Clinical trial NCT01753297
Conditions: Prostate Cancer
Sponsor: Ipsen
Start date: 2012-12-11; Completion date: 2019-09-09
Enrollment: 226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the benefit of immediate hormonal treatment after Radical Prostatectomy in Chinese and Russian patients with high risk prostate cancer. To reach this target, the trial will compare a group of patients treated with triptorelin at 8 weeks after the surgery and for a duration of 9 months (3 injections) versus another group (called "active surveillance group") who will be not receiving triptorelin. Both groups will be followed every 3 months to monitor any sign of disease progression during a minimum of 36 months

Detailed description:
This trial is a phase IV (in Russia and China) as approved indication is locally advanced or metastatic prostate cancer in both countries.

Arms: arm 1: Triptorelin, powder and solvent for suspension (prolonged released form) arm 2: Active surveillance after radical prostatectomy (RP)
Interventions: intervention 1: Triptorelin 11.25 mg
Intervention descriptions: intervention 1: Triptorelin, one injection every 3 months. A total of 3 injections (at baseline, 3 and 6 months)

Protocol documents:
Prot_000.pdf: 
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A MULTICENTRIC, MULTINATIONAL (CHINA AND RUSSIA), RANDOMISED, 
OPEN, CONTROLLED STUDY OF IMMEDIATE 9 MONTHS ADJUVANT HORMONE 
THERAPY WITH TRIPTORELIN 11.25 MG VERSUS ACTIVE SURVEILLANCE AFTER 
RADICAL PROSTATECTOMY IN HIGH RISK PROSTATE CANCER PATIENTS  
 
STUDY PROTOCOL 
STUDY NUMBER: A-38-52014-194  
Study Short Title: PRIORITI 
[TRIPTORELIN 11.25 mg FORMULATION] 
 
Version 3.0: 07 June 2013 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
Ipsen Pharma SAS 
 
Oncology Franchise 
Ipsen Group 
65 Quai Georges Gorse 
Ipsen Pharma SAS, Ipsen Group 
92650 Boulogne Billancourt Cedex 
65 Quai Georges Gorse 
FRANCE 
92650 Boulogne Billancourt Cedex 
Tel: 
+ 33 1 58 33 50 00 
FRANCE 
Fax: 
+ 33 1 58 33 50 01 
 
 
Monitoring Office:  
Co-ordinating Investigator:  
 
Ipsen Pharma SAS, Ipsen Group 
65 Quai Georges Gorse 
92 650 Boulogne Billancourt 
FRANCE 
CHINA 
 
Pharmacovigilance/Emergency Contact: 
 
 
Ipsen Group 
190 Bath Road 
Slough 
 
 
Berkshire SL1 3XE 
ENGLAND 
 
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. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the study A-38-52014-194 “A multicentric, multinational (China and 
Russia), randomised, open, controlled study of immediate 9 months adjuvant hormone 
therapy with triptorelin 11.25 mg versus active surveillance after radical prostatectomy in 
high risk prostate cancer patients”. I am aware of my responsibilities as an Investigator under 
the guidelines of Good Clinical Practice (GCP)1, 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 INVESTIGATOR: 
SIGNATURE: 
 
 
 
 
DATE: 
 
OFFICE: 
 
 
 
Full investigational site contact details, including telephone numbers, will be documented in 
the Trial Master File. 
 
On behalf of the Sponsor: 
NAME: 
 
 
 
 
 
TITLE: 
 
 
 
SIGNATURE: 
 
 
DATE: 
 
OFFICE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996. 


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SYNOPSIS 
Study Title: 
A multicentric, multinational (China and Russia), randomised, open, 
controlled study of immediate 9 months adjuvant hormone therapy 
with triptorelin 11.25 mg versus active surveillance after radical 
prostatectomy in high risk prostate cancer patients. 
Study Objectives: 
Primary objective: 
• 
To assess the benefit of immediate adjuvant 
chemical castration after radical prostatectomy (RP) 
in patients with high-risk prostate cancer expressed 
as biochemical relapse-free survival (BRFS). 
Secondary objectives: 
• 
To compare the two arms in terms of:  
- 
Event-Free Survival (EFS), Overall Survival 
(OS), Specific-Mortality rate and prostate 
specific antigen doubling time (PSADT)  
- 
Impact on health-related quality of life 
(HRQoL)  
• 
To assess overall safety of immediate chemical 
castration 
Ancillary Exploratory Objectives: 
Phase of Trial: 
Phase IV  
Study Design: 
This open, prospective, multicentric, multinational, randomised, 
controlled study with two parallel arms is designed to compare the 
efficacy and safety of immediate 9-month adjuvant treatment using 
triptorelin 11.25 mg versus active surveillance after RP. Immediate 
adjuvant treatment is defined as a treatment being initiated 8 weeks 
after RP. 
Visit 1: Screening visit:  
Six weeks (± 3 days) after RP, the patient will be proposed 
participation in the study. After the patient has given his written 
CCI


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informed consent, he will undergo, among other assessments, a 
blood sampling for serum post-RP prostate specific antigen (PSA) 
level. 
Visit 2: Baseline visit (Randomisation):  
Two weeks after the screening visit, and no more than 8 weeks 
(± 3 days) after RP when post-RP PSA level is available, eligible 
patients will be randomised to one of two arms, either the triptorelin 
treatment arm or to the active surveillance arm. 
For patients randomised to the triptorelin treatment arm, triptorelin 
11.25 mg will be administered intramuscularly every 3 months 
(± 7 days), for a total of three injections (at the Baseline, 3, and 
6 month visits). 
For patients randomised to the active surveillance arm, no adjuvant 
treatment with any method (hormonal or surgical castration and/or 
or radiation therapy) should be initiated prior to evidence of disease 
progression (clinical or biochemical). They will be monitored in the 
same way as for the triptorelin treatment arm. 
Visit 3 to Visit 14: Monitoring Period: 
All randomised patients (in both arms) will be followed every 
3 months (± 1 week) to monitor the occurrence of biochemical 
relapse (BR) and/or clinical disease progression over a period of 
36 months after randomisation (from Visit 3 to Visit 14). 
Disease progression is defined as BR and/or clinical disease 
progression (whichever occurs first):  
• 
BR is defined as the first elevated PSA value 
>0.2 ng/mL confirmed by a second measurement 
recorded 4 to 6 weeks later. The time-point at which 
the first PSA value above 0.2 ng/mL is recorded, 
will be deemed to be the time of BR. 
• 
Clinical disease progression is defined as evidence 
of local/locoregional recurrence and/or lymph node 
involvement and/or distant metastases documented 
by relevant standard investigations (such as 
ultrasound (US) guided biopsy, X-ray, computed 
tomography (CT) scan, or magnetic resonance 
imaging (MRI) guided biopsy). 
Any patient (in either arm) who has disease progression at any time 
will receive appropriate medical care from the Investigator. 
New/additional therapy (for example radiation therapy, surgical 
castration, or hormonal treatment) will be proposed according to the 
Investigator’s decision and in line with local standard of care. In 
both arms and depending on the time of occurrence of disease 
progression, the patient’s visit schedule will be as follows:  
• 
If BR and/or clinical disease progression occurs 
before 36 months, the patient will continue to be 
monitored until 36 months post-randomisation 
(Visit 14) at which point he will be considered to 


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have completed the study.  
• 
If at 36 months (Visit 14), the patient has not shown 
any sign of BR and/or clinical disease progression, 
and if the statistically required 61 BRs were not 
observed at the global study level, he will enter the 
follow-up period.  
Post-Visit 14: Follow-up Visits: 
If at 36 months post-baseline (at Visit 14), the patient does not have 
BR and/or clinical disease progression and if the statistically 
required 61 BRs are not observed at the global study level, he will 
continue to be followed every 3 months until: 
• 
He has a BR and/or clinical disease progression 
• 
Or, the 61 required BRs are observed on the global 
study level.  
PSA levels, physical examinations and clinical disease progression 
assessments (where deemed necessary by the Investigator and in 
accordance with local standards of care) will continue to be 
performed at each follow-up visit to monitor disease progression.  
The study will be considered to be terminated when:  
• 
All included patients have completed their 
minimum monitoring period of 36 months.  
• 
And, when 61 BRs are observed at the global study 
level. 
Study Completion/Early Withdrawal Visit:  
Patients who have disease progression (BR and/or clinical disease 
progression) within 36 months (event documented before Visit 14) 
will continue to be monitored until Visit 14 which will be 
considered as the Study Completion Visit. 
Patients who have disease progression after 36 months (event 
documented during or after Visit 14) will be considered to have 
completed the trial. Their last study visit would be the visit when 
disease progression is documented.  
After 36 months, patients who do not have disease progression 
during the whole study will be considered to have completed the 
trial once the statistically required 61 BR events occur on the study 
global level.  
At any time during the study and for any reason, in the case of early 
withdrawal/discontinuation, the Investigator should perform a last 
monitoring/follow-up visit considered as the early withdrawal visit. 
Study Duration: 
Estimated recruitment period: 24 months 
Minimum patient participation duration: 36 months after 
randomisation (for both arms) 
Estimated study duration: a minimum of 60 months 
Study Population:  
Number of expected patients: 113 in each arm (226 in total).  
Number of sites: approximately 10 sites will participate to the study, 
in China and Russia. 


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Inclusion criteria: 
All patients must fulfil the following: 
1. Provide written informed consent signed by the patient prior 
to any study-related procedure 
2. Men aged ≥18 years  
3. Histo-pathologically confirmed adenocarcinoma of the 
prostate  
4. Radical Prostatectomy with curative intent performed no 
more than 8 weeks before randomisation  
5. High-risk criteria of disease progression, defined as follows:  
• 
Gleason score ≥8 on prostatectomy specimen, 
and/or 
• 
Pre-RP PSA level ≥20 ng/mL, and/or  
• 
Primary tumour stage 3a (pT3a) (with any PSA 
level and any Gleason score)  
6. Post-RP PSA levels ≤0.2 ng/mL at 6 weeks. 
7. Eastern cooperative oncology group (ECOG)/world health 
organisation (WHO) performance status of 0 to 1 
Exclusion criteria 
Patients will not be included in the study if any of the following 
apply: 
1. Has evidence of lymph nodes or distant metastasis 
2. Has positive margins  
3. Has evidence of any other malignant disease, not treated 
with a curative intent 
4. Previously received or is currently receiving any other 
treatment of prostatic cancer besides the concerned RP 
5. Had surgical castration 
6. Has a life expectancy <5 years 
7. Suffers from a significant comorbidity or an untreated 
infection 
8. Is likely to require treatment during the study with drugs that 
are not permitted by the study protocol 
9. Has a history of hypersensitivity to triptorelin or any 
luteinising hormone-releasing hormone (LHRH) analogues 
or to any of the excipients of triptorelin 11.25 mg 
10. Was treated with any investigational drug within 4 weeks 
before the study entry 
11. Has abnormal baseline findings, any other medical 
condition(s) or laboratory findings that, in the opinion of the 
Investigator, might jeopardise the patient’s safety or 
decrease the chance of obtaining satisfactory data needed to 
achieve the objective(s) of the study 
12. Is unable to undergo regular follow-up 
13. Has any mental condition rendering him unable to 
understand the nature, scope and possible consequences of 
the study, and/or evidence of an uncooperative attitude 


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14. Has a history of, or known current, problems with alcohol or 
drug abuse 
Study Treatment: 
Investigational medicinal product (IMP):  
Triptorelin 11.25 mg  
Pharmaceutical form:  
Powder and solvent for suspension for intramuscular injection, 
prolonged released formulation. 
Active component:  
Triptorelin pamoate, as triptorelin 11.25 mg  
Drug name:  
• 
China: Triptorelin pamoate for injection, 15 mg 
• 
Russia: Diphereline® 11.25 mg 
Posology and method of administration: 
Triptorelin will be administered as a hormonal adjuvant to RP for 
patients randomised to the triptorelin treatment arm. These patients 
will receive one intramuscular injection of the product, which will 
be repeated every 3 months for a total of three injections: at 
Baseline and at the 3 month and 6 month visits. 
Study Evaluations: 
Primary Efficacy Endpoint(s) and Evaluation(s):  
Biochemical Relapse-Free Survival (BRFS) is defined for each 
patient by the period of time from randomisation to time of BR. 
Biochemical Relapse (BR) definition: increased PSA >0.2 ng/mL 
confirmed by a second measurement performed 4 to 6 weeks later. 
The time point at which the first elevated PSA measurement is 
>0.2 ng/mL is recorded will be deemed to be the time of BR. 
BRFS data will be censored on the date of the last assessment on 
study for patients who do not have BR or on the date of clinical 
disease progression for those who progress before BR while on 
study or on the date of death for those who die before BR while on 
study (of any cause). 
 
Secondary Efficacy Endpoints And Evaluations: 
• 
EFS as defined for each patient as the period of time 
from randomisation to time of first diagnosed 
locoregional disease recurrence (positive biopsy 
and/or node involvement) or first metastases (bone 
or visceral) documented by relevant standard 
investigations (US guided biopsy, X-ray, CT scan, 
or MRI guided biopsy) or death from any cause. 
• 
OS defined as the time between randomisation and 
death from any cause.  
• 
Disease-specific mortality measured as the time 
between randomisation and death related to prostate 
cancer. 
• 
PSADT defined as the time from the first 
documented PSA increase >0.2 ng/mL to the time 
of the first value more than twice that of the first 
increased value.  


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• 
Serum testosterone in the triptorelin arm at 
Baseline, 3, 6 and 9 months.  
• 
HRQoL assessed using the Functional Assessment 
of Cancer Therapy–Prostate (FACT-P) 
questionnaire, version 4, and the 36-item short form 
(SF-36) health survey, version 2 in both treatment 
arms at Baseline, 9, 24, and 36 months. 
 
Exploratory Endpoints and Evaluations: 
 
Safety Endpoints and Evaluations: 
Signs and symptoms, incidence and severity of all AEs, regardless 
of relationship to the study drug, graded according to the National 
Cancer Institute - Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), version 4.0, including serious AEs (SAEs) 
and treatment discontinuations due to toxicity will be monitored 
from the time that the patient gives informed consent until 
Visit 5/Month 9 (3 months after the last injection for those patients 
in the triptorelin arm). After this period, only AEs/SAEs related to 
triptorelin will be reported. 
Statistical 
Methods: 
This study is designed to demonstrate that RP and immediate 
adjuvant hormonal therapy can significantly improve BRFS 
compared with RP alone. 
Sample size:  
Assuming that with RP alone, the probability of biochemical (PSA) 
relapse at 36 months after RP is 40% in high risk patients, and 
anticipating that immediate adjuvant hormonal therapy added to RP 
will reduce this probability to 20%, 113 patients per treatment group 
(226 in total) will be required in order to detect such a difference 
using a two-sided log-rank test at a significance level of 5% and a 
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power of 90% assuming a common 1% exponential dropout rate 
(corresponding to an approximate 5% dropout rate per year).  
These 226 patients will be required to observe the 61 BRs in order 
to achieve the 90% power. For those with no sign of disease 
progression, patient monitoring will continue beyond 36 months 
post-randomisation as long as the 61 BR events are not observed 
across all patients. If the 61 BR events are observed before all 
patients have completed the 36 month monitoring period, the study 
will be continued until those patients reach their 36 month visit 
(Visit 14). 
Populations: 
Three study populations are defined: 
• 
Safety Population: all randomised patients that have 
received at least one injection for patients from the 
triptorelin arm or that have undergone at least one 
day of active surveillance for patients from the 
active surveillance arm. 
Patients will be analysed as treated for the safety 
analyses. 
• 
Intent-to-Treat (ITT) Population: includes all 
randomised patients analysed according to the arm 
to which they were randomised.  
• 
Per Protocol Population: all patients in the ITT 
population for whom no major protocol 
violations/deviations occurred. 
Analyses: 
All efficacy endpoints and patient demographics will be evaluated in 
the ITT. 
Treatment administration/compliance and safety will be analysed in 
the safety population. 
The primary endpoint is BRFS, which is defined as the time from 
date of randomisation to BR. BRFS data will be censored on the 
date of the last assessment on study for patients who do not have BR 
or on the date of clinical disease progression for those who progress 
before BR while on study or on the date of death for those who do 
die before BR while on study (for any cause). The primary analyses 
of BRFS will be performed in the ITT population. A two-sided 
log-rank test will be used to compare BRFS time between the two 
treatment groups with nominal significance level 0.05 (two-sided). 
The Kaplan-Meier method will be used to obtain the estimates of 
median event-free time associated with each treatment. The 95% 
confidence intervals (CI) of the median event-free time will be 
provided also. The Cox Proportional hazards model will be fitted to 
compute hazard ratio and the corresponding 95% CI. 
 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 14 
2 
INTRODUCTION ......................................................................................................... 17 
2.1 
Disease Review ............................................................................................................... 17 
2.2 
Compound Review ........................................................................................................ 18 
2.3 
Clinical Trial Rationale ................................................................................................ 19 
3 
STUDY OBJECTIVES ................................................................................................. 20 
3.1 
Primary Study Objective .............................................................................................. 20 
3.2 
Secondary Study Objectives ......................................................................................... 20 
3.3 
Ancillary Exploratory Study Objectives ..................................................................... 20 
4 
STUDY DESIGN ........................................................................................................... 21 
4.1 
Overview ........................................................................................................................ 21 
4.1.1 
Population Characteristics .......................................................................... 21 
4.1.2 
Design .......................................................................................................... 21 
4.1.3 
Structure ...................................................................................................... 21 
4.1.4 
Stopping Rules and Discontinuation Criteria ............................................ 24 
4.1.5 
Early Study Termination ............................................................................. 24 
4.2 
Endpoints ....................................................................................................................... 24 
4.2.1 
Efficacy Endpoints ...................................................................................... 24 
4.2.2 
Exploratory Endpoints ................................................................................ 25 
4.2.3 
Safety Endpoints .......................................................................................... 25 
4.3 
Justification of Design ................................................................................................... 26 
4.3.1 
Study Population for Analysis .................................................................... 26 
4.3.2 
Study Duration ............................................................................................ 26 
4.3.3 
Justification of Exploratory Endpoints ...................................................... 26 
5 
COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
CONSIDERATIONS & INFORMED CONSENT .................................................... 27 
5.1 
Compliance with Good Clinical Practice and Ethical Considerations ..................... 27 
5.2 
Informed Consent ......................................................................................................... 28 
6 
STUDY POPULATION ............................................................................................... 28 
6.1 
Screening Log and Number of Patients ...................................................................... 28 
6.2 
Inclusion Criteria .......................................................................................................... 29 
6.3 
Exclusion Criteria ......................................................................................................... 29 
6.4 
Patient Withdrawal Criteria ........................................................................................ 30 
6.5 
Discontinuation/Withdrawal Procedures.................................................................... 30 
7 
METHODOLOGY ........................................................................................................ 31 
7.1 
Study Schedule .............................................................................................................. 31 
7.2 
Study Visits .................................................................................................................... 34 
7.2.1 
Screening Visit (Visit 1) Week –2 (±3 Days) .............................................. 34 
7.2.2 
Baseline (Visit 2) Day 1 ............................................................................... 34 
7.2.3 
Monitoring Period (Visits 3 to 14) .............................................................. 34 
7.2.4 
Follow-up Period (>36 Months After Randomisation) .............................. 35 
7.2.5 
Study Completion or Early Withdrawal Visit ............................................. 36 
8 
STUDY EVALUATIONS ............................................................................................. 37 
8.1 
Efficacy Endpoints and Evaluations ........................................................................... 37 
8.1.1 
Primary Efficacy Endpoint and Evaluations ............................................. 37 


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8.1.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 37 
8.2 
Safety Endpoints and Evaluations ............................................................................... 38 
8.2.1 
Safety Endpoints .......................................................................................... 38 
8.2.2 
Adverse Events, Signs and Symptoms ........................................................ 38 
8.2.3 
Physical Examination ................................................................................. 38 
8.2.4 
Vital Signs .................................................................................................... 38 
8.2.5 
Clinical Laboratory Tests ............................................................................ 39 
8.3 
Exploratory Endpoints and Evaluations ..................................................................... 39 
9 
STUDY TREATMENTS .............................................................................................. 42 
9.1 
Study Treatments Administered .................................................................................. 42 
9.2 
Patient Identification and Allocation to Study Treatment ........................................ 43 
9.2.1 
Randomisation ............................................................................................. 43 
9.2.2 
Blinding, Emergency Envelopes and Breaking the Blind ......................... 43 
9.3 
Study Treatment Supply, Packaging and Labelling .................................................. 44 
9.4 
Compliance .................................................................................................................... 44 
9.5 
Study Treatment Storage and Accountability ............................................................ 45 
9.6 
Concomitant Medication/Therapy .............................................................................. 45 
9.7 
Treatment of Overdose of IMP .................................................................................... 45 
10 
ADVERSE EVENT REPORTING .............................................................................. 45 
10.1 Disease Progression ....................................................................................................... 46 
10.2 Categorisation of Adverse Events ................................................................................ 46 
10.2.1 
Intensity Classification ................................................................................ 46 
10.2.2 
Causality Classification ............................................................................... 46 
10.2.3 
Assessment of Expectedness ....................................................................... 47 
10.2.4 
Laboratory Test Abnormalities ................................................................... 47 
10.2.5 
Abnormal Physical Examination Findings ................................................ 47 
10.2.6 
Other Investigation Abnormal Findings .................................................... 47 
10.3 Recording and Follow-up of Adverse Events ............................................................. 47 
10.4 Serious Adverse Events ................................................................................................ 48 
10.4.1 
Definitions ................................................................................................... 48 
10.4.2 
Reporting Requirements ............................................................................. 49 
10.4.3 
Mandatory Information for Reporting an SAE ......................................... 49 
10.4.4 
Reporting Exemptions ................................................................................. 49 
10.5 Pregnancy ...................................................................................................................... 49 
10.6 Deaths ............................................................................................................................. 50 
10.7 Discontinuation/Withdrawal Due to Adverse Events/Serious Adverse Events ....... 50 
10.8 Reporting to Competent Authorities/IECs/IRBs/Other Investigators ..................... 50 
11 
STATISTICAL CONSIDERATIONS ........................................................................ 51 
11.1 Patient Classification and Definitions ......................................................................... 51 
11.2 Analyses Populations Definitions ................................................................................. 51 
CCI


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11.2.1 
Populations Analysed .................................................................................. 51 
11.2.2 
Patient Allocation and Reasons for Exclusion from the Analyses ............ 51 
11.3 Sample Size Determination .......................................................................................... 52 
11.3.1 
Significance Testing and Estimations ........................................................ 52 
11.4 Statistical/Analytical Methods ..................................................................................... 52 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 53 
11.4.1.1 
Homogeneity of Treatment Groups .............................................................. 53 
11.4.1.2 
Patient Disposition and Withdrawals .......................................................... 53 
11.4.1.3 
Efficacy Evaluation ...................................................................................... 53 
11.4.1.4 
Adjustment for Country/Centre Effect .......................................................... 54 
11.4.1.5 
Safety Evaluation ......................................................................................... 54 
11.5 Subgroup Analyses ........................................................................................................ 55 
11.6 Interim Analyses and Data Monitoring ...................................................................... 55 
11.7 Final Analysis ................................................................................................................ 55 
12 
MONITORING PROCEDURES ................................................................................. 55 
12.1 Routine Monitoring ....................................................................................................... 55 
13 
STUDY MANAGEMENT ............................................................................................ 55 
13.1 Inspections and Auditing Procedures ......................................................................... 55 
13.2 Data Recording of Study Data ..................................................................................... 56 
13.3 Source Data Verification .............................................................................................. 56 
13.4 Data Quality ................................................................................................................... 57 
13.5 Data Management ......................................................................................................... 57 
13.6 Study Management Committees .................................................................................. 58 
13.7 Record Archiving and Retention ................................................................................. 58 
14 
ADMINISTRATION PROCEDURES ........................................................................ 58 
14.1 Regulatory Approval .................................................................................................... 58 
14.2 Publication Policy .......................................................................................................... 59 
14.3 Clinical Study Report ................................................................................................... 59 
14.4 Contractual and Financial Details ............................................................................... 59 
14.5 Insurance, Indemnity and Compensation ................................................................... 60 
15 
PROTOCOL AMENDMENTS ................................................................................... 60 
16 
REFERENCES .............................................................................................................. 61 
 


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LIST OF TABLES 
Table 1 
Survival in “High-Risk” Prostate Cancer Patients after Radical 
Prostatectomy ....................................................................................................... 18 
Table 2 
Schedule of Assessments ..................................................................................... 32 
Table 3 
Total Blood Volume Required During the Study ............................................. 41 
 
LIST OF FIGURES 
Figure 1 
Scenarios of Schedules of Patient Visits ............................................................ 23 
Figure 2 
Study Flow Chart ................................................................................................. 24 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
Word Definition 
AD 
Androgen Deprivation 
AE 
Adverse Event/Experience 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of co-variance 
ANOVA 
Analysis of variance 
AST 
Aspartate Aminotransferase 
BR 
Biochemical Relapse 
BRFS 
Biochemical Relapse-Free Survival 
CA 
Competent Authorities 
CDDS 
Clinical Development Data Sciences (relates to Sponsor) 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
  
  
 
  
e 
Electronic 
EBRT 
Electron Beam Radiation Therapy 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EFS 
Event-Free Survival  
EU 
European Union 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FDA 
Food and drug administration 
FSA 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practices 
GnRH 
Gonadotrophin Releasing Hormone 
HRQoL 
Health-Related Quality of Life 
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ABBREVIATION 
Word Definition 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
LH 
Luteinising hormone 
LHRH 
Luteinising Hormone-Releasing Hormone 
MCHC 
Mean Cell Haemoglobin Concentration 
MCH 
Mean Cell Haemoglobin 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFS 
Metastases-Free Survival 
MRI 
Magnetic Resonance Imaging 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NOS 
Not Otherwise Specified 
OS 
Overall Survival 
PCSS 
Prostate Cancer Specific Survival 
PI 
Package Insert 
PP 
Per Protocol 
PSA 
Prostate Specific Antigen 
PSADT 
PSA Doubling Time 
pT3a 
Primary tumour stage 3a 
 
 
RAP 
Reporting and Analysis Plan 
RBC 
Red Blood Cell 
 
 
RP 
Radical Prostatectomy 
SAE 
Serious Adverse Event/Experience 
SD 
Standard Deviation 
SF-36 
36-Item Short Form Health Survey 
SmPC 
Summary of Product Characteristics 
CCI
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ABBREVIATION 
Word Definition 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TMF 
Trial Master File 
 
 
US 
Ultrasound 
WBC 
White Blood Cell 
WHO 
World Health Organisation 
 
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2 
INTRODUCTION 
2.1 
Disease Review 
Prostate cancer is the most common cancer in men, the second most common cause 
of cancer death and the most common cause of cancer death in men over the age of 
70. Its incidence and prevalence have dramatically increased over the past 20 years 
due to the growing practice of prostate specific antigen (PSA) mass screening of 
men aged 50 and over. As a consequence, there has been a “stage migration” 
towards less advanced stages at diagnosis, allowing for more patients to be 
candidates for radical curative treatment, notably radical prostatectomy (RP) for 
those with organ-confined disease. 
However, the question has arisen as to whether some patients with indolent prostate 
cancer discovered by systematic screening could be over-treated. Such patients 
could thus unduly suffer from the relatively common complications of radical 
treatments, such as urinary incontinence and sexual impotence. As a consequence, 
prognostic factors have been established as guidance for initial therapeutic decisions 
[1, 2]. 
Whereas patients with low or intermediate-risk prostate cancer may benefit from 
“watchful waiting”, those patients with high-risk features should be treated with 
radical approaches, such as RP or electron beam radiation therapy (EBRT). The 
usual definition of high risk patients at diagnosis is any of the following [1]:  
• 
Pathologic Gleason score of 8 to10 
• 
PSA ≥20 ng/mL 
• 
Tumour stage T3 to 4 
Among these patients, RP is indicated for those with organ-confined tumour 
(tumour stage 3a (T3a) or lower). Several retrospective and prospective studies have 
suggested that RP is an appropriate therapy for high-risk, organ-confined tumours 
[3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13], with favourable long-term outcomes, even 
without adjuvant therapy (Table 1). Importantly, some studies have shown that RP 
achieves outcomes similar to, or better than, those reported with EBRT [4, 10]. It is 
important to note that the population defined according to these high-risk criteria is 
heterogeneous. Patients with Gleason score >8 as the only criterion have a worse 
outcome than those with T3a as the only criterion [3]. Moreover, patients with two 
or three criteria have a worse prognosis than those with only one criterion [6]. 


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Table 1 
Survival in “High-Risk” Prostate Cancer Patients after Radical Prostatectomy 
Author 
High-risk 
definition 
N[a] 
BRFS (%) 
MFS (%) 
PCSS (%) 
 
 
 
3-y 
5-y 
10-y 
5-y 
10-y 
5-y 
10-y 
Ploussard 2011 
[5] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
813 
- 
74.1 
- 
96.1 
- 
98.6 
- 
Walz 2011 [6] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
887 
- 
47.4 
- 
- 
- 
- 
- 
Ku 2011 [7] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
199 
61.9 
49.2 
- 
- 
- 
- 
- 
Loeb 2010 [8] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
175 
- 
- 
68 
- 
84 
- 
92 
Masson-Lecomte 
2010 [9] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
138 
- 
40 
- 
- 
- 
- 
- 
Arcangeli 2009 
[10] 
Gleason 8–10 
or 
PSA>20 ng/mL, 
≥T2c 
122 
69.8 
- 
- 
- 
- 
- 
- 
Hsu 2010 [11] 
T3 
164 
- 
50.4 
43 
79.7 
68.7 
93.4 
80.3 
Oefelein 1997 
[12] 
“High grade” 
and ≥T2c 
116 
- 
83 
(T2c) 
34 
(T3) 
53 
(T2c) 
22 
(T3) 
96 
(T2c) 
81 
(T3) 
96 
(T2c) 
62 
(T3) 
- 
93 
(T2c) 
78 
(T3) 
Gerber 1996 [13] 
“Grade 3” 
N/A 
- 
- 
- 
- 
52 
- 
77 
BRFS, biochemical relapse-free survival; MFS, metastasis-free survival; N, number of patient; N/A, not available; PCSS, prostate 
cancer specific survival; T, tumour stage; y, year;  
a 
Most studies specified that patients with adjuvant hormone therapy were to be excluded. 
2.2 
Compound Review 
Triptorelin, 
a 
synthetic 
decapeptide 
(pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-
Pro-Gly-NH2), is a gonadotrophin releasing hormone (GnRH) analogue. Studies in 
animals and man have shown that continued administration of triptorelin exerts, 
after a short initial stimulation, an inhibitory effect on the gonadotropin secretion 
with consequent suppression of testicular and ovarian hormonal secretion.  
Triptorelin acts by stimulating the pituitary, causing a decrease in the secretion of 
the gonadotropins, luteinising hormone (LH) and follicle stimulating hormone 
(FSH). After the first administration there is a transient increase in plasma 
testosterone levels (“flare-up”), which then decreases to castration levels after 
approximately 20 days. Castration levels are maintained for as long as the product is 
administered. Following intramuscular injection, a peak in plasma triptorelin is 
observed approximately 3 hours after injection, gradually decreasing over the first 
month after the initial administration. Circulating levels remain stable for 3 months 
with subsequent injections every 3 months. 
Triptorelin is available under a variety of tradenames and in different formulations. 
It is approved for treatment of locally advanced, and metastatic prostate cancer, 


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endometriosis, uterine fibromyomas, breast cancer, female infertility, and central 
precocious puberty (onset before 8 years in girls and 10 years in boys). 
Further details can be found in the Summary of Product Characteristics (SmPC) or 
the Investigator’s Brochure where applicable. 
2.3 
Clinical Trial Rationale 
In contrast to the setting of low risk patients, for whom the concern is to avoid 
over-treating, the concern with high-risk patients is to avoid “under-treating” them, 
and as such decrease the rate of relapse after initial radical therapy. The question of 
the benefit of neoadjuvant or adjuvant therapy before or after radical therapy, 
respectively, is therefore crucial.  
The benefit of early adjuvant androgen deprivation (AD) in high-risk patients has 
been demonstrated after EBRT [14, 15, 16] and is considered as a standard of care 
[1, 2]. However, there is no scientific evidence for the benefit of adjuvant AD after 
RP (except for patients with N+ disease) [17], and this treatment approach is not 
officially recommended [1, 2, 14]. There are data suggesting that RP alone could be 
superior to EBRT alone and equivalent to EBRT plus AD [4]. Although many 
patients worldwide with high-risk prostate cancer already receive early androgen 
suppression after RP based upon the extrapolation of results observed after EBRT, 
the real benefit and benefit/risk ratio of AD after RP remains to be established in 
prospective randomised studies. 
The present study is designed to assess the benefit of early adjuvant castration with 
triptorelin for 9 months after RP versus active surveillance, in Chinese and Russian 
patients with high-risk prostate cancer. 
The Chinese guidelines indicate that after radical surgery, patients with pre-surgical 
PSA levels of ≥20 ng/mL and Gleason score >7, or having extensive positive 
surgical margins, should be given hormonal therapy as early as possible. However, 
this recommendation is not based upon robust scientific evidence, and the present 
study is also designed to confirm the anticipated benefit of early AD. Therefore, 
such patients with positive margins, who require additional treatment after RP 
(EBRT plus AD), and who could raise specific therapeutic issues outside of the 
scope of the present study will not be included. In addition, patients with 
undetectable post-RP PSA, a criterion which will limit the rate of positive margins, 
will be selected. The study will not include patients with pathologically positive 
lymph nodes after RP with lymph node dissection, for whom there is sufficient 
evidence of the benefit from AD [17] and who will be given AD outside the context 
of a clinical trial.  
The primary efficacy endpoint is biochemical (PSA) relapse-free survival (BRFS). 
However, it should be noted that the clinical significance of biochemical failure is 
equivocal, since PSA elevation may precede the onset of metastases by years. In 
high-risk patients, metastasis-free survival (MFS) could be as high as 60%, 3 years 
after PSA relapse [18]. Moreover, hormonal intervention at first PSA increase is 
controversial [19] and not officially recommended [1, 2], except in the case of local 
symptoms, concurrent occurrence of metastases, or rapid PSA doubling time 
(PSADT) <3 months [1]. Event-free survival (EFS) or MFS would be more 
clinically relevant primary endpoints than BRFS. However, the high MFS 
probability at 5 years after RP (Table 1) and the fact that most patients will receive 
AD at the time of biochemical recurrence, according to institutional guidelines, 


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resulted in the selection of BRFS as a realistic primary endpoint to show a 
significant difference within the follow-up period of this study (3 to 5 months after 
RP). 
The conventional definition of PSA failure is PSA >0.2 ng/mL, confirmed by a 
second measurement. This definition could be considered very restrictive and 
unjustified from a practical perspective and has been challenged, especially for 
clinical trials [20]. Nevertheless, the standard definition has been maintained, taking 
into account: (1) that all patients will have undetectable PSA levels at study entry 
and (2) that the decision to start and when to start AD will be left to the 
Investigator’s judgment and institutional standard of care. 
Although the duration of adjuvant and neoadjuvant hormonal therapy given after 
radiotherapy has been studied by several groups [1, 5, 16], the optimal timing and 
the duration of hormonal therapy administered after RP are still controversial and to 
our knowledge, no recommendation exists. According to Messing et al, early AD 
treatment after RP improves survival and reduces the risk of recurrence in patients 
node-positive PC [17]. Moul et al showed in their retrospective observational 
multicentre database analysis that early hormonal therapy delayed clinical 
metastasis in patients with a pathological Gleason sum >7 or PSADT of 12 months 
or less [19]. 
The current study is designed to evaluate the effectiveness of the AD induced by the 
triptorelin, a GnRH analogue, given within 8 weeks after RP for a duration of 
9 months. 
3 
STUDY OBJECTIVES 
3.1 
Primary Study Objective 
To assess the benefit of immediate adjuvant chemical castration after RP in patients 
with high-risk prostate cancer expressed as BRFS. 
3.2 
Secondary Study Objectives 
• 
To compare the two arms in terms of: 
- 
EFS, Overall Survival (OS), Specific-Mortality rate and PSADT 
- 
Impact on health-related quality of life (HRQoL) 
• 
To assess overall safety of immediate chemical castration. 
3.3 
Ancillary Exploratory Study Objectives  
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4 
STUDY DESIGN 
4.1 
Overview  
4.1.1 
Population Characteristics 
The study will be performed in males aged at least 18 years, with 
histo-pathologically confirmed adenocarcinoma of the prostate, without positive 
margins, pathological positive lymph nodes or metastases and with a high risk of 
disease progression (Gleason score ≥8 by prostatectomy and/or pre-RP PSA level 
≥20 ng/mL and/or pT3a). Patients must have undergone RP no more than 8 weeks 
prior to randomisation, with post-RP PSA levels ≤0.2 ng/mL, however no other 
treatment for prostate cancer was permitted. A total of 226 patients will be included 
from approximately 10 centres, 113 in each arm. 
4.1.2 
Design 
This open, prospective, multicentric, multinational, randomised, controlled study 
with two parallel arms is designed to compare the efficacy and safety of immediate 
9-month adjuvant treatment using triptorelin 11.25 mg (treatment onset no later than 
8 weeks after RP) versus active surveillance, after RP.  
Both arms will be monitored at the same frequency of visits (one visit every 
3 months). Assessments will be performed to identify any BR/Clinical Disease 
Progression.  
This study will be conducted in a Phase IV setting in Russia and China, where 
triptorelin is approved for the treatment of locally advanced or metastatic prostate 
cancer.  
4.1.3 
Structure 
Visit 1: Screening Visit 
Six weeks (±3 days) after RP, the patient will give written informed consent and 
will undergo the screening assessments to include a blood sample for serum post-RP 
PSA level.  
Visit 2: Baseline Visit (Randomisation) 
Two weeks after the screening visit and no more than 8 weeks (± 3 days) after RP, 
when post-RP PSA level is available, eligible patients will be randomised to one of 
two arms, either the triptorelin treatment arm or to the active surveillance arm. 
For patients randomised to the triptorelin treatment arm, triptorelin 11.25 mg will be 
administered intramuscularly every 3 months (±7 days), for a total of three 
injections (at the Baseline, 3 and 6 months visits). 
For patients randomised to the active surveillance arm, no adjuvant treatment with 
any method (hormonal or surgical castration and/or radiation therapy) should be 
initiated prior to evidence of disease progression (clinical or biochemical). They will 
be monitored in the same way as for the triptorelin treatment arm. 
Visits 3 to 14: Monitoring Period 
All randomised patients (in both arms) will be followed every 3 months (± 1 week) 
to monitor the occurrence of BR and/or clinical disease progression over a period of 
36 months after randomisation (from Visit 3 to Visit 14).  
Disease progression is defined as BR and/or clinical disease progression (whichever 
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• 
BR is defined as the first elevated PSA value >0.2 ng/mL confirmed by a 
second measurement recorded 4 to 6 weeks later. The time-point at which the 
first PSA value above 0.2 ng/mL is recorded, will be deemed to be the time of 
BR. 
• 
Clinical disease progression is defined as evidence of local/locoregional 
recurrence and/or lymph node involvement and/or distant metastases 
documented by relevant standard investigations (such as ultrasound (US) 
guided biopsy, X-ray, computed tomography (CT) scan, or magnetic 
resonance imaging (MRI) guided biopsy). 
Any patient (in either arm) who has disease progression at any time will receive 
appropriate medical care from the Investigator. New/additional therapy (for example 
radiation therapy, surgical castration, or hormonal treatment) will be proposed 
according to the Investigator’s decision and in line with local standard of care. In 
both arms and depending on the time of occurrence of disease progression, the 
patient’s visit schedule will be as follows:  
• 
If BR and/or clinical disease progression occurs before 36 months, the patient 
will continue to be monitored until 36 months post-randomisation (Visit 14) 
at which point he will be considered to have completed the study.  
• 
If at 36 months (Visit 14), the patient has not shown any sign of BR and/or 
clinical disease progression, and if the statistically required 61 BRs were not 
observed at the global study level, he will enter the follow-up period.  
Post-Visit 14: Follow-up Visits: 
If at 36 months post-baseline (at Visit 14), the patient does not have BR and/or 
clinical disease progression and if the statistically required 61 BRs are not observed 
at the global study level, he will continue to be followed every 3 months until: 
• 
He has a BR and/or clinical disease progression 
• 
Or, the 61 required BRs are observed on the global study level.  
PSA levels, physical examinations and clinical disease progression assessments 
(where deemed necessary by the Investigator and in accordance with local standards 
of care) will continue to be performed at each follow-up visit to monitor disease 
progression.  
The study will be considered to be terminated when:  
• 
All included patients have completed their minimum monitoring period of 
36 months.  
• 
And, when 61 BRs are observed at the global study level. 
Study Completion/Early Withdrawal Visit:  
Patients who have disease progression (BR and/or clinical disease progression) 
within 36 months (event documented before Visit 14) will continue to be monitored 
until Visit 14 which will be considered as the Study Completion Visit. 
Patients who have disease progression after 36 months (event documented during or 
after Visit 14) will be considered to have completed the trial. Their last study visit 
would be the visit when disease progression is documented.  
After 36 months, patients who do not have disease progression during the whole 
study will be considered to have completed the trial once the statistically required 
61 BR events occur on the study global level.  


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At any time during the study and for any reason, in case of early 
withdrawal/discontinuation, 
the 
Investigator 
should 
perform 
a 
last 
monitoring/follow-up visit considered as the early withdrawal visit. 
Figure 1 describes the different scenarios of the schedules of patient visits. Figure 2 
provides an overview of the study. See Section 7.1 for the schedule of study 
assessments. 
Figure 1 Scenarios of Schedules of Patient Visits  
 
SCENARIO 1:  
BR and/or clinical disease 
progression occurs before 36 months  
(i.e. event documented before V14)  
 
SCREENING VISIT  
BASELINE  VISIT  
SCENARIO 2:  
BR and/or clinical disease progression 
occurs after 36 months  
(i.e. event documented during or after 
V14)  
 
SCENARIO 3:  
The subject did not have disease 
progression (BR and/or clinical 
disease progression) at all  
 
DECISION:  
The subject may receive 
new/additional therapy (as decided 
by the investi gator) and will be 
followed until 36 months  
 
END OF STUDY:  
Visit 14 (36 months) is considered 
as the end of study  
 
DECISION:  
The subject may receive 
new/additional therapy (as decided 
by the investigator) and will be 
considered to have completed the 
t rial  
 
END OF STUDY:  
The visit when BR and/or clinical 
disease progression is documented 
will be considered as the end of study  
END OF STUDY:  
The sponsor will inform the sites 
when the 61 events are observed. 
At that time, all ongoing subjects 
who performed the required 36 
months monitoring period will be 
asked to perform a last follow - up 
visit considered as the end of study 
DECISION:  
The subj ect will be monitored every 
3 months until Visit 14. He will 
then enter the follow - up period and 
continue to be followed until 61 BR 
are observed on the study global 
level  
 


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Figure 2 Study Flow Chart  
 
 
4.1.4 
Stopping Rules and Discontinuation Criteria 
Patients will be discontinued from study medication (triptorelin) in the event of 
unacceptable toxicity, evidence of lack of castration at 3 Months/Visit 3 
(documented by serum testosterone ≥50 ng/dL (or ≥0.50 ng/mL) confirmed by a 
second elevated serum testosterone level at least 2 weeks later).  
Patients will be discontinued from the study at the study cut-off date, or in the event 
of death, patient withdrawal of consent, lost to follow-up or noncompliance with the 
protocol. 
Patients will not be withdrawn from the study if study medication is discontinued. 
Follow-up will continue for all patients every 3 months and for at least 36 months. 
Only one reason for withdrawal must be recorded in the case report form (CRF). All 
Adverse events (AEs) leading to patient withdrawal should be followed until 
resolution unless confirmed by the Investigator that the event is not going to resolve. 
Patient withdrawal criteria are detailed in Section 6.4 
4.1.5 
Early Study Termination 
The Sponsor may terminate this study at any time. Reasons for termination may 
include but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies point to a potential 
health hazard for trial patients 
• 
Insufficient patient enrolment 
• 
Any information becoming available during the study that .substantially 
changes the expected benefit risk profile of the study treatments 
4.2 
Endpoints 
4.2.1 
Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be BRFS as defined for each patient by the 
period of time from randomisation to time of BR. 
Biochemical Relapse (BR) definition: increased PSA >0.2 ng/mL confirmed by a 
second measurement performed 4 to 6 weeks later. The time point at which the first 


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elevated PSA measurement is >0.2 ng/mL is recorded will be deemed to be the time 
of BR. 
BRFS data will be censored on the date of the last assessment on study for patients 
who do not have BR or on the date of clinical disease progression for those who 
progress before BR while on study or on the date of death for those who die before 
BR while on study (of any cause). 
Secondary efficacy endpoints 
• 
EFS as defined for each patient as the period of time from randomisation to 
time of first diagnosed locoregional disease recurrence (positive biopsy 
and/or node involvement) or first metastases (bone or visceral) documented 
by relevant standard investigations (US-guided biopsy, X-ray, CT scan, or 
MRI-guided biopsy) or death from any cause. 
• 
OS defined as the time between randomisation and death from any cause.  
• 
Disease-specific mortality measured as the time between randomisation and 
death related to prostate cancer. 
• 
PSADT defined as the time from the first documented PSA increase 
>0.2 ng/mL to the time of the first value more than twice that of the first 
increased value.  
• 
Serum testosterone in the triptorelin arm at Baseline, 3, 6 and 9 months.  
• 
Health-Related Quality of Life (HRQoL) assessed using the Functional 
Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire, version 4, 
and the 36-item short form (SF-36) health survey, version 2 in both treatment 
arms at Baseline, 9, 24, and 36 months. 
4.2.2 
Exploratory Endpoints 
4.2.3 
Safety Endpoints 
Signs and symptoms, incidence and severity of all AEs, regardless of relationship to 
the study drug, graded according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0, including 
serious AEs (SAEs) and treatment discontinuations due to toxicity will be 
monitored from the time that the patient gives informed consent until 
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Visit 5/Month 9 (three months after the last injection for those patients in the 
triptorelin arm). After this period, only AEs/SAEs related to triptorelin will be 
reported. 
4.3 
Justification of Design 
The rationale for the present study assessing the benefit of early adjuvant ADT in 
men with high risk features/locally advanced prostate cancer was based on the 
evidence derived from adjuvant ADT in a radiation therapy setting. 
Indeed, several studies on adjuvant ADT with a definitive radiation therapy have 
shown an improvement in disease-free survival in patients with high risk/ locally 
advanced prostate cancer. 
For patients undergoing surgery, the benefit of ADT and its timing as adjuvant 
hormonal therapy or at PSA relapse, is still a subject of debate. Little clinical 
evidence exists to date. Furthermore long-term survival outcomes for these patients 
primarily treated with RP are good, therefore the choice of “biochemical relapse” as 
a primary endpoint is justified.  
An open, prospective, multicentric, randomised, controlled study with two parallel 
arms, with 5 years study duration is appropriate to address the above clinical 
question. See also Section 2.3 for additional information. 
4.3.1 
Study Population for Analysis 
Patients with high-risk features/locally advanced prostate cancer who undergo to 
RP. Patients at high risk of disease progression are defined as those having at least 
one of the following features: pre-RP PSA ≥20 ng/mL and/or Gleason ≥8 (RP 
Specimen) and/or pT3a. 
See Section 6.2 for detailed information of patient inclusion and exclusion criteria. 
4.3.2 
Study Duration 
The anticipated recruitment period of this study is 2 years. Screening will be 
performed up to 2 weeks before randomisation. For each patient, study participation 
is planned to be at least 36 months.  
The overall duration of the study will be approximately 60 months. The study will 
be considered to have started when the first patient has provided signed informed 
consent, and will be considered to have finished after the last patient has completed 
the last follow-up visit. 
Where possible, all randomised patients will be monitored every 3 months, over at 
least a period of 36 months, after randomisation. Follow-up may continue beyond 
this if BR is not reported at 36 months and the statistically required 61 BRs have not 
yet been reached, in which case the patient will continue on study until one of these 
events occurs. See Section 4.1.3 for further details. 
The study will be considered to be terminated when:  
• 
All included patients have completed their minimum monitoring period of 
36 months  
• 
And, when 61 BRs are observed on the study global level. 
4.3.3 
Justification of Exploratory Endpoints 
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5 
COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICE, 
ETHICAL 
CONSIDERATIONS & INFORMED CONSENT 
5.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with independent ethics 
committees/institutional review boards (IECs/IRBs), informed consent regulations, 
the Declaration of Helsinki and International Conference on Harmonisation (ICH) 
[32] Good Clinical Practice (GCP) guidelines, FDA, 21 CFR Part 11, Electronic 
Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized 
Systems Used in Clinical Trials.  
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the trial protocol/amendment(s), 
written informed consent form, any consent form updates, patient emergency study 
contact cards, patient recruitment procedures (e.g. advertisements), any written 
information to be provided to patients and a statement from the IEC/IRB that they 
comply with GCP requirements. The IEC/IRB approval must identify the protocol 
version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study 
has started, amendments should be made only in exceptional circumstances. 
Changes that do not affect patient safety or data integrity are classified as 
administrative changes and generally do not require ethical approval. If ethically 
relevant aspects are concerned, the IEC/IRB must be informed and, if necessary, 
approval sought prior to implementation. Ethical approval on administrative 
changes will be obtained if required by local/site IEC/IRB. 
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5.2 
Informed Consent 
Prior to study entry, the Investigator, or a person designated by the Investigator, will 
explain the nature, purpose, benefits and risks of participation in the study to each 
patient, patient’s legally acceptable representative or impartial witness. Written 
informed consent must be obtained prior to the patient entering the study (before 
initiation of any study-related procedure and administration of the investigational 
medicinal product [IMP]). Sufficient time will be allowed to discuss any questions 
raised by the patient. 
The Sponsor will provide a sample informed consent form. The final version 
controlled form must be agreed to by the Sponsor, and the IEC/IRB and must 
contain all elements included in the sample form, in language readily understood by 
the patient. Each patient’s original consent form, personally signed and dated by the 
patient or by the patient’s legally acceptable representative, and by the person who 
conducted the informed consent discussion, will be retained by the Investigator. The 
Investigator will supply all enrolled patients with a copy of their signed informed 
consent. 
The consent form may need to be revised during the trial should important new 
information become available that may be relevant to the safety of the patient or as a 
result of protocol amendments. In this instance approval should always be given by 
the IEC/IRB. It is the Investigator’s responsibility to ensure that all patients 
subsequently entered into the study and those currently in the study sign the 
amended form. This is documented in the same way as previously described. 
Patients who have completed the study should be informed of any new information 
that may impact on their welfare/wellbeing. 
The Investigator should, with the consent of the patient, inform the patient’s primary 
physician about their participation in the clinical trial. 
6 
STUDY POPULATION 
6.1 
Screening Log and Number of Patients 
Each Investigator will maintain a record of all patients who were considered eligible 
for entry into the study but who were not enrolled. For each patient, the primary 
reason for exclusion will be recorded. 
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Each Investigator will also maintain a record of all patients enrolled into the study 
(i.e., who signed the informed consent form). In the event that a patient randomised 
to the triptorelin treatment arm does not receive triptorelin, the primary reason will 
be recorded. 
It is planned to recruit approximately 226 patients at approximately 10 centres in 
Russia and China. Section 11.3 provides a discussion of sample size. 
6.2 
Inclusion Criteria 
All patients must fulfil the following: 
(1) 
Provide written informed consent by the patient prior to any study-related 
procedure  
(2) 
Men aged ≥18 years  
(3) 
Histo-pathologically confirmed adenocarcinoma of the prostate  
(4) 
Radical Prostatectomy with curative intent performed no more than 8 weeks 
before randomisation 
(5) 
High-risk criteria of disease progression, defined as follows:  
• 
Gleason score ≥8 on prostatectomy specimen, and/or 
• 
Pre-RP PSA level ≥20 ng/mL, and/or  
• 
Primary tumour stage 3a (pT3a) (with any PSA and any Gleason score) 
(6) 
Post-RP PSA levels ≤0.2 ng/mL at 6 weeks. 
(7) 
Eastern cooperative oncology group (ECOG)/world health organisation 
(WHO) performance status of 0 to 1 
6.3 
Exclusion Criteria 
Patients will not be included in the study if any of the following apply: 
(1) 
Has evidence of lymph nodes or distant metastasis 
(2) 
Has positive margins  
(3) 
Has evidence of any other malignant disease, not treated with a curative intent 
(4) 
Previously received or is currently receiving any treatment of prostatic cancer 
besides the concerned RP 
(5) 
Had a surgical castration 
(6) 
Has a life expectancy of <5 years 
(7) 
Suffers from a significant comorbidity or an untreated infection 
(8) 
Is likely to require treatment during the study with drugs that are not 
permitted by the study protocol 
(9) 
Has a history of hypersensitivity to triptorelin or any luteinising hormone 
releasing hormone (LHRH) analogues or to any of the excipients of triptorelin 
11.25 mg 
(10) Was treated with any investigational drug within 4 weeks before the study 
entry 
(11) Has abnormal baseline findings, any other medical condition(s) or laboratory 
findings that, in the opinion of the Investigator, might jeopardise the patient’s 
safety or decrease the chance of obtaining satisfactory data needed to achieve 
the objective(s) of the study 
(12) Is unable to undergo regular follow-up 
(13) Has any mental condition rendering him unable to understand the nature, 
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(14) Has a history of, or known current, problems with alcohol or drug abuse. 
6.4 
Patient Withdrawal Criteria  
If one or more of the following occurs, the patient will be discontinued from study 
medication if randomised in the triptorelin arm: 
• 
Unacceptable toxicity linked to the treatment 
• 
Evidence of lack of castration at 3 Months/Visit 3 (documented by serum 
testosterone ≥50 ng/dL ≥0.50 ng/mL) confirmed by a second elevated serum 
testosterone level at least two weeks later). 
If one or more of the following occurs, the patient will be withdrawn from the study: 
• 
The study cut-off date 
• 
Death 
• 
Withdrawal of consent 
• 
Lost to follow-up 
• 
Noncompliance with the protocol 
Patients will not be withdrawn from the study if study medication is discontinued. 
Monitoring will continue for all randomised patients every 3 months and for at least 
36 months. 
No patients will be replaced or enrolled more than once.  
All efforts should be made to contact patients to maintain adequate follow-up. 
Reason for withdrawal from treatment and/or study, and the date of withdrawal 
should be documented. 
Whenever possible, the tests and evaluations planned every 3 months over the 
36 months post-RP (see schedule of assessments, Section 7.1) should be performed. 
In particular at least one assessment should be performed for any patient 
withdrawing during the 9 months of triptorelin treatment, to obtain all safety data.  
Following discontinuation from the study, there is no study-specific provision of 
further treatment and additional medical care of the patients once their participation 
in the trial has ended. 
6.5 
Discontinuation/Withdrawal Procedures 
If the patient is withdrawn from the study (ceases participation in the study before 
completion of the assessments planned in the protocol), the primary reason should 
be recorded in the CRF. Withdrawal due to AEs should be distinguished from 
withdrawal due to insufficient efficacy.  
The Investigator will provide or arrange for appropriate follow-up (if required) for 
patients withdrawing from the study treatment, and will document the course of the 
patient’s condition. When a patient withdraws due to an AE, the Investigator should 
follow the procedures documented in Section 10 to assess the safety of triptorelin. 
Any patient (i.e. in both arms) who develops BR and/or clinical disease progression 
(whichever occurs first) at any time, will receive the appropriate medical care from 
his Investigator. New/additional therapy (such as radiation therapy, surgical 
castration, or hormonal treatment) will be proposed to him at the decision of the 
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7 
METHODOLOGY 
7.1 
Study Schedule  
The schedule of observations and assessments during the study are summarised in 
Table 2. 


 
 
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Table 2 
Schedule of Assessments 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
XX 
 
Screening  Baseline 
3M 
6M 
9M 
12M 
15M 
18M 
21M 
24M 
27M 
30M 
33M 
36M 
Every 
3M  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG/WHO 
Performance Status 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone Level 
[a], [b] 
 
X 
X [c] 
X[d] 
X[d] 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
and Haematology 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PSA Level [e] 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Disease 
Progression 
Assessment [f] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FACT-P 
Questionnaire 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
SF-36 Health 
Survey 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Triptorelin Injection 
[a] 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication/Therapy  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and 
Concomitant 
Non-Drug Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs [l] 
X 
X 
X 
X 
X 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
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Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
XX 
Visit Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE, adverse event; 
 ECOG, Eastern Cooperative Oncology Group; FACT P, functional assessment of cancer therapy prostate; M, month; PSA, prostate specific antigen; 
 
a 
Only for the triptorelin adjuvant treatment arm (± 7 days) 
b 
Always prior to each triptorelin injection (Baseline, 3 months, and 6 months) 
c 
Evidence of lack of castration at 3 months/Visit 3 will be documented by serum testosterone ≥50 ng/dL (≥0.50 ng/mL) confirmed by a second elevated serum testosterone level at least two 
weeks later. For the other testosterone assessment time points (Baseline, and 6 and 9 months), no confirmation test is required. 
d 
If evidence of lack of castration at 3 months/Visit 3, therefore testosterone sampling is not required anymore at Visit 4/Month 6 and Visit 5/Month 9. 
e 
Starting from Visit 3, any elevated PSA concentration >0.2 ng/mL should be confirmed by a second measurement performed 4 to 6 weeks later. No confirmation test is required after evidence 
of disease progression (biochemical relapse (BR) and/or clinical disease progression). 
f 
Clinical disease progression assessments (such as ultrasound [US] guided-biopsy, X-ray, computed tomography [CT] scan, magnetic resonance imaging [MRI]) can be performed at any time 
during the study at the Investigator’s discretion and as per local standard care. 
l 
Adverse events (AEs) will only be collected until Visit 5/Month 9; this corresponds to three months after the last triptorelin injection for those patients in the triptorelin arm. After this visit, 
only AEs and SAEs related to triptorelin according to Investigator's judgement should be reported. 
 
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7.2 
Study Visits 
7.2.1 
Screening Visit (Visit 1) Week –2 (±3 Days) 
Screening (Visit 1) will be performed 6 weeks (±3 days) after RP. Written informed 
consent must be obtained prior to enrolment when the following assessments will be 
performed: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Demography (country, date of birth, sex, ethnic origin/race)  
• 
Prostate Cancer history (prior to RP: date of first histological diagnosis, 
Gleason score, TNM staging, last available PSA level, last available 
testosterone level) 
• 
Radical Prostatectomy procedure (date, lymphadenectomy procedure details, 
pathological features (Gleason Score and TNM staging)) 
• 
Significant Medical or Surgical history (including ongoing medical history 
other than prostate cancer related)  
• 
Physical examination 
• 
Blood sampling for PSA level, haematology and biochemistry 
7.2.2 
Baseline (Visit 2) Day 1 
At the Baseline Visit (Visit 2), 2 weeks after the screening visit and no more than 
8 weeks (±3 days) after RP, when post-RP PSA level is available, eligible patients 
will be randomised to one of two arms. During this visit, the following procedures 
will be performed (for patients in the triptorelin arm they must be performed prior to 
drug administration): 
• 
Physical examination 
• 
Vital signs (heart rate, blood pressure [sitting], height and weight) 
• 
ECOG/WHO performance status assessment  
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Randomisation 
• 
Blood sampling for testosterone level (in triptorelin treatment arm only) 
• 
Review of pre-treatment AEs and new or changed concomitant 
medications/nondrug therapy 
• 
HRQoL questionnaires (FACT-P questionnaire and SF-36 health survey) 
• 
Triptorelin injection, for patients randomised to the triptorelin treatment arm 
only. 
7.2.3 
Monitoring Period (Visits 3 to 14) 
The patient monitoring visits should be performed every 3 months (±1 week) for a 
period of 36 months post-randomisation (Visits 3 to Visit 14) for all patients, unless 
otherwise indicated (for patients in the triptorelin arm, the assessments must be 
performed prior to drug administration): 
• 
Physical examination  
• 
ECOG/WHO performance status assessment at Months 9, 24, and 36 
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• 
Blood sampling for PSA level, every 3 months (note that the elevated PSA 
concentration >0.2 ng/mL must be confirmed by a second measurement 
performed 4 to 6 weeks later. No confirmation test is required after evidence 
of disease progression (BR and/or clinical disease progression):  
- 
If the first disease progression is a BR, for the following PSA rises, 
no confirmation test is required.  
- 
If clinical disease progression occurs before BR, no PSA rise 
confirmation test is required neither  
• 
Blood sampling for testosterone level, at Months 3, 6 and 9 (in the triptorelin 
treatment arm only). Evidence of lack of castration will be evaluated at 
Month 3/Visit 3 documented by serum testosterone ≥50 ng/dL (≥0.50 ng/mL) 
and must be confirmed by a second elevated serum testosterone level at least 
two weeks later. For the other testosterone assessment time points (Baseline, 
6 and 9 months), no confirmation test is required.  
• 
If lack of castration is confirmed at Visit 3, the testosterone sampling at 
Visit 4 and Visit 5 are not required.  
• 
Blood sampling for haematology and biochemistry, at Month 9 (Visit 5) 
• 
Clinical disease progression assessments (US, biopsy, X-ray, CT scan, MRI, 
etc.) can be performed at any time during the study at the Investigator’s 
discretion and as per local standard care.  
• 
HRQoL questionnaires (FACT-P questionnaire and SF-36 health survey), at 
Months 9, 24 and 36.  
• 
Documentation of new or changed concomitant medications and nondrug 
therapy, including documentation of new/additional therapy, if any. 
• 
Evaluation of existing and new AEs and symptoms: AEs will be collected 
until Visit 5, after this visit, only AEs and SAEs related to triptorelin 
according to Investigator's judgement should be reported. 
• 
Triptorelin injection at Months 3 and 6 (±7 days) only for patients 
randomised to the triptorelin arm. 
• 
Survival status. 
7.2.4 
Follow-up Period (>36 Months After Randomisation) 
For any patients followed beyond 36 months post-randomisation, the following 
assessments should be performed: 
• 
Physical examination should be performed every 3 months  
• 
Blood sampling for PSA level should be performed every 3 months (note that 
the first PSA value that is >0.2 ng/mL must be confirmed by a second 
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measurement performed 4 to 6 weeks later. For any following PSA rises, no 
confirmation retest is required. In cases where clinical disease progression 
occurs before BR, no confirmation retest is required).  
• 
Clinical Disease Progression assessments (US, biopsy, X-ray, CT scan, MRI, 
etc.) can be performed at any time during the study at the Investigator’s 
discretion and as per local standard care  
• 
Documentation of new or changed concomitant medications and nondrug 
therapy 
• 
Evaluation of existing and new AEs and symptoms: at this level, only AEs 
and SAEs related to triptorelin according to investigator's judgement should 
be reported. 
• 
Survival status. 
7.2.5 
Study Completion or Early Withdrawal Visit 
Patients who have a disease progression (BR and/or clinical disease progression) 
before 36 months (i.e. event documented before Visit 14) will continue to be 
monitored until Visit 14, which will be considered as their study completion visit.  
Patients who have disease progression (BR and/or clinical disease progression) after 
36 months (i.e. event documented during or after Visit 14) will be considered to 
have completed the trial. Their last study visit would be the visit when disease 
progression is documented.  
After 36 months, patients who do not have disease progression during the whole 
study will be considered to have completed the trial once the statistically required 
61 BR events occur.  
At any time during the study and for any reason, in cases of early 
withdrawal/discontinuation, 
the 
Investigator 
should 
perform 
a 
last 
monitoring/follow-up visit.  
The required assessments are similar to those of any follow-up visit:  
• 
Physical examination  
• 
Blood sampling for PSA level  
• 
Clinical Disease Progression assessments (US, biopsy, X-ray, CT scan, MRI, 
etc.), as appropriate  
• 
Documentation of new or changed concomitant medications and nondrug 
therapy 
• 
Evaluation of existing and new AEs and symptoms. 
• 
Survival status 
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8 
STUDY EVALUATIONS 
For the timing of assessments during the study, refer to the study schedule in 
Section 7.1. 
8.1 
Efficacy Endpoints and Evaluations  
For the timing of evaluations during the study, refer to the study schedule in Section 
7.1.  
8.1.1 
Primary Efficacy Endpoint and Evaluations 
Biochemical Relapse-Free Survival (BRFS) is defined for each patient by the period 
of time from randomisation to time of BR. 
Biochemical Relapse definition: increased PSA >0.2 ng/mL confirmed by a second 
measurement performed 4 to 6 weeks later. The time point at which the first 
elevated PSA measurement is >0.2 ng/mL is recorded will be deemed to be the time 
of BR. 
BRFS data will be censored on the date of the last assessment on study for patients 
who do not have BR or on the date of clinical disease progression for those who 
progress before BR while on study or on the date of death for those who die before 
BR while on study (of any cause). 
PSA levels will be evaluated on a per patient basis and assessed in terms of the 
overall population (see Section 11 for further details). Blood samples to obtain the 
required serum volume for PSA testing will be taken every 3 months. Testing will 
be performed in a central laboratory designated by the Sponsor. Details of the 
methodology and reference ranges will be provided in the Trial Master File (TMF) 
and the laboratory manual. 
8.1.2 
Secondary Efficacy Endpoints and Evaluations 
• 
EFS as defined for each patient as the period of time from randomisation to 
time of first diagnosed locoregional disease recurrence (positive biopsy 
and/or node involvement) or first metastases (bone or visceral) documented 
by relevant standard investigations (US guided biopsy, X-ray, CT scan, or 
MRI guided biopsy) or death from any cause. 
• 
OS defined as the time between randomisation and death from any cause.  
• 
Disease-specific mortality measured as the time between randomisation and 
death related to prostate cancer. 
• 
PSADT defined as the time from the first documented PSA increase 
>0.2 ng/mL to the time of the first value more than twice that of the first 
increased value.  
• 
Serum testosterone in the triptorelin arm at Baseline, 3, 6 and 9 months.  
• 
Health-Related Quality of Life (HRQoL) assessed using the FACT-P 
questionnaire, version 4, and the 36-item short form (SF-36) health survey, 
version 2 in both treatment arms at Baseline, 9, 24, and 36 months. 
Clinical disease progression assessments  
These can be performed to identify the presence of locoregional disease recurrence 
(positive biopsy and/or node involvement) or metastases (bone or visceral), using 
standard investigations (US, biopsy, X-ray, CT scan, MRI, etc.), performed 
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Disease-specific mortality  
This will be determined according to documented cause of death being disease 
progression. 
PSA  
See Section 8.1.1 for details of PSA evaluations. 
Testosterone  
Blood samples to obtain the required serum volume for testosterone testing will be 
collected at Baseline, and at Months 3, 6 and 9 in patients treated in the triptorelin 
arm only (before the triptorelin injection). Testing will be performed in a central 
laboratory designated by the Sponsor. Standard testosterone blood sample collection 
procedures should be used. Details of the methodology and reference ranges will be 
provided in the TMF and the laboratory manual.  
HRQoL  
Each patient will complete the FACT-P HRQoL questionnaire [33], version 4 and 
the SF-36 health survey, version 2 at Baseline and at Months 9, 24 and 36. Patients 
will be provided with a paper version of each questionnaire in the local language, 
which will be completed during the visit.  
All secondary endpoint evaluations will be performed on a per patient basis and 
assessed in terms of the overall population (see Section 11 for further details). 
8.2 
Safety Endpoints and Evaluations 
8.2.1 
Safety Endpoints 
Signs and symptoms, incidence and severity of all AEs, regardless of relationship to 
the study drug (graded according to the NCI-CTCAE, version 4.0), including SAEs 
and treatment discontinuations due to toxicity will be monitored from the time that 
the patient gives informed consent until Visit 5/Month 9 (three months after the last 
injection for those patients in the triptorelin arm). In addition, data relating to related 
AEs and SAEs will continue to be monitored and recorded after Visit 5/Month 9 
until the end of the study. 
8.2.2 
Adverse Events, Signs and Symptoms 
AEs will be monitored from the time that the patient gives informed consent until 
Visit 5/Month 9 (three months after the last injection is administered for those 
patients in the triptorelin arm). In addition, data relating to related AEs and SAEs 
will continue to be monitored and recorded after Visit 5/Month 9 until the end of the 
study. AEs will be elicited by direct, nonleading questioning at each study visit or 
by spontaneous reports. Further details for AE reporting can be found in Section 10. 
8.2.3 
Physical Examination 
A physical examination will be performed by a physician (Investigator or designee). 
If in the opinion of the Investigator there are any clinically significant changes in the 
physical examination findings (abnormalities) they will be recorded as AEs. 
8.2.4 
Vital Signs  
Height, weight, heart rate, and blood pressure (sitting) will be measured at Baseline. 


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8.2.5 
Clinical Laboratory Tests 
Blood samples for clinical laboratory tests will be taken at Screening (Visit 1) and 
Month 9 (Visit 5), and will consist of the following: 
Haematology: full blood count including red blood cells (RBC), haemoglobin, 
haematocrit, mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell 
haemoglobin concentration (MCHC), white blood cells (WBC) with differential and 
platelet count; neutrophils, lymphocytes, monocytes, eosinophils, basophils. 
Biochemistry: urea, creatinine, total bilirubin, chloride, bicarbonate, sodium, 
potassium, calcium, inorganic phosphate, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transferase (GGT), albumin, total protein, total cholesterol, triglycerides, and fasting 
glucose. 
Clinical laboratory tests will be performed in a central laboratory designated by the 
Sponsor. Standard haematological and biochemical blood sample collection should 
be used. Details of the methodology and reference ranges will be provided in the 
TMF. 
All clinically relevant abnormal laboratory tests occurring during the study will be 
repeated at appropriate intervals until they return to baseline or to a level deemed 
acceptable by the Investigator and the Sponsor’s clinical monitor (or his/her 
designated representative), or until the abnormality is explained by an appropriate 
diagnosis. See Section 10.2.4 for abnormal laboratory tests that should be recorded 
as AEs in the eCRF. 
8.3 
Exploratory Endpoints and Evaluations 
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8.4 
Total Blood Volume 
The required blood volume per assessment is show in Table 3. 
Table 3 
Total Blood Volume Required During the Study 
Assessment  
Blood Volume 
PSA 
When performed alone: 2.5 mL of blood 
When performed with testosterone and/or biochemistry: 
5 mL of blood for all assessments 
Testosterone 
When performed alone: 2.5 mL of blood 
When performed with PSA and/or biochemistry: 5 mL of 
blood for all assessments 
Biochemistry 
When performed alone : 2.5 mL of blood 
When performed with PSA/and or testosterone: 5 mL of 
blood for all assessments 
Haematology 
2 mL of blood 
Note that : 
• 
The first elevated PSA concentration >0.2 ng/mL must be confirmed by a 
second PSA concentration >0.2 ng/mL (additional 2.5 mL of blood).  
The total blood volume per patient is variable depending on the time of occurrence 
of disease progression. The required amount of blood will vary between a minimum 
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of 64 mL and a maximum of 87 mL for a patient performing the 36 months 
monitoring period. For any additional visit post-36 months, the volume needed is 
2.5 mL of blood for PSA analysis. 
9 
STUDY TREATMENTS 
9.1 
Study Treatments Administered 
It is forbidden to use IMP for purposes other than as defined in this protocol. 
Administration of the IMP will be supervised by the Investigator, or designee. 
Pharmaceutical form  
Powder and solvent for suspension for intramuscular injection prolonged released 
form. 
Active component  
Triptorelin pamoate, as triptorelin 11.25 mg.  
Drug name  
China: Triptorelin pamoate for injection; 15 mg 
Russia: Diphereline® 11.25 mg 
Posology and method of administration  
Triptorelin will be administered as a hormonal adjuvant to RP for patients 
randomised to the triptorelin treatment arm. These patients will receive one 
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intramuscular injection of the product, which will be repeated every 3 months for a 
total of three injections: at Baseline, 3 and 6 months. 
Patients in the active surveillance arm will be treated according to each study 
centre’s standard of care, excluding administration of any method of adjuvant 
treatment (hormonal treatment and/or surgical castration and/or radiation therapy).  
Relapsing patients (BR and/or clinical disease progression) in both arms can receive 
new/additional therapy, according to the Investigator’s decision and the local 
standard of care. 
9.2 
Patient Identification and Allocation to Study Treatment 
All patients enrolled must be identifiable throughout the study. At Screening, 
potential patients will be allocated a patient number.  
Patients will be enrolled sequentially and assigned the lowest identification number 
available. This identification number is unique and will be composed of five digits: 
the first two digits will correspond to the site number, and the three other digits will 
be implemented chronologically depending on patient inclusion. The Investigator 
will maintain a list of patient numbers and names to enable records to be found at a 
later date if required. 
9.2.1 
Randomisation 
The Sponsor’s randomisation manager who is a statistician independent from the 
study, will prepare the master randomisation list for this study. The block size of 
this computer-generated randomisation list will ensure a balanced ratio between the 
two treatment arms. 
After eligibility is confirmed at Visit 2 (Baseline), patients will be assigned a 
randomisation number and will be randomised in one of two treatment arms 
(“Triptorelin treatment” or “Active surveillance”). This will be done by opening the 
first not used treatment allocation envelope in the set allocated to the site. Under no 
circumstances will the Investigator change the treatment arm allocated to the 
patient. 
Recruitment will stop once 226 patients have been randomised. Randomised 
patients who terminate their study participation for any reason before starting the 
treatment will retain their randomisation number (the randomisation number will not 
be reused). The next patient is given the next randomisation number. 
Randomised patients who leave the study early will not be replaced. 
The Sponsor’s randomisation manager will keep the confidential master list in a 
secure location. Access to this list must be restricted until authorisation is given for 
analysis. 
9.2.2 
Blinding, Emergency Envelopes and Breaking the Blind 
This is an open-label study. However, the treatment arm assigned to a randomisation 
number must be blinded while it is not allocated. Therefore, for each randomisation 
number, a treatment allocation envelope containing the treatment arm to be 
considered will be prepared by the Sponsor’s randomisation manager. 
As soon as a study treatment allocation envelope is opened, specifications are to be 
written on it, in the pre-printed area (opener’s identification, opening date and time 
and signature). Monitors should routinely check these specifications on the allocated 


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envelopes and the integrity of all other envelopes. All the study treatment allocation 
envelopes must be kept in the TMF in the coordinating office at study completion. 
9.3 
Study Treatment Supply, Packaging and Labelling 
A commercial formulation of triptorelin (Diphereline®) will be supplied by Ipsen 
Pharma. Triptorelin will be supplied as a powder which will be mixed with a 0.8% 
mannitol solution at the time of administration. A homogeneous suspension will be 
obtained by mixing and should be injected immediately. 
Triptorelin powder will be supplied in a 4 mL glass vial with a rubber stopper and 
an aluminium cap. Each vial will contain slightly more than 11.25 mg to ensure that 
the full dose will be administered to the patient. Suspension vehicle (2 mL) will be 
supplied in a 3 mL capacity glass ampoule. Both products should be stored below 
25°C. 
Triptorelin will be provided in a pack containing one clear glass vial containing the 
triptorelin powder, one glass ampoule containing the suspension vehicle, one 
syringe and two needles. 
The core label texts for all packaging units will be translated or adjusted to be in 
compliance with applicable regulatory requirements, national laws in force and in 
accordance with the local languages. A description of the core text of the IMP labels 
is displayed below: 
• 
Name, address and telephone number of the Sponsor  
• 
Study number 
• 
Pharmaceutical dosage form 
• 
Route of administration 
• 
Quantity of dose units 
• 
Batch number 
• 
Treatment number 
• 
Randomisation number: information completed on site 
• 
For clinical trial use only 
• 
Investigator Name: information completed on site (the main contact for 
information on the product, clinical trial)  
• 
Storage conditions 
• 
Expiry date 
• 
Directions for use (reference may be made to the leaflet for the person 
administering the product) 
Triptorelin will be delivered to the investigational sites. A sufficient quantity will be 
supplied as well as an acknowledgment of receipt form.  
The Investigator, or designee, will only dispense triptorelin to patients included in 
this study and randomised to the triptorelin treatment arm. Dispensing for each 
patient will be documented in the CRF.  
See the SmPC/product leaflet (PL) of the concerned countries for further details. 
9.4 
Compliance 
In the treatment arm, triptorelin will be administered via intramuscular injection by 
a medically-trained individual. Any incomplete or missed injections will be 
documented in the CRF including the reason.  
Compliance will be assessed by reporting of study drug administration in the 
patient’s record and by the drug accountability forms. 


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9.5 
Study Treatment Storage and Accountability 
The Investigator, or an approved representative (e.g. pharmacist), will ensure that 
triptorelin is stored in a secured area, under recommended temperature monitored 
storage conditions, in accordance with applicable regulatory requirements and will 
be reconstituted and dispensed by qualified staff members. 
All study treatments are to be accounted for on the accountability log provided by 
the Sponsor. It is essential that all used and unused supplies are retained for 
verification (by the Sponsor or Sponsor’s representative). The Investigator should 
ensure adequate records are maintained via the accountability log. 
In accordance with good manufacturing practice (GMP) guidelines, destruction of 
the unused and used investigational product once administration has taken place 
should be carried out for a given trial site or a given trial period only after any 
discrepancies have been investigated and satisfactorily explained and the 
reconciliation have been accepted. Any destruction should be documented using a 
certificate of destruction. 
9.6 
Concomitant Medication/Therapy 
No adjuvant treatment with any method (hormonal treatment and/or surgical 
castration and/or radiation therapy) should be initiated in the active surveillance arm 
prior to evidence of recurrence (clinical or biochemical). 
New/additional therapy (radiation therapy, surgical castration, hormonal treatment, 
etc.) will be proposed to any patient (in either treatment arm) who develops BR 
and/or clinical disease progression (whichever occurs first) at any time, according to 
the local standard of care. Patients are not permitted to receive any other IMP during 
the study or during the 4 weeks prior to randomisation. 
9.7 
Treatment of Overdose of IMP 
The incidence of overdose during the clinical development of triptorelin is low, with 
no significant sequelae reported. Based on these data, there is no evidence to 
suggest an associated risk of overdose with triptorelin treatment. Animal data do not 
suggest any effects other than those on sex hormone concentration and the 
consequent effect on the reproductive tract. If overdose occurs, symptomatic 
management is indicated. Any appropriate treatment of overdose will be determined 
by the Investigator according to the characteristics of the events and will be 
recorded in the patient’s CRF. An event resulting from an overdose of the trial 
medication is not considered as serious unless it meets the definition of an SAE and 
consequently should be reported on the SAE form (see Section 10.4). 
10 
ADVERSE EVENT REPORTING 
An AE is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
An undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs 
(e.g. tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. 
laboratory findings, electrocardiogram). In clinical studies an AE can include an 
undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.  


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This definition includes events occurring from the time of the patient giving 
informed consent until the end of the study (as defined in Section 4.3.2). 
10.1 
Disease Progression 
Natural progression or deterioration of the malignancy under study will be recorded 
as part of the efficacy evaluation and should not be recorded as an AE/SAE. 
Likewise, death due to disease progression will be recorded as part of the efficacy 
evaluation and will not be regarded as an SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related 
to a relapse or an expected change or progression of the baseline malignant disease. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
Investigator’s judgement) if they are: 
• 
Judged by the Investigator to be unusually severe or accelerated (for stage of 
malignant disease), or 
• 
If the Investigator considers the deterioration of malignancy-related signs and 
symptoms to be caused directly by the study drug. 
As a rule, if there is any uncertainty about an AE being due solely to the malignancy 
under study, it should be reported as an AE/SAE as appropriate. This definition 
includes events occurring from the time of the patient giving informed consent until 
the end of the study. 
Symptoms of disease progression that are not considered to be AEs should be 
documented in the CRF. 
10.2 
Categorisation of Adverse Events 
10.2.1 
Intensity Classification 
AEs will be recorded and graded according to the NCI-CTCAE, version 4. In view 
of meta-analyses, and for conversion purposes, the following conversion mapping 
will apply if the NCI-CTCAE scale is not available for a given AE: 
• 
NCI-CTCAE Grade 1 corresponds to mild, 
• 
NCI-CTCAE Grade 2 corresponds to moderate, 
• 
NCI-CTCAE Grade 3 corresponds to severe, 
• 
NCI-CTCAE Grade 4 corresponds to life threatening/disabling, 
• 
NCI-CTCAE Grade 5 corresponds to death. 
Where:  
Mild: 
symptoms do not alter the patient’s normal functioning 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the patient 
Severe: 
symptoms definitely hazardous to well-being, significant impairment of 
function or incapacitation. 
Life-threatening:  any event that places the patient at immediate risk of death from 
the reaction as it occurred, i.e. it does not include a reaction that, had it occurred in a 
more severe form, might have caused death. Also see Section 10.4.1. 
10.2.2 
Causality Classification 
The relationship of an AE to the IMP will be classified according to the following: 
Related: 
reports including good reasons and sufficient information (e.g. 
plausible time sequence, dose-response relationship, pharmacology, 
positive de-challenge and/or re-challenge) to assume a causal 


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relationship with the IMP in the sense that it is plausible, 
conceivable or likely. 
Not related: 
reports including good reasons and sufficient information (e.g. 
implausible time sequence and/or attributable to concurrent disease 
or other drugs) to rule out a causal relationship with the IMP. 
10.2.3 
Assessment of Expectedness  
The expectedness of an AE/reaction shall be determined by the Sponsor according 
to the Investigator’s Brochure for an unapproved IMP or SmPC or Package Insert 
(PI) for an authorised medicinal product which is being used according to the terms 
and conditions of the marketing authorisation.  
The reference document for assessing expectedness of AEs/reactions in this study 
will be the current Investigator’s Brochure. 
10.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the 
following apply:  
• 
they result in a change in triptorelin schedule of administration (change in 
dosage, delay in administration, triptorelin discontinuation), 
• 
they require intervention or a diagnosis evaluation to assess the risk to the 
patient, 
• 
they are considered as clinically significant by the Investigator. 
10.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the Investigator, in physical 
examination findings (abnormalities) will be recorded as AEs.  
10.2.6 
Other Investigation Abnormal Findings 
Abnormal objective test findings as judged by the Investigator as clinically 
significant (e.g., electrocardiogram changes) that result in a change in IMP dosage 
or administration schedule, or in discontinuation of the IMP, or require intervention 
or diagnostic evaluation to assess the risk to the patient, should be recorded as AEs. 
10.3 
Recording and Follow-up of Adverse Events 
At each visit the patient should be asked a nonleading question such as: “Do you 
feel different in any way since starting the new treatment/the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to triptorelin, will be recorded on the AE page(s) of the CRF up to and 
including Visit 5/Month 9. Events involving drug reactions, accidents, illnesses with 
onset during the treatment phase of the study, or exacerbations of pre-existing 
illnesses should be recorded according to the NCI terminology if applicable.  
AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the Investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as an SAE requiring immediate notification to the Sponsor or its 
designated representative. For all AEs, sufficient information should be obtained by 
the Investigator to determine the causality of the AE (i.e., triptorelin or other 
illness). The Investigator is required to assess causality and record that assessment 


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on the CRF. Follow-up of the AE, after the date of therapy discontinuation, is 
required if the AE or its sequelae persist. Follow-up is required until the event or its 
sequelae resolve or stabilise at a level acceptable to the Investigator and the 
Sponsor’s clinical monitor or his/her designated representative 
10.4 
Serious Adverse Events 
10.4.1 
Definitions  
All SAEs (as defined below) regardless of treatment group or suspected relationship 
to IMP must be reported immediately (within 24 hours of the Investigator’s 
knowledge of the event) to the pharmacovigilance contact specified at the beginning 
of this protocol. If the immediate report is submitted by telephone, this must be 
followed by detailed written reports using the SAE report form. 
A SAE is any AE occurring at any dose that: 
(1) 
Results in death; 
(2) 
Is life threatening, that is any event that places the patient at immediate 
risk of death from the reaction as it occurred. It does not include a 
reaction that, had it occurred in a more severe form, might have caused 
death; 
(3) 
Results in in-patient hospitalisation or prolongation of existing 
hospitalisation, excluding admission for social or administrative reasons 
(see further); 
(4) 
Results in a persistent or significant disability/incapacity, where 
disability is a substantial disruption of a person's ability to conduct 
normal life functions; 
(5) 
Results in congenital anomaly/birth defect in the offspring of a patient 
who received the IMP; 
(6) 
Is an important medical event that may not result in death, be 
life-threatening, or require hospitalisation when, based upon appropriate 
medical judgement, may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalisation, or the development of drug dependency or drug abuse. 
Regardless of the above criteria, any additional AE that the Sponsor or an 
Investigator considers serious should be immediately reported to the Sponsor and 
included in the corporate SAEs database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 
24 hours). For chronic or long-term in-patients, in-patient admission also 
includes transfer within the hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the Investigator or treating 
physician. 
For 
protocol-specified 
hospitalisation 
in 
clinical 
trials, 
prolongation is defined as any extension beyond the length of stay described 
in the protocol. Prolongation in the absence of a precipitating, 
treatment-emergent, clinical AE (i.e., not associated with the development of 


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a new AE or worsening of a pre-existing condition) may meet criteria for 
"seriousness" but is not an adverse experience and thus is not subject to 
immediate reporting to the Sponsor.  
• 
Pre-planned or elective treatments/surgical procedures should be noted in the 
patient’s screening documentation. Hospitalisation for a pre-planned or 
elective treatment/surgical procedure should not be reported as an SAE unless 
there are complications or sequelae which meet the criteria for seriousness 
described above. 
10.4.2 
Reporting Requirements 
Any SAE must be reported immediately (within 24 hours), independent of the 
circumstances or suspected cause, if it occurs or comes to the attention of the 
Investigator at any time from the signing of the informed consent, until 
Visit 5/Month 9 (three months after the last injection for those patients in the 
triptorelin arm). 
Any SAE with a suspected causal relationship to triptorelin occurring at any other 
time after Visit 5/Month 9 must be promptly reported. 
10.4.3 
Mandatory Information for Reporting an SAE 
The following information is the minimum that must be provided to the Sponsor's 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Trial number 
• 
Centre number 
• 
Patient number 
• 
AE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the 
Sponsor or representative as soon as it is available. Upon receipt of the initial report, 
the Sponsor will ask for the Investigator's causality assessment if it was not 
provided with the initial report. 
The Investigator should report a diagnosis or a syndrome rather than individual 
signs or symptoms. The Investigator should also try to separate a primary AE 
considered as the foremost untoward medical occurrence from secondary AEs 
which occurred as complications. 
10.4.4 
Reporting Exemptions 
Relapse or progression of disease that is not worse in terms of time-course or 
severity of the disease expected in that patient is considered an efficacy outcome 
parameter (as described in Section 10.1), and is excluded from the definition of an 
AE/SAE. These events will not be reported as AEs or SAEs. 
Tumour-related signs and symptoms will only be recorded as AEs during the trial if 
they worsen in severity or increase in frequency beyond that normally expected for 
disease progression as determined by the Investigator. 
Death due to disease progression during the study or follow-up period will be 
regarded as an efficacy endpoint and will not be included as an SAE (see Section 
10.1). 
10.5 
Pregnancy 
Since this study will be conducted in men, this is not applicable. 


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10.6 
Deaths 
All AEs resulting in death at any time until the end of the study (except those listed 
in Sections 10.1 and 10.4.4) must be reported as an SAE within 24 hours of the 
Investigator’s knowledge of the event, as described in Section 10.4.2.  
The convention for recording death is as follows:  
• 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction). 
• 
Outcome: fatal. 
For AEs leading to death, NCI-CTCAE Grade 5 is the only appropriate grade (see 
Section 10.2.1). Deaths that cannot be attributed to an NCI-CTCAE term associated 
with Grade 5 or that cannot be reported within an NCI-CTCAE category as ‘Other’, 
have to be reported as one of these four AE options: 
• 
Death not otherwise specified (NOS) 
• 
Disease progression NOS 
• 
Multi-organ failure 
• 
Sudden death. 
10.7 
Discontinuation/Withdrawal Due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient efficacy of triptorelin (see 
Sections 6.4 and 6.5). 
If triptorelin is discontinued due to an SAE it must be reported immediately to the 
Sponsor’s designated representative (see Section 10.4). 
In all cases the Investigator must ensure the patient receives appropriate medical 
follow-up (see Section 10.3). 
10.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The Sponsor will ensure that processes are in place for submission of reports of 
Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring during the 
study to the Competent Authorities (CA), IECs, IRBs and other Investigators 
concerned by triptorelin. Reporting will be done in accordance with the applicable 
regulatory requirements.  


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Patient Classification and Definitions 
• Enrolled patient: 
Patient fully informed about the study who has given 
written informed consent to participate (before any 
occurrence of trial related procedure)  
• Screened failure 
patient: 
Enrolled patient who fails to fulfil one or more entry 
criteria and thus does not proceed to the treatment phase 
of the study. Although not exposed to study medication 
or treatment approach, they may have been exposed to 
some study related procedures. Records up to the time of 
premature termination should be completed including the 
reason for termination 
• Treated patient : 
Enrolled patient who is treated with at least one dose of 
study medication or followed the treatment approach 
• Randomised 
patient: 
Enrolled patient who is allocated to a treatment group at 
random. 
• Study Completed 
patient: 
Randomised/Treated patient who has completed all 
specified phases/assessments of the study. 
• Drop-out: 
Randomised/Treated patient who did not complete the 
study and or treatment.  
11.2 
Analyses Populations Definitions 
• Screened population: 
All patients enrolled  
• Randomised 
population: 
All patients randomised 
• Safety population: 
All randomised patients that have received at least 
one injection for patients from the triptorelin arm or 
that have undergone at least one day of active 
surveillance for patients from the active surveillance 
arm. 
Patients will be analysed as treated for the safety 
analyses. 
• Intention-to-treat (ITT) 
population:  
All randomised patients analysed according to the 
arm to which they were randomised (i.e. regardless 
of treatment approach followed) 
• Per protocol (PP) 
population: 
All patients in the ITT population for whom no 
major protocol violations/deviations occurred  
11.2.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint(s) will be performed 
on the ITT population. Per protocol analyses will only be considered as exploratory. 
The analyses of safety data will be performed in the safety population. 
11.2.2 
Patient Allocation and Reasons for Exclusion from the Analyses 
The rules for the allocation of patients to each of the analysis populations will be 
defined and documented during a data review meeting held prior to database lock. 


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During the data review meeting, based on minor or major protocol 
violations/deviations, patients may be excluded from the ITT/PP population. 
Patients may be excluded from the analyses if one or more of the following 
violations/deviations occur: 
• 
Randomisation criteria violations 
• 
Inclusion/exclusion criteria violations 
• 
Did not receive any study medication (triptorelin arm only) 
• 
Inadequate compliance of study medication 
• 
Prohibited medication intake 
• 
Deviations from time windows  
• 
Deviations from study medication administration 
• 
No baseline evaluation of PSA 
• 
No valid post-baseline evaluation of PSA 
• 
Other protocol violation/deviations 
11.3 
Sample Size Determination 
The sample size estimation was based on the primary efficacy endpoint of BRFS. 
Assuming that with RP alone, the probability of biochemical (PSA) relapse as 
defined in Section 4.2.1 at 36 months after RP is 40% in high-risk patients 
(Section 2.1, Table 1), and anticipating that immediate adjuvant hormonal therapy 
added to RP will reduce this probability to 20% (percentage considered to be 
clinically relevant), 113 patients per treatment group (226 in total) are required in 
order to detect such a difference using a two-sided log-rank test at a significance 
level of 5% and a power of 90%, assuming a common 1% exponential dropout rate 
(corresponding to an approximate 5% dropout rate per year). 
These 226 patients are required to observe 61 BR in order to achieve 90% power. 
For patients with no sign of disease progression at 36 months post-randomisation, 
monitoring will continue until the 61 BR events are observed at the study global 
level. If the 61 events are observed before all patients complete the 36 months 
post-randomisation monitoring period, the study will be continued until those 
patients reach their 36 month visit (Visit 14). 
It is planned to recruit 226 patients in approximately 10 centres in two countries 
(China and Russia). 
11.3.1 
Significance Testing and Estimations 
All statistical tests will be performed two-sided with a type I error rate set at 5%. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external Contract Research 
Organisation (CRO) managed by the Sponsor’s Clinical Development Data 
Sciences Department. 
A reporting and analysis plan (RAP) describing the planned statistical analysis in 
detail with tables, figures and listings (TFLs) templates will be developed as a 
separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® 
(Version 8 or higher). 


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11.4.1 
Demographic and Other Baseline Characteristics 
In order to ensure balance of treatment groups, descriptive summary statistics (n, 
mean, standard deviation (SD), median, minimum, maximum) or frequency counts 
of demographic and baseline data (medical history, concomitant disease 
(pre-treatment AEs and ongoing medical history, prior medications and therapies, 
baseline symptoms etc.) will be presented by treatment group and overall for the 
ITT population. 
11.4.1.1 Homogeneity of Treatment Groups 
Homogeneity of treatment groups at baseline will be assessed descriptively, or by 
95% confidence interval (CI). No formal statistical significance testing will be 
performed. 
11.4.1.2 Patient Disposition and Withdrawals 
The numbers and percentages of patients enrolled and included in the ITT/PP and 
safety populations will be tabulated by country and centre. The reasons for patient 
exclusions from each of the populations will also be tabulated. In addition, the 
numbers of patients who were randomised, discontinued and completed the study 
will be tabulated by treatment group. Primary reasons for discontinuation of study 
treatment will be tabulated. 
11.4.1.3 Efficacy Evaluation 
Primary and secondary endpoints are defined in Section 8.1. The primary efficacy 
variable is BRFS, which is defined as the time from date of randomisation to first 
BR. BRFS data will be censored on the date of the last assessment on study for 
patients who do not have BR or on the date of clinical disease progression for those 
who progress before BR while on study or on the date of death for those who die of 
any cause before BR while on study. The primary analyses of BRFS will be 
performed in the ITT population. A log-rank test (two-sided) will be used to 
compare BRFS time between the two treatment groups with nominal significance 
level 0.05 (two-sided). The Kaplan-Meier method will be used to obtain the 
estimates of median EFS associated with each treatment. The 95% CI of the median 
event-free time will also be provided. The Cox Proportional hazards model will be 
fitted to compute hazard ratios and the corresponding 95% CI. The primary analysis 
will be repeated on the PP population. 
To identify which factors are associated with BRFS outcome, Cox proportional 
hazards regression models will be used. To explore prognostic factors analysis of 
deviance will be conducted. Each factor will be assessed individually for prognostic 
value (p<0.05) using a univariate Cox model. Factors that are deemed to have 
prognostic value (p<0.2) will be included as covariates in a multivariate Cox model 
to assess their significance in the presence of other factors. A backward selection 
process will be used to identify the final set of prognostic factors (exit p-value set to 
be 0.05). Treatment will then be added to this final model to assess the effect of 
treatment when adjusted for these factors. 
The secondary efficacy variables are EFS, OS and PSADT, serum testosterone in 
the triptorelin-treated arm at 3, 6, 9 months post-RP, and HRQoL measured at 9, 24 
and 36-months post-RP. 


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Time-to-event data will be analysed as the primary efficacy variable. All 
quantitative variables will be analysed with either analysis of variance (ANOVA) or 
analysis of covariance (ANCOVA) adjusting for baseline variable score when 
measured. 
Missing data will not be imputed and dropouts will not be replaced. For 
time-to-event analyses, the handling of patients without the event will be specified 
separately for each parameter in the RAP. 
HRQoL changes from baseline for each scale/dimension will be calculated for each 
arm at each time point. Missing data imputation rules will be defined in the RAP. 
Treatment groups will be compared based on ANCOVA adjusting for baseline score 
and 95% CI will be presented to display treatment effect estimates. 
11.4.1.4 Adjustment for Country/Centre Effect 
Descriptive analysis will be performed to describe any possible country effect. 
11.4.1.5 Safety Evaluation 
All safety data will be included in the patient data listings. Analyses and summary 
tables will be based upon the safety population. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; latest version available) and will be classified by MedDRA preferred 
term and system organ class. AE listings will be presented by patient, system organ 
class and preferred term. 
Incidence of all reported AEs, treatment emergent AEs (TEAE) and SAEs will be 
tabulated by treatment group and overall. In addition, summary tables will be 
presented by maximum intensity, drug relationship and AEs/TEAEs associated with 
premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of triptorelin, or  
• 
it was present prior to receiving the first dose of triptorelin but the intensity 
increased during the active phase of the study, or  
• 
it was present prior to receiving the first dose of triptorelin, the intensity is the 
same but the drug relationship became related during the active phase of the 
study.  
TEAEs will be flagged (*) in the AEs listings.  
Concomitant medication will be coded by using WHO Drug Dictionary (latest 
version available) and will be summarised by treatment group and overall with the 
number and percentage of patients receiving concomitant medication by drug class 
and preferred drug name. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group 
and overall will be presented for clinical laboratory tests 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 of the number and percentage of patients with low, 
normal or high values and normal or abnormal exams.  
AEs reported by Investigators using the NCI-CTCAE classification (version 4) will 
be coded using the MedDRA dictionary (latest version available).  
Summary incidence tables will be provided, classified by body system, preferred 
term and associated NCI-CTCAE worst grade. In the event of multiple occurrences 


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of the same AEs being reported by the same patient, the maximum intensity 
(Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing > not applicable) will 
be chosen. Dose delays and dose interruptions will be listed by cycle. 
Haematological and biochemistry toxicities will be recorded and graded according 
to the NCI-CTCAE criteria 
11.5 
Subgroup Analyses 
If subgroup analyses are deemed necessary, they will be described in the RAP. 
11.6 
Interim Analyses and Data Monitoring 
No interim analysis will be performed. 
11.7 
Final Analysis 
Final analysis will be performed after 61 BR events have been observed. 
A total of 61 events are required in the final analysis to demonstrate a 20% absolute 
improvement in rate of BR with 90% power using a significance level of 0.05. 
12 
MONITORING PROCEDURES 
The Investigator is responsible for the validity of all data collected at the site. The 
Sponsor is responsible for monitoring this data to verify that the rights and 
wellbeing of patients are protected, that trial data are accurate (complete and 
verifiable to source data) and that the trial is conducted in compliance with the 
protocol, GCP and regulatory requirements. 
12.1 
Routine Monitoring 
Sponsor-assigned monitors will conduct regular site visits. The Investigator will 
allow direct access to all relevant files (for all patients) and clinical trial supplies 
(dispensing and storage areas) for the purpose of verifying entries made in the 
eCRF, and assist with the monitor’s activities, if requested. Adequate time and 
space for monitoring visits should be made available by the Investigator. 
The site must complete the eCRFs within 5 days of the patient’s visit and on an 
ongoing basis to allow regular review by the study monitor, both remotely via the 
internet and during site visits. The central study monitor at Ipsen will use functions 
of the Electronic Data Capture (EDC) system to address any queries raised while 
reviewing the data entered by the study site personnel in a timely manner. 
Whenever a patient name is revealed on a document required by the Sponsor (e.g., 
laboratory print-outs) the name must be blacked out permanently by the site 
personnel, leaving the initials visible, and annotated with the patient number as 
identification. 
13 
STUDY MANAGEMENT  
13.1 
Inspections and Auditing Procedures 
Authorised personnel from external CAs and Sponsor-authorised Quality Assurance 
personnel may carry out inspections and audits. The purpose of an audit is to ensure 
that ethical, regulatory and quality requirements are fulfilled in all studies performed 
by the Sponsor. 
Auditors and inspectors must have direct access to study documents and site 
facilities as specified in section 12.1, and to any other locations used for the purpose 
of the study in question (e.g., laboratories). 


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In the event of the site being notified directly of a regulatory inspection, the 
Investigator must notify the Sponsor representative as soon as possible, to assist 
with preparations for the inspection. 
13.2 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly 
marked and permit easy identification of a patient’s participation in the specified 
clinical trial. 
The Investigator must record all data relating to protocol procedures, triptorelin 
administration, laboratory data, safety data and efficacy ratings on the eCRFs 
provided for the study. The Investigator, by completing the signature log, may 
formally designate authority to complete eCRFs to appropriately qualified staff 
having certified user access to the eCRF.  
FACT-P and SF-36 patient questionnaires will be printed and completed using 
paper versions. 
The Investigator must, as a minimum, provide an electronic signature (e-signature) 
to the whole case book to attest to the accuracy and completeness of all the data. If 
any changes are made to the eCRF after a form has been electronically signed, the 
Investigator will be required to perform an additional e-signature authorising 
agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is 
always required. In the eCRF, the audit trail function will allow the changes made to 
be viewed on each item entered. 
13.3 
Source Data Verification 
The FDA 21 CFR Part 11, is a regulation which provides criteria for acceptance by 
the FDA, under certain circumstances, of electronic records, e-signatures and 
handwritten signatures executed to electronic records as equivalent to paper records 
and handwritten signatures on paper. 
As required by GCP, the Sponsor assigned monitor must verify, by direct reference to 
the source documents, that the data required by the protocol are accurately reported on 
the eCRF.  
The source documents must, as a minimum, contain the following:  
• 
A statement that the patient is included in a clinical trial  
• 
The date that informed consent was obtained prior to participation in the study  
• 
The identity of the study, visit dates (with patient status) 
• 
Demographics 
• 
Diagnosis and eligibility criteria,  
• 
Results of physical examinations, vital signs 
• 
Medical history  
• 
Required laboratory test 
• 
Clinical disease progression assessments, if any 
• 
HRQoL questionnaires administration 
• 
Triptorelin administration  
• 
Associated concomitant medication 
• 
All AEs with start/end dates 
• 
The date the patient completed or withdrew from the study and the reason for 
withdrawal, if applicable 


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Definition for source data and source documents are given below: 
• Source Data: 
All original records and certified copies of original 
records of clinical findings, observations, or other 
activities necessary for the reconstruction and evaluation 
of the trial. Source data are contained in source 
documents (original records or certified copies). [ICH 
GCP Section 1.51] 
• Source Documents: Original documents, data and records (e.g. hospital 
records, clinical and office charts, laboratory notes, 
memoranda, patients’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, 
x-rays, patient files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments 
involved in the clinical trial). [ICH GCP Section 1.52] 
The patient must have consented to their medical records being viewed by 
Sponsor-authorised personnel, and by local, and possibly foreign, CAs. This 
information is included in the informed consent. 
13.4 
Data Quality 
Monitored eCRFs will be reviewed (secondary monitoring) for completeness, 
consistency, legibility and protocol compliance by the CRO assigned by Data 
Management group. 
Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the Investigator by the monitor for 
clarification/correction. The Investigator must ensure that queries are dealt with 
promptly. All data changes and clarifications can be viewed in the audit trail 
function of the eCRF. 
13.5 
Data Management 
Electronic Data Capture will be used for collecting patient data. Each site is required 
to have a computer and internet connection available for site entry of clinical data. 
All entries in the eCRF will be done under the electronic 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. 
Paper CRFs will be available to ensure business continuity in case the eCRFs are 
unavailable at the site for a prolonged period, they will be used only after prior 
permission is gained from the Sponsor. 
Data management will be conducted by a CRO, directed by the Sponsor’s Data 
Management Department. All data management procedures will be completed in 
accordance with Ipsen and the contracted CRO Standard Operating Procedures 
(SOPs). Data will be monitored at the Investigator site (for further details see 


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Section 12 and any documentation removed from the Investigator site(s) will be 
tracked by the CRO and the monitor (e.g. patient questionnaires). 
The Sponsor will ensure that an appropriate eCRF is developed to capture the data 
accurately, and suitable queries are raised to resolve any missing or inconsistent 
data. The Investigator will receive their data, from the clinical trial, in an electronic 
format (PDF files) which will be an exact copy of the eCRF, and will include the 
full audit trail, for archiving purposes and future reference. 
Any queries raised within the EDC system during the data management process will 
also be tracked by the contracted data management CRO. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant 
parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent 
with information provided to the Sponsor’s pharmacovigilance department (and vice 
versa).  
The coding of AEs, medical history and concomitant medication terms will be 
performed by the contracted CRO and reviewed and approved by the Sponsor’s 
Coding group. 
13.6 
Study Management Committees 
There will be no study management committees. 
13.7 
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure the archiving 
facilities are adequate and archiving/retention responsibilities of the Investigator 
have been discussed.  
Trial documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or planned 
marketing applications in an ICH region (that is at least 15 years or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the 
product. However, these documents should be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the 
Sponsor. The Investigator should take measures to prevent accidental or premature 
destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing-out the site. The Sponsor will inform the Investigator, in 
writing, as to when these documents no longer need to be retained. 
If the Principal Investigator relocates or retires, or otherwise withdraws his/her 
responsibility for maintenance and retention of study documents, the Sponsor must 
be notified (preferably in writing) so that adequate provision can be made for their 
future maintenance and retention. 
14 
ADMINISTRATION PROCEDURES 
14.1 
Regulatory Approval 
As required by local regulations, the Sponsor’s Regulatory Affairs group will ensure 
all legal regulatory aspects are covered, and obtain approval of the appropriate 
regulatory bodies, prior to study initiation in regions where an approval is required. 


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14.2 
Publication Policy 
The Sponsor encourages acknowledgement of all individuals/organisations involved 
in the funding or conduct of the study, including medical writers or statisticians 
patient to the consent of each individual and entity concerned, including 
acknowledgement of the Sponsor. 
The results of this study may be published or communicated to scientific meetings 
by the Investigators involved in the study. For multicentre studies, a plan for 
scientific publication and presentation of the results may be agreed and 
implemented by the study Investigators or a Steering Committee. The Sponsor 
requires that reasonable opportunity be given to review the content and conclusions 
of any abstract, presentation, or paper before the material is submitted for 
publication or communicated. This condition also applies to any amendments that 
are subsequently requested by referees or journal editors. The Sponsor will 
undertake to comment on the draft documents within the time period agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the Sponsor and authors (or the author’s institution). 
Requested amendments will be incorporated by the author, provided they do not 
alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until 
(i) a patent application is filed for the content of the publication in accordance with 
applicable provisions of the clinical trial agreement concerned, (ii) the Sponsor 
consents to the publication, or (iii) the time period as may be agreed in the 
contractual arrangements, including clinical trial agreements, governing the 
relationship between the Sponsor and authors (or authors’ institution) after receipt 
of the proposed publication by the Sponsor, whichever of (i), (ii) or (iii) occurs first. 
The author undertakes to reasonably consider the Sponsor's request for delay to the 
proposed publication should the Sponsor reasonably deem premature to publish the 
results obtained at the then stage of the study. 
14.3 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on 
structure and contents of clinical study reports. A final CSR will be prepared where 
any patient has signed informed consent, regardless of whether the trial is completed or 
prematurely terminated. Where appropriate an abbreviated report may be prepared. 
The CSR will be in compliance with any applicable regulatory requirements, national 
laws in force and will be in English. 
14.4 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and 
the Sponsor will sign a clinical study agreement prior to the start of the study, outlining 
overall Sponsor and Investigator responsibilities in relation to the study. Financial 
remuneration will cover the cost per included patient, based on the calculated costs of 
performing the study assessments in accordance with the protocol, and the specified 
terms of payment will be described in the contract. The contract should describe 
whether costs for pharmacy, laboratory and other protocol-required services are being 
paid directly or indirectly. 


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14.5 
Insurance, Indemnity and Compensation 
The Sponsor will provide Product Liability insurance for all patients included in the 
clinical study. Where required, a hospital specific indemnity agreement will be used. 
15 
PROTOCOL AMENDMENTS 
In the event that an amendment to this protocol is required (see section 5.1), it will 
be classified into one of the following three categories: 
• 
Non-Substantial Amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the 
IECs/IRBs or CA for information purposes. 
• 
Substantial Amendments are those considered ‘substantial’ to the conduct of 
the clinical trial where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the patients; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of the IMP used in the trial. 
Substantial amendments must be notified to the IECs/IRBs and CA. Prior to 
implementation, documented approval must be received from the IECs/IRBs. In 
the case of the CA in the European Union (EU) member states, approval or 
‘favourable opinion’ can be assumed if the CA has raised no grounds for 
nonacceptance during an allocated time period (to be confirmed with the 
Sponsor’s Regulatory Affairs (RA) representative) following acknowledgment 
of receipt of a valid application to make a substantial amendment.  
• 
Urgent Amendments are those that require urgent safety measures to protect 
the trial patients from immediate hazard and as such may be implemented 
immediately by the Sponsor with subsequent IECs/IRBs and CA notification, 
forthwith. 


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16 
REFERENCES 
 
1  
Horwich A, Parker C, Bangma C, et al. Prostate cancer: ESMO clinical practice 
guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl 5): 
v129-v133. 
2  
Heidenreich A, Aus G, Bolla M, et al. EAU Guidelines on Prostate Cancer. Eur Urol 
2008; 53:68–80. 
3  
You D, Jeong IG, Kim CS. Role of radical prostatectomy for high-risk prostate cancer. 
Korean J Urol. 2010; 51(9):589–595. 
4  
Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical 
prostatectomy versus external-beam radiotherapy for patients with high-risk prostate 
cancer. Cancer. 2011; 117(13):2883-2891. 
5  
Ploussard G, Masson-Lecomte A, Beauval JB, et al. Radical Prostatectomy for 
High-risk Prostate Cancer Defined by Preoperative Criteria: Oncologic Follow-up in 
National Multicenter Study in 813 Patients and Assessment of Easy-to-use Prognostic 
Substratification. Urology. 2011; 78(3):607–613. 
6  
Walz J, Joniau S, Chun FK, et al. Pathological results and rates of treatment failure in 
high-risk prostate cancer patients after radical prostatectomy. BJU Int. 2011; 
107(5):765–770. 
7  
Ku JH, Jeong CW, Park YH, et al. Biochemical recurrence after radical prostatectomy 
with or without pelvic lymphadenectomy in Korean men with high-risk prostate 
cancer. Jpn J Clin Oncol. 2011; 41(5):656–662. 
8  
Loeb S, Schaeffer EM, Trock BJ, et al. What are the outcomes of radical 
prostatectomy for high-risk prostate cancer? Urology. 2010; 76(3):710–714. 
9  
Masson-Lecomte A, Hupertan V, Comperat E, et al. Pathological findings and 
oncological control afforded by radical prostatectomy in men with high-risk prostate 
cancer: a single-centre study. World J Urol. 2010; 29(5):665–670. 
10  
Arcangeli G, Strigari L, Arcangeli S, et al. Retrospective comparison of external beam 
radiotherapy and radical prostatectomy in high-risk, clinically localized prostate 
cancer. Int J Radiat Oncol Biol Phys. 2009; 75(4):975–982. 
11  
Hsu CY, Wildhagen MF, Van Poppel H, Bangma CH. Prognostic factors for and 
outcome of locally advanced prostate cancer after radical prostatectomy. BJU Int. 
2010; 105(11):1536–1540. 
12  
Oefelein MG, Smith ND, Grayhack JT, et al. Long-term results of radical retropubic 
prostatectomy in men with high grade carcinoma of the prostate. J Urol. 1997; 
158(4):1460–1465. 
 


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13  
Gerber GS, Thisted RA, Scardino PT, et al. Results of radical prostatectomy in men 
with clinically localized prostate cancer. JAMA. 1996; 276(8):615–619. 
14  
Kumar S, Shelley M, Harrison C, et al. Neo-adjuvant and adjuvant hormone therapy 
for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006; 
CD006019. 
15  
Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and 
radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman 
Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005; 6: 
841–845. 
16  
Pilepich MV, Winter K, John MJ, et al. Phase III Radiation Therapy Oncology Group 
(RTOG) trial 86-10 of androgen deprivation adjunct to definitive radiotherapy in 
locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phhys 2001; 
50:1243–1252. 
17  
Messing EM, Manola J, Yao J, et al. Eastern Cooperative Oncology Group study EST 
3886: immediate versus deferred androgen deprivation treatment in patients with 
node-positive prostate cancer after radical prostatectomy and pelvic 
lymphadenectomy. Lancet Oncol 2006; 7:472–479 
18  
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after 
PSA elevation following radical prostatectomy. JAMA. 1999; 281(17):1591–1597. 
19  
Moul JW,Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate 
specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 
2004; 171:1141–1147. 
20  
Scher HI, Halabi S, Tannock I, et al. Design and endpoints of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations 
of the prostate cancer clinical trials working group. J Clin Oncol 2008; 26:1148–1159. 
21  
Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific 
biological properties of disseminating tumour cells. Nat Rev Cancer. 2008 
May;8(5):329–340. 
22  
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating 
tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J 
Med. 2004 Aug 19;351(8):781–791. 
23  
Cristofanilli M, Hayes DF, Budd GT, Ellis MJ, Stopeck A, Reuben JM, et al. 
Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic 
breast cancer. J Clin Oncol. 2005 Mar 1;23(7):1420–1430. 
 


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24  
de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. 
Circulating tumor cells predict survival benefit from treatment in metastatic 
castration-resistant prostate cancer. Clin Cancer Res. 2008 Oct 1;14(19):6302–6309. 
25  
Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, et al. 
Relationship of circulating tumor cells to tumor response, progression-free survival, 
and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008 
Jul 1;26(19):3213–3221. 
32  
International Conference on Harmonisation (ICH) E9 and Federal register Vol 63, No. 
179 (September 1998). 
33  
Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer 
using the functional assessment of cancer therapy-prostate instrument. Urology 1997; 
50(6):920–928. 
CCI

SAP_001.pdf: 
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1
 
REPORTING AND ANALYSIS PLAN 
 
 
 
A MULTICENTRIC, MULTINATIONAL (CHINA AND RUSSIA), RANDOMISED, 
OPEN, CONTROLLED STUDY OF IMMEDIATE 9 MONTHS ADJUVANT HORMONE 
THERAPY WITH TRIPTORELIN 11.25 MG VERSUS ACTIVE SURVEILLANCE AFTER 
RADICAL PROSTATECTOMY IN HIGH RISK PROSTATE CANCER PATIENTS.  
 
 
 
 
PROTOCOL VERSION AND DATE: FINAL 3.0 - 7 JUNE 2013 
 
 
 
 
RAP Version 
Date 
Draft – Version 0.1 
28-MAR-2013 
Draft – Version 0.2 
24-MAY-2013 
Draft – Version 0.3 
12-JUN-2013 
Draft – Version 0.4 
26-AUG-2013 
Draft – Version 0.5 
20-NOV-2013 
Draft – Version 0.6 
08-JAN-2014 
Final – Version 1.0 
29-JAN-2014 
Final – Version 1.1 
21-NOV-2016 
Final – Version 2.0 
13-JAN-2017 
Final – Version 2.1 
13-JUN-2019 
Final – Version 3.0 
22-JUL-2019 
 


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2
 
 
STUDY NUMBER: 
A-38-52014-194 
EUDRACT NUMBER 
None 
PROTOCOL TITLE: 
A MULTICENTRIC, MULTINATIONAL (CHINA 
AND RUSSIA), RANDOMISED, OPEN, 
CONTROLLED STUDY OF IMMEDIATE 9 
MONTHS ADJUVANT HORMONE THERAPY 
WITH TRIPTORELIN 11.25 MG VERSUS ACTIVE 
SURVEILLANCE AFTER RADICAL 
PROSTATECTOMY IN HIGH RISK PROSTATE 
CANCER PATIENTS.  
 
 
RAP VERSION: 
Final version 3.0 
RAP DATE: 
22-JUL-2019 
 
 
Further to your review and agreement to the Reporting and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Clinical Statistics 
Manager or 
designee 
 
IPSEN PHARMA 
65, quai Georges Gorse   
92650 Boulogne Billancourt, 
France  
 
 
Clinical Study Co-
ordinator 
 
IPSEN PHARMA 
65, quai Georges Gorse   
92650 Boulogne Billancourt, 
France 
 
 
Medical Director 
  
Urology-Oncology Franchise 
IPSEN PHARMA 
65, quai Georges Gorse   
92650 Boulogne Billancourt, 
France 
 
 
 
 
 
PPD
PPD
PPD


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3
 
 
RESPONSIBILITY NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Statistician / 
Project Manager 
 
 
Lincoln 
4, rue Danjou, Bâtiment B 
92517 Boulogne-Billancourt 
cedex, France 
 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Reporting and Analysis Plan version became the Final Reporting and 
Analysis Plan 
PPD


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4
TABLE OF CONTENTS 
REPORTING AND ANALYSIS PLAN ................................................................................. 1 
1. 
INFORMATION TAKEN FROM THE PROTOCOL ............................................... 7 
1.1. Study objectives ............................................................................................................... 7 
1.1.1. 
Primary objective ........................................................................................... 7 
1.1.2. 
Secondary objectives ..................................................................................... 7 
1.1.3. 
Ancillary Exploratory objectives ................................................................... 7 
1.2. Study design ..................................................................................................................... 7 
1.2.1. 
Study population ............................................................................................ 8 
1.2.1.1. 
Inclusion criteria ............................................................................................ 8 
1.2.1.2. 
Exclusion criteria ........................................................................................... 8 
1.2.2. 
Study exposure ............................................................................................... 9 
1.3. Methods and procedures ................................................................................................ 9 
1.3.1. 
Patient identification and allocation to study treatment .............................. 9 
1.3.2. 
Patients assessments ...................................................................................... 9 
1.3.2.1. 
Efficacy assessments ...................................................................................... 9 
1.3.2.2. 
Safety assessments ........................................................................................ 10 
1.3.2.3. 
Other assessments ........................................................................................ 11 
1.3.2.4. 
Withdrawal / discontinuation from the study ............................................... 11 
1.3.2.5. 
Compliance .................................................................................................. 11 
1.3.3. 
Schedule of assessments .............................................................................. 13 
1.3.4. 
Planned sample size .................................................................................... 16 
2. 
PATIENT POPULATIONS (ANALYSIS SETS) ...................................................... 17 
2.1. Screened population ...................................................................................................... 17 
2.2. Enrolled population ...................................................................................................... 17 
2.3. Randomised population ................................................................................................ 17 
2.4. Safety population ........................................................................................................... 17 
2.5. Intention-to-treat population ....................................................................................... 17 
2.6. Modified ITT population .............................................................................................. 17 
2.7. Per Protocol population ................................................................................................ 17 
2.8. Primary populations ..................................................................................................... 18 
3. 
STATISTICAL METHODS ........................................................................................ 18 
3.1. Statistical analysis strategy........................................................................................... 18 
3.1.1. 
Primary efficacy endpoint ........................................................................... 18 
3.1.2. 
Secondary efficacy endpoint(s) ................................................................... 18 
3.1.3. 
Safety endpoint(s) ........................................................................................ 19 
3.1.4. 
Multiplicity ................................................................................................... 19 
3.1.5. 
Significance testing and estimation ............................................................ 19 
3.2. Analysis methods ........................................................................................................... 20 
3.2.1. 
Efficacy ........................................................................................................ 20 
3.2.1.1. 
Primary efficacy analysis ............................................................................. 20 
3.2.1.2. 
Secondary efficacy analysis ......................................................................... 22 
3.2.1.3. 
Exploratory efficacy analysis ....................................................................... 26 
3.2.2. 
Safety ............................................................................................................ 27 
3.2.2.1. 
Adverse events .............................................................................................. 27 


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5
3.2.2.2. 
Laboratory data ........................................................................................... 28 
3.2.2.3. 
Vital signs ..................................................................................................... 29 
3.2.3. 
Missing data and outliers ............................................................................ 29 
3.2.3.1. 
Missing data ................................................................................................. 29 
3.2.3.2. 
Missing or incomplete dates ......................................................................... 29 
3.2.3.3. 
Outliers ......................................................................................................... 29 
3.2.4. 
Patient disposition ....................................................................................... 30 
3.2.5. 
Withdrawals from study .............................................................................. 30 
3.2.6. 
Demographic and baseline characteristics ................................................. 30 
3.2.7. 
Medical and surgical history ....................................................................... 31 
3.2.8. 
Compliance .................................................................................................. 31 
3.2.9. 
Prior and concomitant medications and non-drug therapies .................... 31 
3.2.10. 
Derived data ................................................................................................. 32 
3.2.11. 
Visit windows ............................................................................................... 39 
3.2.12. 
Window for assessment for the PSA and testosterone parameters ............ 40 
3.2.13. 
Rules and data formats ............................................................................... 40 
3.2.14. 
Pooling of Centres ....................................................................................... 41 
3.2.15. 
Interim analysis ........................................................................................... 41 
3.2.16. 
Covariates and analysis of subgroups ........................................................ 41 
4. 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 41 
4.1. Hardware ....................................................................................................................... 41 
4.2. Software ......................................................................................................................... 41 
4.3. Validation programs ..................................................................................................... 42 
4.4. Restitution of the programs.......................................................................................... 42 
5. 
CHANGES FROM PROTOCOL ................................................................................ 42 
6. 
REFERENCES .............................................................................................................. 43 
7. 
DATA PRESENTATION ............................................................................................. 43 
 
 
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6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE  
Adverse Event/Experience  
BR  
Biochemical Relapse  
BRFS  
Biochemical Relapse-Free Survival  
CI  
Confidence Interval  
CRO  
Contract Research Organisation  
  
   
  
  
ECOG  
Eastern Cooperative Oncology Group  
EFS  
Event-Free Survival  
FACT-P  
Functional Assessment of Cancer Therapy - Prostate  
HRQoL  
Health-Related Quality of Life  
ITT  
Intention to Treat  
LHRH 
Luteinising Hormone-Releasing Hormone 
MedDRA  
Medical Dictionary for Regulatory Activities  
MRI  
Magnetic Resonance Imaging  
NCI-CTCAE  
National Cancer Institute - Common Terminology Criteria for  
 
Adverse Events  
OS  
Overall Survival  
PP  
Per Protocol  
PSA  
Prostate Specific Antigen  
PSADT  
PSA Doubling Time  
  
  
RAP  
Reporting and Analysis Plan  
  
  
RP  
Radical Prostatectomy  
SAE  
Serious Adverse Event/Experience  
SD  
Standard Deviation  
SF-36  
36-Item Short Form Health Survey  
SOP  
Standard Operating Procedure  
TEAE  
Treatment Emergent Adverse Event  
  
  
US  
Ultrasound  
WHO  
World Health Organisation  
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1. 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1. 
Study objectives 
1.1.1. 
Primary objective 
To assess the benefit of immediate adjuvant chemical castration after radical 
prostatectomy (RP) in patients with high-risk prostate cancer expressed as 
biochemical relapse-free survival (BRFS).  
 
1.1.2. 
Secondary objectives 
To compare the two groups in terms of: 
- 
Event-Free Survival (EFS), Overall Survival (OS), Disease Specific-mortality 
rate and prostate specific antigen doubling time (PSADT) 
- 
Impact on health-related quality of life (HRQoL) 
 
To assess overall safety of immediate chemical castration.  
 
1.1.3. 
Ancillary Exploratory objectives 
1.2. 
Study design 
This open, prospective, multicentric, multinational, randomised, controlled study 
with two parallel groups is designed to compare the efficacy and safety of 
immediate 9-month adjuvant treatment using triptorelin 11.25 mg (treatment onset 
no later than 8 weeks after RP) versus active surveillance, after RP.  Both groups 
will be monitored at the same frequency of visits (one visit every 3 months). 
Assessments will be performed to identify any BR/Clinical Disease Progression. 
This study will be conducted in a Phase IV setting in Russia and China, where 
triptorelin is approved for the treatment of locally advanced or metastatic prostate 
cancer. 
 
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1.2.1. 
Study population 
The study will be performed in males aged at least 18 years, with histo-
pathologically confirmed adenocarcinoma of the prostate, without positive margins, 
no pathological positive lymph nodes or metastases and with a high risk of disease 
progression (Gleason score ≥8 on prostatectomy specimen and/or pre-RP PSA level 
≥20 ng/mL and/or pT3a). Patients must have undergone RP no more than 8 weeks 
prior to randomisation, with post-RP (6 weeks) PSA levels ≤0.2 ng/mL, however no 
other treatment for prostate cancer was permitted. A total of 226 patients will be 
included from approximately 10 centres, 113 in each group. 
 
1.2.1.1. Inclusion criteria 
Each patient must meet the following criteria: 
x 
Provide written informed consent by the patient prior to any study-related 
procedure  
x 
Men aged ≥18 years  
x 
Histo-pathologically confirmed adenocarcinoma of the prostate   
x 
Radical Prostatectomy with curative intent performed no more than 8 
weeks before randomisation  
x 
High-risk criteria of disease progression, defined as follows:   
 Gleason score ≥8 on prostatectomy specimen, and/or  
 Pre-RP PSA level ≥20 ng/mL, and/or   
 Primary tumour stage 3a (pT3a) (with any PSA and any Gleason score)  
x 
Post-RP PSA levels ≤0.2 ng/mL at 6 weeks.  
x 
Eastern cooperative oncology group (ECOG)/world health organisation 
(WHO) performance status of 0 to 1 
 
1.2.1.2. Exclusion criteria 
Patients presenting any of the following criteria were not included in the study: 
x 
Has evidence of lymph nodes or distant metastasis  
x 
Has positive margins   
x 
Has evidence of any other malignant disease, not treated with a curative 
intent  
x 
Previously received or is currently receiving any treatment of prostatic 
cancer besides the concerned RP  
x 
Had a surgical castration  
x 
Has a life expectancy of <5 years  
x 
Suffers from a significant comorbidity or an untreated infection  
x 
Is likely to require treatment during the study with drugs that are not 
permitted by the study protocol  
x 
Has a history of hypersensitivity to triptorelin or any luteinising hormone 
releasing hormone (LHRH) analogues or to any of the excipients of 
triptorelin 11.25 mg  
x 
Was treated with any investigational drug within 4 weeks before the study 
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x 
Has abnormal baseline findings, any other medical condition(s) or 
laboratory findings that, in the opinion of the Investigator, might 
jeopardise the patient’s safety or decrease the chance of obtaining 
satisfactory data needed to achieve the objective(s) of the study  
x 
Is unable to undergo regular follow-up  
x 
Has any mental condition rendering him unable to understand the nature, 
scope and possible consequences of the study, and/or evidence of an 
uncooperative attitude  
x 
Has a history of, or known current, problems with alcohol or drug abuse.  
 
1.2.2. 
Study exposure 
The anticipated recruitment period of this study is 2 years.  
For each patient, study participation is planned to be at least 36 months. Follow-up 
may continue beyond this if BR is not reported at 36 months and the statistically 
required 61 BRs have not yet been reached, in which case the patient will continue 
on study until one of these events occurs.  
The overall duration of study is estimated to be approximately 60 months. 
  
1.3. 
Methods and procedures 
1.3.1. 
Patient identification and allocation to study treatment 
All patients enrolled must be identifiable throughout the study. At Screening, 
potential patients will be allocated a patient number. Patients will be enrolled 
sequentially and assigned the lowest identification number available. 
After eligibility is confirmed, patients will be assigned a randomisation number and 
will be randomised in one of two treatment arms (“Triptorelin treatment” or “Active 
surveillance”) in accordance with the randomisation procedure. 
For patients randomised to the triptorelin treatment group, triptorelin 11.25 mg will 
be administered intramuscularly every 3 months (±7 days), for a total of three 
injections (at the Baseline, 3 and 6 months visits). For patients randomised to the 
active surveillance group, no adjuvant treatment with any method (hormonal or 
surgical castration and/or radiation therapy) should be initiated prior to evidence of 
disease progression (clinical or biochemical). 
 
1.3.2. 
Patients assessments 
Methods for derivation of calculated variables are detailed in Section 3.2.10. 
1.3.2.1. Efficacy assessments 
PSA 
Blood samples for PSA testing will be taken every 3 months (except at Visit 2 
(Baseline, Day 1 Month 0) where PSA level is not required).  
 


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10 
Biochemical Relapse  
Biochemical Relapse definition: increased PSA >0.2 ng/mL confirmed by a second 
measurement performed 4 to 6 weeks later. The time-point at which the first 
elevated PSA measurement is >0.2 ng/mL is recorded will be deemed to be the time 
of BR. 
To note, for the identification of BR; all PSA samples will be taken into account, 
even if several samples are within the same time windows. 
 
Clinical disease progression 
Clinical disease progression is defined as evidence of local/locoregional recurrence 
and/or lymph node involvement and/or distant metastases documented by relevant 
standard investigations (such as ultrasound (US) guided biopsy, X-ray, computed 
tomography (CT) scan, or magnetic resonance imaging (MRI) guided biopsy). 
 
Survival status 
Survival status will be recorded at each visit. 
 
Serum Testosterone 
Serum testosterone in the triptorelin treatment group will be recorded at baseline, 3, 
6 and 9 months. It will be assessed both as a continuous and as a qualitative variable 
(< 50 ng/dL / ≥ 50 ng/dL). 
 
Health-Related Quality of Life 
Health-Related Quality of Life (HRQoL) will be assessed using the FACT-P 
questionnaire, version 4, and the 36-item short form (SF-36) health survey, version 
2 in both treatment arms at Baseline, 9, 24, and 36 months..  
 
1.3.2.2. Safety assessments 
- 
AE(s) and SAE(s) according to the NCI-CTCAE version 4.0 scale 
- 
Clinical laboratory tests (haematology (full blood count including red blood 
cells (RBC), haemoglobin, haematocrit, mean cell volume (MCV), mean 
cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), 
white blood cells (WBC) with differential and platelet count; neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) and  biochemistry (urea, 
creatinine, total bilirubin, chloride, bicarbonate, sodium, potassium, 
calcium, inorganic phosphate, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glumatyl 
transferase (GGT), albumin, total protein, total cholesterol, triglycerides, 
and fasting glucose)). 
- 
Concomitant medications/therapies and non-drug therapies. 
- 
Concomitant and surgical procedures 
- 
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11 
- 
Physical examination and vital signs (height, weight, heart rate and sitting 
blood pressure (systolic and diastolic).  
1.3.2.3. Other assessments 
The other assessments will be the following: 
 
x 
Demography and characteristics at screening:  
 Country, 
 Race (Asian; Black/African American; Caucasian/White; Native 
Hawaiian/Other Pacific Islander, American Indian/Alaska Native, 
Multiple), 
 Date of visit,  
 Date of birth. 
 
x 
Prostate Cancer History (prior to RP) 
 Date of first histological diagnosis 
 Gleason Score (Primary Pattern, Secondary Pattern, Total Score), 
 cTNM Staging (T, N, M) and method used (MRI, CT Scan, X-Ray, 
Transrectal Ultrasound, Clinical Judgment, Other), 
 Last available PSA level (ng/mL), 
 Last available testosterone level (ng/dL). 
 
x 
Radical Prostatectomy Procedure  
 Date of surgery 
 Pelvic lymphadenectomy (Yes; No), 
 If yes, extended / not extended,  
 Gleason Score (Primary Pattern, Secondary Pattern, Total Score), 
 pTNM Staging (T, N, M). 
 
x 
WHO/ECOG Performance Status Scale. 
 
x 
Significant Medical or Surgical history (including ongoing medical history 
other than prostate cancer related). 
 
x 
Prior and concomitant medications/therapies and non-drug therapies. 
 
1.3.2.4. Withdrawal / discontinuation from the study 
The date of early withdrawal and the primary reason for early withdrawal will be 
recorded (adverse event, protocol violation, consent withdrawn, lost-to follow-up, 
other).  
 
1.3.2.5. Compliance 
Compliance assessments will be the following: 
x Injection triptorelin administration performed (Yes/No), 


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12 
x Date of drug administration, 
x Date of surgery (radical prostatectomy), 
x Dose : 
o Planned volume administered (Yes/No), 
o If no, reason and volume administered (ml). 
 


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1.3.3. 
Schedule of assessments 
Table 1. Schedule of Assessments 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
XX  
 
Screening  Baseline  3M  
6M  
9M  
12M  
15M  
18M  
21M  
24M  
27M  
30M  
33M  
36M  
Every 
3M  
Informed Consent  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vital Signs  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG/WHO 
Performance Status  
 
X  
 
 
X  
 
 
 
 
X  
 
 
 
X  
 
Randomisation  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone Level 
[a], [b]  
 
X  
X [c]  
X[d]  
X[d]  
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
and Haematology  
X  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
PSA Level [e]  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Clinical Disease 
Progression 
Assessment [f]  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
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14 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
14  
XX  
FACT-P 
Questionnaire  
 
X  
 
 
X  
 
 
 
 
X  
 
 
 
X  
 
SF-36 Health 
Survey  
 
X  
 
 
X  
 
 
 
 
X  
 
 
 
X  
 
Triptorelin Injection 
[a]  
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication/Therapy  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Prior and 
Concomitant Non-
Drug Therapy  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
AEs [l]  
X  
X  
X  
X  
X  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
X [l]  
Visit Status  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
AE, adverse event; 
 ECOG, Eastern Cooperative Oncology Group; FACT P, functional assessment of cancer therapy prostate; M, month; PSA, 
prostate specific antigen;  
  
a  
Only for the triptorelin adjuvant treatment group (± 7 days)  
b  
Always prior to each triptorelin injection (Baseline, 3 months, and 6 months)  
c  
Evidence of lack of castration at 3 months/Visit 3 will be documented by serum testosterone ≥50 ng/dL (≥0.50 ng/mL) confirmed by a second elevated serum testosterone 
level at least two weeks later. For the other testosterone assessment time points (Baseline, and 6 and 9 months), no confirmation test is required.  
d  
If evidence of lack of castration at 3 months/Visit 3, therefore testosterone sampling is not required anymore at Visit 4/Month 6 and Visit 5/Month 9.  
e  
Starting from Visit 3, any elevated PSA concentration >0.2 ng/mL should be confirmed by a second measurement performed 4 to 6 weeks later. No confirmation test is 
required after evidence of disease progression (biochemical relapse (BR) and/or clinical disease progression).  
f 
Clinical disease progression assessments (such as ultrasound [US] guided-biopsy, X-ray, computed tomography [CT] scan, magnetic resonance imaging [MRI]) can be 
performed at any time during the study at the Investigator’s discretion and as per local standard care.  
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l  
Adverse events (AEs) will only be collected until Visit 5/Month 9; this corresponds to three months after the last triptorelin injection for those patients in the triptorelin 
group. After this visit, only AEs and SAEs related to triptorelin according to Investigator's judgement should be reported (with the exception of AEs resulting in death 
that should be reported until the end of the study).  
Patients will not be withdrawn from the study if study medication is discontinued. Follow-up will continue for all patients 
every 3 months and for at least 36 months. 
 
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1.3.4. 
Planned sample size 
It is planned to recruit 226 patients in approximately 10 centres in two countries 
(China and Russia) according to the Sample Size Determination.  
 
The sample size estimation was based on the primary efficacy endpoint of BRFS. 
Assuming that with RP alone, the probability of biochemical (PSA) relapse as defined 
in Section 4.2.1 of the study protocol at 36 months after RP is 40% in high-risk 
patients (Section 2.1 of the study protocol, Table 1), and anticipating that immediate 
adjuvant hormonal therapy added to RP will reduce this probability to 20% 
(percentage considered to be clinically relevant), 113 patients per treatment group 
(226 in total) are required in order to detect such a difference using a two-sided log-
rank test at a significance level of 5% and a power of 90%, assuming a common 1% 
exponential dropout rate (corresponding to an approximate 5% dropout rate per year). 
These 226 patients are required to observe 61 BR in order to achieve 90% power. For 
patients with no sign of disease progression at 36 months post-randomisation, 
monitoring will continue until the 61 BR events are observed at the study global level. 
If the 61 events are observed before all patients complete the 36 months post-
randomisation monitoring period, the study will be continued until those patients 
reach their 36 month visit (Visit 14). 
 


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2. 
PATIENT POPULATIONS (ANALYSIS SETS) 
2.1. 
Screened population 
The screened population is defined as all patients with Visit 1 (Screening, Day - 14) 
performed and who have given informed consent. 
 
2.2. 
Enrolled population  
The enrolled population is defined as all patients from the screened population with 
visit 2 (Baseline, Day 1) performed. 
 
2.3. 
Randomised population 
The randomised population is defined as all patients from enrolled population who 
were randomised (i.e. with a randomisation number). 
 
2.4. 
Safety population 
The safety population (SS) is defined as all randomised patients that have received at 
least one injection for patients from the triptorelin arm or that have undergone at least 
one day of active surveillance for patients from the active surveillance arm (patient 
that attended at least one visit after Visit 2 (Baseline, Day 1) or with at least one 
collected safety data). The patients will be analysed according to the treatment 
received. 
 
2.5. 
Intention-to-treat population 
The Intention-to-treat population (ITT) is defined as all randomised patients analysed 
according to the group to which they were randomised (i.e. regardless of treatment 
approach followed). 
 
2.6. 
Modified ITT population 
The Modified ITT (mITT) is defined as all patients in the ITT population excluding 
those not treated or without any visit after Visit 2 (Baseline, Day 1). The patients will 
be analysed according to the group to which they were randomised (i.e. regardless of 
treatment approach followed). 
 
2.7. 
Per Protocol population  
The Per Protocol (PP) population is defined as all patients in the mITT population for 
whom no major protocol violations/deviations occurred.  
Definition of protocol deviations will be managed in a separate document. 
The final status of deviations (minor/major) will be finalized during a blind data 
review meeting. 
 


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Listings of patients regarding inclusion in each population (i.e. satisfying the 
population definition) and associated data will be reviewed by the study team. Data 
will be excluded from the PP population on a patient basis and not on a visit basis. 
Reasons for exclusion from PP population will be presented in a summary table. 
 
2.8. 
Primary populations 
Baseline data (medical history, concomitant disease (pre-treatment AEs and ongoing 
medical history, prior medications and therapies, baseline symptoms etc.)) will be 
presented by treatment group and overall for the ITT population. Baseline and 
demographics characteristics will be repeated on the safety population if there is at 
least 10 % difference between the safety and the ITT population 
 
The analysis based on the primary efficacy endpoints will be performed on ITT, 
mITT and PP populations. mITT and PP analyses will only be considered as 
exploratory.  
The secondary efficacy endpoints will be analysed on the ITT population. 
 
The analyses of safety data will be performed on the safety population. 
 
3. 
STATISTICAL METHODS 
3.1. 
Statistical analysis strategy 
All statistical analyses will be performed by the biostatistics unit of AIXIAL using 
the Statistical Analysis System® (SAS®) software version 9.4 (SAS Institute Inc., 
Cary, North Carolina, USA). 
 
The statistical analyses will be performed in accordance with International 
Conference on Harmonisation (ICH) E9 guideline. 
 
3.1.1. 
Primary efficacy endpoint 
BRFS is defined for each patient by the period in months of time from randomisation 
to time of Biochemical Relapse. 
 
3.1.2. 
Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are: 
 
x 
EFS (defined for each patient as the period of time (in months) from 
randomisation to time of first clinical disease progression or death from any 
cause). 
 
x 
OS (defined for each patient as the period of time (in months) between 
randomisation and death from any cause). 
 


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x 
Disease-specific mortality (measured as the time (in months) between 
randomisation and death related to prostate cancer). 
 
x 
PSADT (defined as the time (in months) from the first documented PSA 
increase >0.2 ng/mL to the time of the first value more than twice that of the 
first increased value). 
 
x 
PSA level at each visit. 
 
x 
Serum testosterone in the triptorelin treatment group at baseline, 3, 6 and 9 
months. 
 
x 
HRQoL (assessed using the Assessment of Cancer Therapy – Prostate 
(FACT-P) questionnaire, version 4, and the 36-item short form (SF-36) 
health survey, version 2) in both treatment arms at baseline, 9, 24 and 36 
months. 
 
3.1.3. 
Safety endpoint(s) 
The safety endpoints are: 
- 
Signs and symptoms, incidence and severity of all AE(s) regardless of 
relationship to the study drug graded according to the NCI-CTCAE version 
4.0 scale including SAEs and treatment discontinuations due to toxicity.  
- 
Clinical laboratory tests 
- 
Concomitant medications and non-drug therapies 
- 
Concomitant and surgical procedures 
 
3.1.4. 
Multiplicity 
No adjustment for multiplicity will be performed. 
 
3.1.5. 
Significance testing and estimation 
All statistical tests will be performed two-sided with a type I error rate set at 5%.  
 
Quantitative variables will be summarised in statistical tables indicating the number 
of non missing observations (n), the mean and standard deviation (SD), the two-sided 
95% confidence interval (CI) of the mean, the median, the quartiles (Q1 and Q3), the 
minimum and maximum.  
 
Qualitative variables will be summarised in statistical tables indicating the number of 
non missing observations (n), frequency, percentage of each modality and the two-
sided 95% CI associated. 
 
For all parameters, the number of missing values will also be reported in the tables, 
but they will not be counted for the percentage calculation (qualitative data). 
 


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Time to event data will be analysed using Kaplan-Meier method to obtain the 
estimates of survival median, their associated 95% CI, survival curves for each 
treatment group and log-rank test p-value will be provided for treatment comparison. 
The Cox Proportional hazard model will be fitted to compute hazard ratios and the 
corresponding 95% CI. 
All quantitative variables will be analysed with either analysis of variance (ANOVA) 
or analysis of covariance (ANCOVA) adjusting for baseline when measured. 
Treatment effect estimates (differences between treatment groups) will be provided 
with their associated 95% CI. 
 
3.2. 
Analysis methods  
3.2.1. 
Efficacy 
3.2.1.1. Primary efficacy analysis 
The primary efficacy analysis will be performed after 61 BR events have been 
observed and this analysis will be repeated on the number of BR events observed 
until the end of study.  
 
The primary efficacy analyses of BRFS will be performed on the ITT population (cf. 
Section 3.2.10 for derived BRFS). 
An exploratory analysis will be performed on the mITT and PP population (only on 
the total number of BR at the end of the study).  
BRFS will be provided by treatment group. A log-rank test (two-sided) will be used 
to compare BRFS time between the two treatment groups. The Kaplan-Meier method 
will be used to obtain the estimates of median BFRS associated with each treatment. 
The 95% CI of the median BRFS time will also be provided. 
 
The syntax with SAS using the LIFETEST procedure will be: 
 
 
The Cox Proportional hazard model will be fitted to compute hazard ratios and the 
corresponding 95% CI with treatment group, country (China as reference), nested 
effect centre(country) (the largest centre as reference) and Gleason score on 
prostatectomy specimen (in categories: ≤ 6 / = 7 / ≥ 8, with ≤ 6 considered as the 
reference) as fixed factors. 
 
The syntax with SAS using the TPHREG procedure will be: 
 
 
 
 
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Interactions between treatment group and each covariate (country, centre(country) 
and Gleason score) will be tested one by one in separate models as follows: 
 
 
 
 
 
 
 
P-value of covariates effect as well as interactions effect will be provided. Interaction 
will be considered as suggestive if p-value < 0.20. Suggestive interaction will be 
kept: 
 
 
 
 
 
 
 
 
 
 
The validity of the model will be checked as follows: 
o Check of hypothesis of proportional hazards (graphically), 
This check of hypothesis of proportional hazards can be performed using plots the log 
of negative log of estimated survivor functions versus the log of time. 
The syntax with SAS using LIFETEST procedure will be: 
 
 
 
If the curves are parallel then the hypothesis is checked.  
 
Results will be presented in terms of hazard ratios associated with 95% CI and p-
value for treatment group and each other fixed factors. 
 
Survival curves for each treatment group will be plotted on the same graph. Median 
BRFS time for each group and number of events will be provided. 
 
Should 
there 
be 
a 
suggestive 
country*treatment 
interaction 
or 
a 
centre(country)*treatment interaction, BRFS will also be analysed respectively by 
country/centre in order to describe any possible country/centre effect. Similarly, 
should there be a suggestive Gleason score*treatment interaction, BRFS will also be 
analysed by Gleason score categories (≤ 6 / = 7 / ≥ 8, with ≤ 6 considered as the 
reference) in order to describe treatment effect within each subgroup. 
 
 
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Sensitivity analyses: 
 
If a patient had at least two consecutive missing visits before the BR, a sensitivity 
analysis will be performed by censoring this patient at the date of the last visit 
preceding the missing consecutive visits (cf Section 3.2.10 for derived BRFS). 
 
If patients died (whatever the cause) without BR, a sensitivity analysis will be 
performed by considering the death as an event (cf Section 3.2.10 for derived BRFS). 
 
If lost to follow-up (prior to BR) is ≥ 5 %. Baseline characteristics will be compared 
between groups of lost to follow-up and the other patients. If the lost to follow-up 
baseline characteristics differ from those of the other patients (as shown by 95 % CI), 
a sensitivity analysis will be performed excluding the lost-to follow-up patients.  
 
Sensitivity analyses will be performed on ITT population on the first 61 BR events 
and repeated on the number of BR events observed until the end of the study if there 
is a difference of at least 5% of number of events (i.e. ≥65 events). The Log-rank test 
will be provided as well as the Cox Proportional hazard model. The interactions will 
be tested only if suggestive interactions were founded in the main analysis.  
 
 
The primary efficacy analyses are summarised in the table below: 
 
 
ITT population 
mITT 
population 
PP population 
61 BR 
events 
All BR 
events 
All BR events 
All BR events 
Main analysis 
X(1) 
X 
X 
X 
Sensitivity analysis 1 
(censoring of patients with 
missing visits) 
X 
X(2) 
 
 
Sensitivity analysis 2  
(death as an event) 
X 
X(2) 
 
 
Sensitivity analysis 3 
(excluding lost-to-FUP 
patients) 
X 
X(2) 
 
 
(1) Primary analysis 
(2) Only if the number of BR events observed until the end of the study is different of at least 5% (i.e. ≥65 
events) 
 
3.2.1.2.  Secondary efficacy analysis 
The secondary efficacy analyses will be performed on the ITT population. In these 
analyses, no interaction will be tested for EFS, OS, disease-specific mortality and 
PSA doubling time. For serum testosterone, only patients in the triptorelin-treated 
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3.2.1.2.1. Event-Free Survival 
EFS will be provided by treatment group (cf. Section 3.2.10 for derived EFS).  
EFS will be compared between groups using the same analysis and strategy used for 
BRFS. 
3.2.1.2.2. Overall Survival 
OS will be provided by treatment group (cf. Section 3.2.10 for derived OS).  
OS will be compared between groups using the same analysis and strategy used for 
BRFS. 
 
3.2.1.2.3. Disease-specific mortality 
Disease-specific mortality will be provided by treatment group (cf. Section 3.2.10 for 
derived disease-specific mortality).  
Disease-specific mortality will be compared between groups using the same analysis 
and strategy used for BRFS. 
 
3.2.1.2.4. PSA Doubling Time 
PSADT will be provided by treatment group (cf. Section 3.2.10 for derived PSADT).  
PSADT will be compared between groups using the same analysis and strategy used 
for BRFS. 
 
3.2.1.2.5. PSA level 
The PSA level (ng/ml) at each visit (except at Visit 2 (Baseline, Day 1 Month 0) 
where PSA level is not required) will be described using descriptive quantitative 
statistics. 
PSA level will be described both in its continuous format and in categories (≤0.2 
ng/ml; >0.2 ng/ml - <4 ng/ml; ≥4 ng/ml - <10 ng/ml; ≥10 ng/ml) 
 
The percentage change from baseline (defined as the screening values) will be also 
presented. 
In addition, a shift table of the change in categories between baseline and each visit 
will be presented. 
 
At baseline the last test available before first injection of treatment will be used. 
Otherwise, in case of several samples (with a result) in the same time windows 
(excluding the confirmation samples), the value of the last sample will be used. 
 
3.2.1.2.6. Serum testosterone 
The proportion of castrated (serum testosterone < 50 ng/dL) patients at baseline and 
3, 6 and 9 months post-RP will be provided for the triptorelin treatment group. Shift 
tables between two consecutive visits and between baseline and end of study will be 
presented of the number and percentage of patients castrated or not. 


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The serum testosterone level at baseline and at 3, 6 and 9 months post-RP, as well as 
the serum testosterone level changes from baseline to 3, 6 and 9 months post-RP will 
be described using descriptive quantitative statistics.  
In case of several samples (with a result) in the same time windows, the value of the 
first sample will be used. 
 
Changes will be analysed using a repeated-measures analysis of covariance using a 
mixed linear model with patient as a random effect, baseline and visit (Month 3, 
Month 6 and Month 9) as fixed factors. Correlation structures (auto-regressive 
(AR(1)), compound symmetry (CS) and unstructured (UN)) will be tested and the 
best one will be considered for the model (the model with the smaller AIC will be 
chosen) : 
 
Change = baseline + visit + e 
With:  
o Baseline and visit as fixed effects, 
o e: error ~ N (0, σ e ²). 
 
The syntax with SAS using the MIXED procedure will be: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.1.2.7. Health-Related Quality of Life 
The HRQoL measurements (FACT-P and SF-36v2) are defined as follows: 
 
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FACT-P measurements 
SF-36v2 measurements 
x Subscales: 
o Physical well-being 
o Social well-being 
o Emotional well-being 
o Functional well-being 
x Dimensions: 
o General well-being 
o Prostate-specific concerns 
x Total FACT-P score 
 
x Health Domain Scales: 
o Physical functioning (Raw) 
o Role-Physical (Raw) 
o Bodily Pain (Raw) 
o General Health (Raw) 
o Social Functioning (Raw) 
o Mental Health (Raw) 
o Role-Emotional (Raw) 
o Vitality (Raw) 
o Physical functioning (Norm-based) 
o Role-Physical (Norm-based) 
o Bodily Pain (Norm-based) 
o General Health (Norm-based) 
o Social Functioning (Norm-based) 
o Mental Health (Norm-based) 
o Role-Emotional (Norm-based) 
o Vitality (Norm-based) 
x Component Summary measures 
calculated from a combination of norm-
based scales scores: 
o Physical Component Summary 
o Mental Component Summary  
 
These HRQoL measurements at baseline and at 9, 24 and 36 months post-RP, will be 
described using descriptive quantitative statistics for each treatment group (cf. 
Section 3.2.10 for derived FACT-P and SF-36v2). In addition the change from 
baseline will also be presented for each of these HRQoL measurements. 
 
For each HRQoL measurement (subscales, dimensions, scales, component summary 
measures), changes will be analysed using a repeated-measures analysis of covariance 
using a mixed linear model with patient as a random effect, baseline, group, visit 
(Month 9, Month 24 and Month 36) and the interaction between group and visit as 
fixed effects. Correlation structures (auto-regressive (AR(1)), compound symmetry 
(CS) and unstructured (UN)) will be tested and the best one will be considered for the 
model (the model with the smaller AIC will be chosen): 
 
Change = baseline + group + visit + group*visit + e 
With:  
o baseline, group, visit and group*visit as fixed effects, 
o e: error ~ N (0, σ e ²). 
 


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The syntax with SAS using the MIXED procedure will be: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.1.3. Exploratory efficacy analysis 
To identify prognostic factors among Gleason score on prostatectomy specimen (≤ 6 / 
= 7 / ≥ 8, with ≤ 6 considered as the reference), country, Pre-RP PSA level (<20 / ≥20 
ng/mL), primary tumour stage (T1 / T2 / T3 / T4 with T3 considered as the reference) 
and age (<65 years / ≥65 years) are associated with BRFS outcome, Cox proportional 
hazard regression models will be used. Each parameter will be analysed in an 
univariate model where the hypothesis of proportional risks will be checked 
graphically. Significant parameters at a 20%-level will be retained for the 
multivariate Cox model. Associations between significant parameters will be tested in 
order to keep only non correlated variables in the multivariate model. The association 
between two categorical or binary variables will be tested using Chi-square or 
Fisher’s exact test. Associations will be considered as statistically significant if 
p<0.01. A backward selection method will be used to identify the final set of 
prognostic factors (exit p-value set to be 0.05). Treatment will then be added to this 
final model to assess the effect of treatment when adjusted for these factors. 
 
The syntax with SAS using the PHREG procedure will be: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2.2. 
Safety 
Safety analysis will be analysed on safety population according to the actual 
treatment approach followed. 
 
3.2.2.1. Adverse events 
Adverse events will be graded by the investigator according to the NCI CTCAE 
version 4.0. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; version 16.0) and will be classified by PT and SOC. 
 
Listings will be presented for all patients (description, time to onset, duration, 
seriousness, grade, relationship to study drug, action taken and outcome) and sorted 
by treatment group, patient id, start time of AEs, primary system organ class, 
preferred term and verbatim text for all adverse events recorded during the study.  
 
Listings of serious adverse events (SAE), adverse events leading to study withdrawal, 
leading to study drug discontinuation, drug related adverse events, adverse events 
with NCI CTC Grade > 2 and listings of deaths will also be presented.  
Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the adverse 
events listing and will be summarised.  
 
For the triptorelin treatment group, a TEAE is defined as any AE that occurs during 
the active phase of the study if:  
x it occurred up to 12 months after the first injection, 
and 
x it was not present prior to receiving the first dose of study drug, or  
x it was present prior to receiving the first dose of study drug but the intensity 
increased during the active phase of the study, or  
x it was present prior to receiving the first dose of study drug, the intensity is 
the same but the drug relationship became related during the active phase of 
the study. 
 
Summary tables of adverse events will be provided with the number and percentage 
of patients with adverse events classified by primary system organ class, preferred 
term (ordered alphabetically) and associated NCI/CTC worst grade. In the event of 
multiple occurrences of the same adverse events being reported by the same patient, 
the maximum intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing 
> not applicable) and the most serious causality (related) will be chosen.  
 
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A summary table of all adverse events will be presented by treatment arm up to visit 
6. An overall summary table of all adverse events will be presented starting at visit 6. 
 
For the first year (visit 6 excluded), summary tables of adverse events will be 
presented separately for each treatment arm:  
x For the triptorelin treatment group, treatment emergent adverse events per 
decreasing frequency, treatment emergent serious adverse events, treatment 
emergent non serious adverse events, treatment emergent drug related adverse 
events, treatment emergent drug related serious adverse events, treatment 
emergent drug related non serious adverse events, treatment emergent adverse 
events leading to study withdrawal and treatment emergent adverse events 
leading to study drug discontinuation (drug withdrawn or drug interrupted). 
 
x For the active surveillance group, adverse events per decreasing frequency, 
serious adverse events, non serious adverse events and adverse events leading 
to study withdrawal will be presented.  
 
For AEs starting from visit 6, the summary tables of adverse events will be presented 
overall. The following summary tables will be presented: adverse events per 
decreasing frequency, serious adverse events, non serious adverse events and adverse 
events leading to study withdrawal. 
 
3.2.2.2. Laboratory data 
A separate listing of normal ranges for SI units will be provided by age where 
relevant.  
Laboratory data (haematology, biochemistry) will be listed in SI units and abnormal 
values will be flagged (High [H], Low [L], clinically significant [C], NCI-CTC grade 
(G)) where applicable. Any unscheduled laboratory assessments will be flagged [U] 
in the listings.  
For haematology and biochemistry parameters the baseline will be defined as the 
screening values.  
Summary statistics (mean, median, SD and range as appropriate) by treatment group 
and overall will be presented for clinical laboratory tests at each assessment 
(screening and 9 month) with change from baseline. 
Shift tables will be presented of the number and percentage of patients with below, 
within or above normal range. For laboratory data, abnormal values will be flagged in 
the data listings and a list of clinically significant abnormal values will be presented. 
 
In case of available retest sample, values of retest sample will be used instead of the 
first sample, except at baseline where the last test available before first injection of 
treatment will be used. 
 


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3.2.2.3. Vital signs 
Descriptive summary statistics will be provided on safety population according to the 
actual treatment approach followed for vital signs. It includes assessments as detailed 
in the Section 1.3.2.3 ‘Vital signs’. 
 
3.2.3. 
Missing data and outliers 
3.2.3.1. Missing data 
Missing data will not be imputed and dropouts will not be replaced.  
Rules for missing data imputation for HRQoL will be addressed in 3.2.10 Derived 
Data. 
3.2.3.2. Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following methods 
will be used: 
x 
The most conservative approach will be systematically considered (i.e. if the 
onset date concomitant medication is missing / incomplete, it is assumed to 
have occurred during the study treatment phase except if the partial onset 
date or other data [stop date, …] indicates differently). 
x 
A missing/incomplete date of medical history or disease diagnosis will be 
assumed to have occurred before the study inclusion. 
x 
If a partial date and the associated information do not allow to state about 
the assignation to a group / category, all the possible groups / categories will 
be considered (i.e.: a medication with partial start and stop dates could be 
considered as prior and concomitant treatment). 
x 
Where this is possible, the derivations based on a partial date will be 
presented as superior inequalities (i.e. for a medication started in FEB2004 
after the administration performed on 31JAN2004, the days since last dose 
will be “≥2”, similarly the duration of ongoing medication will be“≥xx” 
according to the start and last visit dates). 
 
3.2.3.3. Outliers 
Any outlier identified prior to data base lock which is impossible/implausible will be 
excluded from the analysis.  
For other identified outliers, the impact should be assessed by performing the 
statistical analysis with the actual values and at least one other analysis eliminating or 
reducing the outlier effect.  
If any outliers are identified after the database lock, the statistical analysis should be 
performed with the actual values and at least one other analysis eliminating or 
reducing the outlier effect.  
A search of outliers for the PSA result will be performed before the database lock and 
actions with the sponsor will be defined during data review meeting. 
 


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3.2.4. 
Patient disposition  
A summary table will present the number and percentages of patients enrolled 
included in each analysis set by treatment group and overall, by country and centre.  
The reason for patients’ exclusion from each of the analysis set will also be tabulated. 
 
The numbers of patients who were randomised, discontinued and completed the study 
will be tabulated by treatment group and overall. A patient is considered as having 
completed the study when “Completed the study” is ticked in the CRF at visit 14 
(Month 36) or at one of the follow-up visit. The primary reason for early withdrawal 
will be provided (adverse event, protocol violation, consent withdrawn, lost-to 
follow-up, other) by treatment group and overall. 
 
A summary table (and a flow chart) will be performed for each analysis set (Safety 
population, ITT and PP population) presenting the number and proportion of patients 
by treatment group and overall at each visit. 
 
A summary table will present the duration of study drug exposure and the extent of 
patient exposure in the study (months). The length of exposure is defined as the 
number of days between the date of consent and the last study visit date. 
A listing of dates of visit and calculated time interval since baseline visit (days) will 
be presented by patient. 
 
3.2.5. 
Withdrawals from study 
Discontinued patients will be listed and a summary table of the number and 
percentage of patients who withdrew from the study and the reasons for withdrawal 
will be presented overall and by treatment group.  
 
3.2.6. 
Demographic and baseline characteristics 
Descriptive summary statistics will be provided by treatment group and overall on the 
ITT population and on the safety population if there is at least 10 % difference 
between the safety and the ITT population, for demographic and baseline 
characteristics. It includes assessments as detailed in the Section 1.3.2.3 
(‘Demography and characteristics at baseline’, ‘Prostate cancer history’, ‘Radical 
prostatectomy procedure’ and ‘WHO/ECOG Performance Status Scale’). To assess 
homogeneity of treatment groups at baseline, 95% CI of proportion for qualitative 
variable or 95% CI of mean for quantitative variable will be provided. 
In addition the proportion of patients with a Gleason score ≥8 on prostatectomy 
specimen and with a Pre-RP PSA level ≥ 20 ng/mL; with a Gleason score ≥8 on 
prostatectomy specimen and with a primary tumour stage 3a; with a Pre-RP PSA 
level ≥ 20 ng/mL and with a primary tumour stage 3a; with a Gleason score ≥8 on 
prostatectomy specimen and with a Pre-RP PSA level ≥ 20 ng/mL and with a primary 
tumour stage 3a will be tabulated. 
 


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3.2.7. 
Medical and surgical history 
Descriptive summary statistics will be provided by treatment group and overall on the 
ITT population for ‘Significant Medical or Surgical History’. 
 
A frequency table of the number and percentage of patients will be provided for 
medical history by SOC and PT. 
 
3.2.8. 
Compliance 
Descriptive summary statistics will be provided by treatment group and overall on the 
ITT population, for current prostate cancer therapy. It includes assessments as 
detailed in the Section 1.3.2.5 ‘Compliance’ and the time between first drug 
administration and RP (days) and the time between each drug intake (days). . 
 
If the drug intake occurs outside the allowed time-window (time between each drug 
intake should be between 84 and 99 days (3*30.4375 ± 7 days)), the date of dose 
intake and the number of days since the last drug intake will be listed.  
 
3.2.9. 
Prior and concomitant medications and non-drug therapies 
 
Descriptive summary statistics will be provided by treatment group and overall on the 
safety population for ‘Prior and concomitant medications and non-drug therapies’. 
 
Prior and concomitant medications: 
 
Prior and concomitant medications will be coded using WHO-Drug Dictionnary 
March 2013 version. The therapeutic class will correspond to the second level of 
Anatomic Therapeutic Class (ATC) code. 
 
Listings containing prior and concomitant medications will be presented for the 
therapeutic class, preferred name and verbatim text, and will be sorted by country, 
centre, patient, chronological start date, therapeutic class, preferred name and 
verbatim text. 
 
A frequency table of the number and percentage of patients will be provided for prior 
and concomitant medications only by therapeutic class and preferred name. 
 
Prior and concomitant non-drug therapies and surgical procedures: 
 
Prior and concomitant non-drug therapies will be coded using MedDRA version 16.0 
and will be classified by Preferred Term (PT) and System Organ Class (SOC). 
 
A concomitant therapy will be defined as a therapy started prior to baseline visit date 
and ongoing at baseline visit date, or started the day of baseline visit or after.  
 


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Listings containing prior and concomitant non-drug therapies will be presented for 
the SOC, PT and verbatim text, and will be sorted by country, centre, patient, 
chronological start date, SOC, PT and verbatim text. 
 
A frequency table of the number and percentage of patients will be provided for prior 
and concomitant non-drug therapies only by SOC and PT. 
 
An individual data listing containing concomitant surgical procedures will also be 
provided.   
3.2.10. 
Derived data 
The derived data are variables which are calculated from the raw data and not 
included in the database. 
Age 
Patient age (years) will be derived as (baseline visit date – birth date)/365.25 and 
truncated to the largest integer that is less than or equal to the calculated result. 
 
Time since the first histological diagnosis 
Time since the first histological diagnosis (months) will be derived as 
(Date of screening visit – Date of first histological diagnosis +1)/ 30.4375 and 
truncated to the largest integer that is less than or equal to the calculated result. 
 
Partial dates of histological diagnosis will be imputed to calculate times: 
x If the day is missing and month is present, the 15 of the month will be 
used. 
x If the day and month are missing, the 15 of June will be used. 
 
Radical Prostatectomy Procedure 
Time between screening visit and surgery (weeks) will be derived as (Screening Visit 
Date - Date of radical prostatectomy+1) / 7. 
 
Compliance 
Time between first drug administration and RP (weeks) will be derived as (Date of 
first drug administration - Date of radical prostatectomy+1) / 7. 
 
Time between each drug intake (weeks) will be derived as (Date of drug intake at 
Visit t – Date of drug intake at visit t-1 +1) / 7. 
 
Partial dates of treatment will be imputed to calculate times: 
x If the day is missing and month is present the 15 of the month will be 
used. 
x If year is present and day and month are missing then the difference 
between years will be used. 
 


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Changes from baseline  
Changes from baseline will be calculated as a difference from baseline (e.g. 
assessment at the visit – assessment at baseline). 
 
Length of patient exposure in the study 
Length of patient exposure in the study (months) will be calculated as [(Date of last 
visit attended – informed consent date) +1] / 30.4375. 
 
Duration of study drug exposure 
Duration of study drug exposure (months) will be calculated as [(Date of last drug 
administration – Date of first drug administration) / 30.4375] + 3. 
 
Adverse event 
Time to onset of AE (days) = AE start date – date of randomisation. 
 
Duration of AE (days) = (AE resolution date – AE start date) + 1. 
 
Time-to-event criteria 
BRFS (months) will be derived as (Date of first BR – date of randomisation + 1) / 
30.4375. 
 
EFS (months) will be derived as (Date of clinical disease progression or death from 
any cause – date of randomisation + 1) / 30.4375. 
 
OS (months) will be derived as (Date of death from any cause – date of 
randomisation + 1) / 30.4375. 
 
Disease specific mortality will be derived as (Date of death related to prostate cancer 
– date of randomisation + 1) / 30.4375. 
 
PSADT (months) will be derived as (Date of sample when the first PSA value > than 
twice that of the first increased value – Date of sample of the first PSA value 
increased value (i.e. > 0.2 ng/mL) + 1) / 30.4375. 
 
All of these time-to-event variables will be rounded to 1 decimal. 
For BRFS, EFS, OS and Disease specific mortality, if the date of event or censor is 
prior to the date of randomisation, the data of event or censor taken into account will 
be the date of randomisation. 
 


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Rules for time-to-event data 
The following table defines the rules for censoring data (for Kaplan-Meier analysis) 
 
x BRFS 
Event 
Decision 
Date of event or censor to consider 
for analysis 
BR 
Not 
censored 
Date of BR (i.e. date of the first 
elevated PSA measurement is >0.2 
ng/mL*) 
No BR and no clinical disease 
progression and new hormonal 
treatment (ie triptorelin or similar) 
Censored  
Date of last evaluable sample before 
the start of new hormonal treatment 
No BR and no clinical disease 
progression and no premature 
withdrawal from the study 
Censored 
Date of last evaluable sample 
assessment 
No BR and no clinical disease 
progression and patient premature 
withdrawal from the study or lost to 
follow-up 
Censored 
Date of last evaluable sample before 
withdrawal from the study or last 
contact 
Clinical disease progression before BR 
Censored 
Date of clinical disease progression 
No BR but death 
Censored 
Date of last evaluable sample 
assessment 
 
x BRFS – Sensitivity Analysis 1 
Event 
Decision 
Date of event or censor to consider 
for analysis 
BR 
Not 
censored 
Date of BR (i.e. date of the first 
elevated PSA measurement is >0.2 
ng/mL*) 
At least two consecutive visits missing 
before BR 
Censored 
Date of last visit preceding the 
missing consecutive visits 
No BR and no clinical disease 
progression and new hormonal 
treatment (ie triptorelin or similar) 
Censored  
Date of last evaluable sample before 
the start of new hormonal treatment 
No BR and no clinical disease 
progression and no premature 
withdrawal from the study 
Censored 
Date of last evaluable sample 
assessment 
No BR and no clinical disease 
progression and patient premature 
withdrawal from the study or lost to 
follow-up 
Censored 
Date of last evaluable sample before 
withdrawal from the study or last 
contact 
Clinical disease progression before BR 
Censored 
Date of clinical disease progression 
No BR but death 
Censored 
Date of last evaluable sample 
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x BRFS – Sensitivity 2 
Event 
Decision 
Date of event or censor to consider 
for analysis 
BR  
Not 
censored 
Date of BR (i.e. date of the first 
elevated PSA measurement is >0.2 
ng/mL*)  
Death (whatever the reason) without 
BR 
Not 
censored 
Date of death 
No BR and no clinical disease 
progression and new hormonal 
treatment (ie triptorelin or similar) 
Censored  
Date of last evaluable sample before 
the start of new hormonal treatment 
No BR and no clinical disease 
progression and no premature 
withdrawal from the study 
Censored 
Date of last evaluable sample 
assessment 
No BR and no clinical disease 
progression and patient premature 
withdrawal from the study or lost to 
follow-up 
Censored 
Date of last evaluable sample before 
withdrawal from the study or last 
contact 
Clinical disease progression before BR 
Censored 
Date of clinical disease progression 
 
x EFS 
Event 
Decision 
Date of event or censor to consider 
for analysis 
Clinical disease progression or death 
from any cause 
Not 
censored 
Date of clinical disease progression 
or death 
No clinical disease progression and no 
death and no premature withdrawal 
from the study 
Censored 
Date of last visit 
No clinical disease progression no 
death and patient premature withdrawal 
from the study or lost to follow-up 
Censored 
Date of withdrawal from the study or 
last contact 
 
x OS 
Event 
Decision 
Date of event or censor to consider 
for analysis 
Death from any cause 
Not 
censored 
Date of death 
Patient alive and no premature 
withdrawal from the study 
Censored 
Date of last visit 
Patient premature withdrawal from the 
study or lost to follow-up 
Censored 
Date of withdrawal from the study or 
last contact 
 


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x Disease-specific mortality 
Event 
Decision 
Date of event or censor to consider 
for analysis 
Death related to prostate cancer 
Not 
censored 
Date of death 
Death not related to prostate cancer 
Censored 
Date of death 
Patient alive and no premature 
withdrawal from the study 
Censored 
Date of last visit 
Patient premature withdrawal from the 
study or lost to follow-up 
Censored 
Date of withdrawal from the study or 
last contact 
 
x PSADT 
Event 
Decision 
Date of event or censor to consider 
for analysis 
First PSA value > than twice that of the 
first increased value (> 0.2 ng/mL) 
Not 
censored 
Date of sample when the first PSA 
value > than twice that of the first 
increased value 
No PSA value 2 times higher than the 
first increased value or no increased 
value and no premature withdrawal 
from the study 
Censored 
Date of last evaluable sample 
Patient premature withdrawal from the 
study or lost to follow-up 
Censored 
Date of last evaluable sample before 
withdrawal from the study or last 
contact 
 
 
Incomplete dates for time-to-event analyses will be handled as follows: 
x If the day of the randomisation is missing and month is present, the 15 of the 
month will be used. 
x If the day of the BR, clinical progression or death is missing and month is 
present, the 01 of the month will be used. 
x If the month (or the date) of the death is missing, the date of the last contact 
will be used. 
x The other dates with missing month will be studied case by case. 
 
Castrated patients 
 
A patient will be considered as: 
x Castrated if the testosterone level is inferior to 50 ng/dL for the test or 
confirmation test. 
x Not castrated if the testosterone level is superior or equal to 50 ng/dL for the 
test and confirmation test. 
 


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HRQoL 
 
x FACT-P 
The FACT-P score is composed of 27 general questions about physical, social, 
emotional, and functional well-being as well as a 12-item questionnaire about 
prostate-specific concerns. A maximum score of 156 points indicates the highest level 
of QoL. The total FACT-P score will be calculated as the sum of 39 item scores. 
 
Dimensions 
Subscales 
Number of items 
N° item 
General well-being 
Physical well-being 
Social well-being 
Emotional well-being 
Functional well-being 
7 
7 
6 
7 
GP1 to GP7 
GS1 to GS7 
GE1 to GE6 
GF1 to GF7 
Prostate-specific concerns 
-- 
12 
C2, C6 
P1 to P8 
BL2 to BL5 
For missing data, if less than 50 % of the items are missing, subscale scores will be 
prorated. This will be done by using the formula below:  
 
Prorated subscale score = (Sum of item scores)*(Number of items in the subscale)/ 
(Number of items answered).  
 
If more than 50 % of the items are missing from any subscale, the subscale will not be 
imputed.  
 
For any given scale, if the missing values represent more than 10 % of the population; 
two analyses will be performed. One analysis using the available values and a second 
analysis imputing the missing values by the mean value of the available data at the 
concerned timepoint will be performed.   
 
x SF-36v2 
The SF-36 health survey version 2 [1] is composed of 36 items about 8 Health 
Domain Scales: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), 
Social Functioning (SF), Mental Health (MH), Role-Emotional (RE), Vitality (VT) 
and General Health (GH). 
All but one of the 36 items (item n°2: self-reported health transition) are used to score 
the eight raw Health Domain Scales. Each item is used in scoring only one scale. The 
response for each item is recoded according to the table below.  
Then, the eight Health Domain Scales Total Raw Scores are calculated, according to 
the table on the following page. Each score will range from 0 to 100, where 0 
represent the lowest possible score (worst health state) and 100 represent the highest 
possible score (best health state). 


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Finally, the eight health domain scales scores are normed to the 2009 U.S. general 
population to have a mean of 50 and a standard deviation of 10.  These are health 
domain scales norm-based scores. 
 
Two summary measures are calculated, using the eight health domain scales norm-
based scores and an algorithm: an overall score of physical health (Physical 
Component Summary or PCS) and overall score of mental health (Mental Component 
Summary or MCS)  
 
Item numbers 
Precoded response value 
Final response value 
3a to 3j 
 
1 
2 
3 
3 
2 
1 
2 
4a to 4d 
5a, 5b, 5c 
9b, 9c, 9f, 9g, 9i 
10, 11a, 11c 
1 
2 
3 
4 
5 
5 
4 
3 
2 
1 
7 
1 
2 
3 
4 
5 
6 
6 
5 
4 
3 
2 
1 
1 
6 
8 
9a, ,9d, 9e, 9h 
11b, 11d 
1 
2 
3 
4 
5 
5 
4 
3 
2 
1 
 
Component Summary 
measures (calculated from 
a combination of norm-
based scales scores) 
Health Domain Scales 
(raw and norm-based) 
Number of items 
Items 
Physical Health (PCS) 
Physical functioning (PF) 
Role-Physical (RP) 
Bodily Pain (BP) 
General Health (GH) 
10 
4 
2 
5 
3a to 3j 
4a to 4d 
7, 8 
1, 11a to 11d 
Mental Health (MCS) 
Social Functioning (SF) 
Mental Health (MH) 
Role-Emotional (RE) 
Vitality (VT) 
2 
5 
3 
4 
6, 10 
9b, 9c, 9d, 9f, 9h 
5a, 5b, 5c 
9a, 9e, 9g, 9i 
 


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The derivations of the eight Health Domain Scales Total Scores (Raw and norm-
based) and the two component summary measures (calculated from a combination of 
norm-based scales scores) will be performed using software application delivered by 
QualityMetric. 
 
Missing data are ignored and the scale is calculated without the missing item. If more 
than 50 % of the items are missing from any scale, the scale score will not be 
calculated.  
 
For any given value, if the missing values represent more than 10 % of the 
population; two analyses will be performed. One analysis using the available values 
and a second analysis imputing the missing values by the mean value of the available 
data at the concerned timepoint will be performed. 
 
3.2.11. 
Visit windows 
All data will be organised and analysed according to the scheduled visits outlined in 
the protocol. However, actual observation times may differ from the scheduled visit 
times and where this occurs the results should be allocated to the most appropriate 
visit. Therefore, time intervals (e.g. visit windows) have been constructed so that 
every observation collected after baseline visit can be allocated to a particular time 
point. If more than one record occurs within the same visit window where only one 
assessment is expected then the following rule should be applied (except for PSA and 
testosterone sample): for pre-study assessments only one record is expected and 
corresponds to the baseline visit; for post-treatment assessments the closest non-
missing result to the scheduled visit should be used.  
 
Scheduled visit 
Time interval (days) 
Baseline [V2] 
1 
Month 3 [V3] 
2 to 138 
Month 6 [V4] 
139 to 229 
Month 9 [V5](a) 
230 to 321 
Month 12 [V6] 
322 to 412 
Month 15 [V7] 
413 to 503 
Month 18 [V8] 
504 to 595 
Month 21 [V9] 
596 to 686 
Month 24 [V10](a) 
687 to 777 
Month 27 [V11] 
778 to 868 
Month 30 [V12] 
869 to 960 
Month 33 [V13] 
961 to 1051 
Month 36 [V14](a) 
1052 to 1142 
X visit post Month 36 - Every 3 months ((36+3*X-1.5)*30.4375+2) to 
((36+3*X+1.5)*30.4375+1) 
Time interval (days): Date of visit – Date of baseline visit +1 
(a) sHRQoL assessment 
 


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3.2.12. 
Window for assessment for the PSA and testosterone parameters  
Testosterone (only in the triptorelin treatment group) should be assessed at 3; 6 and 9 
months (±14 days). At visit 3, evidence of lack of castration will be confirmed by a 
second test at least 2 weeks later.  
 
PSA should be assessed every 3 month (±14 days) except at Visit 2 (Baseline, Day 1 
Month 0). Elevated PSA concentration (>0.2 ng/mL) must be confirmed by a second 
test 4 to 6 weeks later (acceptable delta of 14 days).   
 
Scheduled visit 
Time interval (days)  
for serum testosterone 
assessment  
Time interval (days) for PSA Level 
assessment 
As per 
protocol  
(±14 days) 
Used for analysis 
(Consecutive 
intervals) 
As per 
protocol  
(±14 days) 
Used for analysis 
(Consecutive 
intervals) 
Month 3 [V3](a,b) 
78 to 106 
2 to 138 
78 to 106 
2 to 138 
Month 6 [V4](a,b) 
170 to 198 
139 to 229 
170 to 198 
139 to 229 
Month 9 [V5](a,b) 
261 to 289 
230 to 321 
261 to 289 
230 to 321 
Month 12 [V6] (b) 
-- 
-- 
352 to 380 
322 to 412 
Month 15 [V7] (b) 
-- 
-- 
444 to 472 
413 to 503 
Month 18 [V8] (b) 
-- 
-- 
535 to 563 
504 to 595 
Month 21 [V9] (b) 
-- 
-- 
626 to 654 
596 to 686 
Month 24 [V10](b) 
-- 
-- 
718 to 746 
687 to 777 
Month 27 [V11] (b) 
-- 
-- 
809 to 837 
778 to 868 
Month 30 [V12] (b) 
-- 
-- 
900 to 928 
869 to 960 
Month 33 [V13] (b) 
-- 
-- 
991 to 1019 
961 to 1051 
Month 36 [V14](b) 
-- 
-- 
1083 to 1111 
1052 to 1142 
Time interval (days): Date of assessment – Date of baseline visit +1 
(a) serum testosterone assessment 
(b) PSA Level assessment 
 
3.2.13. 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the 
number of decimal places used does not imply undue precision). Raw data will be 
presented to the number of decimal places collected, and derived data will be 
presented to an appropriate number of decimal places.  The appropriate number of 
decimal places will be determined by general practice, mathematical rationale or 
scientific rationale (e.g. age should be presented in whole numbers).  
For summary statistics, the following will be presented: n, arithmetic mean, standard 
deviation, median, first quartile, third quartile, minimum and maximum. 
  
Mean, median, quartiles and standard deviation values will be reported to one 
decimal place greater than the raw/derived data that they summarise. Minimum and 
maximum values will be reported with the same precision as the raw data. 


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Percentages will be reported to one decimal place and 0% will not be presented.  
Percentages will be calculated using a denominator of all patients in a specified 
population with non-missing observations. The denominator will be specified in a 
footnote to the tables for clarification if necessary. 
 
P-values will be reported to three decimal places (e.g.: p=0.037), after rounding. P-
values which are less than 0.001 will be presented as ‘<0.001’. 
 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as 
such. In summaries of data values below limit of detection will be set to the limit of 
detection. Values above limit of detection will be set to limit of detection. 
 
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. Dates and 
times will be presented in the format as defined in the data-base, i.e.  [ddmmmyyyy] 
and [hh:mm] respectively. 
 
3.2.14. 
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
To compute hazard ratios on the primary endpoint a Cox Proportional hazard model 
will be fitted including treatment group, Gleason score, country and pooled centres.  
In each country, the centres with a randomized number of patients strictly above 10 
will be pooled in one centre.  
 
3.2.15. 
Interim analysis 
Primary endpoint analysis will be performed once the 61 BRs are provided. 
Tables/figures/listings to be produced for this analysis are flagged in the index by a *. 
 
3.2.16. 
Covariates and analysis of subgroups 
If analysis of primary efficacy criterion can highlight a country effect then an 
adjustment for country will be done for efficacy analyses. 
 
4. 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1. 
Hardware 
The statistical analysis will be performed using Microsoft Windows 7 Enterprise and 
PCs will be used to run the SAS programs. 
 
4.2. 
Software 
All tables, listings and figures will be produced and statistical analysis performed 
using SAS version 9.4. All output will be in Microsoft Word Format. 
 


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4.3. 
Validation programs 
Validation of SAS programs will be performed by Lincoln as described in Lincoln 
Standard Operating Procedure “Analyse statistique”. 
The CRO will provide a Validation Plan to Ipsen identifying the methods of 
validation.  
The Program Reviewer is responsible for reviewing each project program and output 
associated with the deliverable product. Program logs are reviewed for logical, syntax 
and fatal errors. The review in SAS includes, but is not limited to, all ERRORS, 
WARNINGS, BY-VALUE merge messages, NOTES, and UNINITIALIZED 
variables. Program logs are also reviewed for accurate and consistent variable and 
observation counts following each procedure and data step. 
The Reviewing/QC Statistician is responsible for checking and reviewing the work 
produced using whatever method he/she feels is appropriate (e.g., SAS code review, 
hand calculation, etc.) to reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values or 
results and to check the consistency with the reporting and analysis plan. Outputs are 
cross-checked against each other for accuracy and consistency. For statistical tables, 
listings, appendix listings, and figures, this procedure includes comparison of patient 
group numbers, counts of patients at each observation point, and consistency of 
results for variables between outputs. 
Findings of the quality control reviews are communicated to the party responsible for 
making necessary changes. The programs will be retested after modifications. 
After final review, and when no further changes are required to produce the 
deliverable, the Program Reviewer and Reviewing/QC Statistician need to complete 
and sign the CRO’s Validation Checklist/Sign-off Sheet, to indicate that they have 
successfully performed all of their responsibilities. 
 
Copies of the internal QC forms produced for the validation process and the 
Lincoln’s sign-off forms will be provided to the sponsor to support the validation. 
 
4.4. 
Restitution of the programs 
All programs (including Macros specifically written for this study and analysis 
datasets) producing the tables, listings and statistical output along with associated 
logs should be given to the sponsor when the tables, listings, figures and statistical 
analysis has been finalised. 
 
5. 
CHANGES FROM PROTOCOL 
The screened population have been defined as all patients with Visit 1 (Screening, 
Day - 14) performed and who have given informed consent. 
 
The enrolled population have been defined as all patients from the screened 
population with visit 2 (Baseline, Day 1) performed. 
 


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The safety population have been defined as all randomised patients that have received 
at least one injection for patients from the triptorelin arm or that have undergone at 
least one day of active surveillance for patients from the active surveillance arm 
(patient that attended at least one visit after Visit 2 (Baseline, Day 1)) or with at least 
one collected safety data). The patients will be analysed according to the treatment 
received. 
 
The mITT population has been added. 
 
For primary endpoint, two other sensitivity analyses have been added: 
x Censor the subjects if there are at least two missing consecutive visits before 
the BR. 
x Consider death (whatever the cause) as an event. 
 
The rules to apply if more than one record occurs within the same visit window have 
been changed for PSA and testosterone samples: 
 
6. 
REFERENCES 
1. 
Maruish, M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). 
Lincoln, RI: QualityMetric Incorporated 
 
7. 
DATA PRESENTATION 
Data listings are presented for all enrolled and randomised patients. 
Footnotes should be used to clarify ambiguities (e.g.: the denominator used to 
calculate a percentage or for notes for the programmer). If the number of footnotes is 
high, they could be presented only in the last page, with on each page the following 
footnote “See last page for listing notes”.  The order of the footnotes for key symbols 
(*, ~) will be in the order that they appear in the listing. 
The title of each generated table, listing and figure should appear bookmarked within 
Word (one single bookmark per table/listing/figure) to allow document publishing by 
Ipsen.