PLATO: Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01995513
• Collaborator: Astellas Pharma Inc (Industry), Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
• Enrollment: 509
• Locations: 90
• Arms: 2
• Anticipated Duration (Months): 127.3
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if continued treatment with Enzalutamide is effective in patients with metastatic prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Enzalutamide; Drug: Abiraterone; Drug: Placebo for Enzalutamide; Drug: Prednisone	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 509 participants
• Allocation: Randomized
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A PHASE 4, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF CONTINUED ENZALUTAMIDE TREATMENT BEYOND PROGRESSION IN PATIENTS WITH CHEMOTHERAPY-NAÏVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER
• Actual Study Start Date: Oct 22, 2013
• Actual Primary Completion Date: Nov 15, 2016
• Anticipated Study Completion Date: May 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide & Abiraterone/prednisone Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with abiraterone (1000 mg) administered as four 250-mg tablets by mouth once daily and prednisone (10 mg) administered as one 5-mg tablet by mouth twice daily	Drug: Enzalutamide; 160 mg by mouth once daily; Other Names: MDV3100 Xtandi ; Drug: Abiraterone; 1000 mg by mouth once daily; Other Names: Abiraterone acetate Zytiga ; Drug: Prednisone; 5 mg by mouth twice daily; Other Names: prednisolone
Active Comparator: Enzalutamide placebo & Abiraterone/prednisone Enzalutamide placebo (placebo) capsules (identical in appearance to enzalutamide) administered as 4 capsules by mouth once daily in combination with abiraterone (1000 mg) administered as four 250-mg tablets by mouth once daily and prednisone (10 mg) administered as one 5-mg tablet by mouth twice daily.	Drug: Abiraterone; 1000 mg by mouth once daily; Other Names: Abiraterone acetate Zytiga ; Drug: Placebo for Enzalutamide; Sugar pill manufactured to mimic Enzalutamide 40 mg capsule; Drug: Prednisone; 5 mg by mouth twice daily; Other Names: prednisolone

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [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])]

   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.

Secondary Outcome Measures

1. Time to Prostate Specific Antigen (PSA) Progression [From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (up to the data cutoff date [07 Oct 2016])]

   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.

2. Prostate Specific Antigen (PSA) Response Rate [From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (up to the data cutoff date [07 Oct 2016])]

   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.

3. Objective Response Rate (ORR) [From randomization until CR or PR, whichever occurred first (up to the data cutoff date [07 Oct 2016])]

   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.

4. Rate of Pain Progression [Month 6]

   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.

5. Time to First Use of New Antineoplastic Therapy for Prostate Cancer [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])]

   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.

6. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

   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.

7. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Social/Family Well-Being Domain Scores [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

   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.

8. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Emotional Well-Being Domain Scores [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

   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.

9. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Functional Well-Being Domain Scores [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

   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.

10. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Prostate Cancer Domain Scores [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

    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.

11. Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Physical Well-Being Domain Scores [Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89]

    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.

12. Time to Degradation of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score [From randomization up to data cutoff date (07 Oct 2016)]

    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.

Other Outcome Measures

1. Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [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])]

   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.

2. Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation [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])]

   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'.

3. Percentage of Participants With Adverse Events (AEs) Leading to Death [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])]

   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'.

4. Percentage of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [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])]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men with metastatic castration-resistant prostate cancer

• Progressive disease on androgen deprivation therapy

• Patients must agree to continue androgen deprivation therapy with a GnRH agonist/antagonist throughout the study or have had a prior bilateral orchiectomy

• ECOG performance score ≤ 1

• Estimated life expectancy of ≥ 12 months

Exclusion Criteria:

• Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone, or enzalutamide for the treatment of prostate cancer

• Prior participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless the treatment was placebo)

• History of brain metastasis, active leptomeningeal disease or seizure

• Severe cardiovascular or hepatic disease

• Pituitary or adrenal dysfunction

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
2	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
3	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
4	Urology of Virginia, PLLC	Virginia Beach	Virginia	United States	23462
5	Regional Imaging Border	Albury	New South Wales	Australia	2640
6	Terry White Chemist	Albury	New South Wales	Australia	2640
7	Concord Cancer Centre, Medical Oncology Department	Concord	New South Wales	Australia	2139
8	Epic Pharmacy Lismore	Lismore	New South Wales	Australia	2480
9	Macquarie University Hospital Pharmacy	North Ryde	New South Wales	Australia	2109
10	Macquarie University	North Ryde	New South Wales	Australia	2109
11	Epic Pharmacy Port Macquarie base hospital	Port Macquarie	New South Wales	Australia	2444
12	Port Macquarie Base Hospital,North Coast Cancer Institute	Port Macquarie	New South Wales	Australia	2444
13	North Shore Radiology and Nuclear Medicine	St Leonards	New South Wales	Australia	2065
14	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
15	Sydney Adventist Hospital	Sydney	New South Wales	Australia	2076
16	Northern NSW Local Health District	Tweed Heads	New South Wales	Australia	2485
17	Pharmacy Department, The Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
18	Queensland Diagnostic Imaging	Tweed Heads	New South Wales	Australia	2485
19	Sydney Adventist Hospital	Wahroonga	New South Wales	Australia	2076
20	Westmead Hospital	Westmead	New South Wales	Australia	2145
21	Icon Cancer Care Wesley	Auchenflower	Queensland	Australia	4066
22	River City Pharmacy - APHS	Auchenflower	Queensland	Australia	4066
23	Icon Cancer Care Chermside	Chermside	Queensland	Australia	4032
24	Gold Coast Radiology PTY LTD	Hope Island	Queensland	Australia	4212
25	Icon Cancer Care South Brisbane	South Brisbane	Queensland	Australia	4101
26	Icon Cancer Care	South Brisbane	Queensland	Australia	4101
27	South Coast Radiology	Tugun	Queensland	Australia	4224
28	Adelaide Cancer Centre	Kurralta Park	South Australia	Australia	5037
29	Ashford Cancer Centre Research	Kurralta Park	South Australia	Australia	5037
30	Cancer Care SA Pty Ltd	Kurralta Park	South Australia	Australia	5037
31	Tenpharm Pty Ltd trading as EPIC Pharmacy Tennyson	Kurralta Park	South Australia	Australia	5037
32	Box Hill Hospital	Box Hill	Victoria	Australia	3128
33	Monash Medical Centre	Clayton	Victoria	Australia	3168
34	Cabrini Health - Cabrini Hospital	Malvern	Victoria	Australia	3144
35	Border Medical Oncology	Wodonga	Victoria	Australia	3690
36	Algemeen Ziekenhuis Groeninge	Kortrijk	West-vlaanderen	Belgium	8500
37	Cliniques universitaires saint-Luc	Bruxelles		Belgium	1200
38	Universitaire Ziekenhuizen Leuven	Leuven		Belgium	3000
39	Rigshospitalet CPC 7521	Copenhagen	Norrebro	Denmark	2200
40	Arhus Universitetshospital	Arhus N		Denmark	8200
41	Rigshospitalet	Copenhagen		Denmark	2100
42	Frederiksberg Hospital	Frederiksberg		Denmark	2000
43	Helsingin yliopistollinen keskussairaala, Meilahden sairaala	Helsinki		Finland	00290
44	Oulun yliopistollinen sairaala	Oulu		Finland	90220
45	Tampereen yliopistollinen Sairaala	Tampere		Finland	33520
46	Institut Gustave Roussy - Service d'Urologie	Villejuif Cedex		France	94805
47	U.O. Oncologia Medica, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura	Meldola	FC	Italy	47014
48	Farmacia, Azienda Ospedaliera "Istituti Ospitalieri" di Cremona	Cremona		Italy	26100
49	Medicina Nucleare, Azienda Ospedaliera "Istituti Ospitalieri" di Cremona	Cremona		Italy	26100
50	Servizio di Radiologia, Azienda Ospedaliera "Istituti Ospitalieri" di Cremona	Cremona		Italy	26100
51	U.O di Oncologia-Presidio Ospedaliero di Cremona-Istituti Ospitalieri di Cremona	Cremona		Italy	26100
52	Laboratorio Farmaci Antiblastici	Meldola (FC)		Italy	47014
53	UO Radiologia	Meldola (FC)		Italy	47014
54	Farmacia Ospedaliera, A.O.U. San Luigi Gonzaga	Orbassano TO		Italy	10043
55	SCDU Oncologia Medica II Pad, A.O.U. San Luigi Gonzaga	Orbassano TO		Italy	10043
56	SCDU Radiodiagnostica, A.O.U. San Luigi Gonzaga	Orbassano TO		Italy	10043
57	SS Medicina Nucleare, A.O.U. San Luigi Gonzaga	Orbassano TO		Italy	10043
58	Azienda Ospedaliera S. Camillo Forlanini, UOC per il governo clinico in Oncologia Medica	Roma		Italy	00152
59	Farmacia, Azienda Ospedaliera S. Camillo Forlanini	Roma		Italy	00152
60	UOC Radiologia Piasta, Azienda Ospedaliera S. Camillo Forlanini	Roma		Italy	00512
61	Fakultna nemocnica s poliklinikou F.D. Roosevelta	Banska Bystrica		Slovakia	975 17
62	Institut nuklearnej a molekularnej mediciny	Banska Bystrica		Slovakia	975 17
63	Fakultna nemocnica s poliklinikou F.D. Roosevelta	Banska Bystrica		Slovakia	97517
64	Bratislavske radiodiagnosticke centrum,a.s.	Bratislava		Slovakia	814 99
65	CUIMED, s.r.o., urologicka ambulancia	Bratislava		Slovakia	851 05
66	Univerzitna nemocnica martin	Martin		Slovakia	036 59
67	Jessenius-diagnosticke centrum, a.s.	Nitra		Slovakia	949 01
68	Uroexam, spol. s r.o., Urologicka ambulancia	Nitra		Slovakia	949 01
69	IZOTOPCENTRUM, s.r.o.	Nitra		Slovakia	950 01
70	GAMMALAB, spol.s r.o., Oddelenie nuklearnej mediciny	Trnava		Slovakia	917 01
71	CO Badalona-Instituto Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
72	ALTAHIA, Xarxa Assistencial Universitaria de Manresa	Manresa	Barcelona	Spain	08243
73	Hospital Universitari Parc Tauli	Sabadell	Barcelona	Spain	08208
74	Hospital Universitario Son Espases	Palma	Islas Baleares	Spain	07120
75	Hospital del Mar	Barcelona		Spain	08003
76	Hospital Clinic de Barcelona	Barcelona		Spain	08036
77	Hospital Universitario Madrid Sanchinarro	Madrid		Spain	28050
78	Urologmottagningen	Goteborg		Sweden	41345
79	Urologiska kliniken	Malmo		Sweden	20502
80	Oriola	Molnlycke		Sweden	435 25
81	Apoteket AB Kliniska Provningar Molnlycke	Molnlycke		Sweden	435 33
82	Rontgenkliniken	Orebro		Sweden	701 85
83	Urologmottagningen	Orebro		Sweden	701 85
84	East and North Hertfordshire NHS Trust	Northwood	Middlesex	United Kingdom	HA6 2RN
85	The Royal Marsden NHS Foundation Trust	Sutton	Surrey	United Kingdom	SM2 5PT
86	Velindre NHS Trust	Cardiff		United Kingdom	CF14 2TL
87	University College Hospitals NHS Trust	London		United Kingdom	NW1 2BU
88	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SW3 6JJ
89	University College London Hospitals NHS Foundation Trust	London		United Kingdom	WC1E 6AG
90	Oxford University Hospitals NHS Trust	Oxford		United Kingdom	OX3 7LE

Sponsors and Collaborators

• Pfizer
• Astellas Pharma Inc
• Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer
• Study Director: Medical Director, Medviation, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01995513
• Other Study ID Numbers: MDV3100-10; 2013-000722-54; C3431013; PLATO, C3431013
• First Posted: Nov 26, 2013
• Last Update Posted: Oct 6, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Prednisolone; Abiraterone Acetate

Study Results

Participant Flow

Pre-assignment Detail	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
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
Period Title: Open Label Treatment Period
STARTED	0	126	125
Treated	0	125	124
COMPLETED	0	0	0
NOT COMPLETED	0	126	125

Baseline Characteristics

Arm/Group Title	Enzalutamide 160 mg
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 Participants	509
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.3 (8.31)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	509 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
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])

Outcome Measure Data

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
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.
Measure Participants	126	125
Median (95% Confidence Interval) [months]	5.7	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.828
	Confidence Interval	(2-Sided) 95%; 0.612 to 1.119
	Parameter Dispersion	Type: Value:
	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
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])

Outcome Measure Data

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
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.
Measure Participants	126	125
Median (95% Confidence Interval) [months]	2.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.874
	Confidence Interval	(2-Sided) 95%; 0.617 to 1.239
	Parameter Dispersion	Type: Value:
	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
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])

Outcome Measure Data

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
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.
Measure Participants	124	122
>= 50%	0.8 0.2%	2.5 NaN
>= 30%	2.4 0.5%	2.5 NaN

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
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
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -4.82 to -1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in response rate was based upon standard normal approximation.

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
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
Method of Estimation	Estimation Parameter	Difference in Response Rate
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -3.90 to 3.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in response rate was based upon standard normal approximation.

4. Secondary Outcome

Title	Objective Response Rate (ORR)
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])

Outcome Measure Data

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
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.
Measure Participants	38	40
CR + PR	0.0 0%	5.0 NaN
CR + PR + SD	68.4 13.4%	57.5 NaN

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
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
Method of Estimation	Estimation Parameter	Difference in Objective Response Rate
	Estimated Value	-5.00
	Confidence Interval	(2-Sided) 95%; -11.75 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in objective response rate was based upon standard normal approximation.

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
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
Method of Estimation	Estimation Parameter	Difference in Objective Response Rate
	Estimated Value	10.92
	Confidence Interval	(2-Sided) 95%; -10.37 to 32.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in objective response rate was based upon standard normal approximation.

5. Secondary Outcome

Title	Rate of Pain Progression
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

Outcome Measure Data

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
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.
Measure Participants	58	59
Number (95% Confidence Interval) [percentage of participants]	36.2 7.1%	27.1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
Method of Estimation	Estimation Parameter	Difference in Progression Rate
	Estimated Value	9.09
	Confidence Interval	(2-Sided) 95%; -7.69 to 25.87
	Parameter Dispersion	Type: Value:
	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
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])

Outcome Measure Data

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
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.
Measure Participants	126	125
Median (95% Confidence Interval) [months]	10.3	8.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.861
	Confidence Interval	(2-Sided) 95%; 0.616 to 1.204
	Parameter Dispersion	Type: Value:
	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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	116.4 (20.10)	119.0 (19.08)
Change at Week 9	-3.3 (14.90)	-2.2 (13.90)
Change at Week 13	-4.4 (14.44)	-0.5 (13.02)
Change at Week 17	-3.7 (12.40)	-2.3 (13.90)
Change at Week 21	-2.5 (12.33)	-2.7 (13.57)
Change at Week 25	-3.1 (13.47)	-2.1 (10.87)
Change at Week 29	-6.8 (13.98)	0.3 (12.10)
Change at Week 33	-5.9 (15.35)	-0.2 (12.90)
Change at Week 37	-6.1 (14.25)	0.9 (12.57)
Change at Week 41	-5.7 (12.17)	1.3 (14.13)
Change at Week 45	-6.0 (9.56)	-2.6 (16.27)
Change at Week 49	-4.2 (11.36)	1.8 (10.74)
Change at Week 53	-4.8 (10.17)	1.8 (14.68)
Change at Week 57	-4.3 (9.73)	0.1 (7.45)
Change at Week 61	-5.5 (10.63)	0.6 (12.94)
Change at Week 65	-7.0 (7.86)	1.9 (9.50)
Change at Week 69	-3.5 (11.37)	4.4 (13.29)
Change at Week 73	-0.7 (7.26)	-35.0 (NA)
Change at Week 77	-4.0 (9.81)	6.5 (30.41)
Change at Week 81	10.8 (9.24)
Change at Week 85	-5.5 (3.54)
Change at Week 89	-2.0 (NA)

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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	22.1 (5.80)	22.4 (4.84)
Change at Week 9	-0.5 (4.33)	-0.8 (4.13)
Change at Week 13	-0.4 (3.46)	-0.4 (3.86)
Change at Week 17	-0.1 (3.68)	-0.6 (4.64)
Change at Week 21	-0.5 (3.24)	-1.2 (5.75)
Change at Week 25	0.1 (2.79)	-1.0 (5.25)
Change at Week 29	-0.1 (3.20)	-0.2 (5.18)
Change at Week 33	-0.2 (3.21)	0.0 (4.95)
Change at Week 37	-0.8 (3.04)	0.8 (2.79)
Change at Week 41	-1.4 (3.75)	-0.1 (3.51)
Change at Week 45	-0.9 (3.36)	-0.8 (3.75)
Change at Week 49	-0.6 (2.88)	0.0 (2.65)
Change at Week 53	-1.0 (3.15)	0.4 (2.56)
Change at Week 57	-2.0 (3.06)	0.2 (1.29)
Change at Week 61	-1.5 (2.77)	-0.2 (1.80)
Change at Week 65	-1.5 (2.54)	-0.5 (0.96)
Change at Week 69	-1.4 (2.03)	-0.5 (0.96)
Change at Week 73	-0.6 (3.22)	-1.0 (NA)
Change at Week 77	-0.9 (3.41)	-0.5 (0.71)
Change at Week 81	6.2 (5.42)
Change at Week 85	-1.0 (1.41)
Change at Week 89	0.0 (NA)

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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	18.1 (3.80)	18.5 (4.06)
Change at Week 9	-0.1 (2.81)	0.1 (3.40)
Change at Week 13	-0.1 (3.55)	0.2 (3.09)
Change at Week 17	-0.2 (3.44)	0.4 (2.88)
Change at Week 21	0.3 (3.48)	0.1 (3.36)
Change at Week 25	0.3 (2.58)	0.3 (3.33)
Change at Week 29	-0.5 (3.56)	0.3 (3.27)
Change at Week 33	0.1 (3.33)	0.9 (2.99)
Change at Week 37	-0.7 (4.04)	0.9 (2.49)
Change at Week 41	0.1 (2.99)	1.4 (2.60)
Change at Week 45	-0.5 (3.23)	1.2 (2.76)
Change at Week 49	0.0 (3.00)	1.3 (2.75)
Change at Week 53	0.1 (2.72)	1.2 (3.23)
Change at Week 57	-0.4 (2.32)	1.6 (2.53)
Change at Week 61	-0.3 (3.14)	1.1 (3.62)
Change at Week 65	-0.9 (3.57)	2.9 (2.54)
Change at Week 69	-0.5 (2.93)	1.5 (2.93)
Change at Week 73	1.0 (2.83)	-5.0 (5.66)
Change at Week 77	0.1 (2.67)	2.0 (2.83)
Change at Week 81	1.5 (3.54)
Change at Week 85	-1.5 (0.71)
Change at Week 89	-3.0 (NA)

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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	20.2 (5.54)	20.3 (5.84)
Change at Week 9	-1.0 (4.23)	-0.7 (4.62)
Change at Week 13	-1.2 (4.07)	-0.4 (4.54)
Change at Week 17	-1.3 (4.00)	-0.5 (4.11)
Change at Week 21	-1.2 (5.03)	-0.7 (4.03)
Change at Week 25	-1.0 (3.41)	-0.3 (4.41)
Change at Week 29	-2.4 (4.67)	-0.2 (4.38)
Change at Week 33	-2.0 (5.14)	-0.7 (4.49)
Change at Week 37	-1.5 (5.22)	0.2 (5.72)
Change at Week 41	-2.1 (4.44)	0.8 (5.74)
Change at Week 45	-2.0 (3.37)	-0.3 (6.28)
Change at Week 49	-2.1 (4.55)	1.5 (5.02)
Change at Week 53	-1.6 (4.67)	1.3 (4.92)
Change at Week 57	-1.4 (4.06)	2.0 (4.37)
Change at Week 61	-0.8 (3.34)	2.9 (5.56)
Change at Week 65	-1.2 (2.21)	1.7 (2.75)
Change at Week 69	0.2 (1.48)	2.3 (4.23)
Change at Week 73	-0.6 (3.02)	4.0 (12.73)
Change at Week 77	-1.6 (3.91)	2.5 (9.19)
Change at Week 81	-1.5 (7.78)
Change at Week 85	-1.5 (2.12)
Change at Week 89	1.0 (NA)

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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	33.2 (6.85)	34.2 (6.45)
Change at Week 9	-0.7 (5.97)	-0.9 (5.18)
Change at Week 13	-1.9 (5.91)	-0.1 (5.36)
Change at Week 17	-1.0 (5.36)	-1.4 (5.10)
Change at Week 21	-0.4 (5.13)	-0.6 (4.83)
Change at Week 25	-0.8 (6.93)	-0.8 (4.42)
Change at Week 29	-1.3 (5.75)	-0.3 (4.77)
Change at Week 33	-1.4 (5.16)	-0.6 (4.88)
Change at Week 37	-1.5 (4.88)	-0.8 (4.32)
Change at Week 41	-1.0 (5.13)	-0.7 (5.34)
Change at Week 45	-0.8 (4.88)	-1.7 (7.02)
Change at Week 49	-0.8 (4.26)	-0.9 (4.63)
Change at Week 53	-1.1 (3.65)	-1.8 (5.78)
Change at Week 57	-0.5 (3.67)	-3.3 (4.48)
Change at Week 61	-2.1 (4.29)	-3.1 (5.68)
Change at Week 65	-2.0 (4.05)	-2.6 (6.32)
Change at Week 69	-1.5 (3.30)	1.1 (5.79)
Change at Week 73	-0.2 (3.17)	-6.4 (9.32)
Change at Week 77	-1.0 (3.71)	-1.5 (13.44)
Change at Week 81	3.1 (1.22)
Change at Week 85	-0.5 (0.71)
Change at Week 89	0.0 (NA)

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
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

Outcome Measure Data

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
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.
Measure Participants	126	125
Baseline	22.9 (4.50)	23.6 (4.42)
Change at Week 9	-0.8 (4.04)	0.1 (3.20)
Change at Week 13	-1.0 (4.11)	0.0 (2.63)
Change at Week 17	-1.1 (3.26)	-0.3 (2.97)
Change at Week 21	-0.8 (3.11)	-0.8 (4.48)
Change at Week 25	-1.7 (4.23)	-0.4 (2.90)
Change at Week 29	-2.5 (4.89)	0.3 (2.67)
Change at Week 33	-2.5 (5.37)	0.1 (3.18)
Change at Week 37	-1.8 (4.50)	0.4 (3.13)
Change at Week 41	-1.5 (3.94)	0.4 (2.80)
Change at Week 45	-2.0 (3.72)	-0.4 (3.59)
Change at Week 49	-0.9 (3.78)	0.6 (2.12)
Change at Week 53	-0.2 (3.78)	0.7 (2.85)
Change at Week 57	-0.4 (3.25)	0.4 (2.37)
Change at Week 61	-0.8 (3.11)	0.4 (2.32)
Change at Week 65	-1.9 (4.25)	0.4 (1.99)
Change at Week 69	-0.3 (4.08)	-0.5 (2.67)
Change at Week 73	-0.3 (2.05)	-3.0 (5.66)
Change at Week 77	-0.7 (2.81)	4.0 (4.24)
Change at Week 81	1.5 (2.12)
Change at Week 85	-1.0 (0.00)
Change at Week 89	0.0 (NA)

13. Secondary Outcome

Title	Time to Degradation of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score
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)

Outcome Measure Data

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
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.
Measure Participants	126	125
Median (95% Confidence Interval) [months]	4.6	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg, Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.399
	Confidence Interval	(2-Sided) 95%; 0.967 to 2.025
	Parameter Dispersion	Type: Value:
	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)
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])

Outcome Measure Data

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
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.
Measure Participants	509	125	124
AEs	93.3 18.3%	89.6 NaN	91.1 NaN
SAEs	27.9 5.5%	30.4 NaN	28.2 NaN

15. Other Pre-specified Outcome

Title	Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
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])

Outcome Measure Data

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
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.
Measure Participants	509	125	124
Number [percentage of participants]	9.8 1.9%	19.2 NaN	12.1 NaN

16. Other Pre-specified Outcome

Title	Percentage of Participants With Adverse Events (AEs) Leading to Death
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])

Outcome Measure Data

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
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.
Measure Participants	509	125	124
Number [percentage of participants]	4.7 0.9%	3.2 NaN	2.4 NaN

17. Other Pre-specified Outcome

Title	Percentage of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
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])

Outcome Measure Data

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
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.
Measure Participants	509	125	124
AEs	65.4 12.8%	43.2 NaN	35.5 NaN
SAEs	3.5 0.7%	4.8 NaN	4.8 NaN

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Enzalutamide 160 mg		Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg		Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	142/509 (27.9%)		38/125 (30.4%)		35/124 (28.2%)
Blood and lymphatic system disorders
Anaemia	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Cardiac disorders
Acute coronary syndrome	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Acute myocardial infarction	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Angina pectoris	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Angina unstable	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Atrial fibrillation	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Atrioventricular block complete	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cardiac arrest	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cardiac failure	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Cardiac failure congestive	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Cardio-respiratory arrest	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Coronary artery disease	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Coronary artery stenosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mitral valve disease	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Myocardial infarction	1/509 (0.2%)		0/125 (0%)		2/124 (1.6%)
Myocardial ischaemia	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Palpitations	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pericardial effusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sick sinus syndrome	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Ear and labyrinth disorders
Vertigo	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vertigo positional	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Eye disorders
Exophthalmos	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastrointestinal disorders
Abdominal pain	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Colonic fistula	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Constipation	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Diarrhoea	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Duodenal ulcer haemorrhage	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dysphagia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastric ulcer	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastrointestinal perforation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Haemorrhoidal haemorrhage	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hiatus hernia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Intestinal ischaemia	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Large intestine perforation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Melaena	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Nausea	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Oesophageal perforation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Peptic ulcer	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rectal polyp	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Retroperitoneal haematoma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Small intestinal obstruction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Upper gastrointestinal haemorrhage	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vomiting	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
General disorders
Asthenia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Chest pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Disease progression	5/509 (1%)		2/125 (1.6%)		1/124 (0.8%)
Fatigue	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
General physical health deterioration	4/509 (0.8%)		1/125 (0.8%)		0/124 (0%)
Malaise	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Multi-organ failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Oedema peripheral	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pain	1/509 (0.2%)		1/125 (0.8%)		1/124 (0.8%)
Pyrexia	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Hepatobiliary disorders
Bile duct obstruction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cholecystitis chronic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatic lesion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Jaundice cholestatic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Infections and infestations
Abscess jaw	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Abscess limb	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Appendicitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Bronchitis	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Cellulitis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Enterococcal sepsis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Gastroenteritis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lower respiratory tract infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Meningitis tuberculous	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Ophthalmic herpes zoster	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pneumonia	5/509 (1%)		1/125 (0.8%)		3/124 (2.4%)
Pneumonia respiratory syncytial viral	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Pulmonary sepsis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Sepsis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Septic shock	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Urinary tract infection	5/509 (1%)		1/125 (0.8%)		0/124 (0%)
Urinary tract infection enterococcal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Urosepsis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Injury, poisoning and procedural complications
Acetabulum fracture	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Burns third degree	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cervical vertebral fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cystitis radiation	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Fall	5/509 (1%)		1/125 (0.8%)		0/124 (0%)
Femoral neck fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Femur fracture	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Hip fracture	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Lower limb fracture	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Musculoskeletal injury	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pelvic fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Radius fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Road traffic accident	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Spinal compression fracture	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Spinal fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Toxicity to various agents	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vascular pseudoaneurysm	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Investigations
Alanine aminotransferase increased	0/509 (0%)		2/125 (1.6%)		0/124 (0%)
Aspartate aminotransferase increased	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Blood bilirubin increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Liver function test abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Dehydration	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dystrophic calcification	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Hypercalcaemia	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Hyponatraemia	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Malnutrition	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Back pain	4/509 (0.8%)		1/125 (0.8%)		0/124 (0%)
Bone pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cervical spinal stenosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Chondrocalcinosis pyrophosphate	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Intervertebral disc protrusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mobility decreased	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Muscular weakness	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Musculoskeletal chest pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Neck pain	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Osteoarthritis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Osteonecrosis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Osteonecrosis of jaw	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Osteoporosis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Osteoporotic fracture	1/509 (0.2%)		1/125 (0.8%)		1/124 (0.8%)
Pathological fracture	4/509 (0.8%)		0/125 (0%)		2/124 (1.6%)
Spinal osteoarthritis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
B-cell lymphoma	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Bladder transitional cell carcinoma	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Bowen's disease	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Cancer pain	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Chronic myelomonocytic leukaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Laryngeal squamous cell carcinoma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lentigo maligna	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lung adenocarcinoma	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Lung squamous cell carcinoma stage 0	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Malignant neoplasm progression	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Malignant pleural effusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metastases to bone	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Metastases to central nervous system	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Metastases to liver	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metastases to spine	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Metastasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metastatic pain	3/509 (0.6%)		3/125 (2.4%)		2/124 (1.6%)
Neuroendocrine carcinoma metastatic	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Pancreatic carcinoma	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Prostate cancer	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Prostate cancer metastatic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal cell carcinoma	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Squamous cell carcinoma of skin	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Transitional cell carcinoma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Transitional cell carcinoma metastatic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Nervous system disorders
Brain oedema	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cerebellar infarction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cerebral haemorrhage	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Cerebral infarction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cerebrovascular accident	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Cognitive disorder	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Dementia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Dysarthria	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Ischaemic stroke	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Loss of consciousness	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Nerve root compression	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Presyncope	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Spinal cord compression	4/509 (0.8%)		4/125 (3.2%)		2/124 (1.6%)
Stupor	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Syncope	5/509 (1%)		0/125 (0%)		0/124 (0%)
Transient ischaemic attack	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Unresponsive to stimuli	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Psychiatric disorders
Confusional state	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Delirium	2/509 (0.4%)		1/125 (0.8%)		1/124 (0.8%)
Depression	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal and urinary disorders
Calculus bladder	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Calculus ureteric	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Calculus urethral	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Haematuria	10/509 (2%)		3/125 (2.4%)		1/124 (0.8%)
Hydronephrosis	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Nephrolithiasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Obstructive uropathy	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Prerenal failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal failure acute	2/509 (0.4%)		0/125 (0%)		2/124 (1.6%)
Ureteric obstruction	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Urinary incontinence	1/509 (0.2%)		2/125 (1.6%)		1/124 (0.8%)
Urinary retention	2/509 (0.4%)		2/125 (1.6%)		2/124 (1.6%)
Urinary tract obstruction	1/509 (0.2%)		2/125 (1.6%)		1/124 (0.8%)
Reproductive system and breast disorders
Balanitis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Chronic obstructive pulmonary disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Haemothorax	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pleural effusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pneumonia aspiration	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Pneumothorax	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pulmonary embolism	4/509 (0.8%)		0/125 (0%)		2/124 (1.6%)
Respiratory failure	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Vascular disorders
Aortic stenosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Arterial rupture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Arteriosclerosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Circulatory collapse	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Deep vein thrombosis	4/509 (0.8%)		0/125 (0%)		1/124 (0.8%)
Hypertension	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Hypotension	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Hypovolaemic shock	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lymphoedema	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Other (Not Including Serious) Adverse Events
	Enzalutamide 160 mg		Enzalutamide 160mg+Abiraterone 1000mg+ Prednisone 10mg		Placebo+Abiraterone 1000mg+ Prednisone 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	473/509 (92.9%)		111/125 (88.8%)		111/124 (89.5%)
Blood and lymphatic system disorders
Anaemia	30/509 (5.9%)		5/125 (4%)		5/124 (4%)
Bone marrow failure	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Haemorrhagic anaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Iron deficiency anaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Leukocytosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lymphadenopathy	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Lymphopenia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Pancytopenia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Pernicious anaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Thrombocytopenia	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Cardiac disorders
Angina pectoris	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Aortic valve stenosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Arrhythmia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Atrial fibrillation	4/509 (0.8%)		3/125 (2.4%)		4/124 (3.2%)
Atrial flutter	5/509 (1%)		0/125 (0%)		0/124 (0%)
Bradycardia	5/509 (1%)		0/125 (0%)		1/124 (0.8%)
Bundle branch block right	1/509 (0.2%)		1/125 (0.8%)		1/124 (0.8%)
Cardiac failure	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Cardiac failure congestive	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Chordae tendinae rupture	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Coronary artery stenosis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Diastolic dysfunction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Extrasystoles	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Left ventricular dysfunction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mitral valve disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mitral valve prolapse	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Myocardial infarction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Myocardial ischaemia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Palpitations	2/509 (0.4%)		1/125 (0.8%)		1/124 (0.8%)
Right ventricular dysfunction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sinus bradycardia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Sinus tachycardia	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Supraventricular extrasystoles	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Tachycardia	7/509 (1.4%)		0/125 (0%)		2/124 (1.6%)
Ventricular extrasystoles	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Congenital, familial and genetic disorders
Phimosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Ear and labyrinth disorders
Cerumen impaction	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Deafness bilateral	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Deafness neurosensory	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hearing impaired	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Motion sickness	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Tinnitus	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Vertigo	13/509 (2.6%)		0/125 (0%)		1/124 (0.8%)
Vertigo positional	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Endocrine disorders
Adrenal insufficiency	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Cushingoid	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Goitre	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hyperthyroidism	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Hypothyroidism	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Thyroid mass	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Eye disorders
Amaurosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cataract	6/509 (1.2%)		1/125 (0.8%)		1/124 (0.8%)
Conjunctival haemorrhage	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Conjunctivitis	9/509 (1.8%)		2/125 (1.6%)		1/124 (0.8%)
Diplopia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dry eye	5/509 (1%)		1/125 (0.8%)		0/124 (0%)
Exophthalmos	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Eye disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Eye inflammation	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Eye irritation	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Eye pain	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Eye swelling	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Eyelid margin crusting	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Glaucoma	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Iritis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lacrimation increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Macular fibrosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Night blindness	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Ocular icterus	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Optic ischaemic neuropathy	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Photophobia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Retinal artery occlusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Strabismus	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Trichiasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vision blurred	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Visual acuity reduced	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Visual impairment	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Vitreous floaters	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vitreous haemorrhage	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastrointestinal disorders
Abdominal discomfort	5/509 (1%)		0/125 (0%)		0/124 (0%)
Abdominal distension	8/509 (1.6%)		0/125 (0%)		0/124 (0%)
Abdominal pain	14/509 (2.8%)		7/125 (5.6%)		7/124 (5.6%)
Abdominal pain lower	5/509 (1%)		2/125 (1.6%)		1/124 (0.8%)
Abdominal pain upper	19/509 (3.7%)		0/125 (0%)		2/124 (1.6%)
Anal haemorrhage	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Apical granuloma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Barrett's oesophagus	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Breath odour	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cheilitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Colitis microscopic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Constipation	78/509 (15.3%)		17/125 (13.6%)		12/124 (9.7%)
Dental caries	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Diarrhoea	66/509 (13%)		7/125 (5.6%)		12/124 (9.7%)
Diverticulum intestinal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dry mouth	4/509 (0.8%)		2/125 (1.6%)		1/124 (0.8%)
Dyspepsia	16/509 (3.1%)		3/125 (2.4%)		4/124 (3.2%)
Epigastric discomfort	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Erosive oesophagitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Eructation	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Faecaloma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Faeces hard	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Food poisoning	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Frequent bowel movements	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Gastric mucosa erythema	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastric ulcer	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Gastritis	1/509 (0.2%)		0/125 (0%)		2/124 (1.6%)
Gastrooesophageal reflux disease	13/509 (2.6%)		4/125 (3.2%)		5/124 (4%)
Gingival bleeding	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gingival inflammation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gingival pain	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Haematochezia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dysphagia	3/509 (0.6%)		2/125 (1.6%)		1/124 (0.8%)
Faecal incontinence	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Flatulence	12/509 (2.4%)		3/125 (2.4%)		1/124 (0.8%)
Haemorrhoids	4/509 (0.8%)		0/125 (0%)		1/124 (0.8%)
Hiatus hernia	2/509 (0.4%)		0/125 (0%)		2/124 (1.6%)
Inguinal hernia	3/509 (0.6%)		0/125 (0%)		2/124 (1.6%)
Large intestine polyp	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Lip dry	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Lip oedema	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Localised intraabdominal fluid collection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Melaena	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mouth ulceration	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Nausea	97/509 (19.1%)		21/125 (16.8%)		11/124 (8.9%)
Odynophagia	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Oesophageal pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Oesophagitis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Pancreatic disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pancreatitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Paraesthesia oral	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Periodontal disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Proctalgia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Rectal haemorrhage	2/509 (0.4%)		2/125 (1.6%)		0/124 (0%)
Retching	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Salivary hypersecretion	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Tongue disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Toothache	7/509 (1.4%)		0/125 (0%)		1/124 (0.8%)
Umbilical hernia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vomiting	28/509 (5.5%)		7/125 (5.6%)		2/124 (1.6%)
General disorders
Abasia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Asthenia	25/509 (4.9%)		5/125 (4%)		3/124 (2.4%)
Catheter site haemorrhage	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Chest discomfort	3/509 (0.6%)		2/125 (1.6%)		0/124 (0%)
Chest pain	2/509 (0.4%)		4/125 (3.2%)		3/124 (2.4%)
Chills	5/509 (1%)		1/125 (0.8%)		2/124 (1.6%)
Cyst	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Device failure	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Device occlusion	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Dysplasia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Face oedema	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Facial pain	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Fatigue	200/509 (39.3%)		17/125 (13.6%)		18/124 (14.5%)
Feeling abnormal	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Feeling drunk	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Feeling hot	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gait disturbance	7/509 (1.4%)		1/125 (0.8%)		2/124 (1.6%)
General physical health deterioration	5/509 (1%)		0/125 (0%)		0/124 (0%)
Hyperpyrexia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypothermia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Inflammation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Influenza like illness	6/509 (1.2%)		1/125 (0.8%)		1/124 (0.8%)
Infusion site extravasation	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Injection site swelling	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Irritability	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Local swelling	5/509 (1%)		4/125 (3.2%)		0/124 (0%)
Malaise	5/509 (1%)		1/125 (0.8%)		0/124 (0%)
Medical device complication	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mucosal inflammation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Non-cardiac chest pain	7/509 (1.4%)		3/125 (2.4%)		2/124 (1.6%)
Oedema	3/509 (0.6%)		2/125 (1.6%)		0/124 (0%)
Oedema peripheral	49/509 (9.6%)		7/125 (5.6%)		16/124 (12.9%)
Pain	7/509 (1.4%)		6/125 (4.8%)		2/124 (1.6%)
Performance status decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pyrexia	11/509 (2.2%)		4/125 (3.2%)		3/124 (2.4%)
Hunger	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Hepatobiliary disorders
Cholelithiasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatic lesion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatic steatosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatomegaly	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatotoxicity	0/509 (0%)		2/125 (1.6%)		2/124 (1.6%)
Hyperbilirubinaemia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Hypertransaminasaemia	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Jaundice	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Non-alcoholic steatohepatitis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Pneumobilia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Immune system disorders
Contrast media allergy	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Drug hypersensitivity	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Hypersensitivity	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypogammaglobulinaemia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Milk allergy	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Seasonal allergy	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Infections and infestations
Abdominal abscess	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Abscess	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Abscess neck	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Atypical mycobacterial infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Bronchitis	4/509 (0.8%)		1/125 (0.8%)		1/124 (0.8%)
Bronchopneumonia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Carbuncle	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Catheter site infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cellulitis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Conjunctivitis infective	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Cystitis	4/509 (0.8%)		1/125 (0.8%)		2/124 (1.6%)
Diverticulitis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Ear infection	2/509 (0.4%)		2/125 (1.6%)		1/124 (0.8%)
Erysipelas	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Escherichia urinary tract infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Eye infection	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Eyelid infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Folliculitis	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Fungal skin infection	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Furuncle	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastroenteritis	4/509 (0.8%)		1/125 (0.8%)		0/124 (0%)
Genital candidiasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gingival infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gingivitis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Helicobacter infection	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Herpes simplex	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Herpes zoster	5/509 (1%)		4/125 (3.2%)		2/124 (1.6%)
Herpes zoster oticus	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Infected cyst	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Infected dermal cyst	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Infection	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Infection parasitic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Influenza	20/509 (3.9%)		4/125 (3.2%)		5/124 (4%)
Injection site infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Labyrinthitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Laryngitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lip infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lobar pneumonia	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Localised infection	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Lower respiratory tract infection	16/509 (3.1%)		2/125 (1.6%)		4/124 (3.2%)
Lung infection	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Mediastinitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Nail infection	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Nasopharyngitis	31/509 (6.1%)		0/125 (0%)		7/124 (5.6%)
Oral candidiasis	9/509 (1.8%)		1/125 (0.8%)		1/124 (0.8%)
Oral herpes	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Otitis media	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Peritonitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pharyngitis	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Pneumonia	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Pulpitis dental	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Rash pustular	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Respiratory tract infection	4/509 (0.8%)		0/125 (0%)		1/124 (0.8%)
Respiratory tract infection viral	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rhinitis	5/509 (1%)		0/125 (0%)		0/124 (0%)
Scrotal abscess	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sialoadenitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sinusitis	4/509 (0.8%)		0/125 (0%)		3/124 (2.4%)
Skin candida	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Skin infection	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Soft tissue infection	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Tinea cruris	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Tooth abscess	0/509 (0%)		2/125 (1.6%)		0/124 (0%)
Tooth infection	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Tracheitis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Upper respiratory tract infection	25/509 (4.9%)		9/125 (7.2%)		5/124 (4%)
Urethritis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Urinary tract infection	29/509 (5.7%)		9/125 (7.2%)		6/124 (4.8%)
Urosepsis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Viral infection	3/509 (0.6%)		1/125 (0.8%)		1/124 (0.8%)
Onychomycosis	2/509 (0.4%)		1/125 (0.8%)		1/124 (0.8%)
Injury, poisoning and procedural complications
Accident	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Accidental overdose	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Ankle fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Arthropod bite	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Bone contusion	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Chest injury	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Contusion	7/509 (1.4%)		2/125 (1.6%)		3/124 (2.4%)
Excoriation	4/509 (0.8%)		1/125 (0.8%)		2/124 (1.6%)
Eye contusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Face injury	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Fall	45/509 (8.8%)		11/125 (8.8%)		8/124 (6.5%)
Femur fracture	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Foreign body in eye	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Fractured coccyx	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gastroenteritis radiation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hand fracture	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Head injury	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Humerus fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Injection related reaction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Joint injury	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Laceration	9/509 (1.8%)		2/125 (1.6%)		1/124 (0.8%)
Ligament sprain	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Limb injury	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Lumbar vertebral fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Multiple injuries	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Muscle injury	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Muscle strain	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Overdose	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Pelvic fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Periorbital contusion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Post procedural haematuria	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Post-traumatic pain	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Procedural hypotension	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Procedural nausea	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Procedural pain	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Procedural vomiting	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Radius fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rib fracture	4/509 (0.8%)		1/125 (0.8%)		1/124 (0.8%)
Skeletal injury	1/509 (0.2%)		1/125 (0.8%)		1/124 (0.8%)
Skin wound	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Spinal compression fracture	3/509 (0.6%)		1/125 (0.8%)		1/124 (0.8%)
Thoracic vertebral fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Toxicity to various agents	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Traumatic fracture	0/509 (0%)		1/125 (0.8%)		2/124 (1.6%)
Urethral injury	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Wound	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Wound dehiscence	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Wound secretion	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Wrist fracture	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Investigations
Activated partial thromboplastin time prolonged	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Alanine aminotransferase increased	1/509 (0.2%)		8/125 (6.4%)		6/124 (4.8%)
Aspartate aminotransferase increased	0/509 (0%)		4/125 (3.2%)		2/124 (1.6%)
Bacterial test positive	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood albumin increased	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Blood alkaline phosphatase increased	3/509 (0.6%)		1/125 (0.8%)		2/124 (1.6%)
Blood bilirubin increased	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Blood calcium decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood calcium increased	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Blood cholesterol increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood creatine phosphokinase increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood creatinine increased	6/509 (1.2%)		3/125 (2.4%)		2/124 (1.6%)
Blood glucose increased	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Blood iron decreased	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Blood lactate dehydrogenase increased	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Blood potassium decreased	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Blood potassium increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood pressure increased	2/509 (0.4%)		2/125 (1.6%)		1/124 (0.8%)
Blood pressure orthostatic decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Blood urine present	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cardiac murmur	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Cardioactive drug level increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cystoscopy	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Ejection fraction decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Electrocardiogram QT prolonged	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Gamma-glutamyltransferase abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Haemoglobin decreased	5/509 (1%)		0/125 (0%)		2/124 (1.6%)
Heart rate increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Heart rate irregular	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Heart sounds abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hepatic enzyme increased	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
International normalised ratio increased	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Liver function test abnormal	0/509 (0%)		3/125 (2.4%)		1/124 (0.8%)
Lymph node palpable	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lymphocyte count decreased	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Norovirus test positive	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Respiratory rate increased	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Transaminases increased	0/509 (0%)		2/125 (1.6%)		0/124 (0%)
Troponin increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Urine output decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vitamin B12 decreased	0/509 (0%)		1/125 (0.8%)		1/124 (0.8%)
Weight increased	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Weight decreased	22/509 (4.3%)		2/125 (1.6%)		3/124 (2.4%)
White blood cell count decreased	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
White blood cell count increased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metabolism and nutrition disorders
Abnormal loss of weight	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Decreased appetite	82/509 (16.1%)		13/125 (10.4%)		10/124 (8.1%)
Diabetes mellitus	1/509 (0.2%)		0/125 (0%)		2/124 (1.6%)
Dehydration	4/509 (0.8%)		2/125 (1.6%)		1/124 (0.8%)
Dyslipidaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Fluid overload	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gout	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Fluid retention	0/509 (0%)		2/125 (1.6%)		0/124 (0%)
Hypercalcaemia	5/509 (1%)		0/125 (0%)		0/124 (0%)
Hypercholesterolaemia	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Hyperglycaemia	8/509 (1.6%)		0/125 (0%)		0/124 (0%)
Hyperkalaemia	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Hyperlipidaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypernatraemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypoalbuminaemia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypocalcaemia	6/509 (1.2%)		2/125 (1.6%)		0/124 (0%)
Hypoglycaemia	1/509 (0.2%)		1/125 (0.8%)		3/124 (2.4%)
Hypokalaemia	7/509 (1.4%)		9/125 (7.2%)		7/124 (5.6%)
Hypomagnesaemia	3/509 (0.6%)		1/125 (0.8%)		2/124 (1.6%)
Hyponatraemia	5/509 (1%)		0/125 (0%)		1/124 (0.8%)
Increased appetite	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Iron deficiency	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lactic acidosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Malnutrition	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Type 2 diabetes mellitus	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Vitamin B complex deficiency	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Vitamin B12 deficiency	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Vitamin D deficiency	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	74/509 (14.5%)		18/125 (14.4%)		14/124 (11.3%)
Arthritis	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Arthropathy	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Back pain	104/509 (20.4%)		25/125 (20%)		28/124 (22.6%)
Bone fistula	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Bone pain	21/509 (4.1%)		3/125 (2.4%)		4/124 (3.2%)
Bursitis	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Coccydynia	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Flank pain	5/509 (1%)		2/125 (1.6%)		0/124 (0%)
Groin pain	12/509 (2.4%)		1/125 (0.8%)		5/124 (4%)
Inguinal mass	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Intervertebral disc protrusion	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Joint range of motion decreased	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Joint stiffness	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Joint swelling	4/509 (0.8%)		2/125 (1.6%)		1/124 (0.8%)
Mobility decreased	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Muscle atrophy	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Muscle tightness	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Muscular weakness	21/509 (4.1%)		6/125 (4.8%)		4/124 (3.2%)
Musculoskeletal chest pain	23/509 (4.5%)		13/125 (10.4%)		7/124 (5.6%)
Musculoskeletal discomfort	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Musculoskeletal pain	33/509 (6.5%)		11/125 (8.8%)		8/124 (6.5%)
Musculoskeletal stiffness	4/509 (0.8%)		3/125 (2.4%)		0/124 (0%)
Myalgia	23/509 (4.5%)		1/125 (0.8%)		2/124 (1.6%)
Myopathy	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Myositis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Osteoarthritis	6/509 (1.2%)		0/125 (0%)		1/124 (0.8%)
Osteonecrosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Osteonecrosis of jaw	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Osteopenia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Osteoporosis	0/509 (0%)		2/125 (1.6%)		0/124 (0%)
Pain in extremity	33/509 (6.5%)		9/125 (7.2%)		6/124 (4.8%)
Pain in jaw	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Pathological fracture	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Plantar fasciitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Scoliosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Spinal column stenosis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Spinal osteoarthritis	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Spinal pain	4/509 (0.8%)		0/125 (0%)		1/124 (0.8%)
Synovial cyst	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Synovitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Tendonitis	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Trismus	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Neck pain	23/509 (4.5%)		2/125 (1.6%)		3/124 (2.4%)
Muscle fatigue	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Muscle spasms	7/509 (1.4%)		4/125 (3.2%)		9/124 (7.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	11/509 (2.2%)		1/125 (0.8%)		1/124 (0.8%)
Benign urinary tract neoplasm	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Bowen's disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cancer pain	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Choroidal haemangioma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Fibroma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Metastases to central nervous system	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal neoplasm	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Seborrhoeic keratosis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Skin cancer	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Skin papilloma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Squamous cell carcinoma	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Squamous cell carcinoma of skin	5/509 (1%)		0/125 (0%)		0/124 (0%)
Tumour pain	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Nervous system disorders
Ageusia	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Amnesia	9/509 (1.8%)		0/125 (0%)		0/124 (0%)
Ataxia	5/509 (1%)		0/125 (0%)		0/124 (0%)
Balance disorder	8/509 (1.6%)		1/125 (0.8%)		0/124 (0%)
Burning sensation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Carpal tunnel syndrome	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cauda equina syndrome	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Cognitive disorder	11/509 (2.2%)		1/125 (0.8%)		0/124 (0%)
Dementia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dementia Alzheimer's type	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Disturbance in attention	7/509 (1.4%)		1/125 (0.8%)		1/124 (0.8%)
Dizziness	41/509 (8.1%)		6/125 (4.8%)		4/124 (3.2%)
Dizziness postural	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dysaesthesia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Dysarthria	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Dysgeusia	24/509 (4.7%)		3/125 (2.4%)		1/124 (0.8%)
Dyskinesia	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Head discomfort	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Headache	49/509 (9.6%)		5/125 (4%)		2/124 (1.6%)
Hemiparesis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hyperreflexia	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Hypoaesthesia	10/509 (2%)		4/125 (3.2%)		3/124 (2.4%)
Hypoglossal nerve paralysis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Hypokinesia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lethargy	34/509 (6.7%)		3/125 (2.4%)		1/124 (0.8%)
Loss of consciousness	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Memory impairment	16/509 (3.1%)		2/125 (1.6%)		2/124 (1.6%)
Migraine	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Nerve compression	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Neuralgia	5/509 (1%)		0/125 (0%)		1/124 (0.8%)
Neuropathy peripheral	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Paraesthesia	21/509 (4.1%)		1/125 (0.8%)		0/124 (0%)
Parkinsonian gait	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Parkinson's disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Parosmia	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Peripheral sensory neuropathy	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Poor quality sleep	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Post herpetic neuralgia	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Presyncope	4/509 (0.8%)		1/125 (0.8%)		1/124 (0.8%)
Radicular pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Restless legs syndrome	9/509 (1.8%)		0/125 (0%)		1/124 (0.8%)
Sciatica	4/509 (0.8%)		0/125 (0%)		1/124 (0.8%)
Somnolence	7/509 (1.4%)		1/125 (0.8%)		1/124 (0.8%)
Syncope	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Tension headache	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Tongue paralysis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Transient ischaemic attack	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Tremor	5/509 (1%)		0/125 (0%)		2/124 (1.6%)
Trigeminal neuralgia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Seventh nerve paralysis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Psychiatric disorders
Abnormal dreams	7/509 (1.4%)		0/125 (0%)		1/124 (0.8%)
Agitation	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Anxiety	16/509 (3.1%)		1/125 (0.8%)		1/124 (0.8%)
Apathy	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Bruxism	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Confusional state	10/509 (2%)		4/125 (3.2%)		1/124 (0.8%)
Delirium	3/509 (0.6%)		1/125 (0.8%)		1/124 (0.8%)
Depressed mood	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Depression	11/509 (2.2%)		1/125 (0.8%)		5/124 (4%)
Disorientation	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Emotional disorder	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Flat affect	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hallucination	2/509 (0.4%)		1/125 (0.8%)		0/124 (0%)
Initial insomnia	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mood altered	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Insomnia	37/509 (7.3%)		6/125 (4.8%)		5/124 (4%)
Mood swings	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Nightmare	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Sleep disorder	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Stress	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal and urinary disorders
Bladder dysfunction	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Bladder pain	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Calculus bladder	4/509 (0.8%)		1/125 (0.8%)		0/124 (0%)
Bladder spasm	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Calculus ureteric	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dysuria	12/509 (2.4%)		1/125 (0.8%)		5/124 (4%)
Haemorrhage urinary tract	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Haematuria	18/509 (3.5%)		6/125 (4.8%)		11/124 (8.9%)
Hydronephrosis	3/509 (0.6%)		1/125 (0.8%)		1/124 (0.8%)
Incontinence	7/509 (1.4%)		2/125 (1.6%)		1/124 (0.8%)
Micturition urgency	6/509 (1.2%)		0/125 (0%)		0/124 (0%)
Lower urinary tract symptoms	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Nephrolithiasis	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Pollakiuria	12/509 (2.4%)		2/125 (1.6%)		4/124 (3.2%)
Polyuria	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Nocturia	18/509 (3.5%)		1/125 (0.8%)		4/124 (3.2%)
Prerenal failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal colic	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal impairment	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Renal failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Strangury	1/509 (0.2%)		1/125 (0.8%)		2/124 (1.6%)
Ureteric obstruction	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Urethral dilatation	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Urethral pain	1/509 (0.2%)		2/125 (1.6%)		0/124 (0%)
Urethral stenosis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Urethritis noninfective	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Urge incontinence	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Urinary hesitation	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Urinary incontinence	16/509 (3.1%)		2/125 (1.6%)		1/124 (0.8%)
Urinary retention	8/509 (1.6%)		2/125 (1.6%)		2/124 (1.6%)
Urine odour abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Urinary tract obstruction	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Reproductive system and breast disorders
Balanitis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Breast pain	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Breast tenderness	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Genital rash	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Gynaecomastia	9/509 (1.8%)		0/125 (0%)		1/124 (0.8%)
Pelvic pain	8/509 (1.6%)		2/125 (1.6%)		3/124 (2.4%)
Perineal pain	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Prostatic pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Prostatitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pruritus genital	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Scrotal pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Allergic sinusitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Alveolitis	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Asthma	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Atelectasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cough	27/509 (5.3%)		5/125 (4%)		8/124 (6.5%)
Dysphonia	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Dyspnoea	36/509 (7.1%)		5/125 (4%)		5/124 (4%)
Dyspnoea exertional	7/509 (1.4%)		1/125 (0.8%)		0/124 (0%)
Dyspnoea paroxysmal nocturnal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Epistaxis	9/509 (1.8%)		3/125 (2.4%)		2/124 (1.6%)
Emphysema	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Haemoptysis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hiccups	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Interstitial lung disease	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Laryngeal disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Laryngeal erythema	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Laryngeal oedema	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Lung infiltration	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Nasal congestion	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Nasal obstruction	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Oropharyngeal pain	8/509 (1.6%)		1/125 (0.8%)		1/124 (0.8%)
Pleural effusion	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Pneumonia aspiration	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Pleuritic pain	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pneumothorax	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Productive cough	3/509 (0.6%)		0/125 (0%)		1/124 (0.8%)
Pulmonary fibrosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pulmonary embolism	3/509 (0.6%)		0/125 (0%)		2/124 (1.6%)
Pulmonary mass	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rales	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Respiratory failure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Respiration abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rhinorrhoea	2/509 (0.4%)		2/125 (1.6%)		0/124 (0%)
Rhonchi	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sleep apnoea syndrome	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Sinus disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Sneezing	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Wheezing	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Skin and subcutaneous tissue disorders
Actinic keratosis	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Actinic prurigo	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Alopecia	11/509 (2.2%)		0/125 (0%)		0/124 (0%)
Blister	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Cold sweat	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Cutaneous lupus erythematosus	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dermal cyst	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Decubitus ulcer	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Dermatitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dermatitis acneiform	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Diabetic foot	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dermatitis contact	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dry skin	5/509 (1%)		0/125 (0%)		2/124 (1.6%)
Eczema	5/509 (1%)		0/125 (0%)		0/124 (0%)
Granuloma annulare	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Erythema	3/509 (0.6%)		1/125 (0.8%)		0/124 (0%)
Haemorrhage subcutaneous	0/509 (0%)		0/125 (0%)		1/124 (0.8%)
Hair growth abnormal	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hypertrichosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Hyperhidrosis	11/509 (2.2%)		2/125 (1.6%)		0/124 (0%)
Intertrigo	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Miliaria	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Nail disorder	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Night sweats	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Onychoclasis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Pain of skin	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Penile ulceration	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Panniculitis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Petechiae	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Photodermatosis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Psoriasis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Pruritus	8/509 (1.6%)		0/125 (0%)		0/124 (0%)
Rash	14/509 (2.8%)		6/125 (4.8%)		4/124 (3.2%)
Rash erythematous	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Rash macular	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Rash maculo-papular	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Rash papular	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Rash pruritic	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Skin exfoliation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Skin lesion	4/509 (0.8%)		1/125 (0.8%)		1/124 (0.8%)
Skin ulcer	2/509 (0.4%)		2/125 (1.6%)		0/124 (0%)
Sticky skin	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Urticaria	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Swelling face	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Social circumstances
Physical assault	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Surgical and medical procedures
Cataract operation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Dupuytren's contracture operation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Endodontic procedure	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Glaucoma surgery	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Mole excision	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Nasal polypectomy	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Peripheral nerve decompression	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Pterygium operation	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Skin neoplasm excision	2/509 (0.4%)		0/125 (0%)		1/124 (0.8%)
Tendon sheath incision	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Tooth extraction	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Vascular disorders
Aortic aneurysm	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Deep vein thrombosis	3/509 (0.6%)		1/125 (0.8%)		1/124 (0.8%)
Haematoma	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Flushing	3/509 (0.6%)		0/125 (0%)		0/124 (0%)
Haemorrhage	1/509 (0.2%)		1/125 (0.8%)		0/124 (0%)
Hot flush	90/509 (17.7%)		6/125 (4.8%)		3/124 (2.4%)
Hypotension	9/509 (1.8%)		0/125 (0%)		3/124 (2.4%)
Hypertension	43/509 (8.4%)		24/125 (19.2%)		9/124 (7.3%)
Lymphoedema	1/509 (0.2%)		0/125 (0%)		1/124 (0.8%)
Orthostatic hypotension	4/509 (0.8%)		0/125 (0%)		0/124 (0%)
Peripheral coldness	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Peripheral artery thrombosis	0/509 (0%)		1/125 (0.8%)		0/124 (0%)
Phlebitis	2/509 (0.4%)		0/125 (0%)		0/124 (0%)
Phlebitis superficial	1/509 (0.2%)		0/125 (0%)		0/124 (0%)
Thrombosis	1/509 (0.2%)		0/125 (0%)		0/124 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.