Clinical trial NCT01977651
Conditions: Metastatic Castration-resistant Prostate Cancer (mCRPC)
Keywords: enzalutamide Xtandi seizure Central Nervous System MDV3100 metastatic castration-resistant prostate cancer (mCRPC)
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2013-09-25; Completion date: 2019-01-11
Enrollment: 424 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study was to evaluate the incidence of seizures and monitor the safety of enzalutamide treatment in participants with metastatic castration-resistant prostate cancer (mCRPC) known to have risk factor(s) for seizure.

Detailed description:
This was a multicenter, single-arm, open-label, postmarketing safety study to evaluate the risk of seizure among patients with mCRPC treated with enzalutamide who were at potential increased risk of seizure.

Participants who met all inclusion and none of the exclusion criteria were enrolled into the study and participated in a 4-month treatment period, during which once daily dosing of enzalutamide (160 mg/day) occurred. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment were allowed to continue in the extension period where participants continued to receive enzalutamide until 1 of the following criteria was met:

1. The participant experienced bone disease progression per Prostate Cancer Working Group 2 (PCWG2) guidelines or soft tissue disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
2. The participant initiated treatment with another anticancer therapy or, in the opinion of the investigator, continued dosing would have led to undue risk to the patient
3. The participant met a discontinuation criterion
4. The sponsor terminated the study

Participants who continued to receive clinical benefit from treatment with enzalutamide and did not meet any discontinuation criteria may have transitioned to an open label roll-over extension study upon approval of the study protocol at the institution where they were receiving treatment.

Participants who did not continue in the extension period or who met a discontinuation criterion were discontinued from enzalutamide therapy and completed a follow-up visit 30 days from the last dose of enzalutamide or prior to the initiation of another anticancer therapy, whichever occurred first.

For participants who continued on treatment after the 12-month extension period, data collection was limited to dosing information, concomitant medications, and all adverse events (AEs) including serious adverse events (SAEs).

Arms: arm 1: Participants received 160 mg of enzalutamide orally once a day, for 4 months. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment continued in the extension period. The total study drug treatment duration for the extended period depended on individual clinical benefit. If a participant experienced a Grade 3 or higher toxicity that was attributed to enzalutamide and could not be ameliorated by the use of adequate medical intervention, treatment with enzalutamide was allowed to be interrupted for 1 week or until the toxicity grade improved to Grade 2 or lower severity. Subsequently, enzalutamide was restarted at the original dose 160 mg per day or a reduced dose 120 or 80 mg per day in consultation with the medical monitor.
Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: Participants received 4 capsules (40 mg each) of enzalutamide orally once a day, for a total daily dose of 160 mg. Treatment was given with or without food and as close as possible to the same time each day.

Protocol documents:
Prot_000.pdf: 
A Multicenter, Single-Arm, Open-Label, Post-Marketing Safety 
Study to Evaluate the Risk of Seizure Among Subjects with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Treated with Enzalutamide Who Are at Potential Increased Risk 
of Seizure (UPWARD)
ISN/Protocol 9785-CL-0403
ClinicalTrials.gov Identifier: NCT01977651
Date of Protocol v3.1: 20 Oct 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
Astellas
Page 1 of 81
Version 3.1 Incorporating Non-Substantial Amendment 3
A Multicenter, Single-Arm, Open-Label, Post-Marketing Safety 
Study to Evaluate the Risk of Seizure Among Subjects with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Treated with Enzalutamide Who Are at 
Potential Increased Risk of Seizure (UPWARD)
Protocol for Phase 4 Study of Enzalutamide
ISN/Protocol 9785-CL-0403
Version 3.1
Incorporating Non-Substantial Amendment 3 [See Attachment 1]
20 October 2016
IND 74,563
EudraCT 2013-003022-92
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Document History:
Original Version 1.0 [24Jun2013] 
Reissue Version 2.0 Incorporating Substantial Amendment 1 [25Nov2013]
Reissue Version 2.1 SE Incorporating Country-Specific Non-Substantial Amendment 1 [11Feb2014]         
Reissue Version 2.2 DE Incorporating Country-Specific Non-Substantial Amendment 2 [04Mar2014]
Reissue Version 3.0 Incorporating Substantial Amendment 2 [20Aug2014]
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
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Version 3.1 Incorporating Non-Substantial Amendment 3
Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································14
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································25
1
INTRODUCTION·················································································28
1.1
Background ····················································································28
1.2
Non-clinical and Clinical Data ······························································28
1.2.1
Summary of Relevant Nonclinical Experience with Enzalutamide ···············28
1.2.2
Summary of Relevant Clinical Experience with Enzalutamide····················29
1.2.2.1
Pharmacokinetics and Drug Metabolism ·······································29
1.3
Summary of Key Safety Information for Enzalutamide··································30
1.4
Risk-Benefit Assessment·····································································31
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································32
2.1
Study Objective ···············································································32
2.2
Study Design and Dose Rationale···························································32
2.2.1
Study Design·············································································32
2.2.2
Dose Rationale···········································································35
2.3
Endpoints·······················································································35
2.3.1
Primary Endpoints·······································································35
2.3.2
Secondary Endpoints····································································36
2.3.3
Exploratory Endpoints··································································36
3
STUDY POPULATION··········································································36
3.1
Selection of Study Population ·······························································36
3.2
Inclusion Criteria··············································································36
3.3
Exclusion Criteria·············································································37
4
TREATMENT(S)··················································································38
4.1
Identification of Investigational Product ···················································38
4.1.1
Enzalutamide·············································································38
4.1.2
Comparative Drug(s)····································································39
4.1.3
Seizure Therapy ·········································································39


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
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Version 3.1 Incorporating Non-Substantial Amendment 3
4.2
Suspected Seizure Event Management ·····················································39
4.3
Packaging and Labeling······································································41
4.4
Study Drug Handling ·········································································41
4.5
Blinding ························································································42
4.6
Assignment and Allocation ··································································42
5
TREATMENTS AND EVALUATION························································42
5.1
Dosing and Administration of Enzalutamide and Other Medication(s) ················42
5.1.1
Dose/Dose Regimen and Administration Period ····································42
5.1.2
Increase or Reduction in Dose of Enzalutamide·····································42
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································43
5.1.4
Treatment Compliance··································································44
5.1.5
Criteria for Continuation of Treatment ···············································44
5.2
Demographics and Baseline Characteristics ···············································45
5.2.1
Demographics············································································45
5.2.2
Medical History··········································································45
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············45
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics Assessment··························45
5.4
Safety Assessment ············································································45
5.4.1
Vital Signs················································································45
5.4.2
Adverse Events ··········································································45
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································46
5.4.3
Laboratory Assessments································································46
5.4.4
Physical Examination···································································47
5.4.5
Neurological Examination······························································47
5.4.6
Seizure Evaluation by a Neurologist··················································47
5.4.7
Electrocardiogram (ECG) ······························································47
5.4.8
Performance Status······································································47
5.5
Adverse Events and Other Safety Aspects ·················································48
5.5.1
Definition of Adverse Events (AEs) ··················································48
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································48
5.5.3
Criteria for Causal Relationship to the Study Drug ·································49
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························50
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································50


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
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Version 3.1 Incorporating Non-Substantial Amendment 3
5.5.6
Follow-up of Adverse Events··························································51
5.5.7
Monitoring of Common Serious Adverse Events ···································51
5.5.8
Procedure in Case of Pregnancy·······················································52
5.5.9
Emergency Procedures and Management of Overdose ·····························52
5.5.10
Supply of New Information Affecting the Conduct of the Study··················52
5.6
Test Drug Concentration ·····································································53
5.7
Other Measurements, Assessments or Methods ···········································53
5.7.1
Blood Sample for Future PGx Analysis (Retrospective PGx Analysis) ··········53
5.8
Total Amount of Blood·······································································53
6
DISCONTINUATION············································································53
6.1
Discontinuation of Individual Subject(s)···················································53
6.2
Discontinuation of the Site···································································54
6.3
Discontinuation of the Study ································································55
7
STATISTICAL METHODOLOGY ···························································55
7.1
Sample Size····················································································55
7.2
Analysis Set····················································································55
7.2.1
Safety Analysis Set (SAF)······························································55
7.2.2
Seizure Risk Evaluation Set (SRES)··················································56
7.3
Demographics and Other Baseline Characteristics········································56
7.4
Analysis of  Efficacy··········································································56
7.4.1
Analysis of Primary Endpoint ·························································56
7.4.1.1
Primary Analysis···································································56
7.4.1.2
Secondary Analysis································································56
7.4.1.3
Subgroup Analysis·································································56
7.5
Analysis of Safety·············································································56
7.5.1
Adverse Events ··········································································56
7.5.2
Laboratory Assessments································································57
7.5.3
Vital Signs················································································57
7.5.4
Physical Examination Including Neurological Status·······························57
7.5.5
ECGs······················································································57
7.6
Analysis of Pharmacokinetics ·······························································57
7.7
Analysis of Pharmacodynamics ·····························································57
7.8
Protocol Deviations and Other Analyses···················································57


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
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7.9
Interim Analysis (and Early Discontinuation of Subjects Subgroup)···················57
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········58
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················58
8.1
Procedure for Clinical Study Quality Control ·············································58
8.1.1
Data Collection ··········································································58
8.1.2
Specification of Source Documents···················································58
8.1.3
Clinical Study Monitoring······························································59
8.1.4
Direct Access to Source Data/Documents············································59
8.1.5
Data Management ·······································································59
8.1.6
Protocol Deviations ·····································································59
8.1.7
End of Trial in All Participating Countries···········································60
8.2
Ethics and Protection of Subject Confidentiality··········································60
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································60
8.2.2
Ethical Conduct of the Study···························································61
8.2.3
Informed Consent of Subjects ·························································61
8.2.3.1
Subject Information and Consent················································61
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························62
8.2.4
Subject Confidentiality ·································································62
8.3
Administrative Matters ·······································································63
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····63
8.3.2
Documents and Records Related to the Clinical Study ·····························63
8.3.3
Protocol Amendment and/or Revision················································64
8.3.4
Insurance of Subjects and Others······················································64
8.3.5
Signatory Investigator for Clinical Study Report····································64
9
QUALITY ASSURANCE········································································65
10
STUDY ORGANIZATION······································································66
10.1
Data and Safety Monitoring Board (DSMB) | Independent Adjudication 
Committee (IAC)··············································································66
11
REFERENCES ····················································································67
12
APPENDICES ·····················································································68
12.1
List of Drugs that May Lower Seizure Threshold·········································68
12.2
Liver Safety Monitoring and Assessment··················································69


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
Astellas
Page 6 of 81
Version 3.1 Incorporating Non-Substantial Amendment 3
12.3
Common Serious Adverse Events···························································72
12.4
Retrospective PGx Sub-Study ·······························································73
12.5
Planned Countries·············································································75
12.6
Study Milestones··············································································76
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 3···························77
14
SPONSOR’S SIGNATURES····································································81


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
Astellas
Page 7 of 81
Version 3.1 Incorporating Non-Substantial Amendment 3
I.
SIGNATURES
1.  
SPONSOR’S SIGNATURES
Required signatures (e.g., protocol author’s reviewers and contributors) are located in Section 14, 
Sponsor’s Signatures; e-signatures (when applicable) are located at the end of this document. 


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
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Page 8 of 81
Version 3.1 Incorporating Non-Substantial Amendment 3
2.  COORDINATING INVESTIGATOR’S SIGNATURE
A Multicenter, Single-Arm, Open-label, Post-Marketing Safety Study to Evaluate 
the Risk of Seizure Among Subjects with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) Treated with Enzalutamide Who Are at Potential Increased Risk 
of Seizure (UPWARD)
ISN/Protocol 9785-CL-0403
Version 3.1 / Incorporating Non-Substantial Amendment 3 
20 October 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
that it contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:


Sponsor: APGD
ISN/Protocol 9785-CL-0403
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3. INVESTIGATOR’S SIGNATURE 
A Multicenter, Single-Arm, Open-label, Post-Marketing Safety Study to Evaluate 
the Risk of Seizure Among Subjects with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) Treated with Enzalutamide Who Are at Potential Increased Risk 
of Seizure (UPWARD)
ISN/Protocol 9785-CL-0403
Version 3.1 / Incorporating Non-Substantial Amendment 3 
20 October 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ADT
Androgen Deprivation Therapy
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
APGD
Astellas Pharma Global Development
AR
Androgen Receptor
AST
Aspartate Aminotransferase (GOT)
AUC
Area under the curve
AUST
Astellas US Technologies, Inc
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum concentration
CRF
Case Report Form
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebrovascular Accident
CYP
Cytochrome P450
DHEA
Dehydroepiandrosterone
DILI
Drug-induced Liver Injury
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EEG
Electroencephalogram
GCP
Good Clinical Practice
GMP
Good Manufacturing Practices
HR
Hazard Ratio
IAC
Independent Adjudication Committee
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISN
International Study Number
LA-eCRF
Liver Abnormality Electronic Case Report Form
LFT
Liver Function Tests
mCRPC
Metastatic Castration Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MRP2
Multidrug Resistance-associated Protein 2
NASH
Non-alcoholic steatohepatitis
PFS
Progression-free Survival
PGx
Pharmacogenomics


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Abbreviations
Description of abbreviations
PK
Pharmacokinetic
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SMQ
Standardized MedDRA Query 
SOP
Standard Operating Procedure
SRES
Seizure Risk Evaluation Set
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin
tmax
the time after dosing when Cmax occurs
ULN
Upper Limit of Normal


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Definition of Key Study Terms  
Terms
Definition of terms
Baseline
A period that begins at the Screening visit where all initial subject assessments 
and findings will be obtained prior to study drug administration on Day 1.
Discontinuation
A discontinuation is a subject who is enrolled in the study and for whom study 
drug is terminated for any reason.  Subject will discontinue if he experiences 
bone disease progression per PCWG2 guidelines, or soft tissue disease 
progression per RECIST 1.1, the subject initiates treatment with another 
anticancer therapy, continued dosing would lead to undue risk to the subject in 
the opinion of the Investigator, subject meets a discontinuation criterion or the 
Sponsor terminates the study.
Enroll
To enter into the study following the signing of informed consent.  
Evaluable subject
Subject with a confirmed seizure (confirmed by the Independent Adjudication 
Committee) during the 4-month treatment period of the study or who 
completed at least 3 months (75%) of the planned treatment. Only an enrolled 
subject who discontinues the study before completing 3 months on treatment 
may be replaced at the discretion of the Sponsor, however, an enrolled subject 
who is discontinued due to a confirmed seizure event will not be replaced.
Extension period
Period of time where a subject continues to receive enzalutamide after 
completing a 4-month treatment period. A subject in the extension period may 
discontinue for any reasons listed in Discontinuation.
Screening period
30 days prior to Day 1 of Treatment
Screening failure
Screened subject, but did not fulfill protocol inclusion and/or exclusion criteria
and failed to receive study treatment, or decided not to participate anymore 
(withdrew consent) prior to completing pre-treatment period.
Treatment period
Period of time where major interests of protocol objectives are observed, and 
where the test drug is usually given to a subject which continues until the last 
assessment after completing administration of the test drug.
Follow-up visit
A visit occurring approximately 30 days following the last dose of 
enzalutamide or prior to the initiation of another anticancer therapy, whichever 
comes first.
Subject
An individual who participates in this clinical trial, and will be a recipient of 
the study drug.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
20 October 2016 / Version 3.1
Sponsor: 
Astellas Pharma Global Development Inc (APGD)
Protocol Number:  
9785-CL-0403
Name of Study Drug: 
Enzalutamide
Phase of Development:  
Phase 4
Title of Study:  
A Multicenter, Single-arm, Open-Label, Post-Marketing Safety Study to Evaluate the Risk of 
Seizure Among Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated 
with Enzalutamide Who Are at Potential Increased Risk of Seizure
Planned Study Period: 
From 3Q2013 to 2Q2018
Study Objective(s): 
To evaluate the incidence of seizures and monitor the safety of enzalutamide treatment in subjects 
with metastatic castration-resistant prostate cancer known to have risk factor(s) for seizure
Planned Total Number of Study Centers and Location(s):  
Approximately 135 centers; globally
Study Population:  
Subjects with metastatic castration-resistant prostate cancer known to have risk factor(s) for seizure
Number of Subjects to be Enrolled / Randomized:  
Approximately 400 subjects will be enrolled to achieve a minimum of 350 evaluable subjects 
assuming a drop-out rate of approximately 13% for this population.
In order to avoid patient enrollment being dominated by single patient characteristics in the study, 
the number of subjects enrolled under each risk factor will be monitored closely. Subjects enrolled 
under a specific risk category i.e., class of medication may be limited.  
Study Design Overview:  
This is a multicenter, single-arm, open-label, post-marketing safety study to evaluate the risk of 
seizure among subjects with metastatic castration-resistant prostate cancer (mCRPC) treated with 
enzalutamide who are at potential increased risk of seizure. 
Subjects who meet all inclusion and exclusion criteria will be enrolled into the study and 
participate in a 4-month treatment period during which once daily dosing of enzalutamide (160 
mg/day) will occur, followed by an approximate 30-day follow-up visit for those who do not 
continue on the extension treatment.
At the end of the 4-month treatment visit, subjects who are assessed as deriving benefit from 
enzalutamide treatment may continue in the extension period where subjects will continue to 
receive enzalutamide until one of the following criteria is met:
1.
The subject experiences bone disease progression per PCWG2 guidelines or soft tissue disease 
progression per RECIST 1.1, 
2.
The subject initiates treatment with another anticancer therapy, or continued dosing would lead 
to undue risk to the subject in the opinion of the Investigator, 


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3.
The subject meets a discontinuation criterion or
4.
The Sponsor terminates this study.
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide and have 
not met any discontinuation criteria may transition to an open label roll-over extension study upon 
approval of the study protocol at the institution they are receiving treatment at. 
Subjects who meet a discontinuation criterion will be discontinued from enzalutamide therapy and
complete a 30-day follow-up visit from the last dose of enzalutamide or prior to the initiation of 
another anticancer therapy, whichever occurs first.
An independent Data Safety and Monitoring Board (DSMB) will monitor seizure data emerging 
from this study. The DSMB charter will outline the details of the composition and responsibility of 
the DSMB including early stopping rules.
An Independent Adjudication Committee (IAC) will assess all suspected seizure events occurring 
during the study. The IAC charter will outline the details of the composition and responsibility of 
the IAC including classification of those events to be adjudicated and the specification of the event-
related documents, listings, data flow, method(s) for data collection, and any applicable data 
transfers.
Disease assessments will be performed regularly, per standard of care, or when there is clear 
clinical evidence of progression, while the subject is receiving enzalutamide. Disease assessment 
will also be performed after a seizure occurs to ensure favorable risk/benefit profile to continue 
enzalutamide. Disease assessments may include clinical, radiographic and/or PSA assessments.
Inclusion/Exclusion Criteria:  
Inclusion:  
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations (e.g., Health Insurance 
Portability Accountability Act authorization for sites in the United States) must be obtained 
from the subject or legally authorized representative prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable).
2.
Subject has histologically confirmed metastatic adenocarcinoma of the prostate.
3.
Subject has ongoing androgen deprivation therapy with a GnRH analogue (agonist or 
antagonist) or bilateral orchiectomy (i.e., surgical or medical castration).
4.
Subject has disease progression by at least one of the following:
a)
PSA progression defined by a minimum of 2 rising PSA levels with an interval of 
at least 1 week between each draw;
b) Bone disease progression as defined by Prostate Cancer Working Group 2 guidelines 
(at least 2 new lesions) on bone scan; or
c)
Soft tissue disease progression as defined by RECIST 1.1
5.
For subjects who have not had an orchiectomy, there must be a plan to maintain effective 
GnRH-analogue therapy for the duration of the study.
6.
Subject must have failed at least one course of androgen deprivation therapy (ADT), i.e., 
treatment with GnRH analogues.
7.
Subject has an ECOG performance status of 0-2.
8.
Subject has been evaluated by a local neurologist prior to study entry who has determined the 
subject has at least one risk factor for seizure including.
a)
past history of seizure due to any cause except a single febrile seizure in childhood. 


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Patients with a history of seizures should not have had a seizure within 12 months of 
Screening and must have had no anticonvulsants for 12 months prior to Screening,  
b) history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),
c)
history of traumatic brain or head injury with loss of consciousness 
d) unexplained loss of consciousness within the last 12 months,
e)
presence of a space occupying lesion in the brain including previously treated brain 
metastasis(es) or primary CNS tumor,
f)
history of arteriovenous malformations of the brain, 
g)
history of brain infection (i.e., abscess, meningitis, or encephalitis), 
h) current use of medication that may lower seizure threshold (see Appendix 12.1),
i)
presence of Alzheimer’s disease, meningioma, leptomeningeal disease from prostate 
cancer.
9.
Male subject and his female partner who is of childbearing potential must use two acceptable 
methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at Screening and continuing throughout the study period and for 
3 months after final study drug administration.
a)
Two acceptable forms of birth control include:
i.
Condom (barrier method of contraception), AND
ii.
One of the following acceptable forms of contraception is required:
1.
Established use of oral, injected or implanted hormonal methods of 
contraception.
2.
Placement of an intrauterine device (IUD) or intrauterine system (IUS).
3.
Barrier methods of contraception: Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository).
4.
Vasectomy or surgical castration at least 6 months prior to Screening.
10. Male subject must use a condom, if having sex with a pregnant woman.
11. Male subject must not donate sperm starting at Screening and throughout the study period and 
for at least 3 months after final drug administration.
12. Subject is able to swallow the study drug and comply with study requirements.
13. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed.
Exclusion: 
1.
Subject with a history of exposure to enzalutamide.
2.
Subject has severe concurrent disease, infection, or co-morbidity that, in the judgment of the 
Investigator, would make the subject inappropriate for enrollment.
3.
Subject is currently being treated with anti-epileptics.
4.
Subject has a history of seizure within the past 12 months of Screening as assessed by 
neurology examination and history.
5.
Subject with rapidly progressing visceral disease who has not received and is thought to be able 
to tolerate cytotoxic chemotherapy. (However, subject who has previously received cytotoxic 
chemotherapy is permitted).
6.
Subject has clinical signs suggestive of high or imminent risks for pathological fracture, spinal 
cord compression and/or cauda equina syndrome.
7.
Subject’s absolute neutrophil count is < 1500/µL, platelet count is < 100,000/µL, or 


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hemoglobin is < 5.6 mmol/L (9 g/dL) at Screening.
8.
Subject’s total bilirubin is ≥ 1.5 x ULN (except for subjects with documented Gilbert’s disease) 
or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is ≥ 2.5x ULN at 
Screening. 
9.
Subject’s estimated creatinine clearance (Cer)  is less than 30 mL/min by the Cockcroft and 
Gault formula (Creatinine Clearance (mL/min) = (140 – age)(wt kg) / 72 x serum creatinine 
(mg/100 ml) [Cockroft, 1976] at Screening.
10. Subject has uncontrolled hypertension as indicated by a resting systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg at Screening.
11. Subject has received an investigational agent within 4 weeks or 5 half- lives whichever is 
longer prior to Day 1.
12. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any 
of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated 
hydroxytoluene.
13. Subject has any condition which, in the Investigator’s opinion, makes the subject unsuitable 
for study participation.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
Enzalutamide
Dose(s):  
160 mg once daily
Mode of Administration:
Oral
Enzalutamide Dose Reduction/Dose Adjustment
Subjects who experience a Grade 3 or higher toxicity that is attributed to enzalutamide and cannot 
be ameliorated by the use of appropriate medical intervention may interrupt treatment with 
enzalutamide for 1 week or until the toxicity grade improves to Grade 2 or lower severity.  
Subsequently, study drug dosing may be restarted at the original dose (160 mg/day) or a reduced 
dose (120 or 80 mg/day) in consultation with the Medical Monitor. 
If enzalutamide is co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide 
should be reduced to 80 mg once daily. If co-administration of strong CYP2C8 inhibitor is 
discontinued, the enzalutamide dose should return to the dose used prior to initiation of the strong 
CYP2C8 inhibitor. 
If the adverse event is considered not related to enzalutamide by the Investigator, enzalutamide 
may be resumed at the same dose. 
The Sponsor Medical Monitor may be contacted with any questions or concerns on managing dose.


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Seizure Therapy: 
Standard anticonvulsant measures, if indicated in the event of a seizure (note: concomitant 
medication restrictions below). 
If the decision is made to continue a subject in the study after a first seizure, treatment including 
anti-seizure medication may be administered as recommended by the local neurologist and guided 
by the following restrictions. Enzalutamide has the potential to interact with some anti-seizure 
drugs.
Seizure Therapy continued: 

Acceptable drugs unlikely to cause interactions are 
o
Levetiracetam
o
Gabapentin
o
Pregabalin

Drugs which are acceptable but should be administered with caution include:
o
Ethosuccimide
o
Lacosamide
o
Lamotrigine
o
Oxcarbazepine
o
Topiramate
o
Valproate
o
Zonisamide

Benzodiazepines should not be used for maintenance therapy of seizure.

Other anti-seizure medications not permitted in the study include:
o
Carbamazepine
o
Phenytoin
o
Phenobarbital
o
Primidone
o
Felbamate
o
Vigabatrin
o
Retigabine
Concomitant Medication Restrictions or Requirements:   
The following medications are prohibited during the course of the study: 

Therapies to treat prostate cancer including but not limited to:
o Cytotoxic chemotherapy 
o Hormonal therapies (e.g., anti-androgens, abiraterone acetate, estrogens; testosterone, 
dehydroepiandrosterone [DHEA], etc.), 5-alpha reductase inhibitors, ketoconazole;
o Anticonvulsant substrates of CYP3A4, CYP2C9 or CYP2C19 with a narrow 
therapeutic index (e.g., carbamazepine, phenytoin, phenobarbital, and primidone);. 

Note: GnRH analogues (agonists or antagonists), bone-targeting agents, such as 
bisphosphonates and denosumab, and glucocorticoids are allowed. Palliative radiotherapy is 
also allowed (provided the subject does not meet discontinuation criteria).

Any other investigational agent.
There is a potential for enzalutamide to affect exposures to other medicinal products, or for other 


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medicinal products to affect exposure to enzalutamide:

Strong CYP2C8 inhibitors (e.g., gemfibrozil) or inducers (e.g. rifampicin) are to be avoided. If 
subject must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should
be reduced to 80 mg once daily. If a co-administration of the strong inhibitor is discontinued, 
the enzalutamide dose should be returned to the dose used prior to initiation of the strong 
CYP2C8 inhibitor.

Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19. Uridine 5’-diphospho-glucuronosyltransferase (UGT1A1) may also be induced.  
Medicinal products with a narrow therapeutic range that are substrates of  CYP3A4, CYP2C9, 
CYP2C19, or UGT1A1 should be used with caution when administered concomitantly with 
enzalutamide and may require dose adjustment to maintain therapeutic plasma concentrations
as drug levels may be reduced by the interaction with enzalutamide. Such substrates include,
but are not limited to: 
o Macrolide antibiotics (e.g. clarithromycin)
o Benzodiazepines (e.g. diazepam, midazolam, alprazolam, triazolam)
o Immune modulators (e.g. cyclosporine, tacrolimus)
o HIV antivirals (e.g. indinavir, ritonavir)
o Anti-epileptics (e.g. phenobarbital, phenytoin). 
o Coumarins (e.g. warfarin)

If enzalutamide is co-administered with warfarin (CYP2C9 substrate), additional INR 
monitoring should be conducted.

Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g., digoxin, 
colchicine, dabigatran etexilate) or for the breast cancer resistant protein (BCRP) or the 
multidrug resistance-associated protein 2 (MRP2), should be used with caution when 
administered concomitantly with enzalutamide and may require dose adjustment to maintain 
optimal plasma concentrations.

No other new systemic therapy or new radiotherapy for treatment (exception for spinal cord 
compression, pain management, etc) for prostate cancer is permitted while subject is on the 
study. Subjects with pre-existing non-target lesions (e.g., bone metastases) receiving palliative 
radiography for pain treatment before participation in the study are allowed to continue 
receiving radiotherapy during the study.


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Duration of Treatment:  
A total of 4 months in duration, starting from the date of the first dose. At the end of the 4-month 
treatment period, subjects who are assessed as deriving benefit from enzalutamide treatment may
continue in the extension period where subjects will continue to receive enzalutamide until one of 
the following criteria is met:
1.
The subject experiences bone disease progression per PCWG2 guidelines or soft tissue disease 
progression per RECIST 1.1,
2.
The subject initiates treatment with another anticancer therapy, continued dosing would lead to 
undue risk to the subject in the opinion of the Investigator, 
3.
The subject meets a discontinuation criterion or
4.
The Sponsor terminates the study. 
The total study drug treatment duration for the extension period will depend on individual clinical 
benefit with enzalutamide treatment as assessed by the Investigator.
Subjects may be asked to complete their extension period participation in another Astellas 
sponsored study upon activation of the roll-over extension study at the institution.
Discontinuation Criteria:
The following safety/compliance events will result in the removal of subjects from enzalutamide 
therapy and from the study, if:
●
Any adverse event that is intolerable to the subject and that cannot be ameliorated by the use 
of adequate medical intervention, or that in the opinion of the Investigator would lead to 
undue risk to the subject if dosing continued;  
●
Any first confirmed seizure requiring treatment with maintenance anticonvulsant therapy if the 
only anticonvulsant(s) the patient can tolerate is carbamazepine, phenytoin, phenobarbital, 
primidone, felbamate, vigabatrin, or retigabine.
●
Any second seizure confirmed by the independent Adjudication Committee;
●
Inability to maintain the absolute neutrophil count above 500/µL (Grade 4) or 500-1000/µL
(Grade 3) with evidence of infection;
●
Inability to maintain the platelet count above 25,000/µL (Grade 4) or 25,000-50,000/µL 
(Grade 3) with spontaneous bleeding;
●
Subject who has unequivocal evidence of disease progression (upon bone disease progression 
per PCWG2 guidelines or soft tissue disease progression per RECIST 1.1) or, is no longer 
deriving clinical benefit;
●
Subject who is, in the opinion of the Investigator or the Medical Monitor, grossly non-
compliant with the protocol requirements.
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease, presence of liver metastases, or exposure to other agents associated with liver injury, 
the subject may be discontinued from the study. The Investigator may determine that it is not in the 
subject’s best interest to continue study enrollment. Discontinuation of treatment should be 
considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases)


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●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
Formal Stopping Rules
The study design considers early stopping criteria that can be applied to a study as a whole or a 
specific risk factor group, if any, based on the statistical boundary calculated from Maximized 
Sequential Probability Ratio Test [Kulldorff, 2011]. The statistical boundary will be provided in the 
DSMB charter. Evaluation of the seizure risk is performed by DSMB for the study as a whole and 
for the risk factor group at the same time using the same stopping boundary based on false stopping 
probability of 0.1. Recommendation will be made by DSMB to either stop the study or stop further 
enrollment of a specific risk factor group. 
Endpoints for Evaluation:  
Primary:
The proportion of evaluable subjects with at least one confirmed seizure as adjudicated by the 
Independent Adjudication Committee (IAC) during the 4-month treatment duration.
Secondary:
Not applicable
Exploratory:
Not applicable


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Suspected Seizure Event Management: 
Each subject will be given a patient card with the following information; a list of signs and 
symptoms of a suspected seizure (Seizure Description Subject Information) and a Suspected 
Seizure Event Questionnaire list as well as instructions regarding what to do in the event of a 
suspected seizure for awareness. 
The subject will contact the Investigator immediately (within 24 hours) after onset of a suspected 
seizure event and return to the site with best efforts in 3 days after event for evaluation by the local 
neurologist. 
Investigator will: 
Instruct the subject to stop taking the enzalutamide study drug until after the clinical assessment 
has been completed by the neurologist. (Note: this could be a temporary stoppage, if the event 
turns out not to have been deemed a seizure, or is a 1st seizure with good benefit/risk ratio for 
continuing study drug.)
Instruct the subject to complete the Suspected Seizure Event Questionnaire with input from any 
witness(es) to suspected events.
Schedule a clinic visit to be evaluated by the local neurologist.
Evaluation by a local neurologist is required including electroencephalogram (EEG) and magnetic 
resonance imaging (MRI of the brain) procedures as soon as possible after a potential seizure event 
occurrence. A description of the events leading up to the seizure will be obtained from the 
individual and any witnesses. 
The study site will interview the subject and any witnesses, if possible, regarding the event. The 
study site will complete a Suspected Seizure Event Questionnaire including a Cover Sheet which 
will be signed by the PI/Sub-Investigator and be included as part of the package to the IAC. The 
site will review the Suspected Seizure Event Questionnaire completed by the subject, if available.
The subject Suspected Seizure Event Questionnaire is a tool to capture information of the suspected 
event which the PI/Sub-Investigator will utilize for completion of their evaluation when available. 
The Questionnaire completed by the subject will not be collected.
Subjects will be treated as indicated by the local neurologist including the use of acceptable anti-
convulsants Anticonvulsant substrates of CYP3A4, CYP2C9  or CYP2C19 with a narrow 
therapeutic index are not permitted (e.g., anticonvulsant medications including carbamazepine, 
phenytoin, phenobarbital, primidone, felbamate, vigabatrin, and retigabine). 
If the treating neurologist deems the event not to have been a seizure, enzalutamide may be 
restarted. If the neurologist determines that a seizure has occurred and the event is a first seizure, 
prior to the IAC assessment, an allowable anticonvulsant may be administered on a maintenance 
basis and enzalutamide may be restarted if desired by the investigator and subject, AFTER 
confirmation of clinical benefit as assessed by the Investigator. Results of the assessment of the 
IAC will be provided to the investigator and the subject will be allowed to continue in the study if 
the event is determined to be a first confirmed seizure.
In the event of a second seizure, enzalutamide will be held until the IAC’s review is completed. 
Upon IAC confirmation of a second seizure, enzalutamide may not be restarted and the subject will
be discontinued from the study.
All relevant information, including the completed seizure assessment questionnaire, the 
neurologist’s evaluation, and results of the MRI of the brain and EEG, will be submitted to the IAC
for evaluation. Results of the assessment of the IAC will be provided to the investigator and the 
subject will be allowed to continue in the study if the event is determined to be a first confirmed 
seizure. If the seizure is determined by the IAC to be a second confirmed seizure event in the study, 


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the subject will be withdrawn from the study. If it is determined that the event did not meet criteria 
for a confirmed seizure, the subject can continue in the study if no other discontinuation criteria 
have been met.
DSMB and IAC
A DSMB will be established for this study and remain active for the study duration. The DSMB 
will examine safety data and be informed of seizure events as expediently as possible. The role and 
responsibilities of the DSMB will be described in the DSMB charter which will be in place for the 
start of the study. Details of statistical boundaries for monitoring of the seizure event will be 
provided in the DSMB charter.
An IAC will be established to assess all suspected seizure events occurring during the study. The 
committee will consist of independent members of appropriate expertise who are not directly 
involved in the conduct of the clinical study. Suspected seizure adverse events and related 
information of the cases will be sent to the committee for assessment. The IAC charter will 
describe the classification of those events to be adjudicated and the specification of the event-
related documents, listings, data flow, method(s) for data collection, and any applicable data 
transfers.
Statistical Methods: 
Sample size justification: 
Approximately four hundred (400) subjects will be enrolled to target approximately 350 evaluable 
subjects assuming an early discontinuation of study drug of approximately 13% for this population
and based on the recommendation from the FDA, respectively. Assuming the true incidence of 
seizure in the first 4 months as 0.9%, based on the incidence rate of 2.8 per 100 patient years, 
which is obtained from the previous studies and the sample size of 350, the chance of observing 
5 or less subjects with seizure events is 88.9%. Given 5 out of 350 subjects, i.e., point estimate of 
1.43%, the upper limit 95% exact confidence interval will be 3.31% and the width of the exact 
confidence interval will be 2.84%.
Efficacy:  
Efficacy data will be listed.
Pharmacokinetics:  
Not applicable
Pharmacodynamics:  
Not applicable
Safety:  
An evaluable subject is defined as a subject with a confirmed seizure during the 4-month treatment 
period of the study or who completed at least 3 months (75%) of the treatment. Only an enrolled 
subject who discontinues the study before completing 3 months on treatment may be replaced at 
the discretion of the Sponsor, however, an enrolled subject who is discontinued due to a confirmed 
seizure event will not be replaced.
Primary endpoint, the proportion of evaluable subjects with at least one confirmed seizure as 
adjudicated by the IAC during the 4-month treatment duration, will be estimated using a point 
estimate and its 95% exact confidence interval. 
In addition, a cumulative summary to include all seizure events, including those occurring beyond 
the 4 month-treatment period, will be reported using all evaluable subjects. Seizures will continue 


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to be monitored for subjects entering the extension study.
A data-cut off for a cumulative summary will be one year after the primary 4-month treatment visit. 
For any subject who continues on treatment after his 1 year extension period, data collection will 
be limited to dosing information, and all AEs including serious adverse events (SAEs). 
All other safety analyses will include subjects who receive at least one dose of enzalutamide (safety 
population). 
All adverse events will be coded to preferred term, higher level term, and system organ class using 
the Medical Dictionary for Regulatory Activities (MedDRA). The number and proportion of 
subjects with adverse events will be presented by MedDRA system organ class and preferred term, 
relationship to enzalutamide, and severity. Laboratory values will be classified as applicable by the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
severity grade (version 4.03). Laboratory shift tables of the baseline results to the worst values will 
be produced.
Interim analyses: 
No formal interim analysis is planned for a specific timepoint.






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a.
Informed consent form must be obtained prior to any study-specific procedures being performed.
b.
A Follow-up Visit will be performed approximately 30 days after the last dose of enzalutamide, or prior to the initiation of another anticancer therapy, whichever occurs first.
c.
Suspected seizure visit occurring any time during the 4 month therapy as well as during extension period.
d.
Full physical exams will be performed including neurological exam. The physical examination performed at the Screening Visit does not need to be repeated on Day 1, if the Day 
1 visit occurs within 72 hours of Screening.
e.
At Screening, a thorough neurological history and examination will be performed by a local neurologist to obtain complete medical history relating to seizure risk, to confirm that 
a subject has met seizure risk entry criteria and to complete neurological baseline examination.
f.
The laboratory assessments performed at the Screening visit do not need to be repeated on Day 1, if the Day 1 visit occurs within 72 hours of Screening. 
g.
This is the Questionnaire to be completed both by Subject (if available) and by PI/Sub-investigator. The Questionnaire completed by the subject will not be collected.
h.
Disease assessments will be performed regularly, per standard of care, or when there is clear clinical evidence of progression, while the subject is receiving enzalutamide. Disease 
assessments will also be performed after a first confirmed seizure to ensure favorable risk/benefit profile to continue enzalutamide. Disease assessments may include clinical, 
radiographic and/or PSA assessments. The method Investigator uses for disease assessment must remain constant throughout the study. Radiographic disease assessments 
performed at Week 13 (Visit 4) do not need to be repeated at Week 17/End of Treatment (Visit 5).
i.
Serious adverse events (SAEs) including death will be collected from the time the subject signs the consent form until 30 days after last dose of enzalutamide. Non-serious adverse 
events will be collected from time of study drug administration on Day 1 until 30 days after last dose of enzalutamide.
j.
Extension period will begin for subjects who are assessed as deriving benefit from enzalutamide treatment after completion of the 4-month treatment. For any subject who 
continues on treatment after his 12-month extension period, data collection will be limited to dosing information, concomitant medication, and all AEs including SAEs. Subjects 
continuing into the Extention period may be asked to complete their extension period participation in another Astellas sponsored study upon activation of the roll-over extension 
study at the institution.  A Follow-up visit will not be required if subject move into the roll-over extension study.
k.
For only subjects continuing in the extension period who do not continue into the roll-over extension study at the institution.


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1
INTRODUCTION
1.1
Background
Enzalutamide (formerly MDV3100) is an androgen receptor (AR) inhibitor that blocks 
multiple steps in the AR signaling pathway. Enzalutamide competitively inhibits binding of 
androgens to ARs, inhibits nuclear translocation of receptors and inhibits the association of 
the AR with DNA even in the setting of AR over expression and in prostate cancer cells 
resistant to anti-androgens. By inhibiting AR signaling, enzalutamide elicits several 
downstream effects, which include reduced expression of AR-dependent genes, decreased 
growth of prostate cancer cells, induction of cancer cell death, and tumor regression. 
Enzalutamide lacks agonist activities such as those that may limit the sustained efficacy of 
current anti-androgens.
In the Phase 3 study CRPC2 (AFFIRM), the prespecified interim analysis at the time of 
520 events demonstrated a statistically significant improvement in overall survival in patients 
with metastatic CRPC treated with enzalutamide versus placebo (hazard ratio [HR] = 0.631; 
95% CI: 0.529, 0.752, p < 0.0001). Median survival was 18.4 months in the enzalutamide 
arm and 13.6 months in the placebo arm (Δ = 4.8 months). 
In the AFFIRM study, 7 of 800 (0.9%) patients treated with enzalutamide 160 mg once daily 
experienced a seizure. No seizures occurred in patients treated with placebo. Seizures 
occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure 
were permanently discontinued from therapy and all seizures resolved. 
This study is being conducted to assess the risk of seizure in patients with characteristics that 
were previously excluded from clinical studies and to monitor the safety of enzalutamide in 
patients with metastatic castration-resistant prostate cancer who are known to have risk 
factor(s) for seizure. Although no direct comparison is planned in this study, the results from 
the study will be interpreted in the context of all available data on enzalutamide and seizure 
risk in the general patient population and available epidemiological data at the timing of 
study reporting.
1.2
Non-clinical and Clinical Data
1.2.1
Summary of Relevant Nonclinical Experience with Enzalutamide
A complete assessment of toxicity has been conducted with enzalutamide, including evaluation 
of impurities. The species included in the toxicity program were mice, rats, dogs, and 
cynomolgus monkeys. Toxicokinetic evaluations demonstrated that all of these species 
produce the 2 major human metabolites of enzalutamide, N-desmethyl enzalutamide and an 
inactive carboxylic acid derivative.  
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of 
enzalutamide.  
Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and 
was not genotoxic in either the in vitro cytogenetic assay with mouse lymphoma thymidine 
kinase gene mutation or the in vivo mouse micronucleus assay.  


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In a cell-based activity assay both enzalutamide (formerly MDV3100) and its active metabolite 
functionally inhibited the GABA-gated chloride channel (α1β3 and α1β3γ2 GABA-A receptor 
subtype). In addition enzalutamide treatment was associated with dose-dependent convulsions 
in mice, and convulsions were also observed in 1 rat and 2 dogs in repeat dose toxicity studies.  
Both enzalutamide and its active metabolite cross the blood-brain barrier, and comparison of 
brain concentrations of these compounds in mice with and without convulsions shows that 
seizurogenic activity is mainly dependent on the extent of brain penetration.
Additional information on the nonclinical experience with enzalutamide is provided in the 
Enzalutamide Investigator Brochure.  
1.2.2
Summary of Relevant Clinical Experience with Enzalutamide
The key clinical studies evaluating enzalutamide in men with prostate cancer are described 
briefly as follows:
S-3100-1-01:  The pharmacokinetics (PK), tolerability, and antitumor activity of enzalutamide 
(then known as MDV3100) were first studied in a multicenter, open-label, first-in-human, 
dose-escalation study in 140 patients with CRPC. Patients who were chemotherapy-naïve or 
who had previous docetaxel-based chemotherapy failure were treated with enzalutamide at 
doses of 30 to 600 mg/day until disease progression or intolerable side effects developed. The 
maximum tolerated dose was determined to be 240 mg daily. After review of all data available 
from S-3100-1-01, the optimal dose of enzalutamide for evaluation in Phase 3 clinical trials 
was determined to be 160 mg/day.  
CRPC2 (AFFIRM):  A multinational Phase 3, randomized, double-blind, placebo-controlled, 
efficacy and safety study of enzalutamide (160 mg daily) in patients with progressive CRPC 
previously treated with docetaxel-based chemotherapy was conducted in 1199 men, 800 of 
whom received treatment with enzalutamide. The primary endpoint was overall survival. The 
FDA and EU approval of enzalutamide was based on the results of this study.  
MDV3100-03 (PREVAIL):  A multinational, Phase 3, randomized, double-blind, 
placebo-controlled, efficacy and safety study of enzalutamide (160 mg daily) in 
chemotherapy-naïve patients with progressive metastatic prostate cancer who have failed 
androgen deprivation therapy is ongoing. Enrollment is complete with 1717 men, 
approximately half of whom received treatment with enzalutamide. The coprimary endpoints 
are overall survival (OS) and radiographic progression-free survival (PFS).  
1.2.2.1 Pharmacokinetics and Drug Metabolism
In PK investigations in men with CRPC, enzalutamide was absorbed rapidly after oral 
administration, with the time to maximum plasma concentration (tmax) after a single dose 
typically occurring at 1 hour post dose. No major deviations from dose proportionality were 
observed over the dose range 30 mg to 600 mg.  
Terminal half-life was approximately 5.8 days. The average difference between the peak 
(maximum plasma concentration, Cmax) and trough (predose plasma concentration, Ctrough) 
concentrations was ≤25%.  Therefore, plasma profiles at steady state resembled a constant 


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infusion. Time-liner PK was observed beyond steady state at Day 28. Plasma concentrations 
of enzalutamide and the active metabolite, N-desmethyl enzalutamide, were approximately 
the same.  
In a drug-drug interaction study in male patients with CRPC (9785-CL-0007), a single oral 
dose of a substrate for cytochrome P450 (CYP) 2C8, CYP2C9, CYP2C19, or CYP3A4 was 
administered before and concomitantly with enzalutamide (after at least 55 days of dosing at 
160 mg daily). Enzalutamide at steady state reduced the plasma exposure to midazolam 
(CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) by 
86%, 56%, and 70%, respectively. Based on the magnitude of the decreases in exposure, 
enzalutamide is considered a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 
and CYP2C19. Substrates of CYP3A4, CYP2C9, and CYP2C19 with a narrow therapeutic 
index should be avoided when possible, as enzalutamide may decrease plasma exposure of 
these drugs. If enzalutamide is coadministered with warfarin (CYP2C9 substrate), additional 
international normalized ratio (INR) monitoring should be conducted. Enzalutamide did not 
cause clinically meaningful changes in exposure to pioglitazone (CYP2C8 substrate).  
In a drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 160 mg 
oral dose of enzalutamide was administered alone or after multiple oral doses of gemfibrozil 
(strong CYP2C8 inhibitor). Gemfibrozil increased the composite area under the curve from 
time zero to infinity (AUC0-∞) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold 
with minimal effect on Cmax; therefore, strong CYP2C8 inhibitors should be avoided when 
possible as they can increase plasma exposure to enzalutamide plus N-desmethyl 
enzalutamide.  If coadministration with a strong CYP2C8 inhibitor is necessary, the dose of 
enzalutamide should be reduced to 80 mg once daily. If coadministration of the strong 
CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used 
prior to initiation of the strong CYP2C8 inhibitor. The effects of CYP2C8 inducers on the PK 
of enzalutamide have not been evaluated in vivo.
In the drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 
160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of 
itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the composite AUC0-∞of 
enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax. As this 
small change is not clinically meaningful, no starting dose adjustment is needed when 
coadministering enzalutamide with CYP3A4 inhibitors. The effects of CYP3A4 inducers on 
the PK of enzalutamide have not been evaluated in vivo.
Additional information on the PK and drug metabolism of enzalutamide is provided in the 
Enzalutamide Investigator Brochure.  
1.3
Summary of Key Safety Information for Enzalutamide
The most common adverse reactions (≥5%) in patients treated with enzalutamide (N = 800) 
in the Phase 3 study CPRC2 (AFFIRM) (N = 1199) were asthenia/fatigue, back pain, 
diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper 
respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, 


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spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and 
hypertension. Discontinuations due to adverse events were reported for 16% of 
enzalutamide-treated patients and 18% of placebo-treated patients. The most common 
adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of 
the enzalutamide-treated patients and none (0%) of the placebo-treated patients.  
Seizure is an identified risk associated with enzalutamide, based on nonclinical findings, the
results of the dose-escalation study in patients with CRPC, S-3100-1-01, and events observed
in subsequent clinical trials. In Study S-3100-1-01, seizures were reported in 3 patients and
identified as dose-limiting toxicities (DLTs), 1 each at daily doses of 360, 480 and 600 mg
enzalutamide. No seizures were reported in patients receiving daily doses of 240 mg
enzalutamide or below in this study. Given the potential risk of seizure associated with
enzalutamide, investigators were instructed to have a heightened vigilance for seizures or any
events suggesting seizure activity in the controlled Study CRPC2 and all subsequent studies. 
In the randomized clinical trial CRPC2, 7 of 800 (0.9%) patients treated with enzalutamide 160 
mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. The 
onset of seizure events ranged from 31 to 603 days after initiation of enzalutamide. Patients 
experiencing seizure were permanently discontinued from enzalutamide therapy and all seizures 
resolved. There is no clinical trial experience re-administering enzalutamide to patients who 
experienced seizures. The safety of enzalutamide in patients with predisposing factors for 
seizure is not known because these patients were excluded from the trial. These exclusion 
criteria included a history of seizure, underlying brain injury with loss of consciousness, 
transient ischemic attack within the previous 12 months, cerebral vascular accident, brain 
metastases, brain arteriovenous malformation or the use of concomitant medication that may 
lower the seizure threshold. 
As of the cutoff date of 01Jan 2014, seizure occurred in <1% of prostate cancer patients 
receiving enzalutamide who previously received docetaxel (chemotherapy), and < 0.1% of 
prostate cancer patients receiving enzalutamide who had not received chemotherapy.
1.4
Risk-Benefit Assessment
In the Phase 3 study CRPC2 (AFFIRM), the pre-specified interim analysis at the time of 
520 events demonstrated a statistically significant improvement in overall survival in patients 
with metastatic CRPC treated with enzalutamide versus placebo (hazard ratio [HR] = 0.631; 
95% CI: 0.529, 0.752, p < 0.0001). Median survival was 18.4 months in the enzalutamide 
arm and 13.6 months in the placebo arm (Δ = 4.8 months). The overall survival benefit was 
consistent across all subgroups, including age, baseline pain intensity, geographic region, and 
type of disease progression at entry. Enzalutamide treatment was superior to placebo for all 
secondary endpoints including proportion of patients with a reduction in PSA level by 
50% or more (54% vs. 2%, p < 0.001), soft tissue response rate (29% vs. 4%, p < 0.001), 
quality-of-life response rate (43% vs. 18%, p < 0.001), time to PSA progression (8.3 vs. 
3.0 months; HR 0.25, p < 0.001), radiographic PFS (8.3 vs. 2.9 months; HR 0.40, p < 0.001), 
and time to first skeletal-related event (16.7 vs. 13.3 months; HR 0.69, p < 0.001).  Based on 


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the AFFIRM data, the US FDA approved enzalutamide in August 2012 for men with 
metastatic CRPC who previously received docetaxel therapy.  
Review of the enzalutamide program safety information obtained through Jan 2014 
confirmed that the previously identified potential risk of seizure is an “important identified 
risk” per International Conference on Harmonisation (ICH) definition, with an estimated 
incidence of <1% based on cumulative data.  In addition to seizures, hypertension, falls, 
hallucinations, non-pathologic fractures, neutrophil count decrease, and Cognitive/memory 
impairment were defined as important identified risks
The confirmed benefit of enzalutamide in the randomized CRPC2 trial in terms of overall 
survival advantage over placebo indicates a favorable benefit risk profile even in patients 
who were systematically excluded from clinical studies and may be at potential increased risk 
of seizure described in this protocol.
This study will enroll metastatic CRPC patients who have at least one risk factor which has 
the potential to increase risk for seizure. All subjects will have a baseline neurology 
assessment prior to treatment initiation with enzalutamide. 
This study will have an independent DSMB to monitor the safety, including being informed 
of every seizure event occurring during the trials as well as the assessment from the IAC as to 
whether the event actually qualifies as a seizure. 
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objective
The study objective is to evaluate the seizure rate and monitor the safety of enzalutamide 
treatment in subjects with metastatic castration-resistant prostate cancer known to have risk 
factor(s) for seizure.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This study is being conducted to assess the risk of seizure in patients with characteristics that 
were previously excluded from clinical studies and to monitor the safety of enzalutamide in 
patients with metastatic castration-resistant prostate cancer who are at potential increased risk 
of seizure.
Seizure is an identified important risk and known toxicity of enzalutamide, based on 
nonclinical findings and the results of the dose-escalation study in patients with castration 
resistant prostate cancer (S-3100-1-01) and the AFFIRM study (CRPC2). However, it needs 
to be noted that the exact mechanism by which enzalutamide may lower the seizure threshold 
is not known, but could be related to the affinity of enzalutamide and the metabolite M2 for 
the GABA-gated chloride channel.


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Risk factors that could contribute to the risk of seizure were excluded in the ongoing and 
closed studies; however, some risk factors were unknowingly present in several patients 
which may have independently increased their risk of seizure (i.e., brain metastasis). 
The current study will assess to the best of the current knowledge, the risk of seizure in a 
patient population at risk, with the potential limitation that not all factors that could 
contribute to that risk may be known or identified. Additionally, this study does not include a 
comparator arm, therefore any comparison to other drugs used in that indication will be 
indirect and only reflect the published literature. One additional limitation is that the study 
population may also not entirely reflect the patient population at potential risk as there are 
other inclusion/exclusion criteria that determine enrollment. 
This trial has been designed to analyze the incidence of seizure in the presence of potential 
risk factors. This approach will lead to reducing the potential bias which can be caused by 
dominating risk factor(s). However, there may be a situation where very few patients are 
enrolled with a particular risk factor making estimation of seizure incidence associated with 
that risk factor not feasible. 
This is a multicenter, single-arm, open-label, post-marketing safety study to evaluate the risk 
of seizure among subjects with metastatic castration-resistant prostate cancer (mCRPC) 
treated with enzalutamide who are at potential increased risk of seizure. 
Eligible patients may be drawn from various sources including hospitals and private practices 
of urologists and oncologists, and community based organizations where patients will be 
screened for the eligibility criteria of the study. 
Subjects who meet all inclusion and exclusion criteria will be enrolled into the study and 
participate in a 4-month treatment period during which once daily dosing of enzalutamide 
(160 mg/day) will occur followed by an approximate 30-day follow-up visit for those who do 
not continue on the extension treatment or prior to the initiation of another anticancer 
therapy, whichever occurs first.
At the end of the 4-month treatment visit, subjects who are assessed as deriving benefit from 
enzalutamide treatment may continue in the extension period where subjects will continue to 
receive enzalutamide until one of the following criteria is met:
1. The subject experiences bone disease progression per PCWG2 guidelines or soft tissue 
disease progression per RECIST 1.1,
2. The subject initiates treatment with another anticancer therapy, or continued dosing 
would lead to undue risk to the subject in the opinion of the Investigator, 
3. The subject meets a discontinuation criterion or, 
4. The Sponsor terminates this study.
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide and have 
not met any discontinuation criteria may transition to an open label roll-over extension study upon 
approval of the study protocol at the institution they are receiving treatment.


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Subjects who do not continue in the extension period or who meet a discontinuation criterion 
will be discontinued from enzalutamide therapy and complete a 30-day follow-up visit from 
the last dose of enzalutamide or prior to the initiation of another anticancer therapy 
whichever occurs first.
When any subject who continues on treatment after his 12-month extension period, data 
collection will be limited to dosing information, concomitant medications, and all AEs
including serious adverse events (SAEs). 
Each subject will be given a patient card with the following information; a list of signs and 
symptoms of a suspected seizure (Seizure Description Subject Information) and a Suspected 
Seizure Event Questionnaire list as well as instructions regarding what to do in the event of a 
suspected seizure for awareness. 
The subject will contact the Investigator immediately (within 24 hours) after onset of a 
suspected seizure event and return to the site with best efforts in 3 days after event for
evaluation by the local neurologist.
Investigator will:

Instruct the subject to stop taking the enzalutamide study drug until after the clinical 
assessment has been completed by the neurologist. (Note: this could be a temporary 
stoppage, if the event turns out not to have been deemed a seizure, or is a 1st seizure with 
good benefit/risk ratio for continuing study drug.)

Instruct the subject to complete the Suspected Seizure Event Questionnaire with input 
from any witness(es) to suspected events.

Schedule a clinic visit to be evaluated by the local neurologist.
Evaluation by a local neurologist is required including electroencephalogram (EEG) and 
magnetic resonance imaging (MRI of the brain) procedures as soon as possible after a 
potential seizure event occurrence. A description of the events leading up to the seizure will 
be obtained from the individual and any witnesses. 
The study site will interview the subject and any witnesses, if possible, regarding the event. 
The study site will complete a Suspected Seizure Event Questionnaire including a Cover 
Sheet which will be signed by the PI/Sub investigator and included as part of the package to 
the IAC. The site will review the Suspected Seizure Event Questionnaire completed by the 
subject, if available. The subject Suspected Seizure Event Questionnaire is a tool to capture 
information of the suspected event which the PI/Sub-investigator will utilize for completion 
of their evaluation when available. The Questionnaire completed by the subject will not be 
collected.
Subjects will be treated as indicated by the local neurologist including acceptable anti-
convulsants, if indicated.  
If the treating neurologist deems the event not to have been a seizure, enzalutamide may be 
restarted.


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If the neurologist determines that a seizure has occurred and the event is a first seizure prior 
to the IAC assessment, an allowable anticonvulsant may be administered on a maintenance 
basis and enzalutamide may be restarted if desired by the investigator and subject, AFTER 
confirmation of clinical benefit as assessed by the Investigator. Results of the assessment of 
the IAC will be provided to the investigator and the subject will be allowed to continue in the 
study if the event is determined to be a first confirmed seizure.
In the event of a second seizure, enzalutamide will be held until the IAC’s review is 
completed. Upon IAC confirmation of a second seizure, enzalutamide may not be restarted 
and the subject will be discontinued from the study. 
All relevant information, including the completed seizure assessment questionnaire, the local 
neurologist’s evaluation, and results of the MRI of the brain and EEG, will be submitted to 
the IAC for evaluation. Results of the assessment of the IAC will be provided to the 
Investigator and the subject will be allowed to continue in the study if the event is determined 
to be a first confirmed seizure. If the seizure is determined by the IAC to be a second 
confirmed seizure event, the subject will be withdrawn from the study. If it is determined that 
the event did not meet criteria for a confirmed seizure, the subject can continue in the study if 
no other discontinuation criteria have been met.
Disease assessments should be performed regularly per standard of care or when there is 
clear clinical evidence of progression, while the subjects are receiving enzalutamide and also 
upon confirmation of a first seizure to confirm clinical risk/benefit profile to continue 
enzalutamide.
2.2.2
Dose Rationale
A dose of 160 mg enzalutamide (four 40 mg capsules) once daily administered orally is the 
recommended daily dose by regulatory agencies in countries where the drug has been approved. 
2.3
Endpoints 
2.3.1
Primary Endpoints
The proportion of evaluable subjects with at least one confirmed seizure as adjudicated by 
the Independent Adjudication Committee (IAC) during the 4-month treatment duration. 
An evaluable subject is defined as a subject with a confirmed seizure during the 4-month 
treatment period of the study or who completed at least 3 months (75%) of the planned 
treatment. Only an enrolled subject who discontinues the study before completing 3 months 
on treatment may be replaced at the discretion of the Sponsor, however, an enrolled subject 
who is discontinued due to a confirmed seizure event will not be replaced.
A cumulative summary to include all seizure events, including those occurring beyond the 
4 month treatment period will be included.
In case the drop-out rate is higher than expected, appropriate method such as Kaplan-Meier 
estimations may be considered.


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2.3.2
Secondary Endpoints 
Not applicable.
2.3.3
Exploratory Endpoints
Not applicable.
3
STUDY POPULATION
3.1
Selection of Study Population 
The study population will include approximately 400 men with metastatic castration-resistant 
prostate cancer known to have risk factor(s) for seizure.
In order to avoid patient enrollment being dominated by single patient characteristics in the 
study, the number of subjects enrolled under each risk factor will be monitored closely. 
Subjects enrolled under a specific risk category i.e., class of medication may be limited.  
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
1.
written Informed Consent and privacy language as per national regulations (e.g., Health 
Insurance Portability Accountability Act (HIPAA) authorization for United States sites) 
must be obtained from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable).
Subject has histologically confirmed metastatic adenocarcinoma of the prostate.
2.
Subject has ongoing androgen deprivation therapy with a GnRH analogue (agonist or 
3.
antagonist) or bilateral orchiectomy (i.e., surgical or medical castration).
Subject has disease progression by at least 1 of the following:
4.
a) PSA progression defined by a minimum of 2 rising PSA levels with an interval of at 
least 1 week between each draw;
b)
Bone disease progression as defined by Prostate Cancer Working Group 2 
guidelines (at least 2 new lesions) on bone scan; or
c)
Soft tissue disease progression as defined by RECIST 1.1
For subjects who have not had an orchiectomy, there must be a plan to maintain effective 
5.
GnRH-analogue therapy for the duration of the study.
Subject must have failed at least one course of androgen deprivation therapy (ADT), i.e., 
6.
treatment with GnRH analogues.
Subject has an ECOG performance status of 0-2.
7.
Subject has been evaluated by a local neurologist prior to study entry who has 
8.
determined the subject has at least one risk factor for seizure including:


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a) past history of seizure due to any cause except a single febrile seizure in childhood. 
Patients with a history of seizures should not have had a seizure within 12 months of 
Screening and must have had no anticonvulsants for 12 months prior to Screening. 
b) history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),
c) history of traumatic brain or head injury with loss of consciousness,
d) unexplained loss of consciousness within the last 12 months,
e) presence of a space occupying lesion in the brain including previously treated brain 
metastasis(es) or primary CNS tumor,
f)
history of arteriovenous malformations of the brain, 
g) history of brain infection (i.e., abscess, meningitis, or encephalitis), 
h) current use of medication that may lower seizure threshold (see Appendix 12.1),
i)
presence of Alzheimer’s disease, meningioma, leptomeningeal disease from 
prostate cancer.
Male subject and his female partner who is of childbearing potential must use two 
9.
acceptable methods of birth control (one of which must include a condom as a barrier 
method of contraception) starting at Screening and continuing throughout the study 
period and for 3 months after final study drug administration.
a) Two acceptable forms of birth control include:
i.
Condom (barrier method of contraception), AND
ii.
One of the following acceptable forms of contraception is required:
1. Established use of oral, injected or implanted hormonal methods of 
contraception.
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
3. Barrier methods of contraception: Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository).
4. Vasectomy or surgical castration at least 6 months prior to Screening.
Male subject must use a condom, if having sex with a pregnant woman.
10.
Male subject must not donate sperm starting at Screening and throughout the study 
11.
period and for at least 3 months after final drug administration.
Subject is able to swallow the study drug and comply with study requirements.
12.
Subject agrees not to participate in another interventional study while on treatment.
13.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
Subject with a history of exposure to enzalutamide.
1.
Subject has severe concurrent disease, infection, or co-morbidity that, in the judgment of 
2.
the Investigator, would make the subject inappropriate for enrollment.
Subject is currently treated with anti-epileptics.
3.


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Subject has a history of seizure in the past 12 months of Screening as assessed by
4.
neurology examination and history.
Subject with rapidly progressive visceral disease who has not received and is thought 
5.
able to tolerate cytotoxic chemotherapy. (However, subject who has previously received 
cytotoxic chemotherapy is permitted).
Subject has clinical signs suggestive of high or imminent risks for pathological fracture, 
6.
spinal cord compression and/or cauda equina syndrome.
Subject’s absolute neutrophil count is < 1500 /µL, platelet count is < 100,000/µL, or 
7.
hemoglobin is < 5.6 mmol/L (9 g/dL) at Screening.
Subject’s total bilirubin is ≥ 1.5 x ULN (except for subjects with documented Gilbert’s 
8.
disease) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is 
≥ 2.5x ULN at Screening. 
Subject’s estimated creatinine clearance (Cer)  is less than 30 mL/min by the Cockcroft 
9.
and Gault formula (Creatinine Clearance (mL/min) = (140 – age)(wt kg) / 72 x serum 
creatinine (mg/100 ml) [Cockcroft, 1976] at Screening.
Subject has uncontrolled hypertension as indicated by a resting systolic blood pressure 
10.
> 160 mmHg or diastolic blood pressure > 100 mmHg at Screening.
Subject has received an investigational agent within 4 weeks or 5 half lives whichever is 
11.
longer prior to Day 1.
Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or 
12.
any of the capsule components, including Labrasol, butylated hydroxyanisole, and 
butylated hydroxytoluene.
Subject has any condition which, in the Investigator’s opinion, makes the subject 
13.
unsuitable for study participation.
Waivers to the exclusion criteria will NOT be allowed. 
4
TREATMENT(S)
4.1
Identification of Investigational Product
4.1.1
Enzalutamide
Enzalutamide has the chemical name 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. It is a white to off-
white solid that is insoluble in water and no salt forms are available at ~pH 2 to 10.
Enzalutamide capsules are white to off-white oblong capsules. The soft gelatin capsules are 
filled with a clear, yellowish solution which contains the two antioxidants, butylated 
hydroxyanisole, and butylated hydroxytoluene , and enzalutamide active ingredient (40 mg), 
all dissolved in the non-ionic surfactant, Labrasol® (Caprylocaproyl Polyoxylglycerides).


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Enzalutamide should be stored in a secure location with limited access at 77°F (25°C), with 
excursions permitted to 59°F to 86°F (15°C to 30°C). Subjects will be instructed to store study 
drug at room temperature out of the reach of children.
4.1.2
Comparative Drug(s) 
This section is not applicable as this is a single-arm study.
4.1.3
Seizure Therapy
Standard anticonvulsant measures, if indicated in the event of a seizure (NOTE: concomitant 
medication restrictions).
If the decision is made to continue a subject in the study after a first seizure, treatment 
including anti-seizure medication may be administered as recommended by the local 
neurologist and guided by the following restrictions. 

Enzalutamide has the potential to interact with some anti-seizure drugs. 

Acceptable drugs unlikely to cause interactions are
o
Levetiracetam 
o
Gabapentin
o
Pregabalin

Drugs which are acceptable but should be administered with caution include
o
Ethosuccimide
o
Lacosamide
o
Lamotrigine
o
Oxcarbazepine
o
Topiramate
o
Valproate
o
Zonisamide

Benzodiazepines should not be used for maintenance therapy of seizure

Other anti-seizure medications not permitted in the study include
o
Carbamazepine
o
Phenytoin
o
Phenobarbital
o
Primidone
o
Felbamate
o
Vigabatrin
o
Retigabine
4.2
Suspected Seizure Event Management
Each subject will be given a patient card with the following information; a list of signs and 
symptoms of a suspected seizure (Seizure Description Subject Information) and a Suspected 
Seizure Event Questionnaire list as well as instructions regarding what to do in the event of a 
suspected seizure for awareness. 


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The subject will contact the Investigator immediately (within 24 hours) after onset of a 
suspected seizure event and return to the site with best efforts in 3 days after event for 
evaluation by the local neurologist.
Investigator will:

Instruct the subject to stop taking the enzalutamide study drug until after the clinical 
assessment has been completed by the neurologist. (Note: this could be a temporary 
stoppage, if the event turns out not to have been deemed a seizure, or is a 1st seizure with 
good benefit/risk ratio for continuing study drug.)

Instruct the subject to complete the Suspected Seizure Event Questionnaire with input 
from any witness(es) to suspected events. 

Schedule a clinic visit to be evaluated by the local neurologist.
Evaluation by a local neurologist is required including electroencephalogram (EEG) and 
magnetic resonance imaging (MRI) procedures as soon as possible after a potential seizure 
event occurrence. A description of the events leading up to the seizure will be obtained from 
the individual and any witnesses. 
The study site will interview the subject and any witnesses, if possible, regarding the event. 
The study site will complete a Suspected Seizure Event Questionnaire including a Cover 
Sheet which will be signed by the PI/Sub-Investigator and included as part of the package to 
the IAC. The site will review the Suspected Seizure Event Questionnaire completed by the 
subject, if available. The subject Suspected Seizure Event Questionnaire is a tool to capture 
information of the suspected event which the PI/Sub-Investigator will utilize for completion 
of their evaluation when available. The Questionnaire completed by the subject will not be 
collected.
Subjects will be treated as indicated by the local neurologist including acceptable anti-
convulsants. Anticonvulsant substrates of CYP3A4, CYP2C9  or CYP2C19 with a narrow 
therapeutic index are not permitted (e.g., anticonvulsant medications including carbamazepine, 
phenytoin, phenobarbital, primidone, felbamate, vigabatrin, and retigabine). 
Subjects may continue on enzalutamide at the discretion of Investigator while the evaluation 
for a first possible seizure is ongoing. The dose of enzalutamide may be continued while the 
subject is on treatment with anticonvulsant therapy. If a subject experiences a second 
confirmed seizure by IAC, the subject will be discontinued from the study.
All relevant information, including the completed seizure assessment questionnaire, the local 
neurologist’s evaluation, and results of the MRI of the brain and EEG, will be submitted to 
the IAC for evaluation. Results of the assessment of the IAC will be provided to the 
Investigator and the subject will be allowed to continue in the study if the event is determined 
to be a first confirmed seizure. If the seizure is determined by the IAC to be a second 
confirmed seizure event in the study, the subject will be withdrawn from the study. If it is 
determined that the event did not meet criteria for a confirmed seizure, the subject can 
continue in the study if no other discontinuation criteria have been met.


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4.3
Packaging and Labeling
Enzalutamide used in this study will be prepared, packaged, and labeled, and final release 
under the responsibility of qualified staff at Astellas US Technologies, Inc (AUST) or 
designee in accordance with AUST Standard Operating Procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local 
laws/regulations.
Enzalutamide capsules are packaged in a white, opaque, high-density polyethylene (HDPE) 
bottles.  Each bottle will bear a label conforming to regulatory guidelines, Good 
Manufacturing Practice and local laws and regulations which identifies the contents as 
investigational drug.
Site pharmacist or medically qualified staff will dispense the study treatment to each subject 
in accordance with this protocol.
A qualified person of Astellas Pharma Europe B.V. (APEBV) or Sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13.
4.4
Study Drug Handling 
Current ICH GCP Guidelines require the Investigator to ensure that study drug deliveries 
from the Sponsor are received by the Investigator/or designee and
●
that such deliveries are recorded,
●
that study drug is handled and stored according to labeled storage conditions,
●
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
that any unused study drug is returned to the Sponsor.
Drug inventory and accountability records for the study drugs will be kept by the 
Investigator/or designee. Study drug accountability throughout the study must be documented 
and reconciled. The following guidelines are therefore pertinent:
●
The Investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The Investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the Investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the Investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the Investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
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●
The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration unless permission to destroy the study drug at the site is granted by the 
Sponsor.
4.5
Blinding
This section is not applicable as this is an open-label study.
4.6
Assignment and Allocation
Assignment will be performed via Interactive Response Technology (IRT). IRT will be used 
for the management of enrollment, screening, subject tracking and clinical supplies. Specific 
procedures for assignment through the IRT are contained in the study procedures manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Enzalutamide and Other Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Subjects will be instructed to take 4 capsules (40 mg each) per day orally. Enzalutamide may 
be taken with or without food and should be taken as close to the same time each day as 
possible. The total duration of treatment is 4 months. At the end of the 4-month treatment 
period, subjects who are assessed as deriving benefit from enzalutamide treatment may
continue in the extension period. Subjects in the extension period may continue to receive 
enzalutamide until they experience bone disease progression per PCWG2 guidelines or soft 
tissue disease progression per RECIST 1.1, they initiate treatment with another anticancer 
therapy, continued dosing would lead to undue risk to the subject in the opinion of the 
Investigator, they meet a discontinuation criterion or the Sponsor terminates the study. The 
total study drug treatment duration for the extended period will depend on individual clinical 
benefit to enzalutamide treatment. 
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide and 
have not met any discontinuation criteria may transition to an open label roll-over extension 
study upon approval of the study protocol at the institution they are receiving treatment at.
5.1.2
Increase or Reduction in Dose of Enzalutamide
Subjects who experience a Grade 3 or higher toxicity that is attributed to enzalutamide and 
cannot be ameliorated by the used of adequate medical intervention may interrupt treatment 
with enzalutamide for 1 week or until the toxicity grade improves to Grade 2 or lower
severity. Subsequently, study drug dosing may be restarted at the original dose (160 mg/day) 
or a reduced dose (120 or 80 mg/day) in consultation with the Medical Monitor. 
If the adverse event is considered not related to enzalutamide by the Investigator, enzalutamide 
may be resumed at the same dose. 
If the adverse event is considered possibly or probably related to enzalutamide, enzalutamide 
may be resumed with medical monitor approval either at the same dose or at a reduced dose 
of 120 or 80 mg/day once daily. 


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If enzalutamide is co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide 
should be reduced to 80 mg once daily. If co-administration of strong CYP2C8 inhibitor is 
discontinued, the enzalutamide dose should return to the dose used prior to initiation of the 
strong CYP2C8 inhibitor.
The Sponsor Medical Monitor may be contacted with any questions or concerns on managing 
dose.
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication
Therapy)
Medication taken within four weeks prior to Screening visit will be collected. 
All concomitant medications must be documented at each visit, at the time of discontinuation, 
and at the 30 day follow-up visit. 
The following medications are prohibited during the course of the study: 
●
Therapies to treat prostate cancer including but not limited to:
o Cytotoxic chemotherapy 
o Hormonal therapies (e.g., anti-androgens, abiraterone acetate, estrogens; testosterone, 
dehydroepiandrosterone [DHEA], etc.), 5-alpha reductase inhibitors, ketoconazole;
o Anticonvulsant substrates of CYP3A4, CYP2C9 or CYP2C19 with a narrow 
therapeutic index (e.g., carbamazepine, phenytoin, phenobarbital, and primidone are 
not permitted in this study. Felbamate, vigabatrin, and retigabine are also not 
permitted for reasons of potential toxicity. 
●
Note: GnRH analogues (agonists or antagonists), bone-targeting agents, such as 
bisphosphonates and denosumab, and glucocorticoids are allowed. Palliative radiotherapy 
is also allowed (provided the subject does not meet discontinuation criteria).
●
Any other investigational agent.
There is a potential for enzalutamide to affect exposures to other medicinal products, or for 
other medicinal products to affect exposure to enzalutamide:
●
Strong CYP2C8 inhibitors (e.g., gemfibrozil) or inducers (e.g. rifampicin) are to be 
avoided.  If subject must be co-administered a strong CYP2C8 inhibitor, the dose of 
enzalutamide must be reduced to 80 mg once daily. If a co-administration of the strong 
inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior 
to initiation of the strong CYP2C8 inhibitor.
●
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19. Uridine 5’-diphospho-glucuronosyltransferase (UGT1A1) may also be induced.  
Medicinal products with a narrow therapeutic range that are substrates of CYP3A4, 
CYP2C9, CYP2C19, or UGT1A1 should be used with caution when administered 
concomitantly with enzalutamide and may require dose adjustment to maintain therapeutic 
plasma concentrations. Such substrates include, but are not limited to: 


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o Macrolide antibiotics (e.g. clarithromycin)
o Benzodiazepines (e.g. diazepam, midazolam, alprazolam, triazolam)
o Immune modulators (e.g. cyclosporine, tacrolimus)
o HIV antivirals (e.g. indinavir, ritonavir)
o Anti-epileptics (e.g. phenobarbital, phenytoin). 
o Coumarins (e.g. warfarin)
●
If enzalutamide is co-administered with warfarin (CYP2C9 substrate), additional INR 
monitoring should be conducted.
●
Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g., 
digoxin, colchicine, dabigatran etexilate) or for the breast cancer resistant protein (BCRP) 
or the multidrug resistance-associated protein 2 (MRP2), should be used with caution 
when administered concomitantly with enzalutamide and may require dose adjustment to 
maintain optimal plasma concentrations.
●
No other new systemic therapy or new radiotherapy for treatment (exception for spinal 
cord compression, pain management, etc) for prostate cancer is permitted while subject is
on the study. Subjects with pre-existing non-target lesions (e.g., bone metastases) 
receiving palliative radiography for pain treatment before participation in the study are 
allowed to continue receiving radiotherapy during the study.
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. Compliance will be verified by the accounting of study drug at each monthly visit
after Baseline. When study drug is administered at the research facility, it will be
administered under the supervision of study personnel.
Compliance of the study drug will be monitored by the accounting of unused medication
returned by the subject at visits. Compliance will be documented.
If compliance is 80%, the Investigator or designee is to counsel the subject and ensure steps
are taken to improve compliance. Subjects who are less than 80% compliant with the dosage
regimen for any two consecutive visit periods during the study should be withdrawn from the
study.
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the Sponsor.
5.1.5
Criteria for Continuation of Treatment 
At the end of the 4-month treatment visit, subjects who are assessed as deriving benefit from 
enzalutamide treatment may continue in the extension period. Subjects in the extension 
period will continue to receive enzalutamide until they experience bone disease progression 
per PCWG2 guidelines or soft tissue disease progression per RECIST 1.1, they initiate 
treatment with another anticancer therapy, continued dosing would lead to undue risk to the 


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subject in the opinion of the Investigator, they meet a discontinuation criterion or the Sponsor 
terminates the study.
When any subject who continues on treatment after his 12-month extension period, data 
collection will be limited to dosing information, concomitant medications and all AEs 
including serious adverse events (SAEs), 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information is to be obtained at screening and will include date of birth or age 
as local regulations allow, ethnicity, race as described by the subject, height and weight. It is 
anticipated that the age range of subjects enrolled in this study would be similar to that of 
patients with mCRPC in general. In AFFIRM, the pivotal phase 3 study of enzalutamide the 
median age was 69 years (range 41-92).
5.2.2
Medical History
Medical history will include any significant conditions or diseases other than prostate cancer 
that occurred prior to informed consent. Subjects with a history of alcoholism are permitted 
to enroll in the study if eligibility criteria are met. Subjects with Alzheimer’s disease are 
permitted to be enrolled into the study based on existing clinical diagnosis. 
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A complete medical history of the target disease will be recorded at screening. This includes 
documenting the subject’s initial diagnosis of prostate cancer, Gleason score at time of 
diagnosis dates and type of primary therapy and other disease specific information as 
designated in the eCRF.
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics Assessment
Assessments of efficacy, pharmacokinetics, and pharmacodynamics will not be performed 
for this protocol.
5.4
Safety Assessment
5.4.1
Vital Signs
Vital signs including blood pressure, pulse rate, and temperature will be assessed at 
Screening and at every clinic visit while on study drug and at the safety follow-up visit.
5.4.2
Adverse Events
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding adverse 
event collection and data handling.
Adverse events will be collected from time of study drug administration on Day 1 until 30 
days after last dose of enzalutamide.
Serious adverse events (SAEs) including death will be collected from the time the subject 
signs the consent form until 30 days after last dose of enzalutamide. 


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5.4.2.1 Adverse Events of Possible Hepatic Origin
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g., AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) abnormalities 
should be carefully monitored.
5.4.3
Laboratory Assessments
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
This study will utilize local laboratories. See Schedule of Assessments for study visit 
collection dates. 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the Investigator/sub-investigator who is a qualified physician.
Routine laboratory assessments for hematology and chemistry will be collected and analyzed at 
the site laboratory. Laboratory assessments will be assessed at Screening and at each study 
visit as per the Schedule of Assessments.  
The laboratory assessments performed at the Screening Visit do not need to be repeated on Day
1 if the Day 1 visit occurs within 72 hours of Screening.
Laboratory assessments must be obtained prior to study drug administration.
CHEMISTRY
HEMATOLOGY
Sodium (Na)
Potassium (K)
Chloride (Cl)
Bicarbonate (HCO3)
Blood Urea Nitrogen (BUN)
Creatinine (Cr)
Glucose
Calcium (Ca)
Phosphate (Pi)
Magnesium (Mg)
Albumin
Total Protein
Alkaline Phosphatase
Lactate Dehydrogenase (LDH)
Creatine Phosphokinase (CK)
Liver Function Tests including:

Bilirubin Total (TBL)

Alanine Aminotransferase (ALT)

Aspartate Aminotransferase (AST)
White Blood Cell Count (WBC)
WBC Differential
Red Blood Cell Count (RBC)
Hemoglobin (Hgb)
Hematocrit (Hct)
Mean Corpuscular Volume
Platelet Count


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5.4.4
Physical Examination 
Standard, full physical examinations will be performed to assess weight, general appearance, 
head, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status (see Section 5.4.5 Neurological Examination), mental status, lymphatic, and 
genitourinary system. Any clinically significant abnormalities will be collected as medical 
history or adverse events. Weight and height will be recorded at the screening visit only. The 
physical examination performed at the screening visit does not need to be repeated on Day 1 if 
the Day 1 visit occurs within 72 hours of Screening visit.
5.4.5
Neurological Examination
At Screening, a thorough neurological history and examination will be performed by a local 
neurologist to obtain complete medical history relating to seizure risk, to confirm that a 
subject has met seizure risk entry criteria and to complete neurological baseline examination.
5.4.6
Seizure Evaluation by a Neurologist
If a suspected seizure event occurs, an evaluation by a local neurologist is required including 
electroencephalogram (EEG) and magnetic resonance imaging (MRI) procedures as soon as 
possible after a potential seizure event occurrence.
5.4.7
Electrocardiogram (ECG)
A standard 12-lead ECG will be performed on all subjects at Screening, Week 13, End of 
Treatment (EOT), 30 days post treatment and Suspected Seizure visit, if applicable. Parameters 
that include heart rate, PR interval, RR interval, QRS interval, QT interval will be collected on 
the (e)CRF. Abnormalities and clinical significance as judged by the Investigator will be 
reported as well. 
An ECG will be performed as per schedule of assessment. All ECGs will be performed prior to 
study drug administration. The subject should have rested in supine position (or semi-
recumbent, if supine is not tolerated) for 5-10 minutes.
5.4.8
Performance Status
The ECOG scale [Oken et al, 1982] will be used to assess performance status at Screening.
Table 2
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the eCRF accordingly. 
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event is considered “serious” if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes:
●
Results in death
●
Is life threatening (an adverse event is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious)
●
Other medically important events
For the purpose of this study, all potential seizures will be reported as SAEs. Seizures
due to enzalutamide overdose will be reported similar to all other seizure events.
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 


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subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, background therapy) that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above should be recorded on the (e)CRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the (e)CRF and marked ‘serious’ on the SAE worksheet.
The Sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal  relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge).


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5.5.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) guidelines 
(Version 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 will be 
assessed according to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the Investigator must contact the Sponsor by 
telephone or fax immediately (within 24 hours of awareness).
The Investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 24 
hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax the 
SAE Worksheet to:
Astellas Pharma Global Development, Inc. – United States
Product Safety & Pharmacovigilance, Fax number 1- (847) 317-1241; 
Email: safety-us@us.astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.
Full details of the SAE should be recorded on the medical records and on the (e)CRF.
The following minimum information is required:
●
ISN/Study number,
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and


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●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e. IND Safety 
Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the Investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) within timelines set 
by regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the site.
The Sponsor/delegated CRO will notify all Investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements 
IRB/IEC / head of the study site.
The heads of the study sites/Investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor.
The Investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject.
For Suspected Unexpected Serious Adverse Reactions (SUSAR) from this trial, a CIOMS-I 
report will be submitted to the IRB/IEC where required. SUSAR will be submitted to the 
authorities by means of a MedWatch report (FDA) or an E2B report (Eudravigilance).
5.5.6
Follow-up of Adverse Events
Adverse event collection will begin at the time of the first dose of study drug and continue 
through approximately 30 days post last dose or immediately prior to start of another 
antineoplastic therapy. All adverse events reported during this safety reporting period are to 
be followed at appropriate intervals until resolution or until judged to be no longer clinically 
significant, or until the event becomes chronic to the extent that the event can be fully 
characterized or until new antineoplastic treatment is initiated. 
If during AE follow-up, the adverse event progresses to an "SAE", or if a subject experiences 
a new SAE, the Investigator must immediately report the information to the Sponsor. 
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed
instructions on Drug Induced Liver Injury (DILI).
5.5.7
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure. SAEs classified as “common” are provided in 
Appendix 12.3 Common Serious Adverse Events for your reference. The list does NOT change 
your reporting obligations or prevent the need to report an AE meeting the definition of an 
SAE as detailed above. The purpose of this list is to alert you that some events reported as 
SAEs may not require expedited reporting to the regulatory authorities based on the 
classification of “common serious adverse events” as specified in Appendix 12.3 Common 


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Serious Adverse Events. The Sponsor will monitor these events throughout the course of the 
study for any change in frequency. Any changes to this list will be communicated to the 
participating investigational sites. Investigators must report individual occurrences of these 
events as stated in Section 5.5.5 Reporting of Serious Adverse Events. 
5.5.8
Procedure in Case of Pregnancy
If during the conduct of a clinical trial (from first dose through the safety follow-up period 
approximately 30 days after discontinuation of dosing), a male subject makes his partner 
pregnant, the subject should report the pregnancy to the Investigator. The Investigator will 
report the pregnancy to the Sponsor in the same manner as an SAE. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
The Investigator should report the outcome of the pregnancy (independent of outcome, e.g., 
full term delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death 
of newborn, congenital anomaly (including anomaly in a miscarried fetus), in accordance 
with the same reporting procedure as for SAEs. The date of outcome of the pregnancy, 
gestational age, date of birth and neonatal data, etc., should be included in this information. 
Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
5.5.9
Emergency Procedures and Management of Overdose
There is no antidote for enzalutamide. In the event of an overdose, stop treatment with 
enzalutamide and initiate general supportive measures based on the clinical presentation of 
the patient. Subjects may be at increased risk of seizure following an overdose.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all Investigators involved in the clinical study as well as 
the regulatory authorities including the change in the most common serious adverse events 


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stated in Section 5.5.7  Investigators should inform the IRB/IEC of such information when 
needed. 
5.6
Test Drug Concentration
Not applicable for this study.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Future PGx Analysis (Retrospective PGx Analysis) 
A PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics, and toxicity/safety issues. Any time  during the Screening 
Period, and after the patient has signed the study PGx informed consent form (see schedule of 
assessments), a 5 mL sample of whole blood for possible retrospective PGx analysis will be 
collected using a vacutainer tube containing EDTA. After collection, gently invert the blood 
sample 8 to 10 times. The blood collection tube may either be stored upright at 4°C for up to 
5 days prior to shipment or stored frozen at -20°C or below at the site for extended storage. 
Samples will be shipped to a Sponsor designated banking CRO.
Labels should uniquely identify each sample and contain at least:
●
Protocol number (9785-CL-0403),
●
Subject number, and
●
Purpose and biological matrix (i.e., “biobanking”, “whole blood”).
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See Appendix 12.4, Retrospective PGx Sub-study for further details on the banking procedures.
5.8
Total Amount of Blood
The total amount of blood collected for each subjects will vary depending on how long the 
subjects stays on the study. If a subject is found to have laboratory abnormalities or adverse 
events, additional blood may be drawn for evaluation and/or monitoring. Additional diagnostic 
blood for routine work may also be drawn. 
In addition, the total amount of blood collected for each subject for the optional pharmaco-
genomics (PGx) sample is approximately 4-6 mL.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued for any reason.  
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide and have 
not met any discontinuation criteria may transition to an open label extension study upon approval of 
the study protocol at the institution they are receiving treatment at.  The subject is free to withdraw
from the study treatment and/or study for any reason and at any time without giving reason 


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for doing so and without penalty or prejudice. The Investigator is also free to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the Investigator will attempt 
to provide follow-up until the condition stabilizes or no longer is clinically significant. 
The following safety/compliance events will result in the removal of subjects from 
enzalutamide therapy and from the study if:
●
Any adverse event that is intolerable to the subject and that cannot be ameliorated by the 
use of adequate medical intervention, or that in the opinion of the Investigator would lead 
to undue risk to the subject if dosing continued;  
●
Any first confirmed seizure requiring treatment with maintenance anticonvulsant therapy
if the only anticonvulsant(s) the patient can tolerate is carbamazepine, phenytoin, 
phenobarbital, primidone, felbamate, vigabatrin, or retigabine.
●
Any second seizure confirmed by independent adjudication committee;
●
Inability to maintain the absolute neutrophil count above 500/µL (Grade 4) or 500-
1000/µL (Grade 3) with evidence of infection;
●
Inability to maintain the platelet count above 25,000/µL (Grade 4) or 25,000-50,000/ µL 
(Grade 3) with spontaneous bleeding;
●
Subject who has unequivocal evidence of disease progression (upon bone disease 
progression per PCWG2 guidelines or soft tissue disease progression per RECIST 1.1) or 
is no longer deriving clinical benefit;
●
Subject who is, in the opinion of the Investigator or the Medical Monitor, grossly non-
compliant with the protocol’s requirements.
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The Investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is applicable/
evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
6.2
Discontinuation of the Site
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor.


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6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
Investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specification for tables, listings, and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the Clinical Study Report (CSR).
Prior to database lock, a final review of data and Table Listing Figures (TLFs) meeting will 
be held to allow a review of the clinical trial data and to verify the data that will be used for 
analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database lock. 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
Approximately four hundred (400) subjects will be enrolled to target approximately 350 
evaluable subjects, assuming a drop-out rate of approximately 13% for this population and 
based on the recommendation from the FDA, respectively. Assuming the true incidence of 
seizure in the first 4 months as 0.93%, based on the incidence rate of 2.8 per 100 patient 
years, which is obtained from the previous studies and the sample size of 350, the chance of 
observing 5 or less subjects with seizure events is 88.9%. Given 5 out of 350 subjects, i.e., 
point estimate of 1.43%, the upper limit 95% exact confidence interval will be 3.31% and the 
width of the exact confidence interval will be 2.84%.
7.2
Analysis Set
7.2.1
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least one dose of study medication, and will be used 
for safety analyses. Detailed criteria for analysis sets will be laid out in Classification 
Specifications and the allocation of subjects to analysis sets will be determined prior to 
database hard-lock.


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7.2.2
Seizure Risk Evaluation Set (SRES)
For the statistical summary and analysis of seizure events, seizure risk evaluation set (SRES) 
will be used by including all evaluable subjects. An evaluable subject is defined as a subject 
with a confirmed seizure during the 4-month treatment period of the study or who completed 
at least 3 months (75%) of the planned treatment.
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the SAF. 
Descriptive statistics will include number of subjects, mean, standard deviation, minimum, 
median and maximum for continuous endpoints, and frequency and percentage for 
categorical endpoints.
7.4
Analysis of Efficacy
Efficacy data will be collected at baseline and at the time of seizure event for this study. No 
statistical analysis will be conducted. Instead, disease assessments including clinical, radio-
graphic and/or PSA assessments collected will be listed.
7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
Primary endpoint, the proportion of evaluable subjects with at least one confirmed seizure as 
adjudicated by the IAC during the 4-month treatment duration will be analyzed estimated 
using point estimate and its 95% exact confidence interval using all SRES.
In case the drop-out rate is higher than expected, appropriate method such as Kaplan-Meier 
estimations [Kaplan and Meier, 1958; Greenwood, 1926] may be considered to efficiently 
estimate the proportion of seizure events with accounting for the censored observations in the 
SAF.
7.4.1.2 Secondary Analysis
The same analysis of the primary endpoint as described in 7.4.1.1 will be conducted for a 
cumulative proportion to include all seizure events, including those occurring beyond the 
4 month-treatment period using all SRES. Incidence of seizure events per patient-time 
exposure will be summarized. 
7.4.1.3 Subgroup Analysis
In case subgroups which may have association with the risk of  seizure are identified during 
the study, the incidence of seizure events will be summarized using a proportion estimate and 
its 95% exact confidence interval for the subgroups of the SRES.
7.5
Analysis of Safety
7.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of AEs, SAEs, AEs leading to discontinuation, and 


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AEs related to study drug will be summarized by system organ class and preferred term. The 
number and percentage of AEs by severity will also be summarized. All AEs will be listed.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by time point. Using the definitions provided in the NCI 
CTCAE Version 4.03, lab values will be classified as Grade 1 through 5, where possible. 
Shifts from baseline will be tabulated regarding either normal ranges or CTC CTCAE grade. 
Laboratory data will be displayed in listings and summary tables.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by timepoint. Vital signs data will be displayed in listings and summary tables.
7.5.4
Physical Examination Including Neurological Status
Physical examination including neurological status will be summarized.
7.5.5
ECGs 
The 12-lead ECG results will be summarized.
7.6
Analysis of Pharmacokinetics
No pharmacokinetic analysis is planned.
7.7
Analysis of Pharmacodynamics
No pharmacodynamics analysis is planned.
7.8
Protocol Deviations and Other Analyses  
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be listed by site and 
subject.
The protocol deviation criteria will be uniquely identified in the listing. The unique 
identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.9
Interim Analysis (and Early Discontinuation of Subjects Subgroup)
No formal interim analysis is planned for a specific timepoint.
The DSMB will examine safety data and be informed on seizure events as expediently as 
possible. Statistical boundaries for continuously monitoring of the seizure event will be 
provided in the DSMB charter as a guidance for early stopping criteria. The DSMB will use 
them to appropriately recommend either stop the enrollment of specific risk factor group(s) 


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identified during the DSMB review period or in extreme circumstance DSMB may ask 
sponsor to stop the study. 
The study design considers early stopping criteria that can be applied to a study as a whole or 
a specific risk factor group, if any, based on the statistical boundary calculated from 
Maximized Sequential Probability Ratio Test [Kulldorff, 2011]. Statistical boundary will be 
provided in the DSMB charter. Evaluation of the seizure risk is performed by DSMB for the 
study as a whole and for the risk factor group at the same time using the same stopping 
boundary based on false stopping probability of 0.1. Recommendation will be made by 
DSMB to either stop the study or stop further enrollment of a specific risk factor group.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to determine
whether an AE is/is not treatment emergent. Listings of the AEs and concomitant medications 
will present the actual partial dates; imputed dates will not be shown.
See the SAP for details of the definitions for windows to be used for analyses by visit.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The Investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the Investigator
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within the timeframe defined for the study after the subject visit.
The Investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at local laboratory. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria will be collected in the eCRF.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  


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The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
Adverse events and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable)
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
Investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The Investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 "Specification of Source Documents") when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Global Data Science department of the Sponsor 
in accordance with the standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. (e)CRF 
completion will be described in the (e)CRF instructions. Coding of medical terms and 
medications will be performed using MedDRA and World Health Organization (WHO) Drug 
Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The Investigator is responsible for ensuring 


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the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The Investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and not withdrawn.
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
Investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the Investigator must contact the Sponsor 
immediately.
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF).  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.


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Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The Investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet reporting criteria, as dictated by local regulations, will 
be reported to both responsible Ethics Committees and Regulatory Agencies, as required.
During the conduct of the study, the Investigator should promptly provide written reports 
(e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the 
IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects. Written documentation of the submission to the IEC/IRB should also be provided to 
Sponsor.
If required by local regulations, the Investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
Investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days
after the close-out visit for APGD-sponsored studies within one year after last subject out 
(LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the subject or 
his guardian or legal representative, and answer all questions regarding this study. Prior to 
any study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed including information regarding treatment options (abiraterone, 
chemotherapy, etc) and signed and dated by the subject or his guardian or  legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed informed consent form will be given to 
the subject and the original will be placed in the subject’s medical record. An entry must also 
be made in the subject’s dated source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.


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8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
The Investigator or his/her representative will immediately inform the subject orally
1.
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
The Investigator must update their ICF and submit it for approval to the IRB/IEC. The 
2.
Investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The Investigator
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The Investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the informed consent 
form. A copy of the signed informed consent form will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must be made in the 
subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the Investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e. HIPAA).


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8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The Investigator may use this information for the purpose 
of the study only. It is understood by the Investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical Investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
Investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the Investigator and/or institution with the following:
●
Study protocol (and amendments, where applicable)
●
Investigator’s Brochure (and amendments, where applicable)
●
eCRFs and SAE Report Worksheet
●
Study drug with all necessary documentation
●
Study contract
In order to start the study, the Investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
●
Financial disclosure in compliance with federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572, if conducted under a U.S. IND
●
Signed Investigator's Statement in this protocol and CRF
●
Current Curricula Vitae of all investigators
●
List of sub-investigators and collaborators 
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY)
●
Instruction and decision of the head of the study site
●
Study contract
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
At the end of the study, the sponsor is responsible for the collection of:
●
Unused study documentation,
●
Unused study drug
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs, and Investigator's File) and relevant correspondence.  These documents are to 


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be kept on file for the appropriate term determined by local regulation (for US sites, two 
years after approval of the NDA or discontinuation of the IND). The Sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD is discontinued.  
The Investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject. 
The Investigator and sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments.
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the Sponsor, the Investigator, the regulatory authority, and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the Sponsor and the Investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others 
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File. 
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.


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9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.


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10
STUDY ORGANIZATION
10.1
Data and Safety Monitoring Board (DSMB) | Independent Adjudication 
Committee (IAC)
A DSMB will be established for this study and remain active for the study duration. The 
DSMB will examine safety data and be informed of seizure events as expediently as possible. 
The role and responsibilities of the DSMB will be described in the DSMB charter which will 
be in place for the start of the study. Details of statistical boundaries for monitoring of the 
seizure event will be provided in the DSMB charter.
An IAC will be established to assess all suspected seizure events occurring during the study. 
The committee will consist of independent members of appropriate expertise who are not 
directly involved in the conduct of the clinical study. Suspected seizure adverse events and 
related information of the cases will be sent to the committee for assessment. A separate 
charter will describe the classification of those events to be adjudicated and the specification 
of the event-related documents, listings, data flow, method(s) for data collection, and any 
applicable data transfers.


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11
REFERENCES 
Cockcroft DW, Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
1976;16;31-41.
Greenwood, M. The Natural Duration of Cancer. Reports of Public Health and Related Subjects.
Vol. 33, 1-26
Kaplan E. L., Meier P., Nonparametric Estimation from Incomplete Observations, Journal of the 
American Statistical Association, 1958; Vol. 53, No 282: 457-481Kulldorff M, Davis RL, 
Kolczakâr M, Lewis E, Lieu T, Platt R. A Maximized Sequential Probability Ratio Test for 
Drug and Vaccine Safety Surveillance. Sequential Analysis: Design Methods and Applications. 
2011; 30: 58-78. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 
5:649-655.
Enzalutamide Investigator’s Brochure


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12
APPENDICES
12.1
List of Drugs that May Lower Seizure Threshold
Category
Drug
Antiasthmatics
Aminophylline, theophylline
Antibiotics
Isoniazid, lindane, metronidazole, nalidixic acid, penicillins, and 
certain cephalosporins
Antidepressants
Tricyclics, serotonin-specific agents, bupropion, mirtazepine
General anesthetics
enfluraneketamine
Hormones
Insulin, estrogen
Immunosuppressants
Chlorambucil, cyclosporine 
Local anesthetics
Lidocaine, bupivicaine, procaine
Narcotics
Fentanyl, meperidine, pentazocine, propoxyphene
Psychostimulants
Amphetamines, cocaine, methylphenidate, phenylpropanolamine
Neuroleptics
Anti-psychotics including but not limited to clozapine, 
phenothiazines, butyrophenones; also the anti-emetic 
prochlorperazine.
Other
Anticholinergics, anticholinesterases, antihistamines, baclofen, 
heavy metals, hyperbaric oxygen, lithium, mefenamic acid, oral 
hypoglycemic, oxytocin
Source include from:  http://professionals.epilepsy.com/page/table_seniors_drugs html


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy who reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, ALP, and TBL). Testing should be repeated within 48-72 hours of notification of 
the test results. For studies in which a central laboratory is used, alerts will be generated by the 
central lab regarding moderate and severe liver abnormality to inform the Investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN (in patients without 
liver metastases), > 5 x ULN (in 
patients with liver metastases)
or
> 2 x ULN
Severe*
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases)
●
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
The Investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-eCRF) that has been developed globally and can be activated for the study. Subjects 
with confirmed abnormal liver function testing should be followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above , in the absence of another 
etiology may be considered an important medical event and may be reported as a Serious 


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Adverse Event (SAE). The Sponsor should be contacted and informed of all subjects for whom 
severe hepatic liver function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the Investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ‘adverse events’ on the AE page of 
(e)CRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The Investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function.    
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the (e)CRF. Information on alcohol, other substance use, and diet 
should be entered on the LA-eCRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
○
acute viral hepatitis (A,B, C, D, E or other infectious agents). 
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-eCRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The Investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant).” The two “requirements” for Hy’s Law are:1. Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated patients to be discriminating”). 2. Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.]
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Common Serious Adverse Events
The following is a list of serious adverse events that the Sponsor considers to be common for 
the study population defined in this protocol and should be reported by the Investigator as 
described in Section 5.5.5 Reporting of Serious Adverse Events (SAE).
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicate they occur more 
frequently with study drug, an expedited IND safety report may be submitted to the FDA.

Anemia 

Anorexia 

Asthenia / Fatigue

Back pain 

Bone pain

Catheter related infection 

Dyspnea

Haematuria 

Hydronephrosis 

Metastases to bone 

Metastases to central nervous system 

Nausea 

Obstructive uropathy 

Pain 

Prostate cancer metastatic 

Renal failure 

Renal failure acute 

Spinal compression fracture 

Spinal cord compression 

Urinary retention 

Urinary tract infection 

Urinary tract obstruction 

Vomiting


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12.4
Retrospective PGx Sub-Study
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies 
(GWAS), the relationship between gene profiles and a drug’s kinetics, efficacy or toxicity 
may be better understood. As many diseases may be influenced by one or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics, and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx sub-
study. As part of this sub-study, subjects must provide separate written consent prior to 
providing any blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide one 4-6 ml  tube of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique subject number 
(first code). Samples will be shipped frozen to a designated banking CRO either directly from 
site or via a central laboratory as directed by Astellas.
BANKING CRO STORAGE AND SAMPLE CODING 
Once received at the banking CRO, the samples will be assigned a unique sample code (second 
code) and stored frozen. A table linking the subject number (first code) with the newly-assigned 
sample code (second code) will be kept by the banking CRO. 
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and / or safety. Prior to initiating any analysis on the banked samples, the 
Astellas ethical committee (AREC) must approve the analysis plan.


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DISPOSAL OF PGx SAMPLES / DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.
INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any Investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas. 


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ISN/Protocol 9785-CL-0403
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Version 3.1 Incorporating Non-Substantial Amendment 3
12.5
Planned Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, Czech Republic, Finland, France, 
Germany, Greece, Hong Kong, Hungary, Israel, Italy, Mexico, New Zealand, Russia, 
Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States 


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12.6
Study Milestones
Following are the planned study milestone dates:
Start of Data Collection 
September 2013
End of Data Collection or Date of Early 
Termination, if applicable
June 2018
Study Progress Report(s)
Progress reports will be submitted as agreed 
with relevant national competent authorities  
or in any periodic safety reports and RMP 
updates, where applicable
Interim Report(s) of Study Results, where 
applicable
No formal interim analysis is planned for the 
study
Final Report of Study Results
March 2019
Date of Protocol Approval by IRB/EC
US (August 2013)


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Version 3.1 Incorporating Non-Substantial Amendment 3
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 3
I   The purpose of this amendment is:
Non-Substantial Changes
Update contact information
1.
DESCRIPTION OF CHANGE 
Update contact information to reflect the current responsible personnel.
RATIONALE
Astellas Sponsor contact information has been updated to identify current and additional 
study team.
Update to study design, dose regimen and discontinuation
2.
DESCRIPTION OF CHANGE 
Update the continuation and duration of subjects who receive enzalutamide to roll-over to a 
separate open-label extension study.
RATIONALE
The sponsor may decide to potentially roll-over subjects who receive enzalutamide and 
clinical benefit the treatment, and not have met any discontinuation criteria, to continue into a 
separate Astellas sponsored open-label extension study.
Update to criteria for continuation of treatment
3.
DESCRIPTION OF CHANGE
Addition of concomitant medications to criteria for continuation of treatment when subjects 
continued in the extension period, and revision of text.
RATIONALE
Concomitant medications were omitted from the previous protocol when subjects continued 
in the extension period.  




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ISN/Protocol 9785-CL-0403
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20 Oct 2016
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Version 3.1 Incorporating Non-Substantial Amendment 3
IV Synopsis, 2 Study Objectives, Design, and Endpoints, 5. Treatments and Evaluation, 
6 Discontinuation
Study Design Overview, Section 2.2.1 Study Design, Section 5.1.1Dose/Dose regimen and 
Administration, Section 6.1 Discontinuation of Individual Subject(s)
ADDED:
Subjects who are continuing to receive clinical benefit from treatment with 
enzalutamide and have not met any discontinuation criteria may transition to an open 
label roll-over extension study upon approval of the study protocol at the institution 
where they are receiving treatment.
IV Synopsis
Duration of Treatment
ADDED :
Subjects may be asked to complete their extension period participation in another 
Astellas sponsored study upon activation of the roll-over extension study at the 
institution.
IV Synopsis
Table 1: Schedule of assessments, footnote j and k
WAS:   
j. Extension period will begin for subjects who are assessed as deriving benefit from 
enzalutamide treatment after completion of the 4-month treatment. For any subject who 
continues on treatment after his 12-month extension period, data collection will be limited 
to dosing information, and all AEs including SAEs. 
k. For only subjects continuing in the extension period.  
IS AMENDED TO: 
j. Extension period will begin for subjects who are assessed as deriving benefit from 
enzalutamide treatment after completion of the 4-month treatment.  For any subject who 
continues on treatment after his 12-month extension period, data collection will be limited 
to dosing information, concomitant medication, and all AEs including SAEs.  Subjects 
continuing into the extension period may be asked to complete their extension period 
participation in another Astellas sponsored study upon activation of the roll-over 
extension study at the institution. A Follow-up visit will not be required if subject 
move into the roll-over extension study.
k. For only subjects continuing in the extension period who do not continue into the roll-
over extension study at the institution.
5.1 Treatments and Evaluation
Section 5.1.5, Criteria for Continuation of Treatment
WAS:   


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Version 3.1 Incorporating Non-Substantial Amendment 3
When any subject who continues on treatment after his 12-month extension period, data 
collection will be limited to dosing information and all AEs including SAEs.
IS AMENDED TO: 
When any subject who continues on treatment after his 12-month extension period, data 
collection will be limited to dosing information, concomitant medications and all AEs 
including SAEs.
III. Non-Substantial Amendment Rationale:
Rationale for Non-Substantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety or 
scientific value of the clinical study.


Sponsor: APGD
ISN/Protocol 9785-CL-0403
EudraCT number 2013-003022-92
- CONFIDENTIAL -
20 Oct 2016
Astellas
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Version 3.1 Incorporating Non-Substantial Amendment 3
[GPF V4.0]
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
A Multicenter, Single-Arm, Open-Label, Post-Marketing Safety 
Study to Evaluate the Risk of Seizure Among Subjects with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Treated with Enzalutamide Who Are at Potential Increased Risk 
of Seizure (UPWARD)
ISN/Protocol 9785-CL-0403
ClinicalTrials.gov Identifier: NCT01977651
Date of SAP v1: 25 Mar 2014
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 1 of 21
STATISTICAL ANALYSIS PLAN
Final Version 1.00, dated 25-Mar 2014
A Multicenter, Single-Arm, Open-Label, Post-Marketing Safety Study to Evaluate the Risk 
of Seizure Among Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Treated with Enzalutamide Who Are at Potential Increased Risk of Seizure
ISN: 9785-CL-0403
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way,
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 2 of 21
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 7
Flow Chart·································································································· 7
Table 1: Schedule of Assessments······································································· 8
3
STUDY OBJECTIVE(S) AND DESIGN······················································10
3.1
Study Objective(s) ············································································10
3.2
Study Design···················································································10
3.3
Randomization·················································································10
4
SAMPLE SIZE ····················································································10
5
ANALYSIS SETS ·················································································11
5.1
Safety Analysis Set (SAF) ···································································11
5.2
Seizure Risk Evaluation Set (SRES)························································11
6
ANALYSIS VARIABLES ·······································································11
6.1
Efficacy Variables ············································································11
6.2
Safety Variables···············································································11
6.2.1
Primary Endpoint········································································11
6.2.2
Other Safety Variables··································································12
6.3
Other Variables················································································12
7
STATISTICAL METHODOLOGY ···························································13
7.1
General Considerations·······································································13
7.2
Study Population ··············································································13
7.2.1
Disposition of Subjects ·································································13
7.2.2
Protocol Deviations ·····································································13
7.2.3
Demographic and Other Baseline Characteristics ···································14
7.2.4
Previous and Concomitant Medications ··············································14
7.3
Study Drugs····················································································14
7.3.1
Exposure··················································································14
7.3.2
Treatment Compliance··································································15
7.4
Analysis of Efficacy ··········································································15
7.5
Analysis of Safety·············································································15


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 3 of 21
7.5.1
Analysis of Primary Endpoint ·························································15
7.5.2
Adverse Events ··········································································16
7.5.3
Clinical Laboratory Evaluation ························································16
7.5.4
Vital Signs················································································17
7.5.5
Electrocardiograms (ECGs)····························································18
7.5.6
Pregnancies···············································································18
7.6
Analysis of PK·················································································19
7.7
Analysis of PD·················································································19
7.8
Subgroups of Interest ·········································································19
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················19
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········19
7.10.1
Missing Data ·············································································19
7.10.2
Outliers ···················································································19
7.10.3
Visit Windows ···········································································20
8
DOCUMENT REVISION HISTORY·························································20
9
REFERENCES ····················································································20
10
APPENDICES ·····················································································21
10.1
Appendix 1: Signatures·······································································21


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 4 of 21
I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
APGD
Astellas Pharma Global Development
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
CI
Confidence Intervals
CRF
Case Report Form
CSR
Clinical Study Report
DBP
Diastolic Blood Pressure
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
EOS
End of Study
H
High
ICH
International Conference on Harmonization
L
Low
LLN 
Lower Limit of Normal
MedDRA
Medical Dictionary for Regulatory Activities
N
Normal
PT
Preferred Term
QTc
Corrected Q-T Interval
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS 
Statistical Analysis Software
SBP
Systolic Blood Pressure
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
TLF
Tables, Listings and Figures
ULN
Upper Limit of Normal


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 5 of 21
List of Key Terms
Terms
Definition of terms
Endpoint
A variable that pertains to the trial objectives
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 6 of 21
1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.
The SAP is finalized and signed prior to database hard lock to ensure lack of bias. For 
operational efficiency an earlier time is usually targeted. If needed, revisions to the approved 
SAP may be made prior to database hard lock. Revisions will be version controlled.
This statistical analysis is coordinated by the responsible biostatistician of APGD-US. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock.


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 7 of 21
2
FLOW CHART AND VISIT SCHEDULE
Flow Chart




Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 9 of 21
a.
Informed consent form must be obtained prior to any study-specific procedures being performed.
b.
A Follow-up Visit will be performed 30 days after the last dose of enzalutamide, or prior to the initiation of another anticancer therapy, 
whichever occurs first.
c.
Suspected seizure visit occurring any time during the 4 month therapy as well as during extension period.
d.
Full physical exams will be performed including neurological exam. The physical examination performed at the Screening Visit does not need 
to be repeated on Day 1, if the Day 1 visit occurs within 72 hours of Screening.
e.
At Screening, a thorough neurological history and examination will be performed by a local neurologist to obtain complete medical history 
relating to seizure risk, to confirm that a subject has met seizure risk entry criteria and to complete neurological baseline examination.
f.
The laboratory assessments performed at the Screening visit do not need to be repeated on Day 1, if the Day 1 visit occurs within 72 hours of 
Screening. 
g.
Disease assessments will be performed regularly, per standard of care, or when there is clear clinical evidence of progression, while the subject 
is receiving enzalutamide. Disease assessments will also be performed after a first confirmed seizure to ensure favorable risk/benefit profile to 
continue enzalutamide. Disease assessments may include clinical, radiographic and/or PSA assessments.
h.
Serious adverse events (SAEs) including death will be collected from the time the subject signs the consent form until 30 days after last dose of 
enzalutamide. Non-serious adverse events will be collected from time of study drug administration on Day 1 until 30 days after last dose of 
enzalutamide.
i.
Extension period will begin for subjects who are assessed as deriving benefit from enzalutamide treatment after completion of the 4-month 
treatment. Data will be collected in the extension period for each subject for a period of 1 year after the 4-month treatment visit or 30 days post 
discontinuation during the one year timeframe. For any subject who continues on treatment after his 12-month extension period, data collection 
will be limited to dosing information, SAE, AEs Grade 3 or higher that are drug related and AEs of special interest or that lead to 
discontinuation.
j.
For only subjects continuing in the extension period. 


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 10 of 21
3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
The study objective is to evaluate the seizure rate and monitor the safety of enzalutamide 
treatment in subjects with metastatic castration-resistant prostate cancer known to have risk 
factor(s) for seizure.
3.2
Study Design
This is a multicenter, single-arm, open-label, post-marketing safety study to evaluate the risk 
of seizure among subjects with metastatic castration-resistant prostate cancer (mCRPC) 
treated with enzalutamide who are at potential increased risk of seizure. 
Subjects will be enrolled into the study and participate in a 4-month treatment period of 
enzalutamide (160 mg/day). At the end of the 4-month treatment visit, subjects who are 
assessed as deriving benefit from enzalutamide treatment may continue in the extension 
period. Data will be collected in the extension period for each subject per the Schedule of 
Assessments for a period of one year after the 4-month treatment visit or 30 days post 
discontinuation during the one year timeframe. 
When any subject who continues on treatment after his 12-month extension period, data 
collection will be limited to dosing information, serious adverse events (SAEs), AEs Grade 3 
or higher that are drug related, and AEs of special interest or that lead to discontinuation. 
Each subject will be given a patient card with the following information; a list of signs and 
symptoms of a suspected seizure (Seizure Description Subject Information) and a Suspected 
Seizure Event Questionnaire list as well as instructions regarding what to do in the event of a 
suspected seizure for awareness. 
3.3
Randomization
This is a single-arm study and no randomization is considered.
4
SAMPLE SIZE
Approximately four hundred (400) subjects will be enrolled to target approximately 350 
evaluable subjects, assuming a drop-out rate of approximately 13%  for this population and 
based on the recommendation from the FDA, respectively. Assuming the true incidence of 
seizure as 1% and the sample size of 350, the chance of observing 5 or less subjects with 
seizure events is 85.9%. Given 5 out of 350 subjects, i.e., point estimate of 1.43%, the upper 
limit 95% exact confidence interval will be 3.31% and the width of the exact confidence 
interval will be 2.84%.


Sponsor: Astellas Pharma Inc
SAP Final 25-Mar-2014
ISN/Protocol 9785-CL-0403
Astellas
Page 11 of 21
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
5.1
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all randomized subjects who received at least one 
dose of study drug and for whom any data is reported after first dose of study drug. 
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
5.2
Seizure Risk Evaluation Set (SRES)
For the statistical summary and analysis of seizure events, seizure risk evaluation set (SRES) 
will be used by including all evaluable subjects. An evaluable subject is defined as a subject 
with a confirmed seizure during the 4-month treatment period of the study or who completed 
at least 3 months (75%) of the planned treatment.
6
ANALYSIS VARIABLES
6.1
Efficacy Variables
Efficacy variables include clinical, radio-graphic and/or PSA assessments.
6.2
Safety Variables
6.2.1
Primary Endpoint
The proportion of subjects in SRES with at least one confirmed seizure as adjudicated by the 
Independent Adjudication Committee (IAC) during the 4-month treatment duration. 
An evaluable subject is defined as a subject with a confirmed seizure during the 4-month 
treatment period of the study or who completed at least 3 months (75%) of the planned 
treatment. Only an enrolled subject who discontinues the study before completing 3 months 
on treatment may be replaced at the discretion of the Sponsor, however, an enrolled subject 
who is discontinued due to a confirmed seizure event will not be replaced.
A cumulative summary to include all seizure events, including those occurring beyond the 
4 month treatment period will be included.


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In case the drop-out rate is higher than expected, appropriate method such as Kaplan-Meier 
estimations may be considered.
6.2.2
Other Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug).
●
Clinical laboratory variables (hematology, biochemistry including liver function tests,
and urinalysis)
●
Vital signs (systolic and diastolic blood pressure and pulse rate)
●
12-lead electrocardiogram (ECG)
TEAE is defined as an adverse event observed after starting administration of the test 
drug/comparative drug. If the adverse event occurs on Day 1 and the onset check box is 
marked “Onset after first dose of study drug” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs on Day 1 
and the onset check box is marked “Onset before first dose of study drug”, then the adverse 
event will not be considered treatment emergent. If a subject experiences an event both 
during the pre-investigational period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity (i.e. it is reported with a new start 
date). All adverse events collected that begin within 30 days after taking the last dose of 
study drug will also be counted as TEAE.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
6.3
Other Variables
●
The duration of exposure
For each subject, the Length of Time on study drug will be calculated in days, using the 
following formula:
(‘Date last dose of study drug’# - ‘Date first dose*) + 1
# = [End of study (EOS)-page of the Case Report Form (CRF)]
* = ‘date first study drug taken since last visit’ [Visit 3-page of the CRF]
●
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date of 
the first dose of study drug. 


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Concomitant medication is defined as medication with at least one dose taken between the
date of first dose (inclusive) and the date of last dose (inclusive) of study drug.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g.10%, 25%, 75% and 90%) will be mentioned in the relevant section.
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e. will add up to 100%.
All data processing, summarization, and analyses will be performed using SAS® Version 
9.1.3 or higher on Unix. Specifications for table, figures, and data listing formats can be 
found in the TLF specifications for this study.
For the definition of subgroups of interest please refer to section 7.8.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number and percentage of subjects in each analysis set;
●
Number and percentage of subjects completed and discontinued 4 month treatment 
period, by primary reason for treatment discontinuation; 
●
Number and percentage of subjects completed and discontinued the 1 year extension 
period, by primary reason for discontinuation; and
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all enrolled subjects. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by total as well as by study site.
Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. A data listing will be provided by site and subject.   
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 


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7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive statistics.
Number and percentage of subjects enrolled in each country and site will be presented for the 
SAF.
Medical history is coded in MedDRA, and will be summarized by System Organ Class
(SOC) and Preferred Term (PT) as well as by PT alone for the SAF.
Baseline tumor burden will be summarized by body system.
Prostate cancer diagnosis and the categories of seizure risk will be summarized using 
frequencies. 
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. 
As with previous medication, concomitant medication will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. Subjects taking the same medication multiple times will be counted once per 
medication and investigational period. A medication which can be classified into several 
chemical and/or therapeutic subgroups is presented in all chemical and therapeutic subgroups.
Prostate cancer treatment history will be summarized.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for the SAF:
●
Descriptive statistics for average daily dose; and
●
Number and percent of subject with dose increases, decreases or interruptions
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented.
●
Exposure time will be categorized according to the following categories:
○
less than 3 months
○
at least 3 month, less than 6 months
○
at least 6 month, less than 9 months 
○
at least 9 month, less than 12 months 
○
at least 12 month, less than 15 months 
○
15 months or more


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○
Unknown.
Counts and percentages of subjects in each of these categories will be summarized for the 
SAF.
7.3.2
Treatment Compliance
Overall compliance will be examined for subjects in the SAF whose total study drug count 
and first and last days of treatment are known. The drug dispense records will be collected as 
a part of IVRS data. 
Percent overall compliance will be summarized in two ways for the SAF:
●
Descriptive statistics will be presented
●
Percent compliance will be categorized according to the following categories:
○
less than 50%
○
at least 50%, less or equal to 75%
○
greater than 75%
○
Unknown.
The summaries described above will be provided for 4 month treatment period and entire 
study period separately.
7.4
Analysis of Efficacy 
Efficacy data will be collected at baseline and at the time of seizure event for this study. No 
statistical analysis will be conducted. Instead, disease assessments including clinical, radio-
graphic and/or PSA assessments collected will be listed.
7.5
Analysis of Safety
All analysis of safety will be presented for SAF, unless specified otherwise. 
7.5.1
Analysis of Primary Endpoint
7.5.1.1 Primary Analysis
Primary endpoint, the proportion of evaluable subjects with at least one confirmed seizure as 
adjudicated by the IAC during the 4-month treatment duration, will be estimated using point 
estimate and its 95% exact confidence interval using all SRES. 
7.5.1.2 Secondary Analysis
The same analysis of the primary endpoint as described in 7.5.1.1 will be conducted for a 
cumulative proportion to include all seizure events, including those occurring beyond the 4 
month-treatment period using all SRES.  Incidence of seizure events, including only the first 
seizure event, per patient-time exposure will be summarized for SAF. Any subsequent 
seizure event(s) will be listed.
In addition, seizure event free rate at 4 months, 12 months, and 16 months will be calculated 
using Kaplan-Meier estimation if data permit in SAF.


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7.5.2
Adverse Events
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT.
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, and
●
Number of deaths.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized. Summaries will be provided for:
●
TEAEs
●
drug related TEAEs, 
●
serious TEAEs, 
●
drug related serious TEAEs,
●
TEAEs leading to permanent discontinuation of study drug, 
●
drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 3.0%, and 
●
common TEAEs that equal to or exceed a threshold of 5.0%
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized.
TEAEs and the number and percentage of subjects with TEAEs, as classified by SOC and PT 
will also be summarized by CTC Grade. If an adverse event changes in CTC Grade, then the 
subject will be counted only once with the worst grade. The adverse event however will be 
presented in each category they were classified to. If a subject has an event more than once 
with missing grade and with non-missing grade, then the subject will be counted as missing. 
7.5.3
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration.  
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and urinalysis will 
be summarized using mean, standard deviation, minimum, maximum and median at each 
visit. Additionally, a within-subject change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way. Each 


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laboratory result will be classified as low (L), normal (N), or high (H) at each visit according 
to the laboratory supplied reference ranges. 
The number and percentage of subjects below and above reference range will be summarized 
at each visit. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented at each visit. 
For hematology and biochemistry two types of shift tables will be presented: 
●
Shift tables of reference range changes from baseline to worst finding during the 
treatment period (low, normal, high), and
●
Shift tables of NCI CTC Grade changes from baseline to worst grade during the 
treatment period.
7.5.3.1 Liver function tests
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
investigational period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
function tests during the investigational period will be presented.
7.5.4
Vital Signs and physical exam
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by visit. 


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Additionally, a within-subject change will be calculated per visit as the post-baseline 
measurement minus the baseline measurement and summarized by visit.  
7.5.5
Electrocardiograms (ECGs)
ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median at each treatment visit and time point, including changes from baseline. 
Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12 lead ECG will be 
tabulated at each treatment visit and time point. 
The QTc interval will be summarized using frequency tables for each treatment visit and time 
point for values of clinical importance using the range criteria below.
QTc Interval Criteria Value (msec)
Normal
Borderline
Prolonged
Clinically significant
≤ 450
> 450 to ≤ 480
> 480 to ≤ 500
> 500
The QTc interval will also be summarized by the frequencies of subjects with a change from 
baseline of clinical importance using the criteria identified below. These summaries will be 
provided for each treatment visit and time point.
Variable
Change from Baseline
QTc Interval (msec)
<0 
≥ 0 to <30 
≥ 30 to < 60 
≥60 
Number and percent of subjects with 12 lead ECG abnormalities as well as number and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated at each treatment visit and time point. 
7.5.6
Pregnancies
Not applicable.
7.5.7
Brain Imaging and Electroencephalogram
Brain imaging and electroencephalogram results collected from suspected seizure visit will 
be listed.


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7.6
Analysis of PK
No analysis of PK is planned. 
7.7
Analysis of PD
No analysis of PD is planned.
7.8
Subgroups of Interest 
In case subgroups which may have association with the risk of  seizure are identified during 
the study, the incidence of seizure events, will be summarized using a proportion estimate 
and its 95% exact confidence interval for the subgroups of the SRES.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned for a specific timepoint.
The study design considers early stopping criteria that can be applied to a study as a whole or 
a specific risk factor group, if any, based on the statistical boundary calculated from 
Maximized Sequential Probability Ratio Test [Kulldorff, 2011]. 
The DSMB will examine safety data and be informed of seizure events as expediently as 
possible. Statistical boundaries for continuously monitoring of the seizure event will be 
provided in the DSMB charter as guidance for early stopping criteria. The DSMB will use 
them to appropriately recommend either stop the enrollment of specific subgroup(s) 
identified during the DSMB review period or in extreme circumstance DSMB may ask 
sponsor to stop the study. 
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other
Information
Refer to the data specification document in which more details are provided.
7.10.1
Missing Data
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication. The imputed dates 
will be used to allocate the concomitant medication and AEs, in addition to determining 
whether an AE is/is not treatment emergent. Listings of the AEs and concomitant medications 
will present the actual partial dates; imputed dates will not be shown.
7.10.2
Outliers
All values will be included in the analyses.


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7.10.3
Visit Windows
The study protocol gives the overall study schedule and the permissible intervals for the
study visits. Analyses will not exclude subject data due to the subject’s failure to comply 
with the visit schedule.
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
DD-MMM-YYYY
NA
Document finalized
9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)