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Clinical Trial Results:
PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Summary
EudraCT number	2012-005665-12
Trial protocol	SE IT AT BE GB SK FI NL ES GR FR DK DE
Global end of trial date

Results information
Results version number	v2(current)
This version publication date	31 Oct 2020
First version publication date	15 Jul 2018
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

C3431005

ISRCTN number

US NCT number

NCT02003924

WHO universal trial number (UTN)

Other trial identifiers

MDV3100-14: Alias Study Number

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

15 Oct 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Jun 2017

Global end of trial reached?

Main objective of the trial

To determine the efficacy of enzalutamide compared with placebo as assessed by Metastasis-free survival (MFS).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Nov 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

7 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 99

Country: Number of subjects enrolled

United States: 105

Country: Number of subjects enrolled

Austria: 7

Country: Number of subjects enrolled

Belgium: 12

Country: Number of subjects enrolled

Denmark: 83

Country: Number of subjects enrolled

Finland: 33

Country: Number of subjects enrolled

France: 103

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Greece: 42

Country: Number of subjects enrolled

Italy: 58

Country: Number of subjects enrolled

Netherlands: 12

Country: Number of subjects enrolled

Poland: 35

Country: Number of subjects enrolled

Russian Federation: 23

Country: Number of subjects enrolled

Serbia: 13

Country: Number of subjects enrolled

Slovakia: 47

Country: Number of subjects enrolled

Spain: 47

Country: Number of subjects enrolled

Sweden: 30

Country: Number of subjects enrolled

Turkey: 14

Country: Number of subjects enrolled

Ukraine: 52

Country: Number of subjects enrolled

United Kingdom: 70

Country: Number of subjects enrolled

Argentina: 12

Country: Number of subjects enrolled

Australia: 136

Country: Number of subjects enrolled

Brazil: 104

Country: Number of subjects enrolled

Chile: 12

Country: Number of subjects enrolled

China: 79

Country: Number of subjects enrolled

Hong Kong: 10

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 54

Country: Number of subjects enrolled

Malaysia: 8

Country: Number of subjects enrolled

New Zealand: 27

Country: Number of subjects enrolled

Singapore: 3

Country: Number of subjects enrolled

Taiwan: 48

Country: Number of subjects enrolled

Thailand: 14

Worldwide total number of subjects

1401

EEA total number of subjects

588

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

190

From 65 to 84 years

1108

85 years and over

103

Subject disposition

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Recruitment details

Screening details

The study was conducted at 254 sites in 32 countries. Data reported based on primary analysis date (28 June 2017).

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Enzalutamide 160 mg

Arm description

Subjects received 4 capsules of Enzalutamide 40 mg each (total dose 160 mg per day) orally, once daily in double-blind and open-label phase (up to a maximum of 68.8 months) until radiographic progression. Subjects after last dose of study drug, were followed up for safety up to 30 days, and were long term followed up (for survival status and new prostate cancer therapies) from last dose to the death date or last known survival date.

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

MDV3100

Other name

Xtandi

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Four capsules of Enzalutamide 40 mg each (total dose 160 mg per day) orally, once daily.

Placebo

Arm description

Subjects received 4 capsules of placebo (matched to Enzalutamide) orally, once daily in double blind phase (up to a maximum of 51.3 months) until radiographic progression. Subjects were given an opportunity to switch to open-label enzalutamide after completion of double blind phase. Subjects after last dose of study drug, were followed up for safety up to 30 days and were long term followed up (for survival status and new prostate cancer therapies) to the death date or last known survival date.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Four capsules of Placebo (matched to Enzalutamide) orally, once daily.

Placebo Subjects Crossover to Enzalutamide 160 mg

Arm description

Subjects who received placebo in double-blind phase and who agreed to proceed to open-label phase, received 4 capsules of Enzalutamide 40 mg each (total dose of 160 mg per day), orally once daily (up to a maximum of 18.8 months) until radiographic progression. Subjects after last dose of study drug, were followed up for safety up to 30 days and were long term followed up (for survival status and new prostate cancer therapies) to the death date or last known survival date.

Arm type

Experimental

Investigational medicinal product name

Enzalutamide

Investigational medicinal product code

MDV3100

Other name

Xtandi

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Four capsules of Enzalutamide 40 mg each (total dose 160 mg per day) orally, once daily.

Number of subjects in period 1	Enzalutamide 160 mg	Placebo	Placebo Subjects Crossover to Enzalutamide 160 mg
Started	933	468	87
Treated in double blind phase	930	465	0 ^[1]
Completed in double-blind phase	478 ^[2]	87 ^[3]	0 ^[4]
Treated in open label phase	478 ^[5]	0 ^[6]	87
Completed in open label phase	378 ^[7]	0 ^[8]	70 ^[9]
Completed	566	231	80
Not completed	367	237	7
Withdrew Consent to Be Followed	66	55	1
Death	288	174	4
Unspecified	5	2	1
Lost to follow-up	8	6	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects in Enzalutamide 160 mg continued treatment in double blind and open-label phase. Subjects in placebo arm received treatment only in double blind phase and after protocol amendment they had an opportunity to receive open label Enzalutamide 160 mg. Subjects who discontinued treatment were followed up in long term phase.

Baseline characteristics

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Reporting group title

Overall period

Reporting group description

All subjects those who were randomized.

Reporting group values	Overall period	Total
Number of subjects	1401	1401
Age categorical
The intent-to-treat (ITT) population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.
Units: Subjects
Adults (18-64 years)	190	190
From 65-84 years	1108	1108
85 years and over	103	103
Age Continuous
The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.
Units: years
arithmetic mean (standard deviation)	73.5 ± 7.77	-
Sex: Female, Male
The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.
Units: Subjects
Female	0	0
Male	1401	1401
Race/Ethnicity, Customized
The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.
Units: Subjects
Asian	230	230
Black or African American	31	31
Native Hawaiian or Other Pacific Islander	5	5
White	991	991
Multiple	8	8
Other	20	20
Missing	116	116

End points

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Reporting group title

Enzalutamide 160 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Placebo Subjects Crossover to Enzalutamide 160 mg

Reporting group description

Primary: Metastasis Free Survival (MFS)

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End point title

Metastasis Free Survival (MFS) ^[1]

End point description

MFS:time from randomization to first date of radiographic progression (RP) at any time or death within 112 days of treatment discontinuation without evidence of RP.RP for bone disease:appearance of 1 or more metastatic lesions on bone scan.RP for soft tissue disease:per RECIST,v1.1-at least 20% increase in the sum of diameters of target lesions,reference to smallest sum on study.Subjects who did not have MFS event at the time of analysis data cut-off (28 June 2017) were censored at date of last assessment showing no objective evidence of RP prior to skeletal-related event or two or more consecutive missed tumor assessments. Subjects randomized but later confirmed to have metastatic disease before randomization were censored on date of randomization.ITT population:subjects randomly assigned to study treatment and based on randomized treatment assignment regardless of whether or not treatment was administered.The upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Primary

End point timeframe

From randomization until radiographic progression at any time, or death within 112 days of treatment discontinuation, whichever occurred first (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	36.6 (33.1 to 99999)	14.7 (14.2 to 15.0)

Enzalutamide 160 mg Vs. Placebo

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.292

Confidence interval

level

95%

sides

2-sided

lower limit

0.241

upper limit

0.352

Notes
[2] - P-value was based on stratified log-rank test by prostate-specific antigen (PSA) doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no). Threshold for significance at 0.05 level.

Secondary: Time to Prostate-Specific Antigen (PSA) Progression

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End point title

Time to Prostate-Specific Antigen (PSA) Progression ^[3]

End point description

Time to PSA progression:time from randomization to the date of first PSA value indicating progression,which was subsequently confirmed. For subjects with PSA decline at Week 17,PSA progression was defined according to PCWG2 guidelines as date that a 25% or greater increase and an absolute increase of 2 nanograms per milliliter (ng/mL) above the nadir (or baseline for subjects with no PSA decline by Week 17) was documented, which was confirmed by a second consecutive value obtained at least 3 weeks or later.Subjects without confirmed PSA progression at the time of analysis were right censored at the date of last PSA assessment before the analysis data cut-off date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates.ITT population:all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Secondary

End point timeframe

From randomization until first PSA progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	37.2 (33.1 to 99999)	3.9 (3.8 to 4.0)

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

To maintain the family-wise 2-sided type I error rate at 0.05, a parallel testing strategy between OS (with allocated type I error rate 0.03) and remaining key secondary endpoints (time to PSA progression and time to first use of new antineoplastic therapy with allocated type I error rate 0.02) was performed. Testing was performed only if the primary endpoint was statistically significant.

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

0.054

upper limit

0.081

Notes
[4] - P-value was based on a stratified log-rank test by PSA doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no) as per IXRS. Threshold for significance at 0.02 level.

Secondary: Time to First Use of New Antineoplastic Therapy

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End point title

Time to First Use of New Antineoplastic Therapy ^[5]

End point description

Time to first use of new antineoplastic therapy was defined as the time from randomization to first use of new antineoplastic for prostate cancer. Subjects not starting treatment with a new antineoplastic therapy at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Secondary

End point timeframe

From randomization until first use of new antineoplastic therapy(until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	39.6 (37.7 to 99999)	17.7 (16.2 to 19.7)

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.208

Confidence interval

level

95%

sides

2-sided

lower limit

0.168

upper limit

0.258

Notes
[6] - P-value was based on a stratified log-rank test by PSA doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no) as per IXRS. Threshold for significance at 0.02 level.

Secondary: Overall Survival

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End point title

Overall Survival ^[7]

End point description

Overall survival (OS) was defined as the time (in months) from randomization to death from any cause. For subjects who were alive at the time of the analysis data cutoff, OS time was censored at the last date the subject was known to be alive or analysis data cutoff date, whichever was earlier. Subjects with no post baseline survival information were censored on the date of randomization. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The upper limit of 95% CI was not reached and has been denoted as '99999'.

End point type

Secondary

End point timeframe

From randomization until death (up to a maximum of 68.8 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	67.0 (64.0 to 99999)	56.3 (54.4 to 63.0)

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

To maintain family-wise 2-sided type I error rate at 0.05,parallel testing strategy between OS(with allocated type I error rate 0.03)and remaining key secondary endpoints(time to PSA progression and time to first use of new antineoplastic therapy with allocated type I error rate 0.02)was performed.OS tested at error rate 0.05 when both time to PSA progression and time to first use of new antineoplastic therapy were significant. When either failed to show significance.OS was tested at error 0.03.

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0011 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.734

Confidence interval

level

95%

sides

2-sided

lower limit

0.608

upper limit

0.885

Notes
[8] - P-value was based on a stratified log-rank test by PSA doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no) as per interactive voice/web recognition system (IXRS).

Secondary: Time to Pain Progression

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End point title

Time to Pain Progression ^[9]

End point description

Pain was assessed using the score from the Brief Pain Inventory-Short Form (BPI-SF) question 3: “Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 24 hours.” Time to this event was defined as the time from randomization to onset of pain progression, where pain progression was defined as a 2-point or more increase from baseline in the question 3 score. Subjects without observed pain progression at the time of analysis were right censored at the date of last pain assessment for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.

End point type

Secondary

End point timeframe

From randomization until onset of pain progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	18.5 (17.0 to 22.1)	18.4 (14.8 to 22.1)

Enzalutamide 160 mg Vs. Placebo

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6534 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.959

Confidence interval

level

95%

sides

2-sided

lower limit

0.801

upper limit

1.149

Notes
[10] - P-value was based on a stratified log-rank test by PSA doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no) as per IXRS.

Secondary: Time to First Use of Cytotoxic Chemotherapy

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End point title

Time to First Use of Cytotoxic Chemotherapy ^[11]

End point description

Time to first use of cytotoxic chemotherapy was defined as the time from randomization to the first use of cytotoxic chemotherapy for prostate cancer. Subjects not starting treatment with a cytotoxic chemotherapy for prostate cancer at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The median and upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Secondary

End point timeframe

From randomization up to the first use of cytotoxic chemotherapy (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	99999 (38.1 to 99999)	39.7 (38.9 to 41.3)

Enzalutamide 160 mg Vs. Placebo

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.378

Confidence interval

level

95%

sides

2-sided

lower limit

0.282

upper limit

0.507

Notes
[12] - P-value was based on a stratified log-rank test by PSA doubling time (< 6 months, >= 6 months) and prior or concurrent use of a bone targeting agent (yes, no) as per IXRS.

Secondary: Chemotherapy-Free Disease Specific Survival

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End point title

Chemotherapy-Free Disease Specific Survival ^[13]

End point description

Chemotherapy-free disease-specific survival was defined as the time from randomization to first use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer as assessed by the investigator. Subjects not starting treatment with a cytotoxic chemotherapy or not known to have died due to prostate cancer at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Secondary

End point timeframe

From randomization up to first use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	39.6 (37.7 to 99999)	38.9 (30.9 to 41.3)

No statistical analyses for this end point

Secondary: Chemotherapy-Free Survival

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End point title

Chemotherapy-Free Survival ^[14]

End point description

Chemotherapy-free survival was defined as the time from randomization to first use of cytotoxic chemotherapy for prostate cancer or death due to any cause. Subjects not starting treatment with a cytotoxic chemotherapy or not known to have died at the time of analysis were censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. The upper limit of 95% CI was not reached and has been denoted as 99999.

End point type

Secondary

End point timeframe

From randomization up to first use of cytotoxic chemotherapy for prostate cancer or death due to any cause (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: months
median (confidence interval 95%)	38.1 (37.7 to 99999)	34.0 (30.3 to 39.7)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Prostate Specific Antigen (PSA) Response

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End point title

Percentage of Subjects With Prostate Specific Antigen (PSA) Response ^[15]

End point description

PSA response was calculated at each visit as a decline from baseline in PSA (ng/mL) to the maximal PSA response with thresholds at 50% and 90%. Additionally, PSA response was assessed as a decline to undetectable levels, where undetectable level was defined as below the limit of quantification of the centrally assessed PSA results (the lower limit of quantification was 0.02 ng/mL). PSA response was confirmed by a second consecutive value at least 3 weeks later. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered.

End point type

Secondary

End point timeframe

From randomization until first PSA progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: percentage of subjects
number (confidence interval 95%)
Decrease from Baseline >= 50%	76.3 (73.5 to 79.0)	2.4 (1.2 to 4.2)
Decrease from Baseline >= 90%	55.9 (52.7 to 59.2)	0.4 (0.1 to 1.5)
Decrease to Undetectable Level	9.6 (7.8 to 11.7)	0.0 (0 to 0.8)

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

Decrease from Baseline >= 50%

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rate

Point estimate

73.96

Confidence interval

level

95%

sides

2-sided

lower limit

70.91

upper limit

77.02

Notes
[16] - P-value was based on a Cochran-Mantel-Haenszel mean score test stratified by PSA doubling time (<6 months, >= 6 months) and prior concurrent use of a bone targeting agent (yes, no) as per IXRS.

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

Decrease from Baseline >= 90%

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[17]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rate

Point estimate

55.52

Confidence interval

level

95%

sides

2-sided

lower limit

52.28

upper limit

58.76

Notes
[17] - P-value was based on a Cochran-Mantel-Haenszel mean score test stratified by PSA doubling time (<6 months, >= 6 months) and prior concurrent use of a bone targeting agent (yes, no) as per IXRS.

Enzalutamide 160 mg Vs. Placebo

Statistical analysis description

Decrease to Undetectable Level

Comparison groups

Enzalutamide 160 mg v Placebo

Number of subjects included in analysis

1401

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[18]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Response Rate

Point estimate

9.65

Confidence interval

level

95%

sides

2-sided

lower limit

7.75

upper limit

11.54

Notes
[18] - P-value was based on a Cochran-Mantel-Haenszel mean score test stratified by PSA doubling time (<6 months, >= 6 months) and prior concurrent use of a bone targeting agent (yes, no) as per IXRS.

Secondary: Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score

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End point title

Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score ^[19]

End point description

The FACT-P questionnaire is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess subject function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess prostate-related symptoms. Each item was 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 ranged from 0 to 156 where higher scores represented better quality of life. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points. Standard deviation was not analyzed since only 1 subject was evaluable and has been denoted by '99999'.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: units on a scale
arithmetic mean (standard deviation)
Baseline(n=887,439)	119.5 ± 17.75	120.8 ± 16.73
Change at Week 17(n=815,403)	-4.0 ± 14.03	-3.0 ± 13.87
Change at Week 33(n=718,329)	-4.6 ± 14.82	-3.5 ± 13.74
Change at Week 49(n=621,239)	-3.9 ± 14.70	-5.0 ± 15.71
Change at Week 65(n=522,183)	-4.0 ± 15.84	-5.7 ± 15.04
Change at Week 81(n=427,139)	-4.1 ± 15.01	-7.5 ± 16.42
Change at Week 97(n=354,90)	-4.9 ± 15.31	-5.9 ± 15.80
Change at Week 113(n=264,68)	-5.5 ± 16.07	-5.8 ± 13.16
Change at Week 129(n=186,37)	-6.3 ± 17.33	-8.1 ± 13.99
Change at Week 145(n=109,17)	-5.5 ± 18.75	-9.8 ± 15.47
Change at Week 161(n=38,6)	-8.9 ± 19.88	-7.0 ± 10.95
Change at Week 177(n=5,1)	-4.8 ± 13.19	-5.0 ± 99999

No statistical analyses for this end point

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Mobility Domain Score

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End point title

Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Mobility Domain Score ^[20]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of subjects with various responses to the mobility questionnaire are reported. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline-No problem in walking(n=884,439)	578	298
Baseline-slight problem in walking(n=884,439)	183	100
Baseline-moderate problem in walking(n=884,439)	100	33
Baseline-severe problem in walking(n=884,439)	21	7
Baseline-unable to walk(n=884,439)	2	1
Week 17-no problem in walking(n=840,419)	526	274
Week 17-slight problem in walking(n=840,419)	190	88
Week 17-moderate problem in walking(n=840,419)	87	50
Week 17-severe problem in walking(n=840,419)	32	6
Week 17-unable to walk(n=840,419)	5	1
Week 33-no problem in walking(n=738,342)	431	223
Week 33-slight problem in walking(n=738,342)	162	85
Week 33-moderate problem in walking(n=738,342)	103	24
Week 33-severe problem in walking(n=738,342)	36	10
Week 33-unable to walk(n=738,342)	6	0
Week 49-no problem in walking(n=635,250)	362	156
Week 49-slight problem in walking(n=635,250)	158	57
Week 49-moderate problem in walking(n=635,250)	86	27
Week 49-severe problem in walking(n=635,250)	25	8
Week 49-unable to walk(n=635,250)	4	2
Week 65-no problem in walking(n=536,193)	319	121
Week 65-slight problem in walking(n=536,193)	109	44
Week 65-moderate problem in walking(n=536,193)	75	22
Week 65-severe problem in walking(n=536,193)	29	6
Week 65-unable to walk(n=536,193)	4	0
Week 81-no problem in walking(n=435,148)	236	88
Week 81-slight problem in walking(n=435,148)	111	39
Week 81-moderate problem in walking(n=435,148)	61	15
Week 81-severe problem in walking(n=435,148)	26	4
Week 81-unable to walk(n=435,148)	1	2
Week 97-no problem in walking(n=365,95)	189	59
Week 97-slight problem in walking(n=365,95)	94	24
Week 97-moderate problem in walking(n=365,95)	54	8
Week 97-severe problem in walking(n=365,95)	22	4
Week 97-unable to walk(n=365,95)	6	0
Week 113-no problem in walking(n=275,73)	140	45
Week 113-slight problem in walking(n=275,73)	76	14
Week 113-moderate problem in walking(n=275,73)	41	11
Week 113-severe problem in walking(n=275,73)	14	2
Week 113-unable to walk(n=275,73)	4	1
Week 129-no problem in walking(n=193,41)	94	26
Week 129-slight problem in walking(n=193,41)	48	9
Week 129-moderate problem in walking(n=193,41)	36	5
Week 129-severe problem in walking(n=193,41)	15	1
Week 129-unable to walk(n=193,41)	0	0
Week 145-no problem in walking(n=116,21)	56	13
Week 145-slight problem in walking(n=116,21)	35	5
Week 145-moderate problem in walking(n=116,21)	18	2
Week 145-severe problem in walking(n=116,21)	7	1
Week 145-unable to walk(n=116,21)	0	0
Week 161-no problem in walking(n=40,8)	22	2
Week 161-slight problem in walking(n=40,8)	7	5
Week 161-moderate problem in walking(n=40,8)	6	1
Week 161-severe problem in walking(n=40,8)	5	0
Week 161-unable to walk(n=40,8)	0	0
Week 177-no problem in walking(n=6,1)	3	0
Week 177-slight problem in walking(n=6,1)	2	1
Week 177-moderate problem in walking(n=6,1)	1	0
Week 177-severe problem in walking(n=6,1)	0	0
Week 177-unable to walk(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Self-Care Domain Score

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End point title

Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Self-Care Domain Score ^[21]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ VAS. EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of subjects with various responses to the self-care questionnaire are reported. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline (B), Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
B:no problems washing/dressing(n=884,439)	805	415
B:slight problems washing/dressing(n=884,439)	51	23
B:moderate problems washing/dressing(n=884,439)	22	1
B:severe problems washing/dressing(n=884,439)	2	0
B:unable to wash/dress(n=884,439)	4	0
Week 17:no problems washing/dressing(n=840,419)	752	388
Week 17:slightproblems washing/dressing(n=840,419)	60	26
Week17:moderateproblems wash/dressing(n=840,419)	21	5
Week 17:severe problems wash/dressing(n=840,419)	6	0
Week 17:unable to wash/dress(n=840,419)	1	0
Week 33:no problems washing/dressing(n=738,342)	642	310
Week 33:slight problems wash/dressing(n=738,342)	64	20
Week 33:moderate problems wash/dressing(n=738,342)	21	10
Week 33:severe problems wash/dressing(n=738,342)	4	1
Week 33:unable to wash/dress(n=738,342)	7	1
Week 49:no problems washing/dressing(n=635,250)	546	230
Week 49:slight problems wash/dressing(n=635,250)	59	9
Week 49:moderate problems wash/dressing(n=635,250)	23	7
Week 49:severe problems wash/dressing(n=635,250)	3	3
Week 49:unable to wash/dress(n=635,250)	4	1
Week 65:no problems wash/dressing(n=536,193)	453	179
Week 65:slight problems wash/dressing(n=536,193)	57	11
Week 65:moderate problems wash/dressing(n=536,193)	14	3
Week 65:severe problems wash/dressing(n=536,193)	9	0
Week 65:unable to wash/dress(n=536,193)	3	0
Week 81:no problems wash/dressing(n=435,148)	356	132
Week 81:slight problems wash/dressing(n=435,148)	57	11
Week 81:moderate problems wash/dressing(n=435,148)	17	3
Week 81:severe problems wash/dressing(n=435,148)	3	1
Week 81:unable to wash/dress(n=435,148)	2	1
Week 97:no problems wash/dressing(n=365,95)	292	85
Week 97:slight problems wash/dressing(n=365,95)	51	8
Week 97:moderate problems wash/dressing(n=365,95)	16	2
Week 97:severe problems wash/dressing(n=365,95)	1	0
Week 97:unable to wash/dress(n=365,95)	5	0
Week 113:no problems wash/dressing(n=275,73)	214	60
Week 113:slight problems wash/dressing(n=275,73)	46	7
Week 113:moderate problems wash/dressing(n=275,73)	11	5
Week 113:severe problems wash/dressing(n=275,73)	0	0
Week 113:unable to wash/dress(n=275,73)	4	1
Week 129:no problems wash/dressing(n=193,41)	147	35
Week 129:slight problems wash/dressing(n=193,41)	28	5
Week 129:moderate problems wash/dressing(n=193,41)	16	1
Week 129:severe problems wash/dressing(n=193,41)	2	0
Week 129:unable to wash/dress(n=193,41)	0	0
Week 145:no problems wash/dressing(n=116,21)	92	15
Week 145:slight problems wash/dressing(n=116,21)	16	5
Week 145:moderate problems wash/dressing(n=116,21)	6	0
Week 145:severe problems wash/dressing(n=116,21)	2	0
Week 145:unable to wash/dress(n=116,21)	0	1
Week 161:no problems wash/dressing(n=40,8)	33	7
Week 161:slight problems wash/dressing(n=40,8)	3	0
Week 161:moderate problems wash/dressing(n=40,8)	2	1
Week 161:severe problems wash/dressing(n=40,8)	1	0
Week 161:unable to wash/dress(n=40,8)	1	0
Week 177:no problems wash/dressing(n=6,1)	3	1
Week 177:slight problems wash/dressing(n=6,1)	3	0
Week 177:moderate problems wash/dressing(n=6,1)	0	0
Week 177:severe problems wash/dressing(n=6,1)	0	0
Week 171:unable to wash/dress(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Usual Activities Domain Score

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End point title

Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Usual Activities Domain Score ^[22]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of subjects with various responses to the usual activities questionnaire are reported. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline (B), Weeks (W) 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
B:no problems doing usual activities(n=884,439)	646	356
B:slightproblems doing usual activities(n=884,439)	167	64
B:moderate problems(n=884,439)	56	14
B:severe problems(n=884,439)	10	5
B:unable to do usual activities(n=884,439)	5	0
W 17:no problems in usual activities(n=840,419)	571	305
W 17:slightproblems in usual activities(n=840,419)	181	89
W 17:moderate problems(n=840,419)	60	24
W 17:severe problems(n=840,419)	21	0
W 17:unable to do usual activities(n=840,419)	7	1
W 33:no problems doing usual activities(n=738,342)	474	249
W 33:slightproblems in usual activities(n=738,342)	170	68
W 33:moderate problems(n=738,342)	68	18
W 33:severe problems(n=738,342)	21	7
W 33:unable to do usual activities(n=738,342)	5	0
W 49:no problems doing usual activities(n=635,250)	418	185
W 49:slightproblems in usual activities(n=635,250)	137	43
W 49:moderate problems(n=635,250)	55	14
W 49:severe problems(n=635,250)	20	6
W 49:unable to do usual activities(n=635,250)	5	2
W 65:no problems doing usual activities(n=536,193)	338	136
W 65:slightproblems in usual activities(n=536,193)	123	42
W 65:moderate problems(n=536,193)	60	11
W 65:severe problems(n=536,193)	5	4
W 65:unable to do usual activities(n=536,193)	10	0
W 81:no problems doing usual activities(n=435,148)	267	106
W 81:slightproblems in usual activities(n=435,148)	105	29
W 81:moderate problems(n=435,148)	49	7
W 81:severe problems(n=435,148)	10	3
W 81:unable to do usual activities(n=435,148)	4	3
W 97:no problems doing usual activities(n=365,95)	224	69
W 97:slightproblems in usual activities(n=365,95)	90	16
W 97:moderate problems(n=365,95)	39	8
W 97:severe problems(n=365,95)	9	0
W 97:unable to do usual activities(n=365,95)	3	2
W 113:no problems doing usual activities(n=275,73)	165	47
W 113:slightproblems in usual activities(n=275,73)	69	16
W 113:moderate problems(n=275,73)	33	6
W 113:severe problems(n=275,73)	5	3
W 113:unable to do usual activities(n=275,73)	3	1
W 129:no problems doing usual activities(n=193,41)	108	30
W 129:slightproblems in usual activities(n=193,41)	56	8
W 129:moderate problems(n=193,41)	26	3
W 129:severe problems(n=193,41)	3	0
W 129:unable to do usual activities(n=193,41)	0	0
W 145:no problems doing usual activities(n=116,21)	67	14
W 145:slightproblems in usual activities(n=116,21)	35	4
W 145:moderate problems(n=116,21)	11	2
W 145:severe problems(n=116,21)	3	1
W 145:unable to do usual activities(n=116,21)	0	0
W 161:no problems doing usual activities(n=40,8)	23	5
W 161:slightproblems in usual activities(n=40,8)	9	2
W 161:moderate problems(n=40,8)	5	1
W 161:severe problems(n=40,8)	2	0
W 161:unable to do usual activities(n=40,8)	1	0
W 177:no problems doing usual activities(n=6,1)	3	0
W 177:slightproblems in usual activities(n=6,1)	2	1
W 177:moderate problems(n=6,1)	1	0
W 177:severe problems(n=6,1)	0	0
W 177:unable to do usual activities(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Pain/Discomfort Domain Score

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End point title

Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Pain/Discomfort Domain Score ^[23]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of subjects with various responses to the pain/discomfort questionnaire are reported The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline (B), Weeks (W) 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
B:no pain or discomfort(n=884,439)	546	292
B:slight pain or discomfort(n=884,439)	240	117
B:moderate pain or discomfort(n=884,439)	86	25
B:severe pain or discomfort(n=884,439)	10	4
B:extreme pain or discomfort(n=884,439)	2	1
W17:no pain or discomfort(n=840,419)	464	248
W17:slight pain or discomfort(n=840,419)	269	128
W17: moderate pain or discomfort(n=840,419)	92	41
W17:severe pain or discomfort(n=840,419)	13	2
W17:extreme pain or discomfort(n=840,419)	2	0
W33:no pain or discomfort(n=738,342)	405	204
W33:slight pain or discomfort(n=738,342)	237	110
W33:moderate pain or discomfort(n=738,342)	79	21
W33:severe pain or discomfort(n=738,342)	16	7
W33:extreme pain or discomfort(n=738,342)	1	0
W49:no pain or discomfort(n=635,250)	340	134
W49:slight pain or discomfort(n=635,250)	209	82
W49:moderate pain or discomfort(n=635,250)	75	32
W49:severe pain or discomfort(n=635,250)	10	1
Week49:extreme pain or discomfort(n=635,250)	1	1
W65:no pain or discomfort(n=536,193)	298	102
W65:slight pain or discomfort(n=536,193)	162	72
W65:moderate pain or discomfort(n=536,193)	61	15
W65:severe pain or discomfort(n=536,193)	11	3
W65:extreme pain or discomfort(n=536,193)	4	1
W81:no pain or discomfort(n=435,148)	231	86
W81:slight pain or discomfort(n=435,148)	133	45
W81:moderate pain or discomfort(n=435,148)	61	13
W81 :severe pain or discomfort(n=435,148)	10	2
W81:extreme pain or discomfort(n=435,148)	0	2
W97:no pain or discomfort(n=365,95)	202	58
W97:slight pain or discomfort(n=365,95)	115	28
W97:moderate pain or discomfort(n=365,95)	43	7
W97:severe pain or discomfort(n=365,95)	5	2
W97:extreme pain or discomfort(n=365,95)	0	0
W113:no pain or discomfort(n=275,73)	152	47
W113:slight pain or discomfort(n=275,73)	80	19
W113:moderate pain or discomfort(n=275,73)	37	5
W113:severe pain or discomfort(n=275,73)	6	2
W113:extreme pain or discomfort(n=275,73)	0	0
W129:no pain or discomfort(n=193,41)	108	27
W129:slight pain or discomfort(n=193,41)	55	11
W129:moderate pain or discomfort(n=193,41)	28	3
W129:severe pain or discomfort(n=193,41)	2	0
W129:extreme pain or discomfort(n=193,41)	0	0
W145:no pain or discomfort(n=116,21)	62	12
W145:slight pain or discomfort(n=116,21)	38	8
W145:moderate pain or discomfort(n=116,21)	15	1
W145:severe pain or discomfort(n=116,21)	1	0
W145:extreme pain or discomfort(n=116,21)	0	0
W161:no pain or discomfort(n=40,8)	24	2
W161:slight pain or discomfort(n=40,8)	8	5
W161:moderate pain or discomfort(n=40,8)	5	1
W161:severe pain or discomfort(n=40,8)	3	0
W161:extreme pain or discomfort(n=40,8)	0	0
W177:no pain or discomfort(n=6,1)	3	0
W177:slight pain or discomfort(n=6,1)	1	1
W177:moderate pain or discomfort(n=6,1)	2	0
W177:severe pain or discomfort(n=6,1)	0	0
W177:extreme pain or discomfort(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Anxiety/ Depression Domain Score

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End point title

Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Anxiety/ Depression Domain Score ^[24]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of subjects with various responses to the anxiety/depression questionnaire are reported. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
B:not anxious or depressed(n=884,439)	595	310
B:slightly anxious or depressed(n=884,439)	231	100
B:moderately anxious or depressed(n=884,439)	51	24
B:severely anxious or depressed(n=884,439)	6	5
B:extremely anxious or depressed(n=884,439)	1	0
W17:not anxious or depressed(n=840,419)	517	265
W17:slightly anxious or depressed(n=840,419)	251	119
W17:moderately anxious or depressed(n=840,419)	62	31
W17:severely anxious or depressed(n=840,419)	7	4
W17:extremely anxious or depressed(n=840,419)	3	0
W33:not anxious or depressed(n=738,342)	458	223
W33:slightly anxious or depressed(n=738,342)	208	89
W33:moderately anxious or depressed(n=738,342)	61	23
W33:severely anxious or depressed(n=738,342)	9	5
W33:extremely anxious or depressed(n=738,342)	2	2
W49:not anxious or depressed(n=635,250)	410	155
W49:slightly anxious or depressed(n=635,250)	172	72
W49:moderately anxious or depressed(n=635,250)	41	20
W49:severely anxious or depressed(n=635,250)	8	2
W49:extremely anxious or depressed(n=635,250)	4	1
W65:not anxious or depressed(n=536,193)	336	128
W65:slightly anxious or depressed(n=536,193)	149	56
W65:moderately anxious or depressed(n=536,193)	43	8
W65:severely anxious or depressed(n=536,193)	8	1
W65:extremely anxious or depressed(n=536,193)	0	0
W81:not anxious or depressed(n=435,148)	288	86
W81:slightly anxious or depressed(n=435,148)	106	48
W81:moderately anxious or depressed(n=435,148)	34	9
W81:severely anxious or depressed(n=435,148)	7	3
W81:extremely anxious or depressed(n=435,148)	0	2
W97:not anxious or depressed(n=365,95)	220	61
W97:slightly anxious or depressed(n=365,95)	114	27
W97:moderately anxious or depressed(n=365,95)	26	6
W97:severely anxious or depressed(n=365,95)	4	0
W97:extremely anxious or depressed(n=365,95)	1	1
W113:not anxious or depressed(n=275,73)	167	43
W113:slightly anxious or depressed(n=275,73)	87	27
W113:moderately anxious or depressed(n=275,73)	18	3
W113:severely anxious or depressed(n=275,73)	3	0
W113:extremely anxious or depressed(n=275,73)	0	0
W129:not anxious or depressed(n=193,41)	121	28
W129:slightly anxious or depressed(n=193,41)	51	10
W129:moderately anxious or depressed(n=193,41)	18	2
W129:severely anxious or depressed(n=193,41)	2	1
W129:extremely anxious or depressed(n=193,41)	1	0
W145:not anxious or depressed(n=116,21)	73	12
W145:slightly anxious or depressed(n=116,21)	30	8
W145:moderately anxious or depressed(n=116,21)	10	1
W145:severely anxious or depressed(n=116,21)	2	0
W145:extremely anxious or depressed(n=116,21)	1	0
W161:not anxious or depressed(n=40,8)	23	3
W161:slightly anxious or depressed(n=40,8)	16	4
W161:moderately anxious or depressed(n=40,8)	0	1
W161:severely anxious or depressed(n=40,8)	0	0
W161:extremely anxious or depressed(n=40,8)	1	0
W177:not anxious or depressed(n=6,1)	2	1
W177:slightly anxious or depressed(n=6,1)	2	0
W177:moderately anxious or depressed(n=6,1)	2	0
W177:severely anxious or depressed(n=6,1)	0	0
W177:extremely anxious or depressed(n=6,1)	0	0

No statistical analyses for this end point

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Status Visual Analog Score (VAS)

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End point title

European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Status Visual Analog Score (VAS) ^[25]

End point description

EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ VAS. EQ-5D-5L-VAS records subject’s self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points. Standard deviation was not analysed since only 1 subject was evaluable and has been denoted by '99999'.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=884,439)	76.2 ± 16.92	77.5 ± 15.97
Week 17 (n=840,419)	74.7 ± 17.19	74.9 ± 16.79
Week 33 (n=738,342)	74.6 ± 16.69	74.0 ± 17.51
Week 49 (n=635,250)	74.7 ± 18.02	73.7 ± 18.28
Week 65 (n=536,193)	74.5 ± 17.79	73.0 ± 17.11
Week 81 (n=435,148)	75.5 ± 17.06	73.3 ± 16.82
Week 97 (n=365,95)	74.4 ± 17.39	75.2 ± 17.88
Week 113 (n=275,73)	73.6 ± 18.05	74.7 ± 15.06
Week 129 (n=193,41)	72.8 ± 18.25	77.1 ± 12.83
Week 145 (n=116,21)	75.3 ± 17.02	74.2 ± 18.13
Week 161 (n=40,8)	74.6 ± 21.28	73.8 ± 17.60
Week 177 (n=6,1)	74.5 ± 19.31	69.0 ± 99999

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 31

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 31 ^[26]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 31 are reported. Question 31 was following: “Have you had to urinate frequently during the day?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	285	162
Baseline: a little(n=884,439)	348	160
Baseline: quite a bit(n=884,439)	207	92
Baseline: very much(n=884,439)	44	25
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	275	134
Week 17: a little(n=839,419)	324	168
Week 17: quite a bit(n=839,419)	194	90
Week 17: very much(n=839,419)	46	27
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	236	105
Week 33: a little(n=737,341)	285	145
Week 33: quite a bit(n=737,341)	176	70
Week 33: very much(n=737,341)	40	21
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	200	82
Week 49: a little(n=635,250)	260	92
Week 49: quite a bit(n=635,250)	148	67
Week 49: very much(n=635,250)	27	9
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	172	54
Week 65: a little(n=536,193)	209	79
Week 65: quite a bit(n=536,193)	125	48
Week 65: very much(n=536,193)	30	12
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	141	46
Week 81: a little(n=434,148)	181	60
Week 81: quite a bit(n=434,148)	92	31
Week 81: very much(n=434,148)	20	11
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	118	33
Week 97: a little(n=365,95)	146	40
Week 97: quite a bit(n=365,95)	80	19
Week 97: very much(n=365,95)	21	3
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	101	17
Week 113: a little(n=275,73)	112	40
Week 113: quite a bit(n=275,73)	46	14
Week 113: very much(n=275,73)	16	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	70	11
Week 129: a little(n=192,41)	79	16
Week 129: quite a bit(n=192,41)	39	10
Week 129: very much(n=192,41)	4	4
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	42	2
Week 145: a little(n=116,21)	51	14
Week 145: quite a bit(n=116,21)	20	4
Week 145: very much(n=116,21)	3	1
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	9	2
Week 161: a little(n=40,8)	20	4
Week 161: quite a bit(n=40,8)	7	1
Week 161: very much(n=40,8)	4	1
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	0	0
Week 177: a little(n=6,1)	4	1
Week 177: quite a bit(n=6,1)	2	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 32

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 32 ^[27]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 32 are reported. Question 32 was following: “Have you had to urinate frequently at night?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	193	108
Baseline: a little(n=884,439)	423	195
Baseline: quite a bit(n=884,439)	200	103
Baseline: very much(n=884,439)	68	33
Baseline: not answered(n=884,439)	0	0
Week 17: not at all (n=839,419)	194	88
Week 17: a little (n=839,419)	407	199
Week 17: quite a bit (n=839,419)	184	98
Week 17: very much (n=839,419)	54	34
Week 17: not answered (n=839,419)	0	0
Week 33: not at all(n=737,341)	173	83
Week 33: a little(n=737,341)	351	161
Week 33: quite a bit(n=737,341)	169	69
Week 33: very much(n=737,341)	44	28
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	148	59
Week 49: a little(n=635,250)	313	116
Week 49: quite a bit(n=635,250)	141	59
Week 49: very much(n=635,250)	33	16
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	118	41
Week 65: a little(n=536,193)	266	89
Week 65: quite a bit(n=536,193)	111	48
Week 65: very much(n=536,193)	41	15
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	91	38
Week 81: a little(n=434,148)	231	60
Week 81: quite a bit(n=434,148)	89	38
Week 81: very much(n=434,148)	23	12
Week 81: not answeredv(n=434,148)	0	0
Week 97: not at all(n=365,95)	88	19
Week 97: a little(n=365,95)	169	53
Week 97: quite a bit(n=365,95)	82	19
Week 97: very much(n=365,95)	26	4
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	67	16
Week 113: a little(n=275,73)	137	32
Week 113: quite a bit(n=275,73)	54	23
Week 113: very much(n=275,73)	17	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	50	9
Week 129: a little(n=192,41)	97	18
Week 129: quite a bit(n=192,41)	37	10
Week 129: very much(n=192,41)	8	4
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	31	2
Week 145: a little(n=116,21)	59	14
Week 145: quite a bit(n=116,21)	24	5
Week 145: very much(n=116,21)	2	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	9	0
Week 161: a little(n=40,8)	23	7
Week 161: quite a bit(n=40,8)	5	0
Week 161: very much(n=40,8)	3	1
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	2	0
Week 177: a little(n=6,1)	2	1
Week 177: quite a bit(n=6,1)	2	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 33

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 33 ^[28]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 33 are reported. Question 33 was following: “When you felt the urge to pass urine, did you have to hurry to get to the toilet?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	406	197
Baseline: a little(n=884,439)	266	147
Baseline: quite a bit(n=884,439)	150	70
Baseline: very much(n=884,439)	62	25
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	350	191
Week 17: a little(n=839,419)	297	150
Week 17: quite a bit(n=839,419)	127	55
Week 17: very much(n=839,419)	65	23
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	279	147
Week 33: a little(n=737,341)	278	126
Week 33: quite a bit(n=737,341)	126	48
Week 33: very much(n=737,341)	54	20
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	272	100
Week 49: a little(n=635,250)	222	95
Week 49: quite a bit(n=635,250)	96	38
Week 49: very much(n=635,250)	45	17
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	213	76
Week 65: a little(n=536,193)	213	72
Week 65: quite a bit(n=536,193)	71	31
Week 65: very much(n=536,193)	39	14
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	181	63
Week 81: a little(n=434,148)	157	52
Week 81: quite a bit(n=434,148)	69	27
Week 81: very much(n=434,148)	27	6
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	146	40
Week 97: a little(n=365,95)	131	40
Week 97: quite a bit(n=365,95)	59	12
Week 97: very much(n=365,95)	29	3
Week 97: not answered(n=365,95)	0	0
Week 113: not at all\|(n=275,73)	114	29
Week 113: a little(n=275,73)	106	34
Week 113: quite a bit(n=275,73)	40	9
Week 113: very much(n=275,73)	15	1
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	86	10
Week 129: a little (n=192,41)	72	21
Week 129: quite a bit(n=192,41)	26	6
Week 129: very much(n=192,41)	8	4
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	51	5
Week 145: a little(n=116,21)	39	12
Week 145: quite a bit(n=116,21)	21	4
Week 145: very much(n=116,21)	5	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	17	0
Week 161: a little(n=40,8)	19	5
Week 161: quite a bit(n=40,8)	3	3
Week 161: very much(n=40,8)	1	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	2	0
Week 177: a little(n=6,1)	1	1
Week 177: quite a bit(n=6,1)	3	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 34

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 34 ^[29]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 34 are reported. Question 34 was following: “Was it difficult for you to get enough sleep, because you needed to get up frequently at night to urinate?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	479	235
Baseline: a little(n=884,439)	273	146
Baseline: quite a bit(n=884,439)	93	40
Baseline: very much(n=884,439)	39	18
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	437	214
Week 17: a little(n=839,419)	295	144
Week 17: quite a bit(n=839,419)	75	45
Week 17: very much(n=839,419)	32	16
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	392	180
Week 33: a little(n=737,341)	246	112
Week 33: quite a bit(n=737,341)	75	33
Week 33: very much(n=737,341)	24	16
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	340	119
Week 49: a little(n=635,250)	211	94
Week 49: quite a bit(n=635,250)	65	28
Week 49: very much(n=635,250)	19	9
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	286	92
Week 65: a little(n=536,193)	183	67
Week 65: quite a bit(n=536,193)	47	29
Week 65: very much(n=536,193)	20	5
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	221	70
Week 81: a little(n=434,148)	165	55
Week 81: quite a bit(n=434,148)	37	18
Week 81: very much(n=434,148)	11	5
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	185	47
Week 97: a little(n=365,95)	122	33
Week 97: quite a bit(n=365,95)	43	14
Week 97: very much(n=365,95)	15	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	135	31
Week 113: a little(n=275,73)	102	33
Week 113: quite a bit(n=275,73)	29	7
Week 113: very much(n=275,73)	9	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	103	13
Week 129: a little(n=192,41)	67	23
Week 129: quite a bit(n=192,41)	19	4
Week 129: very much(n=192,41)	3	1
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	59	9
Week 145: a little(n=116,21)	44	10
Week 145: quite a bit(n=116,21)	11	1
Week 145: very much(n=116,21)	2	1
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	21	2
Week 161: a little(n=40,8)	16	5
Week 161: quite a bit(n=40,8)	3	0
Week 161: very much(n=40,8)	0	1
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	1	1
Week 177: quite a bit(n=6,1)	2	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 35

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 35 ^[30]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 35 are reported. Question 35 was following: “Have you had difficulty going out of the house because you needed to be close to a toilet?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	646	330
Baseline: a little(n=884,439)	177	84
Baseline: quite a bit(n=884,439)	45	18
Baseline: very much(n=884,439)	16	7
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	604	295
Week 17: a little(n=839,419)	174	100
Week 17: quite a bit(n=839,419)	46	15
Week 17: very much(n=839,419)	15	9
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	501	242
Week 33: a little(n=737,341)	171	74
Week 33: quite a bit(n=737,341)	50	20
Week 33: very much(n=737,341)	15	5
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	436	174
Week 49: a little(n=635,250)	153	53
Week 49: quite a bit(n=635,250)	38	20
Week 49: very much(n=635,250)	8	3
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	369	132
Week 65: a little(n=536,193)	125	50
Week 65: quite a bit(n=536,193)	28	9
Week 65: very much(n=536,193)	14	2
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	308	105
Week 81: a little(n=434,148)	94	35
Week 81: quite a bit(n=434,148)	23	8
Week 81: very much(n=434,148)	9	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	241	67
Week 97: a little(n=365,95)	91	21
Week 97: quite a bit(n=365,95)	26	6
Week 97: very much(n=365,95)	7	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	180	47
Week 113: a little(n=275,73)	70	21
Week 113: quite a bit(n=275,73)	18	5
Week 113: very much(n=275,73)	7	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	131	26
Week 129: a little(n=192,41)	48	13
Week 129: quite a bit(n=192,41)	8	1
Week 129: very much(n=192,41)	5	1
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	74	13
Week 145: a little(n=116,21)	36	6
Week 145: quite a bit(n=116,21)	6	0
Week 145: very much(n=116,21)	0	2
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	24	4
Week 161: a little(n=40,8)	13	4
Week 161: quite a bit(n=40,8)	3	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	3	1
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 36

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 36 ^[31]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 36 are reported. Question 36 was following: “Have you had any unintentional release (leakage) of urine?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	550	283
Baseline: a little(n=884,439)	273	124
Baseline: quite a bit(n=884,439)	36	20
Baseline: very much(n=884,439)	25	12
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	511	255
Week 17: a little(n=839,419)	264	126
Week 17: quite a bit(n=839,419)	39	27
Week 17: very much(n=839,419)	25	11
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	428	208
Week 33: a little(n=737,341)	246	104
Week 33: quite a bit(n=737,341)	34	19
Week 33: very much(n=737,341)	29	10
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	369	146
Week 49: a little(n=635,250)	209	78
Week 49: quite a bit(n=635,250)	41	22
Week 49: very much(n=635,250)	16	4
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	307	115
Week 65: a little(n=536,193)	170	66
Week 65: quite a bit(n=536,193)	47	8
Week 65: very much(n=536,193)	12	4
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	248	93
Week 81: a little(n=434,148)	158	41
Week 81: quite a bit(n=434,148)	23	11
Week 81: very much(n=434,148)	5	3
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	195	55
Week 97: a little(n=365,95)	134	33
Week 97: quite a bit(n=365,95)	25	7
Week 97: very much(n=365,95)	11	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	160	42
Week 113: a little(n=275,73)	91	28
Week 113: quite a bit(n=275,73)	17	3
Week 113: very much(n=275,73)	7	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	109	22
Week 129: a little(n=192,41)	68	13
Week 129: quite a bit(n=192,41)	13	5
Week 129: very much(n=192,41)	2	1
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	58	9
Week 145: a little(n=116,21)	45	11
Week 145: quite a bit(n=116,21)	10	0
Week 145: very much(n=116,21)	3	1
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	18	3
Week 161: a little(n=40,8)	21	4
Week 161: quite a bit(n=40,8)	0	1
Week 161: very much(n=40,8)	1	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	1	0
Week 177: a little(n=6,1)	3	1
Week 177: quite a bit(n=6,1)	1	0
Week 177: very much(n=6,1)	1	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 37

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 37 ^[32]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 37 are reported. Question 37 was following: “Did you have pain when you urinated?” The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	775	380
Baseline: a little(n=884,439)	92	47
Baseline: quite a bit(n=884,439)	10	8
Baseline: very much(n=884,439)	7	4
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	762	351
Week 17: a little(n=839,419)	65	58
Week 17: quite a bit(n=839,419)	12	8
Week 17: very much(n=839,419)	0	2
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	662	291
Week 33: a little(n=737,341)	63	39
Week 33: quite a bit(n=737,341)	11	8
Week 33: very much(n=737,341)	1	3
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	577	209
Week 49: a little(n=635,250)	49	34
Week 49: quite a bit(n=635,250)	6	3
Week 49: very much(n=635,250)	3	4
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	492	161
Week 65: a little(n=536,193)	32	29
Week 65: quite a bit(n=536,193)	9	2
Week 65: very much(n=536,193)	3	1
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	389	119
Week 81: a little(n=434,148)	40	27
Week 81: quite a bit(n=434,148)	4	2
Week 81: very much(n=434,148)	1	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	332	84
Week 97: a little(n=365,95)	28	11
Week 97: quite a bit(n=365,95)	4	0
Week 97: very much(n=365,95)	1	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	247	57
Week 113: a little(n=275,73)	26	13
Week 113: quite a bit(n=275,73)	1	3
Week 113: very much(n=275,73)	1	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	173	34
Week 129: a little(n=192,41)	16	7
Week 129: quite a bit(n=192,41)	1	0
Week 129: very much(n=192,41)	2	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	102	15
Week 145: a little(n=116,21)	14	6
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	36	6
Week 161: a little(n=40,8)	3	1
Week 161: quite a bit(n=40,8)	1	1
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	6	0
Week 177: a little(n=6,1)	0	1
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 38

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 38 ^[33]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 38 are reported. Question 38 was following: “Has wearing an incontinence aid been a problem for you?” This question was answered by only those subjects who wore incontinence aid. The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=144,67)	83	37
Baseline: a little(n=144,67)	40	19
Baseline: quite a bit(n=144,67)	15	3
Baseline: very much(n=144,67)	6	8
Baseline: not answered(n=144,67)	0	0
Week 17: not at all(n=839,419)	77	34
Week 17: a little(n=839,419)	48	21
Week 17: quite a bit(n=839,419)	15	7
Week 17: very much(n=839,419)	6	6
Week 17: not answered(n=839,419)	693	351
Week 33: not at all(n=737,341)	76	30
Week 33: a little(n=737,341)	47	28
Week 33: quite a bit(n=737,341)	16	4
Week 33: very much(n=737,341)	5	4
Week 33: not answered(n=737,341)	593	275
Week 49: not at all(n=635,250)	73	18
Week 49: a little(n=635,250)	43	16
Week 49: quite a bit(n=635,250)	12	9
Week 49: very much(n=635,250)	4	2
Week 49: not answered(n=635,250)	503	205
Week 65: not at all(n=536,193)	63	12
Week 65: a little(n=536,193)	40	17
Week 65: quite a bit(n=536,193)	9	5
Week 65: very much(n=536,193)	3	1
Week 65: not answered(n=536,193)	421	158
Week 81: not at all(n=434,148)	52	15
Week 81: a little(n=434,148)	33	9
Week 81: quite a bit(n=434,148)	10	1
Week 81: very much(n=434,148)	3	3
Week 81: not answered(n=434,148)	336	120
Week 97: not at all(n=365,95)	50	8
Week 97: a little(n=365,95)	28	8
Week 97: quite a bit(n=365,95)	7	2
Week 97: very much(n=365,95)	3	0
Week 97: not answered(n=365,95)	277	77
Week 113: not at all(n=275,73)	31	12
Week 113: a little(n=275,73)	18	7
Week 113: quite a bit(n=275,73)	8	2
Week 113: very much(n=275,73)	2	0
Week 113: not answered(n=275,73)	216	52
Week 129: not at all(n=192,41)	27	5
Week 129: a little(n=192,41)	18	5
Week 129: quite a bit(n=192,41)	2	1
Week 129: very much(n=192,41)	0	0
Week 129: not answered(n=192,41)	145	30
Week 145: not at all(n=116,21)	16	2
Week 145: a little(n=116,21)	10	4
Week 145: quite a bit(n=116,21)	5	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	85	15
Week 161: not at all(n=40,8)	10	1
Week 161: a little(n=40,8)	3	2
Week 161: quite a bit(n=40,8)	1	1
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	26	4
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	1	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	2	1

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 39

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 39 ^[34]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 39 are reported. Question 39 was following: “Have your daily activities been limited by your urinary problems?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	666	338
Baseline: a little(n=884,439)	173	80
Baseline: quite a bit(n=884,439)	35	11
Baseline: very much(n=884,439)	10	10
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	632	305
Week 17: a little(n=839,419)	160	99
Week 17: quite a bit(n=839,419)	36	6
Week 17: very much(n=839,419)	11	9
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	523	242
Week 33: a little(n=737,341)	172	79
Week 33: quite a bit(n=737,341)	31	14
Week 33: very much(n=737,341)	11	6
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	444	173
Week 49: a little(n=635,250)	152	58
Week 49: quite a bit(n=635,250)	31	18
Week 49: very much(n=635,250)	8	1
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	382	128
Week 65: a little(n=536,193)	124	51
Week 65: quite a bit(n=536,193)	20	12
Week 65: very much(n=536,193)	10	2
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	310	103
Week 81: a little(n=434,148)	98	35
Week 81: quite a bit(n=434,148)	21	8
Week 81: very much(n=434,148)	5	2
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	242	72
Week 97: a little(n=365,95)	100	18
Week 97: quite a bit(n=365,95)	18	4
Week 97: very much(n=365,95)	5	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	188	54
Week 113: a little(n=275,73)	71	14
Week 113: quite a bit(n=275,73)	13	3
Week 113: very much(n=275,73)	3	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	127	25
Week 129: a little(n=192,41)	55	14
Week 129: quite a bit(n=192,41)	7	1
Week 129: very much(n=192,41)	3	1
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	77	11
Week 145: a little(n=116,21)	34	9
Week 145: quite a bit(n=116,21)	4	1
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	27	2
Week 161: a little(n=40,8)	10	6
Week 161: quite a bit(n=40,8)	3	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	3	1
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 40

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 40 ^[35]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 40 are reported. Question 40 was following: “Have your daily activities been limited by your bowel problems?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	758	393
Baseline: a little(n=884,439)	112	40
Baseline: quite a bit(n=884,439)	9	4
Baseline: very much(n=884,439)	5	2
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	707	352
Week 17: a little(n=839,419)	107	57
Week 17: quite a bit(n=839,419)	19	6
Week 17: very much(n=839,419)	6	4
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	621	292
Week 33: a little(n=737,341)	98	40
Week 33: quite a bit(n=737,341)	14	8
Week 33: very much(n=737,341)	4	1
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	525	211
Week 49: a little(n=635,250)	88	29
Week 49: quite a bit(n=635,250)	20	7
Week 49: very much(n=635,250)	2	3
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	441	165
Week 65: a little(n=536,193)	78	24
Week 65: quite a bit(n=536,193)	11	3
Week 65: very much(n=536,193)	6	1
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	360	121
Week 81: a little(n=434,148)	56	23
Week 81: quite a bit(n=434,148)	17	3
Week 81: very much(n=434,148)	1	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	289	84
Week 97: a little(n=365,95)	58	11
Week 97: quite a bit(n=365,95)	17	0
Week 97: very much(n=365,95)	1	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	219	62
Week 113: a little(n=275,73)	46	11
Week 113: quite a bit(n=275,73)	8	0
Week 113: very much(n=275,73)	2	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	153	36
Week 129: a little(n=192,41)	33	5
Week 129: quite a bit(n=192,41)	5	0
Week 129: very much(n=192,41)	1	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	93	17
Week 145: a little(n=116,21)	19	4
Week 145: quite a bit(n=116,21)	4	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	29	8
Week 161: a little(n=40,8)	9	0
Week 161: quite a bit(n=40,8)	2	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	4	1
Week 177: a little(n=6,1)	2	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 41

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 41 ^[36]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 41 are reported. Question 41 was following: “Have you had any unintentional release (leakage) of stools?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	794	404
Baseline: a little(n=884,439)	78	32
Baseline: quite a bit(n=884,439)	11	2
Baseline: very much(n=884,439)	1	1
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	751	372
Week 17: a little(n=839,419)	79	43
Week 17: quite a bit(n=839,419)	8	3
Week 17: very much(n=839,419)	1	1
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	638	307
Week 33: a little(n=737,341)	92	32
Week 33: quite a bit(n=737,341)	4	1
Week 33: very much(n=737,341)	3	1
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	554	221
Week 49: a little(n=635,250)	73	25
Week 49: quite a bit(n=635,250)	5	4
Week 49: very much(n=635,250)	3	0
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	467	175
Week 65: a little(n=536,193)	57	16
Week 65: quite a bit(n=536,193)	9	1
Week 65: very much(n=536,193)	3	1
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	380	136
Week 81: a little(n=434,148)	51	12
Week 81: quite a bit(n=434,148)	2	0
Week 81: very much(n=434,148)	1	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	315	86
Week 97: a little(n=365,95)	47	9
Week 97: quite a bit(n=365,95)	3	0
Week 97: very much(n=365,95)	0	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	233	66
Week 113: a little(n=275,73)	40	7
Week 113: quite a bit(n=275,73)	2	0
Week 113: very much(n=275,73)	0	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	167	39
Week 129: a little(n=192,41)	25	2
Week 129: quite a bit(n=192,41)	0	0
Week 129: very much(n=192,41)	0	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	93	20
Week 145: a little(n=116,21)	22	1
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	30	8
Week 161: a little(n=40,8)	9	0
Week 161: quite a bit(n=40,8)	0	0
Week 161: very much(n=40,8)	1	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	4	1
Week 177: a little(n=6,1)	2	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 42

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 42 ^[37]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 42 are reported. Question 42 was following: “Have you had blood in your stools?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	836	422
Baseline: a little(n=884,439)	48	17
Baseline: quite a bit(n=884,439)	0	0
Baseline: very much(n=884,439)	0	0
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	801	399
Week 17: a little(n=839,419)	36	18
Week 17: quite a bit(n=839,419)	2	2
Week 17: very much(n=839,419)	0	0
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	707	330
Week 33: a little(n=737,341)	29	11
Week 33: quite a bit(n=737,341)	1	0
Week 33: very much(n=737,341)	0	0
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	608	245
Week 49: a little(n=635,250)	27	5
Week 49: quite a bit(n=635,250)	0	0
Week 49: very much(n=635,250)	0	0
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	514	180
Week 65: a little(n=536,193)	19	13
Week 65: quite a bit(n=536,193)	3	0
Week 65: very much(n=536,193)	0	0
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	420	143
Week 81: a little(n=434,148)	14	4
Week 81: quite a bit(n=434,148)	0	1
Week 81: very much(n=434,148)	0	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	357	93
Week 97: a little(n=365,95)	8	2
Week 97: quite a bit(n=365,95)	0	0
Week 97: very much(n=365,95)	0	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	262	72
Week 113: a little(n=275,73)	13	1
Week 113: quite a bit(n=275,73)	0	0
Week 113: very much(n=275,73)	0	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	186	41
Week 129: a little(n=192,41)	5	0
Week 129: quite a bit(n=192,41)	1	0
Week 129: very much(n=192,41)	0	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all\|=(n=116,21)	114	21
Week 145: a little(n=116,21)	2	0
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	38	8
Week 161: a little(n=40,8)	2	0
Week 161: quite a bit(n=40,8)	0	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	6	1
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 43

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 43 ^[38]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 43 are reported. Question 43 was following: “Did you have a bloated feeling in your abdomen?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	667	320
Baseline: a little(n=884,439)	190	103
Baseline: quite a bit(n=884,439)	22	16
Baseline: very much(n=884,439)	5	0
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	601	283
Week 17: a little(n=839,419)	199	121
Week 17: quite a bit(n=839,419)	31	13
Week 17: very much(n=839,419)	8	2
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	526	235
Week 33: a little(n=737,341)	183	95
Week 33: quite a bit(n=737,341)	22	8
Week 33: very much(n=737,341)	6	3
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	449	174
Week 49: a little(n=635,250)	163	63
Week 49: quite a bit(n=635,250)	20	11
Week 49: very much(n=635,250)	3	2
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	381	135
Week 65: a little(n=536,193)	132	51
Week 65: quite a bit(n=536,193)	19	7
Week 65: very much(n=536,193)	4	0
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	304	103
Week 81: a little(n=434,148)	110	44
Week 81: quite a bit(n=434,148)	18	1
Week 81: very much(n=434,148)	2	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	258	72
Week 97: a little(n=365,95)	87	23
Week 97: quite a bit(n=365,95)	19	0
Week 97: very much(n=365,95)	1	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	199	55
Week 113: a little(n=275,73)	66	18
Week 113: quite a bit(n=275,73)	9	0
Week 113: very much(n=275,73)	1	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	139	25
Week 129: a little(n=192,41)	43	16
Week 129: quite a bit(n=192,41)	8	0
Week 129: very much(n=192,41)	2	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	87	13
Week 145: a little(n=116,21)	24	8
Week 145: quite a bit(n=116,21)	4	0
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	33	6
Week 161: a little(n=40,8)	7	2
Week 161: quite a bit(n=40,8)	0	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	4	0
Week 177: a little(n=6,1)	2	1
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 44

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 44 ^[39]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 44 are reported. Question 44 was following: “Did you have hot flushes?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	374	177
Baseline: a little(n=884,439)	314	166
Baseline: quite a bit(n=884,439)	151	68
Baseline: very much(n=884,439)	45	28
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	265	182
Week 17: a little(n=839,419)	311	153
Week 17: quite a bit(n=839,419)	189	62
Week 17: very much(n=839,419)	74	22
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	253	144
Week 33: a little(n=737,341)	268	116
Week 33: quite a bit(n=737,341)	155	60
Week 33: very much(n=737,341)	61	21
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	227	112
Week 49: a little(n=635,250)	235	94
Week 49: quite a bit(n=635,250)	130	30
Week 49: very much(n=635,250)	43	14
Week 49: not answered\|(n=635,250)	0	0
Week 65: not at all(n=536,193)	203	79
Week 65: a little(n=536,193)	194	77
Week 65: quite a bit(n=536,193)	104	30
Week 65: very much(n=536,193)	35	7
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	175	69
Week 81: a little(n=434,148)	157	58
Week 81: quite a bit(n=434,148)	75	16
Week 81: very much(n=434,148)	27	5
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	155	48
Week 97: a little(n=365,95)	126	34
Week 97: quite a bit(n=365,95)	57	12
Week 97: very much(n=365,95)	27	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	114	33
Week 113: a little(n=275,73)	102	24
Week 113: quite a bit(n=275,73)	44	14
Week 113: very much(n=275,73)	15	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	84	22
Week 129: a little(n=192,41)	74	16
Week 129: quite a bit(n=192,41)	23	3
Week 129: very much(n=192,41)	11	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	45	10
Week 145: a little(n=116,21)	46	10
Week 145: quite a bit(n=116,21)	18	0
Week 145: very much(n=116,21)	7	1
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	18	3
Week 161: a little(n=40,8)	14	3
Week 161: quite a bit(n=40,8)	5	2
Week 161: very much(n=40,8)	3	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	1	1
Week 177: very much(n=6,1)	2	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 45

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 45 ^[40]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 45 are reported. Question 45 was following: “Have you had sore or enlarged nipples or breasts?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	688	333
Baseline: a little(n=884,439)	146	80
Baseline: quite a bit(n=884,439)	38	24
Baseline: very much(n=884,439)	12	2
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	626	315
Week 17: a little(n=839,419)	160	80
Week 17: quite a bit(n=839,419)	39	18
Week 17: very much(n=839,419)	14	6
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	526	260
Week 33: a little(n=737,341)	164	62
Week 33: quite a bit(n=737,341)	34	15
Week 33: very much(n=737,341)	13	4
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	444	188
Week 49: a little(n=635,250)	138	52
Week 49: quite a bit(n=635,250)	41	5
Week 49: very much(n=635,250)	12	5
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	371	149
Week 65: a little(n=536,193)	119	37
Week 65: quite a bit(n=536,193)	31	7
Week 65: very much(n=536,193)	15	0
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	306	115
Week 81: a little(n=434,148)	84	26
Week 81: quite a bit(n=434,148)	34	6
Week 81: very much(n=434,148)	10	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	239	80
Week 97: a little(n=365,95)	92	13
Week 97: quite a bit(n=365,95)	30	1
Week 97: very much(n=365,95)	4	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	190	55
Week 113: a little(n=275,73)	62	12
Week 113: quite a bit(n=275,73)	19	5
Week 113: very much(n=275,73)	4	1
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	128	30
Week 129: a little(n=192,41)	51	8
Week 129: quite a bit(n=192,41)	9	3
Week 129: very much(n=192,41)	4	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	78	17
Week 145: a little(n=116,21)	29	3
Week 145: quite a bit(n=116,21)	7	1
Week 145: very much(n=116,21)	2	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	26	4
Week 161: a little(n=40,8)	11	3
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	2	1
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	2	0
Week 177: a little(n=6,1)	2	1
Week 177: quite a bit(n=6,1)	2	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 46

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 46 ^[41]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 46 are reported. Question 46 was following: “Have you had swelling in your legs or ankles?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	663	323
Baseline: a little(n=884,439)	189	89
Baseline: quite a bit(n=884,439)	22	22
Baseline: very much(n=884,439)	10	5
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	625	284
Week 17: a little(n=839,419)	179	112
Week 17: quite a bit(n=839,419)	30	21
Week 17: very much(n=839,419)	5	2
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	530	243
Week 33: a little(n=737,341)	159	76
Week 33: quite a bit(n=737,341)	41	20
Week 33: very much(n=737,341)	7	2
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	453	176
Week 49: a little(n=635,250)	155	58
Week 49: quite a bit(n=635,250)	23	15
Week 49: very much(n=635,250)	4	1
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	378	135
Week 65: a little(n=536,193)	127	48
Week 65: quite a bit(n=536,193)	27	10
Week 65: very much(n=536,193)	4	0
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	301	104
Week 81: a little(n=434,148)	102	36
Week 81: quite a bit(n=434,148)	27	7
Week 81: very much(n=434,148)	4	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	259	69
Week 97: a little(n=365,95)	79	20
Week 97: quite a bit(n=365,95)	19	5
Week 97: very much(n=365,95)	8	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	191	40
Week 113: a little(n=275,73)	65	27
Week 113: quite a bit(n=275,73)	16	6
Week 113: very much(n=275,73)	3	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	134	27
Week 129: a little(n=192,41)	48	14
Week 129: quite a bit(n=192,41)	8	0
Week 129: very much(n=192,41)	2	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	76	15
Week 145: a little(n=116,21)	34	5
Week 145: quite a bit(n=116,21)	5	1
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	31	6
Week 161: a little(n=40,8)	8	2
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	3	0
Week 177: quite a bit(n=6,1)	0	1
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 47

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 47 ^[42]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 47 are reported. Question 47 was following: “Has weight loss been a problem for you?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	820	399
Baseline: a little(n=884,439)	48	25
Baseline: quite a bit(n=884,439)	10	10
Baseline: very much(n=884,439)	6	5
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	733	375
Week 17: a little(n=839,419)	81	28
Week 17: quite a bit(n=839,419)	15	13
Week 17: very much(n=839,419)	10	3
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	643	296
Week 33: a little(n=737,341)	72	35
Week 33: quite a bit(n=737,341)	13	5
Week 33: very much(n=737,341)	9	5
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	553	215
Week 49: a little(n=635,250)	61	29
Week 49: quite a bit(n=635,250)	15	3
Week 49: very much(n=635,250)	6	3
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	479	168
Week 65: a little(n=536,193)	39	20
Week 65: quite a bit(n=536,193)	11	4
Week 65: very much(n=536,193)	7	1
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	371	136
Week 81: a little(n=434,148)	46	10
Week 81: quite a bit(n=434,148)	14	1
Week 81: very much(n=434,148)	3	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	314	84
Week 97: a little(n=365,95)	36	10
Week 97: quite a bit(n=365,95)	10	0
Week 97: very much(n=365,95)	5	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	235	62
Week 113: a little(n=275,73)	27	8
Week 113: quite a bit(n=275,73)	9	1
Week 113: very much(n=275,73)	4	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	169	37
Week 129: a little(n=192,41)	17	4
Week 129: quite a bit(n=192,41)	5	0
Week 129: very much(n=192,41)	1	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	95	20
Week 145: a little(n=116,21)	17	1
Week 145: quite a bit(n=116,21)	4	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	34	8
Week 161: a little(n=40,8)	5	0
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	5	1
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	1	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 48

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 48 ^[43]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 48 are reported. Question 48 was following: “Has weight gain been a problem for you?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	677	315
Baseline: a little(n=884,439)	153	95
Baseline: quite a bit(n=884,439)	40	16
Baseline: very much(n=884,439)	14	13
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	674	316
Week 17: a little(n=839,419)	118	74
Week 17: quite a bit(n=839,419)	30	19
Week 17: very much(n=839,419)	17	10
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	570	259
Week 33: a little(n=737,341)	133	59
Week 33: quite a bit(n=737,341)	21	18
Week 33: very much(n=737,341)	13	5
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	479	193
Week 49: a little(n=635,250)	125	44
Week 49: quite a bit(n=635,250)	18	10
Week 49: very much(n=635,250)	13	3
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	410	155
Week 65: a little(n=536,193)	92	27
Week 65: quite a bit(n=536,193)	26	9
Week 65: very much(n=536,193)	8	2
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	327	115
Week 81: a little(n=434,148)	71	27
Week 81: quite a bit(n=434,148)	28	5
Week 81: very much(n=434,148)	8	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	267	76
Week 97: a little(n=365,95)	70	16
Week 97: quite a bit(n=365,95)	24	2
Week 97: very much(n=365,95)	4	1
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	200	60
Week 113: a little(n=275,73)	56	10
Week 113: quite a bit(n=275,73)	10	3
Week 113: very much(n=275,73)	9	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	156	32
Week 129: a little(n=192,41)	27	8
Week 129: quite a bit(n=192,41)	5	1
Week 129: very much(n=192,41)	4	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	89	16
Week 145: a little(n=116,21)	18	5
Week 145: quite a bit(n=116,21)	7	0
Week 145: very much(n=116,21)	2	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	31	6
Week 161: a little(n=40,8)	6	2
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	2	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	2	0
Week 177: a little(n=6,1)	3	1
Week 177: quite a bit(n=6,1)	1	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 49

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 49 ^[44]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 49 are reported. Question 49 was following: “Have you felt less masculine as a result of your illness or treatment?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	435	214
Baseline: a little(n=884,439)	234	131
Baseline: quite a bit(n=884,439)	138	59
Baseline: very much(n=884,439)	77	35
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	400	210
Week 17: a little(n=839,419)	244	115
Week 17: quite a bit(n=839,419)	109	57
Week 17: very much(n=839,419)	86	37
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	345	167
Week 33: a little(n=737,341)	207	107
Week 33: quite a bit(n=737,341)	109	38
Week 33: very much(n=737,341)	76	29
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	302	127
Week 49: a little(n=635,250)	187	68
Week 49: quite a bit(n=635,250)	84	36
Week 49: very much(n=635,250)	62	19
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	263	90
Week 65: a little(n=536,193)	142	57
Week 65: quite a bit(n=536,193)	71	24
Week 65: very much(n=536,193)	60	22
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	206	74
Week 81: a little(n=434,148)	124	38
Week 81: quite a bit(n=434,148)	57	17
Week 81: very much(n=434,148)	47	19
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	175	46
Week 97: a little(n=365,95)	98	28
Week 97: quite a bit(n=365,95)	47	10
Week 97: very much(n=365,95)	45	11
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	136	31
Week 113: a little(n=275,73)	78	27
Week 113: quite a bit(n=275,73)	30	8
Week 113: very much(n=275,73)	31	7
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	91	18
Week 129: a little(n=192,41)	49	16
Week 129: quite a bit(n=192,41)	27	5
Week 129: very much(n=192,41)	25	2
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	59	9
Week 145: a little(n=116,21)	31	9
Week 145: quite a bit(n=116,21)	18	1
Week 145: very much(n=116,21)	8	2
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	18	2
Week 161: a little(n=40,8)	15	3
Week 161: quite a bit(n=40,8)	3	1
Week 161: very much(n=40,8)	4	2
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	3	0
Week 177: a little(n=6,1)	3	1
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 50

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 50 ^[45]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 50 are reported. Question 50 was following: “To what extent were you interested in sex?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	586	291
Baseline: a little(n=884,439)	204	101
Baseline: quite a bit(n=884,439)	67	32
Baseline: very much(n=884,439)	27	15
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	637	293
Week 17: a little(n=839,419)	136	92
Week 17: quite a bit(n=839,419)	45	20
Week 17: very much(n=839,419)	21	14
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	542	251
Week 33: a little(n=737,341)	136	66
Week 33: quite a bit(n=737,341)	37	18
Week 33: very much(n=737,341)	22	6
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	483	180
Week 49: a little(n=635,250)	106	50
Week 49: quite a bit(n=635,250)	33	12
Week 49: very much(n=635,250)	13	8
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	417	143
Week 65: a little(n=536,193)	78	37
Week 65: quite a bit(n=536,193)	27	9
Week 65: very much(n=536,193)	14	4
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	320	114
Week 81: a little(n=434,148)	76	24
Week 81: quite a bit(n=434,148)	26	9
Week 81: very much(n=434,148)	12	1
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	286	65
Week 97: a little(n=365,95)	52	19
Week 97: quite a bit(n=365,95)	20	8
Week 97: very much(n=365,95)	7	3
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	218	59
Week 113: a little(n=275,73)	36	11
Week 113: quite a bit(n=275,73)	14	1
Week 113: very much(n=275,73)	7	2
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	156	33
Week 129: a little(n=192,41)	24	6
Week 129: quite a bit(n=192,41)	9	2
Week 129: very much(n=192,41)	3	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	92	14
Week 145: a little(n=116,21)	16	3
Week 145: quite a bit(n=116,21)	7	4
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at al(n=40,8)	30	5
Week 161: a little(n=40,8)	5	2
Week 161: quite a bit(n=40,8)	4	1
Week 161: very much(n=40,8)	1	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	4	1
Week 177: a little(n=6,1)	1	0
Week 177: quite a bit(n=6,1)	1	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 51

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 51 ^[46]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 51 are reported. Question 51 was following: “To what extent were you sexually active (with or without intercourse)?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=884,439)	735	374
Baseline: a little(n=884,439)	98	38
Baseline: quite a bit(n=884,439)	41	19
Baseline: very much(n=884,439)	10	8
Baseline: not answered(n=884,439)	0	0
Week 17: not at all(n=839,419)	734	354
Week 17: a little(n=839,419)	71	44
Week 17: quite a bit(n=839,419)	24	13
Week 17: very much(n=839,419)	10	8
Week 17: not answered(n=839,419)	0	0
Week 33: not at all(n=737,341)	642	299
Week 33: a little(n=737,341)	68	28
Week 33: quite a bit(n=737,341)	20	9
Week 33: very much(n=737,341)	7	5
Week 33: not answered(n=737,341)	0	0
Week 49: not at all(n=635,250)	569	214
Week 49: a little(n=635,250)	46	26
Week 49: quite a bit(n=635,250)	15	6
Week 49: very much(n=635,250)	5	4
Week 49: not answered(n=635,250)	0	0
Week 65: not at all(n=536,193)	485	170
Week 65: a little(n=536,193)	37	14
Week 65: quite a bit(n=536,193)	12	7
Week 65: very much(n=536,193)	2	2
Week 65: not answered(n=536,193)	0	0
Week 81: not at all(n=434,148)	381	130
Week 81: a little(n=434,148)	32	13
Week 81: quite a bit(n=434,148)	15	5
Week 81: very much(n=434,148)	6	0
Week 81: not answered(n=434,148)	0	0
Week 97: not at all(n=365,95)	333	79
Week 97: a little(n=365,95)	20	12
Week 97: quite a bit(n=365,95)	9	4
Week 97: very much(n=365,95)	3	0
Week 97: not answered(n=365,95)	0	0
Week 113: not at all(n=275,73)	250	68
Week 113: a little(n=275,73)	16	3
Week 113: quite a bit(n=275,73)	6	2
Week 113: very much(n=275,73)	3	0
Week 113: not answered(n=275,73)	0	0
Week 129: not at all(n=192,41)	176	37
Week 129: a little(n=192,41)	8	3
Week 129: quite a bit(n=192,41)	5	1
Week 129: very much(n=192,41)	3	0
Week 129: not answered(n=192,41)	0	0
Week 145: not at all(n=116,21)	106	17
Week 145: a little(n=116,21)	4	3
Week 145: quite a bit(n=116,21)	5	1
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	0	0
Week 161: not at all(n=40,8)	35	6
Week 161: a little(n=40,8)	3	2
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	1	0
Week 161: not answered(n=40,8)	0	0
Week 177: not at all(n=6,1)	5	1
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	1	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 52

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 52 ^[47]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 52 are reported. Question 52 was following: “To what extent was sex enjoyable for you?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=50,24)	5	6
Baseline: a little(n=50,24)	23	11
Baseline: quite a bit(n=50,24)	14	5
Baseline: very much(n=50,24)	8	2
Baseline: not answered(n=50,24)	0	0
Week 17: not at all(n=839,419)	7	3
Week 17: a little(n=839,419)	13	9
Week 17: quite a bit(n=839,419)	16	11
Week 17: very much(n=839,419)	3	4
Week 17: not answered(n=839,419)	800	392
Week 33: not at all(n=737,341)	8	4
Week 33: a little(n=737,341)	17	8
Week 33: quite a bit(n=737,341)	11	5
Week 33: very much(n=737,341)	4	0
Week 33: not answered(n=737,341)	697	324
Week 49: not at all(n=635,250)	3	4
Week 49: a little(n=635,250)	6	5
Week 49: quite a bit(n=635,250)	9	5
Week 49: very much(n=635,250)	3	4
Week 49: not answered(n=635,250)	614	232
Week 65: not at all(n=536,193)	4	2
Week 65: a little(n=536,193)	6	4
Week 65: quite a bit(n=536,193)	9	4
Week 65: very much(n=536,193)	3	0
Week 65: not answered(n=536,193)	514	183
Week 81: not at all(n=434,148)	5	2
Week 81: a little(n=434,148)	7	3
Week 81: quite a bit(n=434,148)	4	2
Week 81: very much(n=434,148)	5	1
Week 81: not answered(n=434,148)	413	140
Week 97: not at all(n=365,95)	2	2
Week 97: a little(n=365,95)	5	0
Week 97: quite a bit(n=365,95)	3	3
Week 97: very much(n=365,95)	3	0
Week 97: not answered(n=365,95)	352	90
Week 113: not at all(n=275,73)	0	1
Week 113: a little(n=275,73)	5	1
Week 113: quite a bit(n=275,73)	2	0
Week 113: very much(n=275,73)	2	0
Week 113: not answered(n=275,73)	266	71
Week 129: not at all(n=192,41)	1	0
Week 129: a little(n=192,41)	1	0
Week 129: quite a bit(n=192,41)	1	0
Week 129: very much(n=192,41)	1	0
Week 129: not answered(n=192,41)	188	41
Week 145: not at all(n=116,21)	1	0
Week 145: a little(n=116,21)	0	0
Week 145: quite a bit(n=116,21)	1	1
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	114	20
Week 161: not at all(n=40,8)	1	0
Week 161: a little(n=40,8)	1	0
Week 161: quite a bit(n=40,8)	0	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	38	8
Week 177: not at all(n=6,1)	0	0
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	6	1

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 53

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 53 ^[48]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 53 are reported. Question 53 was following: “Did you have difficulty getting or maintaining an erection?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=50,24)	6	4
Baseline: a little(n=50,24)	19	5
Baseline: quite a bit(n=50,24)	4	4
Baseline: very much(n=50,24)	21	11
Baseline: not answered(n=50,24)	0	0
Week 17: not at all(n=839,419)	10	8
Week 17: a little(n=884,439)	8	8
Week 17: quite a bit(n=884,439)	8	4
Week 17: very much(n=884,439)	13	7
Week 17: not answered(n=884,439)	800	392
Week 33: not at all(n=737,341)	6	2
Week 33: a little(n=737,341)	8	6
Week 33: quite a bit(n=737,341)	8	3
Week 33: very much(n=737,341)	18	6
Week 33: not answered(n=737,341)	697	324
Week 49: not at all(n=635,250)	4	6
Week 49: a little(n=635,250)	6	5
Week 49: quite a bit(n=635,250)	0	1
Week 49: very much(n=635,250)	11	6
Week 49: not answered(n=635,250)	614	232
Week 65: not at all(n=536,193)	3	1
Week 65: a little(n=536,193)	4	4
Week 65: quite a bit(n=536,193)	4	2
Week 65: very much(n=536,193)	11	3
Week 65: not answered(n=536,193)	514	183
Week 81: not at all(n=434,148)	7	3
Week 81: a little(n=434,148)	2	2
Week 81: quite a bit(n=434,148)	3	2
Week 81: very much(n=434,148)	9	1
Week 81: not answered(n=434,148)	413	140
Week 97: not at all(n=365,95)	2	1
Week 97: a little(n=365,95)	5	1
Week 97: quite a bit(n=365,95)	1	1
Week 97: very much(n=365,95)	5	2
Week 97: not answered(n=365,95)	352	90
Week 113: not at all(n=275,73)	1	0
Week 113: a little(n=275,73)	3	1
Week 113: quite a bit(n=275,73)	1	0
Week 113: very much(n=275,73)	4	1
Week 113: not answered(n=275,73)	266	71
Week 129: not at all(n=192,41)	0	0
Week 129: a little(n=192,41)	1	0
Week 129: quite a bit(n=192,41)	0	0
Week 129: very much(n=192,41)	3	0
Week 129: not answered(n=192,41)	188	41
Week 145: not at all(n=116,21)	1	0
Week 145: a little(n=116,21)	0	1
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	1	0
Week 145: not answered(n=116,21)	114	20
Week 161: not at all(n=40,8)	1	0
Week 161: a little(n=40,8)	0	0
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	38	8
Week 177: not at all(n=6,1)	0	0
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	6	1

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 54

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 54 ^[49]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 54 are reported. Question 54 was following: “Did you have ejaculation problems (e.g, dry ejaculation)?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=50,24)	11	7
Baseline: a little(n=50,24)	14	4
Baseline: quite a bit(n=50,24)	3	2
Baseline: very much(n=50,24)	22	11
Baseline: not answered(n=50,24)	0	0
Week 17: not at all(n=839,419)	13	11
Week 17: a little(n=839,419)	5	5
Week 17: quite a bit(n=839,419)	3	1
Week 17: very much(n=839,419)	18	10
Week 17: not answered(n=839,419)	800	392
Week 33: not at all(n=737,341)	12	10
Week 33: a little(n=737,341)	9	1
Week 33: quite a bit(n=737,341)	5	0
Week 33: very much(n=737,341)	14	6
Week 33: not answered(n=737,341)	697	324
Week 49: not at all(n=635,250)	7	6
Week 49: a little(n=635,250)	3	5
Week 49: quite a bit(n=635,250)	1	1
Week 49: very much(n=635,250)	10	6
Week 49: not answered(n=635,250)	614	232
Week 65: not at all(n=536,193)	8	3
Week 65: a little(n=536,193)	2	1
Week 65: quite a bit(n=536,193)	1	2
Week 65: very much(n=536,193)	11	4
Week 65: not answered(n=536,193)	514	183
Week 81: not at all(n=434,148)	7	4
Week 81: a little(n=434,148)	0	0
Week 81: quite a bit(n=434,148)	3	0
Week 81: very much(n=434,148)	11	4
Week 81: not answered(n=434,148)	413	140
Week 97: not at all(n=365,95)	5	2
Week 97: a little(n=365,95)	3	0
Week 97: quite a bit(n=365,95)	0	1
Week 97: very much(n=365,95)	5	2
Week 97: not answered(n=365,95)	352	90
Week 113: not at all(n=275,73)	3	2
Week 113: a little(n=275,73)	1	0
Week 113: quite a bit(n=275,73)	0	0
Week 113: very much(n=275,73)	5	0
Week 113: not answered(n=275,73)	266	71
Week 129: not at all(n=192,41)	1	0
Week 129: a little(n=192,41)	0	0
Week 129: quite a bit(n=192,41)	0	0
Week 129: very much(n=192,41)	3	0
Week 129: not answered(n=192,41)	188	41
Week 145: not at all(n=116,21)	2	0
Week 145: a little(n=116,21)	0	1
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	114	20
Week 161: not at all(n=40,8)	1	0
Week 161: a little(n=40,8)	0	0
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	38	8
Week 177: not at all(n=6,1)	0	0
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	6	1

No statistical analyses for this end point

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 55

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End point title

Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 55 ^[50]

End point description

The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Subjects answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of subjects with various responses to the question 55 are reported. Question 55 was following: “Have you felt uncomfortable about being sexually intimate?" The ITT population was defined as all subjects randomly assigned to study treatment and was based on randomized treatment assignment regardless of whether or not treatment was administered. Here, ‘n’ = subjects evaluable for this end point at specified time points.

End point type

Secondary

End point timeframe

Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	933	468
Units: subjects
Baseline: not at all(n=50,24)	31	13
Baseline: a little(n=50,24)	13	8
Baseline: quite a bit(n=50,24)	4	0
Baseline: very much(n=50,24)	2	3
Baseline: not answered(n=50,24)	0	0
Week 17: not at all(n=839,419)	23	14
Week 17: a little(n=839,419)	11	7
Week 17: quite a bit(n=839,419)	2	3
Week 17: very much(n=839,419)	3	3
Week 17: not answered(n=839,419)	800	392
Week 33: not at all(n=737,341)	24	10
Week 33: a little(n=737,341)	6	4
Week 33: quite a bit(n=737,341)	6	2
Week 33: very much(n=737,341)	4	1
Week 33: not answered(n=737,341)	697	324
Week 49: not at all(n=635,250)	16	10
Week 49: a little(n=635,250)	4	6
Week 49: quite a bit(n=635,250)	1	1
Week 49: very much(n=635,250)	0	1
Week 49: not answered(n=635,250)	614	232
Week 65: not at all(n=536,193)	13	5
Week 65: a little(n=536,193)	7	3
Week 65: quite a bit(n=536,193)	1	2
Week 65: very much(n=536,193)	1	0
Week 65: not answered(n=536,193)	514	183
Week 81: not at all(n=434,148)	13	5
Week 81: a little(n=434,148)	6	1
Week 81: quite a bit(n=434,148)	1	1
Week 81: very much(n=434,148)	1	1
Week 81: not answered(n=434,148)	413	140
Week 97: not at all(n=365,95)	8	3
Week 97: a little(n=365,95)	3	2
Week 97: quite a bit(n=365,95)	1	0
Week 97: very much(n=365,95)	1	0
Week 97: not answered(n=365,95)	352	90
Week 113: not at all(n=275,73)	7	2
Week 113: a little(n=275,73)	0	0
Week 113: quite a bit(n=275,73)	1	0
Week 113: very much(n=275,73)	1	0
Week 113: not answered(n=275,73)	266	71
Week 129: not at all(n=192,41)	3	0
Week 129: a little(n=192,41)	0	0
Week 129: quite a bit(n=192,41)	1	0
Week 129: very much(n=192,41)	0	0
Week 129: not answered(n=192,41)	188	41
Week 145: not at all(n=116,21)	2	1
Week 145: a little(n=116,21)	0	0
Week 145: quite a bit(n=116,21)	0	0
Week 145: very much(n=116,21)	0	0
Week 145: not answered(n=116,21)	114	20
Week 161: not at all(n=40,8)	1	0
Week 161: a little(n=40,8)	0	0
Week 161: quite a bit(n=40,8)	1	0
Week 161: very much(n=40,8)	0	0
Week 161: not answered(n=40,8)	38	8
Week 177: not at all(n=6,1)	0	0
Week 177: a little(n=6,1)	0	0
Week 177: quite a bit(n=6,1)	0	0
Week 177: very much(n=6,1)	0	0
Week 177: not answered(n=6,1)	6	1

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[51]

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A 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. A treatment-emergent AE (TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug through the date of last dose +30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first). AEs included both non-serious adverse events (AEs) and SAEs.The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months)

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects
AEs	808	360
SAEs	226	85

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events Greater Than or Equal to Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0

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End point title

Number of Subjects With Treatment-Emergent Adverse Events Greater Than or Equal to Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0 ^[52]

End point description

AE:any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events,significantly interrupting usual daily activity,require systemic drug therapy/other treatment, Grade 4 events=subject to be in imminent danger of death.Grade 5 events=death.A treatment-emergent AE(TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug through the date of last dose +30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first).Number of subjects with AEs of any of the Grade3 or above(Grade 4, 5) were reported. The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects	292	109

No statistical analyses for this end point

Secondary: Number of Subjects With Discontinuations From Study Treatment Due to Adverse Events (AEs)

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End point title

Number of Subjects With Discontinuations From Study Treatment Due to Adverse Events (AEs) ^[53]

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (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. AEs included both non-serious adverse events (AEs) and SAEs. The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects	87	28

No statistical analyses for this end point

Secondary: Number of Subjects With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline - Hematology

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End point title

Number of Subjects With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline - Hematology ^[54]

End point description

Hematology parameters: Haemoglobin (grams per liter [g/L]); leukocytes (log 10 raised to power 9 per liter [10*9/L]); lymphocytes (log 10 raised to power 6 per liter [10*6/L]); neutrophils (log 10 raised to power 6 per liter [10*6/L]); platelets (log 10 raised to power 9 per litre [10*9/L]). The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects
Haemoglobin (Low)	12	7
Leukocytes (Low)	7	7
Lymphocytes (High)	4	2
Lymphocytes (Low)	44	26
Neutrophils (Low)	13	4
Platelets (Low)	3	2

No statistical analyses for this end point

Secondary: Number of Subjects With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline – Chemistry

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End point title

Number of Subjects With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline – Chemistry ^[55]

End point description

Chemistry parameters: Alanine aminotransferase (units per liter [U/L]); albumin (g/L); alkaline phosphatase (U/L); bilirubin (micromoles per liter [umol/L]); calcium (millimoles per liter [mmol/L]); creatine kinase (U/L); creatinine (umol/L); glucose, magnesium, phosphate, potassium, sodium (mmol/L). The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects
Alanine Aminotransferase (High)	4	1
Albumin (Low)	7	0
Alkaline Phosphatase (High)	3	6
Aspartate Aminotransferase (High)	3	1
Bilirubin (High)	4	1
Calcium (High)	1	1
Calcium (Low)	2	1
Creatine Kinase (High)	4	3
Creatinine (High)	1	7
Glucose (High)	26	8
Glucose (Low)	5	1
Magnesium (High)	1	0
Magnesium (Low)	1	0
Phosphate (Low)	30	13
Potassium (High)	14	5
Potassium (Low)	0	3
Sodium (High)	2	1
Sodium (Low)	12	7

No statistical analyses for this end point

Secondary: Number of Subjects with Clinically Significant Vital Signs

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End point title

Number of Subjects with Clinically Significant Vital Signs ^[56]

End point description

Vital signs included Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and heart rate. The safety population was defined as all subjects randomly assigned to receive at least 1 dose or partial dose of study drug (enzalutamide or placebo) according to the actual treatment received (not the treatment assigned).

End point type

Secondary

End point timeframe

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only in reporting arms: Enzalutamide 160 mg and placebo

End point values	Enzalutamide 160 mg	Placebo
Number of subjects analysed	930	465
Units: subjects
SBP	738	328
DBP	563	229
Heart rate	7	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 30 days after last dose of study drug or till death, whichever occurred first (up to a maximum duration of 69.8 months)

Adverse event reporting additional description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as SAE in 1 subject and as Non-SAE in another, or a subject may have experienced both a SA and Non-SAE.Data reported in this section was collected and analyzed only for subject who were treated with at least 1 dose of study drug.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Enzalutamide 160 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Placebo Patients Crossover to Enzalutamide 160 mg

Reporting group description

Serious adverse events	Enzalutamide 160 mg	Placebo	Placebo Patients Crossover to Enzalutamide 160 mg
Total subjects affected by serious adverse events
subjects affected / exposed	372 / 930 (40.00%)	100 / 465 (21.51%)	12 / 87 (13.79%)
number of deaths (all causes)	285	173	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	6 / 930 (0.65%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder papilloma
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colorectal adenocarcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm of unknown primary site
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Mesothelioma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	2 / 930 (0.22%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Metastases to rectum
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pituitary tumour benign
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Small intestine adenocarcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Waldenstrom's macroglobulinaemia
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder Cancer Recurrent
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypopharyngeal Cancer
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal Cancer Recurrent
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal Squamous Cell Carcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung Adenocarcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung Cancer Metastatic
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant Melanoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic Carcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate Cancer
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Squamous Cell Carcinoma Of Skin
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clear cell renal cell carcinoma
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuroendocrine carcinoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 930 (0.11%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hypertension
subjects affected / exposed	5 / 930 (0.54%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angiopathy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic Rupture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive Crisis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous Thrombosis Limb
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Bladder calculus removal
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystoprostatectomy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transurethral prostatectomy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic Operation
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	7 / 930 (0.75%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 1
Fatigue
subjects affected / exposed	4 / 930 (0.43%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	1 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 930 (0.00%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 930 (0.32%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 5	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stent-graft endoleak
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Vessel puncture site haematoma
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Performance Status Decreased
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden Cardiac Death
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Swelling
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iodine allergy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Penile pain
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic cyst
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic haemorrhage
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic obstruction
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatomegaly
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Choking
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 930 (0.43%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 5	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung Disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary Oedema
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol Abuse
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional State
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood pressure decreased
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis radiation
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Excoriation
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	12 / 930 (1.29%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	3 / 15	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	6 / 930 (0.65%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	5 / 930 (0.54%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heat stroke
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 4	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urostomy complication
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous injury
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical Vertebral Fracture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chemical Cystitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial Bones Fracture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal Compression Fracture
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thoracic Vertebral Fracture
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity To Various Agents
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Phimosis
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	6 / 930 (0.65%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	10 / 930 (1.08%)	2 / 465 (0.43%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	1 / 12	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1
Angina pectoris
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	9 / 930 (0.97%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 10	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	10 / 930 (1.08%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Conduction disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	8 / 930 (0.86%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	10 / 930 (1.08%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 6	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sick sinus syndrome
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular Block Second Degree
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Aneurysm
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Failure Congestive
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic Shock
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiovascular Insufficiency
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Left Ventricular Dysfunction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus Arrest
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tricuspid Valve Disease
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular Tachycardia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Failure Acute
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery occlusion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 930 (0.00%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	7 / 930 (0.75%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	3 / 8	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cranial nerve disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diplegia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	6 / 930 (0.65%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	7 / 930 (0.75%)	2 / 465 (0.43%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	2 / 7	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	5 / 930 (0.54%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	4 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal Ganglia Haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic Stroke
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Headache
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar Radiculopathy
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo Cns Origin
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 930 (1.08%)	1 / 465 (0.22%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	2 / 13	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Anaemia macrocytic
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Normochromic Normocytic Anaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic Haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acquired oesophageal web
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal stenosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	1 / 930 (0.11%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal mucosal disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	4 / 930 (0.43%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal congestion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mesenteric vein thrombosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peptic ulcer
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peptic ulcer haemorrhage
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngo-oesophageal diverticulum
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal Distension
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colonic Pseudo-Obstruction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal Necrosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal Hernia Strangulated
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periproctitis
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal Haemorrhage
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis acute
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Bile Duct Stone
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary Colic
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis Obstructive
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic Function Abnormal
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Azotaemia
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder hypertrophy
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder obstruction
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder outlet obstruction
subjects affected / exposed	1 / 930 (0.11%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	2 / 930 (0.22%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis haemorrhagic
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis noninfective
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	31 / 930 (3.33%)	15 / 465 (3.23%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	3 / 40	0 / 22	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	5 / 930 (0.54%)	3 / 465 (0.65%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	1 / 5	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertonic bladder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	5 / 930 (0.54%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	0 / 930 (0.00%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postrenal failure
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	2 / 930 (0.22%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	7 / 930 (0.75%)	8 / 465 (1.72%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 930 (0.11%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Renal pain
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	2 / 930 (0.22%)	2 / 465 (0.43%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral obstruction
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 930 (0.11%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary fistula
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	3 / 930 (0.32%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	13 / 930 (1.40%)	12 / 465 (2.58%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 19	3 / 13	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	4 / 930 (0.43%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vesical fistula
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anuria
subjects affected / exposed	0 / 930 (0.00%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress Urinary Incontinence
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary Bladder Haemorrhage
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary Tract Disorder
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	4 / 930 (0.43%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 930 (0.11%)	3 / 465 (0.65%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 930 (0.11%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	5 / 930 (0.54%)	3 / 465 (0.65%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain In Extremity
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	6 / 930 (0.65%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 930 (0.22%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	20 / 930 (2.15%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 23	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 4	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	2 / 930 (0.22%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestine gangrene
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	11 / 930 (1.18%)	6 / 465 (1.29%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 11	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	9 / 930 (0.97%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	1 / 9	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral diarrhoea
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial Sepsis
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea Infectious
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lobar Pneumonia
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nail Bed Infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonsillar Abscess
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis Acute
subjects affected / exposed	0 / 930 (0.00%)	2 / 465 (0.43%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 930 (0.65%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Tooth Infection
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	4 / 930 (0.43%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemochromatosis
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	3 / 930 (0.32%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased Appetite
subjects affected / exposed	0 / 930 (0.00%)	1 / 465 (0.22%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 2 Diabetes Mellitus
subjects affected / exposed	1 / 930 (0.11%)	0 / 465 (0.00%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Enzalutamide 160 mg	Placebo	Placebo Patients Crossover to Enzalutamide 160 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	762 / 930 (81.94%)	299 / 465 (64.30%)	45 / 87 (51.72%)
Vascular disorders
Hot flush
subjects affected / exposed	132 / 930 (14.19%)	38 / 465 (8.17%)	3 / 87 (3.45%)
occurrences all number	151	40	3
Hypertension
subjects affected / exposed	158 / 930 (16.99%)	27 / 465 (5.81%)	6 / 87 (6.90%)
occurrences all number	214	34	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	93 / 930 (10.00%)	32 / 465 (6.88%)	10 / 87 (11.49%)
occurrences all number	170	36	13
Fatigue
subjects affected / exposed	344 / 930 (36.99%)	72 / 465 (15.48%)	13 / 87 (14.94%)
occurrences all number	513	80	13
Oedema Peripheral
subjects affected / exposed	59 / 930 (6.34%)	23 / 465 (4.95%)	4 / 87 (4.60%)
occurrences all number	74	25	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	47 / 930 (5.05%)	15 / 465 (3.23%)	1 / 87 (1.15%)
occurrences all number	55	19	1
Psychiatric disorders
Insomnia
subjects affected / exposed	54 / 930 (5.81%)	16 / 465 (3.44%)	2 / 87 (2.30%)
occurrences all number	60	18	2
Investigations
Weight decreased
subjects affected / exposed	80 / 930 (8.60%)	11 / 465 (2.37%)	4 / 87 (4.60%)
occurrences all number	93	11	5
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	159 / 930 (17.10%)	24 / 465 (5.16%)	2 / 87 (2.30%)
occurrences all number	223	25	2
Rib Fracture
subjects affected / exposed	63 / 930 (6.77%)	6 / 465 (1.29%)	1 / 87 (1.15%)
occurrences all number	76	7	1
Nervous system disorders
Dizziness
subjects affected / exposed	112 / 930 (12.04%)	27 / 465 (5.81%)	6 / 87 (6.90%)
occurrences all number	138	35	6
Headache
subjects affected / exposed	102 / 930 (10.97%)	23 / 465 (4.95%)	3 / 87 (3.45%)
occurrences all number	122	28	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	60 / 930 (6.45%)	19 / 465 (4.09%)	6 / 87 (6.90%)
occurrences all number	85	30	6
Gastrointestinal disorders
Constipation
subjects affected / exposed	120 / 930 (12.90%)	39 / 465 (8.39%)	1 / 87 (1.15%)
occurrences all number	145	43	1
Nausea
subjects affected / exposed	123 / 930 (13.23%)	42 / 465 (9.03%)	3 / 87 (3.45%)
occurrences all number	160	48	3
Diarrhoea
subjects affected / exposed	110 / 930 (11.83%)	63 / 465 (13.55%)	3 / 87 (3.45%)
occurrences all number	137	46	5
Renal and urinary disorders
Haematuria
subjects affected / exposed	79 / 930 (8.49%)	33 / 465 (7.10%)	2 / 87 (2.30%)
occurrences all number	113	42	2
Urinary retention
subjects affected / exposed	37 / 930 (3.98%)	31 / 465 (6.67%)	0 / 87 (0.00%)
occurrences all number	43	37	0
Pollakiuria
subjects affected / exposed	43 / 930 (4.62%)	25 / 465 (5.38%)	0 / 87 (0.00%)
occurrences all number	44	28	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	118 / 930 (12.69%)	36 / 465 (7.74%)	3 / 87 (3.45%)
occurrences all number	145	48	3
Back pain
subjects affected / exposed	119 / 930 (12.80%)	38 / 465 (8.17%)	4 / 87 (4.60%)
occurrences all number	139	38	4
Musculoskeletal Pain
subjects affected / exposed	61 / 930 (6.56%)	15 / 465 (3.23%)	1 / 87 (1.15%)
occurrences all number	72	18	1
Pain In Extremity
subjects affected / exposed	56 / 930 (6.02%)	15 / 465 (3.23%)	2 / 87 (2.30%)
occurrences all number	64	15	2
Infections and infestations
Urinary tract infection
subjects affected / exposed	63 / 930 (6.77%)	28 / 465 (6.02%)	1 / 87 (1.15%)
occurrences all number	82	34	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	108 / 930 (11.61%)	22 / 465 (4.73%)	3 / 87 (3.45%)
occurrences all number	138	24	3

More information

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Were there any global substantial amendments to the protocol? Yes

16 May 2013

Requirement for continuing the use of BTAs for bone health during the study for subjects who received prior bisphosphonates or denosumab 4 weeks before enrollment was clarified. Rationale for why progression did not mandate discontinuation of study drug; information on the method for calculating PSA DT, rationale for allowing the use of concomitant medications that lowered the seizure threshold was provided. Determination of radiographic events for the primary efficacy endpoint analysis was clarified. Additionally, the acronym for the clinical trial name was added to the study title.

31 May 2017

The timing and plan for the analyses of the primary endpoint of MFS, as well as the secondary endpoints, based on results from the nonmetastatic CRPC subgroup in the Phase 2 study MDV3100-09 and outcomes of 2 other controlled studies of enzalutamide in chemotherapy-naïve metastatic CRPC (MDV3100-03 and 9785-CL-0222) was revised. Medivation,Inc. became a wholly owned subsidiary of Pfizer Inc as of 28 September 2016. Medivation/Pfizer remained the Sponsor and the responsibility for expedited and periodic safety reporting was transferred to Pfizer Inc from ProductLife.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Metastasis Free Survival (MFS)

Primary: Metastasis Free Survival (MFS)

Secondary: Time to Prostate-Specific Antigen (PSA) Progression

Secondary: Time to Prostate-Specific Antigen (PSA) Progression

Secondary: Time to First Use of New Antineoplastic Therapy

Secondary: Time to First Use of New Antineoplastic Therapy

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Time to Pain Progression

Secondary: Time to Pain Progression

Secondary: Time to First Use of Cytotoxic Chemotherapy

Secondary: Time to First Use of Cytotoxic Chemotherapy

Secondary: Chemotherapy-Free Disease Specific Survival

Secondary: Chemotherapy-Free Disease Specific Survival

Secondary: Chemotherapy-Free Survival

Secondary: Chemotherapy-Free Survival

Secondary: Percentage of Subjects With Prostate Specific Antigen (PSA) Response

Secondary: Percentage of Subjects With Prostate Specific Antigen (PSA) Response

Secondary: Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score

Secondary: Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Mobility Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Mobility Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Self-Care Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Self-Care Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Usual Activities Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Usual Activities Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Pain/Discomfort Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Pain/Discomfort Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Anxiety/ Depression Domain Score

Secondary: Number of Subjects With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Anxiety/ Depression Domain Score

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Status Visual Analog Score (VAS)

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Status Visual Analog Score (VAS)

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 31

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 31

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 32

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 32

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 33

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 33

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 34

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 34

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 35

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 35

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 36

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 36

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 37

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 37

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 38

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 38

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 39

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 39

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 40

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 40

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 41

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 41

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 42

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 42

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 43

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 43

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 44

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 44

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 45

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 45

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 46

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 46

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 47

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 47

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 48

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 48

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 49

Secondary: Number of Subjects With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 49

Clinical Trial Results:
PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer