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Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients (PLATO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01995513
Recruitment Status : Active, not recruiting
First Posted : November 26, 2013
Results First Posted : November 17, 2017
Last Update Posted : December 17, 2019
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;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Prostate Cancer
Interventions Drug: Enzalutamide
Drug: Abiraterone
Drug: Placebo for Enzalutamide
Drug: Prednisone
Enrollment 509
Recruitment Details  
Pre-assignment Details The study comprised of consecutive periods of open-label treatment with enzalutamide (period 1) followed by randomized, double-blind treatment with enzalutamide or placebo, each in combination with open-label abiraterone and prednisone (period 2).
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description Participants received enzalutamide 160 milligram (mg) as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first. Participants with confirmed prostate-specific antigen (PSA) progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer. Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Period Title: Open Label Treatment Period
Started 509 0 0
Completed 251 0 0
Not Completed 258 0 0
Reason Not Completed
Other             9             0             0
Withdrawal by Subject             14             0             0
Protocol Violation             1             0             0
Disease Progression             64             0             0
No PSA response at week 13             43             0             0
Adverse Event             35             0             0
Death             8             0             0
Ongoing as of data cutoff (07 Oct 2016)             84             0             0
Period Title: Double Blind Treatment Period
Started 0 126 125
Treated 0 125 124
Completed 0 0 0
Not Completed 0 126 125
Reason Not Completed
Adverse Event             0             12             5
Other             0             1             2
Withdrawal by Subject             0             4             6
Death             0             0             1
Disease Progression             0             82             93
Ongoing as of data cutoff (07 Oct 2016)             0             27             18
Arm/Group Title Enzalutamide 160 mg
Hide Arm/Group Description Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first.
Overall Number of Baseline Participants 509
Hide Baseline Analysis Population Description
ITT (Intent to treat) population included all participants randomly assigned to study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 509 participants
72.3  (8.31)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 509 participants
Female
0
   0.0%
Male
509
 100.0%
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description PFS = time from randomization to first documentation of radiographic progression (RP),unequivocal clinical progression or death due to any cause (death within 112 days of treatment discontinuation without objective evidence of RP),whichever occurred first as per investigator. Unequivocal disease progression was pain requiring chronic administration of analgesics, decline of prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to 3 or higher or initiation of new anticancer therapy/radiation therapy or surgical intervention due to tumor progression. ECOG score range= 0(no severity) to 5(maximum severity).RP for bone disease was evaluated by appearance of 2 or more new bone lesions as per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) or for soft tissue disease according to Response Evaluation Criteria in Solid Tumor version 1.1. Participants with no PFS event at analysis date were censored at last tumor assessment date prior to data cutoff date.
Time Frame From randomization until disease progression, last tumor assessment without disease progression or death due to any cause, whichever occurred first (up to the data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Median (95% Confidence Interval)
Unit of Measure: months
5.7
(4.6 to 8.1)
5.6
(4.5 to 7.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2176
Comments P-value was based on log-rank test stratified by PSA response (greater than or equal to [>=] 0 percent [%] to less than [<] 30% vs >=30%) at Week 13 in the open-label period.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.828
Confidence Interval (2-Sided) 95%
0.612 to 1.119
Estimation Comments Hazard ratio was based on a Cox regression model (with treatment as the only covariate) stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period and is relative to Enzalutamide-placebo with < 1 favoring Enzalutamide.
2.Secondary Outcome
Title Time to Prostate Specific Antigen (PSA) Progression
Hide Description Time from date of randomization to the date of first confirmed PSA progression as per Prostate Cancer Clinical Trials Working Group 2 (PCWG2). For participant's whose PSA decreased at Week 13 after randomization, progression was defined as 25 percent (%) PSA increase relative to nadir or absolute increase of >=2 nanogram/milliliter (ng/mL) above nadir. Progression was confirmed if another assessment measured at least 3 weeks later met the criterion as well. For participant's whose PSA did not decrease at Week 13 after randomization, progression was defined as 25% PSA increase relative to baseline assessed 12 weeks after baseline. Participants who were not known to have had a PFS event at the analysis date were censored at last PSA assessment date prior to data cutoff date.
Time Frame From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (up to the data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Median (95% Confidence Interval)
Unit of Measure: months
2.8
(2.8 to 2.9)
2.8
(2.8 to 2.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4500
Comments P-value was based on log-rank test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.874
Confidence Interval (2-Sided) 95%
0.617 to 1.239
Estimation Comments Hazard ratio was based on a Cox regression model (with treatment as the only covariate) stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period and is relative to Enzalutamide-placebo with < 1 favoring Enzalutamide.
3.Secondary Outcome
Title Prostate Specific Antigen (PSA) Response Rate
Hide Description PSA response rate was defined as percentage of participants with >=30% and >=50% decrease in PSA from baseline at randomization to the maximal PSA response with a threshold of 30% and 50% respectively. PSA response was confirmed if another assessment measured at least 3 weeks later met the criterion as well.
Time Frame From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (up to the data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable ITT population included all participants with a PSA value at baseline of Period 2 and at least 1 post baseline assessment. Here, overall number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 124 122
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
>= 50%
0.8
(0.0 to 4.4)
2.5
(0.5 to 7.0)
>= 30%
2.4
(0.5 to 6.9)
2.5
(0.5 to 7.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments This analysis is reported for participants with >=50% decrease from baseline in PSA response.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3101
Comments P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -1.65
Confidence Interval (2-Sided) 95%
-4.82 to -1.51
Estimation Comments Difference in response rate was based upon standard normal approximation.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments This analysis is reported for participants with >=30% decrease from baseline in PSA response.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9917
Comments P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Response Rate
Estimated Value -0.04
Confidence Interval (2-Sided) 95%
-3.90 to 3.82
Estimation Comments Difference in response rate was based upon standard normal approximation.
4.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description Objective response rate as assessed by the investigator according to Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST v1.1) was defined as 1) Percentage of participants with confirmed best overall complete response (CR) and partial response (PR); 2) Percentage of participants with CR, PR and stable disease (SD) for target lesions or non-progressive disease for non-target lesions. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to <10 millimeter (mm) in short axis. No new lesions and disappearance of all non-target lesions. PR: >= 30% decrease in sum of diameters of target lesions, compared to the sum at baseline. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.
Time Frame From randomization until CR or PR, whichever occurred first (up to the data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population (with measurable disease at screening) included all subjects randomly assigned to study treatment. Here, N signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 38 40
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
CR + PR
0.0
(0.00 to 9.25)
5.0
(0.61 to 16.92)
CR + PR + SD
68.4
(51.35 to 82.50)
57.5
(40.89 to 72.96)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments This analysis is reported for participants with CR+PR.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1653
Comments P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rate
Estimated Value -5.00
Confidence Interval (2-Sided) 95%
-11.75 to 1.75
Estimation Comments Difference in objective response rate was based upon standard normal approximation.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments This analysis is reported for participants with CR+PR+SD.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3216
Comments P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rate
Estimated Value 10.92
Confidence Interval (2-Sided) 95%
-10.37 to 32.21
Estimation Comments Difference in objective response rate was based upon standard normal approximation.
5.Secondary Outcome
Title Rate of Pain Progression
Hide Description Rate of pain progression was defined as percentage of participants with an increase of >=30% from baseline in the mean Brief Pain Inventory-Short Form (BPI-SF) pain intensity item scores of 4 items assessing average, worst, least, and intermediate pain severity. BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. BPI-sf includes 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). BPI-sf score range for each item was from 0=no pain to 10=worst possible pain. Total score was reported as average of individual questions ranges from 0 to 10, where lower scores indicated less pain or less pain interference.
Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, N signifies those participants who were evaluable for this outcome measure.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 58 59
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
36.2
(24.0 to 49.9)
27.1
(16.4 to 40.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2963
Comments P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Progression Rate
Estimated Value 9.09
Confidence Interval (2-Sided) 95%
-7.69 to 25.87
Estimation Comments Difference in Progression Rate was based upon normal approximation.
6.Secondary Outcome
Title Time to First Use of New Antineoplastic Therapy for Prostate Cancer
Hide Description It was defined as time from randomization to the date of first use of subsequent antineoplastic therapy for prostate cancer. For participants who had not started subsequent antineoplastic therapy as of data analysis cutoff date, the time to first use of subsequent antineoplastic therapy was censored at the date of last assessment.
Time Frame From randomization until date of first use of any antineoplastic therapy (after last dose date of Period 2, up to the data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Median (95% Confidence Interval)
Unit of Measure: months
10.3
(8.7 to 12.1)
8.6
(7.4 to 11.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3818
Comments P-value was based on log-rank test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.861
Confidence Interval (2-Sided) 95%
0.616 to 1.204
Estimation Comments Hazard ratio was based on a Cox regression model (with treatment as the only covariate) stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period and is relative to Enzalutamide-placebo with < 1 favoring Enzalutamide.
7.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score which is the sum of all 5 domain scores and ranges from 0 to 156 where higher scores represent better quality of life.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, number analyzed (n) signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 125 participants 123 participants
116.4  (20.10) 119.0  (19.08)
Change at Week 9 Number Analyzed 102 participants 105 participants
-3.3  (14.90) -2.2  (13.90)
Change at Week 13 Number Analyzed 88 participants 87 participants
-4.4  (14.44) -0.5  (13.02)
Change at Week 17 Number Analyzed 83 participants 77 participants
-3.7  (12.40) -2.3  (13.90)
Change at Week 21 Number Analyzed 69 participants 65 participants
-2.5  (12.33) -2.7  (13.57)
Change at Week 25 Number Analyzed 61 participants 61 participants
-3.1  (13.47) -2.1  (10.87)
Change at Week 29 Number Analyzed 51 participants 49 participants
-6.8  (13.98) 0.3  (12.10)
Change at Week 33 Number Analyzed 44 participants 43 participants
-5.9  (15.35) -0.2  (12.90)
Change at Week 37 Number Analyzed 35 participants 33 participants
-6.1  (14.25) 0.9  (12.57)
Change at Week 41 Number Analyzed 31 participants 29 participants
-5.7  (12.17) 1.3  (14.13)
Change at Week 45 Number Analyzed 28 participants 26 participants
-6.0  (9.56) -2.6  (16.27)
Change at Week 49 Number Analyzed 27 participants 18 participants
-4.2  (11.36) 1.8  (10.74)
Change at Week 53 Number Analyzed 20 participants 15 participants
-4.8  (10.17) 1.8  (14.68)
Change at Week 57 Number Analyzed 17 participants 13 participants
-4.3  (9.73) 0.1  (7.45)
Change at Week 61 Number Analyzed 13 participants 10 participants
-5.5  (10.63) 0.6  (12.94)
Change at Week 65 Number Analyzed 13 participants 7 participants
-7.0  (7.86) 1.9  (9.50)
Change at Week 69 Number Analyzed 10 participants 7 participants
-3.5  (11.37) 4.4  (13.29)
Change at Week 73 Number Analyzed 8 participants 1 participants
-0.7  (7.26) -35.0 [1]   (NA)
Change at Week 77 Number Analyzed 7 participants 2 participants
-4.0  (9.81) 6.5  (30.41)
Change at Week 81 Number Analyzed 2 participants 0 participants
10.8  (9.24)
Change at Week 85 Number Analyzed 2 participants 0 participants
-5.5  (3.54)
Change at Week 89 Number Analyzed 1 participants 0 participants
-2.0 [2]   (NA)
[1]
As only 1 participant was analyzed at Week 73, standard deviation could not be calculated.
[2]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
8.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Social/Family Well-Being Domain Scores
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain. Total subscale score range for social/family well-being domain is from 0 (worst response) to 32 (best response), where higher score indicate better quality of life.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, n signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 125 participants 123 participants
22.1  (5.80) 22.4  (4.84)
Change at Week 9 Number Analyzed 104 participants 108 participants
-0.5  (4.33) -0.8  (4.13)
Change at Week 13 Number Analyzed 89 participants 89 participants
-0.4  (3.46) -0.4  (3.86)
Change at Week 17 Number Analyzed 84 participants 80 participants
-0.1  (3.68) -0.6  (4.64)
Change at Week 21 Number Analyzed 70 participants 67 participants
-0.5  (3.24) -1.2  (5.75)
Change at Week 25 Number Analyzed 62 participants 62 participants
0.1  (2.79) -1.0  (5.25)
Change at Week 29 Number Analyzed 51 participants 50 participants
-0.1  (3.20) -0.2  (5.18)
Change at Week 33 Number Analyzed 44 participants 44 participants
-0.2  (3.21) 0.0  (4.95)
Change at Week 37 Number Analyzed 36 participants 33 participants
-0.8  (3.04) 0.8  (2.79)
Change at Week 41 Number Analyzed 31 participants 29 participants
-1.4  (3.75) -0.1  (3.51)
Change at Week 45 Number Analyzed 28 participants 27 participants
-0.9  (3.36) -0.8  (3.75)
Change at Week 49 Number Analyzed 27 participants 18 participants
-0.6  (2.88) 0.0  (2.65)
Change at Week 53 Number Analyzed 21 participants 15 participants
-1.0  (3.15) 0.4  (2.56)
Change at Week 57 Number Analyzed 17 participants 13 participants
-2.0  (3.06) 0.2  (1.29)
Change at Week 61 Number Analyzed 13 participants 10 participants
-1.5  (2.77) -0.2  (1.80)
Change at Week 65 Number Analyzed 13 participants 7 participants
-1.5  (2.54) -0.5  (0.96)
Change at Week 69 Number Analyzed 10 participants 7 participants
-1.4  (2.03) -0.5  (0.96)
Change at Week 73 Number Analyzed 8 participants 1 participants
-0.6  (3.22) -1.0 [1]   (NA)
Change at Week 77 Number Analyzed 7 participants 2 participants
-0.9  (3.41) -0.5  (0.71)
Change at Week 81 Number Analyzed 2 participants 0 participants
6.2  (5.42)
Change at Week 85 Number Analyzed 2 participants 0 participants
-1.0  (1.41)
Change at Week 89 Number Analyzed 1 participants 0 participants
0.0 [2]   (NA)
[1]
As only 1 participant was analyzed at Week 73, standard deviation could not be calculated.
[2]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
9.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Emotional Well-Being Domain Scores
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain. Total subscale score range for emotional well-being domain is from 0 (worst response) to 24 (best response), where higher score indicate better quality of life.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, n signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 126 participants 124 participants
18.1  (3.80) 18.5  (4.06)
Change at Week 9 Number Analyzed 104 participants 107 participants
-0.1  (2.81) 0.1  (3.40)
Change at Week 13 Number Analyzed 91 participants 88 participants
-0.1  (3.55) 0.2  (3.09)
Change at Week 17 Number Analyzed 84 participants 79 participants
-0.2  (3.44) 0.4  (2.88)
Change at Week 21 Number Analyzed 71 participants 67 participants
0.3  (3.48) 0.1  (3.36)
Change at Week 25 Number Analyzed 62 participants 63 participants
0.3  (2.58) 0.3  (3.33)
Change at Week 29 Number Analyzed 51 participants 51 participants
-0.5  (3.56) 0.3  (3.27)
Change at Week 33 Number Analyzed 44 participants 45 participants
0.1  (3.33) 0.9  (2.99)
Change at Week 37 Number Analyzed 36 participants 34 participants
-0.7  (4.04) 0.9  (2.49)
Change at Week 41 Number Analyzed 31 participants 30 participants
0.1  (2.99) 1.4  (2.60)
Change at Week 45 Number Analyzed 28 participants 27 participants
-0.5  (3.23) 1.2  (2.76)
Change at Week 49 Number Analyzed 27 participants 19 participants
0.0  (3.00) 1.3  (2.75)
Change at Week 53 Number Analyzed 21 participants 16 participants
0.1  (2.72) 1.2  (3.23)
Change at Week 57 Number Analyzed 17 participants 14 participants
-0.4  (2.32) 1.6  (2.53)
Change at Week 61 Number Analyzed 13 participants 11 participants
-0.3  (3.14) 1.1  (3.62)
Change at Week 65 Number Analyzed 13 participants 7 participants
-0.9  (3.57) 2.9  (2.54)
Change at Week 69 Number Analyzed 10 participants 8 participants
-0.5  (2.93) 1.5  (2.93)
Change at Week 73 Number Analyzed 8 participants 2 participants
1.0  (2.83) -5.0  (5.66)
Change at Week 77 Number Analyzed 7 participants 2 participants
0.1  (2.67) 2.0  (2.83)
Change at Week 81 Number Analyzed 2 participants 0 participants
1.5  (3.54)
Change at Week 85 Number Analyzed 2 participants 0 participants
-1.5  (0.71)
Change at Week 89 Number Analyzed 1 participants 0 participants
-3.0 [1]   (NA)
[1]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
10.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Functional Well-Being Domain Scores
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain. Total subscale score range for functional well-being domain is from 0 (worst response) to 28 (best response), where higher score indicate better quality of life.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, n signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 126 participants 124 participants
20.2  (5.54) 20.3  (5.84)
Change at Week 9 Number Analyzed 104 participants 107 participants
-1.0  (4.23) -0.7  (4.62)
Change at Week 13 Number Analyzed 91 participants 87 participants
-1.2  (4.07) -0.4  (4.54)
Change at Week 17 Number Analyzed 84 participants 78 participants
-1.3  (4.00) -0.5  (4.11)
Change at Week 21 Number Analyzed 71 participants 67 participants
-1.2  (5.03) -0.7  (4.03)
Change at Week 25 Number Analyzed 62 participants 63 participants
-1.0  (3.41) -0.3  (4.41)
Change at Week 29 Number Analyzed 51 participants 51 participants
-2.4  (4.67) -0.2  (4.38)
Change at Week 33 Number Analyzed 44 participants 44 participants
-2.0  (5.14) -0.7  (4.49)
Change at Week 37 Number Analyzed 36 participants 34 participants
-1.5  (5.22) 0.2  (5.72)
Change at Week 41 Number Analyzed 31 participants 30 participants
-2.1  (4.44) 0.8  (5.74)
Change at Week 45 Number Analyzed 28 participants 28 participants
-2.0  (3.37) -0.3  (6.28)
Change at Week 49 Number Analyzed 27 participants 19 participants
-2.1  (4.55) 1.5  (5.02)
Change at Week 53 Number Analyzed 21 participants 16 participants
-1.6  (4.67) 1.3  (4.92)
Change at Week 57 Number Analyzed 17 participants 14 participants
-1.4  (4.06) 2.0  (4.37)
Change at Week 61 Number Analyzed 13 participants 11 participants
-0.8  (3.34) 2.9  (5.56)
Change at Week 65 Number Analyzed 13 participants 7 participants
-1.2  (2.21) 1.7  (2.75)
Change at Week 69 Number Analyzed 10 participants 8 participants
0.2  (1.48) 2.3  (4.23)
Change at Week 73 Number Analyzed 8 participants 2 participants
-0.6  (3.02) 4.0  (12.73)
Change at Week 77 Number Analyzed 7 participants 2 participants
-1.6  (3.91) 2.5  (9.19)
Change at Week 81 Number Analyzed 2 participants 0 participants
-1.5  (7.78)
Change at Week 85 Number Analyzed 2 participants 0 participants
-1.5  (2.12)
Change at Week 89 Number Analyzed 1 participants 0 participants
1.0 [1]   (NA)
[1]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
11.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Prostate Cancer Domain Scores
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain. Total subscale score range for prostate cancer domain is from 0 (worst response) to 48 (best response), where higher score indicated better quality of life with fewer symptoms.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, n signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 126 participants 124 participants
33.2  (6.85) 34.2  (6.45)
Change at Week 9 Number Analyzed 104 participants 107 participants
-0.7  (5.97) -0.9  (5.18)
Change at Week 13 Number Analyzed 90 participants 89 participants
-1.9  (5.91) -0.1  (5.36)
Change at Week 17 Number Analyzed 84 participants 79 participants
-1.0  (5.36) -1.4  (5.10)
Change at Week 21 Number Analyzed 71 participants 67 participants
-0.4  (5.13) -0.6  (4.83)
Change at Week 25 Number Analyzed 61 participants 63 participants
-0.8  (6.93) -0.8  (4.42)
Change at Week 29 Number Analyzed 52 participants 51 participants
-1.3  (5.75) -0.3  (4.77)
Change at Week 33 Number Analyzed 44 participants 45 participants
-1.4  (5.16) -0.6  (4.88)
Change at Week 37 Number Analyzed 35 participants 34 participants
-1.5  (4.88) -0.8  (4.32)
Change at Week 41 Number Analyzed 31 participants 30 participants
-1.0  (5.13) -0.7  (5.34)
Change at Week 45 Number Analyzed 28 participants 28 participants
-0.8  (4.88) -1.7  (7.02)
Change at Week 49 Number Analyzed 27 participants 19 participants
-0.8  (4.26) -0.9  (4.63)
Change at Week 53 Number Analyzed 20 participants 16 participants
-1.1  (3.65) -1.8  (5.78)
Change at Week 57 Number Analyzed 17 participants 14 participants
-0.5  (3.67) -3.3  (4.48)
Change at Week 61 Number Analyzed 13 participants 11 participants
-2.1  (4.29) -3.1  (5.68)
Change at Week 65 Number Analyzed 13 participants 7 participants
-2.0  (4.05) -2.6  (6.32)
Change at Week 69 Number Analyzed 10 participants 8 participants
-1.5  (3.30) 1.1  (5.79)
Change at Week 73 Number Analyzed 8 participants 2 participants
-0.2  (3.17) -6.4  (9.32)
Change at Week 77 Number Analyzed 7 participants 2 participants
-1.0  (3.71) -1.5  (13.44)
Change at Week 81 Number Analyzed 2 participants 0 participants
3.1  (1.22)
Change at Week 85 Number Analyzed 2 participants 0 participants
-0.5  (0.71)
Change at Week 89 Number Analyzed 1 participants 0 participants
0.0 [1]   (NA)
[1]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
12.Secondary Outcome
Title Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Physical Well-Being Domain Scores
Hide Description The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain. Total subscale score range for physical well-being domain is from 0 (worst response) to 28 (best response), where higher score indicate better quality of life.
Time Frame Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all participants randomly assigned to study treatment. Here, n signifies those participants who were evaluable at specified time points.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline Number Analyzed 126 participants 124 participants
22.9  (4.50) 23.6  (4.42)
Change at Week 9 Number Analyzed 105 participants 109 participants
-0.8  (4.04) 0.1  (3.20)
Change at Week 13 Number Analyzed 91 participants 89 participants
-1.0  (4.11) 0.0  (2.63)
Change at Week 17 Number Analyzed 85 participants 80 participants
-1.1  (3.26) -0.3  (2.97)
Change at Week 21 Number Analyzed 70 participants 68 participants
-0.8  (3.11) -0.8  (4.48)
Change at Week 25 Number Analyzed 62 participants 63 participants
-1.7  (4.23) -0.4  (2.90)
Change at Week 29 Number Analyzed 51 participants 51 participants
-2.5  (4.89) 0.3  (2.67)
Change at Week 33 Number Analyzed 44 participants 45 participants
-2.5  (5.37) 0.1  (3.18)
Change at Week 37 Number Analyzed 36 participants 34 participants
-1.8  (4.50) 0.4  (3.13)
Change at Week 41 Number Analyzed 31 participants 30 participants
-1.5  (3.94) 0.4  (2.80)
Change at Week 45 Number Analyzed 28 participants 28 participants
-2.0  (3.72) -0.4  (3.59)
Change at Week 49 Number Analyzed 27 participants 19 participants
-0.9  (3.78) 0.6  (2.12)
Change at Week 53 Number Analyzed 21 participants 16 participants
-0.2  (3.78) 0.7  (2.85)
Change at Week 57 Number Analyzed 17 participants 14 participants
-0.4  (3.25) 0.4  (2.37)
Change at Week 61 Number Analyzed 13 participants 11 participants
-0.8  (3.11) 0.4  (2.32)
Change at Week 65 Number Analyzed 13 participants 7 participants
-1.9  (4.25) 0.4  (1.99)
Change at Week 69 Number Analyzed 10 participants 8 participants
-0.3  (4.08) -0.5  (2.67)
Change at Week 73 Number Analyzed 8 participants 2 participants
-0.3  (2.05) -3.0  (5.66)
Change at Week 77 Number Analyzed 7 participants 2 participants
-0.7  (2.81) 4.0  (4.24)
Change at Week 81 Number Analyzed 2 participants 0 participants
1.5  (2.12)
Change at Week 85 Number Analyzed 2 participants 0 participants
-1.0  (0.00)
Change at Week 89 Number Analyzed 1 participants 0 participants
0.0 [1]   (NA)
[1]
As only 1 participant was analyzed at Week 89, standard deviation could not be calculated.
13.Secondary Outcome
Title Time to Degradation of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score
Hide Description Time to degradation of FACT-P was defined as the time from randomization to first assessment with at least a 10-point decrease from baseline in the global FACT-P score for each participant. The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, and functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score which is the sum of all 5 domain scores and ranges from 0 to 156 with higher scores representing better quality of life. Participants with no score degradation at the time of analysis data cutoff were censored at the date of last assessment showing no degradation.
Time Frame From randomization up to data cutoff date (07 Oct 2016)
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable ITT population included all participants with a PSA value at baseline of Period 2 and at least 1 post baseline assessment.
Arm/Group Title Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 126 125
Median (95% Confidence Interval)
Unit of Measure: months
4.6
(3.7 to 6.5)
6.4
(5.5 to 13.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0739
Comments P-value was based on log-rank test stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.399
Confidence Interval (2-Sided) 95%
0.967 to 2.025
Estimation Comments Hazard ratio was based on a Cox regression model (with treatment as the only covariate) stratified by PSA response (>=0% to <30% vs >=30%) at Week 13 in the open-label period and is relative to Enzalutamide-placebo with < 1 favoring Enzalutamide.
14.Other Pre-specified Outcome
Title Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent are events between first dose of study drug and up to 30 days after last dose of study drug that were absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious.
Time Frame Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any amount of study drug.
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first.
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 509 125 124
Measure Type: Number
Unit of Measure: percentage of participants
AEs 93.3 89.6 91.1
SAEs 27.9 30.4 28.2
15.Other Pre-specified Outcome
Title Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Outcome of an AE was response to a question answered by the investigator: 'Is the AE leading to study discontinuation or death?' as 'yes'.
Time Frame Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any amount of study drug.
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first.
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 509 125 124
Measure Type: Number
Unit of Measure: percentage of participants
9.8 19.2 12.1
16.Other Pre-specified Outcome
Title Percentage of Participants With Adverse Events (AEs) Leading to Death
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Outcome of an AE was response to a question answered by the investigator: 'Is the AE leading to study discontinuation or death?' as 'yes'.
Time Frame Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any amount of study drug.
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first.
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 509 125 124
Measure Type: Number
Unit of Measure: percentage of participants
4.7 3.2 2.4
17.Other Pre-specified Outcome
Title Percentage of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.
Time Frame Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to data cutoff date [07 Oct 2016])
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received any amount of study drug.
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description:
Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first.
Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
Overall Number of Participants Analyzed 509 125 124
Measure Type: Number
Unit of Measure: percentage of participants
AEs 65.4 43.2 35.5
SAEs 3.5 4.8 4.8
Time Frame Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to data cutoff date [07 Oct 2016])
Adverse Event Reporting Description Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.
 
Arm/Group Title Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Hide Arm/Group Description Participants received enzalutamide 160 mg as four 40 mg capsules, orally once daily until disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or patient withdrawal, whichever occurs first. Participants were followed-up until 30 days after last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first. Participants with confirmed PSA progression at Week 21 in open label period, received enzalutamide 160 mg as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer. Participants with confirmed PSA progression at Week 21 in open label period, received placebo matched to enzalutamide as four 40 mg capsules, orally once daily along with abiraterone 1000 mg as four 250-mg tablets, orally once daily and prednisone 5 mg tablet, orally twice daily in double blind treatment period, up to disease progression (as defined by radiographic imaging or unequivocal clinical progression or death on study), intolerable toxicity, or participant withdrawal, whichever occurred first. Participants were followed up for 16 weeks at 4-week interval after discontinuation of study drug for survival and subsequent antineoplastic therapy for prostate cancer.
All-Cause Mortality
Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   142/509 (27.90%)   38/125 (30.40%)   35/124 (28.23%) 
Blood and lymphatic system disorders       
Anaemia * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Cardiac disorders       
Acute coronary syndrome * 1  3/509 (0.59%)  1/125 (0.80%)  0/124 (0.00%) 
Acute myocardial infarction * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Angina pectoris * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Angina unstable * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Atrial fibrillation * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Atrioventricular block complete * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cardiac arrest * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cardiac failure * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Cardiac failure congestive * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Cardio-respiratory arrest * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Coronary artery disease * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Coronary artery stenosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mitral valve disease * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Myocardial infarction * 1  1/509 (0.20%)  0/125 (0.00%)  2/124 (1.61%) 
Myocardial ischaemia * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Palpitations * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pericardial effusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Sick sinus syndrome * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Ear and labyrinth disorders       
Vertigo * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vertigo positional * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Eye disorders       
Exophthalmos * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastrointestinal disorders       
Abdominal pain * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Colonic fistula * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Constipation * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Diarrhoea * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Duodenal ulcer haemorrhage * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Dysphagia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastric ulcer * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastrointestinal perforation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Haemorrhoidal haemorrhage * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hiatus hernia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Intestinal ischaemia * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Large intestine perforation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Melaena * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Nausea * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Oesophageal perforation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Peptic ulcer * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Rectal polyp * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Retroperitoneal haematoma * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Small intestinal obstruction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Upper gastrointestinal haemorrhage * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vomiting * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
General disorders       
Asthenia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Chest pain * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Disease progression * 1  5/509 (0.98%)  2/125 (1.60%)  1/124 (0.81%) 
Fatigue * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
General physical health deterioration * 1  4/509 (0.79%)  1/125 (0.80%)  0/124 (0.00%) 
Malaise * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Multi-organ failure * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Oedema peripheral * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pain * 1  1/509 (0.20%)  1/125 (0.80%)  1/124 (0.81%) 
Pyrexia * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Hepatobiliary disorders       
Bile duct obstruction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cholecystitis chronic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatic lesion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Jaundice cholestatic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Infections and infestations       
Abscess jaw * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Abscess limb * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Appendicitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Bronchitis * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Cellulitis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Enterococcal sepsis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Gastroenteritis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lower respiratory tract infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Meningitis tuberculous * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Ophthalmic herpes zoster * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pneumonia * 1  5/509 (0.98%)  1/125 (0.80%)  3/124 (2.42%) 
Pneumonia respiratory syncytial viral * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Pulmonary sepsis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Sepsis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Septic shock * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Urinary tract infection * 1  5/509 (0.98%)  1/125 (0.80%)  0/124 (0.00%) 
Urinary tract infection enterococcal * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Urosepsis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Injury, poisoning and procedural complications       
Acetabulum fracture * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Burns third degree * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cervical vertebral fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cystitis radiation * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Fall * 1  5/509 (0.98%)  1/125 (0.80%)  0/124 (0.00%) 
Femoral neck fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Femur fracture * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Hip fracture * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Lower limb fracture * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Musculoskeletal injury * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pelvic fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Radius fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Road traffic accident * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Spinal compression fracture * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Spinal fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Toxicity to various agents * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vascular pseudoaneurysm * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Investigations       
Alanine aminotransferase increased * 1  0/509 (0.00%)  2/125 (1.60%)  0/124 (0.00%) 
Aspartate aminotransferase increased * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Blood bilirubin increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Liver function test abnormal * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Dehydration * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Dystrophic calcification * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Hypercalcaemia * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Hyponatraemia * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Malnutrition * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Back pain * 1  4/509 (0.79%)  1/125 (0.80%)  0/124 (0.00%) 
Bone pain * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cervical spinal stenosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Chondrocalcinosis pyrophosphate * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Intervertebral disc protrusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mobility decreased * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Muscular weakness * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Musculoskeletal chest pain * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Neck pain * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Osteoarthritis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Osteonecrosis * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Osteonecrosis of jaw * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Osteoporosis * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Osteoporotic fracture * 1  1/509 (0.20%)  1/125 (0.80%)  1/124 (0.81%) 
Pathological fracture * 1  4/509 (0.79%)  0/125 (0.00%)  2/124 (1.61%) 
Spinal osteoarthritis * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenocarcinoma of colon * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
B-cell lymphoma * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Bladder transitional cell carcinoma * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Bowen's disease * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Cancer pain * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Chronic myelomonocytic leukaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Laryngeal squamous cell carcinoma * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lentigo maligna * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lung adenocarcinoma * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Lung squamous cell carcinoma stage 0 * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Malignant neoplasm progression * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Malignant pleural effusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Metastases to bone * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Metastases to central nervous system * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Metastases to liver * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Metastases to spine * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Metastasis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Metastatic pain * 1  3/509 (0.59%)  3/125 (2.40%)  2/124 (1.61%) 
Neuroendocrine carcinoma metastatic * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Pancreatic carcinoma * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Prostate cancer * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Prostate cancer metastatic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Renal cell carcinoma * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Squamous cell carcinoma of skin * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Transitional cell carcinoma * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Transitional cell carcinoma metastatic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Nervous system disorders       
Brain oedema * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cerebellar infarction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cerebral haemorrhage * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Cerebral infarction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cerebrovascular accident * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Cognitive disorder * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Dementia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Dysarthria * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Ischaemic stroke * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Loss of consciousness * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Nerve root compression * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Presyncope * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Spinal cord compression * 1  4/509 (0.79%)  4/125 (3.20%)  2/124 (1.61%) 
Stupor * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Syncope * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Transient ischaemic attack * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Unresponsive to stimuli * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Psychiatric disorders       
Confusional state * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Delirium * 1  2/509 (0.39%)  1/125 (0.80%)  1/124 (0.81%) 
Depression * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Renal and urinary disorders       
Calculus bladder * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Calculus ureteric * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Calculus urethral * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Haematuria * 1  10/509 (1.96%)  3/125 (2.40%)  1/124 (0.81%) 
Hydronephrosis * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Nephrolithiasis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Obstructive uropathy * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Prerenal failure * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Renal failure acute * 1  2/509 (0.39%)  0/125 (0.00%)  2/124 (1.61%) 
Ureteric obstruction * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Urinary incontinence * 1  1/509 (0.20%)  2/125 (1.60%)  1/124 (0.81%) 
Urinary retention * 1  2/509 (0.39%)  2/125 (1.60%)  2/124 (1.61%) 
Urinary tract obstruction * 1  1/509 (0.20%)  2/125 (1.60%)  1/124 (0.81%) 
Reproductive system and breast disorders       
Balanitis * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Bronchospasm * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Chronic obstructive pulmonary disease * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Haemothorax * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pleural effusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pneumonia aspiration * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Pneumothorax * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pulmonary embolism * 1  4/509 (0.79%)  0/125 (0.00%)  2/124 (1.61%) 
Respiratory failure * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Vascular disorders       
Aortic stenosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Arterial rupture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Arteriosclerosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Circulatory collapse * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Deep vein thrombosis * 1  4/509 (0.79%)  0/125 (0.00%)  1/124 (0.81%) 
Hypertension * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Hypotension * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Hypovolaemic shock * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lymphoedema * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA v16.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Enzalutamide 160 mg Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg Placebo+Abiraterone 1000mg+ Prednisone 10mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   473/509 (92.93%)   111/125 (88.80%)   111/124 (89.52%) 
Blood and lymphatic system disorders       
Anaemia * 1  30/509 (5.89%)  5/125 (4.00%)  5/124 (4.03%) 
Bone marrow failure * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Haemorrhagic anaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Iron deficiency anaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Leukocytosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lymphadenopathy * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Lymphopenia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Pancytopenia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Pernicious anaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Thrombocytopenia * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Cardiac disorders       
Angina pectoris * 1  3/509 (0.59%)  1/125 (0.80%)  0/124 (0.00%) 
Aortic valve stenosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Arrhythmia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Atrial fibrillation * 1  4/509 (0.79%)  3/125 (2.40%)  4/124 (3.23%) 
Atrial flutter * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Bradycardia * 1  5/509 (0.98%)  0/125 (0.00%)  1/124 (0.81%) 
Bundle branch block right * 1  1/509 (0.20%)  1/125 (0.80%)  1/124 (0.81%) 
Cardiac failure * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Cardiac failure congestive * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Chordae tendinae rupture * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Coronary artery stenosis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Diastolic dysfunction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Extrasystoles * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Left ventricular dysfunction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mitral valve disease * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mitral valve prolapse * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Myocardial infarction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Myocardial ischaemia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Palpitations * 1  2/509 (0.39%)  1/125 (0.80%)  1/124 (0.81%) 
Right ventricular dysfunction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Sinus bradycardia * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Sinus tachycardia * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Supraventricular extrasystoles * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Tachycardia * 1  7/509 (1.38%)  0/125 (0.00%)  2/124 (1.61%) 
Ventricular extrasystoles * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Congenital, familial and genetic disorders       
Phimosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Ear and labyrinth disorders       
Cerumen impaction * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Deafness bilateral * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Deafness neurosensory * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hearing impaired * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Motion sickness * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Tinnitus * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Vertigo * 1  13/509 (2.55%)  0/125 (0.00%)  1/124 (0.81%) 
Vertigo positional * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Endocrine disorders       
Adrenal insufficiency * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Cushingoid * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Goitre * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hyperthyroidism * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Hypothyroidism * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Thyroid mass * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Eye disorders       
Amaurosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cataract * 1  6/509 (1.18%)  1/125 (0.80%)  1/124 (0.81%) 
Conjunctival haemorrhage * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Conjunctivitis * 1  9/509 (1.77%)  2/125 (1.60%)  1/124 (0.81%) 
Diplopia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Dry eye * 1  5/509 (0.98%)  1/125 (0.80%)  0/124 (0.00%) 
Exophthalmos * 1  2/509 (0.39%)  0/125 (0.00%)  1/124 (0.81%) 
Eye disorder * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Eye inflammation * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Eye irritation * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Eye pain * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Eye swelling * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Eyelid margin crusting * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Glaucoma * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Iritis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lacrimation increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Macular fibrosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Night blindness * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Ocular icterus * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Optic ischaemic neuropathy * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Photophobia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Retinal artery occlusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Strabismus * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Trichiasis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vision blurred * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Visual acuity reduced * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Visual impairment * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Vitreous floaters * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vitreous haemorrhage * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastrointestinal disorders       
Abdominal discomfort * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Abdominal distension * 1  8/509 (1.57%)  0/125 (0.00%)  0/124 (0.00%) 
Abdominal pain * 1  14/509 (2.75%)  7/125 (5.60%)  7/124 (5.65%) 
Abdominal pain lower * 1  5/509 (0.98%)  2/125 (1.60%)  1/124 (0.81%) 
Abdominal pain upper * 1  19/509 (3.73%)  0/125 (0.00%)  2/124 (1.61%) 
Anal haemorrhage * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Apical granuloma * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Barrett's oesophagus * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Breath odour * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cheilitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Colitis microscopic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Constipation * 1  78/509 (15.32%)  17/125 (13.60%)  12/124 (9.68%) 
Dental caries * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Diarrhoea * 1  66/509 (12.97%)  7/125 (5.60%)  12/124 (9.68%) 
Diverticulum intestinal * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Dry mouth * 1  4/509 (0.79%)  2/125 (1.60%)  1/124 (0.81%) 
Dyspepsia * 1  16/509 (3.14%)  3/125 (2.40%)  4/124 (3.23%) 
Epigastric discomfort * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Erosive oesophagitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Eructation * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Faecaloma * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Faeces hard * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Food poisoning * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Frequent bowel movements * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Gastric mucosa erythema * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastric ulcer * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Gastritis * 1  1/509 (0.20%)  0/125 (0.00%)  2/124 (1.61%) 
Gastrooesophageal reflux disease * 1  13/509 (2.55%)  4/125 (3.20%)  5/124 (4.03%) 
Gingival bleeding * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gingival inflammation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gingival pain * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Haematochezia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Dysphagia * 1  3/509 (0.59%)  2/125 (1.60%)  1/124 (0.81%) 
Faecal incontinence * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Flatulence * 1  12/509 (2.36%)  3/125 (2.40%)  1/124 (0.81%) 
Haemorrhoids * 1  4/509 (0.79%)  0/125 (0.00%)  1/124 (0.81%) 
Hiatus hernia * 1  2/509 (0.39%)  0/125 (0.00%)  2/124 (1.61%) 
Inguinal hernia * 1  3/509 (0.59%)  0/125 (0.00%)  2/124 (1.61%) 
Large intestine polyp * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Lip dry * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Lip oedema * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Localised intraabdominal fluid collection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Melaena * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mouth ulceration * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Nausea * 1  97/509 (19.06%)  21/125 (16.80%)  11/124 (8.87%) 
Odynophagia * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Oesophageal pain * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Oesophagitis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Pancreatic disorder * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pancreatitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Paraesthesia oral * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Periodontal disease * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Proctalgia * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Rectal haemorrhage * 1  2/509 (0.39%)  2/125 (1.60%)  0/124 (0.00%) 
Retching * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Salivary hypersecretion * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Tongue disorder * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Toothache * 1  7/509 (1.38%)  0/125 (0.00%)  1/124 (0.81%) 
Umbilical hernia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vomiting * 1  28/509 (5.50%)  7/125 (5.60%)  2/124 (1.61%) 
General disorders       
Abasia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Asthenia * 1  25/509 (4.91%)  5/125 (4.00%)  3/124 (2.42%) 
Catheter site haemorrhage * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Chest discomfort * 1  3/509 (0.59%)  2/125 (1.60%)  0/124 (0.00%) 
Chest pain * 1  2/509 (0.39%)  4/125 (3.20%)  3/124 (2.42%) 
Chills * 1  5/509 (0.98%)  1/125 (0.80%)  2/124 (1.61%) 
Cyst * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Device failure * 1  2/509 (0.39%)  0/125 (0.00%)  1/124 (0.81%) 
Device occlusion * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Dysplasia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Face oedema * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Facial pain * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Fatigue * 1  200/509 (39.29%)  17/125 (13.60%)  18/124 (14.52%) 
Feeling abnormal * 1  4/509 (0.79%)  0/125 (0.00%)  0/124 (0.00%) 
Feeling drunk * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Feeling hot * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gait disturbance * 1  7/509 (1.38%)  1/125 (0.80%)  2/124 (1.61%) 
General physical health deterioration * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Hyperpyrexia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hypothermia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Inflammation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Influenza like illness * 1  6/509 (1.18%)  1/125 (0.80%)  1/124 (0.81%) 
Infusion site extravasation * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Injection site swelling * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Irritability * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Local swelling * 1  5/509 (0.98%)  4/125 (3.20%)  0/124 (0.00%) 
Malaise * 1  5/509 (0.98%)  1/125 (0.80%)  0/124 (0.00%) 
Medical device complication * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Mucosal inflammation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Non-cardiac chest pain * 1  7/509 (1.38%)  3/125 (2.40%)  2/124 (1.61%) 
Oedema * 1  3/509 (0.59%)  2/125 (1.60%)  0/124 (0.00%) 
Oedema peripheral * 1  49/509 (9.63%)  7/125 (5.60%)  16/124 (12.90%) 
Pain * 1  7/509 (1.38%)  6/125 (4.80%)  2/124 (1.61%) 
Performance status decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pyrexia * 1  11/509 (2.16%)  4/125 (3.20%)  3/124 (2.42%) 
Hunger * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Hepatobiliary disorders       
Cholelithiasis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatic lesion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatic steatosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatomegaly * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatotoxicity * 1  0/509 (0.00%)  2/125 (1.60%)  2/124 (1.61%) 
Hyperbilirubinaemia * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Hypertransaminasaemia * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Jaundice * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Non-alcoholic steatohepatitis * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Pneumobilia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Immune system disorders       
Contrast media allergy * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Drug hypersensitivity * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Hypersensitivity * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hypogammaglobulinaemia * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Milk allergy * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Seasonal allergy * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Infections and infestations       
Abdominal abscess * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Abscess * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Abscess neck * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Atypical mycobacterial infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Bronchitis * 1  4/509 (0.79%)  1/125 (0.80%)  1/124 (0.81%) 
Bronchopneumonia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Carbuncle * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Catheter site infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cellulitis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Conjunctivitis infective * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Cystitis * 1  4/509 (0.79%)  1/125 (0.80%)  2/124 (1.61%) 
Diverticulitis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Ear infection * 1  2/509 (0.39%)  2/125 (1.60%)  1/124 (0.81%) 
Erysipelas * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Escherichia urinary tract infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Eye infection * 1  4/509 (0.79%)  0/125 (0.00%)  0/124 (0.00%) 
Eyelid infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Folliculitis * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Fungal skin infection * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Furuncle * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastroenteritis * 1  4/509 (0.79%)  1/125 (0.80%)  0/124 (0.00%) 
Genital candidiasis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gingival infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gingivitis * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Helicobacter infection * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Herpes simplex * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Herpes zoster * 1  5/509 (0.98%)  4/125 (3.20%)  2/124 (1.61%) 
Herpes zoster oticus * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Infected cyst * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Infected dermal cyst * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Infection * 1  2/509 (0.39%)  0/125 (0.00%)  1/124 (0.81%) 
Infection parasitic * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Influenza * 1  20/509 (3.93%)  4/125 (3.20%)  5/124 (4.03%) 
Injection site infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Labyrinthitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Laryngitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lip infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lobar pneumonia * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Localised infection * 1  3/509 (0.59%)  1/125 (0.80%)  0/124 (0.00%) 
Lower respiratory tract infection * 1  16/509 (3.14%)  2/125 (1.60%)  4/124 (3.23%) 
Lung infection * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Mediastinitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Nail infection * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Nasopharyngitis * 1  31/509 (6.09%)  0/125 (0.00%)  7/124 (5.65%) 
Oral candidiasis * 1  9/509 (1.77%)  1/125 (0.80%)  1/124 (0.81%) 
Oral herpes * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Otitis media * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Peritonitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Pharyngitis * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Pneumonia * 1  3/509 (0.59%)  1/125 (0.80%)  0/124 (0.00%) 
Pulpitis dental * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Rash pustular * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Respiratory tract infection * 1  4/509 (0.79%)  0/125 (0.00%)  1/124 (0.81%) 
Respiratory tract infection viral * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Rhinitis * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Scrotal abscess * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Sialoadenitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Sinusitis * 1  4/509 (0.79%)  0/125 (0.00%)  3/124 (2.42%) 
Skin candida * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Skin infection * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Soft tissue infection * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Tinea cruris * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Tooth abscess * 1  0/509 (0.00%)  2/125 (1.60%)  0/124 (0.00%) 
Tooth infection * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Tracheitis * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Upper respiratory tract infection * 1  25/509 (4.91%)  9/125 (7.20%)  5/124 (4.03%) 
Urethritis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Urinary tract infection * 1  29/509 (5.70%)  9/125 (7.20%)  6/124 (4.84%) 
Urosepsis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Viral infection * 1  3/509 (0.59%)  1/125 (0.80%)  1/124 (0.81%) 
Onychomycosis * 1  2/509 (0.39%)  1/125 (0.80%)  1/124 (0.81%) 
Injury, poisoning and procedural complications       
Accident * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Accidental overdose * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Ankle fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Arthropod bite * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Bone contusion * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Chest injury * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Contusion * 1  7/509 (1.38%)  2/125 (1.60%)  3/124 (2.42%) 
Excoriation * 1  4/509 (0.79%)  1/125 (0.80%)  2/124 (1.61%) 
Eye contusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Face injury * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Fall * 1  45/509 (8.84%)  11/125 (8.80%)  8/124 (6.45%) 
Femur fracture * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Foreign body in eye * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Fractured coccyx * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gastroenteritis radiation * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hand fracture * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Head injury * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Humerus fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Injection related reaction * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Joint injury * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Laceration * 1  9/509 (1.77%)  2/125 (1.60%)  1/124 (0.81%) 
Ligament sprain * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Limb injury * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Lumbar vertebral fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Multiple injuries * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Muscle injury * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Muscle strain * 1  4/509 (0.79%)  0/125 (0.00%)  0/124 (0.00%) 
Overdose * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Pelvic fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Periorbital contusion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Post procedural haematuria * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Post-traumatic pain * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Procedural hypotension * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Procedural nausea * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Procedural pain * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Procedural vomiting * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Radius fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Rib fracture * 1  4/509 (0.79%)  1/125 (0.80%)  1/124 (0.81%) 
Skeletal injury * 1  1/509 (0.20%)  1/125 (0.80%)  1/124 (0.81%) 
Skin wound * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Spinal compression fracture * 1  3/509 (0.59%)  1/125 (0.80%)  1/124 (0.81%) 
Thoracic vertebral fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Toxicity to various agents * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Traumatic fracture * 1  0/509 (0.00%)  1/125 (0.80%)  2/124 (1.61%) 
Urethral injury * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Wound * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Wound dehiscence * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Wound secretion * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Wrist fracture * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Investigations       
Activated partial thromboplastin time prolonged * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Alanine aminotransferase increased * 1  1/509 (0.20%)  8/125 (6.40%)  6/124 (4.84%) 
Aspartate aminotransferase increased * 1  0/509 (0.00%)  4/125 (3.20%)  2/124 (1.61%) 
Bacterial test positive * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood albumin increased * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Blood alkaline phosphatase increased * 1  3/509 (0.59%)  1/125 (0.80%)  2/124 (1.61%) 
Blood bilirubin increased * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Blood calcium decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood calcium increased * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Blood cholesterol increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood creatine phosphokinase increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood creatinine increased * 1  6/509 (1.18%)  3/125 (2.40%)  2/124 (1.61%) 
Blood glucose increased * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Blood iron decreased * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Blood lactate dehydrogenase increased * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Blood potassium decreased * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Blood potassium increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood pressure increased * 1  2/509 (0.39%)  2/125 (1.60%)  1/124 (0.81%) 
Blood pressure orthostatic decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Blood urine present * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cardiac murmur * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Cardioactive drug level increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Cystoscopy * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Ejection fraction decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Electrocardiogram QT prolonged * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Gamma-glutamyltransferase abnormal * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Haemoglobin decreased * 1  5/509 (0.98%)  0/125 (0.00%)  2/124 (1.61%) 
Heart rate increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Heart rate irregular * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Heart sounds abnormal * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hepatic enzyme increased * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
International normalised ratio increased * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Liver function test abnormal * 1  0/509 (0.00%)  3/125 (2.40%)  1/124 (0.81%) 
Lymph node palpable * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lymphocyte count decreased * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Norovirus test positive * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Respiratory rate increased * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Transaminases increased * 1  0/509 (0.00%)  2/125 (1.60%)  0/124 (0.00%) 
Troponin increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Urine output decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vitamin B12 decreased * 1  0/509 (0.00%)  1/125 (0.80%)  1/124 (0.81%) 
Weight increased * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Weight decreased * 1  22/509 (4.32%)  2/125 (1.60%)  3/124 (2.42%) 
White blood cell count decreased * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
White blood cell count increased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Metabolism and nutrition disorders       
Abnormal loss of weight * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Decreased appetite * 1  82/509 (16.11%)  13/125 (10.40%)  10/124 (8.06%) 
Diabetes mellitus * 1  1/509 (0.20%)  0/125 (0.00%)  2/124 (1.61%) 
Dehydration * 1  4/509 (0.79%)  2/125 (1.60%)  1/124 (0.81%) 
Dyslipidaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Fluid overload * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Gout * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Fluid retention * 1  0/509 (0.00%)  2/125 (1.60%)  0/124 (0.00%) 
Hypercalcaemia * 1  5/509 (0.98%)  0/125 (0.00%)  0/124 (0.00%) 
Hypercholesterolaemia * 1  4/509 (0.79%)  0/125 (0.00%)  0/124 (0.00%) 
Hyperglycaemia * 1  8/509 (1.57%)  0/125 (0.00%)  0/124 (0.00%) 
Hyperkalaemia * 1  4/509 (0.79%)  0/125 (0.00%)  0/124 (0.00%) 
Hyperlipidaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hypernatraemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hypoalbuminaemia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Hypocalcaemia * 1  6/509 (1.18%)  2/125 (1.60%)  0/124 (0.00%) 
Hypoglycaemia * 1  1/509 (0.20%)  1/125 (0.80%)  3/124 (2.42%) 
Hypokalaemia * 1  7/509 (1.38%)  9/125 (7.20%)  7/124 (5.65%) 
Hypomagnesaemia * 1  3/509 (0.59%)  1/125 (0.80%)  2/124 (1.61%) 
Hyponatraemia * 1  5/509 (0.98%)  0/125 (0.00%)  1/124 (0.81%) 
Increased appetite * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Iron deficiency * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Lactic acidosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Malnutrition * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Type 2 diabetes mellitus * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Vitamin B complex deficiency * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Vitamin B12 deficiency * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Vitamin D deficiency * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  74/509 (14.54%)  18/125 (14.40%)  14/124 (11.29%) 
Arthritis * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Arthropathy * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Back pain * 1  104/509 (20.43%)  25/125 (20.00%)  28/124 (22.58%) 
Bone fistula * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Bone pain * 1  21/509 (4.13%)  3/125 (2.40%)  4/124 (3.23%) 
Bursitis * 1  3/509 (0.59%)  0/125 (0.00%)  1/124 (0.81%) 
Coccydynia * 1  3/509 (0.59%)  0/125 (0.00%)  0/124 (0.00%) 
Flank pain * 1  5/509 (0.98%)  2/125 (1.60%)  0/124 (0.00%) 
Groin pain * 1  12/509 (2.36%)  1/125 (0.80%)  5/124 (4.03%) 
Inguinal mass * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Intervertebral disc protrusion * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Joint range of motion decreased * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Joint stiffness * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Joint swelling * 1  4/509 (0.79%)  2/125 (1.60%)  1/124 (0.81%) 
Mobility decreased * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Muscle atrophy * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Muscle tightness * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Muscular weakness * 1  21/509 (4.13%)  6/125 (4.80%)  4/124 (3.23%) 
Musculoskeletal chest pain * 1  23/509 (4.52%)  13/125 (10.40%)  7/124 (5.65%) 
Musculoskeletal discomfort * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Musculoskeletal pain * 1  33/509 (6.48%)  11/125 (8.80%)  8/124 (6.45%) 
Musculoskeletal stiffness * 1  4/509 (0.79%)  3/125 (2.40%)  0/124 (0.00%) 
Myalgia * 1  23/509 (4.52%)  1/125 (0.80%)  2/124 (1.61%) 
Myopathy * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Myositis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Osteoarthritis * 1  6/509 (1.18%)  0/125 (0.00%)  1/124 (0.81%) 
Osteonecrosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Osteonecrosis of jaw * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Osteopenia * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Osteoporosis * 1  0/509 (0.00%)  2/125 (1.60%)  0/124 (0.00%) 
Pain in extremity * 1  33/509 (6.48%)  9/125 (7.20%)  6/124 (4.84%) 
Pain in jaw * 1  0/509 (0.00%)  0/125 (0.00%)  1/124 (0.81%) 
Pathological fracture * 1  1/509 (0.20%)  1/125 (0.80%)  0/124 (0.00%) 
Plantar fasciitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Scoliosis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Spinal column stenosis * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Spinal osteoarthritis * 1  2/509 (0.39%)  1/125 (0.80%)  0/124 (0.00%) 
Spinal pain * 1  4/509 (0.79%)  0/125 (0.00%)  1/124 (0.81%) 
Synovial cyst * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Synovitis * 1  1/509 (0.20%)  0/125 (0.00%)  0/124 (0.00%) 
Tendonitis * 1  1/509 (0.20%)  0/125 (0.00%)  1/124 (0.81%) 
Trismus * 1  0/509 (0.00%)  1/125 (0.80%)  0/124 (0.00%) 
Neck pain * 1  23/509 (4.52%)  2/125 (1.60%)  3/124 (2.42%) 
Muscle fatigue * 1  2/509 (0.39%)  0/125 (0.00%)  0/124 (0.00%) 
Muscle spasms * 1  7/509 (1.38%)  4/125 (3.20%)  9/124 (7.26%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma * 1  11/509 (2.16%)  1/125&