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Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM)

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ClinicalTrials.gov Identifier: NCT00974311
Recruitment Status : Completed
First Posted : September 10, 2009
Results First Posted : October 30, 2012
Last Update Posted : December 11, 2018
Sponsor:
Collaborators:
Astellas Pharma Inc
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Castration-Resistant Prostate Cancer
Interventions Drug: Enzalutamide
Drug: Placebo
Enrollment 1199
Recruitment Details A total of 1199 participants were enrolled and randomized for double-blind (DB) phase. Out of which, 159 participants entered the optional open-label extension (OLE) phase.
Pre-assignment Details Participants were randomized 2:1 to receive either Enzalutamide or Placebo in DB phase. All participants who continued in OLE phase, received Enzalutamide.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months). In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Period Title: DB Phase (up to 24 Months)
Started 800 399
Completed 109 50
Not Completed 691 349
Reason Not Completed
Lost to Follow-up             5             2
Death             561             298
Withdrawal by Subject             16             7
Study Terminated by Sponsor             108             42
Other             1             0
Period Title: OLE Phase (up to 77 Months)
Started 109 50
Completed 0 0
Not Completed 109 50
Reason Not Completed
Death             14             21
Study Terminated by Sponsor             78             26
Other             15             2
Withdrawal by Subject             2             1
Arm/Group Title Enzalutamide Placebo Total
Hide Arm/Group Description In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months). In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase). Total of all reporting groups
Overall Number of Baseline Participants 800 399 1199
Hide Baseline Analysis Population Description
Intent-to-treat population (ITT) included all participants who were randomized into the study.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 800 participants 399 participants 1199 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
232
  29.0%
130
  32.6%
362
  30.2%
>=65 years
568
  71.0%
269
  67.4%
837
  69.8%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 800 participants 399 participants 1199 participants
68.8  (7.96) 68.6  (8.39) 68.7  (8.11)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 800 participants 399 participants 1199 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
800
 100.0%
399
 100.0%
1199
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 800 participants 399 participants 1199 participants
Hispanic or Latino
32
   4.0%
23
   5.8%
55
   4.6%
Not Hispanic or Latino
768
  96.0%
376
  94.2%
1144
  95.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 800 participants 399 participants 1199 participants
American Indian or Alaska Native
1
   0.1%
1
   0.3%
2
   0.2%
Asian
5
   0.6%
8
   2.0%
13
   1.1%
Native Hawaiian or Other Pacific Islander
1
   0.1%
0
   0.0%
1
   0.1%
Black or African American
27
   3.4%
20
   5.0%
47
   3.9%
White
745
  93.1%
366
  91.7%
1111
  92.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
21
   2.6%
4
   1.0%
25
   2.1%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 800 participants 399 participants 1199 participants
United States
181
  22.6%
107
  26.8%
288
  24.0%
Spain
23
   2.9%
13
   3.3%
36
   3.0%
Austria
15
   1.9%
10
   2.5%
25
   2.1%
Chile
6
   0.8%
5
   1.3%
11
   0.9%
United Kingdom
82
  10.3%
50
  12.5%
132
  11.0%
Italy
20
   2.5%
10
   2.5%
30
   2.5%
France
193
  24.1%
80
  20.1%
273
  22.8%
Canada
82
  10.3%
25
   6.3%
107
   8.9%
Argentina
7
   0.9%
3
   0.8%
10
   0.8%
Belgium
27
   3.4%
18
   4.5%
45
   3.8%
Poland
7
   0.9%
4
   1.0%
11
   0.9%
Australia
60
   7.5%
33
   8.3%
93
   7.8%
South Africa
3
   0.4%
3
   0.8%
6
   0.5%
Germany
62
   7.8%
24
   6.0%
86
   7.2%
Netherlands
32
   4.0%
14
   3.5%
46
   3.8%
1.Primary Outcome
Title Overall Survival
Hide Description Survival was defined as time from randomization to death due to any cause. The duration of overall survival was right-censored for participants who were lost to follow-up since randomization or not known to have died at the data analysis cut-off date (this included participants who were known to have died after the data analysis cut-off date).
Time Frame During study period (up to 101 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT included all participants who were randomized into the study.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 800 399
Median (95% Confidence Interval)
Unit of Measure: Months
18.4 [1] 
(17.3 to NA)
13.6
(11.3 to 15.8)
[1]
The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments Stratified by baseline Eastern Cooperative Oncology Group (ECOG) performance status and mean Brief Pain Inventory – Short Form score (Question #3).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.53 to 0.75
Estimation Comments Hazard Ratio and 95% confidence interval are from Cox regression model.
2.Secondary Outcome
Title Radiographic Progression-free Survival
Hide Description Radiographic progression-free survival was defined as time from randomization to the earliest objective evidence of radiographic progression or death due to any cause. Participants were assessed for objective disease progression at regularly scheduled visits. The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 were taken into consideration for the determination of disease progression. Radiographic disease progression was defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for soft tissue disease, or the appearance of two or more new bone lesions on bone scan. Progression at the first scheduled reassessment at Week 13 required a confirmatory scan 6 or more weeks later. Participants who did not reach the endpoint were right censored at their last assessment.
Time Frame During DB phase (up to 24 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT included all participants who were randomized into the study.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 800 399
Median (95% Confidence Interval)
Unit of Measure: Months
8.3
(8.2 to 9.4)
2.9
(2.8 to 3.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.40
Confidence Interval (2-Sided) 95%
0.35 to 0.47
Estimation Comments Hazard Ratio and 95% confidence interval are from Cox regression model.
3.Secondary Outcome
Title Time to First Skeletal-related Event
Hide Description The time to first skeletal-related event was defined as time from randomization to the occurrence of the first skeletal-related event. Participants were assessed for skeletal-related events at regularly scheduled visits. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Participants who did not reach the endpoint were right censored at their last assessment.
Time Frame During DB Phase (up to 24 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT included all participants who were randomized into the study.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 800 399
Median (95% Confidence Interval)
Unit of Measure: Months
16.7
(14.6 to 19.1)
13.3 [1] 
(9.9 to NA)
[1]
The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Log Rank
Comments Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3).
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.566 to 0.835
Estimation Comments Hazard Ratio and 95% confidence interval are from Cox regression model.
4.Secondary Outcome
Title Percentage of Participants Who Were Responders for Functional Assessment of Cancer Therapy-Prostate (FACT-P)
Hide Description The FACT-P was a 39-item participant questionnaire which assessed physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and additional prostate cancer specific concerns (12 items). All items were scored from 0 (not at all) to 4 (very much). The sum of scores on all 5 domains constitutes the global FACT-P. The global/total FACT-P score ranged from 0 (worst) to 156 (best), higher scores indicate better health status. Responders were those participants who had a 10-point improvement in their total FACT-P score, as compared with baseline, on two consecutive measurements obtained at least 3 weeks apart.
Time Frame Baseline up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable intent to treat (ITT) - all participants who were part of the ITT population and had a global FACT-P score at baseline and at least 1 post-baseline assessment.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 651 257
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
43.2
(39.3 to 47.1)
18.3
(13.8 to 23.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3).
Method of Estimation Estimation Parameter Difference in Percentage of Participants
Estimated Value 24.9
Confidence Interval (2-Sided) 95%
18.8 to 30.9
Estimation Comments Confidence Interval based on standard normal approximation.
5.Secondary Outcome
Title Time to Prostate-specific Antigen (PSA) Progression
Hide Description Time to PSA progression was defined as time from randomization to PSA progression. Participants who did not reach the endpoint were right censored at their last assessment or for participants with no post-baseline PSA assessment, date of randomization. For participants with PSA declines at Week 13, the PSA progression date was defined as the date that a >=25% increase and an absolute increase of >=2 nanogram per milliliter (ng/mL) above the nadir was documented, which was confirmed by a second consecutive value obtained 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment). For participants with no PSA declines at Week 13, PSA progression date was defined as the date that a >=25% increase and an absolute increase of >=2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment).
Time Frame Baseline and at every study visit from Week 13 while on study drug (up to 24 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT included all participants who were randomized into the study.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 800 399
Median (95% Confidence Interval)
Unit of Measure: Months
8.3
(5.8 to 8.3)
3.0
(2.9 to 3.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.248
Confidence Interval (2-Sided) 95%
0.204 to 0.303
Estimation Comments Hazard Ratio and 95% confidence interval are from Cox regression model.
6.Secondary Outcome
Title Percentage of Participants With Pain Palliation
Hide Description The proportion of participants with pain palliation was assessed for participants with a stable and sufficient pain burden at study entry. Pain burden was measured by question #3 of the Brief Pain Inventory (Short Form). This scale measures pain on a 0 to 10 scale with 0 indicating no pain and 10 indicating pain as bad as you can imagine. Pain palliation at Week 13 was determined for the proportion of men with baseline bone metastasis(es) who had baseline pain attributable to the metastasis(es). Palliation was defined as >=30% reduction in average pain score at Week 13 compared to baseline without a >=30% increase in analgesic use.
Time Frame Baseline up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable ITT Population included participants with metastatic bone disease at baseline; provided answers to Question #3 of the Brief Pain Inventory – Short Form for a minimum of 4 out of 7 days in the baseline run-in period; stable baseline pain; stable analgesic use; and had an average pain score during the baseline run-in period of >= 4.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 49 15
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
44.9
(30.7 to 59.8)
6.7
(0.2 to 31.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0079
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by baseline Eastern Cooperative Oncology Group performance status (0–1 vs. 2).
Method of Estimation Estimation Parameter Difference in Rate of Pain Palliation
Estimated Value 38.2
Confidence Interval (2-Sided) 95%
19.4 to 57.0
Estimation Comments Confidence Interval based on standard normal approximation.
7.Secondary Outcome
Title Percentage of Participants With Prostate Specific Antigen (PSA) Response
Hide Description Participants were evaluable for PSA response rate if they had a PSA level measured at baseline and at least 1 post-baseline assessment. Both PSA responses of > 50% and > 90% were determined. PSA responses required confirmation with a subsequent assessment that was conducted at least 3 weeks later.
Time Frame During DB phase (up to 24 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable ITT population included participants who were part of the ITT Population and had a PSA level measured at baseline and at least 1 post-baseline assessment.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 731 330
Measure Type: Number
Unit of Measure: Percentage of participants
Decline >=50% from baseline 54 2
Decline >=90% from baseline 25 1
8.Secondary Outcome
Title Percentage of Participants With Soft-tissue Objective Response
Hide Description The best overall soft tissue response as assessed using RECIST v1.1 during the study was summarized using the investigators’ response assessments and also the derived response assessments by treatment group. Only participants with measurable soft tissue disease at screening were included in this analysis. Participants with measurable disease at screening are participants who had at least 1 target lesion identified per RECIST v1.1 at screening. Percentage of participants summarizes the number of participants with complete or partial objective response (%). Soft Tissue assessment based on Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.
Time Frame During DB phase (up to 24 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT with measurable disease population included participants who were part of the ITT Population and had measurable soft tissue disease at screening, defined by at least 1 target lesion according to RECIST v1.1.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 446 208
Measure Type: Number
Unit of Measure: Percentage of participants
29 4
9.Secondary Outcome
Title European Quality of Life Five-Domain (EQ-5D) Scale
Hide Description EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility or index score. Five parameters (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were assessed on 3-point categorical scale (1= no problems, 2= some/moderate problems and 3= severe problem). Score were transformed and resulted in a total EQ-5D score range of 0 (worst imaginable health state) to 100 (best imaginable health state), with higher scores indicating better health and quality of life.
Time Frame Week 13
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Evaluable ITT included participants who were part of the ITT Population and who were evaluable for EQ-5D.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 126 55
Mean (Standard Deviation)
Unit of Measure: units on a scale
67.2  (19.29) 60.0  (19.26)
10.Secondary Outcome
Title Percentage of Participants With Circulating Tumor Cell (CTC) Conversion
Hide Description CTC conversion was assessed for participants with baseline CTC counts of greater than or equal to (>=) 5 cells per 7.5 milliliter (mL) of blood. A CTC conversion was defined as a decline in the CTC count to less than (<) 5 cells per 7.5 mL of blood. In this outcome measure percentage of participants with CTC conversion was reported.
Time Frame Baseline up to 24 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
CTC evaluable population included participants with a baseline and at least 1 post baseline CTC assessment.
Arm/Group Title Enzalutamide Placebo
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months in DB Phase and 7.7 months in OLE Phase).
Overall Number of Participants Analyzed 127 62
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
48
(39.09 to 57.07)
9.7
(3.63 to 19.88)
11.Other Pre-specified Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Hide Description AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of following outcomes or deemed significant and jeopardized participants or required treatment to prevent other AE outcomes for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events which occurred between first dose of study drug and up to the safety follow-up visit or the initiation of another anti-neoplastic therapy, whichever occurred first (up to 101 months). AEs included both serious and non-serious AEs. Clinically significant physical examination abnormalities were reported as AEs. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant’s request or if deemed necessary by the investigator.
Time Frame Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)
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Hide Analysis Population Description
Safety population was defined as all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Enzalutamide Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months).
Participants who received placebo in DB phase, completed DB Phase and entered in optional OLE Phase, received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 7.7 months).
Overall Number of Participants Analyzed 800 399 50
Measure Type: Count of Participants
Unit of Measure: Participants
AEs
789
  98.6%
390
  97.7%
48
  96.0%
SAEs
319
  39.9%
155
  38.8%
25
  50.0%
12.Other Pre-specified Outcome
Title Number of Participants With Clinically Significant Changes in Vital Signs
Hide Description Criteria for abnormalities in vital signs included: sitting/supine systolic blood pressure (SBP) values: absolute result greater than (>) 180 millimeter of mercury (mmHg) and >40 mmHg increase from baseline (BL) and less than (<) 90 mmHg and >30 mmHg decrease from BL; diastolic blood pressure (DBP) values: absolute result >105 mmHg and >30 mmHg increase from BL and absolute result < 50 mmHg and >20 mmHg decrease from BL; any abnormalities in SBP or DBP; heart rate values: absolute result > 120 beats per minute (bpm) and >30 bpm increase from BL and absolute result < 50 bpm and >20 bpm decrease from BL or any abnormalities in heart rate. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant’s request or if deemed necessary by the investigator.
Time Frame Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)
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Hide Analysis Population Description
Safety population was defined as all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Enzalutamide Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months).
Participants who received placebo in DB phase, completed DB Phase and entered in optional OLE Phase, received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 7.7 months).
Overall Number of Participants Analyzed 800 399 50
Measure Type: Count of Participants
Unit of Measure: Participants
SBP: >180 mmHg and >40 mmHg Increase from BL
28
   3.5%
7
   1.8%
1
   2.0%
SBP: < 90 mmHg and >30 mmHg Decrease from BL
13
   1.6%
5
   1.3%
0
   0.0%
DBP: >105 mmHg and >30 mmHg Increase from BL
5
   0.6%
2
   0.5%
0
   0.0%
DBP: < 50 mmHg and >20 mmHg Decrease from BL
13
   1.6%
3
   0.8%
1
   2.0%
Any abnormalities in SBP or DBP
52
   6.5%
16
   4.0%
2
   4.0%
Heart Rate: > 120 bpm and >30 bpm Increase from BL
7
   0.9%
5
   1.3%
0
   0.0%
Heart Rate: < 50 bpm and >20 bpm Decrease from BL
18
   2.3%
1
   0.3%
0
   0.0%
Any abnormalities in Heart Rate
25
   3.1%
6
   1.5%
0
   0.0%
13.Other Pre-specified Outcome
Title Number of Participants With Any Newly Clinically Significant Abnormal Finding in Electrocardiogram (ECG)
Hide Description Any new post baseline abnormality was defined as any abnormal ECG finding that appeared after baseline assessment which was not seen at the screening or baseline ECG assessment. Where, criteria of abnormality was QTcF interval > 470 millisecond (msec). Participants were counted once only for a specific abnormality. This outcome measure was planned to be analysed in double blind phase only. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant’s request or if deemed necessary by the investigator.
Time Frame Baseline, up to the end of DB phase or unscheduled visit (up to 24 months)
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Hide Analysis Population Description
Safety population was defined as all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Enzalutamide Placebo: DB Phase
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months).
Overall Number of Participants Analyzed 800 399
Measure Type: Count of Participants
Unit of Measure: Participants
28
   3.5%
13
   3.3%
14.Other Pre-specified Outcome
Title Number of Participants With Grade 3/4 Post-Baseline Laboratory Toxicity (Hematology and Chemistry)
Hide Description Laboratory parameters included hematological and chemistry parameters. Chemistry parameters included alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, calcium, creatine kinase, creatinine, glucose, magnesium, phosphate, potassium and sodium. Hematology parameters included haemoglobin, leukocytes, lymphocytes, neutrophils and platelet. Test abnormalities were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 as Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant’s request or if deemed necessary by the investigator.
Time Frame Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)
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Hide Analysis Population Description
Safety population was defined as all randomized participants who received at least 1 dose of study drug.
Arm/Group Title Enzalutamide Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Hide Arm/Group Description:
In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 8.3 months).
In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months).
Participants who received placebo in DB phase, completed DB Phase and entered in optional OLE Phase, received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 7.7 months).
Overall Number of Participants Analyzed 800 399 50
Measure Type: Count of Participants
Unit of Measure: Participants
Alanine Aminotransferase:High
2
   0.3%
2
   0.5%
1
   2.0%
Albumin: Low
7
   0.9%
3
   0.8%
0
   0.0%
Alkaline Phosphatase: High
102
  12.8%
74
  18.5%
3
   6.0%
Aspartate Aminotransferase: High
3
   0.4%
4
   1.0%
1
   2.0%
Bilirubin: High
2
   0.3%
0
   0.0%
0
   0.0%
Calcium: Low
14
   1.8%
15
   3.8%
1
   2.0%
Calcium: High
1
   0.1%
0
   0.0%
0
   0.0%
Creatine Kinase: High
4
   0.5%
2
   0.5%
0
   0.0%
Creatinine: High
0
   0.0%
2
   0.5%
0
   0.0%
Glucose: High
17
   2.1%
10
   2.5%
1
   2.0%
Magnesium: Low
0
   0.0%
1
   0.3%
0
   0.0%
Magnesium: High
1
   0.1%
1
   0.3%
0
   0.0%
Phosphate: Low
28
   3.5%
10
   2.5%
2
   4.0%
Potassium: Low
7
   0.9%
4
   1.0%
1
   2.0%
Potassium: High
2
   0.3%
3
   0.8%
0
   0.0%
Sodium: Low
19
   2.4%
13
   3.3%
0
   0.0%
Sodium: High
0
   0.0%
1
   0.3%
0
   0.0%
Hemoglobin: Low
38
   4.8%
20
   5.0%
4
   8.0%
Hemoglobin: High
1
   0.1%
0
   0.0%
0
   0.0%
Leukocytes: Low
8
   1.0%
1
   0.3%
1
   2.0%
Lymphocytes: Low
80
  10.0%
48
  12.0%
5
  10.0%
Neutrophils: Low
10
   1.3%
0
   0.0%
1
   2.0%
Platelet; Low
4
   0.5%
4
   1.0%
0
   0.0%
Time Frame Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)
Adverse Event Reporting Description An event may be categorized as serious in one participant and non serious in another participant, or one participant may experience both serious and non serious event. All treatment emergent AEs and SAEs were collected and reported. The same event may appear as both AE and SAE. All-cause mortality data included all anticipated and unanticipated deaths due to any cause. Safety population included all randomized participants who received at least 1 dose of study drug.
 
Arm/Group Title Enzalutamide: DB + OLE Phase Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Hide Arm/Group Description In DB Phase, participants received Enzalutamide capsules 160 mg orally per day. Participants who completed DB Phase, entered in optional OLE Phase and received same treatment until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal. In DB Phase, participants received placebo capsules (for Enzalutamide) orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 3.0 months). Participants who received placebo in DB phase, completed DB Phase and entered in optional OLE Phase, received Enzalutamide capsules 160 mg orally per day until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death or withdrawal (median treatment duration was 7.7 months).
All-Cause Mortality
Enzalutamide: DB + OLE Phase Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Enzalutamide: DB + OLE Phase Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   319/800 (39.88%)   155/399 (38.85%)   25/50 (50.00%) 
Blood and lymphatic system disorders       
Anaemia * 1  22/800 (2.75%)  12/399 (3.01%)  2/50 (4.00%) 
Anaemia of malignant disease * 1  2/800 (0.25%)  1/399 (0.25%)  0/50 (0.00%) 
Disseminated intravascular coagulation * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pancytopenia * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Thrombocytopenia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Leukocytosis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Cardiac disorders       
Cardiac failure * 1  3/800 (0.38%)  2/399 (0.50%)  2/50 (4.00%) 
Angina pectoris * 1  2/800 (0.25%)  1/399 (0.25%)  0/50 (0.00%) 
Acute myocardial infarction * 1  3/800 (0.38%)  1/399 (0.25%)  0/50 (0.00%) 
Cardiac failure congestive * 1  2/800 (0.25%)  0/399 (0.00%)  1/50 (2.00%) 
Atrial flutter * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Bradycardia * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Cardiogenic shock * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Left ventricular failure * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Mitral valve incompetance * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Ventricular fibrillation * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Arrhythmia supraventricular * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Atrial fibrillation * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Atrioventricular block complete * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Myocardial ischaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Myocardial infarction * 1  0/800 (0.00%)  2/399 (0.50%)  0/50 (0.00%) 
Acute coronary syndrome * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Aortic valve incompetence * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cardiac arrest * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Congenital, familial and genetic disorders       
Adenomatous polyposis coli * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Ear and labyrinth disorders       
Ear pain * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Vertigo * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Endocrine disorders       
Adrenal insufficiency * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Eye disorders       
Retinal detachment * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Papilloedema * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Visual acuity reduced * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Visual impairment * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Eyelid bleeding * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gastrointestinal disorders       
Vomiting * 1  3/800 (0.38%)  8/399 (2.01%)  1/50 (2.00%) 
Nausea * 1  5/800 (0.63%)  3/399 (0.75%)  1/50 (2.00%) 
Constipation * 1  5/800 (0.63%)  3/399 (0.75%)  0/50 (0.00%) 
Rectal haemorrhage * 1  3/800 (0.38%)  3/399 (0.75%)  0/50 (0.00%) 
Abdominal pain * 1  2/800 (0.25%)  2/399 (0.50%)  0/50 (0.00%) 
Diarrhoea * 1  4/800 (0.50%)  0/399 (0.00%)  0/50 (0.00%) 
Small intestinal obstruction * 1  3/800 (0.38%)  0/399 (0.00%)  1/50 (2.00%) 
Faecaloma * 1  0/800 (0.00%)  2/399 (0.50%)  0/50 (0.00%) 
Gastrointestinal haemorrhage * 1  2/800 (0.25%)  1/399 (0.25%)  1/50 (2.00%) 
Intestinal obstruction * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Abdominal pain lower * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Colitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gastric ulcer haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gastrointestinal obstruction * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Haematochezia * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Intestinal perforation * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Large intestine perforation * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Pancreatitis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Proctalgia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Retroperitoneal haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Intestinal mass * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Pancreatitis acute * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Peptic ulcer * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Diverticulum intestinal haemorrhagic * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Duodenal ulcer haemorrhage * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Inguinal hernia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Large intestinal obstruction * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Lower gastrointestinal haemorrhage * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Proctocolitis * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
General disorders       
General physical health deterioration * 1  22/800 (2.75%)  8/399 (2.01%)  3/50 (6.00%) 
Asthenia * 1  4/800 (0.50%)  2/399 (0.50%)  0/50 (0.00%) 
Pain * 1  5/800 (0.63%)  1/399 (0.25%)  0/50 (0.00%) 
Fatigue * 1  3/800 (0.38%)  2/399 (0.50%)  1/50 (2.00%) 
Pyrexia * 1  2/800 (0.25%)  5/399 (1.25%)  1/50 (2.00%) 
Oedema peripheral * 1  1/800 (0.13%)  2/399 (0.50%)  0/50 (0.00%) 
Malaise * 1  2/800 (0.25%)  2/399 (0.50%)  0/50 (0.00%) 
Chest pain * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Death * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Euthanasia * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
General symptom * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Device dislocation * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Device occlusion * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Disease progression * 1  1/800 (0.13%)  0/399 (0.00%)  2/50 (4.00%) 
Local swelling * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Hepatobiliary disorders       
Bile duct obstruction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cholangitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cholelithiasis * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Immune system disorders       
Anaphylactic reaction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Infections and infestations       
Pneumonia * 1  15/800 (1.88%)  5/399 (1.25%)  1/50 (2.00%) 
Urinary tract infection * 1  9/800 (1.13%)  5/399 (1.25%)  1/50 (2.00%) 
Urosepsis * 1  4/800 (0.50%)  1/399 (0.25%)  0/50 (0.00%) 
Sepsis * 1  4/800 (0.50%)  1/399 (0.25%)  0/50 (0.00%) 
Gastroenteritis * 1  1/800 (0.13%)  2/399 (0.50%)  0/50 (0.00%) 
Bronchitis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Device related infection * 1  3/800 (0.38%)  0/399 (0.00%)  0/50 (0.00%) 
Escherichia sepsis * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Lobar pneumonia * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Staphylococcal sepsis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Cellulitis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Erysipelas * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Lower respiratory tract infection * 1  2/800 (0.25%)  0/399 (0.00%)  1/50 (2.00%) 
Abdominal abscess * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Chest wall abscess * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Clostridium difficile colitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cystitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Extradural abscess * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Infection * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Infective exacerbation of chronic obstructive airways disease * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Kidney infection * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Klebsiella bacteraemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Parotitis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Pneumonia bacterial * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Rectal abscess * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Respiratory tract infection * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Septic Shock * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Tooth Infection * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Upper respiratory tract infection * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Herpes zoster * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Viral pericarditis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Abscess jaw * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Anal abscess * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Atypical mycobacterial pneumonia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Bacteraemia * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Diverticulitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Febrile infection * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gas gangrene * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pleural infection * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Pneumonia pneumococcal * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pulmonary sepsis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pyelonephritis acute * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Injury, poisoning and procedural complications       
Subdural haematoma * 1  3/800 (0.38%)  1/399 (0.25%)  0/50 (0.00%) 
Femur fracture * 1  3/800 (0.38%)  0/399 (0.00%)  0/50 (0.00%) 
Fall * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Femoral neck fracture * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hip fracture * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Lumbar vertebral fracture * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Patella fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Post procedural haematuria * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Post-traumatic pain * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Radiation oesophagitis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Soft tissue injury * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Spinal compression fracture * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Hand fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Thoracic vertebral fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Facial bones fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gastroenteritis radiation * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Head injury * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Heat stroke * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pelvic fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pubis fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Rib fracture * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Investigations       
Liver function test abnormal * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Weight decreased * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Coagulation time prolonged * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Haemoglobin decreased * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Metabolism and nutrition disorders       
Dehydration * 1  4/800 (0.50%)  3/399 (0.75%)  0/50 (0.00%) 
Hyponatraemia * 1  2/800 (0.25%)  3/399 (0.75%)  1/50 (2.00%) 
Hypoglycaemia * 1  1/800 (0.13%)  2/399 (0.50%)  0/50 (0.00%) 
Hypercalcaemia * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Hyperuricaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypocalcaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypokalaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypophosphataemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypovolaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cachexia * 1  0/800 (0.00%)  1/399 (0.25%)  1/50 (2.00%) 
Decreased appetite * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Diabetes mellitus * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Failure to thrive * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Malnutrition * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Hypoalbuminaemia * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Musculoskeletal and connective tissue disorders       
Back pain * 1  11/800 (1.38%)  7/399 (1.75%)  0/50 (0.00%) 
Bone pain * 1  12/800 (1.50%)  3/399 (0.75%)  1/50 (2.00%) 
Pathological fracture * 1  15/800 (1.88%)  2/399 (0.50%)  0/50 (0.00%) 
Pain in extremity * 1  4/800 (0.50%)  2/399 (0.50%)  0/50 (0.00%) 
Arthralgia * 1  3/800 (0.38%)  1/399 (0.25%)  0/50 (0.00%) 
Muscular weakness * 1  2/800 (0.25%)  0/399 (0.00%)  1/50 (2.00%) 
Myalgia * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Osteonecrosis of jaw * 1  2/800 (0.25%)  1/399 (0.25%)  1/50 (2.00%) 
Musculoskeletal chest pain * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Chondrocalcinosis pyrophosphate * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Flank pain * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Intervertebral disc protrusion * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Muscle haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Osteoarthritis * 1  4/800 (0.50%)  0/399 (0.00%)  0/50 (0.00%) 
Rhabdomyolysis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Spinal column stenosis * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Osteitis * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Spinal pain * 1  2/800 (0.25%)  1/399 (0.25%)  0/50 (0.00%) 
Bursitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Metastatic pain * 1  18/800 (2.25%)  3/399 (0.75%)  3/50 (6.00%) 
Cancer pain * 1  10/800 (1.25%)  5/399 (1.25%)  1/50 (2.00%) 
Metastases to central nervous system * 1  5/800 (0.63%)  1/399 (0.25%)  0/50 (0.00%) 
Metastases to Bone * 1  1/800 (0.13%)  5/399 (1.25%)  0/50 (0.00%) 
Malignant pleural effusion * 1  2/800 (0.25%)  1/399 (0.25%)  1/50 (2.00%) 
Tumour pain * 1  0/800 (0.00%)  3/399 (0.75%)  0/50 (0.00%) 
Acute leukaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Acute monocytic leukaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Bone marrow tumour cell infiltration * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Metastases to liver * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Metastases to meninges * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Neoplasm progression * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Small cell lung cancer * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Transitional cell carcinoma * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Bronchial carcinoma * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Gastrointestinal tract adenoma * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Metastases to lung * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Acute lymphocytic leukaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Colon cancer * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Intracranial tumour haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Myelodysplastic syndrome * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Squamous cell carcinoma of head and neck * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Squamous cell carcinoma of lung * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Nervous system disorders       
Spinal cord compression * 1  54/800 (6.75%)  15/399 (3.76%)  3/50 (6.00%) 
Cauda equina syndrome * 1  6/800 (0.75%)  0/399 (0.00%)  0/50 (0.00%) 
Nerve root compression * 1  1/800 (0.13%)  4/399 (1.00%)  0/50 (0.00%) 
Syncope * 1  5/800 (0.63%)  2/399 (0.50%)  0/50 (0.00%) 
Cerebrovascular accident * 1  4/800 (0.50%)  1/399 (0.25%)  0/50 (0.00%) 
Hepatic encephalopathy * 1  1/800 (0.13%)  2/399 (0.50%)  0/50 (0.00%) 
Dizziness * 1  2/800 (0.25%)  1/399 (0.25%)  0/50 (0.00%) 
Transient ischemic attack * 1  3/800 (0.38%)  1/399 (0.25%)  0/50 (0.00%) 
Cerebral haemorrhage * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Convulsion * 1  4/800 (0.50%)  0/399 (0.00%)  2/50 (4.00%) 
Epiduritis * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Nerve compression * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Partial seizures * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Lethargy * 1  3/800 (0.38%)  0/399 (0.00%)  0/50 (0.00%) 
Headache * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Akathisia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Central nervous system lesion * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cranial nerve palsies multiple * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Embolic stroke * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Haemorrhage intracranial * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Haemorrhagic stroke * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Ischaemic stroke * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Lacunar infarction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Loss of consciousness * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Lumbar radiculopathy * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Motor dysfunction * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Pachymeningitis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Presyncope * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Status epilepticus * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypoglossal nerve paresis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Normal pressure hydrocephalus * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Tremor * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Trigeminal neuralgia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Visual field defect * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Ataxia * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Carpal tunnel syndrome * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Complex partial seizures * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cranial nerve disorder * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Myoclonus * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Paraplegia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Sciatica * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Senile dementia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Subarachnoid haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Thalamic infarction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
VIIth nerve paralysis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Neuropathy peripheral * 1  0/800 (0.00%)  0/399 (0.00%)  1/50 (2.00%) 
Psychiatric disorders       
Confusional state * 1  2/800 (0.25%)  2/399 (0.50%)  0/50 (0.00%) 
Depressed mood * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hallucination * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Mental status changes * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Depression * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Disorientation * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Renal and urinary disorders       
Haematuria * 1  18/800 (2.25%)  5/399 (1.25%)  1/50 (2.00%) 
Urinary retention * 1  7/800 (0.88%)  8/399 (2.01%)  0/50 (0.00%) 
Urinary tract obstruction * 1  8/800 (1.00%)  1/399 (0.25%)  0/50 (0.00%) 
Post renal failure * 1  3/800 (0.38%)  3/399 (0.75%)  0/50 (0.00%) 
Renal failure * 1  3/800 (0.38%)  3/399 (0.75%)  0/50 (0.00%) 
Renal failure acute * 1  3/800 (0.38%)  3/399 (0.75%)  0/50 (0.00%) 
Bladder perforation * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Hydronephrosis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Nephrolithiasis * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Cystitis haemorrhagic * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Renal colic * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Bladder obstruction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Dysuria * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Obstructive uropathy * 1  1/800 (0.13%)  0/399 (0.00%)  1/50 (2.00%) 
Ureteric obstruction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Urethral obstruction * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Urethral stenosis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Reproductive system and breast disorders       
Pelvic pain * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism * 1  5/800 (0.63%)  4/399 (1.00%)  0/50 (0.00%) 
Pleural effusion * 1  2/800 (0.25%)  3/399 (0.75%)  1/50 (2.00%) 
Chronic obstructive pulmonary disease * 1  4/800 (0.50%)  0/399 (0.00%)  0/50 (0.00%) 
Pneumothorax * 1  2/800 (0.25%)  2/399 (0.50%)  0/50 (0.00%) 
Epistaxis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Pulmonary oedema * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Dyspnoea * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Acute pulmonary oedema * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Haemoptysis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Respiratory arrest * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Hydropneumothorax * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pleuritic pain * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypoxia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Skin and subcutaneous tissue disorders       
Hyperhidrosis * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Vascular purpura * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Surgical and medical procedures       
Bladder catheter removal * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Limb operation * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pain management * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Cataract operation * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Colon polypectomy * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Oesophageal dilation procedure * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Pleurodesis * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Ureteral stent insertion * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Vascular disorders       
Deep vein thrombosis * 1  3/800 (0.38%)  3/399 (0.75%)  0/50 (0.00%) 
Haematoma * 1  3/800 (0.38%)  0/399 (0.00%)  0/50 (0.00%) 
Lymphoedema * 1  2/800 (0.25%)  0/399 (0.00%)  0/50 (0.00%) 
Hypertensive crisis * 1  1/800 (0.13%)  1/399 (0.25%)  0/50 (0.00%) 
Hypotension * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Peripheral ischaemia * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Orthostatic hypotension * 1  0/800 (0.00%)  1/399 (0.25%)  0/50 (0.00%) 
Haemorrhage * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
Hypertension * 1  1/800 (0.13%)  0/399 (0.00%)  0/50 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Enzalutamide: DB + OLE Phase Placebo: DB Phase Placebo (DB) /Enzalutamide 160 mg (OLE) Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   784/800 (98.00%)   385/399 (96.49%)   47/50 (94.00%) 
Blood and lymphatic system disorders       
Anaemia * 1  123/800 (15.38%)  70/399 (17.54%)  11/50 (22.00%) 
Gastrointestinal disorders       
Nausea * 1  276/800 (34.50%)  166/399 (41.60%)  16/50 (32.00%) 
Constipation * 1  209/800 (26.13%)  109/399 (27.32%)  7/50 (14.00%) 
Diarrhoea * 1  180/800 (22.50%)  70/399 (17.54%)  9/50 (18.00%) 
Vomiting * 1  141/800 (17.63%)  84/399 (21.05%)  8/50 (16.00%) 
Abdominal pain * 1  47/800 (5.88%)  21/399 (5.26%)  2/50 (4.00%) 
Abdominal pain upper * 1  41/800 (5.13%)  13/399 (3.26%)  0/50 (0.00%) 
General disorders       
Fatigue * 1  280/800 (35.00%)  115/399 (28.82%)  14/50 (28.00%) 
Asthenia * 1  148/800 (18.50%)  67/399 (16.79%)  9/50 (18.00%) 
Oedema peripheral * 1  121/800 (15.13%)  46/399 (11.53%)  4/50 (8.00%) 
Pyrexia * 1  59/800 (7.38%)  23/399 (5.76%)  4/50 (8.00%) 
Pain * 1  27/800 (3.38%)  12/399 (3.01%)  3/50 (6.00%) 
Infections and infestations       
Urinary tract infection * 1  68/800 (8.50%)  24/399 (6.02%)  3/50 (6.00%) 
Nasopharyngitis * 1  47/800 (5.88%)  12/399 (3.01%)  2/50 (4.00%) 
Injury, poisoning and procedural complications       
Fall * 1  44/800 (5.50%)  5/399 (1.25%)  5/50 (10.00%) 
Investigations       
Weight decreased * 1  108/800 (13.50%)  42/399 (10.53%)  7/50 (14.00%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  246/800 (30.75%)  121/399 (30.33%)  9/50 (18.00%) 
Hypokalaemia * 1  31/800 (3.88%)  14/399 (3.51%)  3/50 (6.00%) 
Musculoskeletal and connective tissue disorders       
Back pain * 1  225/800 (28.13%)  91/399 (22.81%)  9/50 (18.00%) 
Arthralgia * 1  182/800 (22.75%)  71/399 (17.79%)  2/50 (4.00%) 
Pain in extremity * 1  137/800 (17.13%)  62/399 (15.54%)  5/50 (10.00%) 
Bone pain * 1  101/800 (12.63%)  61/399 (15.29%)  2/50 (4.00%) 
Musculoskeletal pain * 1  121/800 (15.13%)  40/399 (10.03%)  3/50 (6.00%) 
Musculoskeletal chest pain * 1  77/800 (9.63%)  34/399 (8.52%)  2/50 (4.00%) 
Muscular weakness * 1  74/800 (9.25%)  27/399 (6.77%)  1/50 (2.00%) 
Myalgia * 1  56/800 (7.00%)  26/399 (6.52%)  2/50 (4.00%) 
Neck pain * 1  34/800 (4.25%)  17/399 (4.26%)  3/50 (6.00%) 
Nervous system disorders       
Headache * 1  101/800 (12.63%)  21/399 (5.26%)  1/50 (2.00%) 
Dizziness * 1  59/800 (7.38%)  22/399 (5.51%)  4/50 (8.00%) 
Paraesthesia * 1  53/800 (6.63%)  18/399 (4.51%)  1/50 (2.00%) 
Hypoaesthesia * 1  33/800 (4.13%)  7/399 (1.75%)  4/50 (8.00%) 
Psychiatric disorders       
Insomnia * 1  71/800 (8.88%)  24/399 (6.02%)  2/50 (4.00%) 
Anxiety * 1  55/800 (6.88%)  16/399 (4.01%)  6/50 (12.00%) 
Depression * 1  51/800 (6.38%)  19/399 (4.76%)  4/50 (8.00%) 
Confusional state * 1  23/800 (2.88%)  9/399 (2.26%)  3/50 (6.00%) 
Renal and urinary disorders       
Haematuria * 1  51/800 (6.38%)  14/399 (3.51%)  3/50 (6.00%) 
Pollakiuria * 1  44/800 (5.50%)  10/399 (2.51%)  3/50 (6.00%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea * 1  88/800 (11.00%)  39/399 (9.77%)  6/50 (12.00%) 
Cough * 1  60/800 (7.50%)  25/399 (6.27%)  2/50 (4.00%) 
Vascular disorders       
Hot flush * 1  165/800 (20.63%)  41/399 (10.28%)  1/50 (2.00%) 
Hypertension * 1  60/800 (7.50%)  11/399 (2.76%)  2/50 (4.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
The primary objectives (overall survival) of the study had been met and all participants who had remained on study treatment have discontinued and therefore the study has been considered as completed.
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.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer Inc.
Phone: 1-800-718-1021
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00974311     History of Changes
Other Study ID Numbers: CRPC2
2009-013174-41 ( EudraCT Number )
C3431010 ( Other Identifier: Alias Study Number )
First Submitted: September 9, 2009
First Posted: September 10, 2009
Results First Submitted: September 28, 2012
Results First Posted: October 30, 2012
Last Update Posted: December 11, 2018