Conditions: Endometriosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 300
Healthy volunteers: no

Brief summary:
To assess the efficacy of triptorelin pamoate prolonged release (PR) 3-month formulation in Chinese female subjects with endometriosis by demonstrating the non-inferiority of triptorelin pamoate PR 3-month formulation injected once as compared to triptorelin acetate PR 1-month formulation injected 3 times consecutively.

Detailed description:

Arms:
arm 1: Subjects received 15 mg triptorelin pamoate per injection, administered as an intramuscular injection once every 12 weeks (a total of 2 injections, at baseline and Week 12). arm 2: Subjects received 3.75 mg triptorelin acetate per injection, administered as an intramuscular injection once every 4 weeks (a total of 6 injections, at baseline and Weeks 4, 8, 12, 16 and 20).

Interventions: intervention 1: Triptorelin Pamoate PR 3-month intervention 2: Triptorelin Acetate PR 1-month
Intervention descriptions: intervention 1: 15mg/injection, administered as an intramuscular injection once every 12 weeks (a total of 2 injections). intervention 2: 3.75mg/injection, administered as an intramuscular injection once every 4 weeks (a total of 6 injections)

Protocol document:
Prot_000.pdf: 
IPSEN GROUP 
D-CN-52014-220 
 
CONFIDENTIAL 
PROTOCOL: FINAL (VERSION 3.0, AMENDMENT 2.0) 29 SEPTEMBER 2017 
PAGE 1/89 
 
 
PROTOCOL TITLE: A PHASE III, MULTICENTRE, RANDOMISED, OPEN-LABEL, 
PARALLEL, ACTIVE-CONTROLLED STUDY TO COMPARE THE OESTRADIOL 
SUPPRESSION, CLINICAL EFFICACY AND SAFETY OF TWO FORMULATIONS OF 
TRIPTORELIN (TRIPTORELIN PAMOATE PR 3-MONTH AND TRIPTORELIN 
ACETATE PR 1-MONTH) IN CHINESE SUBJECTS WITH ENDOMETRIOSIS 
 
STUDY PROTOCOL 
STUDY NUMBER: D-CN-52014-220 
 
TRIPTORELIN PAMOATE 15 MG PR  
 
Version 3.0 (Amendment 2.0): 29 September 2017 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
 
 
Ipsen Pharma 
Beaufour-Ipsen (Tianjin) Pharmaceutical Co  
65 quai Georges Gorse 
No 1206, Floor 12, Block H, Phoenix Place 
92100 Boulogne-Billancourt 
Shuguang Xili, Chaoyang District 
France 
Beijing 100028, China  
Tel: 
 
Tel: +33 (0) 1 58 33 50 00 
Fax: 
 
Fax: +33 (0) 1 58 33 50 01 
 
Monitoring Office: 
Coordinating Investigator: 
 
 
 
 
 
Beaufour-Ipsen (Tianjin) Pharmaceutical Co 
Peking Union Medical College Hospital 
No 1206, Floor 12, Block H, Phoenix Place 
No 1 Shuaifuyuan, Dongcheng District 
Shuguang Xili, Chaoyang District 
Beijing 100730 
Beijing 100028, China 
China 
Tel: 
 
Tel: 
 
Fax: 
 
Fax: 
 
 
Pharmacovigilance/Emergency Contact: 
 Ipsen 
Biopharm Ltd, 102 Park Drive, Milton Park, Abingdon, OX14 4RY. United Kingdom 
Tel: 
 – mobile telephone for emergencies 
For serious adverse events (SAEs) reporting: 
Fax: 
 
 
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
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol entitled "A phase III, multicentre, randomised, open-label, 
parallel, active-controlled study to compare the oestradiol suppression, clinical efficacy and 
safety of two formulations of triptorelin (triptorelin pamoate PR 3-month1 and triptorelin 
acetate PR 1-month2) in Chinese subjects with endometriosis". I am aware of my 
responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
 
NAME:  
TITLE: 
PRINCIPAL 
 
 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
Sponsor's Representative Signature: 
NAME:  
 
TITLE:  
 
 
SIGNATURE: 
 
 
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
                                                 
1 Marketed in China as Triptorelin pamoate for injection 15 mg (for prostate cancer only). 
2 Marketed in China as Diphereline 3.75 mg. 
PPD
PPD
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IPSEN GROUP 
D-CN-52014-220 
 
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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol entitled "A phase III, multicentre, randomised, open-label, 
parallel, active-controlled study to compare the oestradiol suppression, clinical efficacy and 
safety of two formulations of triptorelin (triptorelin pamoate PR 3-month and triptorelin 
acetate PR 1-month) in Chinese subjects with endometriosis". I am aware of my 
responsibilities as a coordinating investigator under the guidelines of Good Clinical Practice 
(GCP), local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these guidelines and to appropriately direct and assist the staff under my control, 
who will be involved in the study. 
 
NAME:  
 
TITLE: 
COORDINATING 
SIGNATURE: 
INVESTIGATOR 
 
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
PPD


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SUMMARY OF CHANGES 
The initial version of the protocol was released on 12 January 2017. The current version of the 
protocol (Version 3.0) was released on 29 September 2017 and includes Amendment 1.0 
(02 May 2017) and Amendment 2.0. The respective protocol amendment forms were prepared 
and are provided in Appendix 2 and Appendix 3, respectively (Table 1). 
Table 1 
List of Protocol Amendments  
Amendment 
Release date 
Amendment form 
1.0 
02 May 2017 
Appendix 2 
2.0 
29 September 2017 
Appendix 3 
 


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SYNOPSIS 
Name of sponsor/company: Ipsen Pharma 
Name of finished product: Triptorelin pamoate prolonged release (PR) 3-month 
Name of active ingredient(s): Triptorelin pamoate 
Title of study: A phase III, multicentre, randomised, open-label, parallel, active-controlled study to 
compare the oestradiol suppression, clinical efficacy and safety of two formulations of triptorelin 
(triptorelin pamoate PR 3-month and triptorelin acetate PR 1-month) in Chinese subjects with 
endometriosis 
Study number: D-CN-52014-220 
Number of planned centres: Approximately 25 centres in China 
Planned study period: 
May 2017 to November 2019 
Phase of development: 
Phase III 
Objectives: 
It is hypothesised that triptorelin pamoate PR 3-month will offer non-inferior efficacy to triptorelin 
acetate PR 1-month in the treatment of Chinese subjects with endometriosis (as previously 
demonstrated in a European population in Study E-28-52014-705). 
Primary objective: 
• 
To assess the efficacy of triptorelin pamoate PR 3-month formulation in Chinese female 
subjects with endometriosis by demonstrating the noninferiority of triptorelin pamoate 
PR 3-month formulation injected once as compared to triptorelin acetate PR 1-month 
formulation injected 3 times consecutively, assessed by the percentage of subjects 
castrated (oestradiol (E2) ≤184 pmol/L or 50 pg/mL) at Week 12. 
Secondary objectives: 
• 
To assess other efficacy parameters including the percentage of subjects castrated at 
other time points, E2, luteinising hormone (LH) and follicle stimulating hormone (FSH) 
concentrations, and the impact on endometriosis-associated pelvic pain. 
• 
To assess the safety profile of triptorelin pamoate PR 3-month. 
• 
To assess the pharmacokinetics (PK) of triptorelin pamoate PR 3-month and compare to 
triptorelin acetate PR 1-month. 
Exploratory objectives: 
• 
To assess efficacy parameters (percentage of subjects castrated, E2, LH and FSH 
concentrations and impact on endometriosis-associated pelvic pain) after Week 12. 
• 
To explore the PK/pharmacodynamics (PD) of triptorelin pamoate PR 3-month in a 
subset of subjects (PD markers being E2, FSH and LH). 
Methodology:  
This prospective, multicentre, randomised, open-label, parallel-group, active-controlled study will 
compare triptorelin pamoate PR 3-month with triptorelin acetate PR 1-month in the treatment of 
endometriosis in Chinese subjects. 
Subjects with endometriosis will be recruited and screened for eligibility up to 5 weeks prior to the 
first dose of investigational medicinal product (IMP), which must occur during the follicular phase of 
the menstrual cycle. Eligible subjects will be stratified by endometriotic surgical history and 
endometriosis-associated pelvic pain (assessed by a visual analogue scale (VAS)) and randomised in a 
1:1 ratio to receive either triptorelin pamoate PR 3-month once per 12 weeks or triptorelin acetate PR 
1-month once per 4 weeks for a 24-week treatment phase. All subjects will visit the study site every 
4 weeks until Week 24, with the exception of the subgroup participating in the full PK and exploratory 
PD evaluations (up to 32 subjects, including up to 16 from each treatment group; to be enrolled at 


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selected sites), who will have additional study visits during the treatment phase. If needed in the 
opinion of the investigator, "add back" treatment (recommended as, but not limited to, tibolone at a 
dose of 2.5 mg once daily) may be applied from Week 12. After 24 weeks' study treatment, subjects 
will be followed up by telephone every 4 weeks until menses recovery or Week 40 (whichever is 
earlier), except for subjects receiving triptorelin pamoate PR 3-month and participating in the full 
PK/PD subgroup, who will visit the study site. The first visit after the menses recovery or Week 40 
will be considered as the end of study visit. All subjects will attend the study site for the end of study 
visit. 
The duration of the study is a minimum of 24 to 40 weeks, plus up to 5 weeks for the screening period. 
Number of subjects planned: 
300 randomised subjects (150 receiving triptorelin pamoate PR 3-month and 150 receiving triptorelin 
acetate PR 1-month). 
Diagnosis and criteria for inclusion: 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Female subjects aged from 18 to 45 years inclusive at the date of informed consent. 
(2) 
Provided written informed consent. 
(3) 
A history of active and regular menstrual cycles of 21 to 35 days (inclusive) in the 
6 months prior to the screening visit. 
(4) 
A diagnosis of endometriosis, confirmed by laparoscopy or laparotomy within 10 years 
prior to the screening visit.  
(5) 
Requires treatment with a gonadotrophin releasing hormone (GnRH) agonist for a 
period of 6 months in the judgement of the investigator. 
(6) 
A negative pregnancy test prior to the start of treatment. 
(7) 
Not at risk of pregnancy, i.e. subjects of childbearing potential must be actively using 
barrier contraception throughout the study treatment until menses resume. 
Subjects will be excluded from the study if any of the following apply: 
(1) 
Subject is menopausal. 
(2) 
Subject is pregnant or lactating. 
(3) 
A current history of undiagnosed abnormal genital bleeding. 
(4) 
Received treatment with a GnRH agonist within 6 months prior to the screening visit. 
(5) 
A history of hypersensitivity to GnRH agonists and/or any of the excipients. 
(6) 
Received any other hormonal treatment within 3 months prior to the screening visit 
(oestrogens, progestogens, danazol, gestrinone and cyproterone acetate etc). 
(7) 
Has been treated for endometriosis with traditional Chinese medicine within 1 month 
prior to screening. 
(8) 
It is anticipated that the subject will require surgery during the study period. 
(9) 
Chronic pelvic pain that is not caused by endometriosis, that would interfere with the 
assessment of endometriosis-associated pelvic pain. 
(10) 
A significant endocrine disorder (except controlled diabetes mellitus). 
(11) 
Known history of human immunodeficiency virus (HIV) infection. 
(12) 
Known history of chronic active hepatitis, including viral hepatitis carriers (hepatitis B 
or hepatitis C). 
(13) 
Clinically significant hepatic (any liver enzyme > 2× the upper limit of normal (ULN)) 
or renal (creatinine > ULN) abnormalities or any other dysfunction according to the 
investigator’s judgement. 
(14) 
Any psychiatric illness, severe or unstable known illness that in the investigator’s 
opinion could affect the safety, conduct or outcome of the study. 


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(15) 
Use of concomitant therapy, which in the investigator’s opinion may interfere with the 
evaluation of study treatment efficacy and safety. 
(16) 
Treatment with any other experimental drug or device within 90 days prior to the 
screening visit and/or expectation of treatment with any other experimental drug or 
device during the conduct of the study. 
(17) 
Any malignancy except curatively-treated basal cell skin cancer. 
(18) 
Unable or unwilling to comply with the protocol. 
(19) 
A history of alcohol and/or drug abuse. 
(20) 
Abnormal pelvic type B ultrasonography finding that would contraindicate the use of 
triptorelin. 
Test product, dose, mode of administration: 
The test product is triptorelin pamoate PR 3-month formulation (triptorelin pamoate for injection 
15 mg). 
Triptorelin pamoate PR 3-month is a slightly yellow, freeze-dried cake or powder and solvent for 
suspension. For a single dose, the powder comprises triptorelin pamoate, D, L-lactide-coglycolide 
polymer, mannitol, sodium carmellose and polysorbate 80. The solvent provided for injection is a 
2 mL ampoule of mannitol and water. 
The product is administered by the intramuscular route only. The powder is reconstituted with the 
solvent provided and injected immediately after reconstitution. The product is administered as a single 
intramuscular injection every 12 weeks. 
Duration of treatment: 24 weeks 
Reference therapy, dose and mode of administration:  
The comparator product is triptorelin acetate PR 1-month formulation (triptorelin acetate for injection 
3.75 mg).  
Triptorelin acetate PR 1-month is a practically white, freeze-dried cake or powder and solvent for 
suspension. For a single dose, the powder comprises triptorelin acetate, D, L-lactide-coglycolide 
polymer, mannitol, sodium carmellose and polysorbate 80. The solvent provided for injection is a 
2 mL ampoule of mannitol and water. 
This product is administered by the intramuscular route only. The powder is reconstituted with the 
solvent provided and injected immediately after reconstitution. The product is administered as a single 
intramuscular injection every 4 weeks. 
Criteria for evaluation: 
Efficacy: 
Primary endpoint and evaluation: 
• 
Percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12. The primary 
endpoint will be evaluated based on centralised bioanalysis of serum samples for E2.  
Secondary endpoints and evaluations: 
• 
Percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Weeks 4 and 8.  
• 
Percentage of subjects castrated (E2≤110 pmol/L or 30 pg/mL) at Weeks 4, 8 and 12.  
• 
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at Weeks 4, 8 and 12 
compared to baseline.  
• 
E2, FSH and LH concentrations at Weeks 4, 8 and 12.  
• 
Time to menses recovery.  
Pharmacokinetic/pharmacodynamic endpoints and evaluations: 
A full triptorelin PK analysis will be conducted in a subgroup of up to 16 subjects in each treatment 
group (the full PK/PD subgroup: up to 32 subjects in total, to be enrolled at selected sites). Sparse PK 
samples will be taken in all subjects (in addition to the full PK subgroup) at Day 1 (baseline), and 


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Weeks 4, 8, 12 and 24. Additional hormone samples (E2, FSH and LH) will be collected for PD 
assessments at Weeks 1, 2, 3 and 32 in the full PK/PD subgroup. 
Noncompartmental analysis will only be performed on the PK data collected for the PK/PD subgroup 
to assess the PK parameters for the triptorelin pamoate PR 3-month and triptorelin acetate PR 1-month 
formulations. Population PK analysis (modelling) will be performed on PK data from all subjects. 
Exploratory endpoints will include: 
• 
Percentage of subjects castrated (as defined by both E2≤184 pmol/L (50 pg/mL) and 
E2≤110 pmol/L (30 pg/mL)) at Week 24;  
• 
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at Weeks 16, 20 and 
24 and the end of study visit compared to baseline;  
• 
Concentrations of E2, FSH and LH at Week 24. 
• 
The PK/PD relationship will be explored (PD markers being E2, FSH and LH). 
Safety: 
Occurrence of adverse events (AEs) throughout the study, clinical laboratory (biochemistry, 
haematology and urinalysis) test results and electrocardiogram (ECG) findings at screening, Week 12 
and Week 24, serum hormone (E2, FSH and LH) concentrations at Week 40 (for those subjects whose 
menses do not recover at Week 40), vital signs (blood pressure and heart rate) measurements at each 
visit during treatment and end of study visit, physical/pelvic examination at screening, Week 12 and 
Week 24, pelvic type B ultrasound at screening (or within 1 month prior to screening), Week 12 
(optional) and Week 24, and urinary pregnancy test at screening and baseline. 
Statistical methods: 
The analysis sets for the primary and secondary efficacy endpoints will be the full analysis set (FAS) 
and the per protocol (PP) set. If the lower limit of the 95% confidence interval (CI) of the difference in 
percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12 between the triptorelin 
pamoate PR 3-month and triptorelin acetate PR 1-month is >-10%, noninferiority of triptorelin 
pamoate PR 3-month will be confirmed.  
For secondary endpoints relating to the percentage of subjects castrated (either E2≤184 pmol/L or 
E2≤110 pmol/L), the number and percentage of subjects will be presented by treatment group for each 
visit. The difference between the treatment groups will be calculated and displayed with the 95% CI. 
Raw values for serum concentrations of E2, FSH and LH, endometriosis-associated pelvic pain 
(measured by VAS) and change from baseline, will be summarised, using number of available 
observations (n), mean, median, standard deviation (SD), and minimum and maximum values. For 
time to menses recovery, Kaplan-Meier curves, median time to event and 95% CIs will be provided. 
Determination of sample size 
The sample size was estimated based on data from Ipsen Study E-28-52014-705. Assuming the 
percentage of subjects castrated at Week 12 of triptorelin acetate PR 1-month treatment is no less than 
92%, a sample size of 133 subjects in each treatment group will have 85% power to demonstrate the 
noninferiority of triptorelin pamoate PR 3-month to the comparator, when the lower limit of the 
95% CI of the difference in percentage of subjects castrated at Week 12 between the treatment groups 
is >-10% and with a 0.025 one-sided type I error rate. 
Assuming that the dropout rate will be around 10%, a sample size of 300 randomised subjects in total 
is planned for this study. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 14 
1 
BACKGROUND INFORMATION ............................................................................ 16 
1.1 
Introduction ................................................................................................................... 16 
1.2 
Triptorelin ..................................................................................................................... 16 
1.3 
Findings from Clinical Studies .................................................................................... 17 
1.4 
Clinical Trial Rationale ................................................................................................ 17 
1.5 
Population to be Studied .............................................................................................. 17 
1.6 
Compliance Statement .................................................................................................. 17 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 19 
2.1 
Purpose of the Study ..................................................................................................... 19 
2.2 
Study Objectives ........................................................................................................... 19 
3 
STUDY DESIGN ........................................................................................................... 20 
3.1 
General Design and Study Schema ............................................................................. 20 
3.2 
Endpoints and Evaluations .......................................................................................... 21 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 21 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 21 
3.2.3 
Pharmacokinetic/Pharmacodynamic Endpoints and Evaluations ........... 21 
3.2.4 
Exploratory Efficacy Endpoints and Evaluations ..................................... 21 
3.2.5 
Safety Endpoints and Evaluations ............................................................. 22 
3.3 
Randomisation and Blinding ....................................................................................... 22 
3.4 
Study Treatments and Dosage ..................................................................................... 23 
3.5 
Study Duration .............................................................................................................. 23 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 24 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 24 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 24 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 24 
3.7.3 
Investigational Medicinal Product Accountability .................................... 24 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 24 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 24 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 26 
4.1 
Inclusion Criteria .......................................................................................................... 26 
4.2 
Exclusion Criteria ......................................................................................................... 26 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 27 
5 
STUDY PROCEDURES .............................................................................................. 28 
5.1 
Study Schedule .............................................................................................................. 28 
5.2 
Study Visits .................................................................................................................... 33 
5.2.1 
Procedures for Screening and Enrolment (Visit 1; up to -5 weeks) ......... 33 
5.2.2 
Procedures before Study Treatment (Baseline, Visit 2 Predose) .............. 34 


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5.2.2.1 
Pharmacokinetic Blood Sampling ................................................................ 34 
5.2.3 
Procedures during Study Treatment (Visit 2 Postdose to Visit 8) ............. 34 
5.2.3.1 
Full Pharmacokinetic Blood Sampling during Treatment ........................... 36 
5.2.3.2 
Full Pharmacodynamic Assessments ........................................................... 36 
5.2.4 
Procedures during Follow Up Period (Visit 9 to End of Study) ................ 37 
5.2.4.1 
Follow Up Visits to be Conducted by Telephone ......................................... 37 
5.2.4.2 
Full Pharmacokinetic Blood Sampling during Follow Up .......................... 37 
5.2.4.3 
Full Pharmacodynamic Assessments during Follow Up ............................. 37 
5.2.4.4 
End of Study Visit or Early Withdrawal Visit .............................................. 37 
6 
TREATMENT OF SUBJECTS ................................................................................... 39 
6.1 
Study Drugs Administered ........................................................................................... 39 
6.1.1 
Triptorelin Pamoate PR 3-month ............................................................... 39 
6.1.2 
Triptorelin Acetate PR 1-month ................................................................. 39 
6.2 
Concomitant Medication/Therapy .............................................................................. 39 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 40 
7 
ASSESSMENT OF EFFICACY .................................................................................. 41 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 41 
7.2 
Secondary and Exploratory Efficacy Endpoints and Evaluations ........................... 41 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 43 
7.3.1 
Oestradiol, Follicle Stimulating Hormone and Luteinising Hormone 
Concentrations ............................................................................................ 43 
7.3.1.1 
Oestradiol Concentrations ........................................................................... 43 
7.3.1.2 
Luteinising Hormone and Follicle Stimulating Hormone Concentrations .. 43 
7.3.2 
Endometriosis-associated Pelvic Pain ........................................................ 43 
7.3.3 
Recovery of Menses ..................................................................................... 43 
8 
ASSESSMENT OF SAFETY ....................................................................................... 44 
8.1 
Adverse Events .............................................................................................................. 44 
8.1.1 
Definition of an Adverse Event .................................................................. 44 
8.1.2 
Categorisation of Adverse Events ............................................................... 44 
8.1.2.1 
Intensity Classification ................................................................................. 44 
8.1.2.2 
Causality Classification ............................................................................... 44 
8.1.2.3 
Assessment of Expectedness ......................................................................... 44 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 45 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 45 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 45 
8.1.3 
Recording and Follow Up of Adverse Events ............................................ 45 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 45 
8.1.5 
Pregnancy .................................................................................................... 47 
8.1.6 
Deaths .......................................................................................................... 47 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 47 


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8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 48 
8.2 
Clinical Laboratory Tests ............................................................................................ 48 
8.2.1 
Haematology ................................................................................................ 48 
8.2.2 
Blood Biochemistry ..................................................................................... 48 
8.2.3 
Urinalysis ..................................................................................................... 48 
8.2.4 
Pregnancy Test ............................................................................................ 48 
8.2.5 
Hormones .................................................................................................... 49 
8.3 
Physical/Pelvic Examination ........................................................................................ 49 
8.4 
Pelvic Type B Ultrasound Scan ................................................................................... 49 
8.5 
Vital Signs ...................................................................................................................... 49 
8.6 
Electrocardiography ..................................................................................................... 49 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 50 
9.1 
Pharmacokinetics .......................................................................................................... 50 
9.1.1 
Sample Collection ....................................................................................... 50 
9.1.2 
Analytical Procedures ................................................................................. 50 
9.1.3 
Data Analysis ............................................................................................... 50 
9.2 
Pharmacodynamics ....................................................................................................... 50 
9.3 
Pharmacokinetics/Pharmacodynamics Relationship ................................................ 50 
10 
STATISTICS ................................................................................................................. 51 
10.1 Analyses Sets ................................................................................................................. 51 
10.1.1 
Data Sets Analysed ...................................................................................... 51 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 51 
10.2 Sample Size Determination .......................................................................................... 51 
10.3 Significance Testing and Estimations ......................................................................... 52 
10.4 Statistical/Analytical Methods ..................................................................................... 52 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 52 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 52 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 52 
10.4.4 
Pharmacokinetic Data ................................................................................ 52 
10.4.5 
Pharmacodynamic Data ............................................................................. 53 
10.4.6 
Efficacy Evaluation ..................................................................................... 53 
10.4.6.1 
Primary Efficacy Endpoint .......................................................................... 53 
10.4.6.2 
Secondary Efficacy Endpoints ..................................................................... 53 
10.4.6.3 
Exploratory Efficacy Endpoints ................................................................... 54 
10.4.7 
Adjustment for Centre Effect ...................................................................... 54 
10.4.8 
Safety Evaluation ........................................................................................ 54 
10.5 Subgroup Analyses ....................................................................................................... 55 
10.6 Interim Analyses ........................................................................................................... 55 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 56 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 57 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 57 


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12.1.1 
Protocol Amendments ................................................................................. 57 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 57 
12.2 Information to Study Personnel .................................................................................. 57 
12.3 Study Monitoring .......................................................................................................... 57 
12.4 Audit and Inspection .................................................................................................... 58 
12.5 Data Quality Assurance ................................................................................................ 58 
13 
ETHICS ......................................................................................................................... 59 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 59 
13.2 Informed Consent ......................................................................................................... 59 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 60 
13.4 Confidentiality Regarding Study Subjects ................................................................. 60 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 61 
14.1 Data Recording of Study Data ..................................................................................... 61 
14.2 Data Management ......................................................................................................... 61 
14.3 Record Archiving and Retention ................................................................................. 62 
15 
FINANCING AND INSURANCE ............................................................................... 63 
15.1 Contractual and Financial Details ............................................................................... 63 
15.2 Insurance, Indemnity and Compensation .................................................................. 63 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 64 
16.1 Publication Policy ......................................................................................................... 64 
16.2 Clinical Study Report ................................................................................................... 64 
17 
REFERENCES .............................................................................................................. 65 
18 
LIST OF APPENDICES .............................................................................................. 66 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Procedures and Assessments (All Subjects) ........................................... 29 
Table 3 
Full PK/PD Assessments Day 1 to Week 12 (PK/PD Subgroup Subjects) ..... 31 
Table 4 
Full PK/PD Assessments Week 13 to End of Study (PK/PD Subgroup 
Subjects) ............................................................................................................... 32 
Table 5 
Blood Volume Calculation (All Subjects) .......................................................... 33 
Table 6 
Additional Blood Samples (Full PK/PD Subgroup) ......................................... 33 
Table 7 
Secondary and Exploratory Efficacy Endpoints and Evaluations ................. 42 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 20 
 


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LIST OF ABBREVIATIONS 
 
ABBREVIATION Wording Definition  
AE 
Adverse event 
AUCτ 
Area under the plasma concentration-time curve for the dosing interval 
CA 
Competent Authority 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CMC-SC 
Chemistry, Manufacturing and Control-Supply Chain (relates to 
sponsor) 
Cmin 
Minimum observed plasma concentration during the dosing interval 
CRO 
Contract research organisation 
CSR 
Clinical study report 
E2 
Oestradiol 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetracetic acid 
FAS 
Full analysis set 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GnRH 
Gonadotrophin releasing hormone 
HCG 
Human chorionic gonadotrophin 
HIV 
Human immunodeficiency virus 
IB 
Investigator's brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
ISF 
Interim storage facility 
IWRS 
Interactive web response system 
LH 
Luteinising hormone 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 


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MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
Number of available observations 
NCA 
Noncompartmental analysis 
PD 
Pharmacodynamic(s) 
PDD 
Protocol deviation document 
PK 
Pharmacokinetic(s) 
PI 
Package insert 
PP 
Per protocol 
PR 
Prolonged release 
QTc 
Corrected QT interval 
RBC 
Red blood cell(s) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SmPC 
Summary of product characteristics 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent adverse event 
TFL 
Tables, figures and listings 
tmax 
Time to maximum observed plasma concentration 
TMF 
Trial master file 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White blood cell(s) 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Endometriosis is a disorder experienced by approximately 7% to 10% of women. It is 
characterised by the presence of endometrial tissue fragments outside the uterine cavity, most 
commonly in the pelvic area. Endometriosis is an oestradiol (E2) dependent disease and is 
relieved by the administration of antioestrogens, inhibitors of endogenous E2 secretion, and by 
surgical oophorectomy or ectopic tissue surgery.  
The disease may be asymptomatic, but where symptoms occur they usually consist of 
dysmenorrhoea, cyclical abdominal or pelvic pain, and dyspareunia. In addition, 30% to 40% 
of patients with endometriosis are infertile. This means that between 2% and 4% of women 
may be infertile due to endometriosis. Symptom intensity is not necessarily dependent upon 
the extent of the lesions and it is not unusual for endometriosis to be discovered in 
asymptomatic patients undergoing laparoscopy or laparotomy for some other reason. Since 
the symptomatology is also nonspecific, a diagnosis of endometriosis can only be confirmed 
by laparoscopy or other means that provide anatomical or histological evidence.  
Treatment of endometriosis depends on a woman’s symptoms, pregnancy plans, and age, as 
well as the extent of endometriosis. In some cases no treatment is necessary. Where treatment 
is required, two types are currently recommended, and these can be complementary. The first 
is surgery to remove the ectopic endometrial tissue. Furthermore, hormone treatment is used 
to suppress E2 secretion, since E2 stimulates the growth of endometrial tissue. The 
hypogonadotrophic state produced by hormonal suppressants reduces the menstrual flow and 
leads to apoptosis of the endometriotic lesions. The principal hormonal suppressants used are 
gonadotrophin releasing hormone (GnRH) agonists such as triptorelin.  
The purpose of triptorelin treatment of endometriosis is symptomatic relief of the condition 
via suppression of E2 production. The clinical effect is associated with reduction of E2 levels 
to postmenopausal levels, and hence suppression of menses. The suppression of menses is 
known to reduce endometriotic deposits and improve clinical symptoms. At the present time, 
hormonal treatment can be used either as first-line treatment or in combination with surgery, 
particularly in cases of extensive endometriosis. The GnRH analogues are used either pre- or 
postoperatively. 
1.2 
Triptorelin 
Triptorelin is a synthetic decapeptide analogue of natural GnRH, a hormone synthesised by 
the anterior and mediobasal hypothalamus that controls the synthesis and secretion of the 
gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (FSH) [1]. 
Triptorelin is principally characterised by the substitution of the L-glycine at position 6 in the 
natural GnRH decapeptide with D-tryptophan, leading to increased duration of action and 
affinity for the pituitary receptor compared to the parent compound. 
Binding of GnRH agonists to pituitary receptors is specific, saturable and reversible. The 
affinity of the agonist for these receptors is 100 times greater than that of the natural 
substance. At high concentrations and by continuous exposure, initially the agonist causes a 
transitory phase of hyperstimulation (flare-up) corresponding to a series of intracellular 
responses (phospholipase C pathway). Subsequently, the agonist causes a down-regulation of 
GnRH receptor number and a post-receptor desensitisation of the gonadotrophic cell, leading 
to reversible biochemical castration. Base concentrations of LH and FSH decrease, 
accompanied by suppression of response to stimulation by natural exogenous GnRH [2, 3]. 
Different triptorelin formulations are approved for use in China for a number of indications. 
Triptorelin acetate 3.75 mg prolonged release (PR) formulation (for monthly injections, 


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hereafter known as triptorelin acetate PR 1-month) is approved to treat endometriosis, as well 
as precocious puberty, prostate cancer, uterine fibromyomas and for use in female infertility 
as part of an in vitro fertilisation programme. This formulation, which is marketed in China as 
Diphereline 3.75 mg, represents the current standard of care in the management of 
endometriosis. In addition, a formulation for 3-monthly injections, triptorelin pamoate 15 mg 
PR formulation, hereafter referred to as triptorelin pamoate PR 3-month, is also approved for 
the treatment of prostate cancer only. This formulation, which is marketed in China as 
Triptorelin pamoate for injection 15 mg, is designed to deliver equivalent exposure to the 
1-month formulation, without the need for monthly injections. This formulation is widely 
used to treat endometriosis in other territories. 
A more detailed description of the product is given in Section 3.4. Further details may be 
found in the investigator’s brochure (IB). 
1.3 
Findings from Clinical Studies 
The efficacy of triptorelin in the treatment of endometriosis is well established [4]. Clinical 
studies have demonstrated rapid and sustained biochemical castration and improvement in the 
signs and symptoms of endometriosis. Consequently, various triptorelin formulations are 
approved for the treatment of endometriosis in different territories, including triptorelin 
acetate PR 1-month in China. 
The pharmacodynamic (PD) and pharmacokinetic (PK) equivalence of triptorelin pamoate PR 
3-month to triptorelin acetate PR 1-month with endometriosis was previously investigated in 
female European subjects in Ipsen Study E-28-52014-705 [5]. In this study, a total of 
146 subjects received either a single dose of triptorelin pamoate PR 3-month (72 subjects) or 
triptorelin acetate PR 1-month (74 subjects) over 3 months. At 12 weeks, the efficacy of 
triptorelin pamoate PR 3-month (as determined by the percentage of subjects with E2 
concentrations suppressed to castration levels) was found to be noninferior to the 1-month 
formulation. Overall, 97% of subjects receiving triptorelin pamoate PR 3-month were 
castrated at Week 12, compared to 94% receiving the 1-month formulation. 
Further details may be found in the IB. 
1.4 
Clinical Trial Rationale 
This study will be conducted to support the use of a triptorelin pamoate PR 3-month 
formulation for the treatment of endometriosis in Chinese patients. The primary endpoint will 
be to demonstrate similar efficacy to the currently approved triptorelin 1-month formulation 
in terms of the proportion of subjects with E2 concentrations suppressed to castration levels 
after 12 weeks. 
1.5 
Population to be Studied 
The study will enrol adult female subjects with endometriosis who, in the judgement of the 
investigator, require 6 months' treatment with a GnRH agonist. 
1.6 
Compliance Statement 
The study will 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) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. In addition, the study will adhere to all 
local regulatory requirements.  
Before initiating the study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 


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subject recruitment procedures (for example, advertisements), any written information to be 
provided to subjects 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. 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
This phase III registration study will be conducted to evaluate the similar efficacy of two 
different formulations of triptorelin (triptorelin pamoate PR 3-month and triptorelin acetate 
PR 1-month) in Chinese subjects with endometriosis. Triptorelin acetate PR 1-month has been 
marketed in China since 1999 and is the current standard of care for endometriosis. 
Triptorelin pamoate PR 3-month is only approved to treat prostate cancer in China, but is 
widely used to treat endometriosis in other territories. The 3-month formulation combines the 
advantages of E2 suppression with a longer duration of action, which increases the 
acceptability of treatment by limiting the number of injections required. This study will 
support the application for approval of triptorelin pamoate PR 3-month for the treatment of 
endometriosis in Chinese patients by demonstrating similar efficacy to the approved 
formulation, as well as an acceptable safety profile. 
It is hypothesised that triptorelin pamoate PR 3-month will offer non-inferior efficacy to 
triptorelin acetate PR 1-month in the treatment of Chinese subjects with endometriosis (as 
previously demonstrated in a European population in Study E-28-52014-705 [5]). 
2.2 
Study Objectives 
The primary objective of the study is to assess the efficacy of triptorelin pamoate PR 3-month 
formulation in Chinese female subjects with endometriosis by demonstrating the 
noninferiority of triptorelin pamoate PR 3-month formulation injected once as compared to 
triptorelin acetate PR 1-month formulation injected 3 times consecutively, assessed by the 
percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12. 
The secondary objectives of the study are as follows: 
• 
To assess other efficacy parameters including the percentage of subjects 
castrated at other time points, E2, LH, and FSH concentrations, and the impact on 
endometriosis-associated pelvic pain. 
• 
To assess the safety profile of triptorelin pamoate PR 3-month. 
• 
To assess the PK of triptorelin pamoate PR 3-month and compare to triptorelin 
acetate PR 1-month. 
The exploratory objectives of the study are: 
• 
To assess efficacy parameters (percentage of subjects castrated, E2, LH and FSH 
concentrations and impact on endometriosis-associated pelvic pain) after 
Week 12. 
• 
To explore the PK/PD of triptorelin pamoate PR 3-month in a subset of subjects 
(PD markers being E2, FSH and LH). 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a prospective, phase III, multicentre, randomised, open-label, parallel group, 
active-controlled study. A total of 300 Chinese female subjects with endometriosis will be 
randomly assigned in a 1:1 ratio to triptorelin pamoate PR 3-month or triptorelin acetate PR 
1-month. Specific details of the dosage groups are given in Section 6. 
Subjects will be recruited and screened for eligibility up to 5 weeks prior to the first dose of 
investigational medicinal product (IMP) being administered. The first dose of IMP must be 
initiated at the baseline Visit (Day 1) in the follicular phase of subjects (the first to fifth day of 
the menses period). The treatment period will be 24 weeks, with the schedule of injections 
being once per 12 weeks for triptorelin pamoate PR 3-month (with subjects in this group 
receiving a total of two injections, one each at baseline and Week 12), or once per 4 weeks for 
triptorelin acetate PR 1-month (with subjects in this group receiving a total of six injections, 
one each at baseline and Weeks 4, 8, 12, 16 and 20). The subjects visit the study site every 
4 weeks until Week 24, with the exception of the subgroup participating in the full PK and 
exploratory PD evaluations (up to 32 subjects, including up to 16 from each treatment group; 
to be enrolled at selected sites), who will have additional study visits. "Add back" treatment 
(recommended as, but not limited to, tibolone 2.5 mg once daily) may be administered after 
12 weeks if needed based on the investigator’s judgement. After 24 weeks' treatment, the 
subject will be followed up once every 4 weeks via telephone (except for subjects receiving 
triptorelin pamoate PR 3-month and participating in the full PK/PD subgroup, who will visit 
the study site) until menses recovery or Week 40 (whichever is earlier). The first visit after the 
menses recovery or Week 40 will be considered as the end of study visit. All subjects will 
attend the study site for the end of study visit. The principal study design features are 
summarised in Figure 1. 
Figure 1 Study Design 
 
Treatment with GnRH agonists has been proven to be effective and well tolerated in patients 
suffering from endometriosis [5, 6, 7, 8, 9] with the mode of activity being mainly mediated 


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by E2 suppression. Triptorelin acetate PR 1-month has been marketed in China since 1999, 
and represents the current standard of care in the management of endometriosis. As the active 
substance of triptorelin pamoate PR 3-month and triptorelin acetate PR 1-month is the same, 
and triptorelin has a proven mode of activity, it is justified to use E2 suppression as the 
primary endpoint in this study to compare the efficacy and safety between both formulations. 
According to Chinese guidelines, the recommended duration of GnRH agonist treatment for 
endometriosis is 3 to 6 months [10]. The duration of treatment in this study is therefore 
consistent with local treatment guidelines. In order to mitigate the potential for 
hypoestrogenaemia-related symptoms subjects can receive "add back" treatment from 
Week 12. Therefore, the primary efficacy endpoint will be assessed at Week 12. The 
additional 12 weeks of treatment is to allow the collection of additional efficacy and safety 
data. 
As the appearance and the administration frequency of the two treatments are not identical, a 
double-blind study would have to include a "double-dummy" design, which would expose 
subjects to unnecessary additional injections. An open-label design has therefore been 
selected for this study. As the primary efficacy endpoint will be based on an objective 
laboratory parameter, which will be evaluated centrally, it is considered that the bias has been 
sufficiently minimised to support an open-label design. 
3.2 
Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
The percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12. The primary 
endpoint will be evaluated based on centralised bioanalysis of serum samples for E2.  
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
Secondary endpoints for this study include:  
• 
Percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Weeks 4 and 8. 
• 
Percentage of subjects castrated (E2≤110 pmol/L or 30 pg/mL) at Weeks 4, 8 
and 12. 
• 
Change in endometriosis-associated pelvic pain (by 10 cm visual analogue scale 
(VAS)) at Weeks 4, 8 and 12 compared to baseline. 
• 
E2, FSH and LH concentrations at Weeks 4, 8 and 12. 
• 
Time to menses recovery. 
3.2.3 
Pharmacokinetic/Pharmacodynamic Endpoints and Evaluations 
A full triptorelin PK analysis will be conducted in a subgroup of up to 16 subjects in each 
treatment group, to be enrolled at selected sites. Sparse PK samples will be taken in all 
subjects (in addition to the full PK/PD subgroup) at Day 1 (baseline), and Weeks 4, 8, 12 
and 24. Additional hormone samples (E2, FSH and LH) will be collected for PD assessments 
at Weeks 1, 2, 3 and 32 in the full PK/PD subgroup. 
Noncompartmental analysis will only be performed on the PK data collected for the PK/PD 
subgroup to assess the PK parameters for the triptorelin pamoate PR 3-month and triptorelin 
acetate PR 1-month formulations. Population PK analysis (modelling) will be performed on 
PK data from all subjects. 
3.2.4 
Exploratory Efficacy Endpoints and Evaluations 
Exploratory endpoints for this study include:  


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• 
Percentage of subjects castrated (as defined by both E2≤184 pmol/L (50 pg/mL) 
and E2≤110 pmol/L (30 pg/mL)) at Week 24. 
• 
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at 
Weeks 16, 20 and 24 and the end of study visit compared to baseline. 
• 
Concentrations of E2, FSH and LH at Week 24. 
• 
The PK/PD relationship will be explored (PD markers being E2, FSH and LH). 
3.2.5 
Safety Endpoints and Evaluations 
The safety and tolerability of triptorelin will be assessed by evaluating the occurrence of 
adverse events (AEs) throughout the study, clinical laboratory parameters (biochemistry, 
haematology and urinalysis) test results and electrocardiogram (ECG) findings at screening, 
Week 12 and Week 24, serum hormone (E2, FSH and LH) concentrations at Week 40 (for 
those subjects whose menses do not recover at Week 40), vital signs (blood pressure and heart 
rate) measurements at each visit during treatment and end of study visit, physical/pelvic 
examination at screening, Week 12 and Week 24, pelvic type B ultrasound at screening (or 
within 1 month prior to screening), Week 12 (optional) and Week 24, and urinary pregnancy 
test at screening and baseline. 
3.3 
Randomisation and Blinding 
This is an open-label study, and there is no blinding. The sponsor’s randomisation manager, a 
statistician independent from the study, will prepare the master randomisation list for this 
study. This list will be performed in blocks and will be based on a computer-generated 
randomisation list. It will be stratified according to endometriotic surgical history (previous or 
no previous surgery) and the severity of endometriosis-associated pelvic pain (VAS >3 or 
≤3 cm), and will be generated with a balanced ratio (1 triptorelin pamoate PR 3-month to 1 
triptorelin PR 1-month). 
Subjects meeting the randomisation criteria will be allocated a randomisation number through 
an interactive web response system (IWRS) at baseline (Visit 2). This allocation will be 
performed in the order in which they enter the randomised study period and according to their 
endometriotic surgical history and severity of endometriosis-associated pelvic pain at 
baseline. The IWRS will assign subjects to one of two treatment groups based on a predefined 
randomisation list. A treatment number will be allocated by the IWRS each time drug is 
dispensed, according to the allocated treatment group. The IWRS will also manage all the 
logistical aspects of treatment (e.g. drug supplies; replacement of lost, damaged, quarantined, 
expiring or expired kits). 
The investigator will under no circumstances change the randomisation number, the treatment 
number or the treatment arm allocated to the subject. 
The IWRS will provide investigators, site coordinators and project team members with a 
24-hour a day, 7-day a week service. Additional details may be found in the IWRS reference 
manual to be provided to each site. In case of technical, randomisation or dispensation 
queries, a 24-hour helpline will be available: see supporting information in the investigator 
site file. 
Recruitment will stop once approximately 300 subjects have been randomised. Randomised 
subjects who terminate their study participation for any reason before starting the treatment 
will retain their randomisation number and treatment number (these numbers will not be 
reused). The next subject is given another randomisation number and another treatment 
number, even if she should receive the same treatment. Randomised subjects who leave the 
study early will not be replaced. 


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The sponsor’s randomisation manager will keep the master randomisation list. A copy of this 
list will be confidentially supplied to the contract research organisation (CRO) in charge of 
the IWRS. The master list and the copy supplied to the CRO in charge of the IWRS will be 
kept confidential in a secure location. Access to the randomisation list must be restricted until 
authorisation is given to release it for final analysis. 
3.4 
Study Treatments and Dosage 
The test product, triptorelin pamoate PR 3-month, will be administered as an intramuscular 
injection containing 15 mg triptorelin pamoate, once every 12 weeks. A more detailed 
description of administration procedures is given in Section 6.1.  
The comparator is triptorelin acetate PR 1-month, the triptorelin formulation commercially 
approved for the treatment of endometriosis in China. The comparator will be administered as 
an intramuscular injection containing 3.75 mg triptorelin acetate, once every 4 weeks. 
A more detailed description of administration procedures is given in Section 6.1.2.  
The IMP will be packaged by Chemistry, Manufacturing and Control-Supply Chain 
(CMC-SC; Beaufour Ipsen Industrie, Rue Ethe Virton, 28100, Dreux, France) and delivered 
to the interim storage facility (ISF) in China, and then to study sites. A sufficient quantity of 
IMP will be supplied as well as an acknowledgement of receipt form. 
The sponsor’s representative will receive: a Certificate of Analysis for which batch of IMP 
has been used under their study and the Certificate of Compliance which reflects the product 
release statement.  
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 
• 
Subject number/subject ID (this information will be completed by the 
investigator) 
• 
“Keep out of reach of children” 
• 
“For clinical trial use only” 
• 
Storage conditions 
• 
Expiry date 
The investigator, or designee, will only dispense IMPs to subjects included in this study. Each 
subject will only be given the IMP carrying his/her number. The dispensing for each subject 
will be documented in the electronic case report form (eCRF). 
3.5 
Study Duration 
This study will consist of a screening period of up to 5 weeks, a 24-week open-label treatment 
period and a follow up period of up to 16 weeks. The duration of the study is a minimum of 
24 to 40 weeks, plus up to 5 weeks for the screening period.  


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The subject’s participation in the study will be considered to have ended at the time of the last 
visit.  
The overall duration of the study will be approximately 32 months, including approximately 
21 months' recruitment. The study will be considered to have started when the first subject has 
been screened. The study will be considered to have ended after the last subject has completed 
the last visit in the study. 
3.6 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events (SAEs) will be reviewed (see Section 8.1.4) as they are reported from 
the study centre to identify any safety concerns. The study may be terminated by the sponsor 
at any time. 
A subject may discontinue participation in the study at any time for any reason (for 
example, lack of efficacy, withdrawal of consent, AE). The investigator and/or sponsor can 
withdraw a subject from the study at any time for any reason (for example, protocol violation 
or deviation as defined in Section 12.1.2, noncompliance with the protocol conditions or AE). 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (for example, pharmacist), will ensure that all 
IMP and any other study-related material is stored in a secured area, under recommended 
temperature-monitored storage conditions (below +25°C), in accordance with applicable 
regulatory requirements. 
3.7.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (for example, pharmacist), will ensure that all 
IMP is reconstituted and dispensed by qualified staff members. 
3.7.3 
Investigational Medicinal Product Accountability 
All IMP and any other study-related material is to be accounted for on the IMP 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 in the IMP accountability log. The destruction of used and 
unused IMP should be carried out only after any discrepancies have been investigated and 
satisfactorily explained, and the reconciliation has been accepted. The IMP will be destroyed 
either on site or in the ISF. 
3.8 
Maintenance of Randomisation and Blinding 
The investigator will under no circumstances change the randomisation number and the 
treatment arm allocated to the subject via the IWRS. As this is an open-label study, there is no 
blinding of investigator or subjects. 
To mitigate any potential bias due to the open-label design of this study, E2, LH and FSH 
concentrations will be evaluated centrally. 
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with Food and Drug Administration 
(FDA) 21 Code of Federal Regulations (CFR) Part 11. As required by GCP, the 
sponsor-assigned monitor will verify, by direct reference to the source documents, that the 
data required by the protocol are accurately reported on the eCRF.  


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The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the 
study, the identity of the study, diagnosis and eligibility criteria, visit dates (with subject 
status), IMP administration details, and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
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 study. Source data are contained in source documents 
(original records or certified copies). 
• 
Source documents: Original documents, data and records (for example, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ 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, subject files, and records kept at the pharmacy, at the 
laboratories and at medicotechnical departments involved in the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign, competent authorities (CAs). This 
information is included in the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Female subjects aged from 18 to 45 years inclusive at the date of informed 
consent. 
(2) 
Provided written informed consent. 
(3) 
A history of active and regular menstrual cycles of 21 to 35 days (inclusive) in 
the 6 months prior to the screening visit. 
(4) 
A diagnosis of endometriosis, confirmed by laparoscopy or laparotomy within 
10 years prior to the screening visit.  
(5) 
Requires treatment with a GnRH agonist for a period of 6 months in the 
judgement of the investigator. 
(6) 
A negative pregnancy test prior to the start of treatment. 
(7) 
Not at risk of pregnancy, i.e. subjects of childbearing potential must be actively 
using barrier contraception throughout the study treatment until menses resume. 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if any of the following criteria are met: 
(1) 
Subject is menopausal. 
(2) 
Subject is pregnant or lactating. 
(3) 
A current history of undiagnosed abnormal genital bleeding. 
(4) 
Received treatment with a GnRH agonist within 6 months prior to the screening 
visit. 
(5) 
A history of hypersensitivity to GnRH agonists and/or any of the excipients. 
(6) 
Received any other hormonal treatment within 3 months prior to the screening 
visit (oestrogens, progestogens, danazol, gestrinone and cyproterone acetate etc). 
(7) 
Has been treated for endometriosis with traditional Chinese medicine within 
1 month prior to screening. 
(8) 
It is anticipated that the subject will require surgery during the study period. 
(9) 
Chronic pelvic pain that is not caused by endometriosis, that would interfere with 
the assessment of endometriosis-associated pelvic pain. 
(10) A significant endocrine disorder (except controlled diabetes mellitus). 
(11) Known history of human immunodeficiency virus (HIV) infection. 
(12) Known history of chronic active hepatitis, including viral hepatitis carriers 
(hepatitis B or hepatitis C). 
(13) Clinically significant hepatic (any liver enzyme > 2× the upper limit of normal 
(ULN)) or renal (creatinine > ULN) abnormalities or any other dysfunction 
according to the investigator’s judgement. 
(14) Any psychiatric illness, severe or unstable known illness that in the investigator’s 
opinion could affect the safety, conduct or outcome of the study. 
(15) Use of concomitant therapy, which in the investigator’s opinion may interfere 
with the evaluation of study treatment efficacy and safety. 


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(16) Treatment with any other experimental drug or device within 90 days prior to the 
screening visit and/or expectation of treatment with any other experimental drug 
or device during the conduct of the study. 
(17) Any malignancy except curatively-treated basal cell skin cancer. 
(18) Unable or unwilling to comply with the protocol. 
(19) A history of alcohol and/or drug abuse. 
(20) Abnormal pelvic type B ultrasonography finding that would contraindicate the 
use of triptorelin. 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the 
study at any time. The investigator also has the right to withdraw a subject from the study in 
the event of concurrent illness, AEs, pregnancy (see Section 8.1.5), or other reasons 
concerning the health or wellbeing of the subject, or in the case of lack of cooperation. In 
addition, a subject may be withdrawn from the study as described in Sections 3.6, 6.2 
and 8.1.7. 
Should a subject decide to withdraw from the study after administration of the IMP, or should 
the investigator decide to withdraw the subject, all efforts will be made to complete and report 
the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the subject’s withdrawal should be made (see Section 5.2.4.4) and an 
explanation given of why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a 
subject withdraws consent, every attempt will be made to determine the reason. If the reason 
for withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or 
study procedure is made. The specific AE or test result(s) must be recorded on the eCRF. All 
evaluations should be performed, according to the protocol, on the last day the subject 
receives IMP, or as soon as possible thereafter. 


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 2. 
Procedures and assessments specific to the PK and PD subgroups are summarised in Table 3 
and Table 4. 
 


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Table 2 
Study Procedures and Assessments (All Subjects) 
 
Screening 
period 
Treatment period 
Follow up period [a] 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
End of study/early 
withdrawal visit 
Procedures and 
assessments 
Screening 
up 
to -5 weeks 
Baseline 
(1st to 5th 
day of 
menses) 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Within 15 days after 
menses recovery or 
Week 40[b] 
(Day 281±3 days) 
Visit window (days) 
-35 to -1 
Day 1 
Day 29
±3 
Day 57 
±3 
Day 85 
±3 
Day 113 
±3 
Day 141
±3 
Day 169
±3 
Day 197
±3 
Day 225
±3 
Day 253
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Significant medical or 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior medications for 
endometriosis 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
E2, FSH and LH 
 
X[c] 
X[c] 
X[c] 
X[c] 
 
 
X 
 
 
 
X[d] 
VAS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Physical examination[e] 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Pelvic examination 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Blood biochemistry[f] 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Haematology[f] 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Urinalysis[f] 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Pelvic type B ultrasound 
scan 
X[g] 
 
 
 
X[h] 
 
 
X 
 
 
 
 
Sparse PK assessments  
 
X[c] 
X[c] 
X[c] 
X[c] 
 
 
X 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug injection 
(3-month formulation) 
 
X[i] 
 
 
X 
 
 
 
 
 
 
 
Study drug injection 
(1-month formulation) 
 
X[i] 
X 
X 
X 
X 
X 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 2 
Study Procedures and Assessments (All Subjects) 
 
Screening 
period 
Treatment period 
Follow up period [a] 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
End of study/early 
withdrawal visit 
Procedures and 
assessments 
Screening 
up 
to -5 weeks 
Baseline 
 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Within 15 days after 
menses recovery or 
Week 40[b] 
(Day 281±3 days) 
Visit window (days) 
-35 to -1 
Day 1 
Day 29
±3 
Day 57 
±3 
Day 85 
±3 
Day 113 
±3 
Day 141
±3 
Day 169
±3 
Day 197
±3 
Day 225
±3 
Day 253
±3 
Prior and concomitant 
medication/therapies 
X 
X 
X 
X 
X[j] 
X[j] 
X[j] 
X 
X 
X 
X 
X 
Status of menses 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; E2=oestradiol; ECG=electrocardiogram; FSH=follicle stimulation hormone; LH=luteinising hormone; PK=pharmacokinetic; VAS=visual analogue scale 
a 
during the follow up period, the first visit after menses recovery, or Week 40 (whichever is earlier) will be considered the final visit (end of study). The end of study visit should be a clinic 
visit. Follow up visits prior to the end of study visit will be telephone contact visits 
b 
or upon early withdrawal from the study 
c 
samples taken predose, where applicable 
d 
only if subject's menses do not recover before Week 40 
e 
subject height and weight will be assessed at screening only 
f 
samples for clinical laboratory testing will be taken after at least 8 hours fasting 
g 
a result within 1 month prior to the screening visit will be acceptable 
h 
optional, based on the subject's disease condition, as judged by the investigator 
i 
study treatment must be initiated during the subject's follicular phase (first to fifth day of menses period) 
j 
from Week 12, after the primary endpoint evaluation, "add back" treatment will be permitted if needed according to the investigator's judgement. "Add back" treatment will be recommended 
as, but not limited to, tibolone 2.5 mg once daily 


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Table 3 
Full PK/PD Assessments Day 1 to Week 12 (PK/PD Subgroup Subjects) 
 
Treatment period 
Assessment[a] 
Day 1 
Week 1 
(hours post Day 1 dosing) 
Week 2 
Week 3 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Assessment time (study 
day/hours postdose)[b] 
Day 1 
24 
 
48 
 
168 
 
Day 15 
 
Day 22 
 
Day 29 
 
Day 43 
 
Day 57 
 
Day 71 
 
Day 85 
 
PK (3M) 
X[c] 
X 
X 
X 
X 
X 
X 
X 
X 
 
X[c] 
PK (1M) 
X[c] 
X 
X 
X 
X 
X 
X[d] 
 
X[d] 
X 
X[d] 
PD (E2, FSH and LH) 
 
 
 
X 
X 
X 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant 
medication/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1M=triptorelin acetate PR 1-month; 3M=triptorelin pamoate PR 3-month; AE=adverse event; E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; 
PD=pharmacodynamics; PK=pharmacokinetics. 
a 
assessments to be conducted with samples from the subjects in the full PK/PD subgroup (comprising up to 16 subjects receiving 3M and up to 16 subjects receiving 1M; to be enrolled at 
selected sites) 
b 
time windows for full PK/PD assessments will be defined in the Study Manual 
c 
samples taken predose and 0.5, 1, 2, 4, 8 and 12 hours postdose  
d 
samples taken predose 


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Table 4 
Full PK/PD Assessments Week 13 to End of Study (PK/PD Subgroup Subjects) 
 
Treatment period 
Follow up period 
Assessment[a] 
Week 13 
(hours post 
Week 12 dosing) 
Week 14 
Week 15 
Week 16 
Week 18 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
End of study/ 
early 
withdrawal 
Assessment time 
(study day/hours 
postdose)[b] 
24 
 
48 
168 
 
Day 99 
 
Day 106 
Day 113 
 
Day 127 
 
Day 141 
 
Day 169 
 
Day 197 
 
Day 225 
 
Day 253 
 
See Table 2 
PK (3M) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK (1M) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
PD (E2, FSH and LH)  
 
 
 
 
 
 
 
 
 
 
X 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and 
concomitant 
medication/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1M=triptorelin acetate PR 1-month; 3M=triptorelin pamoate PR 3-month; AE=adverse event; E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; 
PD=pharmacodynamics; PK=pharmacokinetics. 
a 
assessments to be conducted with samples from the subjects in the full PK/PD subgroup (comprising up to 16 subjects receiving 3M and up to 16 subjects receiving 1M; to be enrolled at 
selected sites) only 
b 
time windows for full PK/PD assessments will be defined in the Study Manual 


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The total volume of blood drawn for all evaluations throughout this study for each subject not 
in the full PK/PD subgroup will be approximately 47.5 mL (Table 5).  
Additional blood samples for subjects in the full PK/PD subgroup are presented in Table 6. 
The total volume of blood drawn (including blood samples taken from all subjects, and 
additional PK/PD samples) will be 121.5 mL for subjects receiving triptorelin pamoate 
3-month and 93.5 mL for subjects receiving triptorelin acetate 1-month. 
Table 5 
Blood Volume Calculation (All Subjects) 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Haematology 
3 
2 
6 
Blood biochemistry 
3 
2.5 
7.5 
E2, FSH and LH 
6 
4 
24 
Sparse PK 
5 
2 
10 
Total volume (mL)  
 
 
47.5 
E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; PK=pharmacokinetics. 
Table 6 
Additional Blood Samples (Full PK/PD Subgroup) 
Description 
Number of samples 
Volume (mL) 
Total volume (mL) 
Subjects receiving triptorelin pamoate 3-month 
E2, FSH and LH 
4 
4 
16 
PK 
29 
2 
58 
Total volume (mL)  
 
 
74 
Subjects receiving triptorelin acetate 1-month 
E2, FSH and LH 
4 
4 
16 
PK 
15 
2 
30 
Total volume (mL)  
 
 
46 
E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; PD=pharmacodynamics; PK=pharmacokinetics. 
5.2 
Study Visits 
5.2.1 
Procedures for Screening and Enrolment (Visit 1; up to -5 weeks) 
A signed and dated informed consent form will be obtained before screening procedures. 
Evaluations obtained as part of routine medical care and performed during the screening 
period may be used in place of the study specific evaluations. Subjects will acknowledge and 
agree to the possible use of this information for the study by giving informed consent.  
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 
Rescreening will not be permitted in this study. 
The screening visit (Visit 1) will take place up to 5 weeks prior to the first dose of IMP being 
administered. The following assessments will be performed at screening: 
• 
Demographic data (date of birth, sex, ethnicity, and race) 
• 
Significant medical or surgical history, including ongoing medical conditions, 
AEs, gynaecological history, date of last menses 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Physical examination (including subject height and body weight) 
• 
Pelvic examination 
• 
Vital signs (sitting blood pressure and heart rate)  
• 
Laboratory safety tests (blood sampling for biochemistry, haematology and 
urinalysis) 


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• 
Urine pregnancy test, method of contraception 
• 
12-lead ECG 
• 
Pelvic type-B ultrasound scan (a result obtained within 1 month of the screening 
visit will be acceptable) 
• 
Prior and concomitant medications/therapies (including medications and 
therapies for endometriosis) 
• 
Record date of onset of last menses and expected date of onset of next menses 
Each investigator will also maintain a record of all subjects screened into the study (i.e. who 
signed the informed consent form). Records up to the time of premature subject termination 
should be completed and the primary reason for termination will be recorded. 
5.2.2 
Procedures before Study Treatment (Baseline, Visit 2 Predose) 
Subjects will be instructed to contact the study centre by telephone at the onset of their 
menses period to arrange their baseline visit (Visit 2, Day 1), which must occur in the 
follicular phase (from the first to the fifth day of menses). Administration of study treatment 
will be initiated at the baseline visit, following randomisation to one of the two treatment 
groups, as specified in Section 6.1. The following procedures will be performed at baseline on 
Day 1 of the study, prior to administration of study treatment: 
• 
Urine pregnancy test 
• 
Baseline efficacy assessments (E2, LH and FSH concentrations; VAS) 
• 
Samples taken for sparse PK analysis 
• 
Vital signs 
• 
Review of pretreatment AEs 
• 
Prior and concomitant medications/therapies 
• 
Date of onset of menses, current menses status 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Randomisation 
• 
Allocation to the full PK/PD subgroup (selected sites only) 
5.2.2.1 
Pharmacokinetic Blood Sampling 
Predose samples, as described in Section 5.2.2, will be the same for the full PK/PD subgroup 
and the sparse PK analysis. No additional predose samples are planned. 
5.2.3 
Procedures during Study Treatment (Visit 2 Postdose to Visit 8) 
Subjects receiving triptorelin acetate PR 1-month will receive study drug at each visit during 
the treatment period up to and including Visit 7 (Week 20, Day 141±3). Subjects receiving 
triptorelin pamoate PR 3-month will receive study drug at Visit 2 (Day 1) and 
Visit 5 (Week 12, Day 85±3) only. 
The following procedures will be performed on all subjects at Visit 3 (Week 4, Day 29±3) and 
Visit 4 (Week 8, Day 57±3):  
• 
Efficacy assessments (E2, LH and FSH concentrations (samples taken predose 
for subjects receiving triptorelin acetate PR 1-month); VAS) 
• 
Samples taken for sparse PK analysis (samples taken predose for subjects 
receiving triptorelin acetate PR 1-month) 
• 
Vital signs 
• 
Review of AEs 


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• 
New or changed concomitant medications/therapies 
• 
Review of menses status and record date of menses onset (if applicable) 
• 
Injection of IMP (subjects receiving triptorelin acetate PR 1-month only) 
The following procedures will be performed at Visit 5 (Week 12, Day 85±3):  
• 
Efficacy assessments (E2, LH and FSH concentrations (samples taken predose 
for all subjects); VAS) 
• 
Samples taken for sparse PK analysis (samples taken predose for all subjects) 
• 
Physical examination 
• 
Pelvic examination 
• 
Vital signs 
• 
Laboratory safety tests (blood sampling for biochemistry, haematology and 
urinalysis) 
• 
12-lead ECG 
• 
Pelvic type B ultrasound scan (optional based on subject's disease condition, as 
judged by the investigator) 
• 
Review of AEs 
• 
New or changed concomitant medications, including details of any "add back" 
therapy 
• 
Review of menses status and record date of menses onset (if applicable) 
• 
Injection of IMP (all subjects) 
The following procedures will be performed at Visit 6 (Week 16, Day 113±3) and 
Visit 7 (Week 20, Day 141±3):  
• 
VAS assessment 
• 
Vital signs 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies, including details of any 
"add back" therapy 
• 
Review of menses status and record date of menses onset (if applicable) 
• 
Injection of IMP (subjects receiving triptorelin acetate PR 1-month only) 
The following procedures will be performed at Visit 8 (Week 24, Day 169±3):  
• 
Efficacy assessments (E2, LH and FSH concentrations; VAS) 
• 
Physical examination 
• 
Pelvic examination 
• 
Vital signs 
• 
Laboratory safety tests (blood sampling for biochemistry, haematology and 
urinalysis) 
• 
12-lead ECG 
• 
Pelvic type B ultrasound scan 
• 
Samples taken for sparse PK analysis 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies, including details of any 
"add back" therapy 


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• 
Review of menses status and record date of menses onset (if applicable) 
5.2.3.1 
Full Pharmacokinetic Blood Sampling during Treatment 
Triptorelin Pamoate PR 3-month 
The full PK/PD subgroup will include up to 16 subjects receiving triptorelin pamoate PR 
3-month. These subjects will attend the study centre for additional PK blood sampling at the 
following timepoints during the treatment period: 
• 
Visit 2, Day 1 (0.5, 1, 2, 4, 8 and 12 hours postdose) 
• 
Week 1 (24, 48 and 168 hours postdose) 
• 
Week 2 (Day 15) 
• 
Week 3 (Day 22) 
• 
Week 6 (Day 43) 
• 
Visit 5, Week 12 (Day 85, corresponding to the second administration of 
triptorelin pamoate PR 3-month): 0.5, 1, 2, 4, 8 and 12 hours postdose 
• 
Week 13 (24, 48 and 168 hours postdose) 
• 
Week 14 (Day 99) 
• 
Week 15 (Day 106) 
• 
Visit 6, Week 16 (Day 113) 
• 
Week 18 (Day 127) 
• 
Visit 7, Week 20 (Day 141) 
In addition, at each visit, changes to ongoing and new AEs and concomitant medications and 
therapies will be recorded. Note that these PK blood samples are in addition to those 
described in Section 5.2.3. 
Triptorelin Acetate PR 1-month 
The full PK/PD subgroup will include up to 16 subjects receiving triptorelin acetate PR 
1-month. These subjects will attend the study centre for additional PK blood sampling at the 
following timepoints during the treatment period: 
• 
Visit 2, Day 1 (0.5, 1, 2, 4, 8 and 12 hours postdose) 
• 
Week 1 (24, 48 and 168 hours postdose) 
• 
Week 2 (Day 15) 
• 
Week 3 (Day 22) 
• 
Week 10 (Day 71) 
In addition, at each visit, changes to ongoing and new AEs and concomitant medications and 
therapies will be recorded. Note that these PK blood samples are in addition to those 
described in Section 5.2.3. 
5.2.3.2 
Full Pharmacodynamic Assessments 
The full PK/PD subgroup will comprise up to 32 subjects (up to 16 subjects from each 
treatment group; to be enrolled at selected sites). All subjects in the full PK/PD subgroup 
(both treatment groups) will attend the study centre for additional PD efficacy assessments 
(E2, LH and FSH concentrations) at the following timepoints during the treatment period: 
• 
Week 1 (Day 8) 
• 
Week 2 (Day 15) 
• 
Week 3 (Day 22) 


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5.2.4 
Procedures during Follow Up Period (Visit 9 to End of Study) 
The purpose of the follow up period is to monitor menses recovery. Visits 9, 10 and 
11 (Weeks 28, 32 and 36) will be conducted by telephone, primarily to establish if subjects' 
menses have recovered. If menses recover during the follow up period, subjects should attend 
the study site within 15 days after the first day of menses recovery. If there is no menses 
recovery by Week 40, the subject should attend the study site at Week 40 (Day 281±3). The 
first visit after menses recovery, or Week 40 (whichever is earlier) will be considered the end 
of study visit (see Section 5.2.4.4). 
5.2.4.1 
Follow Up Visits to be Conducted by Telephone 
The following procedures will be performed by telephone at Visit 9 (Week 28, Day 197±3), 
Visit 10 (Week 32, Day 225±3) and Visit 11 (Week 36, Day 253±3) if required:  
• 
Review of AEs 
• 
New or changed concomitant medications/therapies 
• 
Review of menses recovery status and record date of menses onset (if applicable) 
5.2.4.2 
Full Pharmacokinetic Blood Sampling during Follow Up 
Subjects included in the full PK/PD subgroup will attend the study centre for PK blood 
sampling at the following timepoints during the follow up period: 
• 
Visit 9, Week 28 (Day 197) 
• 
Visit 10, Week 32 (Day 225) 
• 
Visit 11, Week 36 (Day 253) 
Note that subjects included in the full PK/PD subgroup will be required to attend full PK 
sampling visits during the follow up period, even if their menses recover prior to Week 40. 
5.2.4.3 
Full Pharmacodynamic Assessments during Follow Up 
Subjects included in the full PK/PD subgroup will have an additional PD blood sample at 
Visit 10, Week 32 (Day 225). 
Note that subjects included in the full PK/PD subgroup will be required to attend this PD 
sampling visit during the follow up period, even if their menses recover prior to Week 40. 
5.2.4.4 
End of Study Visit or Early Withdrawal Visit 
The end of study visit will be the first visit within 15 days after the first day of menses 
recovery, or at Week 40 (Day 281±3), whichever is earlier. Subjects who withdraw from the 
study early will also attend an end of study visit. 
Subjects who participate in the study in compliance with the protocol for 24 weeks of study 
drug administration will be considered to have completed study treatment. Subjects who 
participate in the study in compliance with the protocol for the 24 weeks of study drug 
administration, and complete the follow up period, will be considered to have completed the 
study.  
For subjects who complete the study, or for those who withdraw prematurely from the study, 
final evaluations will be performed on the last day the subject receives the study drug, or as 
soon as possible afterwards. Subjects with ongoing AEs or clinically significant laboratory 
test abnormalities (as determined by the investigator) will be monitored as described in 
Section 8.1.3 and Section 8.1.2.4, respectively. 
The following procedures will be performed at the end of study visit: 
• 
E2, LH and FSH concentrations (only if the subject's menses does not recover 
before Week 40) 


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• 
VAS assessment 
• 
Vital signs 
• 
Review of AEs 
• 
New or changed concomitant medications/therapies 
• 
Review of menses recovery status and record the date of menses onset (if 
applicable) 


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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
At screening, subjects will be allocated a subject number. Following confirmation of 
eligibility for the study at baseline (Visit 2, Day 1), subjects will be allocated a randomisation 
number, and assigned to one of the following treatment groups: 
• 
triptorelin pamoate PR 3-month, administered as an intramuscular injection once 
every 12 weeks (a total of 2 injections). 
or 
• 
triptorelin acetate PR 1-month, administered as an intramuscular injection once 
every 4 weeks (a total of 6 injections). 
6.1.1 
Triptorelin Pamoate PR 3-month 
The test product is triptorelin pamoate PR 3-month, which comprises microparticles with the 
active ingredient incorporated in the copolymer. The product is presented as a slightly yellow 
freeze-dried cake or powder containing triptorelin pamoate; D, L-lactide-coglycolide polymer, 
mannitol, sodium carmellose and polysorbate 80. The solvent provided for injection is a 2 mL 
ampoule of mannitol and water. This product is marketed in China as Triptorelin pamoate for 
injection 15 mg, for the treatment of prostate cancer only. 
Triptorelin pamoate PR 3-month is to be administered by the intramuscular route only. The 
powder is reconstituted with the solvent provided and injected immediately after 
reconstitution. The product is administered as a single intramuscular injection every 12 weeks 
(Day 1 and Week 12), as indicated in Table 2. 
6.1.2 
Triptorelin Acetate PR 1-month 
The comparator product is triptorelin acetate PR 1-month, which is formulated as 
microparticles. The comparator is presented as a practically white, freeze-dried cake or 
powder containing triptorelin acetate; D, L-lactide-coglycolide polymer, mannitol, sodium 
carmellose and polysorbate 80. The solvent provided for injection is a 2 mL ampoule of 
mannitol and water. This product is marketed in China as Diphereline 3.75 mg for various 
indications including the treatment of endometriosis. 
Triptorelin acetate PR 1-month is to be administered by the intramuscular route only. The 
powder is reconstituted with the solvent provided and injected immediately after 
reconstitution. The product is administered as a single intramuscular injection every 4 weeks 
(Day 1 and Weeks 4, 8, 12, 16 and 20) as indicated in Table 2. 
6.2 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a subject within 6 months prior to 
screening or during the study will be indicated on the eCRF. Dose and generic name or 
tradename will be indicated. 
The following concomitant therapies or medications will not be permitted during the study: 
• 
GnRH agonists other than the IMP. 
• 
Other hormonal treatments (for example oestrogens, progestogens, danazol, 
gerstrinone, cyproterone acetate, and non-barrier contraception, etc). 
• 
Surgery. 
• 
Any concomitant therapies which, in the investigator's opinion, may interfere 
with the evaluation of study treatment efficacy and safety. 
• 
Any experimental drug or device other than the IMP. 


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• 
Traditional Chinese medicine for the treatment of endometriosis. 
As the primary endpoint will be assessed at Week 12, "add back" treatment will not be 
permitted before that time. If "add back" treatment is needed, according to the investigator's 
judgement, it can be initiated after the primary endpoint evaluation at Week 12. The reason 
for and date/time of all doses of "add back" treatment will be recorded in the eCRF. "Add 
back" treatment is recommended to be, but not limited to, tibolone at a dose of 2.5 mg once 
daily. 
6.3 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 
For this study, all doses of IMP will be administered to the subjects at the study centre by 
study site staff. Administration of IMP must occur at the study day indicated ±3 days. 
Administration compliance will be assessed by comparing the number of doses expected with 
the number of doses administered. Any missing injection at Visits 2, 3 or 4 (Day 1, Week 4 or 
Week 8) will be regarded as a major protocol violation. 
Where a subject is consistently noncompliant with IMP intake they should be discontinued 
from IMP/withdrawn from the study. Please refer to Section 4.3 for the criteria for 
discontinuing the subject from IMP. 


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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 2. 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary efficacy endpoint is the percentage of subjects castrated (E2≤184 pmol/L or 
50 pg/mL) at Week 12. The primary endpoint will be evaluated based on centralised 
bioanalysis of serum samples for E2. 
7.2 
Secondary and Exploratory Efficacy Endpoints and Evaluations 
Secondary and exploratory efficacy endpoints and evaluations are summarised in Table 7. 
 


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Table 7 
Secondary and Exploratory Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable  
Endpoint 
E2 concentration 
Baseline, Weeks 4, 8, 12 
and 24 
 
Castration rate (percentage of 
subjects with E2 below 
castration levels) 
E2 concentration 
 
Secondary endpoints 
Percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Weeks 4 
and 8. 
Percentage of subjects castrated (E2≤110 pmol/L or 30 pg/mL) at Weeks 4, 
8 and 12. 
E2 concentration at Weeks 4, 8 and 12. 
Exploratory endpoints 
Percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 24. 
Percentage of subjects castrated (E2≤110 pmol/L or 30 pg/mL) at Week 24. 
E2 concentration at Week 24. 
Endometriosis-associated 
pelvic pain (by 10 cm VAS) 
Baseline, Weeks 4, 8, 12, 16, 
20, 24 and end of study/early 
withdrawal 
Change in 
endometriosis-associated 
pelvic pain 
Secondary endpoint 
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at 
Weeks 4, 8 and 12 compared to baseline. 
Exploratory endpoint 
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at 
Weeks 16, 20, 24 and the end of study visit compared to baseline. 
FSH and LH concentrations 
Baseline, Weeks 4, 8, 12 
and 24 
FSH concentration 
LH concentration 
Secondary endpoint 
FSH and LH concentrations at Weeks 4, 8 and 12. 
Exploratory endpoint 
FSH and LH concentrations at Week 24. 
Menses recovery 
Baseline, date of first 
observation of menstrual 
bleeding at Weeks 28, 32, 36 
and end of study/early 
withdrawal 
Time to menses recovery 
Secondary endpoint 
Time to menses recovery.  
E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; VAS=visual analogue scale. 


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7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
The methods for assessing efficacy data are described below, and the timing of efficacy 
assessments is discussed in Section 5. Procedures for recording efficacy data are discussed in 
Section 14.1, and methods of analyses are discussed in Section 10.4.6. 
7.3.1 
Oestradiol, 
Follicle 
Stimulating 
Hormone 
and 
Luteinising 
Hormone 
Concentrations 
Assessments of serum E2, FSH and LH concentrations will be performed at study visits at 
Day 1 (baseline) and Weeks 4, 8, 12 and 24, in accordance with Table 2. A further assessment 
will be conducted at Week 40 in subjects whose menses have not recovered by this timepoint. 
This assessment is considered a safety assessment, and is discussed in Section 8.2.5. In 
addition, serum E2, FSH and LH concentrations will also be determined at Weeks 1, 2, 3 
and 32 for subjects in the full PK/PD subgroup, as described in Section 9.2. All E2, FSH and 
LH concentrations will be evaluated by the central laboratory. 
7.3.1.1 
Oestradiol Concentrations  
Measurement of serum E2 concentrations will be performed in a central laboratory in 
accordance with Good Laboratory Practice (GLP). All details of the sample collection, 
handling, shipment, methodology and reference ranges will be provided in the Study Manual 
and archived in the trial master file (TMF). 
Castration rate will be assessed using a cutoff E2 concentration of 184 pmol/L (50 pg/mL) for 
the primary and secondary efficacy endpoints, and 110 pmol/L (30 pg/mL) for the secondary 
efficacy endpoint only. 
7.3.1.2 
Luteinising Hormone and Follicle Stimulating Hormone Concentrations 
Measurement of serum LH and FSH concentrations will be performed in a central laboratory 
in accordance with GLP. All details of the sample collection, handling, shipment, 
methodology and reference ranges will be provided in the Study Manual and archived in the 
TMF. 
7.3.2 
Endometriosis-associated Pelvic Pain 
The severity of endometriosis-associated pain will be assessed by the subject at Day 1 
(baseline), Weeks 4, 8, 12, 16, 20, 24, and at the end of study visit using a 10 cm VAS. 
Subjects will be asked to assess their most severe endometriosis-associated pain over the 
preceding 4 weeks. For the Day 1 (baseline) assessment, if subjects had undergone 
endometriotic surgery within the previous 4 weeks, they will be asked to assess their most 
severe endometriosis-associated pain postsurgery. The VAS to be used is presented in 
Appendix 1. 
7.3.3 
Recovery of Menses 
Status of menses recovery will be assessed at all study visits, including the follow-up period 
(Weeks 28, 32, 36 and at the end of study visit). The date of menses (if available) will be 
recorded at the end of study visit. Time to menses recovery will be defined as the time (in 
days) between the date of the last dose of study drug and the date of the first day that the 
subject observed menstrual bleeding of the next menses period. Any subjects withdrawing 
from the study without menstrual bleeding will be censored in this analysis at the date of 
withdrawal. Any subjects without menstrual bleeding prior to the end of study visit will be 
censored in this analysis at the date of the end of study visit. 


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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study (see Section 3.5 for a definition of the study duration) and will be 
elicited by direct, nonleading questioning or by spontaneous reports. Further details for AE 
reporting can be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
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 (for example, nausea, chest pain), signs (for example, tachycardia, enlarged liver) 
or the abnormal results of an investigation (for example, laboratory findings, ECG). In clinical 
studies an AE can include an undesirable medical condition occurring at any time, including 
run in or washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.5). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be classified as mild, moderate or severe according to the following 
criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are 
not hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of 
function or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (for example 
plausible time sequence, dose response relationship, pharmacology, positive 
dechallenge and/or rechallenge) to assume a causal relationship with IMP 
administration in the sense that it is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (for 
example implausible time sequence and/or attributable to concurrent disease or 
other drugs) to rule out a causal relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the IB for an 
unapproved IMP, or the summary of product characteristics (SmPC) or package insert (PI) for 
an authorised medicinal product that is being used according to the terms and conditions of 
the marketing authorisation. If the IMP has marketing authorisations in several countries with 
different SmPCs or PIs, one will be selected as the reference document for assessing 
expectedness. 


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The reference document for assessing expectedness of AEs/event in this study will be the 
current (at time of study) triptorelin IB for triptorelin PR 3-month, and the PI (China) for 
triptorelin acetate PR 1-month. 
8.1.2.4 
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 IMP schedule of administration (change in dosage, 
delay in administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the 
subject, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant (for example, 
ECG 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 subject, should be recorded as AEs.  
8.1.3 
Recording and Follow Up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have you felt 
since the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF. Events involving drug 
reactions, accidents, illnesses with onset during the treatment phase of the study, or 
exacerbations of pre-existing illnesses should be recorded, with the exception of 
endometriosis-related symptoms, which should only be recorded if they fulfil the criteria for 
an SAE (see Section 8.1.4). 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must follow up and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for classification 
as a 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. IMP or other illness). The investigator is required to assess causality 
and record that assessment on the eCRF. Follow up of the AE, after the date of IMP 
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. 
8.1.4 
Reporting of Serious Adverse Events 
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) 
using the fax number specified at the beginning of this protocol. If the immediate report is 


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submitted by telephone, this must be followed by detailed written reports using the SAE 
report form. 
An SAE is any AE that: 
(1) 
Results in death, 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of 
death from the event as it occurred. It does not include an event 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, 
(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 subject 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 subject 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. 
In addition to 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 studies, 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 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.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a preplanned 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. 
Any SAE must be reported immediately (within 24 hours) using the fax number specified at 
the beginning of this protocol, independent of the circumstances or suspected cause, if it 
occurs or comes to the attention of the investigator at any time during the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any 
other time after completion of the study must be promptly reported. 


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The following information is the minimum that must be provided to the sponsor within 
24 hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject 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. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. 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. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected poststudy and it may be necessary to discontinue 
administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the eCRF and 
reported to the sponsor as an SAE. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of 
the subject should continue until conclusion of the pregnancy, which may involve follow up 
after the subject’s involvement in the study has ended. 
Pregnancies with a conception date within 150 days (for subjects receiving triptorelin 
pamoate PR 3-month), or 90 days (for subjects receiving triptorelin acetate PR 1-month) after 
subject’s last dose of the study drug must also be reported to the investigator for onward 
reporting to the sponsor. 
8.1.6 
Deaths 
All AEs resulting in death during the study period, must be reported as an SAE within 
24 hours of the investigator’s knowledge of the event.  
The convention for recording death is as follows:  
• 
AE term: lead cause of death  
• 
Outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death”. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.3). 


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If the IMP is discontinued due to an SAE, it must be reported immediately, as described in 
Section 8.1.4. 
In all cases, the investigator must ensure the subject receives appropriate medical follow up 
(see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports all SAEs 
occurring during the study to the CA, IECs and other investigators concerned by the IMP. 
Reporting will be in accordance with the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected at screening (Visit 1), Week 12 (Visit 5) and 
Week 24 (Visit 8) for the evaluation of haematology, blood biochemistry and urinalysis.  
The investigator will review the safety laboratory test results, document the review, and 
record any clinically relevant changes occurring or observed during the study in the AE 
section of the eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded 
as AEs).  
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.  
8.2.1 
Haematology 
Blood samples (2 mL) will be collected in a potassium ethylenediaminetetraacetic acid 
(EDTA) tube to assess the following parameters: red blood cell (RBC) count, haemoglobin, 
haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), white blood cell (WBC) count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and platelet 
count. 
8.2.2 
Blood Biochemistry 
Blood samples (2.5 mL) will be collected in an activator gel tube to assess the following 
parameters: 
• 
urea, creatinine, total bilirubin, conjugated bilirubin; 
• 
chloride, bicarbonate, sodium, potassium, calcium, inorganic phosphate; 
• 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
gamma glutamyl transferase; 
• 
albumin, total protein, total cholesterol, triglycerides, fasting glucose. 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, glucose, bilirubin, blood, urobilinogen and specific gravity by dipstick.  
8.2.4 
Pregnancy Test 
A human chorionic gonadotrophin (HCG) urine test will be performed for subjects at 
screening (Visit 1) and baseline (Visit 2, Day 1) and analysed locally. Any subject becoming 
pregnant during the study will be withdrawn. All pregnancies that occur during the study are 
to be reported as described in Section 8.1.5.  


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8.2.5 
Hormones 
Measurements of serum E2, FSH and LH concentrations will be performed at a central 
laboratory at Week 40, only if a subject's menses has not recovered by this timepoint. 
Hormone measurements at other timepoints are considered efficacy assessments, and are 
described, along with methods for the assessment of E2, FSH and LH concentrations, in 
Section 7.3.1. 
8.3 
Physical/Pelvic Examination 
Physical examinations, including pelvic examination, will be conducted at screening (Visit 1), 
Week 12 (Visit 5) and Week 24 (Visit 8). Subject height and weight will be measured at 
screening only. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Pelvic Type B Ultrasound Scan 
A pelvic type B ultrasound investigation will be performed at screening (Visit 1; a result 
within 1 month prior to screening will be acceptable) and at Week 24 (Visit 8). An additional 
(optional) scan may be conducted at Week 12 (Visit 5) based on the subject's condition, as 
judged by the investigator.  
Any clinically significant pelvic type B ultrasound findings (abnormalities) observed during 
the study will be reported as AEs. 
8.5 
Vital Signs 
Blood pressure and heart rate will be recorded at screening (Visit 1), baseline (Visit 2, Day 1) 
Weeks 4, 8, 12, 16, 20, 24 (Visits 3 to 8), and at the end of study/early withdrawal visit. 
Blood pressure and heart rate will be recorded after five minutes rest in a sitting position. 
8.6 
Electrocardiography 
An ECG analysis will be included as a safety evaluation/endpoint in this study. 
The computerised 12-lead ECGs will be recorded at screening (Visit 1), Week 12 (Visit 5) 
and Week 24 (Visit 8). 
Specific machine details will be provided in the Study Manual. Sinus rhythm, heart rate, PR 
interval, QRS interval, QT interval/corrected QT interval (QTc) will be recorded, as well as 
clinical significance. A paper copy of each ECG trace will be printed; these copies must be 
signed by the investigator and identified with subject screening number, initials, date of 
assessment and study visit. The ECG will be recorded with the subject in supine position after 
five minutes of rest until four regular consecutive complexes are available.  
All ECGs will be evaluated by qualified persons at the study site, and any clinically 
significant abnormalities observed during the study will be recorded as AEs.  


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Sparse PK samples will be taken in all subjects (in addition to the full PK/PD subgroup) at 
Day 1 (baseline) and Weeks 4, 8, 12 and 24 (see Table 2). A full triptorelin PK analysis will 
be performed in a subgroup of up to 16 subjects in each treatment group (the full PK/PD 
subgroup; to be enrolled at selected sites). Full PK samples will be collected in accordance 
with Table 3 and Table 4 for subjects in this subgroup. Additional hormone samples (E2, FSH 
and LH) will also be collected at Weeks 1, 2, 3 and 32 in this subgroup. 
9.1 
Pharmacokinetics 
9.1.1 
Sample Collection 
Blood samples for the assay of triptorelin will be collected in Vacutainer tubes at the 
timepoints indicated in Table 2, Table 3 and Table 4. Full details of sample collection, 
processing, required labelling, storage and the shipment process for these samples will be 
documented in the Study Manual. 
On predetermined dates, samples will be shipped to the central laboratory under frozen 
conditions. For security reasons, aliquots of each sample will be shipped separately. The batch 
containing the second aliquot will not be shipped until the first one has arrived.  
Upon receipt at the central laboratory, samples will be checked and stored until analysis. 
Surplus plasma samples may be shipped outside China for the purposes of cross-validating the 
bioanalytical method used in this study. Surplus plasma samples will be managed 
anonymously, and will not be identifiable. 
9.1.2 
Analytical Procedures 
The concentration of triptorelin will be analysed using a validated specific and sensitive 
method, and in accordance with GLP. All details of sample collection, handling, shipment, 
methodology and reference ranges will be provided in the Study Manual and archived in the 
TMF. 
9.1.3 
Data Analysis 
Details of the statistical and analytical methods to be applied to the PK data are provided in 
Section 10.4.4. 
9.2 
Pharmacodynamics 
Additional PD assessments will be conducted on the full PK/PD subgroup, comprising up to 
32 subjects enrolled at selected sites. 
Additional blood samples will be collected at Week 1, Week 2, Week 3 and Week 32 (in 
accordance with Table 3) for the analysis of E2, FSH and LH, as described in Section 7.3.1. 
9.3 
Pharmacokinetics/Pharmacodynamics Relationship 
A PK/PD analysis (PK/PD modelling) will be performed for triptorelin pamoate PR 3-month 
and triptorelin acetate PR 1-month exploring the relationship between plasma triptorelin 
concentrations and serum E2, FSH and LH, where possible.  
Additional population PK/PD modelling may be conducted. This analysis will be described in 
a separate data analysis plan and reported in a standalone report. 


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10 
STATISTICS 
10.1 
Analyses Sets 
The following analysis sets will be used during statistical analyses: 
• 
Screened set: All subjects screened (i.e. who signed the informed consent). 
• 
Randomised set: All subjects randomised (i.e. who were randomly allocated to 
a treatment group). 
• 
Safety set: All subjects who received at least one dose of study medication.  
• 
Full analysis set (FAS): All randomised subjects who received at least one dose 
of study medication with at least one baseline and at least one post-baseline 
assessment of the primary efficacy parameter. 
• 
Per protocol (PP) set: All subjects in the FAS for whom no major protocol 
violations/deviations occurred. 
• 
Full PK profile analysis set (for noncompartmental analysis (NCA)): Subjects 
in the full PK/PD subgroup who have received at least one dose of IMP and have 
no major protocol deviations affecting the PK variables, and who have a 
sufficient number of PK concentration measurements to estimate the main PK 
parameters (maximum observed plasma concentration (Cmax) and time to 
maximum observed plasma concentration (tmax), plus area under the plasma 
concentration-time curve for the dosing interval (AUCτ) for subjects receiving 
triptorelin pamoate PR 3-month). 
• 
Sparse PK sampling analysis set: All subjects who received at least one dose of 
IMP and have no major protocol deviations affecting the PK variables and who 
have at least one valid plasma concentration. 
• 
PD analysis set: All subjects in the full PK/PD subgroup who have a sufficient 
number of PD measurements. 
• 
PK/PD relationships set: All subjects who receive at least one dose of IMP and 
have at least one valid plasma triptorelin concentration and at least one PD 
measurement. 
10.1.1 
Data Sets Analysed 
Analysis of the primary and secondary efficacy endpoints will be performed on the FAS and 
the PP set. All exploratory efficacy analyses will be performed on the FAS. PK analyses will 
be performed on the full PK profile analysis set and the sparse PK sampling analysis set, as 
appropriate. 
The analyses of safety data will be performed based on the safety set. 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation types will be described in the Protocol Deviation Document 
(PDD) and their impact on inclusion in each analysis set for any subject will be specified. The 
final list of protocol deviations impacting each analysis set will be reviewed during the blind 
data review meeting held prior to database lock, without reference to treatment group 
assignment for individual subjects. 
10.2 
Sample Size Determination 
Sample size was estimated based on data from Ipsen Study E-28-52014-705.[5] Assuming the 
percentage of subjects castrated at Week 12 of triptorelin acetate PR 1-month treatment is no 
less than 92%, a sample size of 133 subjects in each treatment group will have 85% power to 


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demonstrate the noninferiority of triptorelin pamoate PR 3-month to the comparator, when the 
lower limit of the 95% confidence interval (CI) of the difference in percentage of subjects 
castrated at Week 12 between the treatment groups is >-10% and with a 0.025 one-sided 
type I error rate.  
Assuming that the dropout rate will be around 10%, a sample size of 300 randomised subjects 
in total is planned for this study. 
10.3 
Significance Testing and Estimations 
A two sided 95% CI for the difference of the two castration rates (triptorelin pamoate PR 
3-month treatment group minus triptorelin acetate PR 1-month treatment group) will be 
calculated. If and only if the lower limit of the 95% CI is greater than the lower limit of 
equivalence region (-10%), triptorelin pamoate PR 3-month treatment will be confirmed to be 
noninferior to triptorelin acetate PR 1-month treatment. 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s 
Biometry Department. 
A statistical analysis plan (SAP) describing the planned statistical analysis in detail with 
tables, figures and listings (TFLs) templates will be developed as a separate document and 
will be approved prior to enrolment of the first subject into the study. 
Statistical evaluation will be performed using Statistical Analysis System (SAS®) (version 9). 
10.4.1 
Demographic and Other Baseline Characteristics 
In order to assess the balance of treatment groups, descriptive summary statistics (number of 
available observations (n), mean, standard deviation (SD), median, minimum, maximum) or 
frequency counts of demographic (age, age category, ethnicity, race) and baseline data 
(endometriosis history, significant medical/surgical history, concomitant disease (predosing 
AEs and ongoing medical history), prior medications and therapies including those for 
endometriosis) will be presented by treatment group and overall for the randomised, safety (if 
different from randomised) and PP sets and the FAS. 
10.4.2 
Homogeneity of Treatment Groups 
In order to assess the homogeneity of treatment groups at baseline, treatment groups will be 
compared descriptively for demographic and baseline characteristics (see Section 10.4.1). 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the PP set, FAS and 
safety set will be tabulated overall, by treatment group and by centre. The reasons for subject 
exclusions from each of the analysis sets will also be tabulated. In addition, the numbers of 
subjects who were randomised, discontinued and completed will be tabulated by treatment 
group and overall. Primary reasons for discontinuation of study treatment will be tabulated. 
10.4.4 
Pharmacokinetic Data 
Individual plasma concentrations of triptorelin for triptorelin pamoate PR 3-month and 
triptorelin acetate PR 1-month will be listed and summarised by timepoint using descriptive 
statistics for continuous variables (n, mean, median, SD, minimum, maximum, geometric 
mean, and geometric coefficient of variation (assuming log normally distributed data)). Linear 
and semilogarithmic plots of individual and mean plasma concentration time profiles, as well 
as spaghetti plots will be reported separately for subjects in the triptorelin pamoate PR 
3-month full PK/PD subgroup. 


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The PK analysis of triptorelin concentrations will be performed using an NCA approach using 
the Phoenix WinNonlin PK program version 6.3 or higher. The following PK parameters will 
be calculated for the triptorelin pamoate PR 3-month: 
• 
Minimum observed plasma concentration during the dosing interval (Cmin) after 
the first dose and at steady state 
• 
Cmax after the first and last administration (steady state) 
• 
tmax after the first and last administration (steady state) 
• 
AUCτ after first and last administration (steady state) estimated by the log linear 
trapezoidal rule 
The following PK parameters will be calculated for the triptorelin acetate PR 1-month group: 
• 
Cmax and tmax after the first dose 
• 
Cmin after the first, and each subsequent administration (steady state) 
Additional PK parameters may be calculated, if appropriate. 
Descriptive statistics of PK parameters will be presented for the full PK profile analysis set. 
PK parameters will be summarised by n, median, minimum, maximum, geometric mean, and 
geometric coefficient of variation except for tmax where only n, median, minimum and 
maximum values will be reported.  
In addition to the NCA described above, analyses will be performed in all subjects 
(population PK modelling), to assess the PK profile of triptorelin pamoate PR 3-month and 
triptorelin acetate PR 1-month in all subjects. These analyses will be described in a separate 
data analysis plan and reported in a standalone report. 
10.4.5 
Pharmacodynamic Data 
A PK/PD analysis (PK/PD modelling) will be performed for triptorelin pamoate PR 3-month 
and triptorelin acetate PR 1-month exploring the relationship between plasma triptorelin 
concentrations and serum E2, FSH and LH, where possible.  
Additional population PK/PD may be conducted. This analysis will be described in a separate 
data analysis plan and reported in a standalone report. 
10.4.6 
Efficacy Evaluation 
10.4.6.1 Primary Efficacy Endpoint 
The primary efficacy variable is the percentage of subjects castrated (E2≤184 pmol/L or 
50 pg/mL) at Week 12. 
The number and percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12 
will be summarised by treatment group and the difference, including 2-sided 95% CI for the 
difference between treatment groups will be presented. If the lower limit of the 95% CI for the 
difference in percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL) at Week 12 
between the triptorelin pamoate PR 3-month and triptorelin acetate PR 1-month is >-10%, 
noninferiority of triptorelin pamoate PR 3-month will be confirmed.  
10.4.6.2 Secondary Efficacy Endpoints 
Percentage of Subjects Castrated (E2≤184 pmol/L or 50 pg/mL) at Weeks 4 and 8 and 
Percentage of Subjects Castrated (E2≤110 pmol/L or 30 pg/mL) at Weeks 4, 8 and 12: 
The number and percentage of subjects castrated (according to each criterion) will be 
presented by treatment group for each visit. The difference between the treatment groups will 
be calculated and displayed with the 95% CI for the true treatment difference. 


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Change in Endometriosis-Associated Pelvic Pain (by 10 cm VAS) at Weeks 4, 8 and 12: 
Endometriosis-associated pelvic pain measured by 10 cm VAS and change from baseline, will 
be summarised overall and for the subgroup of subjects with baseline VAS>3 cm at each time 
point, using summary statistics (n, mean, median, SD and minimum and maximum values) 
and the 95% CI for the true difference in mean VAS score and VAS change from baseline 
scores will be presented. 
Serum E2, FSH and LH Concentration at Weeks 4, 8 and 12: 
Serum E2, FSH and LH concentrations and change from baseline will be summarised at each 
time point, using descriptive statistics (n, mean, median, SD and minimum and maximum 
values) and the 95% CI for the difference between treatment groups in mean concentration 
values and mean change from baseline values will be presented for each parameter. 
Time to Menses Recovery: 
Time to menses recovery will be defined as the time (in days) between date of last dose of 
study drug and date of first day the subject observed menstrual bleeding of the next menstrual 
period. Any subjects withdrawing from the study without menstrual bleeding will be censored 
in the analysis at the date of withdrawal, and any subjects without menstrual bleeding prior to 
the end of study visit will be censored in this analysis at the date of the end of study visit. 
The distribution of times to menses recovery will be estimated using the Kaplan-Meier 
method for each treatment group and presented graphically and median time to event and 
95% CIs will be provided for each treatment group. 
10.4.6.3 Exploratory Efficacy Endpoints 
Percentage of Subjects Castrated 1) E2≤184 pmol/L or 50 pg/mL 2) E2≤110 pmol/L or 
30 pg/mL at Week 24: 
The number and percentage of subjects castrated at Week 24 (according to each criterion) will 
be presented by treatment group. The difference between the treatment groups will be 
calculated and displayed with the 95% CI for the true treatment difference. 
Change in Endometriosis-associated Pelvic Pain (by 10 cm VAS) at Weeks 16, 20 and 24 
and the End of Study Visit Compared to Baseline: 
Endometriosis-associated pelvic pain measured by 10 cm VAS and change from baseline, will 
be summarised overall and for the subgroup of subjects with baseline VAS>3 cm at each time 
point, using summary statistics (n, mean, median, SD and minimum and maximum values) 
and the 95% CI for the true difference in mean VAS score and VAS change from baseline 
scores will be presented. 
Serum E2, FSH and LH Concentration at Week 24:  
Serum E2, FSH and LH concentrations at Week 24 and change from baseline will be 
presented using summary statistics (n, mean, median, SD and minimum and maximum 
values) and the 95% CI for the difference between treatment groups in mean concentration 
values and mean change from baseline values will be presented for each parameter. 
10.4.7 
Adjustment for Centre Effect 
Centre effect will be considered in analysis of the primary endpoint. 
10.4.8 
Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety set. 


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All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version current at the start of the study, and will be classified by MedDRA 
preferred term and system organ class. AE listings will be presented by subject, system organ 
class and preferred term. 
The incidence of all reported treatment-emergent adverse events (TEAEs) and SAEs will be 
tabulated by treatment group and overall. In addition, summary tables will be presented by 
maximum intensity, drug relationship and TEAEs associated with premature withdrawal of 
study medication. 
A TEAE is defined as any AE that occurs from receiving the first dose of study drug to the 
end of study/early withdrawal visit if:  
• 
it was not present prior to receiving the first dose of study drug, or  
• 
it was present prior to receiving the first dose of study drug but the intensity 
increased during the active phase of the study.  
All TEAEs will be flagged in the AE listings. 
Prior and concomitant medication will be coded by using the World Health Organisation 
(WHO) Drug Dictionary (version December 2016 or above) and will be summarised 
separately by treatment group and overall with the number and percentage of subjects 
receiving prior and concomitant medication by drug class and preferred drug name. Prior 
medications/therapies are all those stopped prior to the first dose of study drug and 
concomitant medications/therapies are defined as all those ongoing or started at/after the first 
dose of study drug. 
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 subjects with low, normal or high values and normal or abnormal 
physical/pelvic examination findings between baseline and Week 24 time points.  
Vital signs data will be presented as shift tables, with the number and percentage of subjects 
with normal or abnormal findings between baseline and each assessment. 
ECG data will also be presented as shift tables, with the number and percentage of subjects 
with normal or abnormal findings between baseline and Week 12 and Week 24. 
Serum E2, FSH and LH concentrations at Week 40 will be listed only. 
Detailed methodology for the analysis of safety data will be presented in the SAP. 
10.5 
Subgroup Analyses 
Endometriosis-associated pelvic pain and change from baseline will also be assessed at each 
timepoint for the subgroup of subjects with VAS>3 cm at baseline. 
10.6 
Interim Analyses 
No interim analyses will be performed. 


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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
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 12.4, and to any other locations used for the purpose of the study in 
question (for example laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion of a written amendment by the IEC/IRB, except when 
necessary to eliminate immediate safety concerns to the subjects or when the change involves 
only logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
12.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol-specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or 
GCP guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e. nonadherence on the 
part of the subject, the investigator, or the sponsor to protocol specific inclusion/exclusion 
criteria, primary objective evaluation criteria, and/or GCP guidelines. Protocol violations will 
be identified and recorded, by study centre personnel, on the eCRF.  
As a matter of policy, the sponsor will not grant exceptions to protocol-specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically, and scientifically justified for a particular subject, prior 
approval from the sponsor and the responsible IEC/IRB, in accordance with the Standard 
Operating Procedure (SOP), is required before the subject will be allowed to enter the study. 
If investigative centre personnel learn that a subject who did not meet protocol eligibility 
criteria was entered in a study (a protocol violation), they must immediately inform the 
sponsor. Such subjects will be discontinued from the study, except in an exceptional instance 
following review and written approval by the sponsor and the responsible IEC/IRB, according 
to the applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (for example, when new staff become 
involved). The investigator must assure that all study staff members are qualified by 
education, experience, and training to perform their specific responsibilities. These study staff 
members must be listed on the study centre authorisation form, which includes a clear 
description of each staff member’s responsibilities. This list must be updated throughout the 
study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
12.3 
Study Monitoring 
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 
subjects are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP and regulatory 
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Sponsor-assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study 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 according to the sponsor monitoring manual, of the 
subject’s visit and on an ongoing basis to allow regular review by the study monitor, both 
remotely by the internet and during site visits. The central study monitor at the sponsor 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 subject name is revealed on a document required by the sponsor (for 
example, laboratory print outs) the name must be blacked out permanently by the site 
personnel, leaving the initials visible, and annotated with the subject number as identification. 
12.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 11). 
12.5 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. 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. 


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki and ICH GCP Guidelines (Section 1.6). In addition, this study will 
adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (for example, advertisements), any written information to be 
provided to subjects 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 subject 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. 
13.2 
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 subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related 
procedure and administration of the IMP). Sufficient time will be allowed to discuss any 
questions raised by the subject. 
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 subject. Each subject’s original 
consent form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject 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 subjects 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. Subjects 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 subject, inform the subject’s primary 
physician about their participation in the clinical study. 


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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
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. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (for example, initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons 
on behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 


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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
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 subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, IMP 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. Subject 
completed diaries and questionnaires will be printed or electronic. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each 
eCRF to attest to the accuracy and completeness of all the data. If any changes are made to the 
eCRF, after a form has been locked and 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. 
14.2 
Data Management 
EDC will be utilised for collecting subject 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. 
Data management will be conducted either by a CRO, directed by the sponsor’s data 
management department or by the sponsor’s data management department. All data management 
procedures will be completed in accordance with the sponsor and the contracted CRO SOPs. 
Prior to data being received in-house at the assigned CRO, it will be monitored at the investigator 
site, (for further details please see Section 12.3 Study Monitoring). The eCRF and other data 
documentation removed from the investigator site(s) will be tracked by the CRO and the 
monitor. 
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 study, 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 generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. 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 an AE, medical history and concomitant medication terms will be performed by 
the contracted CRO/a CRO, directed by the sponsor’s Biometry Group, and reviewed and 


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approved by the sponsor. Concomitant medications will be coded using the WHO drug 
dictionary and AEs/medical history terms will be coded using MedDRA (see Section 10.4.8). 
14.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study 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. 


IPSEN GROUP 
 
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15 
FINANCING AND INSURANCE 
15.1 
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 subject, 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. 
15.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


IPSEN GROUP 
 
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16 
REPORTING AND PUBLICATIONS OF RESULTS 
16.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject 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. 
16.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and content of CSRs. A final CSR will be prepared where any subject has signed informed 
consent, regardless of whether the study 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 and Chinese. 


IPSEN GROUP 
 
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17 
REFERENCES 
1 
Conn PM. The molecular basis of gonadotrophin-releasing-hormone action. 
Endocrine Reviews 1986;7:3-10. 
2 
Kiesel 
L. 
Molecular 
mechanisms 
of 
gonadotrophin 
releasing 
hormone-stimulated gonadotrophin secretion. Hum Reprod 1993;8 Suppl 
2:23-8. 
3 
Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin-releasing hormone 
receptors: structure and signal transduction pathways. Endocr Rev 
1994;15:462-99. 
4 
Leone Roberti Maggiore U, Scala C, Remorgida V, et al. Triptorelin for the 
treatment of endometriosis. Expert Opin Pharmacother 2014;15:1153-79. 
5 
Study E-28-52014-705. A Phase II, randomised, open, multicentre study, in 
two parallel groups to assess the equivalence of Decapeptyl SR 3-month (test 
formulation) and Decapeptyl SR 28-day (reference formulation) in patients 
with endometriosis. Ipsen Biotech 11 May 2000. 
6 
Olive DL. Gonadotropin-releasing hormone agonists for endometriosis. N 
Engl J Med 2008;359:1136-42. 
7 
Donnez J, Dewart PJ, Hedon B, et al. Equivalence of the 3-month and 28-day 
formulations of triptorelin with regard to achievement and maintenance of 
medical 
castration 
in 
women 
with 
endometriosis. 
Fertil 
Steril 
2004;81:297-304. 
8 
Hornstein MD, Yuzpe AA, Burry KA, et al. Prospective randomized 
double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis 
associated pelvic pain. Fertil Steril 1995;63:955-62. 
9 
Study E-54-52014-099. A Phase II, open, parallel, multicentre study to 
investigate the pharmacodynamics and pharmacokinetics of a sustained 
release formulation of triptorelin in female patients. Ipsen Biotech. 
14 February 2001 
10 
Cooperative Group of Endometriosis, Chinese Society of Obstetrics and 
Gynecology, 
Chinese 
Medical 
Association; 
Cooperative 
Group 
of 
Endometriosis Chinese Society of Obstetrics and Gynecology Chinese 
Medical Association. Guideline for the diagnosis and treatment of 
endometriosis. Zhonghua Fu Chan Ke Za Zhi 2015;50:161-9. 


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18 
LIST OF APPENDICES 
Appendix 1 Visual Analogue Scale .......................................................................... 67 
Appendix 2 Protocol Amendment Form (Amendment 1.0) ..................................... 69 
Appendix 3 Protocol Amendment Form (Amendment 2.0) ..................................... 72 
 


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Appendix 1 Visual Analogue Scale 
 


IPSEN GROUP 
 
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Visual Analogue Scale:  
 
* 
For the Day 1 (baseline) assessment, subjects who have undergone endometriotic surgery within 4 weeks prior to the 
assessment must assess their most severe level of endometriosis-associated pain post-surgery 
 
Please indicate the subjective level of your most severe endometriosis pain over the last 4 weeks*. 
Mark it with a single vertical mark on the line. 
 
 
 
 
Patients record the severity of their pain on a VAS score from 0 mm to 100 mm. 
absence 
of pain 
unbearable 
pain 

SAP_001.pdf: 
COVANCE INC. CONFIDENTIAL
Page 1 of 34
ST-AD-008 version 03
Ipsen Pharma
Protocol No.: D-CN-52014-220
A Phase III, Multicentre, Randomised, Open-label, 
Parallel, Active-controlled Study to Compare the 
Oestradiol Suppression, Clinical Efficacy and Safety of Two 
Formulations of Triptorelin (Triptorelin Pamoate PR 3-
month and Triptorelin Acetate PR 1-month) in Chinese 
Subjects with Endometriosis
STATISTICAL ANALYSIS PLAN
Version: Final 3.1
Date of Issue: 13DEC2019
Author: 
Ipsen Pharma
Covance Clinical Development Services
65 quai Georges Gorse
92100 Boulogne-Billancourt, France
Tel: +33 (0) 1 58 33 50 00
Fax: +33 (0) 1 58 33 50 01 
R&D Shanghai Innovation Hub
Beaufour-Ipsen (Tianjin) Pharmaceutical Co No 
1206, Floor 12, Block H, Phoenix Place Shuguang 
Xili, Chaoyang District 
Beijing 100028, China
Tel: +86 (0)10 56 30 75 98
Fax: +86 (0)10 56 30 75 99
Room 102, Building 20, Universal Business 
Park,No.10, Jiuxianqiao Road, Chaoyang District, 
Beijing, China
Tel: +86 (0)10 5732 3000
Fax: +86 (0)10 5732 3001
CCI
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Statistical Analysis Plan 
Version: Final 3.1
           Date of Issue: 13DEC2019
Ipsen Pharma;   Protocol No. D-CN-52014-220
                      
COVANCE INC. CONFIDENTIAL
Page 3 of 34
ST-AD-008 version 02
 REVIEWERS  
The following reviews of the SAP were conducted:
Name 
Role
Version Last 
Reviewed
Company/
Organisation
Final 1.1
Ipsen
Draft 1.1
Ipsen
Final 1.1
Ipsen
Final 1.1
Ipsen
Final 1.1
Ipsen
Draft 1.1
Ipsen
Final 1.1
Ipsen
Final 1.1
Ipsen
Final 1.1
Ipsen
Final 1.1
Ipsen
Draft 1.1
Ipsen
Draft 1.1
Ipsen
Final 1.1
Covance
Draft 1.0
Covance
Final 1.1
Covance
Final 1.1
Covance
Final 1.1
Covance
Final 1.1
Covance
CCI
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
Version: Final 3.1
           Date of Issue: 13DEC2019
Ipsen Pharma;   Protocol No. D-CN-52014-220
                      
COVANCE INC. CONFIDENTIAL
Page 4 of 34
ST-AD-008 version 02
VERSION HISTORY 
Version 
Number
Version Date
Summary and rational of change(s)
Final 1.0
July 11, 2017
First final version.
Final 2.0
(amendment 1.0)
February 01, 2018 1. Based on the new version of protocol, the following sections are 
updated:
1) Section 3.1 Primary Efficacy Endpoint: delete “blinded”;
2) Section 7.6.2  Secondary Efficacy Analysis: use “last dose” 
instead of “first dose” in definition of time to menses;
3) Section 7.7.3 Electrocardiograms: delete RR intervals and 
delete QTcF accordingly calculated from RR;
2. Based on the new version of CRF, the following sections are 
updated: 
1) Section 7.7.1 Adverse Event: delete the sentence “AE with 
multiple episodes will be counted as one AE when 
calculating number of events.”, because one AE will be 
collected in one record (no multiple episodes);
3. Delete TFL index in Appendix II, in order to update/maintain a 
separate file of TFL mockup. 
Final 3.0
1. Update based on findings from the first dry run.
1) Include a new Section 6.2.1 Handling of triptorelin BLO 
concentration values (Full PK/PD subgroup) to specify how 
BLQ will be handled when perform statistical summary.
2) Section 7.3 Protocol Deviations: all PD should be listed. A 
new major PD listing to be provided with flagging on PDs 
affects on efficacy and/or PK/PD variables.
3) Section 7.6.2 Secondary Efficacy Analysis – Time to 
Menses Recovery: Additional description on how to handle 
subjects whose menses didn’t stop before last dose.
4) Section 7.7.1 Adverse Events: Replace “Pre-dosing adverse 
events” to “Non-TEAE”.
5) Section 7.7.2 Laboratory Evaluations: Update 
Table 2 PCSA Criteria for Laboratory Tests.
6) Section 7.7.3 Electrocardiograms: Update Table 3 PCSA 
Criteria for ECG.
7) Section 7.7.4 Vital Signs: Include normal range for vital 
signs.
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ST-AD-008 version 02
2. Section 7.8 Pharmacokinetics: Additional imputation provided
by Ipsen.
Final 3.1
1) Add criterion “with primary endpoint measurement at week 
12” in the definition of PP set, as for subjects without 
primary endpoint measurement at week 12, some reported 
PD, while some not.
2) Section 7.3 Protocol Deviations: “Major protocol deviations 
affecting efficacy endpoints leading to exclusion from the 
PP set” replaced by “Major protocol deviations affecting 
primary efficacy endpoint leading to exclusion from the PP 
set”.
3) Section 7.6.2 Secondary Efficacy Analysis – Time to 
Menses Recovery: “before last dose” replaced by “during
the treatment duration (V2 till V8)”.
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Statistical Analysis Plan 
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ST-AD-008 version 02
TABLE OF CONTENTS  
APPROVALS ...............................................................................................................................................2 
REVIEWERS ...............................................................................................................................................3 
VERSION HISTORY..................................................................................................................................4 
TABLE OF CONTENTS.............................................................................................................................6 
GLOSSARY OF ABBREVIATIONS.........................................................................................................8 
1 SOURCE DOCUMENTS......................................................................................................................9 
2 PROTOCOL DETAILS ........................................................................................................................9 
2.1 Study Objectives............................................................................................................................9 
2.2 Overall Study Design ....................................................................................................................9 
2.3 Sample Size and Power...............................................................................................................10 
3 EFFICACY AND SAFETY VARIABLES ........................................................................................11 
3.1 Primary Efficacy Endpoint(s)....................................................................................................11 
3.2 Secondary Efficacy Endpoints ...................................................................................................11 
3.3 Exploratory Efficacy Endpoints ................................................................................................11 
3.4 Safety Variables...........................................................................................................................11 
4 PHARMACOKINETIC VARIABLES..............................................................................................12 
5 ANALYSIS SETS.................................................................................................................................12 
5.1 Screened Set.................................................................................................................................12 
5.2 Randomised Set...........................................................................................................................12 
5.3 Safety Set......................................................................................................................................12 
5.4 Full Analysis Set (FAS)...............................................................................................................12 
5.5 Per Protocol (PP) Set ..................................................................................................................12 
5.6 Full PK Profile Analysis Set.......................................................................................................13 
5.7 Sparse PK Sampling Analysis Set..............................................................................................13 
5.8 PD Analysis Set............................................................................................................................13 
5.9 PK/PD Relationships Set ............................................................................................................13 
6 DATA HANDLING .............................................................................................................................14 
6.1 Time points and Visit Windows.................................................................................................14 
6.2 Handling of Dropouts or Missing Data.....................................................................................14 
6.2.1 Handling of triptorelin BLQ concentration values............................................................15 
6.2.2 Partial dates.......................................................................................................................15 
6.3 Pooled Center ..............................................................................................................................15 
7 STATISTICAL METHODS ...............................................................................................................16 
7.1 General Principles.......................................................................................................................16 
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7.2 Subject Disposition and Data Sets Analysed ............................................................................16 
7.3 Protocol Deviations .....................................................................................................................17 
7.4 Demographics and Other Baseline Characteristics .................................................................17 
7.4.1 Medical History.................................................................................................................18 
7.4.2 Previous and Concomitant Medications............................................................................18 
7.4.3 Previous and Concomitant Non-drug Therapies...............................................................18 
7.4.4 Concomitant Surgical Procedures.....................................................................................19 
7.5 Study Drug Administration........................................................................................................19 
7.6 Efficacy.........................................................................................................................................20 
7.6.1 Primary Efficacy Analysis ................................................................................................20 
7.6.2 Secondary Efficacy Analysis ............................................................................................20 
7.6.3 Subgroup Analysis ............................................................................................................22 
7.6.4 Exploratory Analysis.........................................................................................................22 
7.7 Safety............................................................................................................................................23 
7.7.1 Adverse Events..................................................................................................................23 
7.7.2 Laboratory Evaluations.....................................................................................................24 
7.7.3 Electrocardiograms ...........................................................................................................26 
7.7.4 Vital Signs.........................................................................................................................27 
7.7.5 Physical/Pelvic Examination.............................................................................................27 
7.7.6 Pelvic type B ultrasound ...................................................................................................28 
7.7.7 Hormones..........................................................................................................................28 
7.8 Pharmacokinetics........................................................................................................................28 
7.9 Interim Analysis ..........................................................................................................................28 
8 CHANGES IN PLANNED ANALYSES............................................................................................28 
9 REFERENCES.....................................................................................................................................28 
10 APPENDICES ......................................................................................................................................30 
APPENDIX I - SCHEDULE OF EVENTS..............................................................................................30 
APPENDIX II – TABLE, FIGURE AND LISTING ..............................................................................34 
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ST-AD-008 version 02
GLOSSARY OF ABBREVIATIONS  
Abbreviation
Term
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BLQ
Below the Limit of Quantification
CI
Confidence Interval
E2
Oestradiol
ECG
Electrocardiogram
eCRF
Electronic case report form
FAS
Full Analysis Set
FSH
Follicle stimulating hormone
ICH
International Conference on Harmonization
IMP
Investigational medicinal product
LH
Luteinising hormone
MedDRA
Medical Dictionary for Regulatory Activities
n
Number of available observations
PCSA
Potentially clinically significant abnormalities
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PP
Per protocol 
PR
Prolonged release
PT
Preferred term
QTcF
Fridericia corrected QT interval
RBC
Red blood cell(s)
SAP
Statistical analysis plan
SD
Standard Deviation
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
VAS
Visual analogue scale
WBC
White blood cell(s)
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ST-AD-008 version 02
1
SOURCE DOCUMENTS
This Statistical Analysis Plan (SAP) was written based on the following documents:
x
Protocol final version 3.0 (Amendment 2.0), dated on 29 September 2017
x
Electronic case report forms (eCRF) version 2.00, dated on 29 November 2017
x
International Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: 
Statistical Principles for Clinical Trials” 1
x
ICH E3 guideline entitled, “Guidance for Industry: Structure and Content of Clinical Study 
Reports” 2
2
PROTOCOL DETAILS
2.1
Study Objectives
The primary objective of the study is to assess the efficacy of triptorelin pamoate prolonged release (PR) 3-
month formulation in Chinese female subjects with endometriosis by demonstrating the noninferiority of 
triptorelin pamoate PR 3-month formulation injected once as compared to triptorelin acetate PR 1-month 
formulation injected 3 times consecutively, assessed by the percentage of subjects castrated (oestradiol 
(E2)≤184 pmol/L or 50 pg/mL) at Week 12.
The secondary objectives of the study are as follows:
x
To assess other efficacy parameters including the percentage of subjects castrated at other time 
points, E2, lutenising hormone (LH), and follicle stimulating hormone (FSH) concentrations, and 
the impact on endometriosis-associated pelvic pain.
x
To assess the safety profile of triptorelin pamoate PR 3-month.
x
To assess the pharmacokinetics (PK) of triptorelin pamoate PR 3-month and compare to triptorelin 
acetate PR 1-month.
The exploratory objectives of the study are:
x
To assess other efficacy parameters (percentage of subjects castrated, E2, LH and FSH 
concentrations and the impact on endometriosis-associated pelvic pain) after Week 12.
x
To explore the PK/ pharmacodynamic (PD) relationship of triptorelin pamoate PR 3-month in a 
subset of subjects (PD markers being E2, FSH and LH).
2.2
Overall Study Design
This prospective, Phase III, multicentre, randomised, open-label, parallel group, active-controlled study will 
compare triptorelin pamoate PR 3-month with triptorelin acetate PR 1-month for the treatment of Chinese 
female subjects with endometriosis. 
Subjects with endometriosis will be screened for eligibility up to 5 weeks prior to the first dose of 
investigational medicinal product (IMP), which must occur during the follicular phase of the menstrual 
cycle. A total of 300 eligible subjects will be stratified by endometriotic surgical history (previous vs. no 
previous surgery) and the severity of endometriosis-associated pelvic pain (assessed by a visual analogue 
scale (VAS): VAS>3 or ≤3 cm) and randomised in a 1:1 ratio to receive either triptorelin pamoate PR 3-
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ST-AD-008 version 02
month once per 12 weeks (total 2 injections, one each at baseline and Week 12) or triptorelin acetate PR 1-
month once per 4 weeks (total 6 injections, one each at baseline and Week 4, 8, 12, 16 and 20) for a 24-
week treatment phase.
All subjects will visit the study site every 4 weeks until Week 24. The subgroup participating in the full PK 
and exploratory PD evaluations (up to 32 subjects, 16 from each treatment group, enrolled at the selected 
site) will have additional study visits during the treatment phase. If needed in the opinion of investigator, 
“add back” treatment (recommended as, but not limited to, tibolone at a dose of 2.5 mg once daily) may be 
applied from Week 12. After 24 weeks’ study treatment, subjects receiving triptorelin pamoate PR 3-month 
and participating in the full PK/PD subgroup will visit the study site, and other subjects will be followed up 
by telephone every 4 weeks until menses recovery or Week 40 (whichever is earlier). All subjects will 
attend the study site for the end of study visit (the first visit after menses recovery, or Week 40).
This study will consist of a screening period of up to 5 weeks, a 24-week open-label treatment period and 
a follow up period of up to 16 weeks. The duration of the study is a minimum of 24 to 40 weeks, plus up to 
5 weeks for the screening period. 
The principal study design features are summarised in Figure 1.  The scheduled events at every visit are 
summarised in Table 5 (all subjects) and Table 6 (PK/PD subgroup subjects).
Figure 1
Study Design
2.3
Sample Size and Power
The sample size was estimated based on data from Ipsen Study E-28-52014-705. Assuming the percentage 
of subjects castrated at Week 12 of triptorelin acetate PR 1-month treatment is no less than 92%, a sample 
size of 133 subjects in each treatment group will have 85% power to demonstrate the noninferiority of 
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triptorelin pamoate PR 3-month to the comparator, when the lower limit of the 95% confidence interval (CI) 
of the difference in percentage of subjects castrated at Week 12 between the treatment groups is ≥-10% and 
with a 0.025 one-sided type I error rate.
Assuming that the dropout rate will be around 10%, a sample size of 300 randomised subjects in total is 
planned for this study.
3
EFFICACY AND SAFETY VARIABLES
3.1
Primary Efficacy Endpoint(s)
The percentage of subjects castrated (E2 ≤184 pmol/L or 50 pg/mL) at Week 12. The primary endpoint will 
be evaluated on centralised bioanalysis of serum samples for E2.
3.2
Secondary Efficacy Endpoints
The secondary endpoints for this study include:
x
Percentage of subjects castrated (E2 ≤184 pmol/L or 50 pg/mL) at Weeks 4 and 8.
x
Percentage of subjects castrated (E2 ≤110 pmol/L or 30 pg/mL) at Weeks 4, 8 and 12.
x
Change in endometriosis-associated pelvic pain (by 10 cm VAS) at Weeks 4, 8 and 12 compared
to baseline.
x
E2, FSH and LH concentrations at Weeks 4, 8 and 12.
x
Time to menses recovery.
3.3
Exploratory Efficacy Endpoints
The exploratory endpoints for this study include:
x
Percentage of subjects castrated (as defined by both E2 ≤184 pmol/L (50 pg/mL) and E2 ≤ 110 
pmol/L (30 pg/mL)) at Week 24.
x
Change in endometriosis-associated pelvic pain (by 10cm VAS) at Weeks 16, 20 and 24 and the 
end of study visit compared to baseline.
x
Concentrations of E2, FSH and LH at Week 24.
x
The PK/PD relationship will be explored (PD markers: E2, FSH and LH) for triptorelin acetate PR 
1-month formulation and triptorelin pamoate PR 3-month formulation.
3.4
Safety Variables
The safety and tolerability of triptorelin will be assessed by evaluating as follows:
x
Adverse events (AEs) throughout the study,
x
Clinical laboratory parameters (biochemistry, haematology and urinalysis) test results at screening, 
Weeks 12 and 24,
x
Electrocardiogram (ECG) findings at screening, Weeks 12 and 24,
x
Serum hormone (E2, FSH and LH) concentrations at Week 40 (for those subjects whose menses 
do not recover at Week 40),
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x
Vital signs (blood pressure and heart rate) measurements at each visit during treatment and end 
of study visit,
x
Physical/pelvic examination at screening, Weeks 12 and 24,
x
Pelvic type B ultrasound at screening (or within 1 month prior to screening), Week 12 (optional) 
and Week 24,
x
Urinary pregnancy test at screening and baseline visit.
4
PHARMACOKINETIC VARIABLES
A full triptorelin PK characterisation, using a non-compartmental analysis (NCA) approach, will be 
conducted in a subgroup of up to 16 subjects in each treatment group to be enrolled at selected sites. PK 
parameters (Cmin, Cmax, tmax and AUCtau where applicable) will be calculated for triptorelin acetate PR-1
month after the first administration and triptorelin pamoate PR 3-month after the first and last administration. 
5
ANALYSIS SETS
5.1
Screened Set 
All subjects screened (i.e. who signed the informed consent) are included in Screened set.
5.2
Randomised Set
All subjects randomised (i.e. who were randomly allocated to a treatment group) are included in the 
Randomised Set.
Randomised subjects are analysed according to their assigned treatment.
5.3
Safety Set 
The Safety Set includes all subjects who received at least one dose of study medication.
The Safety Set will be used for safety analyses according to the actual treatment received for each subject.
5.4
Full Analysis Set (FAS)
The full analysis set (FAS) includes all randomised subjects who received at least one dose of study 
medication with at least one baseline and at least one post-baseline assessment of the primary efficacy 
parameter.
The FAS will be used to analyse primary and secondary efficacy endpoints. All exploratory efficacy
endpoints will be performed on the FAS.
FAS subjects are analysed according to their randomised treatment.
5.5
Per Protocol (PP) Set 
The per protocol (PP) set includes all subjects in the FAS with primary endpoint measurement at week 12, 
and without major protocol violations/deviations affecting primary efficacy endpoint.
Major protocol deviations are those that affect the primary efficacy endpoint and the criteria of major 
protocol deviations will be defined in the file of protocol deviation document. The process to review major 
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protocol deviations will be ongoing and the final PP subjects will be determined during the data review 
meeting held prior to database lock.
The PP set will be used to analyse primary and secondary efficacy endpoints.
The PP set will be the primary analysis population for the primary efficacy endpoint.
5.6
Full PK Profile Analysis Set 
The Full PK Profile Analysis Set includes subjects in the full PK/PD subgroup who receive at least one 
dose of IMP, have no major protocol deviations affecting the PK variables, and have a sufficient number of 
PK concentration measurements to estimate the main PK parameters: maximum observed plasma 
concentration (Cmax) and time to maximum observed plasma concentration (tmax), and area under the plasma 
concentration-time curve for the dosing interval (AUCtau) where applicable.
The criteria of Major protocol deviations affecting the PK variables will be defined in the protocol deviation 
document. The process to review major protocol deviations potential impact on PK parameters will be 
ongoing and the final Full PK Profile Analysis Set will be determined during data review meeting.
The Full PK Profile Analysis Set will be used for PK parameter analyses using an NCA approach. The 
detailed PK analysis methodology will be included in a separate PK analysis plan.
5.7
Sparse PK Sampling Analysis Set 
The Sparse PK Sampling Analysis Set includes all subjects who receive at least one dose of IMP, have no 
major protocol deviations affecting the PK variables and have at least one valid plasma concentration.
The criteria of Major protocol deviations affecting the PK variables will be defined in the protocol deviation 
document. The process to review major protocol deviations potential impact on PK parameters will be 
ongoing and the final Sparse PK Sampling Analysis Set will be determined during data review meeting.
Where possible, PK profile will be assessed following PK modeling, for each subject within the Sparse PK 
Sampling Analysis Set. This analysis will be described in a separate data analysis plan and reported in a 
standalone report.
5.8
PD Analysis Set 
The PD Analysis Set includes all subjects in full PK/PD subgroup who have a sufficient number of PD 
measurements.
5.9
PK/PD Relationships Set 
The PK/PD Relationships Set includes all subjects who receive at least one dose of IMP, have at least one 
valid plasma triptorelin concentration and have at least one PD measurement (PD markers: E2, FSH and 
LH).
The PK/PD Relationships Set will be used to describe, where possible, the relationships between plasma 
triptorelin concentration and PD markers (E2, FSH and LH) according to the actual treatment received for 
each subject. This analysis will be described in a separate data analysis plan and reported in a standalone 
report.
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6
DATA HANDLING
6.1
Time points and Visit Windows
Day 1 is defined as the day of first dose of IMP treatment.  Relative days after Day 1 are calculated as 
(assessment date – Day 1 date) + 1.  Relative days prior to Day 1 are calculated as (assessment date – Day 
1 date).  The day prior to Day 1 is Day -1.
Unless specified otherwise, baseline is defined as the last available assessment prior to the first dose of 
IMP; if assessment time and/or drug taken time is not collected, the assessment performed on the same day 
as first dose of IMP will be considered as baseline; if assessment date is missing, the assessments at the 
scheduled visits of screening (Visit 1) and Day 1 or baseline (Visit 2) will be considered as pre-baseline 
visits in flag baseline.
By-visit analyses on data will be analysed according to the scheduled visits outlined in the protocol and/or 
eCRF (Week xx). No visit windows will be applied for summary and analysis.
If subject early discontinued study, the measured safety and efficacy variables at early discontinued visit 
are collected in “End of study/early withdrawal visit”. Then the early withdrawal visit of safety and efficacy 
endpoints (except PD sampling) will be re-mapped to the visits using the time windows in Table 1.
Table 1
Scheduled Visits and Time Window
Scheduled Visit at Study Site
Target Day of the Visit
Protocol Visit Window
Time Window to Re-map 
End of Study Visit or 
Early Withdrawal Visit
Baseline
Day 1
Day 1
Day 1
Week 4
Day 29
Target Day ± 3 days
Day 26 – Day 53 
Week 8
Day 57
Target Day ± 3 days
Day 54 – Day 81 
Week 12
Day 85
Target Day ± 3 days
Day 82 – Day 109 
Week 16
Day 113
Target Day ± 3 days
Day 110 – Day 137 
Week 20
Day 141
Target Day ± 3 days
Day 138 – Day 165 
Week 24
Day 169
Target Day ± 3 days
Day 166 – Day 193 
Week 28
Day 197
Target Day ± 3 days
Day 194 – Day 221
Week 32
Day 225
Target Day ± 3 days
Day 222 – Day 249
Week 36
Day 253
Target Day ± 3 days
Day 250 – Day 277
End of study visit (Week 40)
Day 281 or within 15 days 
after menses recovery
Target Day ± 3 days
≥ Day 278 
Data from end of study visit or early termination assessments will be combined with data from scheduled 
visits in the by-visit analyses only if no scheduled visit data for the same parameters at that visit.
The “final visit” will be added after all scheduled visits in by-visit analyses on safety data including lab 
tests, ECG, vital signs, physical/pelvic examination and pelvic type B ultrasound scan. The final visit means 
the last available measurements at scheduled or unscheduled visits after first study dose during the study.
6.2
Handling of Dropouts or Missing Data
No data imputation will be performed for missing efficacy and safety variables, except efficacy endpoints 
of percentage of subjects castrated. If E2 measurement is missing, the last available E2 measurement at post-
baseline visits will be used in deriving subjects castrated. 
For laboratory values or concentration data below the lower limit of quantification (LLOQ) like “<xxx” or
“<=xxx”, or above the upper limit of quantification (ULOQ) like “>xxx” or “>=xxx”, LLOQ or ULOQ 
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(xxx) will be used for calculation of descriptive statistics. The original laboratory values or concentration
data (“<xxx”, “<=xxx”, “>xxx” or “>=xxx”) are presented in the listing.
6.2.1
Handling of triptorelin BLQ concentration values
For the full PK/PD subgroup (with full PK sampling schedule) only, and for descriptive statistics only (not 
for the individual listings):
x
For the first administration of study drug, BLQ data must be substituted by 0 for concentrations
measured before the first quantifiable concentration, and by missing after the first quantifiable
concentration.
x
For any other administration all BLQ must be set as missing in the dataset
For the sparse PK groups all BLQ must be set as missing in the descriptive statistics datasets. 
For further details of the descriptive statistics for triptorelin concentration data please refer to section 7.8.
6.2.2
Partial dates
If the date of endometriosis diagnosis or date of endometriosis surgery is a partial date, the first day of 
known year and/or month will be used to calculate duration. 
For AEs, concomitant medications, and concurrent procedures, the following conventions will be used for 
imputing partial dates:
x
If day (and month) is missing for AE onset date, or start date of a concomitant medication, or date
of concurrent procedure, the partial date will be set to
-
date of first dose of IMP, if the known year (and month) is same as the year (and month) of first
dose of IMP and no other information indicating the date is before first dose of IMP;
-
the first day of the known year (and month), if the year (and month) of the partial date is
different from the year (and month) of the first dose of IMP or other information indicating the
date is before first dose of IMP;
x
If day (and month) is missing for AE stop date, or the stop date of a concomitant medication, this
day will be set to the last day of the known year (and month) that AE or medication occurred;
x
If AE onset date, or start date of a concomitant medication, or date of concurrent procedure is
completely missing, this date will be set to date of the dose of IMP;
x
If the imputed start date is after stop date, the start date will be set to the stop date.
Partial dates will be presented as original in all listings, and imputed dates will not be presented in listings.
6.3
Pooled Center
If cities have number of PP subjects less than average number of subjects per centre (total number of PP 
subjects divided by total number of centres), these cities will be pooled together or pooled to other cities to
keep all cities with number of subjects equal to or more than average number of subjects per centre. 
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7
STATISTICAL METHODS
7.1
General Principles 
The statistical analyses will be performed in accordance with ICH E9 guideline 1, 3, 4.
Statistical analysis of the efficacy and safety data will be performed by Covance, managed by the Sponsor’s 
Biometry Department.
All data processing, summarisation and analyses will be performed using Version 9.3 (or higher) of
the Statistical Analysis System (SAS) statistical software package.
Unless specified otherwise, data will be displayed using the following treatment group labels, in the order 
presented:
Triptorelin Pamoate PR 3-month
Triptorelin Acetate PR 1-month
Total (if total is presented for all treatment groups)
Continuous variables will be summarised by the number of subjects (n), mean, standard deviation (SD), 
median, minimum and maximum. The summary statistics will be displayed for visits where there are non-
missing data for at least two subjects in one or more treatment groups. Mean, median and SD will have 1 
extra decimal place than the actual values. If 95% CI of mean is presented, lower and upper confidence 
interval values should be presented to one decimal place more than the raw/derived data (i.e. to the same 
number of decimal places as the mean). Minimum and maximum values will be reported with the same 
decimal places as the actual values. A maximum 3 decimal places will be displayed for all summary 
statistics.
For categorical variables, summaries will include counts of subjects or events and percentages (1 decimal), 
0% will not be presented. Percentages will be calculated using a denominator of all subjects in a specified 
population unless otherwise specified. The denominator will be specified in a footnote to the tables for
clarification if necessary. Percentages in the summary tables will be rounded and thus may not always add 
up to exactly 100 percent. The 95% CI of rate or rate difference will have 2 decimal places.
In the summary tables, p-values will be rounded to 4 decimal places if appropriate. If a p-value is greater 
than 0.9999, then “>0.9999” will be presented; if a p-value is less than 0.0001, then “<0.0001” will be 
presented.
All data collected during the study will be presented in listings by treatment group, study centre, subject 
identifier, and visit (where applicable), unless otherwise specified. 
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 will be presented in the format [ddMMMyyyy] and 
times in the format [hh:mm] in a 24-hour basis.
7.2
Subject Disposition and Data Sets Analysed
Subject disposition will be listed and summarised by treatment group and overall and the following subjects 
will be presented:
x
Number of subjects screened (overall);
x
Number of screen failures and reason for non-randomised subjects (overall)
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x
Number of subjects randomised;
x
Number of subjects randomised and not treated;
x
Number of subjects treated;
x
Number of subjects who completed Week12, Week 24 and study;
x
Number of subjects discontinued study, and reason for discontinuation;
x
Number of subjects included in each analysis set (Randomised, Safety, FAS, PP, Full PK Profile, 
Sparse PK Sampling, PD, PK/PD Relationships).
A summary of subject enrollment by centre will also be provided by treatment group and overall for the 
randomised subjects. 
A summary of subjects completed scheduled visits will be presented by treatment group and overall for the 
randomised subjects.
7.3
Protocol Deviations
Major protocol deviations affecting primary efficacy endpoint leading to exclusion from the PP set will be 
summarised by treatment group and overall for the randomised subjects.
Major protocol deviations affecting PK variables leading to exclusion from the Full PK Profile Analysis 
Set and/or Sparse PK Sampling Analysis Set will also be summarised by treatment group and overall for 
the safety set.
All protocol deviations will be listed for the randomised subject with flags indicating if deviations are major 
or minor PDs.
A separate listing for major protocol deviations will be displayed. Flags indicating deviations affecting 
efficacy endpoints and/or PK/PD variables will also be included in the listing.
7.4
Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be listed and summarised by treatment group and overall for 
these analysis sets: randomised, safety (if different from randomised), PP and FAS, including the below 
variables:
x
Age (years) is reported from CRF;
x
Race, Ethnicity; 
x
Weight (kg), height (cm), body mass index (kg/m2) (BMI) [calculated as (weight/height2) where 
weight is in kg and height is in m]; 
x
Gynaecological history:
-
Duration of endometriosis diagnosis (months) [calculated as (informed consent date – date of 
endometriosis diagnosis +1)/ 30.4375 and rounded to 1 decimal place];
-
Method of diagnosis
-
If having endometriosis surgery before; duration of endometriosis surgery (months)
[calculated as (informed consent date – date of endometriosis surgery +1)/ 30.4375 and 
rounded to 1 decimal place];
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-
Age at menarche, number of pregnancies, number of births
-
If having regular menses during the last six months
-
Number of days for shortest cycle and Number of days for longest cycle
Standard descriptive statistics will be presented for the continuous variables and the total counts and 
percentages of subjects will be presented for the categorical variables. No formal tests of statistical
significance will be performed on the demographic and baseline data.  
Other baseline measurements (such as E2, FSH and LH concentrations, VAS, lab test, vital signs, ECG, 
physical/pelvic examination, pelvic type B ultrasound scan) will be summarised by treatment group with 
the post-baseline measurements.
7.4.1
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 
number is the newest version used in Covance coding system at the time of analysis). All medical history 
will be listed and summarised by the number and percentage of subjects with any medical history for 
randomised set by system organ class (SOC) and preferred term (PT) for each treatment group and 
overall. 
7.4.2
Previous and Concomitant Medications
Prior medications for endometriosis and other medications received prior to or concomitantly with study 
treatment will be coded using the WHO Drug Dictionary (version number is the newest version used in 
Covance coding system at the time of analysis), Anatomical Therapeutic Chemical (ATC) Classification 
codes. 
Prior medications for endometriosis from eCRF will be summarised separately by the number and 
percentage of subjects with any medications for randomised set by anatomical level (ATC Level 1),
therapeutic level (ATC Level 2) and generic term for each treatment group and overall.
Prior medications are those taken prior to first study dose of IMP. Concomitant medications are those taken 
on or after the first dose of IMP.
Prior medications and concomitant medications will be summarised separately by the number and 
percentage of subjects with any medications for randomised set by anatomical level (ATC Level 1), 
therapeutic level (ATC Level 2) and generic term for each treatment group and overall.
The number and percentage of subjects taking add-back treatment during the study will be summarised 
separately by anatomical level (ATC Level 1), therapeutic level (ATC Level 2) and generic term for each 
treatment group and overall.
Prior medications for endometriosis will be separately listed. Prior and concomitant medications will be 
presented in the same listing with flags indicating prior or concomitant.
7.4.3
Previous and Concomitant Non-drug Therapies
Prior and concomitant non-drug therapies will be coded using MedDRA (version number is the newest 
version used in Covance coding system at the time of analysis). All prior and concomitant non-drug 
therapies will be listed and summarised by the number and percentage of subjects with any non-drug 
therapies for randomised set by system organ class (SOC) and preferred term (PT) for each treatment group 
and overall.
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Prior non-drug therapies are those taken prior to first study dose of IMP. Concomitant non-drug therapies 
are those taken on or after the first dose of IMP.
Prior non-drug therapies and concomitant non-drug therapies will be summarised separately by the number 
and percentage of subjects with any therapies for randomised set by therapy reason for each treatment group 
and overall.
Prior and concomitant non-drug therapies will be presented in the same listing with flags indicating prior 
or non-drug therapies.
7.4.4
Concomitant Surgical Procedures
Concomitant surgical procedures will be coded using the MedDRA (version number is the newest version 
used in Covance coding system at the time of analysis). All concomitant surgical procedures will be listed 
and summarised on the number and percentage of subjects with any surgical procedures for randomised set 
by surgical reason, SOC and PT for each treatment group and overall.  
Concomitant surgical procedures will be presented in the listing.
7.5
Study Drug Administration
Study drug administration will be summarised separately through Week 12 and Week 24 by treatment group 
and overall for safety subjects, including the below variables:
x
Number of injections during Week 12, Week 24
x
Total actual dose during Week 12, Week 24
x
Treatment compliance through Week 12, Week 24 and compliance groups (grouped as <80%, 80-
120%, >120%)
Standard descriptive statistics will be presented for the continuous variables and the total counts and 
percentages of subjects will be presented for the categorical variables. No formal tests of statistical 
significance will be performed on the study drug administration.  
Treatment compliance will be calculated as follows:
x
Treatment compliance through Week 12 in triptorelin pamoate PR 3-month group = 100% * actual 
dose administered before Week 12 / (total planned dose administered before Week 12);
x
Treatment compliance through Week 24 in triptorelin pamoate PR 3-month group = 100% * sum 
of actual dose administered through Week 24 / (total planned dose administered through Week 
24);
x
Treatment compliance through Week 12 in triptorelin acetate PR 1-month group = 100% * sum 
of actual dose administered before Week 12 / (total planned dose administered before Week 12).
x
Treatment compliance through Week 24 in triptorelin acetate PR 1-month group = 100% * sum 
of actual dose administered through Week 24 / (total planned dose administered through Week 
24).
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7.6
Efficacy 
7.6.1
Primary Efficacy Analysis 
The primary efficacy analysis is to compare the percentage of subjects castrated (E2≤184 pmol/L or 50 
pg/mL) at Week 12 in triptorelin pamoate PR 3-month and triptorelin acetate PR 1-month groups on the PP 
subjects using as-treated assignments. 
The null hypothesis for the primary efficacy analysis is that triptorelin pamoate PR 3-month is inferior to 
triptorelin acetate PR 1-month. The alternative hypothesis is that triptorelin pamoate PR 3-month is
noninferior to triptorelin acetate PR 1-month, where the pre-specified non-inferiority margin is -10%: 
H0: P3-month – P1-month ≤ -10% 
Ha: P3-month – P1-month > -10% 
Where P3-month denotes the percentage of subjects (E2≤184 pmol/L or 50 pg/mL) for triptorelin pamoate PR 
3-month at Week 12, P1-month denotes the percentage of subjects (E2≤184 pmol/L or 50 pg/mL) for triptorelin
acetate PR 1-month at Week 12.
The number and percentage of subjects castrated (E2≤184 pmol/L or 50 pg/mL), and its 95% asymptotic 
CI will be summarised for each treatment group at Week 12. The difference in percentage of subjects 
castrated (triptorelin pamoate PR 3-month – triptorelin acetate PR 1-month) and the 2-sided 95% CI of the 
difference will also be presented and calculated using the Miettinen and Nurminen method, stratified by 
randomisation stratification factors (endometriotic surgical history and the severity of endometriosis-
associated pelvic pain at baseline) with sample size weighting 5. In a case where the stratification factor 
recorded in the eCRF and IWRS are inconsistent, the eCRF data will be retained included as the 
randomization stratification factors as the covariates. If the lower limit of the 95% CI for the difference 
is >-10%, triptorelin pamoate PR 3-month non-inferiority to triptorelin acetate PR 1-month will be 
confirmed. 
The sensitivity analysis will be performed on the same analyses adding centre in the above Miettinen and 
Nurminen method. 
The difference in percentage and its 2-sided 95% CI are also calculated using the Miettinen and Nurminen 
method without stratification factors for support analyses. 
The primary efficacy analyses will be repeated for the FAS subjects using as-randomised assignments. 
7.6.2
Secondary Efficacy Analysis 
The analyses of secondary efficacy endpoints (see Section 3.2) will be performed in the PP subjects and the
FAS subjects using as-randomised assignments. 
Percentage of Subjects Castrated (E2≤184 pmol/L or 50 pg/mL) at Weeks 4 and 8 and Percentage of 
Subjects Castrated (E2≤110 pmol/L or 30 pg/mL) at Weeks 4, 8 and 12:
The number and percentage of subjects castrated (according to each criterion) will be presented by treatment 
group for each visit. The difference in percentage between the treatment groups and its 2-sided 95% CI will 
be presented and calculated using the same method as primary efficacy analysis. 
Change in Endometriosis-associated Pelvic Pain (by 10 cm VAS) at Weeks 4, 8 and 12:
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Endometriosis-associated pelvic pain measured by 10 cm VAS and change from baseline, will be 
summarised by treatment groups at each time point, using summary statistics (n, mean, median, SD and
minimum and maximum values) and the 95% CI for the true difference in mean VAS score and VAS change 
from baseline scores will be presented.
The 95% CI for the difference in mean and change from baseline VAS score are calculated using a linear 
model for repeated measurements adjusting for treatment group and its interaction with visit, and 
randomisation stratification factors (endometriotic surgical history and the severity of endometriosis-
associated pelvic pain at baseline) and its interaction with treatment group
In a case where the stratification factor recorded in the eCRF and IWRS are inconsistent, the eCRF 
data will be retained. This will be applied to all analyses that include the randomization stratification factors 
as the covariates. The SAS code for this model to be used is shown below:
 
 
 
 
 
 
 
; 
In case of model convergence issues, this will be reported in the study report and additional covariance 
structures will be investigated with the following order: heterogeneous compound symmetry (type=csh), 
heterogeneous toeplitz (type=toeph), heterogeneous autoregressive (1) (type=arh(1)), and variance 
components (type=vc).
Serum E2, FSH and LH Concentrations at Weeks 4, 8 and 12:
Serum E2, FSH and LH concentrations and change from baseline will be summarised at each time point, 
using descriptive statistics (n, mean, median, SD and minimum and maximum values) and the 95% CI for 
the difference between treatment groups in mean concentration values and mean change from baseline 
values will be presented for each parameter.
The 95% CI for the difference in mean and change from baseline values are calculated using a linear model 
for repeated measurements adjusting for baseline value and its interaction with visit, treatment group and 
its interaction with visit, and randomisation stratification factors (endometriotic surgical history and the
severity of endometriosis-associated pelvic pain at baseline) and its interaction with treatment group. In a 
case where the stratification factor recorded in the eCRF and IWRS are inconsistent, the eCRF data will be 
retained. Baseline and its interaction with visit will be added in the above SAS code.
Time to Menses Recovery:
Time to menses recovery will be defined as the time (in days) between date of last dose of study drug and 
date of first day the subject observed menstrual bleeding of the next menstrual period. Any subjects 
withdrawing from the study without menstrual bleeding will be censored in the analysis at the date of 
withdrawal, and any subjects without menstrual bleeding prior to the end of study visit will be censored in 
this analysis at the date of the last known menses status study visit. Any subjects who doesn’t stop menses 
during the treatment duration (V2 till V8) are excluded this analysis. “Stop menses” is considered as at least 
one answer “No” for the question “Is the menses recovered since last visit” in CRF page “Status of Menses” 
at least 2 consecutive menses stop during treatment duration (V2 till V8).
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The number and percentage of subjects with menses recovery and censored subjects and their censor reasons 
will be summarised. The median time, 25th and 75th quartile times and their 95% CIs will be estimated using 
the Kaplan-Meier method; Kaplan-Meier curves will be plotted.
7.6.3
Subgroup Analysis
The primary efficacy endpoints and secondary efficacy endpoints (except time to menses recovery) will be 
analysed by subgroups of randomisation stratification factors:
x
Endometriotic surgical history (previous surgery, no previous surgery) 
x
Severity of endometriosis-associated pelvic pain at baseline (VAS>3 cm, VAS≤3cm).
7.6.4
Exploratory Analysis
The analyses of exploratory efficacy endpoints (see Section 3.3) will be performed on the FAS subjects 
using as-randomised assignments.
Percentage of subjects castrated 1) E2≤184 pmol/L (50 pg/mL) 2) E2≤110 pmol/L (30 pg/mL)) at Week 
24:
The number and percentage of subjects castrated (according to each criterion) will be presented by treatment 
group at Week 24. The difference in percentage between the treatment groups and its 2-sided 95% CI will 
be presented and calculated using the same method as primary efficacy analysis.
Change in endometriosis-associated pelvic pain (by 10cm VAS) at Weeks 16, 20 and 24 and the end of 
study visit compared to baseline:
Endometriosis-associated pelvic pain measured by 10 cm VAS and change from baseline, will be 
summarised by treatment groups and overall at each time point, using summary statistics (n, mean, median, 
SD and minimum and maximum values) and the 95% CI for the true difference in mean VAS score and 
VAS change from baseline scores will be presented.
The 95% CI for difference in mean and change from baseline values are calculated using MMRM, same as 
those used in secondary analyses of VAS.
The mean and change from baseline of VAS at each time point are also analysed by subgroups of baseline 
VAS (VAS>3 cm, VAS≤3cm).
Serum E2, FSH and LH Concentrations at Week 24:
Serum E2, FSH and LH concentrations and change from baseline will be summarised at Week 24, using 
descriptive statistics (n, mean, median, SD and minimum and maximum values) and the 95% CI for the 
difference between treatment groups in mean concentration values and mean change from baseline values 
will be presented for each parameter.
The 95% CI for the difference in mean and change from baseline values are calculated using MMRM, same 
as those used in secondary analyses of VAS.
The PK/PD relationship will be explored (PD markers being E2, FSH and LH).
The data for subject individual plasma triptorelin concentration and PD markers in the each treatment 
groups will be combined to explore the relationships between PK concentrations and PD markers on the 
PK/PD relationships analysis set. PK/PD modelling will be described in a separate data analysis plan and 
reported in a standalone report.
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7.7
Safety
All safety data will be included in the data listings. Analyses and summary tables will be based on the Safety 
Set. Safety endpoints will be analysed using descriptive statistics.
7.7.1
Adverse Events
A treatment-emergent adverse event (TEAE) is defined as any AE that occurs or worsens on or after the 
first dose of IMP, through 112 days (16 weeks) after last injection for triptorelin pamoate PR 3-month 
groups or through 56 days (8 weeks) after injection for triptorelin acetate PR 1-month group. Non-TEAEs
and TEAEs will be separately summarised in tables and all AEs will be presented in the listing with flag of 
TEAE status.
All adverse events (AEs) recorded on the eCRF will be coded to SOC and PT using the MedDRA dictionary 
(version number is the newest version used in Covance coding system at the time of analysis). A subject 
will be counted at most once within a SOC and PT in summary tables. 
In the summary table of TEAEs, the numbers and percentages of subjects and events will be tabulated and 
presented by treatment groups and overall for the following categories: 
x
Any TEAEs
x
TEAEs with maximum intensity (Severe, Moderate, Mild)
x
Serious TEAEs 
x
Drug-related TEAEs
x
Drug-related serious TEAEs
x
TEAEs leading to drug withdrawal
x
TEAEs leading to drug interruption
x
Serious TEAEs leading to drug withdrawal
x
Serious TEAEs leading to drug interruption
x
TEAEs leading to death
The numbers and percentages of subjects and events will be also be separately summarised by SOC and PT 
(sorted alphabetically) for each treatment group and overall as the above AE categories. The TEAEs with 
intensity of Severe will be separately summarised by SOC and PT (sorted alphabetically) for each treatment 
group and overall. The TEAEs and drug-related TEAEs will be also separately summarised by maximum 
intensity, SOC and PT (sorted alphabetically) for each treatment group and overall.
TEAEs or drug-related TEAEs with PTs observed ≥5% or ≥10% of subjects in any one of the treatment 
groups will be separately summarised by SOC and PTs.
In the event of multiple events being reported by the same subject, the maximum intensity (severe, missing, 
moderate, mild) and the most serious causality (related, not related) will be chosen. If severity is missing 
for one event and the subject had no intensity of severe in the same category events, “missing” row should 
be added after severe in the summary tables with maximum intensity. 
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The following AEs for each subject will be separately listed, including SOC, PT, and the original (verbatim) 
term reported by Investigator:
x
All AEs
x
Serious AEs 
x
Drug-related AEs
x
AEs leading to drug withdrawal
x
Deaths
7.7.2
Laboratory Evaluations
The central laboratory test results will be collected at screening (Visit 1), Week 12 (Visit 5) and Week 24 
(Visit 8), including the following parameters: 
x
Haematology: red blood cell (RBC) count, haemoglobin, haematocrit, mean corpuscular volume 
(MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin 
concentration (MCHC), white blood cell (WBC) count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils) and platelet count;
x
Biochemistry: urea, creatinine, total bilirubin, conjugated bilirubin, chloride, bicarbonate, sodium, 
potassium, calcium, inorganic phosphate, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, gamma glutamyl transferase,  albumin, 
total protein, total cholesterol, triglycerides, fasting glucose;
x
Urinalysis: pH, protein, ketones, glucose, bilirubin, blood, urobilinogen and specific gravity;
Standard international units will be used for summarising quantitative laboratory parameters. Out of 
reference range values will be flagged as high (H) or low (L) in the listings. 
The quantitative laboratory data will be summarised using standard descriptive statistics on actual values 
and change from baseline at each scheduled visit and final visit for the Safety subjects.  
Shift tables presenting movement in and out of reference range (low, normal, high) from baseline to each 
scheduled post-baseline visit and final visit will be presented by each treatment group and overall.  Shift 
tables presenting movement of clinical evaluation (normal, abnormal not clinically significant, abnormal 
clinically significant) from baseline to each scheduled post-baseline visit and final visit will be presented 
by each treatment group and overall as well.  
Subjects who became pregnant during the study will be summarised by treatment groups.
Potentially Clinically Significant Abnormalities (PCSA) for Laboratory Tests
The PCSA criteria of some selected laboratory tests in this study are listed in the below table. The number 
and percentage of subjects with PCSA for each below parameter will be summarised by treatment group 
and overall at each scheduled visit, final visit and any post-baseline visit. The number and percentage of 
subjects with abnormal PCSA values (PCSA-low and PCSA-high) at any post-baseline will be summarised 
by different baseline values (normal, abnormal) and parameters.
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Table 2
PCSA Criteria for Laboratory Tests
Lab Parameter 
PCSA – Low Criteria 
PCSA– High Criteria 
Unit 
HGB 
≤ 80 
 
g/L 
RBC 
< 2.8 
 
TI/L 
HCT 
< 0.32 and 0.03 decrease from 
baseline 
 
% 
WBC 
≤ 2.0  
≥ 29 
GI/L 
Neutrophil 
< 1 
> 13 
GI/L 
Lymphocyte 
< 0.3 
> 11.0 
GI/L 
Monocytes 
  
> 2.3 
GI/L 
Eosinophil 
  
> 1  
GI/L 
Basophils 
  
> 0.8 
GI/L 
Platelets 
< 50 
≥ 700 
GI/L 
Total Bili 
  
> 3 x ULN 
μmol/L 
Dir Bili 
  
> 3 x ULN 
μmol/L 
Alkaline Phosphatase   
≥ 3 x ULN 
U/L 
ALT(SGPT) 
  
≥ 3 x ULN 
U/L 
AST(SGOT) 
  
≥ 3 x ULN 
U/L 
GGT 
  
≥ 3 x ULN 
U/L 
Urea Nitrogen 
  
> 10 
mmol/L 
Glucose, Fasting 
< 3.9 
≥ 7.1 
mmol/L 
Triglycerides 
 
 
 
 
>1.4 (18-20 years) 
>1.63 (21-30 years) 
> 1.99 (31-40 years) 
>2.42 (41-50 years) 
mmol/L 
mmol/l 
mmol/l 
mmol/l 
Cholesterol 
 
 
>5.48 (18-20 years) 
>5.64 (21-30 years) 
> 6.21 (31-40 years) 
->6.85 (41-50 years) 
mmol/L 
mmol/l 
mmol/l 
mmol/l 
Creatinine 
  
> 154 
μmol/L 
Calcium 
< 1.75 
> 3.12 
mmol/L 
Phosphorus 
< 0.65 
>1.8 
mmol/L 
Total Protein 
< 40 
  
g/L 
Alb BCG 
< 25 
  
g/L 
Sodium 
< 125 
> 147 
mmol/L 
Potassium 
< 3.0 
> 6 
mmol/L 
Chloride 
≤ 90 
≥ 115 
mmol/L 
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All laboratory data collected during the study will be presented in subject listing with flags indicating out 
of reference range (low, high), clinical evaluation (abnormal not clinically significant, abnormal clinically 
significant). If a subject has at least one lab measurement meeting PCSA criteria, all data of that lab 
parameter will be presented in a separate listing with flag indicating PCSA-low or PCSA high.
7.7.3
Electrocardiograms
The 12-lead ECG will be measured at screening (Visit 1), Week 12 (Visit 5) and Week 24 (Visit 8) including 
heart rate (beats/min), PR interval (msec), QRS interval (msec), QT interval (msec), QTc interval (msec) 
and investigator interpretation of ECG. Fridericia corrected QT (QTcF) interval (msec) will be calculated 
as (QT/(60/HR)1/3).
The quantitative ECG data will be summarised using standard descriptive statistics on actual values and 
change from baseline at each scheduled visit and final visit for the Safety subjects.  
Shift tables of investigator assessment of ECG (normal, abnormal not clinically significant, abnormal 
clinically significant) from baseline to each scheduled post-baseline visit and final visit will be presented 
by treatment group and overall. 
Potentially Clinically Significant Abnormalities (PCSA) for ECG
Any case with none sinus rhythm is considered to be PCSA. The PCSA criteria in subjects with sinus 
rhythm are listed in the table below. The number and percentage of subjects with PCSA for each below 
parameter will be summarised by treatment group and overall at each scheduled visit, final visit and any 
post-baseline visit. The number and percentage of subjects with abnormal PCSA values (PCSA-low and 
PCSA-high) at any post-baseline will be summarised by different baseline values (normal, abnormal) and 
parameters
Table 3
PCSA Criteria for ECG 
ECG test Name
PCSA –
Sinus Rhythm 
(Y/N)*
PCSA –
Low 
Criteria
PCSA –
High 
Criteria
PCSA –
Chang 
from 
baseline
Normal range
Unit
Heart Rate (collected 
from CRF)
Y
< 50
≥ 120
NA
60-100
bpm
PR Interval (collected 
from CRF)
Y
< 120
≥ 240
NA
120-200
ms
QRS Interval 
(collected from CRF)
Y
NA
≥ 120
NA
60-100
ms
QT interval (collected 
from CRF)
Y
NA
NA
NA
320-440
ms
QT Interval, Corrected 
(collected from CRF)
Y
≤300
≥ 470
≥ + 45
>300 and <440
ms
QTcF (calculated by 
programming)
Y
≤300
≥ 470
≥ + 45
>300 and <440 
ms
*Y/N= yes/no; Y = sinus rhythm. 
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All ECG data collected during the study will be presented in subject listings. If a subject has at least one 
ECG measurement meeting PCSA criteria, all her data for that ECG parameter will be presented in a 
separate listing with flag indicating PCSA-low or PCSA high.
7.7.4
Vital Signs
The vital signs will be measured at each visit during treatment and the end of study visit, including systolic 
blood pressure (mmHg), diastolic blood pressure (mmHg) and heart rate (beats/min).
Descriptive statistics on actual values and change from baseline will be summarised by treatment group and 
overall at each scheduled visit and the final visit for the Safety subjects.
Potentially Clinically Significant Abnormalities (PCSA) for Vital Signs
The PCSA criteria for selected vital signs in this study are listed in the table below. The number and 
percentage of subjects with PCSA for each below parameter will be summarised by treatment group and 
overall at each scheduled visit, final visit and any post-baseline visit. The number and percentage of subjects 
with abnormal PCSA values (PCSA-low and PCSA-high) at any post-baseline will be summarised by 
different baseline values (normal, abnormal) and parameters.
Table 4
PCSA Criteria for Vital signs 
Parameter
PCSA – Low Criteria
PCSA – High Criteria
Unit
Heart rate
≤50
≥120
bpm
Systolic blood pressure
≤80
≥160
mmHg
Diastolic blood pressure
≤50
≥100
mmHg
The normal ranges for vital signs are defined as below:
x
Heart rate: 60-100 bpm
x
Systolic blood pressure: 90-139 mmHg
x
Diastolic blood pressure: 60-89mmHg
Note: the number is inclusive.
All vital signs data collected during the study will be presented in subject listings. If a subject has at least 
one vital sign measurement meeting PCSA criteria, all her data for that vital sign parameter will be presented 
in a separate listing with flag indicating PCSA-low or PCSA high.
7.7.5
Physical/Pelvic Examination
The physical/pelvic examination will be performed at screening (Visit 1), Week 12 (Visit 5) and Week 24 
(Visit 8). 
Shift tables of test results (normal, abnormal not clinically significant, abnormal clinically significant) from 
baseline to each scheduled post-baseline visit and final visit will be presented by treatment group and 
overall. 
All physical/pelvic examination data collected during the study will be presented in subject listings.
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7.7.6
Pelvic type B ultrasound
The pelvic type B ultrasound scan will be performed at screening (Visit 1), Week 12 (Visit 5, optional based 
on investigator judgment) and Week 24 (Visit 8).
Shift tables of test results (normal, abnormal not clinically significant, abnormal clinically significant) from 
baseline to each scheduled post-baseline visit and final visit will be presented by each treatment group and 
overall.  
All pelvic type B ultrasound scan data collected during the study will be presented in subject listings.
7.7.7
Hormones
Serum E2, FSH and LH concentrations at Week 40 will be listed separately for those subjects with menses 
not recovered before Week 40.
7.8
Pharmacokinetics
The individual plasma triptorelin concentration is measured in all subjects receiving study drug at Day 1 
(Visit 2), Week 4 (Visit3), Week 8 (Visit 4), Week 12 (Visit 5) and Week 24 (Visit 8). Additional sampling 
is performed for subjects within the PK/PD subgroup.
-
The individual plasma triptorelin concentration will be summarised using descriptive statistics (n, 
mean, SD, %CV, geometric mean, geometric CV, median, minimum and maximum) by treatment 
group at each scheduled visit for the Sparse PK Sampling set.
-
The individual plasma triptorelin concentrations for the Full PK Profile Analysis set will be 
summarised using descriptive statistics (n, mean, SD, %CV, geometric mean, geometric CV, 
median, minimum and maximum) by time-point (described as hours/days post-dose), for each 
treatment group, following each administration.
-
To compute descriptive statistics, all BLQ values must be replaced by missing/zero in the data set 
according to the rules set in section 6.2.1. BLQ values substituted by 0 are included in the 
calculation of descriptive statistics whereas missing values are ignored. The descriptive statistics 
should be displayed by visit/time point, and by treatment group only if at least 2/3 (2 out of every 
3 values) of the data are available and above the limit of quantification. Otherwise, only minimum 
and maximum are reported. Individual and mean plasma concentration time profiles, as well as 
spaghetti plots, on the Full PK Profile Analysis Set will be generated separately based on a 
dedicated PK analysis plan.
7.9
Interim Analysis
No interim analyses will be performed.
8
CHANGES IN PLANNED ANALYSES
Not applicable.
9
REFERENCES
1
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf
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2
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports Questions & Answers,
2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs
_R1_Step4.pdf
3
Phillips A and Haudiquet V. ICH E9 guideline “Statistical principles for clinical trials”: a case 
study. Statistics in Medicine 2003; 22:1-11
4
Brown D J. ICH E9 guideline “Statistical principles for clinical trials”: a case study. Response 
to A. Phillips and V. Haudiquet. Statistics in Medicine 2003; 22:13-17
5
Miettinen O and Nurminen M. Comparative Analysis of Two Rates. Statistics in Medicine, VOL.4, 
213-226 91985)
6
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York: Springer 
Series in Statistics 2000; Chapter 8, Sect 8.2.6-8.5..


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10 APPENDICES
Appendix I - Schedule of Events
Table 5
Study Procedures and Assessments (All Subjects)
Screening 
period
Treatment period
Follow up period [a]
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
End of study/early 
withdrawal visit
Procedures and 
assessments
Screening 
up to -5
weeks
Baseline 
(1st to 5th
day of 
menses) Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 28 Week 32 Week 36
within 15 days after 
menses recovery or 
Week 40[b] 
Visit window (days)
-35 to -1
Day 1
Day 29 
±3
Day 57
±3
Day 85
±3
Day 113
±3
Day 141
±3
Day 169
±3
Day 197
±3
Day 225
±3
Day 253
±3
Day 281
±3
Informed consent
X
Demography
X
Significant medical or 
surgical history
X
Prior medications for 
endometriosis
X
Inclusion and exclusion 
criteria
X
X
E2, FSH and LH
X[c]
X[c]
X[c]
X[c]
X
X[d]
VAS
X
X
X
X
X
X
X
X
Physical examination[e]
X
X
X
Pelvic examination
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X


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Blood Biochemistry[f]
X
X
X
Haematology[f]
X
X
X
Urinalysis[f]
X
X
X
Urine pregnancy test
X
X
12-lead ECG
X
X
X
Pelvic type B ultrasound 
scan
X[g]
X[h]
X
Sparse PK assessments
X[c]
X[c]
X[c]
X[c]
X
Randomization
X
Study drug injection (3-
month formulation)
X[i]
X
Study drug injection (1-
month formulation)
X[i]
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medication/therapies
X
X
X
X
X[j]
X[j]
X[j]
X
X
X
X
X
Status of menses
X
X
X
X
X
X
X
X
X
X
X
X
AE=adverse event; E2=oestradiol; ECG=electrocardiogram; FSH=follicle stimulation hormone; LH=luteinising hormone; PK=pharmacokinetic; VAS=visual analogue scale
a
during the follow up period, the first visit after menses recovery, or Week 40 (whichever is earlier) will be considered the final visit (end of study). The end of study visit 
should be a clinic visit. Follow up visits prior to the end of study visit will be telephone contact visits
b
or upon early withdrawal from the study
c
samples taken predose, where applicable
d
only if subject's menses do not recover before Week 40
e
subject height and weight will be assessed at screening only
f
samples for clinical laboratory testing will be taken after at least 8 hours fasting
g
a result within 1 month prior to the screening visit will be acceptable
h
optional, based on the subject's disease condition, as judged by the investigator
i
study treatment must be initiated during the subject's follicular phase (first to fifth day of menses period)
j
from Week 12, after the primary endpoint evaluation, "add back" treatment will be permitted if needed according to the investigator's judgment. "Add back" treatment 
will be recommended as, but not limited to, tibolone 2.5 mg once daily


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Table 6
Full PK/PD Assessments day 1 to Week 12 (PK/PD Subgroup Subjects)
Assessment[a]
Treatment period
Day 1
Week 1
(hours post Day 1 dosing)
Week 2
Week 3
Week 4
Week 6
Week 8
Week 10
Week 12
Assessment time (study 
day/hours postdose)[b]
Day 1
24
48
168
Day 15
Day 22
Day 29
Day 43
Day 57
Day 71
Day 85
PK (3M)
X[c]
X
X
X
X
X
X
X
X
X[c]
PK (1M)
X[c]
X
X
X
X
X
X[d]
X[d]
X
X[d]
PD (E2, FSH and LH)
X
X
X
AEs
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medication/therapies
X
X
X
X
X
X
X
X
X
1M=triptorelin acetate PR 1-month; 3M=triptorelin pamoate PR 3-month; AE=adverse event; E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; 
PD=pharmacodynamics; PK=pharmacokinetics.
a
assessments to be conducted with samples from the subjects in the full PK/PD subgroup (comprising up to 16 subjects receiving 3M and up to 16 subjects receiving 1M; 
to be enrolled at selected sites) only
b
time windows for full PK/PD assessments will be defined in the Study Manual
c
samples taken predose and 0.5, 1, 2, 4, 8 and 12 hours postdose
d
samples taken predose


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Table 7
Full PK/PD Assessments Week 13 to End of Study (PK/PD Subgroup Subjects)
Assessment[a]
Treatment period
Week 12
(hours post Week 
12 dosing)
Week 14 Week 15 Week 16 Week 18 Week 20 Week 24 Week 28 Week 32 Week 36
End of study/ 
early withdrawal
Assessment time (study 
day/hours postdose)[b]
24
48
168
Day 99
Day 106 Day 113
Day 127
Day 141 Day 169 Day 197 Day 225 Day 253
See Table 5
PK (3M)
X
X
X
X
X
X
X
X
X
X
X
X
PK (1M)
X
X
X
X
PD (E2, FSH and LH)
X
AEs
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medication/therapies
X
X
X
X
X
X
X
X
X
X
X
1M=triptorelin acetate PR 1-month; 3M=triptorelin pamoate PR 3-month; AE=adverse event; E2=oestradiol; FSH=follicle stimulating hormone; LH=luteinising hormone; 
PD=pharmacodynamics; PK=pharmacokinetics.
a
assessments to be conducted with samples from the subjects in the full PK/PD subgroup (comprising up to 16 subjects receiving 3M and up to 16 subjects receiving 1M; 
to be enrolled at selected sites) only
b
time windows for full PK/PD assessments will be defined in the Study Manual