
		0.00 (0.00)	0.00 (0.00)
EWB: Change at Week 1	Number Analyzed	104 participants	115 participants
		0.00 (0.00)	0.00 (0.00)
EWB: Change at Week 13	Number Analyzed	88 participants	99 participants
		1.15 (4.15)	1.36 (3.63)
EWB: Change at Week 25	Number Analyzed	60 participants	64 participants
		0.69 (3.85)	1.03 (3.58)
EWB: Change at Week 37	Number Analyzed	55 participants	45 participants
		1.91 (3.85)	1.43 (3.73)
EWB: Change at Week 49	Number Analyzed	38 participants	22 participants
		1.22 (3.62)	0.73 (4.24)
EWB: Change at Week 61	Number Analyzed	18 participants	6 participants
		0.59 (4.52)	2.00 (3.58)
EWB: Change at Week 73	Number Analyzed	11 participants	1 participants
		1.69 (3.13)	-1.00
EWB: Change at Week 85	Number Analyzed	5 participants	1 participants
		1.00 (4.06)	-5.00
EWB: Change at Week 97	Number Analyzed	4 participants	0 participants
		3.90 (4.75)
EWB: Change at Week 109	Number Analyzed	3 participants	0 participants
		2.93 (3.49)
EWB: Change at Week 121	Number Analyzed	2 participants	0 participants
		4.00 (2.83)
EWB: Change at Week 133	Number Analyzed	2 participants	0 participants
		2.00 (0.00)
EWB: Change at Week 145	Number Analyzed	1 participants	0 participants
		2.00
EWB: Change at Week 157	Number Analyzed	1 participants	0 participants
		2.00
EWB: Change at Week 169	Number Analyzed	1 participants	0 participants
		1.00
EWB: Change at Week 181	Number Analyzed	1 participants	0 participants
		2.00
FWB: Baseline	Number Analyzed	122 participants	132 participants
		0.0000 (0.0000)	0.0000 (0.0000)
FWB: Change at Week 1	Number Analyzed	104 participants	115 participants
		0.0000 (0.0000)	0.0000 (0.0000)
FWB: Change at Week 13	Number Analyzed	88 participants	99 participants
		-1.8144 (5.0586)	-0.3121 (4.7437)
FWB: Change at Week 25	Number Analyzed	60 participants	64 participants
		-2.4472 (5.2508)	-0.8229 (5.2563)
FWB: Change at Week 37	Number Analyzed	55 participants	45 participants
		-1.5697 (6.3251)	-0.1459 (3.2857)
FWB: Change at Week 49	Number Analyzed	38 participants	22 participants
		-1.1579 (6.7284)	-1.3818 (4.5238)
FWB: Change at Week 61	Number Analyzed	18 participants	6 participants
		0.0000 (4.7651)	-2.3333 (2.8048)
FWB: Change at Week 73	Number Analyzed	11 participants	1 participants
		-1.8182 (3.5726)	-2.0000
FWB: Change at Week 85	Number Analyzed	5 participants	1 participants
		1.2000 (4.8166)	0.0000
FWB: Change at Week 97	Number Analyzed	4 participants	0 participants
		-0.5000 (1.7321)
FWB: Change at Week 109	Number Analyzed	3 participants	0 participants
		-1.3333 (3.2146)
FWB: Change at Week 121	Number Analyzed	2 participants	0 participants
		-1.5000 (0.7071)
FWB: Change at Week 133	Number Analyzed	2 participants	0 participants
		-0.5000 (2.1213)
FWB: Change at Week 145	Number Analyzed	1 participants	0 participants
		-2.0000
FWB: Change at Week 157	Number Analyzed	1 participants	0 participants
		0.0000
FWB: Change at Week 169	Number Analyzed	1 participants	0 participants
		-1.0000
FWB: Change at Week 181	Number Analyzed	1 participants	0 participants
		0.0000
Global Score: Baseline	Number Analyzed	121 participants	129 participants
		0.0000 (0.0000)	0.0000 (0.0000)
Global Score: Change at Week 1	Number Analyzed	104 participants	113 participants
		0.0000 (0.0000)	0.0000 (0.0000)
Global Score: Change at Week 13	Number Analyzed	84 participants	95 participants
		-0.7836 (17.7356)	1.7986 (16.3294)
Global Score: Change at Week 25	Number Analyzed	58 participants	61 participants
		-5.9204 (18.2107)	1.0762 (17.0168)
Global Score: Change at Week 37	Number Analyzed	52 participants	43 participants
		-1.5351 (20.3721)	0.1649 (15.8335)
Global Score: Change at Week 49	Number Analyzed	37 participants	21 participants
		-4.4880 (24.6865)	-4.6202 (17.9530)
Global Score: Change at Week 61	Number Analyzed	17 participants	6 participants
		-0.2957 (17.6915)	6.0939 (8.8208)
Global Score: Change at Week 73	Number Analyzed	11 participants	0 participants
		-0.3917 (18.3346)
Global Score: Change at Week 85	Number Analyzed	5 participants	0 participants
		1.7636 (11.7476)
Global Score: Change at Week 97	Number Analyzed	4 participants	0 participants
		6.2864 (9.8128)
Global Score: Change at Week 109	Number Analyzed	3 participants	0 participants
		-2.7333 (17.6299)
Global Score: Change at Week 121	Number Analyzed	1 participants	0 participants
		4.0000
Global Score: Change at Week 133	Number Analyzed	2 participants	0 participants
		-7.0000 (4.2426)
Global Score: Change at Week 145	Number Analyzed	1 participants	0 participants
		-11.0000
Global Score: Change at Week 157	Number Analyzed	1 participants	0 participants
		-1.0000
Global Score: Change at Week 169	Number Analyzed	1 participants	0 participants
		-10.0000
Global Score: Change at Week 181	Number Analyzed	1 participants	0 participants
		-4.0000
PWB: Baseline	Number Analyzed	124 participants	133 participants
		0.0000 (0.0000)	0.0000 (0.0000)
PWB: Change at Week 1	Number Analyzed	106 participants	115 participants
		0.0000 (0.0000)	0.0000 (0.0000)
PWB: Change at Week 13	Number Analyzed	90 participants	100 participants
		-1.3322 (6.0823)	-0.6347 (4.4643)
PWB: Change at Week 25	Number Analyzed	62 participants	65 participants
		-3.1317 (6.5208)	-0.4590 (4.2887)
PWB: Change at Week 37	Number Analyzed	56 participants	45 participants
		-2.1786 (5.5611)	-0.9556 (4.3691)
PWB: Change at Week 49	Number Analyzed	38 participants	23 participants
		-2.5316 (8.0882)	-1.3913 (6.1625)
PWB: Change at Week 61	Number Analyzed	18 participants	6 participants
		-1.3889 (6.9886)	1.3333 (3.8297)
PWB: Change at Week 73	Number Analyzed	11 participants	1 participants
		-0.3636 (8.0408)	3.0000
PWB: Change at Week 85	Number Analyzed	5 participants	1 participants
		1.0000 (10.3682)	3.0000
PWB: Change at Week 97	Number Analyzed	4 participants	0 participants
		1.7500 (10.4363)
PWB: Change at Week 109	Number Analyzed	3 participants	0 participants
		-0.6667 (13.6504)
PWB: Change at Week 121	Number Analyzed	2 participants	0 participants
		-4.0000 (1.4142)
PWB: Change at Week 133	Number Analyzed	2 participants	0 participants
		-4.5000 (0.7071)
PWB: Change at Week 145	Number Analyzed	1 participants	0 participants
		-4.0000
PWB: Change at Week 157	Number Analyzed	1 participants	0 participants
		0.0000
PWB: Change at Week 169	Number Analyzed	1 participants	0 participants
		-4.0000
PWB: Change at Week 181	Number Analyzed	1 participants	0 participants
		-2.0000
PCS: Baseline	Number Analyzed	123 participants	130 participants
		0.0000 (0.0000)	0.0000 (0.0000)
PCS: Change at Week 1	Number Analyzed	106 participants	113 participants
		0.0000 (0.0000)	0.0000 (0.0000)
PCS: Change at Week 13	Number Analyzed	86 participants	95 participants
		1.1842 (6.1843)	1.6011 (6.0731)
PCS: Change at Week 25	Number Analyzed	60 participants	63 participants
		-0.4775 (6.2665)	1.8632 (6.3433)
PCS: Change at Week 37	Number Analyzed	53 participants	44 participants
		-1.1433 (7.3006)	0.6988 (7.1353)
PCS: Change at Week 49	Number Analyzed	37 participants	22 participants
		-1.8465 (8.6083)	-0.7223 (7.8442)
PCS: Change at Week 61	Number Analyzed	17 participants	6 participants
		0.3690 (6.0031)	4.2606 (3.1148)
PCS: Change at Week 73	Number Analyzed	11 participants	0 participants
		0.9174 (7.8001)
PCS: Change at Week 85	Number Analyzed	5 participants	0 participants
		2.1636 (5.6123)
PCS: Change at Week 97	Number Analyzed	4 participants	0 participants
		3.8864 (3.3380)
PCS: Change at Week 109	Number Analyzed	3 participants	0 participants
		-1.6667 (5.8595)
PCS: Change at Week 121	Number Analyzed	1 participants	0 participants
		2.0000
PCS: Change at Week 133	Number Analyzed	2 participants	0 participants
		-3.0000 (4.2426)
PCS: Change at Week 145	Number Analyzed	1 participants	0 participants
		-5.0000
PCS: Change at Week 157	Number Analyzed	1 participants	0 participants
		0.0000
PCS: Change at Week 169	Number Analyzed	1 participants	0 participants
		-3.0000
PCS: Change at Week 181	Number Analyzed	1 participants	0 participants
		-2.0000
SWB: Baseline	Number Analyzed	124 participants	133 participants
		0.0000 (0.0000)	0.0000 (0.0000)
SWB: Change at Week 1	Number Analyzed	106 participants	115 participants
		0.0000 (0.0000)	0.0000 (0.0000)
SWB: Change at Week 13	Number Analyzed	90 participants	100 participants
		-0.1581 (4.1893)	-0.2953 (5.0738)
SWB: Change at Week 25	Number Analyzed	62 participants	65 participants
		-0.3634 (5.6959)	-0.0462 (3.7933)
SWB: Change at Week 37	Number Analyzed	56 participants	45 participants
		0.8798 (4.6897)	-0.3963 (3.3279)
SWB: Change at Week 49	Number Analyzed	38 participants	23 participants
		-0.0719 (6.2561)	-0.7536 (4.3164)
SWB: Change at Week 61	Number Analyzed	18 participants	6 participants
		-0.8167 (3.3323)	0.8333 (5.7067)
SWB: Change at Week 73	Number Analyzed	11 participants	1 participants
		-0.8182 (2.7863)	-24.0000
SWB: Change at Week 85	Number Analyzed	5 participants	1 participants
		-3.6000 (3.7815)	-24.0000
SWB: Change at Week 97	Number Analyzed	4 participants	0 participants
		-2.7500 (5.8523)
SWB: Change at Week 109	Number Analyzed	3 participants	0 participants
		-2.0000 (4.3589)
SWB: Change at Week 121	Number Analyzed	2 participants	0 participants
		0.5000 (0.7071)
SWB: Change at Week 133	Number Analyzed	2 participants	0 participants
		-1.0000 (1.4142)
SWB: Change at Week 145	Number Analyzed	1 participants	0 participants
		-2.0000
SWB: Change at Week 157	Number Analyzed	1 participants	0 participants
		-3.0000
SWB: Change at Week 169	Number Analyzed	1 participants	0 participants
		-3.0000
SWB: Change at Week 181	Number Analyzed	1 participants	0 participants
		-2.0000

9. Secondary Outcome

Title	Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
Description	The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are labelled from 0 (worst health imaginable) to 100 (best health imaginable).
Time Frame	Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181

Outcome Measure Data

Analysis Population Description

Participants in the FAS population with available data were analyzed.

Arm/Group Title		Enzalutamide	Placebo
Arm/Group Description:		Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.	Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
Overall Number of Participants Analyzed		121	130
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	121 participants	130 participants
		0.0 (0.0)	0.0 (0.0)
Change at Week 1	Number Analyzed	106 participants	113 participants
		0.0 (0.0)	0.0 (0.0)
Change at Week 13	Number Analyzed	89 participants	100 participants
		2.3 (19.7)	-0.8 (17.8)
Change at Week 25	Number Analyzed	63 participants	64 participants
		-3.0 (18.6)	-0.2 (17.7)
Change at Week 37	Number Analyzed	55 participants	47 participants
		-1.3 (21.7)	0.4 (15.8)
Change at Week 49	Number Analyzed	42 participants	24 participants
		-2.5 (25.7)	-8.3 (23.3)
Change at Week 61	Number Analyzed	19 participants	6 participants
		1.3 (22.6)	2.5 (25.2)
Change at Week 73	Number Analyzed	11 participants	1 participants
		-3.5 (30.8)	-20.0
Change at Week 85	Number Analyzed	5 participants	1 participants
		7.2 (20.7)	-10.0
Change at Week 97	Number Analyzed	4 participants	0 participants
		17.8 (27.0)
Change at Week 109	Number Analyzed	3 participants	0 participants
		17.7 (23.6)
Change at Week 121	Number Analyzed	2 participants	0 participants
		-7.0 (4.2)
Change at Week 133	Number Analyzed	2 participants	0 participants
		0.5 (13.4)
Change at Week 145	Number Analyzed	1 participants	0 participants
		1.0
Change at Week 157	Number Analyzed	1 participants	0 participants
		-4.0
Change at Week 169	Number Analyzed	1 participants	0 participants
		2.0
Change at Week 181	Number Analyzed	1 participants	0 participants
		-4.0

Adverse Events

Time Frame	From first dose up to 30 days after last dose (median duration: 35 weeks)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Period 1: Enzalutamide		Period 2: Enzalutamide		Period 2: Placebo
Arm/Group Description	Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first.		Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.		Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
All-Cause Mortality
	Period 1: Enzalutamide		Period 2: Enzalutamide		Period 2: Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	50/687 (7.28%)		18/136 (13.24%)		14/135 (10.37%)
Serious Adverse Events
	Period 1: Enzalutamide		Period 2: Enzalutamide		Period 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	235/687 (34.21%)		67/136 (49.26%)		52/135 (38.52%)
Blood and lymphatic system disorders
Anaemia † 1	9/687 (1.31%)	17	3/136 (2.21%)	3	2/135 (1.48%)	2
Disseminated intravascular coagulation † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Febrile neutropenia † 1	1/687 (0.15%)	1	10/136 (7.35%)	10	15/135 (11.11%)	17
Leukopenia † 1	0/687 (0.00%)	0	2/136 (1.47%)	3	1/135 (0.74%)	1
Neutropenia † 1	0/687 (0.00%)	0	11/136 (8.09%)	21	5/135 (3.70%)	12
Pancytopenia † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	1/135 (0.74%)	1
Thrombocytopenia † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Cardiac disorders
Acute coronary syndrome † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Acute myocardial infarction † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Angina pectoris † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Arrhythmia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Atrial fibrillation † 1	12/687 (1.75%)	14	3/136 (2.21%)	3	2/135 (1.48%)	2
Atrial flutter † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	1/135 (0.74%)	1
Atrioventricular block † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cardiac arrest † 1	3/687 (0.44%)	3	1/136 (0.74%)	1	0/135 (0.00%)	0
Cardiac failure † 1	6/687 (0.87%)	6	0/136 (0.00%)	0	1/135 (0.74%)	1
Cardiac failure acute † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Cardiac failure congestive † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cardiogenic shock † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cardiopulmonary failure † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Congestive cardiomyopathy † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Coronary artery disease † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Dressler's syndrome † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Ischaemic cardiomyopathy † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Left ventricular failure † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Myocardial infarction † 1	8/687 (1.16%)	9	2/136 (1.47%)	2	0/135 (0.00%)	0
Palpitations † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Stress cardiomyopathy † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Endocrine disorders
Goitre † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Eye disorders
Blindness † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Exfoliation glaucoma † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Retinal detachment † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Vision blurred † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	1/135 (0.74%)	2
Abdominal pain upper † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Ascites † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Constipation † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	2/135 (1.48%)	2
Diarrhoea † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	3/135 (2.22%)	3
Duodenal ulcer perforation † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Gastric haemorrhage † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Ileus † 1	5/687 (0.73%)	7	0/136 (0.00%)	0	1/135 (0.74%)	1
Ileus paralytic † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Incarcerated inguinal hernia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Inguinal hernia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Intestinal ischaemia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Intestinal obstruction † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Large intestine perforation † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Mechanical ileus † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Nausea † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	2/135 (1.48%)	2
Pancreatitis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Pancreatitis acute † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Rectal haemorrhage † 1	3/687 (0.44%)	3	1/136 (0.74%)	3	0/135 (0.00%)	0
Small intestinal haemorrhage † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Vomiting † 1	2/687 (0.29%)	2	2/136 (1.47%)	2	1/135 (0.74%)	1
General disorders
Asthenia † 1	2/687 (0.29%)	2	2/136 (1.47%)	2	0/135 (0.00%)	0
Chest pain † 1	4/687 (0.58%)	5	0/136 (0.00%)	0	1/135 (0.74%)	1
Chills † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Death † 1	4/687 (0.58%)	4	1/136 (0.74%)	1	0/135 (0.00%)	0
Fatigue † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	0/135 (0.00%)	0
Gait disturbance † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
General physical health deterioration † 1	5/687 (0.73%)	6	1/136 (0.74%)	1	3/135 (2.22%)	4
Generalised oedema † 1	0/687 (0.00%)	0	1/136 (0.74%)	2	1/135 (0.74%)	1
Hypothermia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Malaise † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	0/135 (0.00%)	0
Pain † 1	5/687 (0.73%)	6	0/136 (0.00%)	0	0/135 (0.00%)	0
Pyrexia † 1	2/687 (0.29%)	2	6/136 (4.41%)	7	2/135 (1.48%)	2
Sudden death † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	0/135 (0.00%)	0
Hepatobiliary disorders
Cholelithiasis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hepatic function abnormal † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Immune system disorders
Drug hypersensitivity † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	1/135 (0.74%)	1
Infections and infestations
Bronchitis bacterial † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Catheter bacteraemia † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Cellulitis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Dacryocystitis † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Device related infection † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Diverticulitis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Erysipelas † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Infection † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Infective aneurysm † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Influenza † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Klebsiella sepsis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lower respiratory tract infection † 1	1/687 (0.15%)	1	2/136 (1.47%)	3	0/135 (0.00%)	0
Lyme disease † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Meningitis bacterial † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Neutropenic sepsis † 1	1/687 (0.15%)	1	5/136 (3.68%)	6	3/135 (2.22%)	3
Peritonitis † 1	4/687 (0.58%)	4	0/136 (0.00%)	0	0/135 (0.00%)	0
Pneumonia † 1	4/687 (0.58%)	4	4/136 (2.94%)	4	3/135 (2.22%)	3
Pulmonary tuberculosis † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Respiratory tract infection † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Respiratory tract infection fungal † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Sepsis † 1	5/687 (0.73%)	5	2/136 (1.47%)	2	0/135 (0.00%)	0
Septic shock † 1	0/687 (0.00%)	0	3/136 (2.21%)	3	0/135 (0.00%)	0
Streptococcal urinary tract infection † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Upper respiratory tract infection † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urinary tract infection † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	1/135 (0.74%)	1
Urinary tract infection bacterial † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Urinary tract infection pseudomonal † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urosepsis † 1	6/687 (0.87%)	7	0/136 (0.00%)	0	0/135 (0.00%)	0
Injury, poisoning and procedural complications
Ankle fracture † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Clavicle fracture † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Contusion † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Fall † 1	8/687 (1.16%)	9	0/136 (0.00%)	0	0/135 (0.00%)	0
Femoral neck fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Femur fracture † 1	6/687 (0.87%)	7	0/136 (0.00%)	0	0/135 (0.00%)	0
Hand fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hip fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Infusion related reaction † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Injury † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lower limb fracture † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	0/135 (0.00%)	0
Lumbar vertebral fracture † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Medication error † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Overdose † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Patella fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Procedural pain † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Product dispensing error † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Radius fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Rib fracture † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Spinal compression fracture † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Spinal fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Tibia fracture † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urostomy complication † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Aspartate aminotransferase increased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Blood bilirubin increased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Eastern Cooperative Oncology Group performance status worsened † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
General physical condition abnormal † 1	5/687 (0.73%)	8	1/136 (0.74%)	1	0/135 (0.00%)	0
Haemoglobin decreased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Liver function test increased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Neutrophil count decreased † 1	0/687 (0.00%)	0	2/136 (1.47%)	3	1/135 (0.74%)	1
Platelet count decreased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Troponin I increased † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Metabolism and nutrition disorders
Cachexia † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Dehydration † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Diabetes mellitus † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypercalcaemia † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Hyperglycaemia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypocalcaemia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypoglycaemia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypokalaemia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hyponatraemia † 1	1/687 (0.15%)	3	1/136 (0.74%)	1	0/135 (0.00%)	0
Hypophagia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthritis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Back pain † 1	12/687 (1.75%)	14	2/136 (1.47%)	2	3/135 (2.22%)	4
Bone pain † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	1/135 (0.74%)	1
Cervical spinal stenosis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Flank pain † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Intervertebral disc disorder † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lumbar spinal stenosis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Mobility decreased † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Muscular weakness † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Musculoskeletal chest pain † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Musculoskeletal pain † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Myalgia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Osteoarthritis † 1	1/687 (0.15%)	2	1/136 (0.74%)	1	0/135 (0.00%)	0
Osteonecrosis of jaw † 1	2/687 (0.29%)	2	1/136 (0.74%)	2	1/135 (0.74%)	1
Pain in extremity † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Pathological fracture † 1	5/687 (0.73%)	5	0/136 (0.00%)	0	0/135 (0.00%)	0
Spinal pain † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Basal cell carcinoma † 1	2/687 (0.29%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Bladder cancer † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Bladder transitional cell carcinoma † 1	3/687 (0.44%)	5	0/136 (0.00%)	0	0/135 (0.00%)	0
Bladder transitional cell carcinoma recurrent † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Bowen's disease † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	1/135 (0.74%)	1
Cancer pain † 1	4/687 (0.58%)	4	2/136 (1.47%)	2	1/135 (0.74%)	1
Colon cancer † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Gastric cancer † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Intestinal adenocarcinoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lip neoplasm malignant stage unspecified † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Liposarcoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lung adenocarcinoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Lung neoplasm malignant † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	0/135 (0.00%)	0
Lymphoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Malignant neoplasm of pleura † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Malignant neoplasm progression † 1	23/687 (3.35%)	25	6/136 (4.41%)	6	6/135 (4.44%)	6
Malignant peritoneal neoplasm † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Myeloproliferative neoplasm † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Non-small cell lung cancer † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Pancreatic carcinoma † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Plasma cell myeloma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Small cell lung cancer † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Soft tissue sarcoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Squamous cell carcinoma of lung † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Transitional cell carcinoma † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Nervous system disorders
Amnesia † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Amyotrophic lateral sclerosis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Aphasia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Ataxia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Brain compression † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cerebral haemorrhage † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cerebral ischaemia † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Cerebrovascular accident † 1	4/687 (0.58%)	4	1/136 (0.74%)	1	0/135 (0.00%)	0
Dementia Alzheimer's type † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Dizziness † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Epilepsy † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Haemorrhage intracranial † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Headache † 1	3/687 (0.44%)	4	0/136 (0.00%)	0	0/135 (0.00%)	0
Hemiplegia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypertensive encephalopathy † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Ischaemic stroke † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Motor dysfunction † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Paraesthesia † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Paraplegia † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	0/135 (0.00%)	0
Parkinson's disease † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Polyneuropathy † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Presyncope † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Sciatica † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Seizure † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Spinal cord compression † 1	6/687 (0.87%)	6	5/136 (3.68%)	5	1/135 (0.74%)	1
Syncope † 1	5/687 (0.73%)	5	0/136 (0.00%)	0	0/135 (0.00%)	0
Transient ischaemic attack † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Vascular dementia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Product Issues
Device dislocation † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Thrombosis in device † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Psychiatric disorders
Confusional state † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Hallucination † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Renal and urinary disorders
Acute kidney injury † 1	7/687 (1.02%)	8	2/136 (1.47%)	2	2/135 (1.48%)	2
Bladder outlet obstruction † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Bladder tamponade † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Haematuria † 1	12/687 (1.75%)	17	1/136 (0.74%)	1	1/135 (0.74%)	1
Hydronephrosis † 1	6/687 (0.87%)	7	0/136 (0.00%)	0	1/135 (0.74%)	1
Nephrolithiasis † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Urethral obstruction † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urethral stenosis † 1	1/687 (0.15%)	2	0/136 (0.00%)	0	1/135 (0.74%)	1
Urinary bladder polyp † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urinary retention † 1	7/687 (1.02%)	7	0/136 (0.00%)	0	1/135 (0.74%)	1
Urinary tract disorder † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Urinary tract obstruction † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Prostatitis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Scrotal pain † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Dyspnoea † 1	8/687 (1.16%)	9	2/136 (1.47%)	2	1/135 (0.74%)	1
Hydrothorax † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Interstitial lung disease † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Lung disorder † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Pleural effusion † 1	2/687 (0.29%)	2	1/136 (0.74%)	1	0/135 (0.00%)	0
Pneumonitis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Pneumothorax † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Pulmonary embolism † 1	3/687 (0.44%)	3	2/136 (1.47%)	2	0/135 (0.00%)	0
Pulmonary oedema † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Pulmonary thrombosis † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Respiratory failure † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Surgical and medical procedures
Bone operation † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Cardiac pacemaker removal † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Carpal tunnel decompression † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Catheterisation venous † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Vascular disorders
Arterial insufficiency † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Circulatory collapse † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Deep vein thrombosis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Haematoma † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Hypertension † 1	3/687 (0.44%)	3	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypertensive crisis † 1	2/687 (0.29%)	2	0/136 (0.00%)	0	0/135 (0.00%)	0
Hypotension † 1	1/687 (0.15%)	1	1/136 (0.74%)	1	0/135 (0.00%)	0
Malignant hypertension † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Orthostatic hypotension † 1	0/687 (0.00%)	0	0/136 (0.00%)	0	1/135 (0.74%)	1
Shock haemorrhagic † 1	0/687 (0.00%)	0	1/136 (0.74%)	1	0/135 (0.00%)	0
Thrombosis † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
Venous thrombosis limb † 1	1/687 (0.15%)	1	0/136 (0.00%)	0	0/135 (0.00%)	0
1 Term from vocabulary, MedDRA v23; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Period 1: Enzalutamide		Period 2: Enzalutamide		Period 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	521/687 (75.84%)		125/136 (91.91%)		123/135 (91.11%)
Blood and lymphatic system disorders
Anaemia † 1	49/687 (7.13%)	63	27/136 (19.85%)	47	15/135 (11.11%)	32
Leukopenia † 1	1/687 (0.15%)	1	11/136 (8.09%)	37	16/135 (11.85%)	48
Neutropenia † 1	5/687 (0.73%)	5	41/136 (30.15%)	124	43/135 (31.85%)	129
Eye disorders
Lacrimation increased † 1	2/687 (0.29%)	3	25/136 (18.38%)	28	6/135 (4.44%)	7
Gastrointestinal disorders
Constipation † 1	60/687 (8.73%)	64	12/136 (8.82%)	21	15/135 (11.11%)	17
Diarrhoea † 1	63/687 (9.17%)	76	37/136 (27.21%)	51	42/135 (31.11%)	67
Nausea † 1	69/687 (10.04%)	79	26/136 (19.12%)	33	25/135 (18.52%)	31
Stomatitis † 1	2/687 (0.29%)	2	5/136 (3.68%)	5	8/135 (5.93%)	9
Vomiting † 1	22/687 (3.20%)	25	8/136 (5.88%)	8	6/135 (4.44%)	6
General disorders
Asthenia † 1	109/687 (15.87%)	175	46/136 (33.82%)	92	35/135 (25.93%)	64
Fatigue † 1	158/687 (23.00%)	193	40/136 (29.41%)	65	28/135 (20.74%)	41
Mucosal inflammation † 1	3/687 (0.44%)	3	10/136 (7.35%)	14	17/135 (12.59%)	19
Oedema peripheral † 1	26/687 (3.78%)	31	16/136 (11.76%)	18	20/135 (14.81%)	23
Pyrexia † 1	17/687 (2.47%)	18	9/136 (6.62%)	11	7/135 (5.19%)	9
Infections and infestations
Nasopharyngitis † 1	28/687 (4.08%)	33	4/136 (2.94%)	5	8/135 (5.93%)	8
Injury, poisoning and procedural complications
Fall † 1	45/687 (6.55%)	61	6/136 (4.41%)	7	4/135 (2.96%)	4
Investigations
Haemoglobin decreased † 1	15/687 (2.18%)	17	2/136 (1.47%)	3	7/135 (5.19%)	7
Neutrophil count decreased † 1	3/687 (0.44%)	4	7/136 (5.15%)	14	7/135 (5.19%)	27
Weight decreased † 1	30/687 (4.37%)	36	11/136 (8.09%)	11	2/135 (1.48%)	2
White blood cell count decreased † 1	9/687 (1.31%)	12	5/136 (3.68%)	17	7/135 (5.19%)	24
Metabolism and nutrition disorders
Decreased appetite † 1	69/687 (10.04%)	86	23/136 (16.91%)	28	17/135 (12.59%)	18
Musculoskeletal and connective tissue disorders
Arthralgia † 1	70/687 (10.19%)	85	25/136 (18.38%)	27	10/135 (7.41%)	10
Back pain † 1	116/687 (16.89%)	152	13/136 (9.56%)	15	14/135 (10.37%)	15
Bone pain † 1	64/687 (9.32%)	79	12/136 (8.82%)	14	14/135 (10.37%)	16
Musculoskeletal pain † 1	32/687 (4.66%)	37	5/136 (3.68%)	7	7/135 (5.19%)	12
Myalgia † 1	22/687 (3.20%)	23	9/136 (6.62%)	9	7/135 (5.19%)	9
Pain in extremity † 1	43/687 (6.26%)	54	7/136 (5.15%)	10	7/135 (5.19%)	7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	22/687 (3.20%)	25	8/136 (5.88%)	12	11/135 (8.15%)	14
Nervous system disorders
Dizziness † 1	45/687 (6.55%)	49	5/136 (3.68%)	5	6/135 (4.44%)	6
Dysgeusia † 1	10/687 (1.46%)	12	18/136 (13.24%)	22	9/135 (6.67%)	9
Headache † 1	44/687 (6.40%)	56	5/136 (3.68%)	6	8/135 (5.93%)	10
Neuropathy peripheral † 1	2/687 (0.29%)	2	22/136 (16.18%)	29	12/135 (8.89%)	21
Paraesthesia † 1	22/687 (3.20%)	24	8/136 (5.88%)	10	10/135 (7.41%)	21
Peripheral sensory neuropathy † 1	1/687 (0.15%)	1	12/136 (8.82%)	16	14/135 (10.37%)	25
Taste disorder † 1	7/687 (1.02%)	7	6/136 (4.41%)	6	9/135 (6.67%)	11
Renal and urinary disorders
Haematuria † 1	39/687 (5.68%)	48	4/136 (2.94%)	5	7/135 (5.19%)	8
Respiratory, thoracic and mediastinal disorders
Cough † 1	26/687 (3.78%)	30	11/136 (8.09%)	15	10/135 (7.41%)	11
Dyspnoea † 1	28/687 (4.08%)	31	11/136 (8.09%)	13	4/135 (2.96%)	4
Epistaxis † 1	10/687 (1.46%)	11	13/136 (9.56%)	16	7/135 (5.19%)	9
Skin and subcutaneous tissue disorders
Alopecia † 1	2/687 (0.29%)	2	44/136 (32.35%)	56	37/135 (27.41%)	48
Dry skin † 1	14/687 (2.04%)	14	12/136 (8.82%)	12	5/135 (3.70%)	5
Nail disorder † 1	0/687 (0.00%)	0	13/136 (9.56%)	13	7/135 (5.19%)	8
Nail dystrophy † 1	0/687 (0.00%)	0	7/136 (5.15%)	9	2/135 (1.48%)	3
Nail toxicity † 1	0/687 (0.00%)	0	11/136 (8.09%)	16	5/135 (3.70%)	7
Onycholysis † 1	0/687 (0.00%)	0	13/136 (9.56%)	14	12/135 (8.89%)	16
Palmar-plantar erythrodysaesthesia syndrome † 1	0/687 (0.00%)	0	10/136 (7.35%)	15	1/135 (0.74%)	1
Vascular disorders
Hot flush † 1	73/687 (10.63%)	89	1/136 (0.74%)	1	1/135 (0.74%)	1
Hypertension † 1	90/687 (13.10%)	102	3/136 (2.21%)	5	2/135 (1.48%)	2
1 Term from vocabulary, MedDRA v23; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure
• Organization: Astellas Pharma Europe Ltd. (APEL)
• Phone: +31 (0) 71 5455 050
• EMail: astellas.resultsdisclosure@astellas.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Merseburger AS, Attard G, Astrom L, Matveev VB, Bracarda S, Esen A, Feyerabend S, Senkus E, Lopez-Brea Piqueras M, Boysen G, Gourgioti G, Martins K, Chowdhury S. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol. 2022 Nov;23(11):1398-1408. doi: 10.1016/S1470-2045(22)00560-5. Epub 2022 Oct 18.

• Responsible Party: Astellas Pharma Inc ( Astellas Pharma Europe Ltd. )
• ClinicalTrials.gov Identifier: NCT02288247
• Other Study ID Numbers: 9785-MA-1001; 2013-004711-50 ( EudraCT Number )
• First Submitted: November 7, 2014
• First Posted: November 11, 2014
• Results First Submitted: September 29, 2021
• Results First Posted: December 15, 2021
• Last Update Posted: April 5, 2024