Conditions: Prostate Cancer
Keywords: Leuprolide acetate Prostate cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 107
Healthy volunteers: no

Brief summary:
The objective of this study was to evaluate the safety profile of ELIGARD® in ethnic Asian prostate cancer patients.

Detailed description:

Arms:
arm 1: Participants received 22.5 mg of leuprolide acetate (eligard) by subcutaneous injection at baseline, month 3, 6, 9, 12 and 15.

Interventions: intervention 1: Leuprolide
Intervention descriptions: intervention 1: Subcutaneous Injection

Protocol document:
Prot_000.pdf: 
 
 
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A Phase IV Interventional Safety Study of ELIGARD® in Prostate 
Cancer Patients in Asia (ELIGANT)  
 
 
 
ISN/Protocol 7015-MA-3072 
Version 2.0 
18 April 2018 
 
 
 
 
Sponsor: 
Astellas Pharma Singapore Pte Ltd 
6 Temasek Boulevard, #26-03/04/05 
Suntec Tower Four, Singapore 038986 
 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is supplied as a background for clinical investigations. This document 
contains confidential information which is the intellectual property of Astellas. By accepting or reviewing this 
document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) 
where disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of 
such information is made to a member of the investigator’s team who agrees to hold this information in 
confidence.  
 
 
 
NCT03035032
NCT03035032


 
 
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Table of Contents 
 
 
I. 
SIGNATURES 
······················································································ 7 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 9 
III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
·················· 
10 
IV. 
SYNOPSIS 
·························································································· 
17 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
································· 
23 
1 
INTRODUCTION ················································································ 
27 
1.1 
Background 
···················································································· 
27 
1.2 
Non-clinical and Clinical Data 
······························································ 
29 
1.3 
Summary of Key Safety Information for ELIGARD® ··································· 
31 
1.4 
Risk-Benefit Assessment····································································· 
31 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
·································· 
32 
2.1 
Study Objectives 
·············································································· 
32 
2.2 
Study Design and Dose Rationale ·························································· 
32 
2.2.1 
Study Design 
············································································· 
32 
2.2.2 
Dose Rationale ·········································································· 
33 
2.3 
Endpoints ······················································································ 
33 
2.3.1 
Primary Endpoints ······································································ 
33 
2.3.2 
Secondary Endpoints ··································································· 
34 
2.3.3 
Exploratory Endpoints 
·································································· 
34 
3 
STUDY POPULATION 
·········································································· 
35 
3.1 
Selection of Study Population 
······························································· 
35 
3.2 
Inclusion Criteria 
·············································································· 
35 
3.3 
Exclusion Criteria 
············································································· 
36 
4 
TREATMENTS ··················································································· 
37 
4.1 
Identification of Investigational Product 
··················································· 
37 
4.1.1 
Test Drug(s) 
·············································································· 
37 
4.1.2 
Comparative Drug(s) ··································································· 
37 
4.1.3 
Drug(s) for Screening 
··································································· 
37 
4.1.4 
Rescue Drug(s) 
·········································································· 
37 


 
 
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4.2 
Packaging and Labeling 
······································································ 
37 
4.3 
Study Drug Handling 
········································································· 
38 
4.4 
Blinding 
························································································ 
38 
4.5 
Assignment and Allocation 
·································································· 
38 
5 
TREATMENTS AND EVALUATION ······················································· 
39 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) 
················ 
39 
5.1.1 
Dose/Dose Regimen and Administration Period 
···································· 
39 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
································ 
39 
5.1.3 
Previous and Concomitant Treatment ················································ 
39 
5.1.4 
Treatment Compliance ································································· 
39 
5.1.5 
Criteria for Continuation of Treatment 
··············································· 
40 
5.1.6 
Restrictions During the Study ························································· 
40 
5.2 
Assessment at Prescreening Visit 
··························································· 
40 
5.3 
Demographics and Baseline Characteristics 
··············································· 
40 
5.3.1 
Informed Consent and Inclusion/Exclusion Criteria 
································ 
40 
5.3.2 
Demographics ··········································································· 
40 
5.3.3 
Medical History ········································································· 
40 
5.3.4 
Family History for Prostate Cancer 
··················································· 
41 
5.3.5 
Diagnosis of the Target Disease, Severity, and Duration of Disease ············· 
41 
5.3.6 
Most Important Factors for Selection of Treatment 
································· 
41 
5.4 
Efficacy Assessment 
·········································································· 
41 
5.5 
Safety Assessment 
············································································ 
42 
5.5.1 
Vital Signs ··············································································· 
42 
5.5.2 
Adverse Events 
·········································································· 
42 
5.5.3 
Laboratory Assessments 
································································ 
42 
5.5.4 
Imaging 
··················································································· 
42 
5.6 
Adverse Events and Other Safety Aspects 
················································· 
42 
5.6.1 
Definition of Adverse Events (AEs) 
·················································· 
43 
5.6.2 
Definition of Serious Adverse Events (SAEs) 
······································· 
43 
5.6.3 
Criteria for Causal Relationship to the Study Drug 
································· 
44 
5.6.4 
Criteria for Defining the Severity of an Adverse Event ···························· 
45 
5.6.5 
Reporting of Serious Adverse Events (SAEs) 
······································· 
45 
5.6.6 
Follow-up of Adverse Events 
·························································· 
47 
5.6.7 
Monitoring of Common Serious Adverse Events ··································· 
47 


 
 
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5.6.8 
Procedure in Case of Pregnancy of Partner ·········································· 
47 
5.6.9 
Emergency Procedures and Management of Overdose 
····························· 
48 
5.6.10 
Supply of New Information Affecting the Conduct of the Study ················· 
48 
5.7 
Test Drug Concentration 
····································································· 
48 
5.8 
Other Measurements, Assessments or Methods 
··········································· 
48 
5.8.1 
Prostate Cancer Status 
·································································· 
48 
5.8.2 
Supportive Care ········································································· 
48 
5.8.3 
Concomitant Medications Assessment ··············································· 
49 
5.9 
Total Amount of Blood ······································································ 
49 
6 
DISCONTINUATION ··········································································· 
50 
6.1 
Discontinuation of Individual Patients ····················································· 
50 
6.2 
Discontinuation of the Site 
··································································· 
50 
6.3 
Discontinuation of the Study ································································ 
51 
7 
STATISTICAL METHODOLOGY 
··························································· 
52 
7.1 
Sample Size 
···················································································· 
52 
7.2 
Analysis Set ··················································································· 
52 
7.2.1 
Full Analysis Set (FAS) 
································································ 
53 
7.2.2 
Per Protocol Set (PPS) 
·································································· 
53 
7.2.3 
Safety Analysis Set (SAF) ····························································· 
53 
7.2.4 
Pharmacokinetic Analysis Set (PKAS) 
··············································· 
53 
7.2.5 
Pharmacodynamic Analysis Set (PDAS) 
············································· 
53 
7.3 
Demographics and Other Baseline Characteristics ······································· 
53 
7.4 
Analysis of Efficacy 
·········································································· 
54 
7.4.1 
Analysis of Primary Endpoint ························································· 
54 
7.4.2 
Analysis of Secondary Endpoints 
····················································· 
54 
7.4.3 
Analysis of Exploratory Endpoints ··················································· 
54 
7.5 
Analysis of Safety ············································································ 
54 
7.5.1 
Adverse Events 
·········································································· 
54 
7.5.2 
Laboratory Assessments 
································································ 
55 
7.5.3 
Vital Signs ··············································································· 
56 
7.5.4 
Imaging 
··················································································· 
56 
7.6 
Protocol Deviations and Other Analyses 
··················································· 
56 
7.7 
Interim Analysis··············································································· 
56 


 
 
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7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 
56 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
···················· 
57 
8.1 
Procedure for Clinical Study Quality Control 
············································· 
57 
8.1.1 
Data Collection 
·········································································· 
57 
8.1.2 
Specification of Source Documents 
··················································· 
57 
8.1.3 
Clinical Study Monitoring ····························································· 
58 
8.1.4 
Direct Access to Source Data/Documents ··········································· 
58 
8.1.5 
Data Management 
······································································· 
58 
8.1.6 
Protocol Deviations 
····································································· 
59 
8.1.7 
End of Trial in All Participating Countries ·········································· 
59 
8.2 
Ethics and Protection of Patient Confidentiality ·········································· 
60 
8.2.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities 
·································································· 
60 
8.2.2 
Ethical Conduct of the Study ·························································· 
60 
8.2.3 
Informed Consent of Patients 
·························································· 
60 
8.2.4 
Patient Confidentiality 
·································································· 
61 
8.3 
Administrative Matters 
······································································· 
62 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
····· 
62 
8.3.2 
Documents and Records Related to the Clinical Study 
····························· 
62 
8.3.3 
Protocol Amendment and/or Revision 
················································ 
62 
8.3.4 
Insurance of Patients 
···································································· 
63 
8.3.5 
Signatory Investigator for Clinical Study Report ··································· 
63 
9 
QUALITY ASSURANCE ······································································· 
64 
10 
STUDY ORGANIZATION ····································································· 
65 
11 
REFERENCES ···················································································· 
66 
12 
APPENDICES ····················································································· 
67 
12.1 
List of stand-alone documents 
······························································· 
67 
12.2 
List of Excluded Concomitant Medications ··············································· 
68 
12.3 
Liver Safety Monitoring and Assessment 
·················································· 
69 
12.4 
Common Serious Adverse Events ·························································· 
72 
12.5 
EQ5D-5L Questionnaire ····································································· 
72 
12.6 
EORTC QLQ-PR25 Questionnaire 
························································· 
72 
12.7 
Protocol Amendment Summary Document 
················································ 
73 


 
 
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13 
SPONSOR’S SIGNATURES ··································································· 
92 
13.1 
PROTOCOL AUTHORS 
···································································· 
92 
13.2 
PROTOCOL APPROVED BY······························································ 
93 
 
 
 
 
 
 


 
 
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I. 
SIGNATURES 
1. 
SPONSOR’S SIGNATURE 
Required signatures (e.g. Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 13, Sponsor’s Signatures; e-signatures (when applicable) are located at 
the end of this document. 
 
 
 


 
 
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2. 
INVESTIGATOR’S SIGNATURE 
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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II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
Sponsor’s personnel:  
24h- Contact for Serious 
Adverse Events (SAEs):   
See Section 5.6.5 
The SAEs should be reported via eCRF (see Section 
5.6.5).  The email and fax number provided below are 
back-up reporting channels when the eCRF is not 
available: 
 
IQVIA Lifecycle Safety 
Email: QLS_Eligard@quintiles.com  
Fax: +65 6872 8462  
 
Astellas Global Pharmacovigilance-EU 
Email: Safety-EU@astellas.com 
Fax: +31 71 545 5208 
Medical Monitor: 
 
 
 
Clinical Research Contacts: 
 
 
 
 
 
   
 
 
 
 
PPD
 
PPD


 
 
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III. LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADaM 
Analysis Data Model 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate Transaminase 
AT 
Aminotransferase 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRPC 
Castrate Resistant Prostate Cancer 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
EAU 
European Association of Urology 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EORTC 
European Organization for Research and Treatment of Cancer  
EQ5D-5L 
EuroQol 5 Dimension 5 Level Health State Utility Index 
FAS 
Full Analysis Set 
FDA 
Food Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin Releasing Hormone (synonymous to LHRH) 
GPP 
Good Pharmacovigilance Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health Related Quality of Life 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board   
KM 
Kaplan-Meier 
LA-CRF 
Liver Abnormality Case Report Form 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Testing  
LHRH 
Luteinizing Hormone Releasing Hormone (synonymous to GnRH) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
O.D. 
Once Daily 


 
 
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Abbreviations 
Description of abbreviations 
PASS 
Post-Authorization Safety Study  
PD 
Protocol Deviation 
PDAS 
Pharmacodynamic Analysis Set  
PET 
Positron Emission Tomography 
PHI 
Protected Health Information  
PKAS 
Pharmacokinetic Analysis Set  
pPRO 
Paper Patient Reported Outcome 
PPS 
Per Protocol Set 
PS 
Pre-Screening 
PRO 
Patient Reported Outcome 
PSA 
Prostate Specific Antigen 
PT 
Preferred Term 
QC 
Quality Control 
QLQ 
Quality of Life Questionnaire 
QoL 
Quality of Life 
RFT 
Renal Function Test  
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
TBL 
Total Bilirubin 
TMF 
Trial Master File 
TNM 
Tumor, Nodes, Metastasis  
ULN 
Upper Limits of Normal 
VAS 
Visual Analogue Scale 
WD 
Withdrawal 
WHO 
World Health Organization  
WMA 
World Medical Association  


 
 
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Definition of Key Study Terms 
Terms 
Definition of terms 
Adverse Event (AE) 
An adverse event is as any untoward medical occurrence in a patient 
administered a study drug and which does not necessarily have a causal 
relationship with this treatment (see also Eligard-related AE). 
Approval (in relation to 
IRB) 
The affirmative decision of the institutional review board (IRB) that the 
clinical trial has been reviewed and may be conducted at the institution 
site within the constraints set forth by the IRB, the institution, good 
clinical practice (GCP), and the applicable regulatory requirements. 
Baseline 
1. Observed values/findings which are regarded as starting points for 
comparison. 
2. Time when ‘Baseline’ is observed. 
Case Report Form 
(CRF) 
A printed, optical, or electronic document designed to record all of the 
protocol required information to be reported to the sponsor for each trial 
patient. 
Castrate Resistant 
Prostate Cancer (CRPC) 
The European Association of Urology (EAU) Prostate Cancer Guidelines 
2016 defines CRPC as:  
Castrate serum testosterone < 50ng/dL or 1.7 nmol/L plus either; 
Biochemical progression: 3 consecutive rises in prostate specific antigen 
(PSA) at least 1 week apart resulting in two 50% increases over the nadir, 
and a PSA > 2 ng/mL or 
Radiological progression:  the appearance of two or more new bone 
lesions on bone scan or enlargement of a soft tissue lesion using RECIST 
(Response Evaluation Criteria in Solid Tumors).   
Symptomatic progression alone must be questioned and is not sufficient 
to diagnose CRPC.  
Causality Assessment 
An evaluation performed by a medical professional concerning the 
likelihood that a therapy or product caused or contributed to an AE.  A 
positive causality assessment made by either reporter and/or company 
makes an AE into an ADR. 
Clinical Study 
Any investigation in relation to humans intended: 
a) to discover or verify the clinical, pharmacological or other 
pharmacodynamic effects of 1 or more medicinal products; 
b) to identify any adverse reactions to 1 or more medicinal products; or 
c) to study the absorption, distribution, metabolism and excretion of 1 or 
more medicinal products; with the objective of ascertaining their safety 
or efficacy. 
Confidence Interval (CI) A measure of the precision of an estimated value.  
The interval represents 
the range of values, consistent with the data that is believed to encompass 
the “true” value with high probability (usually 95%) upon repeated 
sampling according to frequentist theory. The confidence interval (CI) is 


 
 
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expressed in the same units as the estimate. Wider intervals indicate 
lower precision; narrow intervals, greater precision. 
Confidentiality 
Prevention of disclosure to other than authorized individuals of 
proprietary information or of a patient’s identity. 
Consent Form 
Document used during the informed consent process that is the basis for 
explaining to potential patients the risks and potential benefits of a study 
and the rights and responsibilities of the parties involved.  The informed 
consent document provides a summary of a clinical trial (including its 
purpose, the treatment procedures and schedule, potential risks and 
benefits, alternatives to participation, etc.) and explains an individual’s 
rights as a patient. It is designed to begin the informed consent process, 
which consists of conversations between the patient and the research 
team. 
If the individual then decides to enter the trial, s/he gives her/his official 
consent by signing the document.  Synonym: informed consent form 
(ICF) 
Contract Research 
Organization (CRO) 
A person or an organization (commercial, academic, or other) contracted 
by the sponsor to perform 1 or more of a sponsor’s trial-related duties 
and functions. 
Data Collection 
In the context of clinical research, accessing and recording information 
that provides source data for analysis and interpretation. 
Data Management 
Tasks associated with the entry, transfer, and/or preparation of source 
data and derived items for entry into a clinical trial database. Data 
management could include database creation, data entry, review, coding, 
data editing, data quality control (QC), locking, or archiving; it typically 
does not include source data capture. 
Data Monitoring 
Process by which data are examined for completeness, consistency, and 
accuracy. 
Data Quality 
A dimension of data contributing its trustworthiness and pertaining to 
accuracy, sensitivity, validity, and suitability to purpose.  Key elements 
of data quality include attribution, legibility (decipherable, 
unambiguous), contemporaneousness, originality (i.e., not duplicated), 
accuracy, precision, completeness, consistency (logical, not out of 
range), and those who have modified the data. 
Declaration of Helsinki A set of recommendations or basic principles developed by the World 
Medical Association (WMA) that guide medical doctors in the ethical 
conduct of biomedical research involving human patients. It was 
originally adopted by the 18th World Medical Assembly (Helsinki, 
Finland, 1964). 
Demographic data 
Characteristics of patients or study populations, which include such 
information as age, sex, family history of the disease or condition for 
which they are being treated, and other characteristics relevant to the 
study in which they are participating. 


 
 
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Discontinuation 
The act of concluding participation, prior to completion of all protocol-
required elements, in a study by an enrolled patient.   
Effectiveness 
The capability of an intervention in producing a desired result under 
circumstances that more closely approach real-world practice, with more 
heterogeneous populations, less-standardized treatment protocols, and 
delivery in routine clinical settings.   
Electronic Case Report 
Form (eCRF) 
Auditable electronic record designed to capture information required by 
the clinical trial protocol to be reported to the sponsor on each trial 
patient. 
Eligard-related Adverse 
Event 
An adverse event in a patient administered Eligard where a causal 
relationship is at least a reasonable possibility (drug event with either a 
possible or probable causal relationship), as determined by the opinion 
of the investigator.  
Adverse events listed in the local label should be used by the investigator 
as reference safety information to understand whether an adverse event 
is expected with the use of Eligard.  This understanding should inform 
causality assessments by the investigator.      
Ethnic Asian 
Any of the following races - Chinese, Filipino, Indonesian, Malay, Thai, 
Vietnamese, Indian, Japanese or Korean.  
Final Visit 
The final visit will be the same as the last follow-up visit for each patient.  
It will occur at the 18
th month after enrollment into the study, provided 
that none of discontinuation criteria (see Section 6) are met. 
Hormonal Treatment-
Naive Prostate Cancer  
Prostate cancer that has not received endocrine manipulation. 
Hormone Sensitive 
Prostate Cancer  
Prostate cancer that has been treated with hormonal agents but has not 
progressed. 
Patient Reported 
Outcome (PRO) 
A PRO is a measurement based on a report that comes from the patient 
(i.e., study patient) about the status of a patient’s health condition without 
amendment or interpretation of the patient’s report by a clinician or 
anyone else.  A PRO can be measured by self-report or by interview, 
provided that the interviewer records only the patient’s response. 
Symptoms or other unobservable concepts known only to the patient 
(e.g., pain severity or nausea) can only be measured by PRO measures. 
PROs can also assess the patient perspective on functioning or activities 
that may also be observable by others. 
Post-Authorization 
Safety Study (PASS)  
Any study relating to an authorized medicinal product in the EU, 
conducted with the aim of identifying, characterizing, or quantifying a 
safety hazard (e.g., a potential or identified risk), confirming the safety 
profile of the medicinal product, or of measuring the effectiveness of risk 
management measures [DIR 2001/83/EC Art 1(15)/ GVP Module VIII]. 
A post-authorization safety study may be an interventional clinical trial 
or may follow a non-interventional study design.  
Primary data collection Data collection directly from patients and healthcare professionals. 
Protocol 
A document that describes the objective(s), design, methodology, 
statistical considerations, and organization of a trial. The protocol usually 


 
 
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also gives the background and rationale for the trial, but these could be 
provided in other protocol referenced documents. Throughout the 
International Conference on Harmonisation – Good Clinical Practice 
(ICH GCP) Guideline the term protocol refers to protocol and protocol 
amendments. 
Quality of Life (QoL) 
A broad ranging concept that incorporates an individual’s physical 
health, psychological state, level of independence, social relationships, 
personal beliefs, and their relationships to salient features of the 
environment.  
Note: Quality of Life is one way to measure the benefits or negative 
impacts of an “improvement” measured in terms of a physiological or 
psychological symptom. QoL research seeks to quantify what an 
intervention means to a patient’s sense that their life has changed. 
Questionnaire 
A set of questions or items shown to a respondent in order to get answers 
for research purposes. 
Safety 
Relative freedom from harm. In clinical trials, this refers to an absence 
of harmful side effects resulting from use of the product and may be 
assessed by laboratory testing of biological samples, special tests and 
procedures, psychiatric evaluation, and/or physical examination of 
patients. 
Sample Size 
A subset of a larger population, selected for investigation to draw 
conclusions or make estimates about the larger population. 
Serious Adverse Event 
(SAE) 
An SAE is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  An SAE must fulfill at least 
1 of the following criteria at any dose level: results in death; is life 
threatening, 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; or a medically 
important event. 
Serious Eligard-related 
Adverse Event 
An Eligard-related AE which results in death, is life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/ incapacity, is a congenital 
anomaly/ birth defect, or results in other medically important events. 
Adverse events listed in the local label should be used by the investigator 
as reference safety information to understand whether a serious adverse 
event is expected with the use of Eligard.  This understanding should 
inform causality assessments by the investigator   
Source data 
All information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents (original records or certified 
copies). 


 
 
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Statistical Analysis Plan 
(SAP) 
A document that 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 variables and other data. 
Statistical Method 
The particular mathematical tests and techniques that are to be used to 
evaluate the clinical data in a trial. 
Study Period 
Period of time from the initiation date to the completion date of the study. 
Study Population 
Defined by protocol inclusion/exclusion criteria. 
Visit 
A clinical encounter that encompasses planned and unplanned trial 
interventions, procedures, and assessments that may be performed on a 
patient. A visit has a start and an end, each described with a rule. 
Withdrawal 
The act of discontinuing participation in a clinical study. 
See also discontinuation. 


 
 
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IV. SYNOPSIS 
Date and Version # of Protocol Synopsis: 
18 APR 2018 version 2.0 
Sponsor:   
Astellas Pharma Singapore Pte Ltd 
6 Temasek Boulevard, #26-03/04/05 Suntec 
Tower Four, 
Singapore 038986 
Protocol Number:   
7015-MA-3072 
Name of Study Drug:   
Leuprorelin acetate (ELIGARD®)
 22.5mg 
(subcutaneous injection every 3 months) 
Phase of Development:   
Phase 4  
Title of Study:   
A Phase IV Interventional Safety Study of ELIGARD® in Prostate Cancer Patients in Asia 
(ELIGANT) 
Planned Study Period:   
From Q2 2017 to Q1 2020 
Start of data collection: Q2 2017  
End of data collection: Q1 2020 
Final report of study results: Q3 2020 
Publication: Q3 2021 
Study Objective(s):   
The objectives of this Phase IV, prospective, interventional study are to evaluate the safety, 
efficacy, and impact on quality of life (QoL) of ELIGARD
® in hormone-dependent prostate 
cancer patients in Asia.  
 
Primary Objective: 
To establish the safety profile of ELIGARD
® in ethnic Asian prostate cancer patients 
 
Secondary Objectives: 
(i) 
To describe the efficacy of ELIGARD
® 22.5 mg (3-monthly formulation) in controlling 
prostate specific antigen (PSA) and testosterone levels  
(ii) 
To assess health-related quality of life (HRQoL) through QoL questionnaires – European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-PR25) (prostate cancer disease specific patient reported outcome [PRO]) 
and EuroQol 5 Dimension 5 Level Health State Utility Index (EQ5D-5L) (generic PRO) 
Planned Total Number of Study Centers and Location(s):   
Approximately 20 centers in 8 Asian Countries  
Study Population:  This study is designed for male patients with: 
• Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy and/or radiotherapy (see inclusion criteria 4) 
  
• Hormonal treatment-naive advanced or metastatic prostate cancer 
 
Number of Patients to be Enrolled:   
107 to be entered.  
 


 
 
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Study Design Overview:   
This is a multicenter, prospective, single-arm, interventional study of male patients with prostate 
adenocarcinoma who fulfill the eligibility criteria.    
 
The planned total duration of this study is 30 months from the date that the first patient is enrolled 
until 3 months after the last dose of ELIGARD® 22.5 mg administration.  The enrollment period 
will be up to 12 months.  Patients will be treated for 1.5 years (18 months), with ELIGARD® 22.5 
mg being administered at baseline, 3rd month, 6th month, 9th month, 12th month and 15th month.  
Adverse Event (AE) and Serious Adverse Event (SAE) collection will start at baseline until the 
follow-up visit at 18 months.  QoL will be measured at baseline, 6th month, 12th month and 18th 
month.  The PSA and testosterone will be assessed at all scheduled visits. Patients will be 
followed up to 18th month in the physician’s office. Any other assessments including imaging 
tests are not mandatory and will be performed according to routine standard of care and 
physician’s discretion.   
 
Inclusion/Exclusion Criteria:   
A patient is eligible for the study if he meets all of the inclusion criteria and none of the exclusion 
criteria: 
Inclusion:   
A patient for whom the physician has decided to initiate treatment with a Luteinizing Hormone 
Releasing Hormone (LHRH) agonist in standard clinical practice will be approached for 
enrolment into this study. 
1. Ethnic Asian male patient above 18 years of age 
2. Willing and able to provide written informed consent 
3. Biopsy-proven prostate adenocarcinoma 
4. Locally advanced prostate cancer with biochemical relapse following radical prostatectomy 
and/or radiotherapy.  Biochemical relapse [Mottet et al, 2006] is defined as:  
• PSA > 2 ng/mL following radiotherapy, or 
• Two consecutive PSA values > 0.2 ng/mL and rising above the nadir following 
radical prostatectomy 
OR 
 
Hormonal treatment-naive advanced or metastatic prostate cancer patient who has not 
received chemotherapy and has no plans to undergo treatment with chemotherapy at study 
entry.   
5. Patient who indicates that once the study is completed, he expects having access to androgen 
deprivation therapy (ADT), either medical or surgical, within the local healthcare system 
(either through public/ private health insurance or out of pocket payment). 
 


 
 
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Exclusion:   
1. Patient with castrate resistant prostate cancer (CRPC) 
2. Patient who previously underwent bilateral orchiectomy 
3. Patient who has received prior treatment with LHRH analogues  
4. Prior or concomitant treatment with systemic chemotherapy. A patient  where there is a 
likelihood to receive systemic chemotherapy should not be enrolled  
5. Life expectancy of < 1 year due to comorbidities 
6. Participation in another interventional clinical trial within 1 month prior to study entry or 
during the duration of the study  
7. Physician is planning to give the patient intermittent ADT at the time of study entry  
8. Patient receiving non-palliative radiotherapy within 3 months prior to study entry 
9. Patient receiving adjuvant ADT in combination with definitive radiotherapy 
10. Patient with metastatic hormonal treatment-naive prostate cancer, for whom chemo-hormonal 
treatment (combination of Docetaxel and ADT) is indicated.  
11. Patient with hypersensitivity to gonadotropin releasing hormone (GnRH), GnRH agonist 
analogs or any of the components of ELIGARD
® 
12. Patient with any contraindication for ELIGARD® use based on local prescribing information 
 
Investigational Product(s):   
ELIGARD® 22.5mg  
Note: ELIGARD® will be provided by the Sponsor during the conduct of this study. 
 
Dose:   
ELIGARD® 22.5mg (1 depot injection every 3 months) 
 
Mode of Administration:   
Subcutaneously 
Comparative Drug(s):   
Not applicable as this is a single arm interventional study of ELIGARD®. 
 
Dose(s):   
Not applicable  
 
Mode of Administration:   
Not applicable  
 


 
 
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Concomitant Medication Restrictions or Requirements:   
Bicalutamide 50 mg once daily (O.D.) or similar anti-androgen is an allowed concomitant 
medication for flare prevention only.  
The anti-androgen for flare prevention should be considered beginning at least 3 days to 4 weeks 
prior to the first ELIGARD
® injection and continuing for the first   2 to  3 weeks of treatment.  
This has been reported to prevent the sequelae of an initial rise in serum testosterone.  Use of 
bicalutamide or a similar anti-androgen beyond 3 weeks after starting ELIGARD® therapy and 
for reasons other than flare prevention is not allowed.   
Note: Anti-androgens will not be provided by the Sponsor. 
 
List of Excluded Concomitant Medications: 
1. Other LHRH analogues,  
2. LHRH antagonists and other agents (approved or investigational) which are known to 
impact on testosterone or PSA level,  
3. Ketoconazole,  
4. Estrogens,  
5. Herbal medications that may affect PSA levels (i.e., saw palmetto),  
6. Androgens (testosterone, dihydroepiandrosterone, etc.),  
7. Abiraterone,  
8. Enzalutamide,  
9. Chemotherapy agents including docetaxel and platinum drugs  
Duration of Treatment:   
The planned total duration of this study is30 months from the date the first patient is enrolled 
until 3 months after the last dose of ELIGARD® 22.5 mg administration.  The enrollment period 
will be up to 12 months.  ELIGARD® 22.5 mg will be administered at baseline, 3 months, 6 
months, 9 months, 12 months and 15 months.  Patients will be followed up at 18 months in the 
physician office. 
At the 18th month or last visit, treatment with ELIGARD® or other alternatives as deemed 
appropriate by the investigator may be continued.  ELIGARD
® or other alternatives will not be 
provided after the 15th month dose.  Treatments administered after the 15th month or last visit, not 
limited to LHRH analogues, will be at the investigator’s discretion and such data will not be 
collected. 
Formal Stopping Rules:  
The trial will be closed 18 months after the end of the enrollment period (3 months after the last 
dose of ELIGARD® 22.5 mg has been administered). 
 
Endpoints for Evaluation:   
Primary:  
ELIGARD®-related adverse events (AEs) throughout the entire observation period, as determined 
by the opinion of the investigator 
  
Secondary: 
• Efficacy outcomes of clinical response based on testosterone and PSA levels 
(Testosterone and PSA will be assessed for all patients at each scheduled visit, prior to 
administering ELIGARD®, and at the follow up visit.) 
• HRQoL assessment through QoL questionnaires – EORTC QLQ-PR25 (prostate cancer 
disease specific patient reported outcome [PRO]) and EQ5D-5L (generic PRO) measured 
at 0, 6, 12, and 18 months. 
 


 
 
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Statistical Methods:  
Sample size justification:  
This study targets to enroll approximately 107 prostate cancer patients.  
The sample size was calculated based on the estimated percentage of ELIGARD
®-related AEs, as 
well as the desired width of its 95% Confidence Interval (CI).  Prior clinical studies on 
ELIGARD® have shown that around 50% of patients experience ELIGARD®-related AEs during 
a 6-month treatment period.  With the assumption that the percentage of ELIGARD
®-related AEs 
will be 50%, a sample size of  96 completed patients is sufficient for estimating a Wald 95% CI 
with a width of 20% (+/- 10% from the middle), based on a finite population correction, with 
factor N=10,000.  
Therefore, total sample size of this study, assuming a drop-out rate of 10%, is 107 patients. 
PASS 14 Power Analysis and Sample Size Software (2015) version number 14.0.2 was used in 
the sample size calculation.  
 
Safety:   
Safety is the primary endpoint.  The safety analysis is based on the occurrence of ELIGARD® 
related AEs and ELIGARD
®-related SAEs throughout the entire observation period and 
physician’s assessment of overall drug safety.  All AEs and SAEs, independent of investigator 
assessed causality, occurring during the study will be collected and summarized by Preferred 
Term (PT) and categorized by System Organ Class (SOC), severity and relationship to 
ELIGARD®.  The modification of treatment in response to AEs will be described where 
appropriate.  The safety analysis set (SAF) consists of all patients enrolled in the study for whom 
there is evidence of ELIGARD
® study medication use and for whom any follow-up safety 
information is available. 
 
ELIGARD®-related AEs and SAEs will be summarized according to their severity, grade using 
the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) 
guidelines, outcome, course of event, seriousness, action taken with ELIGARD® and treatment 
required to manage the AE.  Incidence rates of ELIGARD®-related AEs and SAEs will be 
presented using descriptive statistics and a 95% 2-sided CI.  In addition, Kaplan Meier (KM) 
estimates will be used to summarize median time to first related AE, incidence rates at each 
scheduled time-point as well as a visual support to present time-to-event trends.  Summaries of 
ELIGARD®-related AEs and SAEs which occur after receiving CRPC management will be 
presented separately. 
 
 


 
 
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Efficacy:   
Primary efficacy variable:  
Not applicable.  The primary analysis of this study is a safety analysis. 
Secondary efficacy variables 
• Percentage of patients with Testosterone <20, 20-50 and >50 ng/dL at 1 year and at 
1.5 years  
• Time to PSA progression: calculated from date of first administration of ELIGARD
® 
22.5 mg to PSA progression 
• PSA progression will be defined as a 25% or greater increase and an absolute increase of 
2 ng/mL or more from the nadir is documented, which is  
• 
Confirmed by a second value obtained 3 or more weeks later 
• 
If not done based on standard clinical practice, the confirmatory PSA 
measurement will be performed at the next routine study visit. 
Note:  The aim is to detect time to PSA progression and not to assess whether the patient 
has progressed to CRPC.  Imaging and other modalities should be used to determine if 
the patient has moved to CRPC, which is outside the scope of this study. 
• HRQoL using EQ5D-5L questionnaire and QLQ-PR25 prostate cancer questionnaire 
 
Pharmacokinetics:  Not applicable 
Pharmacodynamics: Not applicable 
Interim analyses:  
A minimum of 1 interim analysis will be conducted when 50 patients complete 1 year of follow-
up.  As there are no statistical hypothesis tests in the planned analysis, the conduct of interim 
analyses will not have any statistical implications on the final study outcome. 


 
 
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V. FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
 
 
 
 
 
 
 
 
 
 
Legend: 
 
                  
Administration of ELIGARD®, details are listed in #.  
 
 
 
Data Collection Points 
Notes:  
#: ELIGARD® will be administered at baseline, 3 months, 6 months, 9 months, 12 months, and 15 months.  PSA 
and Testosterone levels to be measured in all the visits.   Visit window is +/- 14 days.  QoL to be measured at 
baseline, 6 months, 12 months and 18 months.  Any other assessments including imaging tests are not mandatory 
and will be performed according to routine standard of care and physician’s discretion.  One month = 30 days. 
 
 
 
 
 
 
M12 
M0 
M18 
M3 
M9 
M6 
Decision has been made by 
clinician to initiate 
treatment of the patient with 
LHRH agonist (3 month 
formulation) before patient 
is consented for entering 
this study.  Anti-androgen 
for at least 3 days to  4 
weeks prior to the first 
ELIGARD® injection and 
continuing for the first two 
to three weeks of treatment 
should be considered.   
Pre-screening / Consent / Baseline visit  
Mandatory collection of testosterone & 
PSA; AE and SAE assessment;  
Other data collection at time of 
administration of ELIGARD® 
Treatment, visit window +/- 14 days 
Follow-up visit at 18 
months: AE, PSA, 
Testosterone, and QoL.   
M15 


 
 
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Table 1: Schedule of Assessments 
 
 
ELIGARD® 22.5 mg treatment 
Early 
withdrawal m 
Follow up 
visit n 
 
Pre-Screening Baseline 
Month 3 
Month 6 
Month 9 
Month 12 Month 15 
WD 
Month 18 
Day/Month 
PS 
0 
3 
6 
9 
12 
15 
WD 
18 
Visit Number 
 
1 
2 
3 
4 
5 
6 
 
7 
Time Windows (days) 
 
 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
 
+/- 14 
STUDY MEDICATION 
 
 
 
 
 
 
 
 
 
ELIGARD® 22.5 mg 3-month depot 
 
X 
X 
X 
X 
X 
X 
 
 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Physician-determined eligibility for 
ELIGARD® 22.5 mg 3-month depot 
X 
 
 
 
 
 
 
 
 
Patient expectation of access to ADT 
post-study
a 
X 
 
 
 
 
 
 
 
 
Informed Consent (mandatory) 
 
X 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
Allocation of Patient Number 
 
X 
 
 
 
 
 
 
 
Demographic Datab 
 
X 
 
 
 
 
 
 
 
Vital Status c 
 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline disease characteristics for 
prostate cancer d 
 
X 
 
 
 
 
 
 
 
Medical History e 
 
X 
 
 
 
 
 
 
 
Prostate Cancer Status f 
 
X 
X 
X 
X 
X 
X 
 
X 
Family History for Prostate Cancer 
 
X 
 
 
 
 
 
 
 
ELIGARD® Use g 
 
X 
X 
X 
X 
X 
X 
 
 
Most important factors for selection of 
treatment (Rising PSA after definitive 
treatment, optimal testosterone control, 
quality of life, convenience of 3-
monthly formulation, other). 
 
X 
 
 
 
 
 
 
 
Details on supportive care (including 
type of treatment, drug dose, schedule 
& duration) or supportive care 
measures, including other concomitant 
 
X 
X 
X 
X 
X 
X 
 
X 


 
 
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ELIGARD® 22.5 mg treatment 
Early 
withdrawal m 
Follow up 
visit n 
 
Pre-Screening Baseline 
Month 3 
Month 6 
Month 9 
Month 12 Month 15 
WD 
Month 18 
Day/Month 
PS 
0 
3 
6 
9 
12 
15 
WD 
18 
Visit Number 
 
1 
2 
3 
4 
5 
6 
 
7 
medications related to cancer (e.g. pain 
medications, bone protective 
medications, spinal cord 
decompression surgery, palliative 
radiotherapy etc.) 
Reasons for discontinuation of 
ELIGARD® including AEs  
 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and SAEs Assessment h 
 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment for AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
PSA level, date and methods of test i 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum testosterone level,  date and 
methods of test j 
 
X 
X 
X 
X 
X 
X 
 
X 
Other laboratory Tests (if done within 
routine practice, last available value 
that is closest to each visit) 
j 
 
X 
X 
X 
X 
X 
X 
 
X 
Tumor evaluation/ Radiographic 
assessments and date of test 
k 
 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ-PR25 (to be measured at 
baseline, 6 months,  12 months and at 
18 months, mandatory) l 
 
X 
 
X 
 
X 
 
 
X 
EQ5D-5L (to be measured at baseline, 
6 months,  12 months and 18 months 
mandatory) l 
 
X 
 
X 
 
X 
 
 
X 
Legend:  X – required by protocol or if available in patient charts based on routine clinical practice. WD: withdrawl.  
Footnotes:  
a The assessment of patient’s access to medical or surgical androgen deprivation therapy after the trial ends will be based on the interview by the physician at 
prescreening visit.  


 
 
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b Demographic data - Date of birth (or age, if local regulations do not allow recording of patient’s date of birth), Race as described by the patient (unless local 
regulations do not allow recording of patient’s race), highest education level 
c Vital status – blood pressure, pulse rate, respiratory rate and weight.  Height to be collected at baseline visit only 
d Baseline disease characteristics for prostate cancer - Time since diagnosis, Gleason score at initial diagnosis, Tumor, Nodes, Metastasis (TNM) classification, 
surgical history, biopsy results, dates and types of anti-neoplastic therapy including radiation therapy prior to study inclusion (including number of cycles, 
treatment duration, time interval since previous treatments), Eastern Cooperative Oncology Group (ECOG) status, bone lesions, soft tissue disease, visceral 
disease, pain. 
e Medical history – diabetes, hypertension, cardiac disorders  
f Prostate cancer status - stage of prostate cancer, bone metastasis, soft tissue disease, visceral disease, pain (using Visual Analogue Scale [VAS] 0-10 which will 
only be collected if done in routine clinical practice), ECOG status 
g ELIGARD® Use - ELIGARD® initiation and cessation.  
h Adverse Events and Serious Adverse Events Assessment 
• Adverse Events (AEs) 
• Serious Adverse Events (Serious AEs) must be reported to the sponsor/ designee within 24 hours. 
• For this study, an  ELIGARD® -related AE is defined as an adverse event in a patient administered ELIGARD®  where a causal relationship is at least a 
reasonable possibility (drug event with either a possible or probable causal relationship), as determined by the investigator.   Adverse events listed in the local 
label should be used by the investigator as reference safety information to understand whether an adverse event is expected with the use of ELIGARD®.  This 
understanding should inform their causality assessments.     
i Prostate specific antigen (PSA) and Testosterone levels will be tested for all patients before ELIGARD
® injection at each of the following visits:  baseline, 
3 months, 6 months, 9 months, 12 months, 15 months and at the follow up visit at 18 months.  PSA progression must be confirmed by a second value obtained 
3 or more weeks later.  If PSA confirmation is not done based on standard clinical practice, the confirmatory PSA measurement will be performed at the next 
routine study visit.    
 
j Other laboratory tests (if done within routine clinical practice, last available value that is closest to each visit will be recorded) – Lactate Dehydrogenase (LDH), 
Alkaline Phosphatase (ALP), Hematology, Liver Function Test (LFT) and Renal Function Test  (RFT) 
k Tumor Evaluation/Radiographic Assessments (if data available) – Computerized Tomography (CT) scan, Positron Emission Tomography (PET) Scan, Magnetic 
Resonance Imaging (MRI), Bone scan, X-ray, ultrasound or any other imaging test 
l European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) and EuroQol 5 Dimension 5 Level Health 
State Utility Index (EQ5D-5L) – to document whether completion of  questionnaires was accomplished through self-administration or through the assistance of 
another person 
m. A patient who discontinues from the study for whatever reason should have a follow up visit that will occur 3 months after the last administration of ELIGARD® 
for safety assessment.  A patient that is unable to comply will be considered as a protocol deviation, provided that the reason for discontinuation is not due to 
patient’s withdrawal of consent.  
n. The final visit and the last follow-up visit will be the same for each patient.  It will occur at 18 months after enrollment, provided that none of discontinuation 
criteria are met.  


 
 
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1 
INTRODUCTION 
1.1 Background 
Epidemiology of Prostate Cancer 
Prostate cancer (PC) is the second most common malignancy in men with nearly 1 million new 
cases being diagnosed worldwide [Baade et al, 2013].  The analysis of GLOBOCAN data showed 
that more developed countries have much greater 5-year prevalence and incidence rates than 
underdeveloped countries [Crawford, 2003]. 
Approximately 14% of all prostate cancers diagnosed worldwide in 2008 were within the Asia-
Pacific region.  Differences in prostate cancer incidence rates and prevalence rates exist both 
regionally within Asia and between Asia and Western nations.  The reported incidence of prostate 
cancer among all cancers affecting men in Asia varies by country; prostate cancer is the third 
most commonly diagnosed male cancer in Singapore and Malaysia, fourth in Japan and Thailand, 
fifth in South Korea, sixth in China, and ninth in India [Crawford, 2003].  The overall incidence 
of, and mortality from, prostate cancer in Asian countries are lower than the rates observed in 
cohorts of migratory Asians in Western countries, and considerably lower than those in native 
Western individuals.  However, there is an increase in prostate cancer incidence in the Asia-
Pacific region, where Hong Kong and Singapore (Chinese population only) recorded annual 
increases of around 6% for males of all ages between 1998-2009 and 1980-2002, respectively 
[Baade et al, 2013].  Smaller, but still significant, increases in prostate cancer incidence rates 
were found for males of all ages in the Philippines and Thailand (3% per year increase between 
1983-2002 and 1983-2009, respectively) [Baade et al, 2013]. 
Prostate cancer is the most common cancer in elderly males.  The incidence rates of prostate 
cancer increase with age. It is relatively rare for prostate cancer to be diagnosed in men <50 years 
of age, but after this age, the incidence and mortality rates increase exponentially [Baade et al, 
2013].  In some Asian countries (Japan, Hong Kong and South Korea) the increase was more 
pronounced after 60 years of age [Baade et al, 2013].  The majority of cancer cases are diagnosed 
between 50-79 years of age [Baade et al, 2013]. 
Prostate cancer rates are highest in Western countries and lowest in Asian countries [Sim &  
Cheng, 2005].  However, Asian populations generally have higher proportions of men with 
advanced stage prostate cancer compared with Western populations, despite overall reports of 
prostate cancer incidence being substantially lower in the former [Ito, 2014].  The 
epidemiological pattern of prostate cancer in Asia suggests that prostate cancer often goes 
unnoticed, at least until later stages of the disease, possibly owing to restricted access to screening 
programs and urology clinics in Asian countries [Ito, 2014].  


 
 
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There was a large disparity in the survival prospects on men with prostate cancer throughout the 
Asia-Pacific region.  Five-year relative survival estimates of 85% and above were reported in 
New Zealand, Australia, Japan, Singapore and South Korea [Baade et al, 2013].  This contrasts 
with estimated 5-year survival rates of between 30% to 40% in parts of China and Thailand 
[Baade et al, 2013]. 
With the expected increases in life expectancy of men and in the incidence of prostate cancer [ 
Center et al, 2012], the disease’s economic burden is also expected to increase substantially.  In 
Europe, it is estimated that the total economic costs of prostate cancer exceed €8.43 billion, with 
a high proportion of the costs of prostate cancer care occurring in the first year after diagnosis 
[Mottet et al, 2006].  In European countries with available data (United Kingdom, Germany, 
France, Italy, Spain, Netherlands), this amounted to €106.7 – 179.0 million for all prostate cancer 
diagnosed in 2006 [Mottet et al, 2006]. 
In Asia, the population over 60 years old is about 4 times greater compared to those of North 
America and Europe [Zhang et al, 2011].  Given that life expectancy is expected to increase 
markedly in many parts of Asia over coming years, the burden of prostate cancer in this region is 
likely to increase in the future.  Health problems will become a greater burden in Asian countries 
despite rapid socioeconomic growth. 
It has been reported that patients with terminal prostate cancer show considerably decreased 
quality of life (QoL) for many years before death, owing to the adverse effects of long-term 
systemic treatments as well as physiological and psychological impairment resulting from 
progression of local disease and distant metastases [Ito, 2014]. 
ELIGARD® (leuprolide acetate for injection) 
ELIGARD® (leuprolide acetate) is an established luteinizing hormone releasing hormone 
(LHRH) agonist that is indicated for the palliative treatment of advanced prostate cancer 
[ELIGARD local prescribing information, May 2014].  ELIGARD® is a long-acting depot 
formulation that uses Atrigel
® delivery system (a biodegradable polymer matrix) that allows 
sustained release of leuprolide acetate following subcutaneous injection. ELIGARD
® is designed 
to deliver leuprolide acetate at a controlled rate over a therapeutic period to reduce testosterone 
levels in men with advanced hormone-dependent prostate cancer.  ELIGARD® is available in 3 
depot formulations of 7.5 mg, 22.5 mg and 45 mg doses for 1-monthly, 3-monthly and 6-monthly 
administration intervals, respectively.  
Study Rationale 
Both the safety and efficacy of ELIGARD® have been well proven in numerous clinical studies. 
However, the safety profile of ELIGARD® was not established in ethnic Asian populations as no 
clinical studies of ELIGARD
® have been conducted in Asia to date.  Since data from controlled 
clinical trials may not necessarily be assumed to apply in their entirety to subpopulations not 


 
 
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studied in those trials, Astellas will conduct this study to establish the safety profile and to 
confirm the efficacy of ELIGARD
® in prostate cancer patients in the Asia region.  This study will 
also aim to assess health-related quality of life (HRQoL) of prostate cancer patients using the 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-PR25, prostate cancer disease specific patient reported outcome [PRO]) and 
EuroQol 5 Dimension 5 Level Health State Utility Index (EQ5D-5L, generic PRO).  
This study is a non-mandated Post-authorization safety study (PASS).   
1.2 Non-clinical and Clinical Data 
Non-clinical data 
In all animal studies, serum testosterone was suppressed below or near the castrate threshold (50 
ng/dl) within 1 to 3 weeks after a single administration of ELIGARD®.  Following a single 
administration, the duration of testosterone suppression to below castrate threshold was > 91 days 
with ELIGARD® 22.5 mg. 
Pharmacokinetic studies with ELIGARD® 22.5 mg established near complete release of 
leuprorelin acetate by Day 106.  Two of 3 studies with ELIGARD
® 22.5 mg suggest that a 
smaller proportion of the total leuprorelin dose is released initially (i.e., 19 - 41% and 22%, 
respectively). 
In single-dose toxicity studies, no untoward systemic or clinical effects (except for the desired 
pharmacodynamic outcome) have been observed for ELIGARD
®.  Similarly, repeated 
administration of ELIGARD
® is not associated with overt toxicity other than that related to the 
pharmacological action of the active ingredient, leuprorelin acetate. 
No acute systemic effects were observed in any of the studies performed with the delivery system 
(with or without leuprorelin acetate), following single-dose or repeated administration.  However, 
in a chronic toxicity study with ELIGARD
® 22.5 mg (LEU_PTX_0220), the delivery system 
control was found to cause mild histopathological lesions in the testis, the epididymis, the 
prostate, and the coagulating gland as observed with the test article, which were exaggerated 
when the active product was given at the high dose level (500 μl/kg, i.e., 100 times the human 
clinical dose). 
Details of preclinical data are summarized in the ELIGARD® Investigator’s Brochure, Edition 5, 
dated 26th June 2008 and the approved Summary of Product Characteristics. 
Clinical data 
Response to ELIGARD® should be monitored by measuring serum concentrations of testosterone 
and prostate specific antigen (PSA) periodically [ELIGARD local prescribing information, May 
2014].  Majority of patients have increased testosterone levels above baseline during the first 
week, declining thereafter to baseline levels or below by the end of the second or third week 


 
 
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[ELIGARD local prescribing information, May 2014].  The patients generally achieve 
testosterone ‘castration levels’ (< 50 ng/dL) within 2 to 6 weeks after the start of ELIGARD® 
treatment, and the effects are reversible upon discontinuation of drug therapy [ELIGARD local 
prescribing information, May 2014]. 
Furthermore, up to 98% of patients showed levels which are less than 20 ng/ dL, comparable to 
those resulting from surgical bilateral orchidectomy [Berges & Bello, 2006].  This is clinically 
important because low serum testosterone (<20 ng/dL) within the first year of Androgen 
Deprivation Therapy (ADT) has been suggested to correlate with improved survival and duration 
of response to androgen deprivation in men being treated with ADT [Klotz et al, 2015].  The 
European Association of Urology Guidelines for Prostate Cancer acknowledges that better results 
are repeatedly observed with lower testosterone levels compared to 50 ng/dL[Mottet et al, 2006].  
As with other gonadotropin releasing hormone (GnRH) agonists, ELIGARD® 22.5 mg causes a 
transient increase in serum concentrations of testosterone (also known as ‘tumor flare’ or 
‘testosterone surge’) during the first week of treatment [ELIGARD local prescribing information, 
May 2014].  Patients may experience worsening of symptoms or onset of new signs and 
symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria or 
bladder outlet obstruction [ELIGARD local prescribing information, May 2014].  Potential 
exacerbations of signs and symptoms of the disease in patients with vertebral metastases and/or 
urinary obstruction or hematuria, may lead to neurological problems such as weakness and/or 
paresthesia of the lower limbs or worsening of urinary symptoms [ELIGARD local prescribing 
information, May 2014].  Patients at risk should be closely monitored during these first 2 weeks 
of therapy and managed as appropriate. Short term anti-androgen therapy may ameliorate these 
symptoms.  
The safety of all ELIGARD® formulations was evaluated in clinical trials involving patients with 
advanced prostate cancer. The most commonly reported adverse reactions are hot flashes, nausea, 
malaise and fatigue and transient local irritation at the site of injection.  Mild hot flashes occur in 
approximately 58% of patients[ELIGARD 22.5 mg, Summary of Product Characteristics 2015].  
Hyperglycemia, an increased risk of developing diabetes and cardiovascular diseases such as 
myocardial infarction, sudden cardiac death and stroke have been reported in men receiving 
GnRH agonists [ELIGARD local prescribing information, May 2014].  It is important to monitor 
patients’ blood glucose level and cardiovascular condition and manage according to current 
clinical practice. Decreased bone density and rare cases of pituitary apoplexy (a clinical 
syndrome secondary to infarction of the pituitary gland) have been reported during post-
marketing experience after the administration of GnRH agonists [ELIGARD local prescribing 
information, May 2014].  Convulsions and QT prolongation have also been reported in the post-
marketing setting [ELIGARD local prescribing information, May 2014]. 
ELIGARD® is contra-indicated in patients with hypersensitivity to GnRH, GnRH agonists or any 
of the components of ELIGARD® [ELIGARD local prescribing information, May 2014].   


 
 
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The pre-clinical and clinical data are summarized in the ELIGARD® Investigator’s Brochure, 
Version 5, dated 26 June 2008 [ELIGARD Investigator
's Brochure, June 2008] and the approved 
Summary of Product Characteristics [ELIGARD 22.5 mg, Summary of Product Characteristics 
2015].   
1.3 Summary of Key Safety Information for ELIGARD
® 
The most commonly reported adverse reactions are hot flushes, nausea, malaise and fatigue and 
transient local irritation at the site of injection.  Mild hot flushes occur in approximately 58% of 
patients. 
The following very common (>1/10) AEs were reported during clinical studies with ELIGARD
® 
in patients with advanced prostatic carcinoma: hot flushes, ecchymoses, erythema, fatigue, 
injection site burning, and injection site paresthesia. 
Other AEs which have been reported in general to occur with leuprorelin acetate treatment 
include decrease in libido (pharmacological consequence of testosterone deprivation), peripheral 
edema, pulmonary embolism, palpitations, myalgia, muscle weakness, chills, dyspnea, peripheral 
vertigo, rash, amnesia, visual disturbances and skin sensation. 
Local AEs reported after injection of ELIGARD® 22.5 mg are typical of those frequently 
associated with similar subcutaneously injected products.  Mild transient burning following 
injection is very common. Stinging, pain and bruising are common.  Generally, these localized 
AEs following subcutaneous injection are mild and described as being of brief duration. 
Decreased bone density has been reported in the medical literature in men who have had 
orchiectomy or who have been treated with GnRH agonists.  It can be anticipated that after long 
periods of treatment with leuprorelin acetate bone may show increasing signs of osteoporosis. 
Treatment with leuprorelin acetate can cause exacerbations of signs and symptoms of the disease 
during the first few weeks.  If conditions such as vertebral metastases and/or urinary obstruction 
or hematuria are aggravated, neurological problems such as weakness and/or paresthesia of the 
lower limbs or worsening of urinary symptoms may occur.  Short term anti-androgen therapy 
may ameliorate these symptoms. 
1.4 Risk-Benefit Assessment 
The expected benefits of treatment in this study are the alleviation of symptoms and improved 
QoL. Expected risks are associated with the AE profile of the drug.  The incidence of expected 
AEs is summarized in Section 1.3.  Study procedures are limited to blood sampling for 
determination of testosterone and PSA levels and QoL assessment. 


 
 
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2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 Study Objectives 
The objectives of this Phase IV, prospective, interventional study are to evaluate the safety, 
efficacy, and QoL of ELIGARD
® in hormone-dependent prostate cancer patients in Asia.  
Primary Objective: 
To establish the safety profile of ELIGARD® in ethnic Asian prostate cancer patients. 
Secondary Objectives: 
1) To describe the efficacy of ELIGARD
® 22.5 mg (3-monthly formulation) in controlling 
PSA and testosterone levels  
2) To assess HRQoL through QoL questionnaires – EORTC QLQ-PR25 and EQ5D-5L  
2.2 Study Design and Dose Rationale 
2.2.1 Study Design 
This is a multicenter, prospective, single-arm, interventional study to assess the safety, efficacy, 
and QoL of ELIGARD
® 
22.5 mg (3-monthly formulation) in male patients with prostate 
adenocarcinoma who fulfill the eligibility criteria in Asia.   
This study will be conducted in approximately  20 centers in 8 countries (Hong Kong, Indonesia, 
Malaysia, Philippines, Singapore, Taiwan, Thailand and Vietnam).  The planned total duration of 
this study is 30 months from the date when the first patient is enrolled until 3 months after the last 
dose of ELIGARD® 
22.5 mg administration.  The patient population includes male Asian patients 
diagnosed with prostate cancer who will receive ELIGARD® 22.5 mg (3-monthly formulation) 
depot formulation between the periods of Q2 2017 through Q3 2018.  Patients for whom the 
treating physician has decided to initiate treatment with ELIGARD
® 22.5 mg will be approached 
for enrollment into this study.  The enrollment period will be up to 12 months.  Patients will be 
prescreened to confirm access to ADT prior to informed consent.  Following written informed 
consent by the patient and confirmation of eligibility, patients will be treated for 1.5 years (18 
months), with ELIGARD® 22.5 mg being administered at baseline, 3rd month, 6th  month, 9th  
month, 12th  month and 15th  month.  AE and SAE collection will start at baseline until the 
follow-up visit at 18 months (see Section 5.6 for AE collection and SAE reporting).  QoL will be 
measured at baseline, 6th month, 12th month and 18th month.  The PSA and testosterone levels 
will be assessed at all scheduled visits and during the follow-up visit.  Any other assessments 
including imaging tests are not mandatory and will be performed according to routine standard of 
care and physician’s discretion. Patients will be followed up at 18
th month in the physician’s 
office.  The time window for each visit following baseline is +/- 14 days.  At the 18th month, 
treatment with ELIGARD
® or other alternatives as deemed appropriate by the investigator may 


 
 
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be continued.  ELIGARD® or other alternatives will not be provided after the 15th month dose.  
Treatments administered after the 15th month or last visit, not limited to LHRH analogues, will be 
at the investigator’s discretion and such data will not be collected.  Patients who discontinue 
ELIGARD® will be followed up for monitoring of AEs for a period of 3 months, provided 
consent is not withdrawn.  The reason for discontinuation of ELIGARD® will also be noted.  Key 
data elements to be collected are detailed in Section V Flow Chart and Schedule of 
Assessments and in Section 8.1.1 Data Collection.  
The sample size planned for this study is approximately 107 enrolled prostate cancer patients.  
The sample size was calculated based on the percentage of ELIGARD
®-related AEs, as well as 
the desired width of its confidence interval (CI).   
A Study Steering Committee was formed to refine the design, conduct, analysis and reporting of 
the study.  It is composed of international experts specializing in the treatment of prostate cancer. 
Outside experts will be designated by the Steering Committee to provide specific guidance as 
needed throughout the study.  A separate Publication Steering Committee will be formed to 
oversee planning of publications related to the ELIGANT study.  Publication Steering Committee 
membership will include at a minimum a Steering Committee representative and a representative 
of the Sponsor.   
This multinational, multi-center study shall start with obtaining written approval from the 
respective Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and 
Regulatory Authorities. Registration with clinical trial registries in respective countries will be 
submitted when necessary. 
2.2.2 Dose Rationale 
ELIGARD
® 22.5 mg (1 injection every 3 months) is the dosage that will be used in this study 
because it is the most widely used formulation in Asian countries and is available in all the Asian 
countries participating in this study.    
ELIGARD® 22.5mg is administered subcutaneously and provides continuous release of 
leuprolide acetate over a 3-month treatment period. ELIGARD® is a long-acting depot 
formulation that uses Atrigel
® delivery system (a biodegradable polymer matrix) to deliver 
leuprolide acetate at a controlled rate over a therapeutic period.  
Subcutaneous administration of ELIGARD® is as per the label and approved indications of 
ELIGARD®.  (Refer to the current local ELIGARD prescribing information.)   
2.3 Endpoints  
2.3.1 Primary Endpoints 
ELIGARD®-related AEs throughout the entire observation period, as determined by the opinion 
of the investigator  


 
 
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2.3.2 Secondary Endpoints  
• Efficacy outcomes of clinical response based on testosterone and PSA levels 
(Testosterone level and PSA will be assessed for all patients at each scheduled visit, prior 
to administering ELIGARD
®, and at the follow-up visit.) 
• HRQoL assessment through QoL questionnaires – EORTC QLQ-PR25 (prostate cancer 
disease specific PRO) and EQ5D-5L (generic PRO) measured at 0, 6, 12, and 18 months. 
2.3.3 Exploratory Endpoints  
Not applicable.  


 
 
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3 
STUDY POPULATION 
3.1 Selection of Study Population  
This study is designed for male patients with:  
• Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy and/or radiotherapy (see inclusion criteria 4) 
• Hormonal treatment-naive advanced or metastatic prostate cancer.  
Centers that decide to initiate treatment of prostate cancer patients with ELIGARD® will be 
identified and requested to approach patients for consent to participate.  In each site, a planned 
number of enrolled patients will be established according to the capability of the site.  Should the 
investigator wish to include more patients than initially planned, the approval of the sponsor must 
be obtained.  
In order to reduce patient selection bias, each patient who is expected to receive ELIGARD
® 
treatment and consent to participate must be assessed at the baseline visit.  Eligible patients who 
fulfill all inclusion criteria and none of the exclusion criteria will be enrolled consecutively into 
the study at each site.  In case a patient is not eligible, the reason for non-eligibility must be 
documented in the patient log file.    
Enrollment will be competitive and will be stopped when the anticipated number of patients has 
been achieved across all study sites.  
3.2 Inclusion Criteria 
A patient for whom the physician has decided to initiate treatment with LHRH agonist 3 monthly 
formulation in standard clinical practice will be approached for enrolment into this study. 
 
1. Ethnic Asian male patient above 18 years of age 
2. Willing and able to provide written informed consent 
3. Biopsy-proven prostate adenocarcinoma 
4. Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy and/or radiotherapy.  Biochemical relapse 
[Mottet et al, 2006]  is defined as:  
• PSA > 2 ng/ML following radiotherapy, or 
• Two consecutive PSA values > 0.2 ng/mL and rising above the nadir following 
radical prostatectomy 
             OR 


 
 
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Hormonal treatment-naive advanced or metastatic prostate cancer patient who has not 
received chemotherapy and has no plans to undergo treatment with chemotherapy at study 
entry 
5. Patient who indicates that once the study is completed, he expects having access to ADT, 
either medical or surgical, within the local healthcare system (either through public/ 
private health insurance or out of pocket payment). 
3.3 Exclusion Criteria 
1. Patient with castrate resistant prostate cancer (CRPC) 
2. Patient who previously underwent bilateral orchiectomy 
3. Patient who has received prior treatment with LHRH analogues  
4. Prior or concomitant treatment with systemic chemotherapy. A patient where there is a 
likelihood to receive systemic chemotherapy should not be enrolled  
5. Life expectancy of < 1 year due to comorbidities 
6. Participation in another interventional clinical trial within 1 month prior to study entry or 
during the duration of the study  
7. Physician is planning to give the patient intermittent ADT at the time of study entry  
8. Patient receiving non-palliative radiotherapy within 3 months prior to study entry 
9. Patient receiving adjuvant ADT in combination with definitive radiotherapy 
10. Patient with metastatic hormonal treatment-naive prostate cancer, for whom chemo-
hormonal treatment (combination of Docetaxel and ADT) is indicated.  
11. Patient with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of 
ELIGARD® 
12. Patient with any contraindication for ELIGARD® use based on local prescribing 
information 
While patients enrolled or expected to be enrolled in clinical trials of investigational therapy are 
not allowed, their participation in this interventional study will not preclude them from future 
participation in other non-interventional studies.   
Waivers to the exclusion criteria will NOT be allowed.  


 
 
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4 
TREATMENTS  
4.1 Identification of Investigational Product 
4.1.1 Test Drug(s) 
ELIGARD® 22.5 mg is intended to be administered subcutaneously and provides continuous 
release of leuprolide acetate over a 3-month treatment period. ELIGARD
® is a long-acting depot 
formulation that uses Atrigel
® delivery system (a biodegradable polymer matrix) to deliver 
leuprolide acetate at a controlled rate over a therapeutic period.  
Subcutaneous administration of ELIGARD® is as per the label and approved indications of 
ELIGARD®.  (Refer to the current local ELIGARD prescribing information.)  
ELIGARD® will be prescribed by treating physician according to local prescribing information.   
ELIGARD® will be provided in this study.  ELIGARD® should be stored in a refrigerator (2-8°C), 
and will be stable for 24 months from the date of manufacturing when stored at 2-8°C. 
4.1.2 Comparative Drug(s)  
Not applicable as this is a single arm interventional study on ELIGARD®.  
4.1.3 Drug(s) for Screening  
Not applicable. 
4.1.4 Rescue Drug(s) 
Not applicable. 
4.2 Packaging and Labeling 
ELIGARD® used in this study will be prepared, packed and labelled under the responsibility of 
the qualified staff at Astellas Pharma Singapore or Sponsor’s designee in accordance with 
Astellas Pharma Singapore or Sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation – Good 
Clinical Practice (ICH GCP) guidelines, and applicable local laws/regulations.  The packaging 
and labeling of the study medication will be outsourced to a preferred contractor. 
ELIGARD® 22.5 mg will be repackaged into another carton box.  A label identifying the contents 
as an investigational drug and other required information will be applied to the outer carton box.  
A medication number will identify the ELIGARD® packages and will be captured in the 
electronic case report form (eCRF).  This number will be used for the allocation of the medication 
at a particular visit to a certain patient.  


 
 
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4.3 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 the study drug is handled and stored according to labeled storage conditions, 
• that the study drug has appropriate expiry/retest and is only dispensed to study patients in 
accordance with the protocol, and 
• that any unused study drug is returned to the Sponsor. 
Drug inventory and accountability records for the study drug 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 
patients 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 patient. 
• 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 
delegated this responsibility. 
• The site must return unused study drug to the Sponsor or designee at the end of the study 
or upon expiration. 
4.4 Blinding 
Not applicable as this is an open label study on ELIGARD®.  
4.5 Assignment and Allocation 
Not applicable as this is a single-arm interventional study on ELIGARD
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5 
TREATMENTS AND EVALUATION 
5.1 Dosing and Administration of Study Drug(s) and Other Medication(s) 
5.1.1 Dose/Dose Regimen and Administration Period 
ELIGARD® 22.5mg is administered subcutaneously and provides continuous release of 
leuprolide acetate over a 3-month treatment duration.  ELIGARD® is a long-acting depot 
formulation that uses Atrigel
® delivery system (a biodegradable polymer matrix) to deliver 
leuprolide acetate at a controlled rate over a therapeutic period.  
Subcutaneous administration of ELIGARD® 22.5mg is as per the label and approved indications 
of ELIGARD®.  Refer to the current local ELIGARD
® prescribing information.  
ELIGARD® will be prescribed by treating physician according to local prescribing information.  
ELIGARD® will be provided by the sponsor during the conduct of this study. 
5.1.2 Increase or Reduction in Dose of the Study Drug(s) 
Only ELIGARD® 22.5mg will be used for this study, thus, dose changes are not allowed. 
5.1.3 Previous and Concomitant Treatment   
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication for 
flare prevention only.  Additional administration of an appropriate anti-androgen should be 
considered beginning at least 3 days to 4 weeks prior to the first ELIGARD
® injection and 
continuing for the first 2 to 3 weeks of treatment to avoid any flare reaction.  Use of bicalutamide 
or similar anti-androgen beyond 3 weeks after starting ELIGARD therapy and for reasons other 
than flare prevention is not allowed. 
Note:  Anti-androgens will not be provided by the Sponsor.  Patients will be responsible for any 
costs associated with anti-androgen therapy.   
5.1.4 Treatment Compliance 
Study patients should be counseled on the need to meet 100% compliance with the study drug.  
The investigator or designee should ensure that study patients meet this goal throughout the study 
period.  Since the study drug will be administered by qualified study personnel at the research site 
during each study visit, compliance will be verified by checking that the study drug was correctly 
administered during each patient’s scheduled visit.  Compliance of the study drug will be 
monitored and documented.  If compliance is 80%, the investigator or designee is to counsel the 
patient and ensure steps are taken to improve compliance and adherence to the study schedule.  
Patients who are less than 80% compliant with the dosage regimen for any 2 consecutive visit 
periods (window ± 14 days) during the study should be withdrawn.  


 
 
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5.1.5 Criteria for Continuation of Treatment  
A patient can continue in this study until the Month 18, provided none of the discontinuation 
criteria (see Section 6.1) are met.   
5.1.6 Restrictions During the Study  
The following drugs are prohibited to be used throughout the study (see Section 12.2): 
1. Other LHRH analogues,  
2. LHRH antagonists and other agents (approved or investigational) which are known to 
impact on testosterone or PSA level,  
3. Ketoconazole,  
4. Estrogens,  
5. Herbal medications that may affect PSA levels (i.e., saw palmetto),  
6. Androgens (testosterone, dihydroepiandrosterone, etc.),  
7. Abiraterone,  
8. Enzalutamide,  
9. Chemotherapy agents including docetaxel and platinum drugs 
5.2 Assessment at Prescreening Visit 
The physicians will review the inclusion/exclusion criteria of patients to assess patients’ 
eligibility for ELIGARD® 22.5 mg 3-month depot at prescreening visit.  The assessment of 
patient’s access to medical or surgical ADT after the trial ends will be based on the interview by 
the physician at prescreening visit. 
5.3 Demographics and Baseline Characteristics 
5.3.1 Informed Consent and Inclusion/Exclusion Criteria  
The informed consent must be obtained at baseline visit.  The investigator will also review the 
inclusion/exclusion criteria for each patient at baseline visit.  
5.3.2 Demographics 
Demographic information will be collected at the baseline visit and will include date of birth (or 
age, if local regulations do not allow recording of patient’s date of birth), race as described by the 
patient (unless local regulations do not allow recording of patient’s race), and highest education 
level. 
5.3.3 Medical History 
Medical history will be collected at the baseline visit and will include diabetes, hypertension, 
cardiac disorders and any significant conditions or diseases other than prostate cancer that 
occurred prior to informed consent. 


 
 
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5.3.4 Family History for Prostate Cancer 
A complete family history of the prostate cancer will be collected at the baseline visit.  This 
includes documenting the patient’s family history of brother(s), father, first-degree relative(s) 
and/or second-degree relative(s) with prostate cancer, including the age at the time of diagnosis. 
5.3.5 Diagnosis of the Target Disease, Severity, and Duration of Disease  
Baseline disease characteristics for prostate cancer will be collected at baseline visit, including 
time since diagnosis, Gleason score at initial diagnosis, Tumor, Nodes, Metastasis (TNM) 
classification, staging, surgical history, biopsy results, dates and types of anti-neoplastic therapy 
including radiation therapy prior to study inclusion (including number of cycles,  treatment 
duration, time interval since previous treatments), Eastern Cooperative Oncology Group (ECOG) 
status, bone lesions, soft tissue disease, visceral disease, and pain (using the Visual Analogue 
Scale [VAS] 0-10). 
5.3.6 Most Important Factors for Selection of Treatment  
The reasons for selection of treatment with ELIGARD® 22.5 mg will be collected at the baseline 
visit.  The most important factors will be determined by physicians and recorded. 
5.4 Efficacy Assessment 
Efficacy outcomes of clinical response based on testosterone and PSA levels, both of which will 
be tested for all patients at each scheduled visit, prior to administering ELIGARD
®, and at the 
follow up visit. 
HRQoL will be assessed through EORTC QLQ-PR25 and EQ5D-5L.  EORTC QLQ-PR25 is a 
prostate cancer module for the assessment of HRQoL.  EORTC QLQ-PR25 is designed for self-
completion by respondents.  It assesses urinary symptoms, bowel symptoms, treatment-related 
symptoms, and sexual activity and functioning.  EQ5D-5L is a standardized instrument for use as 
a measure of health outcome.  It provides a simple descriptive profile and a single index value for 
health status.  EQ5D-5L is designed for self-completion by respondents.  It consists of 2 pages 
comprising the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels and the patient is asked to indicate his health 
state by ticking the box with the most appropriate statement. 
Patients will be asked to complete an EORTC QLQ-PR25 and EQ5D-5L questionnaire at the 
baseline visit, 6 months, 12 months and 18 months. 


 
 
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5.5 Safety Assessment 
5.5.1 Vital Signs 
Vital information will be collected at the baseline visit and every following visit.  The vital status 
information includes blood pressure, pulse rate, respiratory rate and weight.  Height will be 
collected at baseline visit only. 
5.5.2 Adverse Events 
See Section 5.6 Adverse Events and Other Safety Aspects for information regarding AE 
collection and data handling.  
5.5.2.1 Adverse Events of Possible Hepatic Origin 
See Appendix 12.3 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a patient enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g., aspartate 
transaminase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], etc.) or is suspected 
to be due to hepatic dysfunction.  
5.5.2.2 Treatment for AEs and SAEs 
Information pertaining to the treatment for AEs and SAEs will be collected at each visit, if 
applicable.  The information will include any intervention (e.g. medication(s), procedure(s), 
radiography, surgical treatment, visits to Accident & Emergency department and/or ambulatory 
clinic, hospitalization) to treat AEs and SAEs.  The duration of treatment and hospitalization will 
also be collected.   
5.5.3 Laboratory Assessments 
Testosterone and PSA levels will be assessed for all patients at each scheduled visit, prior to 
administering ELIGARD®, and at the follow up visit. Information on other laboratory tests will 
only be collected if the tests are done within routine clinical practice.  The laboratory tests include 
lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hematology, LFT and RFT.  
5.5.4 Imaging  
Data on tumor evaluation/ radiographic assessments will only be collected if available. 
Radiographic evaluation includes computerized tomography (CT) scan, positron emission 
tomography (PET) scan, magnetic resonance imaging (MRI), Bone scan, X-ray, ultrasound or 
any other imaging test which have been performed as part of standard of care. 
5.6 Adverse Events and Other Safety Aspects 
AE and SAE collection will start from signing of informed consent form (ICF) until the follow-
up visit at 18 months, or early withdrawal/discontinuation. 


 
 
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5.6.1 Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a patient 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, 
electrocardiogram [ECG] data, physical exam) should be defined as an AE only if the 
abnormality meets 1 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. 
5.6.2 Definition of Serious Adverse Events (SAEs) 
An adverse event will be considered to be “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 AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE 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 
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 patient or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  These events, 


 
 
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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 patient as part of the study 
(e.g., study drug, comparator, and 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 eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded on 
the AE page of the eCRF and marked ‘serious’ and on SAE worksheet.  Refer to Section 5.6.5 
below for SAE reporting timeline and procedure.  
The Sponsor has a list of events that they classify as “always serious” events (refer to the 
Appendix).  If an AE is reported that is considered to be an event per this classification as 
“always serious”, additional information on the event may be requested.   
5.6.3 Criteria for Causal Relationship to the Study Drug 
AEs that fall under either "Possible" or "Probable" should be defined as "AEs 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. 


 
 
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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). 
For this study, an ELIGARD® -related AE is defined as an adverse event in a patient administered 
ELIGARD®  where a causal relationship is at least a reasonable possibility (drug event with either 
a possible or probable causal relationship), as determined by the investigator.  Adverse events 
listed in the local label should be used by the investigator as reference safety information to 
understand whether an adverse event is expected with the use of ELIGARD®.  This 
understanding should inform their causality assessments.     
5.6.4 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 
 
5.6.5 Reporting of Serious Adverse Events (SAEs) 
In the case of an SAE, the investigator should complete and submit an SAE Worksheet in the 
eCRF containing all information that is required by the Regulatory Authorities to the 
Sponsor/contract research organization (CRO) within 24 hours of awareness following the 
procedure outlined in the Safety Reporting Guide provided to the sites.  AEs should be reviewed 


 
 
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by Investigator in a timely fashion, i.e., if an AE is upgraded to an SAE, these need to be reported 
to the Sponsor /delegated designee within 24 hours.  If completion of the SAE worksheet is not 
possible through the eCRF, email or by fax within 24 hours, the Sponsor’s local drug safety 
contact/ CRO should be informed by phone.    
For contact details, see Section II Contact Details of Key Sponsor’s Personnel. 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor
's Medical Monitor 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 eCRF. 
The following minimum information is required: 
• ISN/Study number,  
• Patient number, sex and age, 
• The date of report, 
• A description of the SAE (event, seriousness of the event), and 
• Causal relationship to the study drug. 
The Sponsor or Sponsor
's designee will submit expedited safety reports to the regulatory agencies 
in accordance to the local regulations, and will inform the investigators of such regulatory 
reports.  Investigators must submit safety reports as required by their IRB/IEC within timelines 
set by regional regulations.  Documentation of the submission to and receipt by the IRB/IEC of 
expedited safety reports should be retained by the site.  The investigators should provide written 
documentation of IRB/IEC notification for each report to the Sponsor. 
Investigators may contact the Sponsor
's Medical Monitor for any other problem related to the 
safety, welfare, or rights of the patient. 
Reporting of SAEs in case of ELIGARD
® treatment discontinuation 
For patients who discontinue ELIGARD® treatment, AE monitoring should be continued for a 
period of 3 months from the date of last administration of ELIGARD®, provided consent is not 
withdrawn.  AE documentation and SAEs reporting should be continued during this period of 
time.  SAEs that are considered to be related to ELIGARD® occurring after the end of the 
observation period or after end of the follow-up period should be reported according to local 
law/guidelines within the spontaneous reporting system. 


 
 
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Safety Observations 
The investigator should take all appropriate measures to ensure the safety of the patients.  The 
outcome of all reported SAEs (e.g., resolution, death) will be followed up and documented.  
Reporting to the relevant Regulatory Authorities according to national regulations will be done by 
the Sponsor.  
5.6.6 Follow-up of Adverse Events 
All AEs occurring during or after the patient has discontinued the study are to be followed-up 
until resolved or judged to be no longer clinically significant, or until they become chronic to the 
extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an "SAE", or if a patient experiences a new SAE, 
the investigator must immediately report the information to the Sponsor.  
Please refer to Appendix 12.3 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury (DILI). 
5.6.7 Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent of 
drug exposure.  SAEs classified as “common” are provided in Appendix 12.4 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 12.4 Common 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 5.6.5 Reporting of 
Serious Adverse Events.  
5.6.8 Procedure in Case of Pregnancy of Partner 
This study involves male prostate cancer patient.  If a partner of a male patient becomes pregnant 
during the study while taking the medication the investigator should report the information to the 
Sponsor/delegated designee within 24 hours of awareness as if it is an SAE.  The expected date of 
delivery or expected date of the end of the pregnancy of partner, paternal drug exposure etc., 
should be included in this information.  If limited data are reported, reasonable effort should be 
made to complete these. 
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. 


 
 
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When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure for 
SAEs.  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 
5.6.9 Emergency Procedures and Management of Overdose 
In the event of suspected overdose, refer to the approved Package Insert or local product 
information supplied by Astellas. 
5.6.10 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.  Investigators should inform the IRB/IEC of such information when needed.  
5.7 Test Drug Concentration 
Not applicable. 
5.8 Other Measurements, Assessments or Methods 
5.8.1 Prostate Cancer Status 
Information on prostate cancer status will be collected at the baseline visit and each follow-up 
visit.  The information will include stage of prostate cancer, bone metastasis, soft tissue disease, 
visceral disease, pain (using VAS 0-10), and ECOG status. 
5.8.2 Supportive Care 
Information on other supportive care treatment will be collected at the baseline visit and each 
follow-up visit, and will be recorded in the eCRF.  The information will include type of 


 
 
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treatment, drug dose, schedule and duration, supportive care measures, other concomitant 
medications related to cancer (e.g., pain medications, bone protective medications, spinal cord 
decompression surgery, palliative radiotherapy) 
5.8.3 Concomitant Medications Assessment 
Information on concomitant medication will be collected at the baseline visit and each follow-up 
visit, and will be recorded in the eCRF.  The information will include generic or brand names of 
the medication, the dose, unit, route, frequency, start and end dates and the reason for taking the 
medication. 
5.9 Total Amount of Blood 
The total volume of blood to be drawn is 35 ml during the entire study (from baseline to follow-
up visit) with 5 ml per visit. 


 
 
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6 
DISCONTINUATION 
6.1 Discontinuation of Individual Patients 
A discontinuation is a patient who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.   
A patient is free to withdraw from the study for any reason, at any time, without reason for doing 
so and without penalty or prejudice.  
A patient will be discontinued from the study in the case of:  
1. Withdrawal of consent - patient decision to withdraw from further participation in the 
study 
2. Patient safety is at risk (at the discretion of the treating physician) 
3. Patient develops CRPC as determined by European Association of Urology (EAU) 
Prostate Cancer Guidelines 2016 
4. Patient is lost to follow-up 
5. Patient death during the study 
6. Patent misses consecutive visit periods (window ± 14 days) during the study   
7. Patient who is less than 80% compliant with the dosage regimen for any 2 consecutive visit 
periods (window ± 14 days) during the study. 
8. Site terminated by the Sponsor 
9. Study terminated by the Sponsor 
10. Cessation of treatment with ELIGARD® (at the discretion of the treating physician).  The 
reasons for stopping treatment will be noted (e.g., PSA progression, radiographic 
progression, clinical progression, AE, drug administration issues, other).  
11. Patient takes prohibited medications as described in Section 5.1.6 and Section 12.2 
For patients that discontinue from the study, the reason for discontinuation should be recorded in 
the eCRF.  Patients that discontinue will have an Early Withdrawal visit 3 months after the last 
administration of ELIGARD
® for safety assessment.  At the end of a patient’s involvement in this 
study, the Investigator must ensure that all outstanding data entry is entered in the eCRF unless 
the patient withdrew consent for their data to be used. 
6.2 Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor/delegated designee.  


 
 
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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. 


 
 
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7 
STATISTICAL METHODOLOGY 
Data analysis will be performed by the designated CRO in accordance with the CRO’s SOPs for 
statistics and clinical programming with oversight from MA Statistics of the Sponsor.  All study 
specific processes and definitions will be documented.  Data analysis will be performed in 
adherence to Astellas data standards.  
Analyses that will be performed on the primary and secondary variables are described in this 
section.  A more technical and detailed elaboration of the statistical analysis of the primary and 
secondary variables and other data will be included in a separate Statistical Analysis Plan (SAP) 
and result tables specification manual.  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.  
Summary statistics of all variables (demographic and clinical) will be produced in the form of 
tables. Descriptive statistics (mean, median, standard deviation [SD], etc.) in addition to graphical 
representation of the data (plots, histograms, etc.) will be presented.  For continuous variables, 
descriptive statistics will include the number of patients (n), mean (for observed values and 
absolute changes from baseline), SD, median, minimum and maximum.  Two-sided 95% CI will 
be calculated for mean changes from baseline.  For categorical variables, the number and 
percentage of patients by each category will be tabulated by visit.  The number of missing values 
will be specified for each variable.  Cross tabulations will be produced to explore relationships 
between variables.  No formal statistical comparisons will be performed.  
7.1 Sample Size 
This study targets to enroll approximately 107 prostate cancer patients.  
The sample size was calculated based on the estimated percentage of ELIGARD®-related AEs, as 
well as the desired width of its 95% CI.  Prior clinical studies on ELIGARD® have shown an 
ELIGARD®-related AEs rate of around 50% of patients during a six-month treatment period 
[ELIGARD Investigator
's Brochure, June 2008; Tombal & Berges, 2007].  With the assumption 
that the percentage of ELIGARD
®-related AEs will be 50%,a sample size of 96 completed 
patients is sufficient for estimating a Wald 95% CI with a width of 20% (+/- 10% from the 
middle), based on a finite population correction, with factor N=10,000.  
Therefore, the total sample size of this study, assuming a drop-out rate of 10%, is 107 patients. 
PASS 14 Power Analysis and Sample Size Software (2015) version number 14.0.2 was used in 
the sample size calculation (NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass).  
7.2 Analysis Set 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of patients to analysis sets will be determined prior to database hard-lock.  


 
 
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7.2.1 Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all patients who are enrolled and receive at least 1 dose 
of study drug and have at least 1 post baseline measurement of PSA and testosterone levels.  This 
will be the primary analysis set for efficacy analyses. 
7.2.2 Per Protocol Set (PPS) 
The per protocol set (PPS) will consist of the subset of the FAS who do not meet criteria for PPS 
exclusion.  These criteria are to capture relevant non-adherence to the protocol and are listed 
below:  
• Entered into the study even though they did not satisfy entry criteria  
• Developed withdrawal criteria during the study and was not withdrawn (Patients who 
discontinued the study for efficacy-related reasons, such as insufficient therapeutic effect, 
will be included in the PPS.) 
• Full dose was not administered or drug reconstitution was not performed as prescribed 
• Patients with treatment compliance <80% 
• Patients who used prohibited concomitant medication as defined in protocol 
Further criteria may be defined in the SAP.  The PPS will be a secondary analysis set for efficacy 
analyses.  Select demographic and baseline characteristics may also be summarized for the PPS. 
7.2.3 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 patients from whom at least 1 ELIGARD® injection is received and any 
follow-up safety information is available. 
7.2.4 Pharmacokinetic Analysis Set (PKAS) 
Not applicable. 
7.2.5 Pharmacodynamic Analysis Set (PDAS)  
Not applicable. 
7.3 Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized for the SAF and PPS. 
Descriptive statistics will include number of patients, mean, SD, minimum, median and 
maximum for continuous endpoints, and frequency and percentage for categorical endpoints.  


 
 
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7.4 Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS and PPS.  The interpretation of results from 
statistical tests will be based on the FAS.  The PPS will be used to assess the robustness of the 
results from the statistical tests based on the FAS.  
7.4.1 Analysis of Primary Endpoint  
Not applicable as the primary analysis of this study is a safety analysis. 
7.4.2 Analysis of Secondary Endpoints 
Descriptive statistics will be presented for the following:   
• Percentage of patients with Testosterone <20, 20-50 and >50 ng/dL at 1 year and at 
1.5 years 
• Time to PSA progression: calculated from date of first administration of ELIGARD
® 
22.5 mg to PSA progression 
• PSA progression will be defined as a 25% or greater increase and an absolute increase of 
2 ng/mL or more from the nadir is documented, which is  
o Confirmed by a second value obtained 3 or more weeks later  
o If not done based on standard clinical practice, the confirmatory PSA 
measurement should be performed at the next routine study visit. 
Note:  The aim is to detect time to PSA progression and not to assess whether the 
patient has progressed to CRPC.  Imaging and other modalities should be used to 
determine if the patient has moved to CRPC, which is outside the scope of this 
study  
• HRQoL: (EORTC QLQ-PR25 and EQ-5D-5L) at baseline and following scheduled visits 
as well as change from baseline 
7.4.3 Analysis of Exploratory Endpoints 
Not applicable as there are no exploratory objectives in this study. 
7.5 Analysis of Safety 
7.5.1 Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of AEs, SAEs, Severe AEs (defined as AEs graded > 3 according to NCI-
CTCAE guidelines Version 4.03), AEs leading to treatment discontinuation, and ELIGARD®-
related AEs will be summarized by System Organ Class (SOC), Preferred Term (PT).  The 
number and percentage of AEs by severity will also be summarized.  AEs that occur after 


 
 
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receiving CRPC management will be presented separately.  All AEs, including information 
described in following subsections, will be listed.  
7.5.1.1 Incidence of ELIGARD®  Related Adverse Events 
ELIGARD®-related AEs are AEs that are reported to be related to ELIGARD
® (possible or 
probable) as determined by the investigator. 
All ELIGARD®-related AEs will be summarized according to their severity, NCI CTCAE Grade, 
outcome, course of event, seriousness, action taken with ELIGARD® and treatment required to 
manage the AE for SAF set. 
To analyze the incidence of ELIGARD®-related AEs and SAEs during the observation period, 2-
sided 95% symmetric CIs of incidence rates based on normal approximation will be presented 
after adjusted for a finite sample size of 10000.  All SAF subjects will be counted, and separate 
summaries shall be performed for ELIGARD
® -related AEs and SAEs. 
Time to first occurrence of ELIGARD® -related AEs and SAEs will be presented using Kaplan-
Meier (KM) plots.  If applicable, estimated median time to first event together with a 95% CI will 
be prepared.  In addition, KM estimates of incidence rates of ELIGARD® -related AEs and SAEs 
will be summarized at each scheduled visit time-point, together with a 95% CI. 
Of note, summaries of ELIGARD®-related AEs and SAEs that occurred after receiving CRPC 
management will be presented separately. 
Details of statistical analyses for primary safety endpoint will be described in the statistical 
analysis plan. 
7.5.1.2 Treatment for ELIGARD® Related Adverse Events 
Interventions taken to manage ELIGARD
® -related AEs, including medications, procedures, 
radiography, and hospitalization together with visits to Accident & Emergency Department 
and/or ambulatory clinic, will be summarized by their categories and coded terms whenever 
applicable.  In addition, occurrence count and cumulative duration of each intervention and 
hospitalization record for each subject will be summarized and presented for SAF. 
7.5.2 Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize results 
and change from baseline by time point.  Shifts relative to normal ranges from baseline to each 
time point during treatment period in lab tests will also be tabulated.  Laboratory data will be 
displayed in listings.  Laboratory data will include LDH, ALP, Hematology, LFT and RFT, etc. 


 
 
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7.5.3 Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline by 
time.  Vital signs data will be displayed in listings. 
7.5.4 Imaging  
Descriptive statistics will be used to summarize imaging data if available. 
7.6 Protocol Deviations and Other Analyses  
Protocol deviations as defined in Section 8.1.6 Protocol Deviations (PD) will be summarized for 
all patients.  A data listing will be provided by site and patient.    
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 - Full dose was not administered or drug reconstitution was not performed as prescribed, 
PD4 - Received excluded concomitant treatment.   
7.7 Interim Analysis 
A minimum of 1 interim analysis will be conducted when 50 patients complete 1 year of follow-
up.  As there are no statistical hypothesis tests in the planned analysis, the conduct of interim 
analyses will not have any statistical implications on the final study outcome. 
7.8 Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
The amount and potential effect of missing data will be explored and detailed further in the SAP.  
In general, missing data will not be imputed and the data will be analyzed as they are recorded in 
the study case report forms (CRFs).  However, if more than 10% of data is missing for 1 or more 
key variables, the impact of missing data on the analysis will be discussed, and the pattern of 
missing data will be explored.  If there is evidence of bias in the missing data, and variables that 
are considered good predictors of the missing data are available, the multiple imputation method 
at the study level may be used to replace missing values as secondary exploratory analyses.  If the 
multiple imputation method is used, a sensitivity analysis will be carried out comparing results 
from the complete case analysis (where records with missing data will be dropped) and the full 
set analysis (with imputed data).  
 


 
 
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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. 
The investigator or site designee is responsible for ensuring 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 each site’s local laboratory.  Laboratory data will be transferred 
electronically to the Sponsor or designee at predefined intervals during the study.  The laboratory 
will provide the Sponsor or designee with a complete and clean copy of the data.  
Paper Patient Reported Outcome (pPRO): 
EORTC QLQ-PR25 and EQ-5D-5L will be completed by the patient on paper.  The investigator 
or site designee should review questionnaire data while the patient is at the site.  The investigator 
or site designee will enter the questionnaire data directly into the EDC system. The paper 
questionnaires will be kept at sites.  
8.1.2 Specification of Source Documents 
Source data must be available at the site to document the existence of the study patients 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 
patient.   
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 ICFs 
● Visit dates 
● Medical history and physical examination details (physical examination is optional) 
● Key efficacy and safety data, if applicable (as specified in the protocol) 
● AEs and concomitant medication  


 
 
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● Results of relevant examinations (e.g., X-ray films, CT scan, MRI, etc.) 
● PSA and testosterone levels 
● Other laboratory printouts (if applicable) 
● Drug administration data 
● Reason for premature discontinuation (if applicable) 
● QoL questionnaires 
8.1.3 Clinical Study Monitoring 
The Sponsor or delegated designee is responsible for monitoring the clinical study to ensure that 
patient
's human rights, safety, and well-being are protected, that the study is properly conducted 
in adherence to the current protocol and ICH 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 designee 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) when they are requested by the Sponsor monitors and auditors, the IRB/IEC, or 
regulatory authorities.  The confidentiality of the patient
's identities shall be well protected 
consistent with local and national regulations when the source documents are patient to direct 
access. 
8.1.5 Data Management 
Data Management will be coordinated by the Sponsor’s designee in accordance with the 
delegated designee’s SOPs for data management.  All clinical study-specific processes and 
definitions will be documented by Data Management.  Coding of medical terms and medications 
will be performed using MedDRA and World Health Organization (WHO) Drug Dictionary 
respectively.   
The Clinical Data Interchange Standards Consortium (CDISC) datasets should be developed 
according to Astellas Data standards (Study Data Tabulation Model [SDTM] and Analysis Data 
Model [ADaM]).     


 
 
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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 the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of patients.  The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial patients.   
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 
patient who:  
● Entered into the study even though they did not satisfy entry criteria.  
● Developed withdrawal criteria during the study and not withdrawn. 
● Received incorrect dose. 
● Full dose was not administered or drug reconstitution was not performed as prescribed.  
● Received any excluded concomitant medication (see Sections 5.1.6 and 12.2) 
When a deviation from the protocol is identified for an individual patient, 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 
patient to determine patient continuation in the study.  
If a deviation impacts the safety of a patient, 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 
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8.2 Ethics and Protection of Patient Confidentiality  
8.2.1 Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities  
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator’s Brochure, the informed consent and all other forms of patient information related 
to the study (e.g., advertisements used to recruit patients) 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 patient information and/or advertising, as relevant, will be obtained prior to the 
authorization of drug shipment to a study site. 
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 SAEs 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 patients.  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 1 year.  
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 Patients 
8.2.3.1 Patient Information and Consent 
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior to 
any study-related screening procedures being performed on the patient, the informed consent 
statement will be reviewed, signed and dated by the patient or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements.  A copy of the signed ICF will be given to the patient and the 
original will be placed in the patient’s medical record.  An entry must also be made in the 


 
 
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patient’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the patient received a signed copy. 
The signed ICFs 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. 
8.2.3.2 Supply of New and Important Information Influencing the Patient’s Consent and 
Revision of the Written Information 
The investigator or his/her representative will immediately inform the patient orally whenever 
new information becomes available that may be relevant to the patient’s consent or may influence 
the patient’s willingness to continue to participate in the study (e.g., report of ELIGARD®-related 
SAEs ).  The communication must be documented in the patient’s medical records and must 
document whether the patient 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 
investigator or his/her representative must obtain written informed consent from the patient on all 
updated ICFs throughout their participation in the study.  The investigator or his/her designee 
must re-consent patients 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 
patient should sign and date the ICF.  A copy of the signed ICF will be given to the patient and 
the original will be placed in the patient’s medical record.  An entry must be made in the patient’s 
records documenting the re-consent process. 
8.2.4 Patient Confidentiality 
Individual patient 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 patient to the patient
's physician or to other appropriate medical personnel 
responsible for the patient
's well-being. 
The Sponsor shall not disclose any confidential information on patients obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
The Sponsor affirms the patient
's right to protection against invasion of privacy.  Only a patient 
identification number and/or initials will identify patient 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., Health Insurance Portability and 
Accountability Act [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 investigator will archive all study data (e.g., Patient Identification Code List, source data, 
CRFs, and Investigator
's File) and relevant correspondence.  These documents are to be kept on 
file for the appropriate term determined by local regulation.  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 patients
' medical 
records and/or study progress notes.  All data will be entered on the CRFs supplied for each 
patient.  
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 patient 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. 


 
 
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If there are changes to the ICF, 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 Patients 
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 Efficacy guidelines 3 (ICH E3) recommend 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 Asia/ Oceania Medical Affairs Department, Astellas Pharma Singapore Pte Ltd will provide 
oversight of study activities that have been assigned to Sponsor’s designee responsible for site 
management and monitoring.  All study specific processes and definitions will be documented by 
the appointed Sponsor’s designee’s management group and in accordance with the Sponsor’s 
designee’s SOPs. 
The Sponsor’s designee will implement and maintain quality assurance and quality control (QC) 
systems with written SOPs to ensure that the study is conducted and data are generated, 
documented and reported in compliance with the protocol, GCP, Good Pharmacovigilance 
Practice (GPP) and applicable regulatory requirements 
Details on data quality management, handling of missing data, validation and plausibility checks, 
query plan and data review will be described in the Sponsor’s designee predefined Data 
Management Plan and Quality Review Plan, as agreed upon with the Sponsor.  National and 
international data protection laws as well as regulations on interventional studies will be 
followed. 
The Sponsor or Sponsor’s designee may arrange to inspect/audit the study at any or all the 
investigational sites.  The auditor is independent from the clinical monitoring and project 
management teams at the Sponsor or the Sponsor’s designee.  The audit may include on-site 
review of regulatory documents, eCRF and source documents.  Direct access to these documents 
will be required by the auditors. 


 
 
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10 STUDY ORGANIZATION 
A Study Steering Committee was formed whose role is to refine the design, conduct, analysis and 
reporting of the study. It is composed of international experts specializing in the treatment of 
prostate cancer.  Outside experts will be designated by the Steering Committee to provide specific 
guidance as needed throughout the study.  A separate Publication Steering Committee will be 
formed to oversee planning of publications related to the ELIGANT study.  Publication Steering 
Committee membership will include at a minimum a Steering Committee representative and a 
representative of the Sponsor.  Authorship will be based on guidelines set forth in the Uniform 
Requirement for Manuscripts Submitted to Biomedical Journals (International Committee of 
Medical Journal Editors, 1997).  
 
 


 
 
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11 REFERENCES 
 
Baade PD, Youlden DR, Cramb SM, Dunn J, Gardiner RA. Epidemiology of prostate cancer 
in the Asia-Pacific region. Prostate international. 2013;1(2):47-58. 
Berges R, Bello U. Effect of a new leuprorelin formulation on testosterone levels in patients 
with advanced prostate cancer. Current Medical Research Opinion. 2006;22(4):649-55. 
Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International 
variation in prostate cancer incidence and mortality rates. European urology. 
2012;61(6):1079-92. 
Crawford ED. Epidemiology of Prostate Cancer. Urology 62 (Supplement 6A ). 2003:3-12. 
ELIGARD 22.5 mg, Summary of Product Characteristics 2015 [updated 2015; cited 2016 
April 06]. Available from: http://www.medicines.ie/medicine/11073/SPC/Eligard+22.5mg/. 
ELIGARD Investigator
's Brochure. 2008(5). Release date 28th June 2008. 
Eligard Local Prescribing Information, Singapore, May 2014 (local Package insert). 2014. 
Ito K. Prostate cancer in Asian men. Nature reviews Urology. 2014;11(4):197-212. 
Klotz L, O'Callaghan C, Ding K, Toren P, Dearnaley D, Higano CS, et al. Nadir testosterone 
within first year of androgen-deprivation therapy (ADT) predicts for time to castration-
resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous 
ADT. Journal of Clincal Oncology. 2015;33(10):1151-6. 
Mottet N, et al. . Guidelines on Prostate Cancer. EAU - ESTRO - SIOG  2016. 
http://uroweb.org/wp-content/uploads/EAU-Guidelines-Prostate-Cancer-2016.pdf 
Sim HG, Cheng CW. Changing demography of prostate cancer in Asia. European journal of 
cancer (Oxford, England : 1990). 2005;41(6):834-45. 
Tombal B, Berges R. Optimal Testosterone Control and Eligard®. European Urology 
Supplements. 2007;6:754-60. 
Zhang L, Yang BX, Zhang HT, Wang JG, Wang HL, Zhao XJ. Prostate cancer: an emerging 
threat to the health of aging men in Asia. Asian journal of andrology. 2011;13(4):574-8. 
 


 
 
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12 APPENDICES 
12.1 List of stand-alone documents 
 
Number 
Document reference 
number 
Date 
Title 
Appendix I 
RG08029 
26th Jun 2008 
 
Tolmar Inc. ELIGARD® IB 
 
Appendix II 
APvS-T-CP01.35/9 
6th Nov 2017 Astellas Always Serious Terms List 
 
 
 
 


 
 
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12.2 List of Excluded Concomitant Medications 
1. Other LHRH analogues,  
2. LHRH antagonists and other agents (approved or investigational) which are known to 
impact on testosterone or PSA level,  
3. Ketoconazole,  
4. Estrogens,  
5. Herbal medications that may affect PSA levels (i.e., saw palmetto),  
6. Androgens (testosterone, dihydroepiandrosterone, etc.),  
7. Abiraterone,  
8. Enzalutamide,  
9. Chemotherapy agents including docetaxel and platinum drugs  
Note:  No pharmacokinetic drug-drug interaction studies have been performed with Leuprorelin 
(ELIGARD®).  There have been no reports of any interactions of leuprorelin acetate with other 
medicinal product.  Anti-androgen should be considered for this study. 
 
 
 


 
 
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12.3 Liver Safety Monitoring and Assessment  
Any patient enrolled in a clinical study with active drug therapy and reveals an increase of serum 
aminotransferases (AT) to > 3 × upper limits of normal (ULN) (to > 5 × ULN in patients 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.  Patients 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 patient 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 international normalized ratio [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-CRF) that has been developed globally and can be activated for any study or appropriate 
document. Patients with confirmed abnormal LFT should be followed as described below.  


 
 
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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 patient 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 an SAE.  The Sponsor 
should be contacted and informed of all patients 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 AEs on the AE page of the eCRF.  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 AT 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 eCRF. Information on alcohol, other substance use, and diet should be entered on the LA-
CRF or an appropriate document. 
● Obtain a history of exposure to environmental chemical agents. 
● Based on the patient’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-CRF 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 patient may be discontinued from the study.  The investigator may determine that it is 
not in the patient’s best interest to continue study enrollment.  Discontinuation of treatment 
should be considered if: 


 
 
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● ALT or AST > 8 × ULN 
● ALT or AST > 5 × ULN for more than 2 weeks (in patients 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 patient with moderate or severe hepatic laboratory tests is 
not possible, drug should be discontinued. 
*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 2 “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 than 
3 times the ULN (“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 the United States Food and Drug Administration (FDA) on July 2009. 
 
 


 
 
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12.4 Common Serious Adverse Events 
The following is a list of serious adverse events that the Sponsor considers to be associated with 
the disease state being studied.  The list does NOT change your reporting obligations or 
prevent the need to report an adverse event meeting the definition of an SAE as detailed in 
Section 5.6.2 Definition of Serious Adverse Event (SAE).  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”.  You are required to 
follow the requirements detailed in Section 5.6.5 Reporting of Serious Adverse Events (SAE).   
Common Serious Adverse Events due to prostate cancer include: 
• Urinary flow obstruction 
• Hematuria 
• Spinal cord compression/ Paraplegia 
• Pleural effusion 
• Bone fractures 
 
12.5 EQ5D-5L Questionnaire 
12.6 EORTC QLQ-PR25 Questionnaire 
 
 


 
 
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12.7 Protocol Amendment Summary Document 
 
Protocol Amendment Summary Document 
ISN/Protocol 7015-MA-3072 
Substantial Amendment Version 2.0 
 
18 April 2018 
 
I.  The purpose of this amendment is: 
 
Substantial Changes 
1. Update Protocol Title   
DESCRIPTION OF CHANGE: 
Remove the description of efficacy and quality of life from the protocol title. 
 
RATIONALE: 
The protocol is revised to reflect the primary objective of this study for establishing the 
safety profile of ELIGARD
® in ethnic Asian prostate cancer patients. 
 
2. Update Sample Size , Study Period and Center Numbers for the Study 
DESCRIPTION OF CHANGE: 
The sample size for this study is revised to approximately 107 enrolled prostate cancer 
patients, with 96 completed patients. The number of participating centers in the study is 
revised to 20 centers. The planned total duration of the study is revised to 30 months from 
the date of first patient enrollment until 3 months after the last dose of ELIGARD
® 
administration. The enrollment period is revised to 12 months. 
 
RATIONALE: 
The sample size is revised based on the rationale that more than 90% of subjects will have 
Testosterone level of 20-50mg/dL. The original sample (N=345) will not lead to effective 
analysis in the study cohorts based on Testosterone levels and hence no added substantial 
impact with reduction in sample size. In addition, this study is not a registration study and 
multiple global data from LHRH analogues is available that a wider confidence interval 
should not have a meaningful risk. 
The study timeline is shortened considering 107 patients rather than 345 patients will be 
enrolled. The number of 20 participating sites is based on the sample size of 345 patients. 
However, because RA approval and EC submission for all 20 countries have been done, it 
has been decided to keep all 20 sites.  
 


 
 
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3. Update Table 1 Schedule of Assessments 
DESCRIPTION OF CHANGE: 
Add language to clarify the choices available in eCRF for the most important factors for 
selection of treatment, including rising PSA after definitive treatment, optimal testosterone 
control, quality of life, convenience of 3-monthly formulation, and other.  
 
Add language in the footnote f to clarify the Visual Analogue Scale (VAS) will only be 
collected if done in routine clinical practice.  
 
RATIONALE: 
The reasons for selection of treatment with ELIGARD® 22.5mg will be collected at the 
baseline visit. Examples for potential factors, such as rising PSA after definitive treatment, 
optimal testosterone control, quality of life and convenience of use, are added as a 
guidance in the assessment schedule table. 
 
4. Update Concomitant Treatment Definition 
DESCRIPTION OF CHANGE: 
Include language to clarify the appropriate anti-androgen should be considered beginning 
at least 3 days to 4 weeks prior to ELIGARD® injection and continuing for the first 2 to 3 
weeks of treatment.  
 
RATIONALE: 
The revision is to keep consistency with the following statement in Section V Flow Chart 
and Schedule of Assessment.  
Anti-androgen for at least 3 days to 4 weeks prior to the first ELIGARD® injection and 
continuing for the first 2 to 3 weeks of treatment should be considered.  
 
5. Add One Additional Definition For Discontinuation 
DESCRIPTION OF CHANGE: 
One additional condition for discontinuation is added to define patients will be 
discontinued from the study in the case of patient taking prohibited medications as 
described in protocol Section 5.1.6 and Section 12.2.  
 
RATIONALE: 
The drugs prohibited to be used throughout the study are described in protocol Section 
5.1.6 and Section 12.2. Individual patients who are enrolled in the study and take 
prohibited medications during the study course should be discontinued prematurely from 
the study.  
 
6. Update Selection of Study Population and Inclusion Criteria 


 
 
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DESCRIPTION OF CHANGE: 
Include wording of “and” to include patients with locally advanced prostate cancer with 
biochemical relapse following radical prostatectomy and radiotherapy.  
 
Include wording of “OR” to make inclusion criteria #4 and #5 as one criterion.  
 
RATIONALE: 
To include the patients with locally advanced prostate cancer with biochemical relapse 
following radical prostatectomy only, radiotherapy only, both radical prostatectomy and 
radiotherapy.  
 
The criteria of “Locally advanced prostate cancer with biochemical relapse following 
radical prostatectomy and/or radiotherapy” and “Hormonal treatment-naive advanced or 
metastatic prostate cancer patient who has not received chemotherapy and has no plans to 
undergo treatment with chemotherapy at study entry” are not both possible to be met in 
one particular patient.  
 
 
7. Update Interim Analyses Cut-Off Time and Condition 
DESCRIPTION OF CHANGE: 
The schedule of the interim analysis is revised to be conducted when 50 of the patients 
complete 1 year of follow-up after the first patient is enrolled.      
 
RATIONALE: 
To specify the estimated number of patients to be included in the interim report, and to 
revise the criteria that patients to be analyzed will be those who complete 1 year of follow 
up instead of those who complete treatment, since treatment may stop for various reasons 
during the study. 
 
 
8. Update background information for ELIGARD® Risk Management Plans 
(RMP) 
DESCRIPTION OF CHANGE: 
Add “QT prolongation” in Section 1.2 Clinical data to include major updates of 
ELIGARD® RMP. 
 
RATIONALE: 
The QT prolongation was added because the ELIGARD RMP was updated to version 7.0 
and submitted at the end of Oct 2017 to the Health Authorities. The summary of the major 
updates is listed below: 
1. QT prolongation was added as one of the new important identified risks. 


 
 
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2. The other safety concerns remained the same, including important identified risks 
renamed as “Transient testosterone flare”, “Diabetes and hyperglycemia” & “Convulsions” 
which has been covered in Section 1.2 of the protocol. 
 
 
Non-Substantial Changes 
1. Update Contact Details of Key Sponsor’s Personnel 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes. 
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures. 
 
2. Update Timeline of Study Period 
DESCRIPTION OF CHANGE: 
Update timeline for each milestone of the study, including start and end of data collection, 
final report of study results and publication.  
 
RATIONALE: 
The study timeline is updated due to the changes of sample size from 345 to 107 enrolled 
patients.   
 
3. Update Flow Chart and Schedule of Assessment 
DESCRIPTION OF CHANGE: 
Add language in the footnote clarifying the definition of “one month=30 days.”  
 
RATIONALE: 
To provide clarifications to the protocol and to ensure complete understanding of study 
population 
 


 
 
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4. Minor Administrative–type Changes  
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes, e.g., document version, format, typo, 
consistency, citation and reference style throughout the protocol following STL1015 
 
RATIONALE: 
To provide clarifications and writing style consistency to the protocol and to ensure 
complete understanding of study population 
 
5. Update Analysis of Secondary Endpoints 
DESCRIPTION OF CHANGE: 
Update language to specify the measurement of time to PSA progression is calculated from 
date of first administration of ELIGARD® 22.5 mg to PSA progression. 
 
RATIONALE: 
Include format type changes to specify the definition for time to PSA progression. 
 
 


 
 
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II.  Amendment Summary of Changes: 
Front Page, IV Synopsis  
Title of Study  
WAS:  
A Phase IV Interventional Safety, Efficacy and Quality of Life Study of ELIGARD® in 
Prostate Cancer Patients in Asia (ELIGANT)    
 
 
IS AMENDED TO: 
A Phase IV Interventional Safety, Efficacy and Quality of Life Study of ELIGARD® in 
Prostate Cancer Patients in Asia (ELIGANT)   
 
 
II. Contact Details of Key Sponsor’s Personnel  
WAS:  
Sponsor’s personnel: 24h-Contact for Serious Adverse Events (SAEs): See Section 5.6.5 
Quintiles Lifecycle Safety 
Email:  PHV_Astellas@Quintiles.com 
Fax: +65 6872 8462    
 
Medical Monitor: 
 
 
 
 
 
Clinical Research Contacts: 
 
 
 
 
 
 
 
  
   
 
IS AMENDED TO: 
Sponsor’s personnel: 24h-Contact for Serious Adverse Events (SAEs): See Section 5.6.5 
Quintiles IQVIA Lifecycle Safety 
Email:  PHV Astellas@Quintiles.com QLS Eligard@quintiles.com 
PPD
PPD
PPD


 
 
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Fax: +65 6872 8462    
 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
Clinical Research Contacts: 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
IV Synopsis 
Planned Study Period  
WAS:  
From Q1 2017 to Q1 2020 
Start of data collection:Q1 2017  
End of data collection:Q1 2020 
Final report of study results:Q4 2020 
Publication:Q4 2021    
 
IS AMENDED TO: 
From Q1 2017 Q2 2017 to Q1 2020 
PPD
PPD
PPD
PPD
PPD


 
 
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Start of data collection: Q1 2017 Q2 2017 
End of data collection: Q1 2020 
Final report of study results: Q4 2020 Q3 2020 
Publication: Q4 2021 Q3 2021 
 
 
V Flow Chart and Schedule of Assessments 
Flow Chart: Footnote  
ADDED: 
One month=30 days   
 
 
V Flow Chart and Schedule of Assessments 
Table 1 Schedule of Assessments  
WAS:  
Most important factors for selection of treatment 
 
IS AMENDED TO: 
Most important factors for selection of treatment (Rising PSA after definitive treatment, 
optimal testosterone control, quality of life, convenience of 3 monthly formulation, 
other). 
 
 
V Flow Chart and Schedule of Assessments 
Table 1 Schedule of Assessments – Footnote f.  
WAS:  
f. Prostate cancer status - stage of prostate cancer, bone metastasis, soft tissue disease, 
visceral disease, pain (using Visual Analogue Scale (VAS) 0-10), ECOG status 
 
IS AMENDED TO: 


 
 
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f. Prostate cancer status - stage of prostate cancer, bone metastasis, soft tissue disease, 
visceral disease, pain (using Visual Analogue Scale [VAS] 0-10 which will only be 
collected if done in routine clinical practice), ECOG status 
 
1. Introduction 
1.2 Non-clinical and Clinical data 
WAS:  
Decreased bone density and rare cases of pituitary apoplexy (a clinical syndrome 
secondary to infarction of the pituitary gland) have been reported during the post-
marketing experience after the administration of GnRH agonists (0).  Convulsions have 
also been reported in the post-marketing setting (8).   
 
IS AMENDED TO: 
Decreased bone density and rare cases of pituitary apoplexy (a clinical syndrome 
secondary to infarction of the pituitary gland) have been reported during post-marketing 
experience after the administration of GnRH agonists (0) [ELIGARD local prescribing 
information, May 2014].  Convulsions and QT prolongation have also been reported in 
the post-marketing setting (0) [ELIGARD local prescribing information, May 2014].   
 
 
2.2 Study Design and Dose Rationale, and IV Synopsis 
2.2.1 Study Design  
WAS:  
This study will be conducted in approximately 15 centers in 8 countries (Hong Kong, 
Indonesia, Malaysia, Philippines, Singapore, Taiwan, Thailand and Vietnam). The planned 
total duration of this study is 36 months from the date when the first patient is enrolled. 
The patient population includes male Asian patients diagnosed with prostate cancer who 
will receive ELIGARD® 22.5 mg (3-monthly formulation) depot formulation between the 
periods of Q1 2017 through Q2 2018.  
 
The enrollment period will be up to 18 months. 
 
The sample size planned for this study is approximately 345 enrolled prostate cancer 
patients.   
 
IS AMENDED TO: 
This study will be conducted in approximately 15 20 centers in 8 countries (Hong Kong, 
Indonesia, Malaysia, Philippines, Singapore, Taiwan, Thailand and Vietnam). The planned 
total duration of this study is 36 30 months from the date when the first patient is enrolled 


 
 
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until 3 months after the last dose of ELIGARD® 22.5 mg administration. The patient 
population includes male Asian patients diagnosed with prostate cancer who will receive 
ELIGARD® 22.5 mg (3-monthly formulation) depot formulation between the periods of 
Q1Q2 2017 through Q3 2018. 
 
The enrollment period will be up to 18 12 months. 
 
The sample size planned for this study is approximately 345 107 enrolled prostate cancer 
patients.   
 
 
 
3 Study Population and IV Synopsis 
3.1 Selection of Study Population  
WAS:  
This study is designed for male patients with: 
• locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy or radiotherapy; and  
• hormonal treatment-naive advanced or metastatic prostate cancer 
 
IS AMENDED TO: 
This study is designed for male patients with: 
• Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy and/or radiotherapy (see inclusion criteria 4)  
• Hormonal treatment-naive advanced or metastatic prostate cancer 
 
 
3 Study Population and IV Synopsis 
3.2 Inclusion Criteria #1, 2, 4, 5  
WAS:  
6. Being ethnic Asian male patient above 18 years of age 
7. Being willing and able to provide written informed consent 
4. Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy or radiotherapy.  Biochemical relapse (1) is defined as:  
• PSA > 2 ng/mL following radiotherapy, or 
• Two consecutive PSA values > 0.2 ng/mL and rising above the nadir 
following radical prostatectomy 


 
 
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5. Hormonal treatment-naive advanced or metastatic prostate cancer patient who has not 
received chemotherapy and has no plans to undergo treatment with chemotherapy at 
study entry.   
6. Patient who indicates that once the study is completed, he expects having access to 
androgen deprivation therapy (ADT), either medical or surgical, within the local 
healthcare system (either through public/ private health insurance or out of pocket 
payment). 
 
 
IS AMENDED TO: 
1. Being Ethnic Asian male patient above 18 years of age 
2. Being Willing and able to provide written informed consent 
4. Locally advanced prostate cancer with biochemical relapse following radical 
prostatectomy and/or radiotherapy.  Biochemical relapse [Mottet et al, 2006] is defined 
as:  
• PSA > 2 ng/mL following radiotherapy, or 
• Two consecutive PSA values > 0.2 ng/mL and rising above the nadir 
following radical prostatectomy 
OR 
Hormonal treatment-naive advanced or metastatic prostate cancer patient who has not 
received chemotherapy and has no plans to undergo treatment with chemotherapy at 
study entry.   
 
5. Patient who indicates that once the study is completed, he expects having access to 
androgen deprivation therapy (ADT), either medical or surgical, within the local 
healthcare system (either through public/ private health insurance or out of pocket 
payment). 
 
 
IV Synopsis 
Concomitant medication restrictions or requirements 
WAS:  
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication 
for flare prevention only.  The anti-androgen for flare prevention should be considered 
beginning 3 days prior to leuprorelin therapy and continuing for the first two to three 
weeks of treatment. 
 


 
 
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IS AMENDED TO: 
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication 
for flare prevention only.  The anti-androgen for flare prevention should be considered 
beginning at least 3 days to 4 weeks prior to leuprorelin therapy 
the first ELIGARD
® 
injection and continuing for the first 2 two to 3 three weeks of treatment. 
 
5 Treatments and Evaluation 
5.1.3 Previous and Concomitant Treatment 
WAS:  
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication 
for flare prevention only.  Additional administration of an appropriate anti-androgen 
should be considered beginning three days prior to ELIGARD treatment and continuing for 
the first two to three weeks of treatment to avoid any flare reaction. 
 
IS AMENDED TO: 
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication 
for flare prevention only.  Additional administration of an appropriate anti-androgen 
should be considered beginning at least three 3 days to 4 weeks prior to ELIGARD 
treatment the first ELIGARD
® injection and continuing for the first two 2 to three 3 
weeks of treatment to avoid any flare reaction. 
 
 
 
5 Treatments and Evaluation, and IV Synopsis 
5.1.6 Restrictions During the Study  
WAS:  
The following drugs are prohibited to be used throughout the study (see Section 12.2): 
10. other LHRH analogues,  
 
IS AMENDED TO: 
The following drugs are prohibited to be used throughout the study (see Section 12.2): 
1. oOther LHRH analogues, 
 
5.6 Adverse Events and Other Safety Aspects 
5.6.1 Definition of Adverse Events  
WAS:  


 
 
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An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
electroniccardiogram [ECG] data, physical exam) should be defined as an AE only if the 
abnormality meets 1 of the following criteria: 
 
IS AMENDED TO: 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
electroniccardiogram electrocardiogram [ECG] data, physical exam) should be defined as 
an AE only if the abnormality meets 1 of the following criteria: 
 
 
6 Discontinuation 
6.1 Discontinuation of Individual Patients  
ADDED:  
A patient will be discontinued from the study in the case of:  
11. Patient takes prohibited medications as described in Section 5.1.6 and Section 12.2  
 
 
7 Statistical Methodology and IV Synopsis 
 
WAS:  
Data analysis will be performed by the designated CRO in accordance with the CRO’s 
SOPs for statistics and clinical programming with oversight from the Global Data Science 
Department of the Sponsor. 
 
7.1 Sample Size  
This study targets to enroll approximately 345 prostate cancer patients.  
The sample size was calculated based on the estimated percentage of ELIGARD®-related 
AEs, as well as the desired width of its 95% Confidence Interval (CI).  Prior clinical 
studies on ELIGARD
® have shown an ELIGARD®-related AEs rate of around 50% of 
patients during a six-month treatment period (12,13). Considering the treatment duration 
will be 18 months in this study, the percent of patients that experienced ELIGARD®-
related AEs is estimated to be 70% for sample size calculation. A sample size of 313 
completed patients is sufficient for estimating a Wald 95% CI with a width of 10% (+/- 5% 
from the middle), based on a finite population correction, with factor N=10,000. 
 
Therefore, the total sample size of this study, assuming a drop-out rate of 10% is 345 
patients. 
 


 
 
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PASS 14 Power Analysis and Sample Size Software (2015) version number 14.0.2 was 
used in the sample size calculation (NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass). 
 
IS AMENDED TO: 
Data analysis will be performed by the designated CRO in accordance with the CRO’s 
SOPs for statistics and clinical programming with oversight from the Global Data Science 
Department of the Sponsor with oversight from MA Statistics of the Sponsor. 
 
7.1 Sample Size  
This study targets to enroll approximately 345 107 prostate cancer patients.  
The sample size was calculated based on the estimated percentage of ELIGARD® -related 
AEs, as well as the desired width of its 95% Confidence Interval (CI).  Prior clinical 
studies on ELIGARD
® have shown an ELIGARD®-related AEs rate of around 50% of 
patients during a six-month treatment period (12,13). [ELIGARD Investigator's 
Brochure, June 2008; Tombal & Berges, 2007].  Considering the treatment duration will 
be 18 months in this study, the percent of patients that experienced ELIGARD® related 
AEs is estimated to be 70% for sample size calculation With the assumption that the 
percentage of ELIGARD®-related AEs will be 50%, a sample size of 313 96 completed 
patients is sufficient for estimating a Wald 95% CI with a width of 10% 20% (+/- 5%10% 
from the middle), based on a finite population correction, with factor N=10,000.  
Therefore, total sample size of this study, assuming a drop-out rate of 10%, is 345 107 
patients. 
PASS 14 Power Analysis and Sample Size Software (2015) version number 14.0.2 was 
used in the sample size calculation. 
 
 
7 Statistical Methodology and IV Synopsis 
7.4.2 Analysis of Secondary Endpoints  
WAS:  
Descriptive statistics will be presented for the following:   
• Percentage of patients with Testosterone <20, 20-50 and >50 ng/dL at one year and 
at 1.5 years 
• Time to PSA progression: PSA progression as the date that a 25% or greater 
increase and an absolute increase of 2 ng/mL or more from the nadir is 
documented, which is:  
o Confirmed by a second value obtained 3 or more weeks later  


 
 
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- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 87 of 93 
Version 2.0 
o Time to PSA progression is calculated from the date of first administration 
of ELIGARD 22.5mg.  
o If not done based on standard clinical practice, the confirmatory PSA 
measurement will be performed at the next routine study visit. 
 
IS AMENDED TO: 
Descriptive statistics will be presented for the following:   
• Percentage of patients with Testosterone <20, 20-50 and >50 ng/dL at 1 year and at 
1.5 years 
• Time to PSA progression: calculated from date of first administration of 
ELIGARD 22.5mg to PSA progression 
• PSA progression as the date that a will be defined as a 25% or greater increase and 
an absolute increase of 2 ng/mL or more from the nadir is documented, which is  
o Confirmed by a second value obtained 3 or more weeks later 
o Time to PSA progression is calculated from the date of first 
administration of ELIGARD 22.5mg  
o If not done based on standard clinical practice, the confirmatory PSA 
measurement will be performed at the next routine study visit. 
 
7 Statistical Methodology  
7.2.1 Full Analysis Set (FAS)  
WAS:  
The full analysis set (FAS) will consist of all patients who are enrolled and receive at least 
one dose of study drug and have at least one post baseline measurement. This will be the 
primary analysis set for efficacy analyses. 
 
IS AMENDED TO: 
The full analysis set (FAS) will consist of all patients who are enrolled and receive at least 
one 1 dose of study drug and have at least one 1 post baseline measurement of PSA and 
testosterone levels. This will be the primary analysis set for efficacy analyses. 
 
 


 
 
Sponsor: ASG 
ISN/Protocol 7015-MA-3072 
- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 88 of 93 
Version 2.0 
7 Statistical Methodology and IV Synopsis 
7.7 Interim Analyses  
WAS:  
A minimum of one interim analysis will be conducted at 21 months after the first patient is 
enrolled for that half of patients will complete one year of treatment. 
 
IS AMENDED TO: 
A minimum of 1 interim analysis will be conducted at 21 months after the first patient is 
enrolled for that half of patients will complete one year of treatment.when 50 patients 
complete 1 year of follow-up.   
 
 
8 Procedure for Clinical Study Quality Control 
8.1.1 Data Collection  
WAS:  
The investigator or site designee will enter the questionnaire data directly into the EDC 
system.  The monitor will collect the questionnaires, and submit them to the Sponsor or 
designee, ensuring a copy remains at site.  
 
IS AMENDED TO: 
The investigator or site designee will enter the questionnaire data directly into the EDC 
system.  The paper questionnaires will be kept at sites. The monitor will collect the 
questionnaires, and submit them to the Sponsor or designee, ensuring a copy remains at 
site.    
 
 
11 REFERENCES 
 
WAS:  
The references were numbered and in order of citation in the text 
 
IS AMENDED TO: 
The references were listed alphabetically by first author, as per STL-1051 
 
 


 
 
Sponsor: ASG 
ISN/Protocol 7015-MA-3072 
- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 89 of 93 
Version 2.0 
12 APPENDICES 
12.1 List of stand-alone documents  
WAS:  
Appendix II   APvS-T-CP01.35/4  2nd Nov 2015  Astellas Always Serious Terms List 
 
IS AMENDED TO: 
Appendix II   APvS-T-CP01.35/49  2nd  6th Nov 2015 2017  Astellas Always Serious 
Terms List 
 
12.7 Protocol Amendment Summary Document 
ADDED:  
  Section12.7 Protocol Amendment Summary Document 
 
 
13 SPONSOR’S SIGNATURES  
WAS:  


 
 
Sponsor: ASG 
ISN/Protocol 7015-MA-3072 
- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 90 of 93 
Version 2.0 
13.1 Protocol Authors 
 
 
 
  
Quintiles 
Major Contributors: 
 
  
Medical Affairs, Asia-Oceania 
Astellas Pharma Singapore Pte Ltd 
 
 
 
Safety Pharmacovigilance 
Astellas Pharma Europe B.V. 
 
 
 
Medical Affairs, Asia-Oceania 
Astellas Pharma Singapore Pte.Ltd 
 
13.2 PROTOCOL APPROVED BY 
 
 
 
IS AMENDED TO: 
PPD
PPD
PPD
PPD
PPD


 
 
Sponsor: ASG 
ISN/Protocol 7015-MA-3072 
- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 91 of 93 
Version 2.0 
13.1 Protocol Authors 
 
 
 
  Real-World Evidence Solutions 
Quintiles IQVIA 
Major Contributors: 
 
  
Medical Affairs, Asia Oceania 
Astellas Pharma Singapore Pte Ltd 
 
 
 
 
 
 
Medical Safety Pharmacovigilance  
Astellas Pharma Europe B.V. 
 
 
 
 
 
Medical Affairs, Asia-Oceania 
Astellas Pharma Singapore Pte.Ltd 
 
 
13.2 PROTOCOL APPROVED BY 
  
 
 
 
 
PPD
 
PPD
PPD
PPD
PPD
PPD










 
 
Sponsor: ASG 
ISN/Protocol 7015-MA-3072 
- CONFIDENTIAL - 
 
18 APR 2018 
Astellas 
Page 93 of 93 
Version 2.0 
13.2 PROTOCOL APPROVED BY  
Protocol Approval Committee 
   
 
  
PPD
 
 



SAP_001.pdf: 
Sponsor: Astellas Pharma Inc. 
SAP Final Version 1.1 
ISN/Protocol 7015-MA-3072 
28-Jan-2020 
Astellas 
Page 1 of 96 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Final Version 1.1, dated 28-Jan 2020 
 
A Phase IV Interventional Safety Study of ELIGARD® in Prostate Cancer Patients in Asia 
(ELIGANT) 
 
 
 
ISN: 7015-MA-3072 
 
 
 
 
 
Astellas Pharma Singapore Pte Ltd 
 
 
 
 
 
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. 
 
 
Approved on 28-Jan-2020 (Document ID: 192880015)
NCT03035032
NCT03035032


Sponsor: Astellas Pharma Inc. 
SAP Final Version 1.1 
ISN/Protocol 7015-MA-3072 
28-Jan-2020 
Astellas 
Page 2 of 96 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
··········································· 
5 
1 
INTRODUCTION 
·················································································· 
9 
2 
FLOW CHART AND VISIT SCHEDULE 
···················································· 
9 
3 
STUDY OBJECTIVE(S) AND DESIGN 
······················································ 
10 
3.1 
Study Objective(s) ············································································ 
10 
3.1.1 
Primary Objective: ······································································ 
10 
3.1.2 
Secondary Objectives: ·································································· 
10 
3.2 
Study Design 
··················································································· 
10 
3.3 
Randomization················································································· 
10 
4 
CHANGES TO ANALYSIS FROM PROTOCOL·········································· 
11 
5 
SAMPLE SIZE ···················································································· 
11 
6 
ANALYSIS SETS ················································································· 
11 
6.1 
All Subjects Enrolled Set (ENR) 
···························································· 
11 
6.2 
Full Analysis Set (FAS) 
······································································ 
11 
6.3 
Per Protocol Set (PPS) 
········································································ 
11 
6.3.1 
Reasons for Exclusion From PPS ····················································· 
12 
6.4 
Safety Analysis Set (SAF) ··································································· 
12 
6.5 
Pharmacokinetics Analysis Set (PKAS) 
···················································· 
12 
6.6 
Pharmacodynamic Analysis Set (PDAS) 
··················································· 
12 
7 
ANALYSIS VARIABLES ······································································· 
12 
7.1 
Efficacy Endpoints 
············································································ 
12 
7.1.1 
Primary Efficacy Endpoint(s) 
·························································· 
12 
7.1.2 
Secondary Efficacy Endpoints 
························································· 
13 
7.1.3 
Exploratory Efficacy Endpoints ······················································· 
13 
7.1.4 
Other Efficacy Variables ······························································· 
13 
7.2 
Safety Variables 
··············································································· 
13 
7.3 
Pharmacokinetic Variables 
··································································· 
14 
7.4 
Pharmacodynamic Variables ································································ 
14 
7.5 
Other Variables 
················································································ 
14 
8 
STATISTICAL METHODOLOGY ··························································· 
15 
8.1 
General Considerations 
······································································· 
15 
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28-Jan-2020 
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Page 3 of 96 
8.2 
Study Population ·············································································· 
16 
8.2.1 
Disposition of Subjects ································································· 
16 
8.2.2 
Protocol Deviations ····································································· 
16 
8.2.3 
Demographic and Other Baseline Characteristics 
··································· 
16 
8.2.4 
Previous and Concomitant Medications 
·············································· 
17 
8.3 
Study Drugs 
···················································································· 
18 
8.3.1 
Exposure 
·················································································· 
18 
8.3.2 
Treatment Compliance 
·································································· 
18 
8.4 
Analysis of Efficacy ·········································································· 
18 
8.4.1 
Analysis of Primary Endpoint(s) ······················································ 
18 
8.4.2 
Analysis of Secondary Endpoints ····················································· 
18 
8.4.3 
Analysis of Exploratory Endpoints 
···················································· 
20 
8.4.4 
Analysis of Other Variables 
···························································· 
20 
8.5 
Analysis of Safety 
············································································· 
20 
8.5.1 
Adverse Events ·········································································· 
20 
8.5.2 
Clinical Laboratory Evaluation 
························································ 
22 
8.5.3 
Vital Signs 
················································································ 
22 
8.5.4 
ECOG Performance Status 
····························································· 
23 
8.5.5 
Pregnancies 
··············································································· 
23 
8.5.6 
Other Safety-Related Observations ··················································· 
23 
8.6 
Analysis of PK················································································· 
23 
8.7 
Analysis of PD················································································· 
23 
8.8 
Subgroups of Interest ········································································· 
23 
8.9 
Other Analyses ················································································ 
23 
8.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
···················· 
23 
8.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 
23 
8.11.1 
Missing Data 
············································································· 
23 
8.11.2 
Outliers ··················································································· 
24 
8.11.3 
Visit Windows 
··········································································· 
24 
8.11.4 
Multicenter 
··············································································· 
24 
8.11.5 
Retests, Unscheduled Visits and Early Termination Data 
·························· 
24 
9 
DOCUMENT REVISION HISTORY 
························································· 
25 
10 
REFERENCES ···················································································· 
25 
11 
APPENDICES ····················································································· 
26 
Approved on 28-Jan-2020 (Document ID: 192880015)


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SAP Final Version 1.1 
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28-Jan-2020 
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11.1 
Appendix 1: Key Contributors and Approvers ············································ 
26 
11.2 
Appendix 2: Programming Conventions for Outputs 
····································· 
28 
11.3 
Appendix 3: Algorithm for Treatment Emergence of Adverse Events ················· 
29 
11.4 
Appendix 4: Algorithm for Prior / Concomitant Medications: ·························· 
30 
11.5 
Appendix 5: EQ-5D-5L Value Sets 
························································· 
31 
11.6 
Appendix 6: Lab Reference Ranges ························································ 
96 
 
 
 
Approved on 28-Jan-2020 (Document ID: 192880015)


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28-Jan-2020 
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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
BMI 
Body Mass Index 
CI 
Confidence Intervals 
CRF 
Case Report Form 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
GD 
Global Development 
H 
High 
ICH 
International Conference on Harmonization 
L 
Low 
LLN  
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Normal 
PD 
Pharmacodynamic 
PD1-x 
Protocol Deviation 1-x 
PDAS 
Pharmacodynamic Analysis Set 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetics Analysis Set 
PPS 
Per-Protocol Analysis Set 
PT 
Preferred Term 
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 
WHO-DD 
World Health Organization Drug Dictionary 
 
List of Key Terms 
Terms 
Definition of terms 
Adverse Event (AE) 
An adverse event is as any untoward medical occurrence in a patient 
administered a study drug and which does not necessarily have a causal 
relationship with this treatment (see also Eligard-related AE). 
Baseline 
1. Observed values/findings which are regarded as starting points for 
comparison. 
2. Time when ‘Baseline’ is observed. 
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Case Report Form 
(CRF) 
A printed, optical, or electronic document designed to record all of the 
protocol required information to be reported to the sponsor for each trial 
patient. 
Castrate Resistant 
Prostate Cancer (CRPC) 
The European Association of Urology (EAU) Prostate Cancer Guidelines 
2016 defines CRPC as:  
Castrate serum testosterone < 50ng/dL or 1.7 nmol/L plus either; 
Biochemical progression: 3 consecutive rises in prostate specific antigen 
(PSA) at least 1 week apart resulting in two 50% increases over the nadir, 
and a PSA > 2 ng/mL or 
Radiological progression:  the appearance of two or more new bone 
lesions on bone scan or enlargement of a soft tissue lesion using RECIST 
(Response Evaluation Criteria in Solid Tumors).   
Symptomatic progression alone must be questioned and is not sufficient 
to diagnose CRPC.  
Causality Assessment 
An evaluation performed by a medical professional concerning the 
likelihood that a therapy or product caused or contributed to an AE.  A 
positive causality assessment made by either reporter and/or company 
makes an AE into an ADR. 
Clinical Study 
Any investigation in relation to humans intended: 
a) to discover or verify the clinical, pharmacological or other 
pharmacodynamic effects of 1 or more medicinal products; 
b) to identify any adverse reactions to 1 or more medicinal products; or 
c) to study the absorption, distribution, metabolism and excretion of 1 or 
more medicinal products; with the objective of ascertaining their safety 
or efficacy. 
Confidence Interval (CI) A measure of the precision of an estimated value. 
 The interval represents 
the range of values, consistent with the data that is believed to encompass 
the “true” value with high probability (usually 95%) upon repeated 
sampling according to frequentist theory. The confidence interval (CI) is 
expressed in the same units as the estimate. Wider intervals indicate 
lower precision; narrow intervals, greater precision. 
Confidentiality 
Prevention of disclosure to other than authorized individuals of 
proprietary information or of a patient’s identity. 
Consent Form 
Document used during the informed consent process that is the basis for 
explaining to potential patients the risks and potential benefits of a study 
and the rights and responsibilities of the parties involved.  The informed 
consent document provides a summary of a clinical trial (including its 
purpose, the treatment procedures and schedule, potential risks and 
benefits, alternatives to participation, etc.) and explains an individual’s 
rights as a patient. It is designed to begin the informed consent process, 
which consists of conversations between the patient and the research 
team. 
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If the individual then decides to enter the trial, s/he gives her/his official 
consent by signing the document.  Synonym: informed consent form 
(ICF) 
Contract Research 
Organization (CRO) 
A person or an organization (commercial, academic, or other) contracted 
by the sponsor to perform 1 or more of a sponsor’s trial-related duties 
and functions. 
Data Monitoring 
Process by which data are examined for completeness, consistency, and 
accuracy. 
Demographic data 
Characteristics of patients or study populations, which include such 
information as age, sex, family history of the disease or condition for 
which they are being treated, and other characteristics relevant to the 
study in which they are participating. 
Discontinuation 
The act of concluding participation, prior to completion of all protocol-
required elements, in a study by an enrolled patient.   
Effectiveness 
The capability of an intervention in producing a desired result under 
circumstances that more closely approach real-world practice, with more 
heterogeneous populations, less-standardized treatment protocols, and 
delivery in routine clinical settings.   
Electronic Case Report 
Form (eCRF) 
Auditable electronic record designed to capture information required by 
the clinical trial protocol to be reported to the sponsor on each trial 
patient. 
Eligard-related Adverse 
Event 
An adverse event in a patient administered Eligard where a causal 
relationship is at least a reasonable possibility (drug event with either a 
possible or probable causal relationship), as determined by the opinion 
of the investigator.  
Adverse events listed in the local label should be used by the investigator 
as reference safety information to understand whether an adverse event 
is expected with the use of Eligard.  This understanding should inform 
causality assessments by the investigator.      
Ethnic Asian 
Any of the following races - Chinese, Filipino, Indonesian, Malay, Thai, 
Vietnamese, Indian, Japanese or Korean.  
Final Visit 
The final visit will be the same as the last follow-up visit for each patient.  
It will occur at the 18
th month after enrollment into the study, provided 
that none of discontinuation criteria (see Section Error! Reference source n
ot found. in protocol) are met. 
Protocol 
A document that describes the objective(s), design, methodology, 
statistical considerations, and organization of a trial. The protocol usually 
also gives the background and rationale for the trial, but these could be 
provided in other protocol referenced documents. Throughout the 
International Conference on Harmonisation – Good Clinical Practice 
(ICH GCP) Guideline the term protocol refers to protocol and protocol 
amendments. 
Quality of Life (QoL) 
A broad ranging concept that incorporates an individual’s physical 
health, psychological state, level of independence, social relationships, 
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personal beliefs, and their relationships to salient features of the 
environment.  
Note: Quality of Life is one way to measure the benefits or negative 
impacts of an “improvement” measured in terms of a physiological or 
psychological symptom. QoL research seeks to quantify what an 
intervention means to a patient’s sense that their life has changed. 
Safety 
Relative freedom from harm. In clinical trials, this refers to an absence 
of harmful side effects resulting from use of the product and may be 
assessed by laboratory testing of biological samples, special tests and 
procedures, psychiatric evaluation, and/or physical examination of 
patients. 
Sample Size 
A subset of a larger population, selected for investigation to draw 
conclusions or make estimates about the larger population. 
Serious Adverse Event 
(SAE) 
An SAE is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  An SAE must fulfill at least 
1 of the following criteria at any dose level: results in death; is life 
threatening, 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; or a medically 
important event. 
Serious Eligard-related 
Adverse Event 
An Eligard-related AE which results in death, is life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/ incapacity, is a congenital 
anomaly/ birth defect, or results in other medically important events. 
Adverse events listed in the local label should be used by the investigator 
as reference safety information to understand whether a serious adverse 
event is expected with the use of Eligard.  This understanding should 
inform causality assessments by the investigator   
Statistical Analysis Plan 
(SAP) 
A document that 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 variables and other data. 
Statistical Method 
The particular mathematical tests and techniques that are to be used to 
evaluate the clinical data in a trial. 
Study Period 
Period of time from the initiation date to the completion date of the study. 
Study Population 
Defined by protocol inclusion/exclusion criteria. 
Visit 
A clinical encounter that encompasses planned and unplanned trial 
interventions, procedures, and assessments that may be performed on a 
patient. A visit has a start and an end, each described with a rule. 
Withdrawal 
The act of discontinuing participation in a clinical study. 
See also discontinuation. 
 
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The table of scheduled assessments can be found in Section V of protocol. 
3 
STUDY OBJECTIVE(S) AND DESIGN 
3.1 Study Objective(s) 
The objectives of this Phase IV, prospective, interventional study are to evaluate the safety, 
efficacy, and QoL of ELIGARD
® in hormone-dependent prostate cancer patients in Asia.  
3.1.1 Primary Objective: 
To establish the safety profile of ELIGARD® in ethnic Asian prostate cancer patients. 
3.1.2 Secondary Objectives: 
1) To describe the efficacy of ELIGARD® 
22.5 mg (3-monthly formulation) in controlling 
PSA and testosterone levels  
2) To assess HRQoL through QoL questionnaires – EORTC QLQ-PR25 and EQ5D-5L 
3.2 Study Design 
This is a multicenter, prospective, single-arm, interventional study to assess the safety, 
efficacy, and QoL of ELIGARD
® 22.5 mg (3-monthly formulation) in male patients with 
prostate adenocarcinoma who fulfill the eligibility criteria in Asia.  The sample size planned 
for this study is approximately 107 enrolled prostate cancer patients. The inclusion/exclusion 
criteria are listed in Section 3.1 and 3.2 in the study protocol. This study will be conducted in 
approximately 20 centers in 8 countries (Hong Kong, Indonesia, Malaysia, Philippines, 
Singapore, Taiwan, Thailand and Vietnam). 
The enrollment period will be up to 12 months. Patients will be prescreened to confirm access 
to Androgen Deprivation Therapy (ADT) prior to informed consent. Following written 
informed consent by the patient and confirmation of eligibility, patients will be treated for 1.5 
years (18 months), with ELIGARD® 22.5 mg being administered at baseline, 3rd month, 6th  
month, 9th  month, 12th  month and 15th  month. AE and SAE collection will start at baseline 
until the follow-up visit at 18 months (see protocol Section Error! Reference source not f
ound. for AE collection and SAE reporting).  QoL will be measured at baseline, 6th month, 
12th month and 18th month. The PSA and testosterone levels will be assessed at all scheduled 
visits and during the follow-up visit. Patients will be followed up at 18th month in the 
physician’s office. The time window for each visit following baseline is +/- 14 days. 
A minimum of 1 interim analysis will be conducted when 50 patients complete 1 year of 
follow-up.  
3.3 Randomization 
Not Applicable. 
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4 
CHANGES TO ANALYSIS FROM PROTOCOL 
1. Patients who are less than 80% compliant with the dosage regimen for any two visit 
periods during the study should be withdrawn. The two visits are not necessarily 
consecutive. 
2. Added Protocol Deviation rule 5 of windowing convention. 
3. Added analyses of PSA reduction in categorical summarization. 
4. Included Kaplan-Meier curve for deterioration of quality of life variables (EQ5D02-
EQ VAS score, EQ-5D-5L score and QLQ-PR25 score) 
5. KM estimates for incidence rate at each scheduled time points will not be provided, as 
incidence rate is not a time to event variable. 
5 
SAMPLE SIZE 
 This study targets to enroll approximately 107 prostate cancer patients meeting all inclusion 
criteria and none of the exclusion criteria. The sample size calculation is based on 
assumptions that percentage of ELIGARD
®-related AEs will be 50%, a drop-out rate of 10%, 
and a Wald 95% CI of width 20%, based on a finite population correction, with factor N 
=10,000 . 
6 
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. 
6.1 All Subjects Enrolled Set (ENR)  
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for 
this study. Subject disposition will be presented using ENR. 
6.2 Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all patients who are enrolled and receive at least 
one dose of study drug and have at least one post baseline measurement of PSA and 
testosterone level.  
Specifically, the following will lead to a subject’s exclusion from the FAS: 
● No study drug taken 
● No post baseline measurement of PSA and testosterone.  
The FAS will be used for summaries and primary analyses of efficacy data. 
6.3 Per Protocol Set (PPS) 
The Per-Protocol Set (PPS) includes all subjects of the FAS who do not meet criteria for 
exclusion from PPS listed in section 6.3.1 of this SAP.  
The PPS will be used for secondary analyses of efficacy data. Also, selected demographic and 
baseline characteristics will be summarized for the PPS. 
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6.3.1 Reasons for Exclusion From PPS 
The following criteria are to capture relevant non-adherence to the protocol and the following 
reasons may lead to subject’s exclusion from PPS: 
● Entered into the study even though they did not satisfy entry criteria  
● Developed withdrawal criteria during the study and was not withdrawn (Patients who 
discontinued the study for efficacy-related reasons, such as insufficient therapeutic effect, 
will be included in the PPS.) 
● Full dose was not administered or drug reconstitution was not performed as prescribed 
● Patients with treatment compliance <80% 
● Patients who used prohibited concomitant medications as defined in the protocol sections 
5.1.6 and 12.2. 
6.4 Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) consists of all subjects who received at least one ELIGARD® 
injection and any follow-up safety information is available. 
The SAF will be used for statistical summaries of safety data. Demographic and baseline 
characteristics and all safety and tolerability related variables will be summarized using SAF 
as well. 
6.5 Pharmacokinetics Analysis Set (PKAS) 
Not Applicable. 
6.6 Pharmacodynamic Analysis Set (PDAS) 
Not Applicable. 
7 
ANALYSIS VARIABLES 
The primary endpoint for this study is ELIGARD®-related AEs throughout the entire 
observation period, as determined by the opinion of the investigator.  
Secondary endpoints include:  
● Efficacy outcomes of clinical response based on testosterone and PSA levels (Testosterone 
level and PSA will be assessed for all patients at each scheduled visit, prior to 
administering ELIGARD
®, and at the follow-up visit.) 
● HRQoL assessment through QoL questionnaires – EORTC QLQ-PR25 (prostate cancer 
disease specific PRO) and EQ5D-5L (generic PRO) measured at 0, 6, 12, and 18 months. 
7.1 Efficacy Endpoints 
7.1.1 Primary Efficacy Endpoint(s) 
As the primary analysis of this study is the safety outcomes, primary efficacy variable is not 
applicable. 
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7.1.2 Secondary Efficacy Endpoints 
The following secondary efficacy endpoints, as derived, are: 
● Percentage of patients with Testosterone <20 ng/dL, 20-50ng/dL and >50 ng/dL at 1 and 
1.5 years 
● Time to PSA progression  
● PSA percent reduction to reach ≥30%, ≥50 and ≥90% 
● Scores and change from baseline for EORTC, QLQ-PR25 and EQ-5D-5L 
Relevant derivations are as below: 
General 
Change from baseline = Test value at visit X – baseline value. 
Percentage of patients with Testosterone <20 ng/dL, 20-50ng/dL and >50 ng/dL at 1 and 1.5 
years 
Percentage = (number of patients with corresponding Testosterone level) / (total number of 
patients in FAS/PPS for that follow-up time). 
Time to PSA progression 
Time to PSA progression (months) = ((date of 25% or greater increase and an absolute increase 
of 2ng/mL) - (date of first administration of ELIGARD® 22.5 mg) + 1)/30. 
PSA response percentage = number of patients with PSA response (at each visit)/ total number 
of patients in FAS/PPS.  
PSA percent reduction to reach ≥30%, ≥50 and ≥90% 
PSA response percent reduction (%) = ((PSA tested– baseline PSA) / baseline PSA)*100%. 
Scores and change from baseline for EORTC, QLQ-PR25 and EQ-5D-5L 
For each respective scale, Raw score (RS) = (I1+I2+…+In)/n,  
with In being the score for each question and n for total number of questions included. 
For functional scale (SAC, SFU), Scale score (S) = (1 – (RS-1)/range) * 100, for symptom 
scales (URI, AID, BOW, HTR), S = ((RS – 1)/range) * 100,  
with range defined as the difference between the maximum and minimum possible value of 
RS, which is 3 for QLQ-PR25. 
7.1.3 Exploratory Efficacy Endpoints 
Not Applicable. 
7.1.4 Other Efficacy Variables 
Not Applicable. 
7.2 Safety Variables 
All outputs for safety outcomes will be based on the Safety Analysis Set. There will be no 
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statistical comparisons as there is no comparative drug.  
Safety will be assessed by evaluation of the following variables: 
• Adverse events (AEs), serious adverse events (SAEs), and treatment-emergent adverse 
events (TEAEs; frequency, severity, seriousness, and relationship to study drug) 
• Treatments including any intervention (e.g. medication(s), procedure(s), radiography, 
surgical treatment, visits to Accident & Emergency department and/or ambulatory 
clinic, hospitalization) to treat AEs and SAEs  
• Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total bilirubin, and urinalysis) 
• Vital signs (systolic and diastolic blood pressure, respiratory rate and pulse rate) 
Treatment emergent adverse events (TEAEs) are defined as AEs with onset dates occurring 
within the treatment periods, i.e., starts on or after the earliest dosing date of any study 
treatment and prior to the latest dosing date of any treatment. If the patient early terminates, 
then AEs happen within early terminate date plus 90 days will be still counted as TEAEs, and 
after that, AEs occurredf will not be seen as TEAEs. TEAEs will be captured and determined 
on “Adverse Events” page of CRF, with “Onset date of adverse event occurred after first dose 
of study drug” marked “yes”. 
For this study, an ELIGARD®-related AE is defined as an adverse event in a patient 
administered ELIGARD
® where a causal relationship is at least a reasonable possibility (drug 
event with either a possible or probable causal relationship), as determined by the investigator. 
Incidence of ELIGARD®-related AE(SAE) is defined as the new ELIGARD®-related 
AE(SAE) cases happen in study population within the specified period of time. Incidence rate 
is defined as the number of new cases per population at risk in a given time period.  
7.3 Pharmacokinetic Variables 
Not Applicable. 
7.4 Pharmacodynamic Variables 
Not Applicable. 
7.5 Other Variables 
● The duration of exposure 
Duration of exposure months = (date of last study medication administration – date of first 
study medication administration + 1) / 30. 
Duration of exposure years = (date of last study medication administration – date of first study 
medication administration + 1) / 365.25. 
● Cumulative dose 
Cumulative dose (mg) = number of injections * 22.5.  
Cumulative dose will be calculated in the cases where response to ‘drug administered?’ and 
‘reconstituted and mixed as per instructions?’ should be ‘YES’.  
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● Study drug compliance 
Overall compliance to the dosing schedule will be examined for subjects in the safety 
population.  
Compliance with ELIGARD®—based on the injection given or not—will be calculated as 
the number of injections taken divided by the prescribed 
number of injections as a percentage, 
see calculations below.  
Compliance for each patient = ((Number of Injections Given provided study drug 
reconstituted and mixed as per instructions) / Number of Injections Prescribed) * 100%; 
While considering number of injections given, study drug must be reconstituted and mixed 
according to the instructions provided. In case study drug administered but not reconstituted 
and mixed as per instructions provided, study drug will not be counted in numerator. 
• Duration of Prostate Cancer 
Duration of Prostate Cancer = (Cutoff date of Data – Baseline Assessment Date of Prostate 
Cancer History+1)/30.  
• Time Since Biopsy 
Time Since Biopsy – (Cutoff Date of Data – Date of Biopsy+1)/30.  
Date of biopsy will be taken from prostate cancer history form.   
8 
STATISTICAL METHODOLOGY 
8.1 General Considerations 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to reference start date (including unscheduled assessments). In the case where the last 
non-missing measurement and the reference start date coincide, that measurement will be 
considered pre-baseline, but Adverse Events (AEs) and medications commencing on the 
reference start date will be considered post-baseline. 
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. 25% and 75%) will be mentioned in the relevant section. Frequencies and 
percentages will be displayed for categorical data. If missing option is not included in 
summaries, percentages by categories will be based on the number of subjects with missing 
data, i.e. might not add up to 100%.  
Summaries based on FAS and PPS (efficacy data), safety analysis and other summaries based 
on SAF will be presented by planned region, unless specifically stated otherwise.  
No statistical tests will be conducted in this study. Confidence intervals will be 95% for 
analyses unless specified in the description. 
All data processing, summarization, and analyses will be performed using SAS® Version 9.4 
or higher on Windows. Sample size is calculated using PASS 14 Power Analysis and Sample 
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Size Software (2015) version 14.0.2 and validated using nQueries v4.0. 
Specifications for table, 
figures, and data listing formats can be found in the TLF specifications for this study. 
For the definition of regions, please refer to section 8.11.4. 
8.2 Study Population 
8.2.1 Disposition of Subjects 
All subjects who provide informed consent will be accounted for in this study. ENR will be 
applied for screened, screen failure, and analysis sets disposition. Summary table will be 
provided in total, and by region defined in Section 8.11.4. 
 The following subject data will be presented: 
● Number of subjects with informed consent, received study medication and screen failure; 
● Number and percentage of subjects allocated to each analysis sets;  
● Number and percentage of subjects completed and discontinued the study, and primary 
reasons for discontinuation and 
● Number and percentage of subjects excluded from each analysis sets for each reason 
defined in Section 5. 
8.2.2 Protocol Deviations 
Protocol deviations as defined in Section Error! Reference source not found. 
in protocol 
will b
e summarized for all patients. Visiting window deviation is added as the 5th protocol deviation. 
A data listing will be provided by site and patient. 
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 – Full dose was not administered or drug reconstitution was not performed as 
prescribed 
● PD4 - Received excluded concomitant treatment 
● PD5 - Window deviation. 
8.2.3 Demographic and Other Baseline Characteristics 
Demographic data and other baseline characteristics will be presented for the SAF and PPS. 
Descriptive statistics will include number of patients, mean, SD, median, minimum, 
maximum, 25th percentile (Q1) and 75th percentile (Q3) for continuous variables, and 
frequency and percentage for categorical variables. No statistical testing will be carried out 
for demographic or other baseline characteristics. The following demographic and other 
baseline characteristics will be reported for this study: 
● Age (years) - calculated relative to date of consent 
● Sex 
● Race 
● Country of the investigational site 
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● Highest education level 
● Medical history 
● Vital Signs 
● Weight(kg) 
● Height(cm) 
● BMI (kg/m2) 
● ECOG performance status 
● Laboratory tests 
Surgical and Medical History (diabetes, hypertension and cardiac disorders) will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) (Version 20.0 or higher). 
Numbers and percentages of patients will be presented for each System Organ Class (SOC) 
and Preferred Term (PT) and will be sorted by incidence rate (high to low) and then alphabetic 
order. The following variables will be summarized to describe the history/status of the disease 
being studied: 
● Prostate cancer history 
● Family history for prostate cancer 
● Disease characteristics for prostate cancer 
● Most important factors for selection of treatment 
Disease characteristics include time since diagnosis, Gleason score at initial diagnosis, Tumor, 
Nodes, Metastasis (TNM) classification, staging, surgical history, biopsy results, dates and 
types of anti-neoplastic therapy including radiation therapy prior to study inclusion (including 
number of cycles,  treatment duration, time interval since previous treatments), Eastern 
Cooperative Oncology Group (ECOG) status, bone lesions, soft tissue disease, visceral disease, 
and pain (using the Visual Analogue Scale [VAS] 0-10). 
 
8.2.4 Previous and Concomitant Medications 
Previous medications are medications which started and stopped prior to the first dose of 
study medication. 
Concomitant medications are medications which:  
● Started prior to, on or after the first dose of study medication 
● AND ended on or after the date of first dose of study medication or were ongoing at the 
end of the study.  
As with previous medication, concomitant medication will be summarized for each regional 
group using SAF and coded using World Health Organization (WHO) Drug Dictionary 
Enhanced Version 01Jun2015 or higher. Prior and concomitant medication data will be 
captured from “Concomitant Medication” page on eCRF. Subjects taking the same 
medication multiple times will be counted once per medication and investigational period.  
Bicalutamide 50 mg O.D. or a similar anti-androgen is an allowed concomitant medication for 
flare prevention only.  Additional administration of an appropriate anti-androgen should be 
considered beginning three days prior to ELIGARD
® treatment and continuing for the first two 
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to three weeks of treatment to avoid any flare reaction. Use of bicalutamide or similar anti-
androgen beyond 3 weeks after starting ELIGARD
® therapy and for reasons other than flare 
prevention is not allowed. 
See Appendix 4 for handling of partial dates for medications, in the case where it is not 
possible to define a medication as prior, or concomitant treatment, the medication will be 
classified by the worst case; i.e. concomitant. 
 
8.3 Study Drugs 
8.3.1 Exposure 
Exposure to study medication in months and dose in mg will be presented for the SAF. The 
dose of each administration is fixed to 22.5mg and can be referenced to “ELIGARD® Use” 
page from CRF. 
The following will be reported: 
● Duration of therapy in months, using descriptive statistics 
● Number of injections in categorical form and with descriptive statistics 
● Cumulative dose with descriptive statistics 
● Treatment compliance  
The date of first study medication administration will be taken from the eCRF “Date of Visit” 
form in Baseline folder. The date of last study medication will be taken from the eCRF “End 
of Treatment” form. In case of missing data, see Appendix 3 for reference to determine the 
first and last date of study medication. Interruptions and incompliance are not taken into 
account for duration of exposure. 
8.3.2 Treatment Compliance 
Overall compliance to study medication will be presented for the SAF. Summary statistics 
for compliance including mean, SD, median, Q1 and Q3 will be reported. As the study is a 
fixed-dose injection study, the compliance for each patient through the study is calculated by 
number of injections divided by total injections administered. Dose injected outside the visit 
periods will be considered as incompliant. In case dose injected but not reconstituted and 
mixed as per instructions, it will be considered as incompliant. Patients who are less than 
80% compliant with the dosage regimen for any two visit periods (window ± 14 days) during 
the study should be withdrawn.  
8.4 Analysis of Efficacy  
8.4.1 Analysis of Primary Endpoint(s) 
Not applicable as the primary endpoint of this study is safety outcomes. 
8.4.2 Analysis of Secondary Endpoints  
The secondary efficacy analyses will be performed for the FAS and PPS will be used to 
assess the robustness of the results. 
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8.4.2.1 Testosterone Level 
Testosterone levels are captured on “Serum Testosterone Level” page in CRF. Numbers and 
percentage of patients with following 
Testosterone level at 1 and 1.5 years will be summarized: 
● <20 ng/dL, 
● 20-50 ng/dL, 
● >50 ng/dL. 
8.4.2.2 PSA Progression and Reduction 
PSA progression is defined as a 25% or greater increase and an absolute increase of 2 ng/mL, 
and confirmed by a second value obtained three or more weeks later (captured on 
“Unscheduled” page in CRF). 
Number and percentage of patients to reach following PSA percent reduction will be 
summarized: 
● ≥30%, 
● ≥50%, 
● ≥90%. 
Time to PSA progression (months) = (date of 25% or greater increase and an absolute 
increase of 2ng/mL) - (date of first administration of ELIGARD
® 22.5 mg)/30. 
If confirmed by a second value obtained later, the date of first value obtained will be used 
for calculation.  
PSA percent reduction (%) = ((PSA tested– baseline PSA) / baseline PSA)*100% 
8.4.2.3 Health-related Quality of Life (HRQoL) 
EORTC QLQ-PR25 and EQ-5D-5L (captured on “EORTC QLQ-PR25” and “EQ-5D-5L” 
page correspondingly in CRF) are used to examine health-related quality of life.  
 
EQ-5D-5L 
Number and frequencies for each summary scale, including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression will be presented for EQ-5D-5L. Index scores will be 
generated using Japan, UK and USA value sets (see Appendix 5 for EQ-5D-5L value sets). 
Absolute index scores, changes from baseline and Kaplan-Meier curves for score deterioration 
will be presented.  
 
EQ5D02-EQ VAS Score (also captured on “EQ-5D-5L” page) will be presented separately 
with absolute index score, change from baseline, Kaplan-Meier curves for score deterioration. 
 
EORTC QLQ-PR25 
The rule of scoring for QLQ-PR25 follows instruction of EORTC QLQ-PR25 Scoring Manual 
2.0. Scale scores after linear transformation (in a 0-100 scale) for each dimension, including 
urinary symptoms, incontinence aid, bowel symptoms, hormonal treatment related symptoms, 
sexual activities and sexual function will be presented for QLQ-PR25. Absolute scores of 
dimensions, changes from baseline and Kaplan-Meier curves for score deterioration will be 
presented.  
 
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8.4.2.4 Tumor Response 
Tumors will be evaluated according to the standard of Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1. Tumor responses are collected and will be summarized for 
each follow-up visits. FAS and PPS will be used for the analysis of tumor response. Best 
overall response will also be presented for both datasets. 
8.4.3 Analysis of Exploratory Endpoints  
Not Applicable. 
8.4.4 Analysis of Other Variables  
Not Applicable. 
8.5 Analysis of Safety 
All analysis of safety will be presented by region for SAF, unless specified otherwise.  
8.5.1 Adverse Events 
7.5.1.1 Adverse events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient 
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. AEs will be captured on CRF page “Adverse Events”, and collected 
after the first administration of study drug.  
Severity is classed 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 described in Section 
5.6.4 in protocol. 
Relationship, as indicated by the Investigator, is classed as “not related”, “possible”, 
“probable” (increasing severity of relationship). Detailed criteria for causal relationship are 
listed in Section 5.6.3 in protocol. 
All AEs (including TEAEs, ELIGARD®-related AEs) will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 20.0 or higher. It will be used to summarize AEs 
by SOC and PT. 
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to 
define an AE as treatment emergent or not, the AE will be classified by the worst case; i.e. 
ELIGARD®-related / treatment emergent. 
An overview table will include the following details: 
● Number of AEs, SAEs, TEAEs, and serious TEAEs, 
● Number and percentage of subjects with AEs, SAEs, TEAEs, and serious TEAEs, 
● Number of ELIGARD®-related AEs, SAEs, 
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● Number and percentage of subjects with ELIGARD®-related AEs, SAEs,  
● Number of TEAEs leading to drug withdrawal and drug interrupted, 
● Number and percentage of subjects with TEAEs leading to drug withdrawal and drug 
interrupted, 
● Number of special adverse events and 
● Number of death. 
 
7.5.1.2 Adverse events by SOC and/or PT 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each region. Summaries will be provided for: 
● TEAEs 
● drug related TEAEs,  
● TEAEs by relationship to study drug, 
● TEAEs and drug related TEAEs by severity, 
● Drug related AEs and SAEs after CRPC managing, 
● TEAEs and drug related TEAEs leading to treatment discontinuation,  
● TEAEs and drug related TEAEs leading to drug interruption and, 
● TEAEs and drug related TEAEs leading to death 
  
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will also be summarized by severity and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted only once with the worst severity and 
highest degree of relationship.  In the adverse event count, the adverse events will be presented 
in each category they were classified to. Drug related TEAEs will be presented in a similar 
way by severity only. 
7.5.1.3 Drug Related Adverse Events 
The ELIGARD®-related AEs will be summarized according to their severity, NCI CTCAE 
Grade, outcome, course of event, seriousness, action taken with ELIGARD® and treatment 
required to manage the AE for SAF set.  
The incidence of ELIGARD®-related AEs and SAEs will be analyzed based on SAF. Two-
sided 95% symmetric confidence intervals of incidence rates will be calculated based on 
normal approximation and adjusting for a finite sample size of 10000. 
If applicable, estimated median time to first event together with a 95% CI will be prepared. In 
addition, incidence rates of ELIGARD
® -related AEs and SAEs will be summarized at each 
scheduled visit time-point, together with a 95% CI. AEs that happen on the scheduled visit date 
will be counted in the visit, and AEs occur after scheduled visit will be counted into next visit. 
Time to first occurrence, in months, of ELIGARD® -related AEs and SAEs will be presented 
graphically using Kaplan-Meier (KM) plots for three regions and all.  
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8.5.2 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 coagulation will 
be summarized using mean, standard deviation, minimum, maximum, and median for each 
region 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 
laboratory result will be classified as low (L), normal (N), or high (H) at each visit according 
to the laboratory supplied reference ranges, if applicable. Values including a comparator will 
be imputed by rounding 0.01 up or down, i.e., <x will be imputed to x-0.01 and >x will be 
imputed to x+0.01. 
The number and percentage of subjects within, below and above reference range will be 
summarized for each region at each visit and last on-treatment.  
Frequency tabulations of qualitative clinical laboratory variables (urinalysis and serology) will 
be presented for each region at each visit.  
Laboratory abnormalities will be evaluated on their clinical significance and decided by 
investigator. Shift tables of change from baseline to each treatment visit, last on-treatment and 
worst finding during the treatment period will be presented for each region and all. 
8.5.3 Vital Signs 
The baseline visit is the last measurement taken prior to initial study drug administration. 
Baseline measurements of systolic and diastolic blood pressure should come from the same 
measurement and not from different dates. 
Vital signs data will be captured on CRF page “Adverse Events” and will be summarized in 
tables and listings using mean, standard deviation, minimum, maximum, median, Q1 and Q3 
by region and visit. The following Vital Signs measurements for both baseline and follow up 
visits will be reported for this study: 
● Systolic Blood Pressure (mmHg) 
● Diastolic Blood Pressure (mmHg) 
● Respiratory Rate (breaths/min) 
● Pulse Rate (bpm) 
● Weight (kg) 
● Height (m) at baseline only 
Additionally, a within-subject change will be calculated per visit as the post-baseline 
measurement minus the baseline measurement and summarized by region and visit.   
Tables for potentially clinically significant vital signs will be presented for SBP, DBP and 
pulse rate. Summaries will be generated using baseline value and highest value obtained during 
treatment for each subject for each region. 
The following potentially clinically significant criteria are defined for the following 
parameters: 
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Sponsor: Astellas Pharma Inc. 
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Vital Sign Variable 
Criteria 
SBP 
≥180 mmHg AND ≥20 mmHg change from baseline 
DBP 
≥105 mmHg AND ≥15 mmHg change from baseline 
Pulse Rate 
≥120 bpm AND ≥15 bpm change from baseline 
8.5.4 ECOG Performance Status  
ECOG performance status data will be captured on CRF page “ECOG Performance Status at 
Present” and will be summarized by listing number and percentage to relevant analysis set 
selecting each score scale for each region at each treatment visit and time point, including 
changes from baseline.  
8.5.5 Pregnancies 
A detailed listing of all pregnancies will be provided. 
8.5.6 Other Safety-Related Observations 
Not Applicable. 
8.6 Analysis of PK 
Not Applicable. 
8.7 Analysis of PD 
Not Applicable.  
8.8 Subgroups of Interest  
Not Applicable. 
8.9 Other Analyses 
Not Applicable. 
8.10 Interim Analysis (and Early Discontinuation of the Clinical Study) 
A minimum of one interim analysis will be conducted at 20 months when 50 patients will 
complete 1 year of treatment after the first patient is enrolled. The 20 months timepoint is 
determined as 50 patients are expected to be recruited at 8 months after the first patient is 
enrolled. A full analysis will be conducted for interim analysis and will be using this Statistical 
Analysis Plan. As there are no statistical hypothesis tests in the planned analysis, the conduct 
of interim analyses will not have any statistical implications on the final study outcome. 
8.11 Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
8.11.1 Missing Data 
In general, missing data will not be imputed and the data will be analyzed as they are recorded 
in the study eCRF. See Appendix 3 for missing value handling of partial dates and treatment 
- emergent adverse events, and Appendix 4 for determination of prior or concomitant 
medications. Specifically, missing severity of AEs will be imputed to greatest severity for 
tabular summarization, and displayed as originally in listings.  Missing relationship will be 
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imputed to “related” for tabular summarization, and displayed as originally in listings. This 
imputation rule will be applied when summarizing AEs in tables, and missing data will be 
displayed directly as they are from raw data in listings.  For categorical endpoints, the 
percentage will be calculated based on total number of patients in relevant analysis sets, 
regardless of whether missing values are present or not. However, if more than 10% of data 
is missing for one or more key variables, i.e., the safety data, the impact of missing data on 
the analysis will be discussed, and the pattern of missing data will be explored. If there is 
evidence of bias in the missing data, and variables that are considered good predictors of the 
missing data are available, the multiple imputation method at the study level may be used to 
replace missing values as secondary exploratory analyses.  If the multiple imputation method 
is used, a sensitivity analysis will be carried out comparing results from the complete case 
analysis (where records with missing data will be dropped) and the full set analysis (with 
imputed data). 
8.11.2 Outliers 
All values will be included in the analyses. 
8.11.3 Visit Windows 
The study protocol gives the overall study schedule and the permissible intervals for these 
visits as ± 14 days. Subject’s failure to comply with the visit schedule will be regarded as 
protocol deviation. 
8.11.4 Multicenter  
This study will be conducted by multiple investigators at 20 centers in 8 countries (Hong 
Kong, Indonesia, Malaysia, Philippines, Singapore, Taiwan, Thailand and Vietnam). 
Data from all centers will be pooled prior to analysis. The analyses will be presented with 
both pooled data and by region. Hong Kong and Taiwan are considered as greater China 
region, Indonesia, Malaysia, and Philippines are considered as Asia-Pacific island region, 
and Singapore, Thailand and Vietnam are considered Indochina Peninsula region. The rule 
applies to tables, figures and listings.  
 
8.11.5 Retests, Unscheduled Visits and Early Termination Data 
In general, for by-visit summaries, data recorded at the scheduled (nominal) visit will be 
presented. Unscheduled measurements will not be included in by-visit summaries.  
In the case of a retest (same visit number assigned), the latest available safety measurement, 
nearest available efficacy measurement, and lab results closest to that visit will be used for 
by-visit summaries.  
Early termination data will be mapped to the next available visit number for by-visit 
summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
Approved on 28-Jan-2020 (Document ID: 192880015)


Sponsor: Astellas Pharma Inc. 
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9 
DOCUMENT REVISION HISTORY  
Version Date 
Changes 
Comment/rationale for change 
0.1 
24-NOV-2017 
NA 
Not applicable – 1
st version 
0.2 
02-APR-2018 
1.Updated to 
Astellas’ template; 
2.Added deterioration 
of HRQoL scores; 
3.Added PSA 
reduction analysis; 
4. Updated analyses 
performed for 
HRQoL; 
5. Revised interim 
analysis time point  to 
50 patients followed 
1 year; 
6. Modified sample 
size calculation. 
1, 2, 3, 4 Updated per request from 
Astellas’ team; 
5,6 Updated to incorporate protocol 
amendment 2.0; 
 
10 
REFERENCES 
7015-MA-3072 ELIGANT Protocol Amendment Version 2.0 Dated 16Jan2018. 
7015-MA-3072 ELIGANT Protocol Version 1.0 Dated 30May2016. 
Case Report Forms Version 2.0 Dated 29May2017. 
EORTC QLQ-PR25 Scoring Manual 2.0 
 
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Sponsor: Astellas Pharma Inc. 
SAP Final Version 1.1 
ISN/Protocol 7015-MA-3072 
28-Jan-2020 
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Page 26 of 96 
11 
APPENDICES 
11.1 Appendix 1: Key Contributors and Approvers 
List of Key Contributors and Approvers 
 
Key Contributors 
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role. 
 
Primary author (s) 
 
 
IQVIA 
Contributors and Reviewers 
 
 
IQVIA 
 
IQVIA 
 
Astellas 
 
Astellas 
 
Astellas 
 
Astellas 
 
 
Astellas 
PPD
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Sponsor: Astellas Pharma Inc. 
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Author and Approver Signatories  
 
 IQVIA, was the study statistician for this study. 
 
 
 
 
, IQVIA was the biostatistics reviewer of this 
Statistical Analysis Plan. 
 
 
 
 
 
 
This Statistical Analysis Plan was approved by: 
 
, Astellas Pharma Global Development Inc.  
 
 
 
 
 
This Statistical Analysis Plan was approved by: 
 
 , Astellas Pharma Singapore Pte Ltd.  
 
 
 
 
 
 
PPD
Approved on 28-Jan-2020 (Document ID: 192880015)
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Sponsor: Astellas Pharma Inc. 
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11.2 Appendix 2: Programming Conventions for Outputs 
Dates & Times 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
Spelling Format 
English US. 
Presentation of Regions 
For outputs, regions will be represented as follows and in that order: 
Region 
For Tables and Graphs 
For Listings (include if 
different to tables) 
Region A: Greater China  Region = Greater China 
Same as tables 
Region B: Asia-Pacific 
Islands 
Region = 
Asia-Pacific 
Islands 
Same as tables 
Region C: Indochina 
Peninsula 
Region  =  Indochina 
Peninsula 
Same as tables 
Total 
 
 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening (Visit 0) 
Scr (V0) 
Baseline (Visit 1) 
BL (V1) 
3 Month (Visit 2) 
M3 (V2) 
… 
… 
18 Month (Visit X) 
M18 (Vx) 
Early Withdrawal 
WD 
Listings 
A listings will be ordered by the following (unless otherwise indicated in the template): 
• center-subject ID, 
• date (where applicable) 
 
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11.6 Appendix 6: Lab Reference Ranges 
For some lab parameters, operational site (
) confirmed that lab ranges 
are missing. Hence corresponding text book ranges will be used in database. Details of those 
ranges are as follows:  
FormName AnalyteName LabLow 
LabHigh 
LabUnits 
Reference 
Urinalysis 
Urine 
Specific 
Gravity 
1.005 
1.030 
  
Laboratory  
and 
Diagnostic Tests, 8 th 
ED. Frances Talaska 
Fishbach,  Marshall 
Barnett  
Dunning, 
Lippincott Williams & 
Wilkins 
- Wolter 
Kluwer, Inc. Page 201 
Urinalysis 
Urine pH 
4.6 
8.0 
  
Laboratory and 
Diagnostic Tests, 8 th 
ED. Frances Talaska 
Fishbach, Marshall 
Barnett Dunning, 
Lippincott Williams 
& Wilkins - Wolter 
Kluwer, 
 Inc. Page 202 
Coagulation 
- Liver 
Abnormality 
Assessment 
Prothrombin 
Time Intl. 
Normalized 
Ratio 
0.93 
1.13 
 
Hematology clinical 
principles and 
applications. 3rd ED.  
Bernadette F Rodak; 
George A Fritsma; 
Kathryn Doig. St. 
Louis,  
Mo Saunders Elsevier 
2007 
 
PPD
Approved on 28-Jan-2020 (Document ID: 192880015)