An Open-label, Multicentre, Single Arm Study to Assess the Efficacy and Safety of Triptorelin 6-month Formulation Administered Subcutaneously in Participants With Locally Advanced and/or Metastatic Prostate Cancer Previously Treated and Castrated With a GnRH Analogue
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Ipsen

 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
PAGE 1/66 
 
080004-FOR Ipsen Protocol template version 8.0 
Protocol Title:  
An open-label, multicentre, single arm study to assess the efficacy and safety of triptorelin 
6-month formulation administered subcutaneously in participants with locally advanced and/or 
metastatic prostate cancer previously treated and castrated with a GnRH analogue  
 
 
Protocol Number: D-FR-52014-245 
 
Compound: Triptorelin pamoate (embonate) salt (IPN52014) 
 
Short Title: Effects of triptorelin when given every 6-months under the skin to adult males 
with cancer in the prostate  
 
Study Phase: III 
 
Sponsor Name: Ipsen Pharma SAS 
 
Legal Registered Address: 
Ipsen Pharma SAS 
65, quai Georges Gorse 
92100 Boulogne Billancourt, France  
  
Regulatory Authority Identifier Number(s)  
 
EudraCT: 2021-005719-29 
 
 
 
Date:  04 December 2023 
Version number: 3.0 
Amendment Number: 2 
 
 
 
 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation.

IPSEN GROUP 
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CONFIDENTIAL 
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PAGE 2/66 
 
 
Sponsor Signatory: 
 
 
Date 
 
 
Medical Monitor Name and Contact Information: 
Ipsen Bioscience, Inc. 
1 Main Street 
Cambridge, Massachusetts 02142 
United States 
Email: 
  
PPD
PPD
PPD

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
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Principal Investigator Signature Page 
I have read and agree to Protocol D-FR-52014-245 entitled An open-label, multicentre, single 
arm study to assess the efficacy and safety of triptorelin 6-month formulation administered 
subcutaneously in participants with locally advanced and/or metastatic prostate cancer 
previously treated and castrated with a GnRH analogue with Amendment 2. I am aware of my 
responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
NAME:  
[ ] 
TITLE: 
[PRINCIPAL] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
PAGE 4/66 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
DOCUMENT HISTORY 
Document 
Version 
Date 
Status 
Amendment 2 
3.0 
04 December 2023 
Effective 
Amendment 1 
2.0 
13 September 2022 
Superseded 
Original Protocol 
1.0 
16 March 2022 
Superseded 
 
The detail of Amendment 1 is provided in Appendix 10.6. 
 
Amendment 2 (04 December 2023) 
This amendment is considered to be non-substantial based on the criteria set forth in Directive 2001/20/EC because it neither significantly impacts 
the safety or rights of participants or on the reliability and robustness of the data generated in the clinical trial. 
 
Overall Rationale for the Amendment: 
Protocol updated to clarify study procedures, as well as the inclusion of minor additions/updates to comply with protocol template guidance.  
 
Summary change table from previous version of the protocol 
Any new or amended text in the protocol is indicated in bold (IS column). Deletions are marked in strikeout text (WAS column). Minor formatting 
and editing are not included. 
 
Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
Sponsor Signatory 
Sponsor Signatory: 
Medical 
Monitor 
Name 
and 
Contact 
Information: 
 
Sponsor Signatory: 
Medical 
Monitor 
Name 
and 
Contact 
Information: 
 
Change in sponsor personnel 
PPD
PPD
PPD
PPD

IPSEN GROUP 
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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
Ipsen Bioscience, Inc. 
1 Main Street 
Cambridge, Massachusetts 02142 
United States 
Email:
 
 
Ipsen Bioscience, Inc. 
1 Main Street 
Cambridge, Massachusetts 02142 
United States 
Email: 
 
7.1.1 Temporary 
Discontinuation 
In case of suspected or confirmed COVID 19 
(SARS CoV 2) infection, the intervention 
administration may be temporarily postponed 
depending on the participant clinical 
presentation. 
In case of clinical study disruption due to a 
regional or national emergency declared by 
a government agency, the intervention 
administration may be temporarily postponed 
depending on the participant clinical 
presentation. 
Minor additions/updates to 
comply with protocol template 
guidance. 
7.3 Lost to Follow-
up 
A participant will be considered lost to 
follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted 
by the study site. 
(…) 
• Should the participant continue to be 
unreachable, he will be considered to have 
withdrawn from the study. 
• Site personnel will attempt to collect the vital 
status of the participant within legal and ethical 
boundaries for all participants randomised, 
including those who did not receive study 
intervention. Public sources may be searched 
for vital status information. If vital status is 
determined as deceased, this will be 
documented, and the participant will not be 
considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts 
to collect vital status information. 
A participant will be considered lost to 
follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be 
contacted by the study site until the end of the 
study. 
(…) 
• Should the participant continue to be 
unreachable, attempts to make contact 
should continue until study closure and 
participant might be confirmed as lost to 
follow up at the time of study closure. 
• Site personnel will attempt to collect the vital 
status of the participant within legal and ethical 
boundaries for all participants randomised, 
including those who did not receive study 
intervention. All sources may be searched for 
vital status information. If vital status is 
determined as deceased, this will be 
documented, and the participant will not be 
Minor additions/updates to 
comply with protocol template 
guidance. 
PPD
PPD
PPD
PPD

IPSEN GROUP 
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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts 
to collect vital status information. 
Section 8 Study 
Assessments and 
Procedures 
• Immediate safety concerns should be 
discussed with the sponsor immediately upon 
occurrence or awareness to determine if the 
participant should continue or discontinue 
study intervention. 
(…) 
• In the event of a significant study-
continuity issue (e.g. caused by a pandemic), 
alternate strategies for participant visits, 
assessments, medication distribution and 
monitoring may be implemented by the 
sponsor or the investigator, as per local 
health authority/ethics requirements. 
(…) 
Minor additions/updates to 
comply with protocol template 
guidance. 
Section 8.4 Adverse 
Events and Serious 
Adverse Events and 
Other Safety 
Reporting 
AEs will be reported by the participant (or, 
when appropriate, by a caregiver, surrogate). 
The investigator and any qualified designees 
are responsible for detecting, documenting, and 
recording events that meet the definition of an 
AE or SAE and remain responsible for 
following up all AEs and SAEs during the 
study (see Section 7). 
The investigator and any qualified designees 
are responsible for detecting, documenting, and 
recording events that meet the definition of an 
AE or SAE and remain responsible for 
following up all AEs and SAEs during the 
study (see Section 7). This includes events 
reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or 
the participant’s legally authorised 
representative). 
Minor additions/updates to 
comply with protocol template 
guidance. 
Section 8.4.5 
Pregnancy 
(…) 
•If a pregnancy is reported, the investigator 
will record pregnancy information on the 
appropriate forms (Pregnancy Notification 
Form  paper form) and submit it to the 
sponsor within 24 hours via email of learning 
of the female partner of male participant 
becoming pregnant (after obtaining the 
necessary signed informed consent from the 
female partner). 
(…) 
• If a pregnancy is reported, the investigator 
will record pregnancy information on the 
appropriate form and submit it to the sponsor 
within 24 hours via email of learning of the 
female partner of male participant becoming 
pregnant (after obtaining the necessary signed 
informed consent from the female partner). 
• While pregnancy itself is not considered to 
be and AE or SAE, any pregnancy 
complication or elective termination of a 
Minor additions/updates to 
comply with protocol template 
guidance. 

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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
• Any pregnancy complication or elective 
termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
 
pregnancy for medical reasons will be reported 
as an AE or SAE. 
Section 8.4.8 
Reporting of Study 
Intervention Errors 
Including Misuse/ 
abuse 
• Study intervention errors and uses outside of 
what is foreseen in the protocol will be 
recorded in the eCRF irrespective of whether 
associated with an AE/SAE or not. It will also 
be documented in the AE section of the eCRF 
if associated with an AE. It will be reported in 
the safety database only if associated with an 
SAE. 
• Study intervention errors and uses outside of 
what is foreseen in the protocol, such as 
misuse, abuse or overdose, will be recorded 
on the appropriate eCRF page irrespective of 
whether associated with an AE/SAE or not, 
within 24 hours of investigator or qualified 
designees’ awareness. If an AE/SAE is 
associated with this study intervention 
error, it should be documented in the 
AE/SAE section of the eCRF. Please refer to 
Sections 6.7 and 10.3.1. 
Minor additions/updates to 
comply with protocol template 
guidance. 
Section 10.1.5 
Dissemination of 
Clinical Study Data 
• The sponsor seeks to publish the results of its 
clinical trials in biomedical journals, whatever 
the outcome. Clinical trial results may also be 
presented at international congresses as posters 
or oral presentations. 
• Protocol and result summary will be made 
publicly available on the United States Clinical 
Trials Registry (ClinicalTrials.gov) and for 
studies run in the EU/EEA on the EU Clinical 
Trials Register (www.clinicaltrialsregister.eu). 
The sponsor also provides clinical trial 
information to other national clinical trial 
registries or databases according to local 
requirements/legislation. 
• Protocol information and final study result 
will be made publicly available on the United 
States website (ClinicalTrials.gov) and for 
studies run in the EU/EEA on the EU Clinical 
Trials Register (www.clinicaltrialsregister.eu) 
or EU Clinical Trials Portal 
(https://euclinicaltrials.eu/home). The 
sponsor also provides clinical trial information 
to other national clinical trial registries or 
databases according to local 
requirements/legislation. 
• A lay language protocol synopsis and a 
summary of the study will be made available 
on the EU Clinical Trials Portal 
(https://euclinicaltrials.eu/home) and/or 
Sponsor website. 
Minor additions/updates to 
comply with protocol template 
guidance. 

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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
Section 10.1.9 
Publication Policy 
• The results of this study may be published or 
presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect 
proprietary information and to provide 
comments. 
• The sponsor seeks to publish the results of 
these clinical trials in biomedical journals, 
whatever the outcome. Clinical trial results 
may also be presented at international 
congresses as posters or oral presentations. 
• The results of this study may be published or 
presented at scientific meetings. If this is 
foreseen, the investigator should discuss 
specific publication concepts, including data 
to be covered, target congress/journal and 
proposed authors, with the sponsor for 
agreement before initiation. The investigator 
agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the 
sponsor to protect proprietary information and 
to provide comments. 
Minor additions/updates to 
comply with protocol template 
guidance. 
Section 10.3.2 
Definition of SAEs 
e. Is a congenital anomaly/birth defect 
 
f. Other situations: 
 
Medical or scientific judgment should be 
exercised by the investigator in deciding 
whether SAE reporting is appropriate in other 
situations such as significant medical events 
that may jeopardize the participant or may 
require medical or surgical intervention to 
prevent one of the other outcomes listed in the 
above definition. These events should usually 
be considered serious.  
 
Examples of such events include invasive or 
malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, 
e. Is a congenital abnormality/birth defect 
 
f. Other situations: 
 
Medical or scientific judgment should be 
exercised by the investigator in deciding 
whether SAE reporting is appropriate in other 
situations such as significant medical events 
that may jeopardize the participant or may 
require medical or surgical intervention to 
prevent one of the other outcomes listed in the 
above definition. These events should usually 
be considered serious. 
 
Examples of such events include invasive or 
malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, 
Deletion of the statement about 
the seriousness assessment of 
COVID-19 adverse events. This 
means that COVID-19 is no 
longer to be reported as a 
serious adverse event unless the 
occurrence of COVID-19 meets 
the defined seriousness criteria.  

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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
convulsions or development of intervention 
dependency or intervention abuse.  
 
A suspected or confirmed coronavirus 
COVID 19 (SARS CoV 2) infection must be 
reported as serious (seriousness criteria should 
be “other medically significant” if no other 
seriousness criteria are present (e.g. 
hospitalisation). 
convulsions or development of intervention 
dependency or intervention abuse. 
 
Section 10.3.4 
Reporting of SAEs 
• The primary mechanism for reporting an SAE 
to the sponsor will be the electronic data 
collection tool. 
(…) 
• Contacts for SAE reporting can be found on 
the SAE form and the cover sheet. 
SAE Reporting to the sponsor via paper 
• Contacts for SAE reporting can be found on 
the SAE form and the cover sheet. 
 
• The primary mechanism for reporting an SAE 
in English language to the sponsor will be the 
electronic data collection tool. 
(…) 
• SAE report should be sent to 
adverse.events@ipsen.com. 
SAE Reporting to sponsor via paper data 
collection tool 
• SAE report should be sent to 
adverse.events@ipsen.com. 
Minor additions/updates to 
comply with protocol template 
guidance. 
Section 10.5.1.7 
Adverse Event 
Reporting 
As per the protocol (Appendix 10.3.2), all 
COVID-19 cases (suspected or confirmed) 
should be considered as SAEs.  
“Other medically significant” should be 
selected as seriousness criterium if no other 
seriousness criteria are present (e.g. 
hospitalisation).  
Details can be collected by site staff via 
telephone call as per the rules relating to use of 
telemedicine in the protocol (Appendix 10.5.2). 
All COVID-19 cases (suspected or confirmed) 
should be seriousness assessed based on the 
reported seriousness criteria. If no 
seriousness criteria is reported by the 
investigator, the COVID-19 event/case will 
be collected and recorded as nonserious. 
Details can be collected by site staff via 
telephone call as per the rules relating to use of 
telemedicine in the protocol (Appendix 10.5.2). 
Amended for consistency with 
Section 10.3.2. 

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Section 
WAS (Version 2.0, 13 SEPTEMBER 2022) 
IS (Version 3.0, 04 DECEMBER 2023) 
Rationale 
Section 10.5.2 
Specific Rules 
Related to Use of 
Telemedicine 
Note that further information about measures 
adopted for the COVID 19 situation to cover 
SAE reporting and temporary discontinuations 
are found in Sections 10.3.4 and 7.1.1, 
respectively. 
 
Amended for consistency with 
Sections 10.3.2 and 10.5.1.7. 
 
Other documents impacted: 
 
Informed consent form  
Yes  
  No  
 
Case report form (CRF)  
Yes  
  No  
 
Statistical analysis plan (SAP)  
Yes  
  No  
 
 

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TABLE OF CONTENTS 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................... 4 
TABLE OF CONTENTS ....................................................................................................... 11 
LIST OF ABBREVIATIONS ................................................................................................ 15 
1 
PROTOCOL SUMMARY ........................................................................................... 16 
1.1 
Synopsis .......................................................................................................................... 16 
1.2 
Schema ........................................................................................................................... 19 
1.3 
Schedule of Activities .................................................................................................... 19 
2 
INTRODUCTION ........................................................................................................ 23 
2.1 
Study Rationale ............................................................................................................. 23 
2.2 
Background ................................................................................................................... 23 
2.3 
Benefit/Risk Assessment ............................................................................................... 24 
2.3.1 
Risk Assessment .......................................................................................... 24 
2.3.2 
Benefit Assessment ...................................................................................... 25 
2.3.3 
Overall Benefit: Risk Conclusion ............................................................... 25 
3 
OBJECTIVES AND ENDPOINTS ............................................................................. 26 
4 
STUDY DESIGN ........................................................................................................... 28 
4.1 
Overall Design ............................................................................................................... 28 
4.2 
Scientific Rationale for Study Design .......................................................................... 28 
4.3 
Justification for Dose .................................................................................................... 29 
4.4 
End of Study Definition ................................................................................................ 29 
5 
STUDY POPULATION ............................................................................................... 30 
5.1 
Inclusion Criteria .......................................................................................................... 30 
5.2 
Exclusion Criteria ......................................................................................................... 30 
5.3 
Lifestyle Considerations ............................................................................................... 31 
5.4 
Screen Failures .............................................................................................................. 31 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ............................ 32 
6.1 
Study Intervention(s) Administered ............................................................................ 32 
6.2 
Preparation, Handling, Storage and Accountability ................................................. 32 
6.3 
Measures to Minimize Bias: Randomisation and Blinding ....................................... 33 
6.3.1 
Randomisation ............................................................................................ 33 
6.3.2 
Maintenance of blinding ............................................................................. 33 
6.4 
Study Intervention Compliance ................................................................................... 33 
6.5 
Dose Modification ......................................................................................................... 33 
6.6 
Continued Access to Study Intervention after the End of the Study ....................... 34 
6.7 
Treatment of Overdose ................................................................................................. 34 
6.8 
Concomitant Therapy ................................................................................................... 34 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 36 
7.1 
Discontinuation of Study Intervention ........................................................................ 36 

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7.1.1 
Temporary Discontinuation ........................................................................ 36 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................ 36 
7.3 
Lost to Follow-up .......................................................................................................... 36 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 38 
8.1 
Demography .................................................................................................................. 38 
8.2 
Efficacy Assessments .................................................................................................... 38 
8.2.1 
Testosterone ................................................................................................. 38 
8.2.2 
Prostate-specific Antigen ............................................................................ 39 
8.3 
Safety Assessments ........................................................................................................ 39 
8.3.1 
Physical Examinations ............................................................................... 39 
8.3.2 
Vital Signs ................................................................................................... 39 
8.3.3 
Electrocardiograms ..................................................................................... 39 
8.3.4 
Imaging Scan .............................................................................................. 39 
8.3.5 
Clinical Safety Laboratory Assessments .................................................... 39 
8.3.6 
Local Tolerance........................................................................................... 40 
8.4 
Adverse Events (AEs) and Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................... 40 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information .... 40 
8.4.2 
Method of Detecting AEs and SAEs........................................................... 41 
8.4.3 
Follow-up of AEs and SAEs ....................................................................... 41 
8.4.4 
Regulatory Reporting Requirements for SAEs .......................................... 41 
8.4.5 
Pregnancy .................................................................................................... 41 
8.4.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ......................................................................... 42 
8.4.7 
Adverse Events of Special Interest ............................................................. 42 
8.4.8 
Reporting of Study Intervention Errors Including Misuse/abuse ............ 42 
9 
STATISTICAL CONSIDERATIONS ........................................................................ 43 
9.1 
Statistical Hypotheses ................................................................................................... 43 
9.2 
Sample Size Determination .......................................................................................... 43 
9.3 
Analysis Sets .................................................................................................................. 43 
9.4 
Statistical Analyses ....................................................................................................... 43 
9.4.1 
Analysis of Demographics and Other Baseline Characteristics ............... 44 
9.4.2 
Efficacy Analyses ........................................................................................ 44 
9.4.3 
Safety Analyse(s) ......................................................................................... 44 
9.5 
Interim Analyses ........................................................................................................... 44 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS .................................................................................................... 45 
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations .................... 45 
10.1.1 
Regulatory and Ethical Considerations ..................................................... 45 
10.1.2 
Financial Disclosure ................................................................................... 45 
10.1.3 
Informed Consent Process .......................................................................... 45 

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10.1.4 
Data Protection ........................................................................................... 46 
10.1.5 
Dissemination of Clinical Study Data ........................................................ 47 
10.1.6 
Data Quality Assurance .............................................................................. 47 
10.1.7 
Source Documents ...................................................................................... 48 
10.1.8 
Study and Site Start and Closure ................................................................ 48 
10.1.9 
Publication Policy ....................................................................................... 49 
10.2 Appendix: Clinical Laboratory Tests ......................................................................... 50 
10.3 Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................ 51 
10.3.1 
Definition of AE .......................................................................................... 51 
10.3.2 
Definition of SAE ........................................................................................ 52 
10.3.3 
Recording and Follow-Up of AE and/or SAE ........................................... 53 
10.3.4 
Reporting of SAEs ....................................................................................... 54 
10.4 Appendix: ECOG Performance Scale ......................................................................... 56 
10.5 Appendix: Temporary Measures and Procedures Related to COVID-19 
Pandemic ........................................................................................................................ 57 
10.5.1 
Specific Guidance for Study Visits and Assessments ................................ 57 
10.5.1.1 
Study Schedule ............................................................................................. 57 
10.5.1.2 
Screening and Enrolment ............................................................................. 57 
10.5.1.3 
Informed Consent (including Re-consent) ................................................... 57 
10.5.1.4 
Dosing Visits ................................................................................................ 58 
10.5.1.5 
Testosterone Assessments ............................................................................ 58 
10.5.1.6 
Concomitant Medications and Procedures .................................................. 58 
10.5.1.7 
Adverse Event Reporting.............................................................................. 59 
10.5.2 
Specific Rules Relating to Use of Telemedicine ........................................ 59 
10.5.3 
Guidance on COVID-19 Vaccine and/or Medications .............................. 59 
10.6 Appendix: Protocol Amendment History ................................................................... 60 
10.6.1 
Amendment 1: (13 September 2022) .......................................................... 60 
11 
REFERENCES .............................................................................................................. 66 
 
LIST OF TABLES 
Table 1 
Schedule of Activities .......................................................................................... 21 
Table 2 
Study Risk Assessment ........................................................................................ 25 
Table 3 
Objectives and Endpoints ................................................................................... 26 
Table 4 
Study Intervention Administered ...................................................................... 32 
Table 5 
Protocol-Required Safety Laboratory Tests ..................................................... 50 
 

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LIST OF FIGURES 
Figure 1 
Study Schema ....................................................................................................... 19 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
AE 
Adverse event 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EoS 
End of study 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing hormone 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LH 
Luteinizing hormone 
LHRH 
Luteinizing hormone releasing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI-CTC 
National Cancer Institute – Common Toxicity Criteria 
PP 
Per protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SoA 
Schedule of activities 
TEAE 
Treatment emergent adverse event 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
An open-label, multicentre, single arm study to assess the efficacy and safety of triptorelin 
6-month formulation administered subcutaneously in participants with locally advanced and/or 
metastatic prostate cancer previously treated and castrated with a GnRH analogue  
 
Short Title: Effects of triptorelin when given every 6-months under the skin to adult males 
with cancer in the prostate 
 
Rationale: 
Triptorelin is an agonist analogue of natural gonadotropin-releasing hormone (GnRH). The 
principal modification consists of substitution of natural glycine in position 6 by a D-amino 
acid (D-tryptophan) leading to improved receptor binding affinity and a longer activity time. 
The GnRH analogues, of which triptorelin belongs to, are used in the treatment of prostate 
cancer. Triptorelin is available on the market for more than 30 years under different 
formulations: 1-month, 3-months and 6-months. Clinical studies have shown that triptorelin 
6-month formulation (22.5 mg) administered intramuscularly rapidly induces and maintains 
castration in patients with locally advanced or metastatic prostate cancer [Lundström 2009, 
Breul 2017]. Since 2009, different authorities, including those in Europe, have approved the 
aforementioned formulation and route of administration which is currently prescribed by many 
physicians for the treatment of advanced prostate cancer. Although intramuscular injection is 
mostly used, physicians prefer subcutaneous administration, as this method has less theoretical 
interactions with some medications patients may take for cardiovascular morbidities. 
Considering the patient age (elderly), as well as their body mass index (obese versus frail) and 
co-morbidities (requiring some to take concomitant medications (e.g. oral anticoagulants)), the 
subcutaneous administration of any injectable is considered more convenient for the patient. 
Positive outcomes from a previous clinical study performed with the triptorelin 3-month 
formulation manufactured by Ipsen (already marketed for intramuscular administration) and 
administered subcutaneously [Lebret 2015] has led to the registration and commercialisation of 
this new route of administration in Europe and worldwide. 
The present study will assess the efficacy and safety of the 6-month triptorelin formulation 
(22.5 mg) administered subcutaneously (twice a year) in participants with locally advanced 
and/or metastatic prostate cancer previously treated and castrated by a GnRH analogue. 
 

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The variable for the primary estimand will be castration maintenance rate during the study, 
which is defined as percentage of participants castrated (testosterone <1.735 nmol/L 
(50 ng/dL)) at Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337, with two 
complete study intervention administrations. Secondary estimands include analyses without 
using the visit window and/or using the ITT population where missing data will be considered 
a non-responder maybe conducted. Further details of the estimand will be specified in the 
statistical analysis plan (SAP). 
 
Overall Design: 
This is a phase III, multicentre, open-label, non-comparative, repeated dose study to evaluate 
the efficacy and safety of triptorelin embonate 22.5 mg 6-month formulation administered 
subcutaneously in participants with locally advanced and/or metastatic prostate cancer 
previously treated and castrated with a GnRH analogue. Approximately 145 adult male 
participants will be enrolled in the study. All enrolled participants will receive a subcutaneous 
injection of triptorelin embonate 22.5 mg 6-month formulation on Day 1 and Day 169. 
Note: participants must receive study intervention on Day 1 in accordance with the treatment 
schedule of their previously received GnRH analogue therapy. 
 
Intervention Groups and Duration: 
Triptorelin embonate 22.5 mg (6-month formulation), subcutaneous injection on Day 1 and 
Day 169. 
 
Visit Frequency: 
The study will consist of a Screening period (up to 28 days before enrolment), first open-label 
injection of the study intervention on Day 1. Following the first treatment, visits will occur on 
Day 3, Day 7, Day 29, Day 85, Day 141, Day 169 (second injection), Day 171, Day 175, 
Day 253, Day 309 and Day 337 for efficacy and safety assessments. (Note: if necessary, 
participants can request home visits, except for visits where study intervention is to be 
administered). 
Participants will receive two injections of triptorelin embonate 22.5 mg (6-month formulation) 
during the study period before they attend the end of study (EoS) visit on Day 337.  
 
Study Participant Duration:  
Participants are expected to participate in this study for 52 weeks, including up to 4 weeks for 
screening. 
 
Number of Participants: 
Approximately 145 participants are planned to be assigned to study intervention.  
 
Statistical Methods: 
Sample Size Determination 
This single-arm study is designed to demonstrate that the percentage of participants remaining 
castrated (maintenance of castration defined as testosterone <1.735 nmol/L (50 ng/dL) at 
Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337) during the study is greater 
than 90%. Considering an observed castration maintenance in 97% of participants, 130 eligible 

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participants are required to demonstrate the efficacy of the triptorelin 6-month formulation with 
approximately 90% power and a one-sided alpha of 0.025 using an exact binomial test. The 
objective will be achieved if the lower bound of the 95% confidence interval (CI) of the 
observed rate is greater than 90%. 
Considering a drop-out rate of 10%, 145 participants will be included in the study. 
Efficacy Analyses 
Due to the single-arm nature of the study, all statistical analyses will be descriptive with 
quantitative data summarised as mean, standard deviation (SD), median, quartiles, 95% CIs and 
range. Qualitative data will be summarised as frequency counts and percentages. The 95% CIs 
will be calculated following the Clopper-Pearson method. The descriptive statistics of treatment 
effects and corresponding 95% CIs for the primary endpoint and secondary endpoints will be 
presented. 
Missing castration level data during the study will be imputed by multiple imputation. Further 
details of the efficacy analyses will be specified in the SAP. 
Safety Analyses 
All adverse events, treatment-emergent adverse events and serious adverse events will be 
summarised and tabulated by system organ class and preferred term, including severity and 
relationship to test product. 
Values of laboratory parameters and vital signs at baseline, on treatment and the change from 
baseline to on-treatment levels will be described. 
The Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0 or higher) 
classification will be used to classify adverse events (AEs) and laboratory abnormalities. The 
CTCAE grade by participant will be tabulated and listed. 
 
1.2 
Schema 
The study schema is shown in Figure 1. 
Figure 1 Study Schema 
 
D=day; ED=early discontinuation; EoS=end of study 
Participants will receive a subcutaneous injection of triptorelin embonate 22.5 mg (6-month formulation) on Day 1 and 
Day 169. 
 
1.3 
Schedule of Activities 
Study assessments to be performed are outlined in Table 1. If the Coronavirus Disease 2019 
(COVID-19) pandemic prevents participants from coming to the site, participants can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor before being implemented. In such a case, the investigator will 
perform a telemedicine visit and will make every effort, where applicable, to contact the 
participant’s general practitioner or specialist physician to ensure all important medical 

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information and safety event(s) occurring since the last visit are collected. Guidance on how to 
collect protocol-planned assessments is provided in Appendix 10.5. Such document will be 
filed in the trial master file.  
 

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Table 1 
Schedule of Activities 
Procedure 
Screening  
(up to 
28 days 
before 
Day 1) 
Intervention Period 
EoS/
ED 
Section 
for 
further 
details 
End of week 
- 
- 
Week 
1 
Week 
1 
Week 
4 
Week 
12 
Week 
20 
Week 
24 
Week 
25 
Week 
25 
Week
36 
Week 
44 
Week 
48 
 
Day [a] 
Day -28 to 
Day -1 
Day 
1 
Day 
3 
Day 
7 
Day 
29 
Day 
85 
Day 
141 
Day 
169 
Day 
171 
Day 
175 
Day 
253 
Day 
309 
Day 
337 
 
Visit window 
 
 
Day 3 
after first 
inj 
Day 7 
after first 
inj 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
Day 3 
after 
last inj 
Day 7 
after last 
inj 
±3 
days 
±3 
days 
±3 
days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.3 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5.1 & 
5.2 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
including body weight 
X [b] 
X 
 
 
 
 
 
X 
 
 
 
 
X 
8.3.1 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior disease-specific 
treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram [c] 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
8.3.3 
Vital signs 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
8.3.2 
Imaging scan [e] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.4 
ECOG score 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
10.4 
Injection triptorelin 6M 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.1 
Blood samples for 
testosterone  
X [d] 
X 
[d] 
X 
X 
X 
X 
X 
X [d] 
X 
X 
X 
X 
X 
8.2 
Blood samples for PSA 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
8.2 
Blood samples for 
laboratory safety tests [f] 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
8.3.5 
Local tolerance [g] 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
8.3.6 

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Procedure 
Screening  
(up to 
28 days 
before 
Day 1) 
Intervention Period 
EoS/
ED 
Section 
for 
further 
details 
End of week 
- 
- 
Week 
1 
Week 
1 
Week 
4 
Week 
12 
Week 
20 
Week 
24 
Week 
25 
Week 
25 
Week
36 
Week 
44 
Week 
48 
 
Day [a] 
Day -28 to 
Day -1 
Day 
1 
Day 
3 
Day 
7 
Day 
29 
Day 
85 
Day 
141 
Day 
169 
Day 
171 
Day 
175 
Day 
253 
Day 
309 
Day 
337 
 
Visit window 
 
 
Day 3 
after first 
inj 
Day 7 
after first 
inj 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
Day 3 
after 
last inj 
Day 7 
after last 
inj 
±3 
days 
±3 
days 
±3 
days 
 
Previous (excluding 
disease-specific) and 
concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6.8 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.4 
Abbreviations: 6M=6-month formulation; AE=adverse event; ALT=alanine aminotransaminase; AST=aspartate aminotransaminase; eCRF=electronic case report form; ECG=electrocardiogram; 
ECOG= Eastern Cooperative Oncology Group; EoS=end of study; Hb=haemoglobin, inj=injection; M=month;  PSA=prostate-specific antigen WBC=white blood cell 
a 
If necessary, participants can request home visits, except for visits where study intervention is to be administered. 
b 
Height to be collected at screening only. 
c 
ECG to be assessed as clinically indicated at any other time during the study as required. 
d 
All testosterone assessments to be performed using the central laboratory, except at screening. At screening, testosterone to be assessed up to 7 days prior to Day 1 using the local laboratory. 
On Day 1 and Day 169, samples for testosterone to be collected pre-dose. 
e 
An imaging scan is not required if performed within 6 months of study screening. 
f 
Haematology (WBC and differential count, platelet count, Hb), blood chemistry (creatinine, glucose, ALT, AST, alkaline phosphatase, total and conjugated bilirubin). Glucose: Non-fasting 
levels in all participants. 
g 
Injection site to be specifically checked for local site injection reactions 2 hours after study intervention administration. Any local reaction AEs will be collected on  
the eCRF. 
 

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2 
INTRODUCTION 
Triptorelin is an agonist analogue of natural GnRH. The principal modification consists of 
substitution of natural glycine in position 6 by a D-amino acid (D-tryptophan). Clinical and 
animal studies have provided positive results of triptorelin’s action in hormone-dependent 
disorders such as prostate cancer, endometriosis, central precocious puberty, uterine 
fibromyomas, in vitro fertilisation and breast cancer. 
2.1 
Study Rationale 
Clinical studies have shown the triptorelin embonate 22.5 mg 6-month formulation rapidly 
induces and maintains castration in patients with locally advanced or metastatic prostate cancer 
[Lundström 2009, Breul 2017]. The marketing-approved and recommended route of 
administration of triptorelin 6-month formulation is intramuscular injection in patients with 
prostate cancer. Although intramuscular injection of triptorelin sustained-release 6-month 
formulation offers the advantage of reduced frequency of injection and a lower rate of injection 
site reactions [Lundström 2009], both patients and doctors find a subcutaneous route of 
administration more convenient. In addition, some patients, such as those receiving 
anticoagulants, are more at risk of haematomas or excessive bleeding with an intramuscular 
route compared with a subcutaneous one [Bithell 1993]. Positive outcomes from a previous 
clinical study performed with the triptorelin 3-month formulation manufactured 
by Ipsen (already marketed for intramuscular administration) administered subcutaneously 
[Lebret 2015] has led to the registration and commercialisation of this new route of 
administration in Europe and worldwide. 
The present study will assess the efficacy and safety, including local tolerability, of repeat 
treatment with the 6-month formulation of triptorelin embonate 22.5 mg administered 
subcutaneously in participants with locally advanced and/or metastatic prostate cancer 
previously treated and castrated by a GnRH analogue. 
2.2 
Background 
Prostate cancer is the second most common cancer in the male population and thus the sixth 
cause of death from cancer in men over 50 in the western world [Sung 2021]. Prostate cancer 
is androgen dependent, with most patients initially responding to androgen deprivation therapy 
(ADT). However, after 1 to 2 years of treatment, advanced prostate cancer eventually 
progresses to castration resistant prostate cancer. 
Androgen receptor signalling plays an important role in the development of prostate cancer. 
Gonadotropin-releasing hormone, also known as luteinizing hormone releasing hormone 
(LHRH) is released in a pulsatile manner by the hypothalamus and stimulates the pituitary to 
release in pulses the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone 
(FSH). LH stimulates the production of testosterone by the testis; however, approximately 5% 
of circulating testosterone is independently produced by the adrenal glands. FSH plays a role 
in the regulation of spermatogenesis. 
Since the pioneering studies of Huggins and Hodges [1941, 1941a] in the 1940's about the role 
played by the testicular androgen development and progression of prostate cancer cells, the 
mainstay of treatment for advanced prostate cancer has been androgen deprivation by bilateral 
orchiectomy and/or oestrogen therapy. The limitations of these therapeutic modalities led to the 
development of GnRH analogues, which have made pharmacological castration the preferred 
option among many patients with metastatic disease [Filicori 1994].  
The therapeutic activity of the GnRH agonists is achieved via pituitary down-regulation of their 
own receptors achieved by continuous and chronic administration, providing almost complete 
suppression of LH and FSH secretion leading to suppression of testicular function. 

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Subcutaneous injection of triptorelin 11.25 mg (3-month formulation) has been evaluated in an 
open-label, single-arm study where treatment was administered twice over a 6-month period 
[Lebret 2015]. Results showed subcutaneous injection of triptorelin was well tolerated and 
maintained castration for up to 6 months, similarly, to results from studies with triptorelin 
administered intramuscularly. Furthermore, results from a clinical study with triptorelin 
embonate 22.5 mg (6-month formulation) administered twice subcutaneously over a 1-year 
period in participants with advanced prostate cancer who were non-castrated, showed induction 
and maintenance of castration (i.e. serum testosterone <1.735 nmol/L) in the majority of 
participants (82.6%) (data on file). Subcutaneous injection of triptorelin 22.5 mg was also well 
tolerated, with mild to moderate injection site AEs reported in 5.0% of participants. 
A more detailed description of the product, including further details on administration 
procedures and dosage are provided in Section 6. 
2.3 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and expected adverse 
events (AEs) of triptorelin may be found in the approved Summary of Product Characteristics. 
2.3.1 
Risk Assessment 
A risk assessment for this study is provided in Table 2. 

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Table 2 
Study Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention: Triptorelin 
There is no major known 
nonclinical risk associated with 
the study intervention 
Clinical risks associated with the 
study intervention may include:  
• 
hot flushes 
• 
erectile dysfunction 
• 
loss of libido 
• 
impaired physical activities 
• 
metabolic syndrome 
• 
cardiovascular events 
• 
anxiety/depression 
• 
decreased bone mineral 
density 
• 
risk of abortion or foetal 
abnormality [a] 
For a full list of adverse events and 
safety concerns with the product, 
please refer to the locally approved 
SmPC  
See approved SmPC 
Participant selection: 
Participants with significant 
medical conditions will be 
excluded from the study (see 
Section 5.1 and 5.2). 
Participant monitoring: 
During the study, there will be 
close monitoring of the 
participants for safety including 
local tolerability (see 
Section 8.3.6) 
Withdrawal criteria: 
Participants who become at risk 
due to any AE or medical 
condition will be withdrawn 
from the study intervention. 
Study Procedures 
There are no specific risks related 
to the study design or procedures. 
All procedures requested for the 
study are commonly used in clinical 
practice and the design does not 
create any specific risk or delay 
possible therapeutic option for 
participants 
Not applicable 
Abbreviations: SmPC=Summary of Product Characteristics 
a 
Pregnancy is highly unlikely in this study population. However, reproductive risks are listed for completeness for female 
partners of participants who may become pregnant. 
 
2.3.2 Benefit Assessment 
To date the triptorelin 6-month formulation given intramuscularly has already proven its 
efficacy and safety leading to the registration and commercialisation in Europe and worldwide. 
Based on existing data from previous clinical studies with triptorelin embonate 22.5 mg 
(6-month formulation) as a subcutaneous injection and the triptorelin 3-month formulation 
(from intramuscular to subcutaneous) as presented in Section 2.2, it is expected that efficacy 
will be maintained (i.e. maintenance of castration) while demonstrating the same safety profile 
as the other triptorelin formulations. 
2.3.3 Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimise risk to participants, the potential risks 
identified in association with the administration of the triptorelin 6-month formulation during 
the study are justified by the anticipated benefits to patients with prostate cancer. 

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participants with locally advanced and/or metastatic prostate cancer previously treated and 
castrated with a GnRH analogue as specified in the inclusion and exclusion criteria (Sections 
5.1 and 5.2), respectively, that have received two scheduled treatment intervention doses (i.e. 
Day 1 and Day 169) and have completed all visits for measurement of testosterone. 
The variable for the primary estimand will be castration maintenance rate during the study, 
which is defined as percentage of participants castrated (testosterone <1.735 nmol/L 
(50 ng/dL)) at Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337, with two 
complete study intervention administrations. Secondary estimands include analyses without 
using the visit window and/or using the ITT population where missing data will be considered 
a non-responder maybe conducted. Further details of the estimand will be specified in the SAP. 
 

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4 
STUDY DESIGN 
4.1 
Overall Design 
This is a phase III, multicentre, open-label, non-comparative, repeat dose study to evaluate the 
efficacy and safety of triptorelin 6-month formulation (22.5 mg) administered subcutaneously 
in participants with locally advanced and/or metastatic prostate cancer previously treated and 
castrated with a GnRH analogue.  
Approximately 145 participants will be assigned to triptorelin embonate 22.5 mg (6-month 
formulation) to be administered on Day 1 and Day 169. Note: participants must receive study 
intervention on Day 1 in accordance with the treatment schedule of their previously received 
GnRH analogue therapy. 
The study will consist of a 4-week screening period, during which participants with prostate 
cancer will be screened for eligibility. On Day 1, all eligible participants will receive a single 
open-label administration of study intervention. Following treatment on Day 1, visits will occur 
on Day 3, Day 7, Day 29, Day 85, Day 141, Day 169 (second administration), Day 171, 
Day 175, Day 253, Day 309 and Day 337. (Note: if necessary, participants can request home 
visits, except for visits where study intervention is to be administered). 
Participants will be considered to have completed the study when final procedures and 
assessments have been performed at the Day 337 visit. Participants who withdraw from the 
study before the completion of the Day 337 visit will have early discontinuation procedures and 
assessments performed at their final visit. 
The study design is illustrated in Figure 1. 
4.2 
Scientific Rationale for Study Design 
This phase III, single-arm, open-label study will investigate the efficacy and safety of triptorelin 
6-month formulation administered subcutaneously in participants with prostate cancer 
previously treated and castrated with a GnRH analogue.  
The non-comparative, open-label clinical study design is acceptable as the primary endpoint 
will assess testosterone levels by the percentage of participants maintaining castrate levels of 
serum testosterone (defined as <1.735 nmol/L (50 ng/dL)) during the study (primary endpoint, 
as outlined in Table 3). 
Assessment of testosterone is a well-established and a widely used efficacy parameter in studies 
investigating hormone deprivation therapies in patients with prostate cancer. Demonstration of 
testosterone castration <1.735 nmol/L (50 ng/dL) as an endpoint is also compliant with 
the European Medicines Agency (EMA) and European Association of Urology guidelines 
[Mottet 2021]. 
Some patients with prostate cancer, particularly those who are elderly and/or receiving 
anticoagulants, are at a higher risk of developing haematomas or excessive bleeding following 
intramuscular injection (see Summary of Product Characteristics). Thus, subcutaneous injection 
may be a better option.  
As presented in Section 2.2, a clinical study was conducted with triptorelin embonate 22.5 mg 
(6-month formulation) administered subcutaneously in participants with advanced prostate 
cancer who were non-castrated. However, the primary endpoint regarding the maintenance rate 
of castration was not met, as maintenance of castration was not observed after the first injection 
in some participants but maintained for all participants after the second injection. The present 
study aims to assess whether castration maintenance is achieved via subcutaneous 
administration in participants already castrated at the beginning of the study. Thus, the 
outcomes of this study intend to fulfil an unmet need and improve treatment convenience.   

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4.3 
Justification for Dose 
For this intervention, the term “dose” refers to the subcutaneous injection of triptorelin 
embonate 22.5 mg (6-month formulation). Triptorelin embonate 22.5 mg is a sustained release 
formulation designed to deliver 22.5 mg of the active moiety over 6 months. In addition, results 
from clinical studies have shown the efficacy of 3-month (triptorelin 11.25 mg) formulation 
and 6-month formulation (22.5 mg) administered subcutaneously to induce and maintain 
castration in participants with locally advanced or metastatic hormone sensitive prostate cancer, 
as well as demonstrate a good safety profile (see Section 2.2). 
4.4 
End of Study Definition 
The end of the study (EoS)/early discontinuation is defined as the date of the last visit of the 
last participant as shown in the SoA (Table 1). 
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit. 
Criteria for study intervention discontinuation and participant discontinuation/withdrawal from 
the study are described in Section 7.1 and Section 7.2, respectively. Loss to follow-up is 
described in Section 7.3. 

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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
(1) 
Participant is male and must be 18 years of age inclusive, at the time of signing the 
informed consent. 
(2) 
Participant has histologically or cytologically proven prostate cancer with rising PSA 
after failed local therapy or metastatic disease, or requiring radiotherapy, and be a 
candidate for long-term (i.e. >1 year) androgen deprivation therapy.  
(3) 
Participant requires a GnRH analogue treatment for a minimum of 18 months, of which 
a minimum of 3 months of GnRH analogue treatment has already been provided prior to 
screening. (Note: participants must receive study intervention on Day 1 in accordance 
with the treatment schedule of their previously received GnRH analogue therapy). 
(4) 
Has serum testosterone levels <1.735 nmol/L (50 ng/dL) at screening. 
(5) 
Has Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 
(see Appendix 10.4). 
(6) 
Has a life expectancy of >18 months. 
(7) 
Male participants must agree that, if their partner is at risk of becoming pregnant 
(although highly unlikely in this study population), they will use an effective method of 
contraception. The participant must agree to use the contraception during the whole of 
the study and for 9 months after the last dose of study intervention.  
(8) 
Capable of giving signed informed consent as described in Appendix 10.1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
(1) 
Presence of another neoplastic lesion or brain metastases. 
(2) 
Metastatic hormone-sensitive prostate cancer with high tumour burden 
(3) 
Metastatic castration-resistant prostate cancer 
(4) 
Any concomitant disorder or resulting therapy that is likely to interfere with participant 
compliance or with the study in the opinion of the investigator. 
Prior/concomitant therapy 
(5) 
Use of finasteride (Proscar®) or dutasteride (Avodart®/Avolve®) within the past 
6 months  
(6) 
Planned intermittent scheme of GnRH analogue 
(7) 
At the time of screening, planned use of any chemotherapy for prostate cancer during the 
study 
(8) 
Prior hypophysectomy or adrenalectomy 

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Prior/concurrent clinical study experience 
(9) 
Participation in another study with an experimental drug within 3 months before signing 
informed consent or within five half-lives of the investigational drug (whichever was the 
longer), or any other type of medical research. 
Diagnostic assessments 
(10) Severe kidney or liver failure (creatinine >2 times the normal range, aspartate 
aminotransferase and alanine aminotransferase >3 times the normal range) 
Other exclusions 
(11) Any concomitant disorder or resulting therapy that is likely to interfere with participant’s 
compliance, the subcutaneous administration of the drug or with the study in the opinion 
of the investigator. 
(12) Previous history of QT prolongation or concomitant use of medicinal products known to 
prolong the QT interval or with a known risk of torsades de pointes 
(13) Known hypersensitivity to triptorelin or any of its excipients, GnRH, other GnRH 
agonist/analogues. 
(14) Known active use of recreational drug or alcohol dependence in the opinion of the 
investigator 
(15) Inability to give informed consent or to comply fully with the protocol. 
5.3 
Lifestyle Considerations 
Participants will be advised to avoid chronic alcohol use and smoking during the study. 
5.4 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes date of informed consent, demography, 
reason for screen failure, eligibility criteria and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. The informed consent process is described in Section 10.1.3. 
 

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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention(s) Administered 
Table 4 
Study Intervention Administered 
Intervention Name 
Triptorelin embonate 
Intervention Description 
A PR formulation of triptorelin pamoate 6-month 
formulation in D,L-lactide-co-glycolide polymers for single 
subcutaneous injection 
Type  
Drug  
Dose Formulation 
A white to slightly yellow freeze-dried cake or powder 
supplied in a single 6 mL glass vial 
Unit Dose Strength(s) 
22.5 mg  
Dosage Level(s) 
Single dose delivered on Day 1 and Day 169 
Route of Administration 
Subcutaneous injection 
Use 
Experimental 
IMP and NIMP/AxMP. 
IMP  
Sourcing 
Manufactured by Debiopharm and provided centrally by the 
sponsor [a] 
Packaging and Labelling 
Study intervention will be provided in a box containing one 
vial, one ampoule, one sterile injection kit with one syringe 
and three needles (one for reconstitution, one for 
subcutaneous injection and one to be retained in the kit for 
reconciliation). 
Each box will be labelled as required per country 
requirement. 
Storage requirements 
To be stored in the outer carton at a temperature below 25°C 
in a dry place, protected from freezing 
Current Name 
Decapeptyl®, Pamorelin®, Diphereline®  
Abbreviations: IMP=investigational medicinal product; PR=prolonged release 
a 
The triptorelin vial is manufactured by Debiopharm. 
 
6.2 
Preparation, Handling, Storage and Accountability 
• 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
• 
Only participants screened in the study and who meet the eligibility criteria may receive 
study intervention and only authorised site staff may supply or administer study 
intervention. All study intervention must be stored in a secure, environmentally 
controlled and monitored (manual or automated) area in accordance with the labelled 
storage conditions with access limited to the investigator and authorised site staff. 
• 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records). 
• 
The sponsor will provide guidance on the destruction of unused study intervention. If 
destruction is authorised to take place at the investigational site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy and any special instructions provided by the sponsor. All 
destruction must be adequately documented.  

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Further guidance and information for the receipt, preparation, management and disposal/return 
of the study intervention are provided in the “Investigational Medicinal Product Handling 
Manual”. 
The investigator or an approved representative (e.g. pharmacist) will ensure that triptorelin is 
reconstituted and dispensed by a member of staff specifically authorised by the Investigator and 
trained for the investigational medicinal product reconstitution and administration. 
The suspension for injection must be reconstituted using an aseptic technique and only using 
the ampoule of solvent for injection. 
The solvent should be drawn into the syringe provided using the reconstitution needle (20 G, 
without safety device) and transferred to the vial containing the powder. The suspension should 
be reconstituted by swirling the vial gently from side to side for long enough until a 
homogeneous, milky suspension is formed. Do not invert the vial. 
It is important to check there is no unsuspended powder in the vial. The suspension obtained 
should then be drawn back into the syringe, without inverting the vial. The reconstitution needle 
should then be changed, and the subcutaneous injection needle (20 G, with safety device) used 
to administer the product. 
As the product is a suspension, the injection should be administered for a single use immediately 
after reconstitution to prevent precipitation. 
At each dispensation (at scheduled and unscheduled visits, if applicable), treatment number(s) 
will be assigned by the Interactive Web Response System (IWRS). The IWRS will also manage 
all logistical aspects of the study intervention (e.g. replacement, drug supplies and expiry dates) 
and the recording of drug accountability/destruction. This service provides the investigator, 
investigational site coordinators and project team members with a service that is available 
24 hours a day, 7 days a week. Additional details may be found in the IWRS reference manual 
provided to each investigational site. In case of technical or dispensation queries, a 24-hour 
helpline is available. If a participant discontinues the study before any intake of study 
intervention, his assigned treatment number(s) will not be reused. 
In addition to the information provided in the IWRS, drug accountability paper records will be 
maintained by the investigator. 
6.3 
Measures to Minimize Bias: Randomisation and Blinding 
6.3.1 
Randomisation 
This is a non-randomised, open-label study. 
6.3.2 
Maintenance of blinding 
This is an open-label study, therefore no procedure for blinding is applicable. 
6.4 
Study Intervention Compliance 
The participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered and volume at the site will 
be recorded in the source documents and in the electronic case report form (eCRF). The dose 
of study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff.  
6.5 
Dose Modification 
Not applicable. No dose modifications are to be performed in the study. 

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6.6 
Continued Access to Study Intervention after the End of the Study 
The participants will not receive any additional study intervention following the end of the 
study. 
6.7 
Treatment of Overdose 
The pharmaceutical properties of triptorelin 6-month formulation and its mode of 
administration make accidental or intentional overdose unlikely. There is no experience of 
overdose from clinical studies (for more information see the summary of package 
characteristics). If overdose occurs, this should be managed symptomatically.  
In the event of an overdose, the investigator should: 
• 
Contact the medical monitor immediately. 
• 
Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities (at least 
up to the Day 337 (Week 48) visit). 
• 
Document the quantity of the excess dose as well as the duration of the overdose. See 
Section 10.3.1 for reporting requirements concerning overdose. If overdose occurs, 
symptomatic management is indicated. 
6.8 
Concomitant Therapy  
Any medication or vaccine (including over the counter prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant has taken within the last 
2 months before or during triptorelin administration must be recorded on the eCRF along with: 
• 
Generic or trade name 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The following concomitant medications are not permitted during the study: 
• 
Finasteride or dutasteride 
• 
Abiraterone 
• 
Medications which are known to affect the metabolism and/or secretion of androgenic 
hormones: ketoconazole, aminoglutethimide, oestrogens. 
• 
Systemic or inhaled corticosteroids (topical application permitted). 
• 
Any herbal products previous used within 1 month prior to study start or plan to be used 
during the study, which are known to have cytotoxic effect or affect the metabolism 
and/or secretion of androgenic hormones. 
• 
Medications known to prolong QT interval (class IA (e.g. quinidine, disopyramide) or 
class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal 
products, methadone, moxifloxacin, antipsychotics). 
The following concomitant medications are permitted during this study, but they must be 
monitored closely, and every effort should be made to keep their dose and dose regimen 
constant throughout the course of the study: 
• 
Enzalutamide, apalutamide or darolutamide 

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• 
Analgesics: are allowed when necessary for pain relief. 
• 
Anticonvulsants (e.g phenobarbital): long-term therapy may have additional risk for 
osteoporosis 
• 
Other medications: any treatment which is considered necessary for the participant’s 
welfare, may be given at the discretion of the investigator. 
Other procedures: any diagnostic, therapeutic or surgical procedure performed during the study 
period should be recorded, including the date, indication, description of the procedure(s), and 
any clinical findings.  

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7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1.8. 
7.1 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to be evaluated for safety. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to 
be completed. 
If participants are lost to follow-up, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law. 
7.1.1 
Temporary Discontinuation 
In case of clinical study disruption due to a regional or national emergency declared by a 
government agency, the intervention administration may be temporarily postponed depending 
on the participant clinical presentation. In some cases, the investigator may request a participant 
be retested before the study intervention administration is resumed. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
compliance reasons. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time 
of study discontinuation and for any further evaluations that need to be completed. 
• 
The reason for discontinuation will be recorded in the eCRF. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such withdrawal of consent. 
• 
If the participant requests to discontinue the study intervention, they will be asked to be 
followed for the study procedures. 
• 
If the participant withdraws consent for any further contact, the investigator will explain 
in the medical records as to whether the withdrawal is only from further receipt of study 
intervention or also from study procedures. This information must be entered in the 
eCRF.  
• 
If a participant withdraws from the study, he may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• 
A participant will be withdrawn from the study if they have inadequate testosterone 
suppression (defined as >50 ng/dL detected at least 30 days after the first administration 
of study intervention and on two consecutive measurements at least 2 weeks apart, at 
either a scheduled or unscheduled study visit).  
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant  repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site until the end of the study. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 

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• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible. The site should counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, attempts to make contact should 
continue until study closure and participant might be confirmed as lost to follow up at 
the time of study closure.  
• 
Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants randomised, including those who did not receive 
study intervention. All sources may be searched for vital status information. If vital status 
is determined as deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information.  

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8 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarised in the SoA. Protocol waivers and 
exemptions are not allowed. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA (Table 1). 
• 
In the event of a significant study-continuity issue (e.g. caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the sponsor or the investigator, as per local health authority/ethics 
requirements. 
• 
The maximum amount of blood for study purposes collected from each participant over 
the duration of the study will not exceed 153 mL.  
• 
Repeat or unscheduled samples may be taken for safety reasons or in case of technical 
issues with the samples. 
8.1 
Demography 
Age, sex and, according to individual country regulations/requirements and if authorised in the 
country, race/ethnicity will be collected. The collection of these data is needed to establish if 
there are potential clinical important racial/ethnic-based differences in the anticipated effects of 
the intervention. 
8.2 
Efficacy Assessments 
Efficacy will be assessed in this study based on testosterone and PSA concentrations. 
Approximately 148 mL of blood will be collected from all participants for measurement of 
testosterone and PSA. Serum, or plasma samples used to evaluate testosterone or PSA will be 
divided into two aliquots (one primary and one back-up). 
Further instructions for the collection, handling and shipment of biological samples will be 
provided by the sponsor and described in the Study Laboratory Manual. 
Note: No exploratory analyses are planned for this study. However, residual plasma and serum 
samples may also be used for exploratory analyses. This could include using leftover plasma 
and serum samples for pharmacokinetic analyses or additional investigations (i.e. long-term 
stability, reproducibility, bioanalytical method cross-validation). If required, exploratory 
analyses related to pharmacokinetics and additional investigations will be captured in a separate 
report. 
8.2.1 
Testosterone 
Blood samples for the determination of testosterone serum concentrations will be collected at 
the timepoints indicated in the SoA (Table 1). Testosterone will be assessed centrally by a 
third-party vendor, as described in the Study Laboratory Manual. Serum will be analysed to 
determine concentrations of testosterone using a validated, specific and sensitive liquid 
chromatography tandem mass spectrometry methods.  

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At screening, testosterone will be assessed up to 7 days prior to Day 1 using the local laboratory.  
8.2.2 
Prostate-specific Antigen 
PSA will be assessed centrally, as described in the Study Laboratory Manual. 
Blood samples for the determination of PSA plasma concentrations will be collected at the 
timepoints indicated in the SoA (Table 1). 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.3.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight will 
also be measured and recorded.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study participation will be reported as AEs. Any physical examination findings (abnormalities) 
persisting at the end of the study will be followed by the investigator until resolution or until 
clinically stable. 
8.3.2 
Vital Signs 
Blood pressure, temperature, respiratory rate and heart rate will be assessed with an automated 
device so that measurements are independent of the observer. Blood pressure and heart rate will 
be recorded after 5 minutes rest in supine position. Absolute values and change from Baseline 
will be analysed. Any clinically significant vital signs will be recorded as AEs. 
8.3.3 
Electrocardiograms 
A 12-lead ECG analysis will be included as a safety evaluation/endpoint in this study at 
timepoints described in Table 1. 
A single 12-lead ECG will be recorded so that the different ECG intervals (RR, PR, QRS, QT, 
QTcF) can be measured automatically. The ECG will be recorded with the participant in supine 
position after five minutes of rest until four regular consecutive complexes are available.  
Based on investigator judgement, any abnormal ECG results will be repeated twice (10 minutes 
apart) to confirm the abnormal finding. Any clinically significant abnormalities will be recorded 
as AEs. 
8.3.4 
Imaging Scan 
An  imaging  scan for the prostate gland or the whole body (only, if necessary, based on 
investigator’s judgement) will be performed as described in the SoA (Table 1) to confirm 
disease stage prior to study entry. An imaging scan is not required if performed within 6 months 
of study screening. 
An imaging scan could be magnetic resonance imaging (MRI), positron emission tomography 
with or without MRI or any other imaging modality which is standard of care at the institute. 
An ultrasonography cannot be considered as a reliable method for staging. 
8.3.5 
Clinical Safety Laboratory Assessments 
• 
See Appendix 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. Assessments will be analysed by the local 
laboratory. 

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• 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
• 
Abnormal laboratory findings associated with the underlying disease, are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 168 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
• 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the aetiology should be identified, and 
the sponsor notified. 
• 
All protocol-required laboratory tests, as defined in Appendix 10.2, must be 
conducted in accordance with each local laboratory practice and the SoA 
(Section 1.3). 
• 
If laboratory values from non-protocol specified laboratory tests performed at the 
study site laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g. SAE or AE or dose modification), 
then the results must be recorded in the eCRF. 
8.3.6 
Local Tolerance 
Local tolerance will be assessed 2 hours after injection. After the single subcutaneous injection 
of the triptorelin 6-month formulation, the injection site will be examined by a physician or 
designee and assessed for characteristics such as but not limited to tenderness, redness, bruising, 
erythema, swelling, rash, pain, itching, induration, haematoma, ulceration or necrosis. If 
present, the extent of erythema, haematoma, rash, ulceration or necrosis will be described. If 
any reactions meet the definition of a treatment-emergent adverse event (TEAE), they are to be 
reported in the eCRF as such. 
8.4 
Adverse Events (AEs) and Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs and SAEs during the study (see Section 7). This includes events reported by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorised representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until EoS at the time points 
specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the case report form. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of awareness of the event, as indicated in 

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Appendix 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs/SAEs will be followed up until resolution or 
stabilisation, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 10.3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor’s policy and forwarded 
to investigators as necessary. 
8.4.5 
Pregnancy 
All participants in this study are male. Participants in this study are chemically castrated and 
partner pregnancy is not an expected event. However, the investigator must instruct all male 
participants to inform the investigator immediately should their partner become pregnant. 
• 
Details of all pregnancies in female partners of male participants will be collected from 
the signing of the ICF and until up to 9 months after the participants last dose of study 
intervention. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours via email of learning of 
the female partner of male participant becoming pregnant (after obtaining the necessary 
signed informed consent from the female partner). 
• 
While pregnancy itself is not considered to be and AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 

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• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• 
The pregnant female partner will be followed up to determine the outcome of the 
pregnancy unless consent is not given/withdrawn. The investigator will collect follow-up 
information on the participant’s pregnant female partner and the neonate and the 
information will be forwarded to the sponsor.  
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information in 
a former study participant’s pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
8.4.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.4.7 
Adverse Events of Special Interest 
 Not applicable.  
8.4.8 
Reporting of Study Intervention Errors Including Misuse/abuse 
• 
Medication errors are unintentional errors in the prescribing, storing, dispensing, 
preparing or administration of a study intervention (medicinal product) while under the 
control of a healthcare professional, participant or consumer. 
• 
Misuse refers to situations where the study intervention is intentionally and 
inappropriately used not in accordance with the protocol. 
• 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
• 
Study intervention errors and uses outside of what is foreseen in the protocol, such as 
misuse, abuse or overdose, will be recorded on  the appropriate eCRF page irrespective 
of whether associated with an AE/SAE or not, within 24 hours of investigator or qualified 
designees’ awareness.  If an AE/SAE is associated with this study intervention error, it 
should be documented in the AE/SAE section of the eCRF. Please refer to Sections 6.7 
and 10.3.1.  

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9 
STATISTICAL CONSIDERATIONS 
The SAP will be finalized prior to the first participant being enrolled and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1 
Statistical Hypotheses 
The primary objective of this study is to evaluate the efficacy triptorelin embonate 22.5 mg 
(6-month formulation) administered subcutaneously in maintaining serum testosterone castrate 
levels during the study (maintenance of castration defined as testosterone <1.735 nmol/L 
(50 ng/dL) at Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337) with two 
complete study intervention administrations. Thus, the null hypothesis to be tested is as follows: 
Null hypothesis: percentage of participants castrated (serum level of testosterone 
<1.735 nmol/L) after 12 months is less than or equal to 90%. 
Alternative hypothesis: percentage of participants castrated (serum level of testosterone 
<1.735 nmol/L) after 12 months is greater than 90%. 
9.2 
Sample Size Determination 
This single-arm study is designed to demonstrate that the percentage of participants remaining 
castrated (maintenance of castration defined as testosterone <1.735 nmol/L (50 ng/dL) at 
Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337) during the study is greater 
than 90%. Considering an observed castration maintenance in 97% of participants, 130 eligible 
participants are required to demonstrate the efficacy of the triptorelin 6-month formulation with 
approximately 90% power and a one-sided alpha of 0.025 using an exact binomial test. The 
objective will be achieved if the lower bound of the 95% confidence interval (CI) of the 
observed rate is greater than 90%. 
Considering a drop-out rate of 10%, 145 participants will be included in the study. 
9.3 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Enrolled Set 
The enrolled set will contain all participants who were enrolled to study 
treatment. A participant will be considered as enrolled if he has signed the 
informed consent form and is assigned to treatment.  
Safety Set 
The safety set will contain all participants who receive at least one dose of 
study intervention.  
Full Analysis Set 
The full analysis set analysis set will contain all participants who signed an 
informed consent form and received two administrations of study 
intervention and completed all visits for testosterone measurement (Day 29, 
Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337). Note, a 
participant will be included in the full analysis set if their testosterone 
measurement is ≥50 ng/dl before the end of treatment, end of study or 
withdrawn from study, whichever is earlier.  
Per Protocol Set 
The per protocol set will contain all participants from the full analysis set 
who did not experience any major protocol deviations that may interfere 
with efficacy evaluation. 
 
9.4 
Statistical Analyses 
The SAP will be developed prior to the first participant entering the study and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 

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section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
Other endpoints as well as demographic, baseline characteristics and disposition will be detailed 
in the SAP. 
9.4.1 
Analysis of Demographics and Other Baseline Characteristics 
Baseline and demographic information will be listed and summarised. For continuous variables, 
the summary will consist of descriptive statistics (number of participants, mean, SD, minimum, 
median, and maximum). For categorical variables, the summary will consist of number and 
percentage of subjects in each category. 
Medical history and concurrent medical conditions will be summarised by system organ class 
and preferred term. Medication history and concomitant medications will be summarised by 
preferred term. 
9.4.2 
Efficacy Analyses 
Due to the single-arm nature of the study, all statistical analyses will be descriptive with 
quantitative data summarised as mean, SD, median, quartiles, 95% CIs and range. Qualitative 
data will be summarised as frequency counts and percentages. The 95% CIs will be calculated 
following the Clopper-Pearson method. The descriptive statistics of treatment effects and 
corresponding 95% CIs for the primary endpoint and secondary endpoints will be presented. 
Missing castration level data during the study will be imputed by multiple imputation. Further 
details of the efficacy analyses will be specified in the SAP. 
9.4.3 
  Safety Analyse(s) 
Safety analyses (AEs and laboratory analyses) will be performed using the safety population. 
Adverse events will be coded using MedDRA (Version 24.1 or higher if available). Severity 
will be graded according to the National Cancer Institute (NCI)-CTCAE Version 5.0 or higher. 
All AEs will be classified by MedDRA (latest version) preferred term and system organ class.  
A TEAE is defined as any AE that occurs during the treatment period of the study if:  
• 
it was not present prior to receiving the first dose of study intervention, or  
• 
it was present prior to receiving the first dose of study intervention but the intensity 
increased during the active phase of the study. 
Summary statistics (mean, median, SD and range as appropriate) will be presented for vital 
signs, blood pressure, heart rate, ECG variables, clinical laboratory tests etc. at each assessment, 
with change from Baseline. For laboratory data, abnormal values will be flagged in the data 
listings and a list of clinically significant abnormal values will be presented. Shift tables will 
be presented for the number and percentage of participants with low, normal or high values and 
normal or abnormal examinations. 
Summary incidence tables will be provided, classified by body system, preferred term and 
associated NCI-CTCAE worst grade. Dose delays and dose interruptions will be listed by cycle. 
Summaries of events that resulted in dose modifications (e.g. delay) will also be provided. 
Haematological and biochemical toxicities will be recorded and graded according to the 
NCI-CTCAE criteria, where available. The NCI-CTCAE grade 3 and 4 haematology and 
biochemistry variables by participant and by cycle will be listed as SAEs. For white blood cells, 
neutrophils, platelets and haemoglobin, with associated grade 3 or 4 toxicities, nadir and day to 
nadir will be calculated. All AEs and SAEs must be captured in the relevant databases.  
9.5 
Interim Analyses 
No interim analyses are planned.  

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10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations such as Regulation European Union (EU) 
536/2014 
• 
The protocol, protocol amendments, ICF, Investigator Brochure and other relevant 
documents (e.g. any participant recruitment materials) must be approved by the IRB/IEC 
before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
The protocol and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
applicable 
local 
regulations, 
ICH 
guidelines 
and 
the 
IRB/IEC 
requirements/procedures. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for one year after completion of the study. 
10.1.3 
Informed Consent Process 
• 
The ICF and any participant recruitment materials must be in compliance with ICH GCP, 
local regulatory requirements, and legal requirements, including applicable privacy laws. 
They must be approved prior to use as described in Section 10.1.1. 
• 
The investigator or his/her authorised representative will explain to the potential 
participant or their legally authorised representative the nature and objectives of the study 
and possible risks and benefits associated with the participation. They will answer all 
questions regarding the study. 

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• 
Participants or their legally authorised representative, when applicable must be informed 
that their participation is voluntary.  
• 
The investigator or his/her authorised representative will obtain written informed consent 
from each participant or the legally authorised representative, when applicable, before 
any study-specific procedure is performed. The investigator will retain the original of 
each participant’s signed ICF. 
• 
A copy of the signed ICF(s) must be provided to the participant or their legally authorised 
representative. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. If changes to the ICF do not apply to all participants, this will 
be communicated to the IRB/IEC with a rationale. IRB/IEC approval must be received 
before implementation as required by local regulations. 
• 
The ICF will contain a separate section that addresses the use of all data and remaining 
material after analysis from mandatory samples for optional future research. These data 
and biosamples may only be used for future research and analysis to advance science and 
public health, including in order to: 
• 
understand and evaluate the study drug and/or other drugs  
• 
better understand the studied disease and associated health problems, 
• 
develop new drugs and find new ways to detect, treat, prevent or cure health 
problems, 
• 
plan new studies or improve scientific analysis methods, 
• 
publish research results in scientific journals or use them for educational purposes, 
• 
conduct additional statistical analysis. 
• 
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the study. A specific consent will be 
required to document a participant’s agreement to allow any data and remaining 
specimens to be used for future research. 
• 
If a pregnancy is reported for a female partner of a male participant during the study, the 
partner will be asked to sign appropriate consent for the sponsor to follow the outcome 
of the pregnancy. 
• 
A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 4 weeks, to be determined on a study-by-study basis, but in any case, 
should not be longer than 4 weeks from the previous ICF signature date. 
10.1.4 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his personal study-related data will be used by the 
sponsor in accordance with local data protection laws. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent.  

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• 
The participant must be informed that his medical records may be examined by the 
sponsor’s auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
• 
The sponsor will ensure that appropriate organisational and technical arrangements are 
implemented to comply with the applicable rules on the protection of personal data. 
• 
In the event of a potential data security breach concerning personal data processed on 
behalf of the sponsor, the data protection officer must be informed without undue delay 
and no later than 24 hours from the discovery of the event. The data protection officer 
will evaluate the event and notify the Data Protection Authorities within 72 hours, if 
required. Corrective actions and preventive actions will be implemented to mitigate the 
possible adverse effects. Affected study participants will be informed accordingly. Ipsen 
Data Protection Officer can be contacted by email: dataprivacy@ipsen.com. 
• 
When permitted by local regulation, the ICF will contain a separate section that addresses 
the remote access by the study monitors to source documents/data for the purpose of 
source data verification. A specific consent will be required to document a participant’s 
agreement. 
10.1.5 
Dissemination of Clinical Study Data 
• 
Protocol information and final study result will be made publicly available on the United 
States website (ClinicalTrials.gov) and for studies run in the EU/EEA on the EU Clinical 
Trials Register (www.clinicaltrialsregister.eu) or EU Clinical Trials Portal 
(https://euclinicaltrials.eu/home). The sponsor also provides clinical trial information to 
other 
national 
clinical 
trial 
registries 
or 
databases 
according 
to 
local 
requirements/legislation. 
• 
A lay language protocol synopsis and a summary of the study will be made available on 
the EU Clinical Trials Portal (https://euclinicaltrials.eu/home) and/or Sponsor website. 
• 
A clinical study report will be prepared if at least one participant has signed informed 
consent and received intervention, regardless of whether the study is completed or 
prematurely terminated. The clinical study report may be disclosed according to 
regulatory requirements.  
10.1.6 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded in the eCRF unless transmitted 
to the sponsor or designee electronically (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by signing the eCRF. 
• 
All entries in the eCRF will be made under the e-signature of the person performing the 
action. This electronic signature consists of an individual and confidential username and 
password combination. It is declared to be the legally binding equivalent of the handwritten 
signature. Only sponsor authorised users will have access to the eCRF as appropriate to 
their study responsibilities. Users must have successfully undergone software application 
training prior to entering data into the eCRF. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections, and provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing, and inspection 
by domestic and foreign regulatory authorities. 
• 
Monitoring details describing strategy, including definition of study critical data items 
and processes (e.g. risk-based initiatives in operations and quality such as Risk 

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Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues 
and monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g. 
Contract Research Organisations). 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
should be retained by the investigator according to the ICH-GCP guidelines, to local 
regulations, or as specified in the study agreement, whichever is longer. No records may 
be destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.7 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
Definition of what constitutes source documents/data and their location will be 
documented in a specific form. 
• 
The investigator must maintain accurate documentation that supports the information 
entered in the eCRF. Source data must be attributable, legible, contemporaneous, 
original, accurate and complete. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. When 
permitted by local regulation and guidance, study monitors will access remotely to source 
documents/data to conduct source data verification, while maintaining appropriate 
security measures and ensuring the protection of the data. This will be described in the 
monitoring plan or equivalent. 
10.1.8 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants or the actual date on which the first participant was enrolled. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.9 
Publication Policy 
• 
The sponsor seeks to publish the results of these clinical trials in biomedical journals, 
whatever the outcome. Clinical trial results may also be presented at international 
congresses as posters or oral presentations. 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator should discuss specific publication concepts, including data to 
be covered, target congress/journal and proposed authors, with the sponsor for agreement 
before initiation. The investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary information 
and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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10.2 
Appendix: Clinical Laboratory Tests 
• 
Refer to SoA Section 1.3 for details of visits. 
• 
The tests detailed in Table 5 will be performed by the local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 
Table 5 
Protocol-Required Safety Laboratory Tests 
Parameters 
Screening 
Intervention 
Period 
EoS/ED 
Haematology 
X 
 
X 
Platelet Count 
X 
 
X 
Haemoglobin 
X 
 
X 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Others 
X 
 
X 
Clinical Chemistry 
 
 
 
Creatinine 
X 
 
X 
Glucose (non-fasting) 
X 
 
X 
Aspartate Aminotransferase 
X 
 
X 
Alanine Aminotransferase 
X 
 
X 
Alkaline phosphatase 
X 
 
X 
Bilirubin (total and conjugated) 
X 
 
X 
EoS=end of study; ED=early discontinuation 
Note: All parameters will be analysed locally. The preparation and storage of samples will be performed per each local 
laboratory practice. 
 
Investigators must document their review of each laboratory safety report. 
 

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10.4 
Appendix: ECOG Performance Scale 
 

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10.5 
Appendix: Temporary Measures and Procedures Related to COVID-19 
Pandemic 
This appendix is intended to provide temporary measures to manage study assessments that 
cannot be done in compliance with the current protocol version because of the COVID-19 
pandemic.  
The implementation of the below measures must be in line with applicable country regulation 
or national temporary COVID-19 measures guidance and must remain temporary until the 
situation resolves, at which point the protocol assessments will return to those specified in the 
current approved protocol effective at that time. The temporary measures may remain in place 
for different periods of time per country/site.  
The temporary measures specified in this appendix must be reported as “protocol deviation 
related to COVID-19” and must still be documented and reported to the IEC/IRB and/or Health 
Authorities, based on the regulatory requirements applicable at your country/site, in addition to 
any deviation to the current protocol.  
Investigators will determine the appropriateness of starting or continuing study intervention on 
a participant-by-participant basis, depending on the ability to conduct safety monitoring and 
provide sites with an adequate supply of study intervention, in accordance with local 
requirements.   
The following guidelines were adapted using suggestions from the TransCelerate publication 
“Beyond 
COVID-19: 
Modernizing 
Clinical 
Trial 
Conduct” 
published 
by TransCelerate Biopharma Inc. July 2020, which was influenced by Food and Drug 
Administration (FDA) and EMA guidance issued for conduct and management of clinical 
studies during the COVID-19 pandemic. 
10.5.1 
Specific Guidance for Study Visits and Assessments 
10.5.1.1 Study Schedule 
If the COVID-19 pandemic prevents participants from coming to the site, apart from the 
mandatory site visits for screening assessments and for days of study intervention 
administrations (Days 1 and 169) as per the protocol (Section 1.3), participants can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor (or sponsor delegate) before being implemented. In such a case, 
the investigator will perform a telemedicine visit and will make every effort to collect all 
important medical information and safety event(s) occurring since the last visit. Guidance on 
how to collect protocol-planned assessments is provided below. 
10.5.1.2 Screening and Enrolment 
Participants can be rescreened within 4 weeks according to the protocol (Section 10.1.3). 
However, if a participant tests positive for COVID-19 during the screening period, this should 
be escalated to the sponsor (or sponsor delegate). In exceptional circumstances, where a 
participant starts screening procedures, which are then delayed due to COVID-19 (for example 
testing positive for COVID-19), the participant might continue with the screening assessments 
after a negative COVID-19 test is confirmed and all eligibility criteria are met prior to 
enrolment, even if this is outside the normal 28-day screening window, after discussion with 
the sponsor. 
10.5.1.3 Informed Consent (including Re-consent) 
As per guidelines issued by the FDA in the United States and in line with guidance in other 
countries, the use of electronic signatures is authorised to obtain the participant’s or legal 
guardian’s informed consent. In such a case, the IRB need to be notified of the use of electronic 

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informed consent signature and the accepted electronic formats need to be clearly documented. 
This is not meant to replace the important discussion between the participant, legal guardian, 
investigator and site staff. Such a discussion must still occur and be part of a screening visit 
(in-person, by telemedicine, or home health visit). A clearly documented process on how 
participants are contacted virtually to explain the study and close monitoring needs to be in 
place.  
Screening visit and assessments (apart from informed consent as described above) must be 
performed on site. 
10.5.1.4 Dosing Visits 
In case of dosing visits delayed due to COVID-19 (e.g. temporary closure of the site, 
participant unable to travel, etc.) 
• 
Dosing visits may be delayed due to COVID-19. These delays are not permitted by the 
protocol. Any potential delay of dosing must be escalated to the sponsor and discussed 
between the investigator and the sponsor. 
In case of suspected COVID-19 infection 
• 
The administration of study intervention may be temporarily discontinued depending on 
the participant’s clinical presentation. In some cases, the investigator may request a 
participant be retested before the administration of study intervention is resumed. 
• 
In all cases, the investigator must ensure that the participant receives appropriate medical 
follow-up. It will be in the investigator’s medical judgement to assess the benefits and 
risks before restarting study intervention. If a participant has temporarily interrupted 
study intervention, the decision to restart participants on study intervention will be 
managed on an individual case basis in discussion with the sponsor (or sponsor delegate) 
and investigator. 
In case of confirmed COVID-19 infection 
• 
Participants who present with COVID-19 positive-confirmed infection should be placed 
on immediate study intervention delay as per institutional guidelines [Curigliano 2020]. 
Any suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection should be 
considered serious and be immediately reported to the sponsor. 
• 
Since there is lack of data on risk/benefit analysis of the study intervention and 
COVID-19 infection, in the absence of a confirmatory negative COVID-19 PCR test in 
an asymptomatic participant, it is in the investigator’s medical judgement to assess the 
benefit and risks of restarting study intervention. The management of participants 
following temporary interruption of the study intervention and decision to restart 
participants on study intervention will be managed on an individual participant basis in 
discussion with the sponsor and investigator. 
10.5.1.5 Testosterone Assessments 
Study home nursing is encouraged to ensure the collection of the testosterone samples. These 
samples will be then sent to the Central Laboratory as planned. Where a study home nursing 
solution is possible, vital signs will be collected at the same time as testosterone sample 
collection. 
10.5.1.6 Concomitant Medications and Procedures 
Details can be collected by site staff via telephone call as per the rules relating to use of 
telemedicine below. COVID-19 vaccines and or medication shall be reported as concomitant 
medication. 

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10.5.1.7 Adverse Event Reporting 
All COVID-19 cases (suspected or confirmed) should be seriousness assessed based on the 
reported seriousness criteria. If no seriousness criteria is reported by the investigator, the 
COVID-19 event/case will be collected and recorded as nonserious.  
Details can be collected by site staff via telephone call as per the rules relating to use of 
telemedicine in the protocol (Appendix 10.5.2). 
10.5.2 
Specific Rules Relating to Use of Telemedicine 
The form of telemedicine used (phone call or use of a platform), the legal and privacy protection 
of the participant, as well as details of the verification of the identity of the participant and site 
personnel conducting the assessment should be documented at site level and should be available 
for review by the monitor.  
10.5.3 
Guidance on COVID-19 Vaccine and/or Medications 
Currently available COVID-19 vaccines for age appropriate participants do not contain a live 
virus, therefore, they are permitted during the study. Future approved COVID-19 vaccines will 
be assessed by the sponsor.   
Participants may receive COVID-19 vaccinations if they have no contraindications to any 
component of the specific vaccine. However, they should be counselled by the investigator 
about benefit/risk of getting the vaccination based on their individual health conditions, as well 
as with the healthcare physician administrating the vaccination, about the unknown vaccine 
safety profile and effectiveness in immunocompromised populations, as well as the potential 
for insufficient immune responses, and the need to continue to follow all current guidance to 
protect themselves against COVID-19.  
The co-administration of the COVID-19 vaccines with the study intervention has not been 
studied. Based on the lack of evidence, the following recent guidance for cancer patients 
participating in oncology studies is recommended [Desai 2021]: 
• 
It is recommended to avoid administration of study intervention within 48 to 72 hours of 
vaccination to minimise confusion and/or inaccurate attribution of AE causation. 
• 
Investigator discretion is necessary to ascertain the benefit/risk to taking the vaccine 
while taking into consideration of the participant’s clinical condition. COVID-19 
vaccines and/or medications shall be reported as concomitant medication. 

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Section 
WAS (Version 1.0, 
16 MARCH 2022) 
IS (Version 2.0, 
13 SEPTEMBER 2022) 
Rationale 
on intercurrent events will be 
imputed by multiple imputation. 
Further details of the estimand 
will be specified in the statistical 
analysis plan (SAP). 
study, which is defined as 
percentage of participants 
castrated (testosterone 
<1.735 nmol/L (50 ng/dL)) 
at Day 29, Day 85, Day 141, 
Day 169, Day 253, Day 309 
and Day 337, with two 
complete study 
intervention 
administrations. 
Secondary estimands 
include analyses without 
using the visit window 
and/or using the ITT 
population where missing 
data will be considered a 
non-responder maybe 
conducted. The reasons for 
participant withdrawal from 
the study will be separate 
intercurrent events. 
Employing a hypothetical 
strategy, missing data 
dependent on intercurrent 
events will be imputed by 
multiple imputation. Further 
details of the estimand will 
be specified in the statistical 
analysis plan (SAP). 
Synopsis / 
Overall Design 
Approximately 153 adult male 
participants will be enrolled in the 
study. 
Approximately 145 adult 
male participants will be 
enrolled in the study. 
Planned 
participants 
adjusted to 
account for 
decrease in 
drop out rate 
from 15% to 
10%. 
Synopsis / 
Number of 
Participants 
Approximately 153 participants 
are planned to be assigned to 
study intervention. 
Approximately 145 
participants are planned to 
be assigned to study 
intervention. 
Planned 
participants 
adjusted to 
account for 
decrease in 
drop out rate 
from 15% to 
10%. 

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Section 
WAS (Version 1.0, 
16 MARCH 2022) 
IS (Version 2.0, 
13 SEPTEMBER 2022) 
Rationale 
Synopsis / 
Statistical 
Methods 
(Sample Size 
Determination) 
Considering a drop-out rate of 
15%, 153 participants will be 
included in the study. 
Considering a drop-out rate 
of 10%, 145 participants 
will be included in the 
study. 
Drop-out rate 
reduced, and 
planned 
participants 
adjusted to 
account for 
decrease in 
drop-out rate. 
4.1 / Overall 
Design 
Approximately 153 participants 
will be assigned to triptorelin 
embonate 22.5 mg (6-month 
formulation) to be administered 
on Day 1 and Day 169. 
Approximately 145 
participants will be assigned 
to triptorelin embonate 22.5 
mg (6-month formulation) 
to be administered on Day 1 
and Day 169. 
Planned 
participants 
adjusted to 
account for 
decrease in 
drop-out rate 
from 15% to 
10%. 
4.2 / Scientific 
Rationale for 
Study Design 
The non-comparative, open-label 
clinical study design is acceptable 
as the primary efficacy endpoint 
will assess testosterone levels by 
the percentage of participants 
maintaining castrate levels of 
serum testosterone (defined as 
<1.735 nmol/L (50 ng/dL)) during 
the study (primary endpoint, as 
outlined in Table 3). 
The non-comparative, open-
label clinical study design is 
acceptable as the primary 
endpoint will assess 
testosterone levels by the 
percentage of participants 
maintaining castrate levels 
of serum testosterone 
(defined as <1.735 nmol/L 
(50 ng/dL)) during the study 
(primary endpoint, as 
outlined in Table 3). 
Amended for 
consistency 
with changes 
made in 
Section 3. 
4.4 / End of 
Study 
Definition 
The overall duration of the study 
(from first participant in, to last 
participant out) will be 
approximately 52 weeks. The 
study will be considered to have 
ended after the last participant has 
completed the last visit (on Day 
337 (Week 48)) in the study. 
 
 
 
Removed to 
provide 
better clarity, 
as text did 
not clearly 
describe the 
end of study 
definition, 
but 
individual 
participation. 
5.2 / Exclusion 
Criteria 
Use of any other therapy for 
prostate cancer during the study 
(e.g. chemotherapy) 
At the time of screening, 
planned use of any 
chemotherapy for prostate 
cancer during the study 
Modified to 
avoid 
exclusion of 
eligible 
participants. 

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
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Section 
WAS (Version 1.0, 
16 MARCH 2022) 
IS (Version 2.0, 
13 SEPTEMBER 2022) 
Rationale 
6.8 / 
Concomitant 
Therapy 
•Finasteride or dutasteride 
•Medications which are known to 
affect the metabolism and/or 
secretion of androgenic hormones: 
ketoconazole, aminoglutethimide, 
oestrogens. 
•Systemic or inhaled 
corticosteroids (topical application 
permitted). 
•Cytotoxic chemotherapy or 
abiraterone 
•Finasteride or dutasteride 
•Abiraterone 
•Medications which are 
known to affect the 
metabolism and/or secretion 
of androgenic hormones: 
ketoconazole, 
aminoglutethimide, 
oestrogens. 
•Systemic or inhaled 
corticosteroids (topical 
application permitted). 
Modified to 
avoid 
exclusion of 
eligible 
participants. 
7.2 / 
Participant 
Discontinuatio
n / Withdrawal 
from the Study 
 
• A participant will be 
withdrawn from the study 
if they have inadequate 
testosterone suppression 
(defined as >50 ng/dL 
detected at least 30 days 
after the first 
administration of study 
intervention and on two 
consecutive measurements 
at least 2 weeks apart, at 
either a scheduled or 
unscheduled study visit). 
Clarification 
added to 
provide 
guidance for 
participants 
who have 
lack of 
efficacy 
during the 
study. 
8 / Study 
Assessments 
and Procedures 
The maximum amount of blood 
collected from each participant 
over the duration of the study, 
including any extra assessments 
that may be required, will not 
exceed 65 mL. 
The maximum amount of 
blood for study purposes 
collected from each 
participant over the duration 
of the study will not exceed 
153 mL. 
Blood 
volume to be 
collected 
over the 
whole 
duration of 
the study 
increased to 
accommodat
e 
requirements 
needed for 
testing at the 
central 
laboratory. 

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
PAGE 64/66 
 
 
Section 
WAS (Version 1.0, 
16 MARCH 2022) 
IS (Version 2.0, 
13 SEPTEMBER 2022) 
Rationale 
8.2 / Efficacy 
Assessments 
Approximately 60 mL of blood 
will be collected from all 
participants for measurement of 
testosterone and PSA. 
Approximately 148 mL of 
blood will be collected from 
all participants for 
measurement of testosterone 
and PSA. 
Blood 
volume to be 
collected 
over the 
whole 
duration of 
the study 
increased to 
accommodat
e 
requirements 
needed for 
testing at the 
central 
laboratory. 
9.1 / Statistical 
Hypothesis 
The primary objective of this 
study is to evaluate the efficacy 
triptorelin embonate 22.5 mg 
(6-month formulation) 
administered subcutaneously in 
maintaining serum testosterone 
castrate levels. 
The primary objective of 
this study is to evaluate the 
efficacy triptorelin 
embonate 22.5 mg (6-month 
formulation) administered 
subcutaneously in 
maintaining serum 
testosterone castrate levels 
during the study 
(maintenance of castration 
defined as testosterone 
<1.735 nmol/L (50 ng/dL) 
at Day 29, Day 85, Day 
141, Day 169, Day 253, 
Day 309 and Day 337) with 
two complete study 
intervention 
administrations. 
Modified to 
provide 
clarification 
of the 
primary 
endpoint. 
9.2 / Sample 
Size 
Determination 
Considering a drop-out rate of 
15%, 153 participants will be 
included in the study. 
Considering a drop-out rate 
of 10%, 145 participants 
will be included in the 
study. 
Planned 
participants 
adjusted to 
account for 
decrease in 
drop-out rate 
from 15% to 
10%. 

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
PAGE 65/66 
 
 
Section 
WAS (Version 1.0, 
16 MARCH 2022) 
IS (Version 2.0, 
13 SEPTEMBER 2022) 
Rationale 
9.3 / Analysis 
Sets  
Full 
Analysis 
Set 
The full analysis set 
analysis set will 
contain all 
participants who 
signed an informed 
consent form and 
receive at least one 
administration of 
study intervention 
and have a serum 
testosterone level 
<1.735 nmol/L (50 
ng/dL) on Day 1 
(pre dose 
measurement).  
 
Full 
Analysi
s Set 
The full 
analysis set 
analysis set 
will contain all 
participants 
who signed an 
informed 
consent form 
and received 
two 
administration
s of study 
intervention 
and completed 
all visits for 
testosterone 
measurement 
(Day 29, 
Day 85, Day 
141, Day 169, 
Day 253, Day 
309 and 
Day 337). 
Note, a 
participant 
will be 
included in 
the full 
analysis set if 
their 
testosterone 
measurement 
is ≥50 ng/dl 
before the 
end of 
treatment, 
end of study  
or withdrawn 
from study, 
whichever is 
earlier.  
Clarification 
of full 
analysis set 
definition. 
 

IPSEN GROUP 
D-FR-52014-245 
CONFIDENTIAL 
PROTOCOL: FINAL: Version 3.0 with Amendment 2, 04 December 2023 
PAGE 66/66 
 
 
11 
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