Clinical trial NCT05458856
Conditions: Prostate Cancer
Sponsor: Ipsen
Start date: 2022-08-30; Completion date: 2024-07-08
Enrollment: 147 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of the study is to determine if triptorelin formulated for use every 6 months (given twice during the study) is effective and safe for when given by injection under the skin for the treatment of adult males with cancer in the prostate.

Detailed description:

Arms: arm 1: All participants will receive triptorelin embonate 22.5 mg
Interventions: intervention 1: Triptorelin embonate 22.5 mg
Intervention descriptions: intervention 1: A prolonged release formulation of triptorelin pamoate 22.5 mg 6-month formulation in D, L-lactide-co-glycolide polymers for single subcutaneous injection on Day 1 and Day 169

Protocol documents:
Prot_000.pdf: 
 
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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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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PAGE 3/66 
 
 
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 
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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


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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


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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. 


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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. 


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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%. 


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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. 
 


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11 
REFERENCES 
Barron JL, Millar RP, Searle D. Metabolic clearance and plasma half-disappearance time of 
DTrp6 and exogenous luteinizing hormone-releasing hormone. J Clin Endocrinol Metab 1982; 
54:1169-73. 
Bithell TC. Thrombosis and anti-thrombotic therapy. In. Wintrobe’s clinical hematology. 9th 
edition. Philadelphia, PA: Lea & Febiger: 1993. 
Botto H, Richard F, Mathieu F et al. Decapeptyl in the treatment of metastatic prostatic cancer. 
Comparative study with pulpectomy. Prog Biol Res 1987; 243A:199-206. 
Breul J, Lundstrom E, Purcea D et al. Efficacy of testosterone suppression with 
sustained-release triptorelin in advanced prostate cancer. Adv Ther 2017;34:513-23. 
Curigliano G, Banerjee S, Cervantes A et al. Managing cancer patients during the COVID-19 
pandemic: an ESMO multidisciplinary expert consensus. Ann Oncol 2020;31(10):1320-35. 
Desai A, Gainor JF, Hegde A et al. COVID-19 vaccine guidance for patients with cancer 
participating in oncology clinical trials. Nat Rev Clin Oncol 2021;18(5):313-19. 
De Sy WA, De Wilde P, De Meyer JM et al. Long term experience in the treatment of advanced 
prostatic cancer with Decapeptyl, compared to orchiectomy. Acta Urol Belgica 1988;56:581-8. 
Filicori M: Gonadotropin-Releasing Hormone Agonists - A guide to use and selection. Drugs 
1994;48:41-58. 
Huggins C, Hodges CV. Studies on prostatic cancer I. The effects of castration, of oestrogen, 
and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. 
J Urol 2002;167:948-51. 
Huggins C, Stevens REJr, Hodges CV. Studies on prostate cancer II. The effects of castration 
on advanced carcinoma of the prostate gland. Arch Surg 1941; 43:209-23. 
Lebret T, Rouanne M, Hublarov O et al. Efficacy of triptorelin pamoate 11.25 mg administered 
subcutaneously for achieving medical castration levels of testosterone in patients with locally 
advanced or metastatic prostate cancer. Ther Adv Urol 2015;7:125-34. 
Lundstrom EA, Rencken RK, van Wyk JH et al. Triptorelin 6-month formulation in the 
management of patients with locally advanced and metastatic prostate cancer: an open-label, 
non-comparative, multicentre, phase III study. Clin Drug Investig 2009; 29:757-65. 
Mottet N, Cornford P, van den Bergh RCN, et al. European Association of Urology. Prostate 
Cancer. 2021. https://uroweb.org/guideline/prostate-cancer/. 
Parmar H, Edwards L, Phillips RH, et al. Orchiectomy versus long-acting D-Trp-6-LHRH in 
advanced prostatic cancer. Br J Urol 1987;59:248-54.  
Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 
2021;71:209-49. 







SAP_001.pdf: 
D oc u me nt Na me: dfr 5 2 0 1 4 2 4 5 1 6. 1. 9 statistical a nal ysis pla n 2 0 2 3 0 1 3 0
A p pr o ve d
Cli nical
0 6- Fe b- 2 0 2 3 1 3: 4 6: 0 6 G M T + 0 0 0 0
Cli nical
0 6- Fe b- 2 0 2 3 1 7: 5 3: 5 2 G M T + 0 0 0 0
Cli nical
0 9- Fe b- 2 0 2 3 1 3: 3 3: 4 9 G M T + 0 0 0 0
P P D
P P D
P P D


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STATISTICAL ANALYSIS PLAN 
 
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 
D-FR-52014-245 
 
This statistical analysis plan is based on: 
PROTOCOL VERSION AND DATE: VERSION 2.0 – 13 SEPTEMBER 2022 
 
SAP Version 
Date 
Final Version 1.0 
30 January 2023 
 




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TABLE OF CONTENTS 
 
APPROVAL PAGE .................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 5 
1 
INTRODUCTION .......................................................................................................... 7 
2 
PROTOCOL OVERVIEW ............................................................................................ 8 
2.1 
Study Objectives and Hypotheses ................................................................................. 8 
2.2 
Overall Study Design and Investigational Plan ........................................................... 9 
2.3 
Sample Size Determination and Power ....................................................................... 10 
2.4 
Randomisation and Blinding ....................................................................................... 10 
2.5 
Schedule of Assessments ............................................................................................... 10 
2.6 
Change from Statistical Section of the Protocol ........................................................ 10 
3 
PLANNED ANALYSES ............................................................................................... 11 
3.1 
Data Monitoring ............................................................................................................ 11 
3.2 
Interim Analysis / Primary Analysis ........................................................................... 11 
3.3 
Final Analysis ................................................................................................................ 11 
4 
ANALYSIS SETS ......................................................................................................... 12 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 13 
5.1 
General Considerations ................................................................................................ 13 
5.1.1 
Outputs Presentation ................................................................................... 13 
5.1.1.1 
Presentation of Visits / Timepoints .............................................................. 13 
5.1.2 
Descriptive Statistics ................................................................................... 13 
5.1.3 
Baseline Value ............................................................................................. 14 
5.1.4 
Reference Start Date and Study Day .......................................................... 14 
5.2 
Enrolment, Disposition and Analysis Sets .................................................................. 14 
5.3 
Protocol Deviations ....................................................................................................... 14 
5.4 
Demography and Other Baseline Characteristics ..................................................... 15 
5.5 
Medical History, Non-Drug Therapies, Medications and Surgical Procedures ..... 15 
5.6 
Compliance .................................................................................................................... 16 
5.7 
Efficacy .......................................................................................................................... 16 
5.7.1 
General Considerations .............................................................................. 16 
5.7.1.1 
Significance Testing and Estimations .......................................................... 16 
5.7.1.2 
Handling of Dropouts and Missing Data ..................................................... 17 
5.7.1.3 
Statistical/Analytical Issues ......................................................................... 17 
5.7.2 
Analysis of Primary Efficacy Endpoint ...................................................... 17 
5.7.2.1 
Primary Efficacy Endpoint, Treatment Effect and Estimand Definition ..... 17 
5.7.2.2 
Primary Analysis .......................................................................................... 18 
5.7.2.3 
Sensitivity Analysis ....................................................................................... 18 


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5.7.2.4 
Supplementary Analysis ............................................................................... 19 
5.7.2.5 
Subgroup Analysis ....................................................................................... 19 
5.7.3 
Analysis of Key Secondary Efficacy Endpoints ......................................... 20 
5.7.3.1 
Secondary Efficacy Endpoints ..................................................................... 20 
5.7.3.2 
Main Secondary Analysis ............................................................................. 20 
5.7.3.3 
Subgroup Analysis ....................................................................................... 20 
5.7.3.4 
Sensitivity Analysis ....................................................................................... 20 
5.7.4 
Analysis of Other Secondary Efficacy Endpoints ...................................... 20 
5.7.5 
Analysis of Exploratory Endpoints ............................................................. 20 
5.8 
Safety .............................................................................................................................. 20 
5.8.1 
General Consideration ................................................................................ 20 
5.8.2 
Extent of Exposure ...................................................................................... 21 
5.8.3 
Adverse Event .............................................................................................. 21 
5.8.4 
Laboratory Data .......................................................................................... 22 
5.8.5 
Vital Signs ................................................................................................... 23 
5.8.6 
Electrocardiogram ...................................................................................... 23 
5.8.7 
Physical Examination ................................................................................. 24 
6 
DATA HANDLING ...................................................................................................... 25 
6.1 
Visit window .................................................................................................................. 25 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit, ........................................................... 25 
7 
DERIVED DATA .......................................................................................................... 26 
8 
CHANGES FROM PROTOCOL ................................................................................ 29 
9 
REFERENCES .............................................................................................................. 30 
10 
APPENDICES ............................................................................................................... 31 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Class 
BMI 
Body Mass Index 
C 
Concomitant  
CHMP 
Committee for Medicinal Products for Human Use  
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ED 
Early discontinuation 
EMA 
European Medicines Agency 
EoS 
End of study 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing hormone 
ICE 
Intercurrent Event 
ICH 
International Council for Harmonisation  
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTC 
National Cancer Institute – Common Toxicity Criteria 
P 
Prior 


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ABBREVIATION 
Wording Definition 
PC  
Prior and Concomitant  
PCSA 
Potentially Clinically Significant Abnormalities 
PK 
Pharmacokinetic 
PN 
Preferred Name 
PP 
Per Protocol 
PR 
Time interval from the start of atrial depolarization to start of 
ventricular depolarization  
PSA 
Prostate-Specific Antigen 
PT 
Preferred Term 
QRS 
Time interval for ventricular depolarization 
QT 
Time interval for ventricular depolarisation and repolarisation 
QTcF 
Corrected QT interval by Fredericia 
RR 
Time between QRS complexes 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TNM 
TNM Classification of Malignant Tumors 
 


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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned analyses to be 
completed to support the completion of the Clinical Study Report (CSR) for protocol D-FR-
52014-245. It describes the rules and conventions to be used in the analysis and presentation of 
data, the data to be summarised and analysed, including specificities of the statistical analyses 
to be performed.  
Exploratory analyses not necessarily included in this SAP may be performed to support the 
clinical development program. Any post-hoc, or unplanned, analyses not included in this SAP 
will be clearly identified in the respective CSR. 
The SAP was planned to be finalised prior to the first participant being enrolled, and the 
finalization was delayed to accommodate protocol amendment. A separate shell will be 
provided for tables, figures and listings (TFLs).  
Any deviations from the SAP will be documented in the CSR (section 9.8 “Changes in the 
conduct of the study or planned analyses” as per International Council for Harmonisation (ICH) 
E3).  
This SAP does not cover pharmacokinetics (PK) analysis which will be described in a separate 
document, if PK analysis is required. 




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Objectives 
Endpoints 
• 
To demonstrate the safety profile of 
triptorelin embonate 22.5mg 6-month 
formulation administered subcutaneously 
• 
Incidence of TEAEs (including local 
tolerability) throughout the study i.e. up to 
Day 337 
• 
Change from baseline in clinical safety 
laboratory parameters (blood chemistry and 
haematology) at Day 337 
• 
Change from baseline in physical 
examination at Day 169 and Day 337 
• 
Change from baseline in ECG at Day 337 
• 
Change from baseline in vital signs (blood 
pressure and heart rate) at each visit up to 
Day 337 
AE=adverse event; ECG=electrocardiogram; PSA=prostate-specific antigen; TEAE=treatment-emergent adverse event 
Note: A list of laboratory parameters to be assessed during the study are presented in Protocol Appendix 10.2. 
 
• 
Hypotheses 
Hypotheses for this study are defined below. 
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) from date of first dose to Day 337 is less than or equal to 90%. 
Alternative hypothesis: percentage of participants castrated (serum level of testosterone 
<1.735 nmol/L) from date of first dose to Day 337 is greater than 90%. 
2.2 
Overall Study Design and Investigational Plan 
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. 


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The study design is illustrated 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. 
2.3 
Sample Size Determination and Power 
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. 
2.4 
Randomisation and Blinding 
This is a non-randomised, open-label study. Therefore, no procedure for blinding is applicable. 
2.5 
Schedule of Assessments 
Schedule of assessments is presented in section 1.3 from the protocol. 
2.6 
Change from Statistical Section of the Protocol 
There is no change from the statistical section of the protocol. 


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3 
PLANNED ANALYSES 
3.1 
Data Monitoring  
No independent Data Monitoring Committee will be used in this study. 
3.2 
Interim Analysis / Primary Analysis 
No interim analysis will be performed. 
3.3 
Final Analysis 
Planned analyses will be done when all participants complete study and after database lock. 


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4 
ANALYSIS SETS 
Screened Set 
The screened set will contain all participants who signed an informed consent for this study. 
In case of re-screening, the participant will be counted once only in the screened set. The 
previous site and assigned subject numbers will be collected to link the first and second 
screening data. 
 
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. 
 
Intent-to-Treat Set 
The intent-to-treat (ITT) Set will contain all participants who signed an informed consent form 
and received 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 Analysis Set  
The full analysis set (FAS) 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 FAS if his 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 (PP) set will contain all participants from the FAS who did not experience any 
major protocol deviations that may interfere with efficacy evaluation (refer to section 5.3 for 
details regarding the management of deviations). 
 
Safety Set 
The safety set will contain all participants who receive at least one dose of study intervention.  


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5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed in accordance with ICH E9 guideline and guidelines 
presented in section 9. 
5.1 
General Considerations 
All tables, listings and figures will be produced, and statistical analysis performed using the 
Statistical Analysis System® software version 9.4 or a later version. 
5.1.1 
Outputs Presentation 
5.1.1.1 
Presentation of Visits / Timepoints 
For by-visit summaries, the nominal visit as collected in the Electronic Case Report Form 
(eCRF) will be used in general for analysis purpose unless stated otherwise. Analysis visit 
window described in Section 6.1 will be used for slotting actual testosterone and prostate-
specific antigen (PSA) assessment dates into planned schedule. Unscheduled visits will not be 
displayed in summaries but will be listed.  
Visits in the TFLs will be presented as follows and in the following order: 
Period 
Long Visit Name  
Short Name 
Protocol Time 
Interval 
Screening 
Day -28 to Day – 1 
(Screening) 
Scr 
 
Intervention 
Period 
Day 1 (Baseline) 
Bsl 
 
Week 1 – Day 3 
D3 
Day 3 after first 
injection 
Week 1 – Day 7 
D7 
Day 7 after first 
injection 
Week 4 – Day 29 
D29 
±3 day 
Week 12 – Day 85 
D85 
±3 day 
Week 20 – Day 141 
D141 
±3 day 
Week 24 – Day 169 
D169 
±3 day 
Week 25 – Day 171 
D171 
Day 3 after last 
injection 
Week 25 – Day 175 
D175 
Day 7 after last 
injection 
Week 36 – Day 253 
D253 
±3 day 
Week 44 – Day 309 
D309 
±3 day 
EoS/ED 
Week 48 – Day 337 
D337 
±3 day 
5.1.2 
Descriptive Statistics 
Due to the single-arm nature of the study, all statistical analyses will be descriptive. All raw 
and derived variables will be listed and described using summary statistics. For categorical 
variables, summary statistics will be displayed using descriptive statistics by frequency count 
and percentages by category. The missing category will be presented if applicable. Unless 
otherwise specified, participants with missing data will be included in the calculation of 
percentages. For quantitative variables, summary statistics will be displayed using descriptive 
statistics by number of observations, mean, standard deviation (SD), first quartile, median, third 
quartile, minimum and maximum. Frequency and proportion of missing data will be displayed.  


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For the efficacy analyses, the descriptive statistics of treatment effects and corresponding 95% 
CIs for the primary endpoint and secondary endpoints will be presented if applicable.  
5.1.3 
Baseline Value 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to first Investigational Medicinal Product (IMP) administration (including unscheduled 
assessments).  
5.1.4 
Reference Start Date and Study Day 
Reference start date is defined as the day of the first IMP administration.  
The day of the first IMP administration will be Day 1. Study day will be calculated as: 
• 
The difference between the event date and the reference date plus one day, if the event is 
on or after the reference date. 
• 
The difference between the event date and the reference date, if the date of event is prior 
to the reference date.  
Study day will appear in any listings where an assessment date or event date appears. 
In case of partial or missing event date, study day will appear missing while any associated 
durations will be presented based on the imputations described in Appendix 2. 
5.2 
Enrolment, Disposition and Analysis Sets 
A Listing presenting study treatment dispensation details will be provided (Listing 16.1.7). 
Following disposition summaries will be provided: 
• 
Summary table with the number and percentage of participants screened, screen failed, 
reason for screen failures, enrolled, treated, having completed the study, withdrawn and 
reason for withdrawal, 
• 
Summary table with the number and percentage of participants enrolled per visit, 
• 
Summary table with the number and percentages of participants screened and enrolled 
per country and site, 
• 
Summary table on duration of subject participation in the study,  
• 
Summary of the number and percentage of participants in each analysis set based on all 
screened participants with reasons for exclusion from each analysis set (see section 5.3 
about the Protocol deviations leading to the subject exclusion from the PP set). 
 
Following listings will be provided: 
• 
Listing of participant disposition including screen failure participants, and withdrawal 
participants, 
• 
Listing of dates of visit including duration of subject participation for the enrolled 
participants, 
• 
Listing including flag for each analysis set and reason for exclusion from each set. 
5.3 
Protocol Deviations 
An exhaustive list of major protocol deviations that may occur during the course of the study 
and any action to be taken regarding exclusion of participants from the PP set is defined in 


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Protocol Deviation Specifications. The protocol deviations related to Coronavirus Disease 2019 
(COVID-19) will also be considered. The list of protocol deviations impacting the PP set will 
be reviewed prior to database lock. The list may be updated, up to the point of database lock, 
to include any additional major protocol deviations impacting inclusion in the PP set.  
Following protocol deviation summary and listing will be provided on the enrolled set: 
• 
Number and percentage of participants with major protocol deviations by deviation 
category (see DV section of Standard Study Data Tabulation Model (SDTM) user guide).  
• 
A listing of all major protocol deviations.  
5.4 
Demography and Other Baseline Characteristics 
Baseline and demographic information (age, ethnicity, race, height, weight at baseline, body 
mass index [BMI] at baseline, Eastern Cooperative Oncology Group [ECOG] at screening) 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 participants in each category. 
All demographic and baseline characteristics summaries and listings will be provided for the 
SAF set. No statistical comparison will be performed. 
Following summaries will be provided on: 
• 
Demographic variables (refer to Appendix 5 for European Union Drug Regulating 
Authorities Clinical Trials Database [EudraCT] age categories), 
• 
Prostate cancer history and disease characteristics (time from histological diagnosis to 
screening, TNM Classification of Malignant Tumors [TNM] Stage, PSA and 
Testosterone from central lab at Baseline). 
Listings will also be provided for all the summaries listed above.  
5.5 
Medical History, Non-Drug Therapies, Medications and Surgical Procedures 
Medical and surgical history, non-drug therapies and surgical procedures will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). Medications will be coded using 
World Health Organization-Drug dictionary. 
Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration to allow classification as either Prior only, Prior and 
Concomitant, or Concomitant only: 
 
Prior (P) 
Start and stop dates prior to the date of the first IMP administration. 
Prior and 
Concomitant (PC) 
Start date before the date of the first IMP administration and stop 
date on or after the date of the first IMP administration. 
Concomitant (C) 
Start date on or after the date of first IMP administration. 
 
Summary tables on prior medications/non-drug therapies/surgical procedures will include “P” 
and “PC”, and summary tables on concomitant medications/non-drug therapies/surgical 
procedures will include “C” and “PC”. 
 
Rules for classification of prior and concomitant medication/non-drug therapies, surgical 
procedures in case of partial/missing date are detailed in Appendix 2. 


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Medical history and concurrent medical conditions will be summarised by system organ class 
(SOC) and preferred term (PT). Medication history and concomitant medications will be 
summarised by Anatomical Therapeutic Class (ATC) code and preferred name (PN). The 
therapeutic class will correspond to the second level of ATC code, that is, corresponding to the 
first three figures. 
 
Following summaries, presenting count and percentages of participants will be provided on the 
enrolled set: 
• 
Medical and surgical history by SOC and PT, 
• 
Prior medications for the studied disease by ATC class and PN (ATC level 2), 
• 
Prior radiotherapies for cancer by primary SOC and PT, 
• 
Prior surgical procedures for the studied disease by primary SOC and PT, 
• 
Concomitant surgical procedures by primary SOC and PT, 
• 
Prior medications by ATC class and PN (ATC level 2), 
• 
Concomitant medications by ATC class and PN (ATC level 2), 
• 
Prior non-drug therapies by primary SOC and PT, 
• 
Concomitant non-drug therapies by primary SOC and PT. 
 
Listings will be provided for prior and concomitant medication/non-drug therapies, and surgical 
procedures. These listings should include a flag indicating the category (P, PC, C) as described 
in the table above.  
5.6 
Compliance 
The compliance will be calculated as defined in section 7. 
Following summary and listing will be provided on the safety set: 
• 
Descriptive statistics of compliance including number of percentage of participants by 
compliance category (<50%, 50 - <70%, 70 -<90%, 90-100%), 
• 
A listing of treatment compliance.  
5.7 
Efficacy  
5.7.1 
General Considerations 
The FAS set will be used for efficacy analyses unless explicitly stated differently. 
 
A listing of all efficacy data (raw and derived) will be provided (see listing detail conventions 
in Appendix 4).  
5.7.1.1 
Significance Testing and Estimations 
The statistical analysis of efficacy is only descriptive therefore no formal statistical significance 
testing will be performed. 


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5.7.1.2 
Handling of Dropouts and Missing Data  
Completely missing data are generally not imputed. Partial missing start and end dates will be 
imputed for medication category and treatment-emergent adverse event (TEAE) 
determinations. Details are provided in the Appendix 2. 
5.7.1.3 
Statistical/Analytical Issues  
Adjustments for Covariates  
Covariates adjustment is not applicable to this study.  
 
Interim Analyses and Data Monitoring 
See section 3. 
 
Multicentre Studies 
This is a multicentre study conducted in seven countries (Belgium, Czech Republic, France, 
Germany, Lithuania, Netherlands, Spain). Due to the limited sample size, this is an open-label 
study, no adjustment for centre effects is planned for this study.   
 
Multiple Comparisons/Multiplicity  
No formal testing will be performed in this study and multiplicity adjustment is not applicable. 
5.7.2 
Analysis of Primary Efficacy Endpoint 
5.7.2.1 
Primary Efficacy Endpoint, Treatment Effect and Estimand Definition 
To assess the primary objective, the primary estimand will be defined by the following 
attributes: 
• 
Population: participants with locally advanced and/or metastatic prostate cancer 
previously treated and castrated with a GnRH analogue as defined by the listed 
Inclusion/Exclusion criteria in sections 5.1 and 5.2 of the protocol, respectively. 
• 
Variable/Endpoint: castration maintenance rate during the study 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.  
• 
Key Intercurrent event (ICE):  
(a) 
ICE 1 - Subjects discontinued from study prior to Day 337 without evidence of 
inadequate testosterone suppression (testosterone measurement >= 50 ng/dL)  
The testosterone values of these participants will not be considered for the main 
analysis (principal stratum strategy).   
(b) 
ICE 2 - Subjects with at least one planned testosterone measurement missing on 
or prior to Day 337 without evidence of inadequate testosterone suppression 
(testosterone measurement >= 50 ng/dL)  
The testosterone values of these participants will not be considered for the main 
analysis (principal stratum strategy). 


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(c) 
ICE 3 - Subjects discontinued treatment prior to receiving the second study 
intervention administration without evidence of inadequate testosterone 
suppression (testosterone measurement >= 50 ng/dL)  
The testosterone values of these participants will not be considered for the main 
analysis (principal stratum strategy).  
(d) 
ICE 4 - Subjects received a prohibited medication during the study  
Prohibited medication with impacts on the testosterone value will be identified 
through blinded data review. Subjects receiving identified prohibited medication 
(for example, finasteride, dustasteride, or abiraterone) will be included in the 
primary analysis as non-responder. In contrast, all testosterone measurements 
from subjects receiving prohibited medications other than identified ones during 
the study will be included in the primary analysis (composite strategy).  
• 
Treatment regimen: triptorelin 6‑month formulation administered subcutaneously and 
potential intake of permitted concomitant medications (for a list, see protocol section 6.3) 
• 
Population-level summary of the treatment effect of interest: percentage of participants 
with a castration maintenance. 
 
5.7.2.2 
Primary Analysis 
Primary analysis of castration maintenance rate will be based on the primary estimand in the 
FAS. Percentage of participants maintaining castrate levels of serum testosterone during the 
study along with the corresponding 95% exact CI will be provided in the FAS. 
 
By-subject listing will be produced for all enrolled subjects.  
5.7.2.3 
Sensitivity Analysis 
Sensitivity analysis for the primary estimand is intended to assess treatment effects when using 
different strategies. Details are listed in the following. 
Estimand ID 
Primary-S1 
Primary-S2 
Primary-S3 
Estimand 
Primary 
Primary 
Primary 
Analysis Type 
Sensitivity 
Sensitivity 
Sensitivity 
Analysis Set 
ITT 
ITT 
ITT 
Variable/Endpoint 
Castration maintenance rate Castration maintenance rate Castration maintenance rate 
Intercurrent Event 
Strategy 
ICE1 
Subjects will be included in 
the analysis regardless early 
withdraw status (Treatment 
policy) 
Subjects will be included in 
the analysis regardless early 
withdraw status (Treatment 
policy) 
Subjects will be included in 
the analysis regardless early 
withdraw status (Treatment 
policy) 


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Estimand ID 
Primary-S1 
Primary-S2 
Primary-S3 
ICE2 
With analysis window 
being applied, subjects 
without 2 consecutive 
missing testosterone value 
will be included in the 
analysis and subjects with 
at least 2 consecutive 
missing testosterone values 
will be considered as non-
responders  (Composite 
policy) 
Without analysis window 
being applied, subjects 
without 2 consecutive 
missing testosterone value 
will be included in the 
analysis and subjects with 
at least 2 consecutive 
missing testosterone values 
will be considered as non-
responders  (Composite 
policy) 
Analysis window is not 
applicable. Subjects with 
only one missing 
testosterone will be 
included in the analysis and 
available testosterone 
values will be analyzed as 
observed. For subjects with 
at least 2 missing 
testosterone values and 
without evidence of 
inadequate testosterone 
suppression (testosterone 
measurement ≥ 50 ng/dL), 
only testosterone values 
prior to the first missing 
will be included in the 
analysis. For subjects  with 
at least 2 missing 
testosterone values and with 
evidence of inadequate 
testosterone suppression 
(testosterone measurement 
≥ 50 ng/dL), available 
testosterone values will be 
analyzed as observed   
(Composite policy) 
ICE3 
Subjects will be included in 
the analysis regardless early 
treatment discontinuation 
status (Treatment policy) 
Subjects will be included in 
the analysis regardless early 
treatment discontinuation 
status (Treatment policy) 
Subjects will be included in 
the analysis regardless early 
treatment discontinuation 
status (Treatment policy) 
ICE4 
Same as primary estimand 
Population-level summary 
Same as primary estimand Same as primary estimand Probability of Castration 
maintenance at Day 337 
based on Kaplan-Meier 
estimate 
 
5.7.2.4 
Supplementary Analysis 
Primary estimand analysis will be conducted in the PP set if more than 10% of FAS subjects 
are excluded in the PP set. 
5.7.2.5 
Subgroup Analysis 
The primary analysis of castration maintenance rate will be summarized within subgroups listed 
along with 95% exact CI in a forest plot. In the case a subgroup includes less than 20 subjects, 
the analysis for the given subgroup will not be carried out or combining subgroups may be 
considered. 
• 
Age (<65, ≥65 years [65 to <75, 75 and above]) 
• 
Race (White, Black, Other) 
• 
Baseline ECOG performance score (0, 1) 


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• 
Baseline weight (<65 kg, 65 to <85 kg, ≥85 kg) 
• 
Time since histological diagnose (<median, ≥ median). 
5.7.3 
Analysis of Key Secondary Efficacy Endpoints 
5.7.3.1 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed below: 
• 
Percentage of participants castrated at each timepoint on Day 29, Day 85, Day 141, Day 
169, Day 253, Day 309 and Day 337 (castration defined as testosterone <1.735 nmol/L 
(50 ng/dL)) 
• 
Percentage of participants with a serum testosterone level <0.694 nmol/L (20 ng/dL) 
during the study 
• 
Percentage of participants with a serum testosterone level <0.69 nmol/L (20 ng/dL) at 
each timepoint on Day 29, Day 85, Day 141, Day 169, Day 253, Day 309 and Day 337 
• 
Percentage of participants castrated on Day 3 and Day 7 after each injection administered 
on Day 1 and Day 169 (castration defined as testosterone <1.735 nmol/L (50 ng/dL)) 
• 
Percent change in PSA from baseline (prior to injection) at Day 169 and Day 337 (Percent 
change in PSA defined as the absolute value of difference between the PSA values at 
Day 169 and Day 337 and the baseline value divided by the baseline value). 
5.7.3.2 
Main Secondary Analysis 
The same strategies as those for the primary estimand will be used for the main secondary 
analysis in the FAS, with castration maintenance criteria being replaced with 0.694 nmol/L (20 
ng/dL) whenever applicable. 
For binary secondary endpoints, including castration maintenance (<50 ng/dL) rate at specific 
timepoints, castration maintenance (<20 ng/dL) rate during the study, castration maintenance 
(<20 ng/dL) rate at each timepoint, castration maintenance rate along with the associated 95% 
exact CI will be provided. For percent change in PSA from baseline at Day 169 and Day 337, 
descriptive statistics will be provided. 
5.7.3.3 
Subgroup Analysis 
No subgroup analyses are planned for the secondary endpoints. 
5.7.3.4 
Sensitivity Analysis 
For castration maintenance (<20 ng/dL) rate during the study, the Kaplan-Meier estimate at 
Day 337 using the same strategies as Primary-S3 with castration maintenance criteria replacing 
with as <20 ng/dL will be provided. 
5.7.4 
Analysis of Other Secondary Efficacy Endpoints 
No other secondary efficacy endpoint analyses are planned for this study. 
5.7.5 
Analysis of Exploratory Endpoints 
No exploratory analyses are planned for this study. 
5.8 
Safety 
5.8.1 
General Consideration 
All safety summaries and analyses will be based upon the Safety Set. All safety data will be 
included in subject data listings (see listing detail conventions in Appendix 4).  


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Baseline value definition is given in section 5.1.3.  
5.8.2 
Extent of Exposure  
Administration of triptorelin embonate 22.5 mg 6-month formulation will be summarized by 
descriptive statistics for the following: duration of exposure, number of injections administered, 
number of subjects with at least one dose reduction or injection delayed. Duration of exposure 
will be defined in months as:  
([last dose date – first dose date] + 1) / (365.25/12).  
• 
Exposure listing will also be generated. 
5.8.3 
Adverse Event 
All adverse events (AEs) recorded in the eCRF will be coded using MedDRA dictionary. All 
AEs will be classified by MedDRA PT and SOC. Severity will be graded according to the 
National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 5.0 or higher. Adverse events will be classified as TEAEs if meeting one of the rules 
below: 
• 
Events with start date/time on or after the date/time of first IMP administration and within 
168 days after the last dose of study treatment, or up to Day 337, whichever is later.  
• 
Events whose severity worsens on or after the date/time of first IMP administration,  
For AE with partial or missing start date, refer to Appendix 2 for TEAE determination 
algorithm. 
In the case where it is not possible to define an AE as treatment emergent or not, the AE will 
be classified by the most conservative case; i.e. treatment emergent. 
 
The following summaries will be presented: 
• 
Overview of TEAE, 
• 
TEAE by SOC and PT, 
• 
TEAE by PT,  
• 
Most common (≥ 10%) TEAEs by SOC and PT, 
• 
TEAE by SOC, PT, and worst toxicity grade, 
• 
Grade 3 or 4 TEAE by SOC and PT, 
• 
TEAE by SOC, PT, and treatment relationship, 
• 
Treatment-related TEAE by SOC, PT, and worst toxicity grade, 
• 
Grade 3 or 4 treatment-related TEAE by SOC and PT, 
• 
Non-serious TEAE by SOC and PT. 
 
TEAE summaries will be presented in decreasing frequency of SOC, decreasing frequency of 
PT within SOC, and then in alphabetical order. TEAE summaries by PT will be presented in 
decreasing frequency of PT, and then alphabetically. 
 
Multiple occurrence of TEAEs will be presented as follows: 
• 
Participants will be counted at most once at the PT, and at most once at the SOC;  


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• 
Participants reporting multiple TEAEs coded within the same SOC/ PT will be presented 
in the worst-case grade category (grade order: 5>4>3>2>1>missing) ever reported in that 
SOC/PT;  
• 
Participants reporting multiple TEAEs coded within the same SOC/ PT will be presented 
in the TEAE with the worst-case relationship to study treatment (order: related > not 
related > missing) ever reported;  
• 
For TEAE summary by worst toxicity grade, participants reported single occurrence 
TEAE while the associated toxicity grade is missing, the participant will be presented in 
the toxicity grade missing category;  
• 
TEAEs with missing relationship to study treatment will be considered treatment-related 
in the summary. 
 
The number of events will also be displayed in the summary tables, when applicable. 
 
Deaths, SAEs, and Other Significant Adverse Events 
The following summaries will be presented: 
• 
Serious TEAE by SOC and PT, 
• 
Most common (≥ 5%) serious TEAEs by SOC and PT, 
• 
Treatment-related serious TEAE by SOC and PT, 
• 
TEAEs leading to treatment discontinuation by SOC and PT, 
• 
TEAE leading to treatment interruption by SOC and PT, 
• 
TEAEs leading to a dose reduction by SOC and PT,  
• 
Death summary. 
 
By-subject listing will be produced for all AEs, all serious adverse events (SAEs), all AEs 
leading to dose reduction, treatment interruption, treatment discontinuation, and fatal AE. 
Treatment emergence status will be flagged in the listing whenever applicable.  
5.8.4 
Laboratory Data 
Clinical safety laboratory tests will be assessed by local laboratories. All laboratory data will 
be presented in the units of International System of Units (SI).  
 
Haematological and biochemical toxicities will be graded according to the NCI-CTCAE 
criteria, where available. The toxicity grades will be assigned programmatically by applying 
the NCI-CTCAE guideline as described in Section 7 (11). All scheduled and unscheduled 
laboratory test results will be included in the worst toxicity grade summary. For white blood 
cells, neutrophils, platelets and haemoglobin, with associated grade 3 or 4 toxicities, nadir and 
day to nadir from most recent injection will be presented in the listing. 
 
The neutrophils values will be imputed as defined in Section 7 (12). 
 
The following summaries will be provided: 


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• 
A summary of the actual and change from baseline in each laboratory haematology 
parameter (platelet count, haemoglobin, white blood cell counts, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) and in each laboratory biochemistry 
parameter (creatinine, non-fasting glucose, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, total bilirubin and conjugated bilirubin) at Day 
337, 
• 
Shift from baseline to end of study based on abnormalities, 
• 
Shift from baseline to end of study based on CTCAE toxicity grading. 
 
The following listings are to be provided: 
• 
A listing of all laboratory data (with flag indicating abnormal values), 
• 
A listing of laboratory data for subjects with at least one post-baseline abnormal value 
(with flag indicating abnormal values), 
• 
A listing of relevant laboratory data for subjects with at least one CTCAE grade 3 or 
higher post-baseline laboratory result. 
5.8.5 
Vital Signs 
The following summaries will be presented: 
• 
Summary of the actual and change from baseline in each vital sign parameter (systolic 
blood pressure, diastolic blood pressure, heart rate, respiratory rate, temperature) by 
timepoint, 
• 
Summary of subjects experiencing Potentially Clinically Significant Abnormalities 
(PCSA). Note: PCSA criteria are defined in Appendix 1 for systolic blood pressure, 
diastolic blood pressure and heart rate. 
• 
Shift from baseline to each post-baseline visit based on clinical abnormality evaluation.  
 
The following listings are to be provided: 
• 
All vital sign data, with abnormal value flagged.  
• 
Listing of PCSA. All relevant vital sign data for subjects with at least one post-baseline 
PCSA record. 
5.8.6 
Electrocardiogram  
The following quantitative electrocardiogram (ECG) measurements will be taken during the 
study: 
• 
RR interval (msec), 
• 
PR interval (msec), 
• 
QRS duration (msec), 
• 
QT interval (msec), 
• 
Fridericia corrected QT (QTcF) interval (msec). 
 
An overall investigator assessment of ECG will be provided as “normal”, “abnormal, not 
clinically significant” and “abnormal, clinically significant”.  
 


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The following summaries of ECG data will be provided:  
• 
Summary of the actual and change from baseline in each ECG parameter by timepoint 
(Baseline and Day 337),  
• 
Summary of subjects experiencing PCSA. Note: PCSA criteria are defined in Appendix 
1 for QTc and delta QTc. 
• 
Shift from baseline based on clinical abnormality evaluation. 
 
A listing of ECG data is to be provided with abnormal value and PCSA records flagged. 
5.8.7 
Physical Examination 
The following summaries will be provided: 
• 
Summary of subjects reporting abnormal finding in physical examination by body system 
(cardiovascular system, respiratory system, gastrointestinal system, neurological system, 
and other) for a shift from baseline (normal versus abnormal) to each post-baseline visit, 
• 
Summary of the actual and change from baseline in weight and BMI by timepoint,  
• 
Summary of subjects meeting PCSA criteria in weight (defined in Appendix 1). 
 
By-subject physical examination listing will be provided with records meeting PCSA criteria 
or being considered as clinical abnormal flagged. 


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6 
DATA HANDLING 
6.1 
Visit window 
The time window for visit/timepoints will be applied as below for the blood samples for 
testosterone. In case of multiple unscheduled and planned visits enclosing within the defined 
analysis time interval, the non-missing value in a visit closest to the target visit day will be used 
in the summary tables. 
 
Study phase 
Scheduled visit 
Protocol Time Interval 
Analysis Time Interval* 
(days) 
 
 
 
 
Screening 
Day -28 to Day -1 
-28 to -1 
Intervention Period 
Day 1 (first injection) 
<1 
<=1 
Week 1 – Day 3 
3 
2 to 5 
Week 1 – Day 7 
7 
6 to 18 
Week 4 – Day 29 
29 
19 to 57 
Week 12 – Day 85 
85 
58 to 113 
Week 20 – Day 141 
141 
114 to 155 
Week 24 – Day 169 
(second injection) 
169 (D2) 
156 to D2  
Week 25 – Day 171 
171 (D2+2) 
D2+1 to D2+4 
Week 25 – Day 175 
175 (D2+6) 
D2+5 to D2+45 
Week 36 – Day 253 
253 (D2+84) 
D2+46 to D2+112 
Week 44 – Day 309 
309 (D2+140) 
D2+113 to D2+154 
End of Study/Early 
Discontinuation 
Week 48 – Day 337 
337 (D2+168) 
≥D2+155 
*Analysis visit window after screening are defined using the mid-point between each scheduled visit and reset 
with the second injection. 
 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit,  
All listings will include retest measurement and assessments from unscheduled visits. For by-
visit summary, only planned visits in the protocol will be presented. 
Assessments from unscheduled visit and retest measurements will be included for baseline 
value determination whenever applicable. These measurements will also be used to determine 
worst toxicity grade for laboratory data, or meeting PCSA criteria in vital signs or ECG. 
If an assessment requires a retest (for example, safety laboratory, vital signs and ECG), the 
closest non-missing value to the scheduled visit will be used in the summary tables. 
Participants who have withdrawn early from the study have their last assessment entered at the 
end of study / early discontinuation visit in the eCRF.  
 


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7 
DERIVED DATA 
The following derived data will be calculated and included in the listings: 
 
(1) Baseline value 
Baseline value is defined as the last non-missing measurement taken prior to first IMP 
administration (including unscheduled assessments) (see section 5.1.3). 
 
(2) Duration of subject participation (study exposure) 
Study exposure will be calculated as: 
Study exposure (days) = last assessment or visit performed – informed consent date +1. It will 
be then divided by 30.4375 to be presented in months. 
 
(3) Age 
Subject age (years) will be as collected in eCRF. 
 
(4) BMI 
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]2 and rounded to the nearest 
decimal. 
 
(5) Time from diagnosis to screening 
Time from diagnosis to screening will be calculated as (date of screening – date of diagnosis). 
It will be then divided by 30.4375 to be presented in months. 
In case of missing screening day, the day will be imputed to 15. In case of missing screening 
month, the month will not be imputed.  
In the same way, in case of missing diagnosis day, the day will be imputed to 15. In case of 
missing diagnosis month, the month will not be imputed.  
No imputation will be performed for missing year. 
 
(6) Compliance 
Compliance will be calculated as: 
Dose administered divided by dose planned to be administered multiplied by 100. The 
percentage of residual will be considered to determine the percentage of dose non-administered, 
and so the dose administered. 
A total of two injections will be considered as planned dose administration in this study. 


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(7) Percent change from baseline 
Percent change from baseline will be calculated as: 
((assessment at the visit – assessment at baseline)/ assessment at baseline)*100. 
Zero will be used if both assessment at baseline and change from baseline are zero. 
 
(8) Changes from baseline  
Changes from baseline will be calculated as a difference from baseline (e.g. assessment at the 
visit – assessment at baseline). 
 
(9) Study drug exposure 
Study drug exposure will be calculated as: 
Study drug exposure (days) = last study drug administration date – first study drug 
administration date +1. It will be then divided by 30.4375 to be presented in months.  
 
(10) 
Time from first study dose for adverse event 
If the start date of the AE is identical to the date of first administration, then “<1” day will be 
presented.  
The time will be calculated as (AE start date – first administration date)+1 and presented in 
days.  
If the AE start date is partial due to missing day, the time from first dose will be presented as a 
superior inequality (e.g.: for an AE started in FEB2004 after the first administration performed 
on 31JAN2004, the time from first dose will be as “≥2” days).  
If the first administration date is partial due to missing day, the time from first dose will be 
presented as a superior inequality (e.g. for an AE started on 01FEB2004 after the first 
administration performed in JAN2004, the time from first dose will be as “≥2” days). 
If both the AE start day and the first administration day are missing, the time from first dose 
will not be presented. 
If the AE start month is missing or the first administration month is missing, the time from first 
dose will not be presented. 
If the AE start date is missing or the first administration date is missing, the time from first dose 
will not be presented. 
 
(11) 
NCI-CTC AE grades for laboratory parameters 
For NCI-CTC gradable laboratory parameters, appropriate grades should be attributed 
according to the coding rules specified in the NCI-CTCAE version 5.0 if this grade is not 
present in the database. The grading will be performed based on the laboratory values. CTCAE 
Grade 0 will be assigned for all non-missing values not graded as 1 or higher.  
 


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(12) 
Neutrophils values 
In some cases, laboratory data may not be reported as they may be difficult to detect. When the 
White Blood Cells (WBC) counts are non-missing and recorded as WBC < 0.5*10^9/L, the 
neutrophils value will be imputed as zero in the analysis and CTCAE grade 4 will be assigned. 
 


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8 
CHANGES FROM PROTOCOL 
In SAP section 2.1, the hypotheses have been rephrased from Protocol section 9.1: “after 12 
months” was updated to “from date of first dose to Day 337” to stick to the protocol endpoints. 
Twelve months would consider the screening period up to 28 days. 
In SAP section 4, the ITT Set was added. The ITT population was mentioned in Protocol section 
3 for second estimand while the definition was missed in the protocol. . 
The multiple imputation was removed in Protocol Section 3, but it is still present in Protocol 
Section 1.1 and Section 9.4.2. The multiple imputation will not be used for the statistical 
analysis considering the new FAS definition and the new estimands definition. 


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9 
REFERENCES 
Reference to ICH regulatory guidelines: 
• 
ICH E3: Structure and Content of Clinical Study Reports (CSRs) 
• 
ICH E6 (R2): Good Clinical Practice (GCP) 
• 
ICH E9: Statistical Principles for Clinical Trials 
• 
ICH E9 (R1) Addendum: Estimands and Sensitivity Analysis in Clinical Trials. 
 
Reference to European Medicines Agency (EMA) or point to consider guidelines: 
• 
Investigation of subgroups in confirmatory clinical trials 
• 
Missing data in confirmatory clinical trials. 
 
Reference to Food and Drug Administration (FDA) guidelines: 
• 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
 
Standard Ipsen Study Data Tabulation Model (SDTM) user guide 
 
Ipsen Global Style guide 
 
• 
Agresti A, Coull BA. Approximate is better than “exact” for interval estimation of 
binomial proportions. The American Statistician, 1998;52:119-26. 
• 
Michael Laposata, MD PhD, SI unit conversion guide. The New England Journal of 
Medicine,1992 
• 
Bodner, T. E. (2008). “What Improves with Increased Missing Data Imputations?” 
Structural Equation Modeling 15:651–675. 
 
References for guidance on analysing ECG data: 
• 
ICH E14 (2005) Note for guidance on the clinical evaluation of QT/QTC interval 
prolongation 
and 
proarrhythmic 
potential 
for 
non-anti-arrhythmic 
drugs 
(CHMP/ICH/2/04) 
• 
Shah R.R, Drugs, QTc interval prolongation and final ICH E14 guideline. Drug Safety 
2005: 28(11):1009-1028 


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10 
APPENDICES 
 


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Appendix 1 List of PCSA Criteria 


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A1. List of PCSA Criteria 
 
PCSA for Vital Signs parameters: 
Parameter 
PCSA 
Systolic Blood Pressure 
≤ 90 mmHg and change from baseline ≤ -20 mmHg 
≥ 180 mmHg and change from baseline ≥ 20 mmHg 
Diastolic Blood Pressure 
≤ 50 mmHg and change from baseline ≤ -15 mmHg 
≥ 105 mmHg and change from baseline ≥ 15 mmHg 
Heart Rate 
≤ 50 bpm and change from baseline ≤ -15 bpm 
≥ 120 bpm and change from baseline ≥ 15 bpm 
 
PCSA for ECG parameters (source ICH E14): 
Parameter 
PCSA 
QTc 
]450; 480] msec 
]480; 500] msec 
>500 msec 
Delta QTc 
]30;60] msec increase from baseline 
>60 msec increase from baseline 
 
PCSA for Weight from Physical Examination parameters: 
Parameter 
PCSA 
Weight 
≤ -5% change from baseline 
≥ 5 % change from baseline 


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Appendix 2 Partial/Missing Date Convention 


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A2. Partial/Missing Date Convention 
In all listings, missing or incomplete dates should be left as they have been recorded.  
 
Algorithm for Prior/ Concomitant  
Medication, non-drug therapies and surgical procedures start and stop dates will be compared 
to the date of the first IMP administration to allow classification as either Prior only, Prior and 
Concomitant, or Concomitant only.  
In case of partial start and/or stop dates, temporary date imputation will be done to determine 
the classification and derive the duration of occurrence: 
• 
If a partial start date is reported, the first day of the month will be imputed for missing 
day and January for missing month, 
• 
If a partial stop date is reported, the last day of the month will be imputed for missing 
days and December will be imputed for missing month. 
In case incomplete start or stop date does not allow the classification, will be classified as 
concomitant. 
The duration of the occurrence will be calculated using the start and end date of the occurrence 
as end date – start date + 1. In case of partial start or end dates, the duration will be reported as 
“≤ xx” since at least one date is imputed and maximised. 
In case of ongoing occurrence (e.g. at the end of the study or at the time of interim analysis): 
• 
If the start date is complete, the duration will be reported as “≥ xx” and the date of end 
of study date or last attended visit will be considered as end date. 
• 
If start date is incomplete, the duration is not calculated. 
 
Algorithm for Medical Histories 
In case of partial start and/or stop dates, temporary date imputations will be done to determine 
the duration of occurrence: 
• 
If a partial start date is reported, the first day of the month will be imputed for missing 
day and January for missing month, 
• 
If a partial stop date is reported, the last day of the month will be imputed for missing 
days and December will be imputed for missing month. 
The duration of the occurrence will be calculated using the start and end date of the occurrence 
as end date – start date + 1. In case of partial start or end dates, the duration will be reported as 
“≤ xx” since at least one date is imputed and maximised. 
In case of ongoing medical history: 
• 
If the start date is complete, the duration will be “≥ xx” using the screening visit date and 
the start date of the medical history. 
• 
If start date is incomplete, the duration is not calculated. 
 




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+ 1. In case of partial start/end date the temporary imputed date will be used. 
The duration of the AE will be calculated using the start and end date of the AE as end date – 
start date + 1. In case of partial start or end dates, the duration will be reported as “≤ xx” since 
at least one date is imputed and maximised. 
 
In case of ongoing AE (e.g. at the end of the study or at the time of interim analysis): 
• 
If the start date is complete, the duration will be reported as “≥ xx” and the date of end 
of study date or last attended visit will be considered as end date. 
• 
If start date is incomplete, the duration is not calculated.


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Appendix 3 Programming Convention for Outputs 


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A3 Programming Convention for Outputs 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5, …) must be decimal justified. 
 
The mean, median, lower quartile, upper quartile, SD, and 95% CI values will be reported to 
one decimal place greater than the raw data recorded in the database.  
The minimum and maximum values will be reported with the same number of decimal places 
as the raw data recorded in the database. 
In general, the maximum number of decimal places reported should be four for any summary 
statistic. 
 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Unless otherwise specified, percentage will be calculated using N as denominator. The 
denominator will be specified in a footnote for clarification if necessary. If sample sizes are 
small, the data displays will show the percentages, but in the CSR only frequency counts should 
be described.  
 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as such.   
 
Dates will be presented in the format [ddmmmyyyy] and times in the format [hh:mm].


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Appendix 4 Listings Conventions 


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A4 Listings Conventions 
Any listings will contain at least the following data: subject identifier and age. When dates are 
presented, the associated study days should be included. They should be sorted by subject 
identifier. Listings should be broken down by centre.


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Appendix 5 EudraCT Categories for Age 


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A5 EudraCT Categories for Age 
For EudraCT results summaries, in addition to quantitative descriptive statistics of age, 
demographic tables should include presentation of age using the following EudraCT categories 
(as applicable). Only adults are planned for this study. 
 
Adolescents (12-17 years old) 
Adults (18-64 years old) 
            From 65 to 84 years old 
            85 years old and over