Clinical trial NCT02427958
Conditions: Central Precocious Puberty
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2015-08-07; Completion date: 2018-11-23
Enrollment: 307 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess long-term safety and efficacy of leuprorelin in the treatment of Central Precocious Puberty (CPP).

Detailed description:
The drug in this study is called leuprorelin. It is administered as a 1 month subcutaneous depot injection. Leuprorelin is used to treat children who have CPP. This study will look at whether leuprorelin can stop early puberty in pre-pubertal children.

The study will enroll approximately 300 participants. Participants with body weight \>=20 kg will receive the recommended dose of leuprorelin 3.75 mg subcutaneous injection every 4 weeks for 96 weeks. Participants with body weight \<20 kg will receive recommended dose of 1.88 mg subcutaneous injection every 4 weeks for 96 weeks.

This trial will be conducted in China. The overall time to participate in this study is 104 weeks. Participants will make 11 visits to the clinic, and will be followed-up by the physician on a long-term basis until stable puberty is reached.

Arms: arm 1: Participants with body weight greater than or equal to (\>=) 20 kilogram (kg) will receive the recommended dose of leuprorelin 3.75 milligram (mg), injection, subcutaneously, once every 4 weeks for 96 weeks. Participants with body weight less than (\<) 20 kg will receive leuprorelin 1.88 mg, injection, subcutaneously, once every 4 weeks for 96 weeks.
Interventions: intervention 1: Leuprorelin
Intervention descriptions: intervention 1: Suspension for injection.

Protocol documents:
Prot_001.pdf: 


•
Title: An Open label, Multicenter Study to Assess the Safety and Efficacy of Leuprorelin in the 
Treatment of Central Precocious Puberty 
NCT Number: NCT02427958
Protocol Approve Date: 16 December2015
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly 
from view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, 
or to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE 
PROTOCOL 
An Open label, Multicenter Study to Assess the Safety and Efficacy of Leuprorelin in the 
Treatment of Central Precocious Puberty 
Leuprorelin-4001, Leuprorelin in the Treatment of Central Precocious Puberty 
Sponsor: 
Takeda Development Center Asia, Pte. Ltd. 
21 Biopolis Road 
Nucleos North Tower, Level 4 
Singapore 138567 
Study Number: 
Leuprorelin-4001 
IND Number: 
NA  
EudraCT Number: 
NA 
Compound: 
Leuprorelin (Enantone) 
Date: 
16 December2015 
Amendment Number: 1 
Amendment History: 
Date
Amendment Number
Amendment Type
Region
01 November 2014 
16 December 2015 
Initial Protocol 
Amendment # 1 
Not applicable 
Substantial  
China 
China 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 


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Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 4 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, package insert and any other product 
information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also to protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol. 
 
 
 
Signature of Investigator 
Date 
 
 
Investigator Name (print or type) 
 
Investigator’s Title 
 
Location of Facility (City, State/Province) 
 
Location of Facility (Country) 
 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 5 of 73 
Protocol Amendment #1 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY.........................................................................................................10 
3.0 
STUDY REFERENCE INFORMATION .........................................................................14 
3.1 
Study-Related Responsibilities ....................................................................................14 
3.2 
Principal Investigator/Coordinating Investigator .........................................................14 
3.3 
List of Abbreviations ...................................................................................................15 
3.4 
Corporate Identification ...............................................................................................16 
4.0 
INTRODUCTION .............................................................................................................17 
4.1 
Background ..................................................................................................................17 
4.2 
Rationale for the Proposed Study ................................................................................18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................19 
5.1 
Objectives ....................................................................................................................19 
5.1.1  Primary Objective ..................................................................................................19 
5.1.2  Secondary Objective ..............................................................................................19 
5.2 
Endpoints .....................................................................................................................19 
5.2.1  Primary Endpoint ...................................................................................................19 
5.2.2  Secondary Endpoint ...............................................................................................19 
5.2.3  Additional Endpoints .............................................................................................19 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................20 
6.1 
Study Design ................................................................................................................20 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................21 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................22 
6.3.1  Criteria for Premature Termination or Suspension of the Study ...........................22 
6.3.2  Criteria for Premature Termination or Suspension of Investigational Sites ..........22 
6.3.3  Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................22 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............23 
7.1 
Inclusion Criteria .........................................................................................................23 
7.2 
Exclusion Criteria ........................................................................................................24 
7.3 
Excluded Medication, Procedures and Treatments ......................................................25 
7.4 
Diet, Fluid, Activity Control ........................................................................................25 


Leuprorelin 
 
Study No. Leuprorelin-4001 
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Protocol Amendment #1 
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CONFIDENTIAL 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................25 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................26 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................27 
8.1 
Study Medication and Materials ..................................................................................27 
8.1.1  Dosage Form, Manufacturing, Packaging, and Labeling ......................................27 
8.1.1.1 Investigational drug .........................................................................................27 
8.1.1.2 Sponsor-Supplied Drug ....................................................................................27 
8.1.2  Storage ...................................................................................................................27 
8.1.3  Dose and Regimen .................................................................................................27 
8.1.4  Overdose ................................................................................................................28 
8.2 
Investigational drug Dispensing Procedures ................................................................28 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................28 
9.0 
STUDY PLAN ...................................................................................................................30 
9.1 
Study Procedures .........................................................................................................30 
9.1.1  Informed Consent Procedure .................................................................................30 
9.1.2  Demographics, Medical History, and Medication History Procedure ...................30 
9.1.3  Physical Examination Procedure ...........................................................................30 
9.1.4  Weight and Height .................................................................................................30 
9.1.5  Vital Sign Procedure ..............................................................................................31 
9.1.6  Documentation of Concomitant Medications ........................................................31 
9.1.7  Documentation of Concurrent Medical Conditions ...............................................31 
9.1.8  Procedures for Clinical Laboratory Samples .........................................................31 
9.1.9  Contraception and Pregnancy Avoidance Procedure .............................................33 
9.1.10  Pregnancy ...............................................................................................................34 
9.1.11  ECG Procedure ......................................................................................................34 
9.1.12  Bone Age ...............................................................................................................34 
9.1.13  Bone Mineral Density ............................................................................................35 
9.1.14  Cranial MRI ...........................................................................................................35 
9.1.15  Pelvic/Testicular Ultrasonography .........................................................................35 
9.1.16  Documentation of Screen Failure ..........................................................................35 
9.1.17  Documentation of Study Entrance .........................................................................36 
9.2 
Monitoring Subject Treatment Compliance .................................................................36 
9.3 
Schedule of Observations and Procedures ...................................................................36 
9.3.1  Screening - Visit 1 .................................................................................................36 
9.3.2  Study Entrance - Visit 2 (Week 0, first dose) ........................................................37 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 7 of 73 
Protocol Amendment #1 
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CONFIDENTIAL 
9.3.3  Treatment Phase - Visit 3 (Week 12) .....................................................................38 
9.3.4  Treatment Phase - Visit 4 (Week 24) .....................................................................38 
9.3.5  Treatment Phase - Visit 5 (Week 36) .....................................................................39 
9.3.6  Treatment Phase - Visit 6 (Week 48) .....................................................................39 
9.3.7  Treatment Phase - Visit 7 (Week 60) .....................................................................40 
9.3.8  Treatment Phase - Visit 8 (Week 72) .....................................................................40 
9.3.9  Treatment Phase - Visit 9 (Week 84) .....................................................................41 
9.3.10  Treatment Phase - Visit 10 (Week 96, last dose) ...................................................41 
9.3.11  Final Safety Visit or Early Termination - Visit 11 (Week 100) ............................42 
9.3.12  Observational Follow-up .......................................................................................43 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................45 
10.1 
Definitions....................................................................................................................45 
10.1.1  PTEs .......................................................................................................................45 
10.1.2  AEs .........................................................................................................................45 
10.1.3  Additional Points to Consider for PTEs and AEs ..................................................45 
10.1.4  SAEs ......................................................................................................................47 
10.1.5  Severity of PTEs and AEs......................................................................................48 
10.1.6  Causality of AEs ....................................................................................................48 
10.1.7  Relationship to Study Procedures ..........................................................................49 
10.1.8  Start Date ...............................................................................................................49 
10.1.9  Stop Date ................................................................................................................49 
10.1.10 
Frequency .........................................................................................................49 
10.1.11 
Action Concerning Study Medication .............................................................49 
10.1.12 
Outcome ...........................................................................................................49 
10.2 
Procedures ....................................................................................................................50 
10.2.1  Collection and Reporting of AEs ...........................................................................50 
10.2.1.1 
PTE and AE Collection Period ..................................................................50 
10.2.1.2 
PTE and AE Reporting ..............................................................................50 
10.2.2  Collection and Reporting of SAEs .........................................................................51 
10.2.3  Reporting of Abnormal Liver Function Tests ........................................................52 
10.3 
Follow-up of SAEs ......................................................................................................52 
10.3.1  Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....52 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................54 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................55 
12.1 
Electronic CRFs.............................................................................................................55 


Leuprorelin 
 
Study No. Leuprorelin-4001 
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Protocol Amendment #1 
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CONFIDENTIAL 
12.2 
Record Retention .........................................................................................................55 
13.0 
STATISTICAL METHODS ..............................................................................................57 
13.1 
Statistical and Analytical Plans ....................................................................................57 
13.1.1  Analysis Sets ..........................................................................................................57 
13.1.2  Analysis of Demographics and Other Baseline Characteristics ............................57 
13.1.3  Efficacy Analysis ...................................................................................................57 
13.1.4  Safety Analysis ......................................................................................................58 
13.1.4.1 
Adverse Events ..........................................................................................58 
13.1.4.2 
Safety Laboratory Evaluation ....................................................................58 
13.1.4.3 
Vital Signs ..................................................................................................58 
13.1.4.4 
Height, Weight and BMI ............................................................................58 
13.1.4.5 
ECG............................................................................................................58 
13.1.5  Other Analysis .......................................................................................................59 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................59 
13.3 
Determination of Sample Size .....................................................................................59 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................60 
14.1 
Study-Site Monitoring Visits .......................................................................................60 
14.2 
Protocol Deviations ......................................................................................................60 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................60 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................61 
15.1 
IRB and/or IEC Approval ............................................................................................61 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................62 
15.3 
Subject Confidentiality ................................................................................................63 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................63 
15.4.1  Publication and Disclosure ....................................................................................63 
15.4.2  Clinical Trial Registration ......................................................................................64 
15.4.3  Clinical Trial Results Disclosure ...........................................................................64 
15.5 
Insurance and Compensation for Injury .......................................................................64 
16.0 
REFERENCES ..................................................................................................................65 
 
LIST OF IN-TEXT TABLES 
Table 9.a 
Clinical Laboratory Tests .......................................................................................32 
Table 10.a 
Takeda Medically Significant AE List ..................................................................48 
 


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Study No. Leuprorelin-4001 
Page 9 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................21 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................66 
Appendix B 
Responsibilities of the Investigator ........................................................................68 
Appendix C 
Elements of the Subject Informed Consent ...........................................................70 
Appendix D 
Investigator Consent to Use of Personal Information ............................................73 
 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 10 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Development Center Asia, Pte. Ltd. 
 
Compound:
Leuprorelin 
Title of Protocol: 
An Open label, Multicenter Study to Assess the Safety and 
Efficacy of Leuprorelin in the Treatment of Central 
Precocious Puberty 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: 
Leuprorelin-4001 
Phase: 
4 
Study Design: 
This is a phase 4, open label study to be conducted in China, to assess long-term safety and efficacy of Leuprorelin in 
the treatment of central precocious puberty (CPP). Approximately 300 subjects will be enrolled. The treatment 
duration is 96 weeks. The study will consist of 3 periods including a 4-week Screening Period, a 96-week Treatment 
Period and a 4-week Safety Follow-up Period. After the end of the study, subjects will participate in an observational 
follow-up, in which subjects who remain on treatment will be observed at least every 24 weeks. All subjects will be 
followed up annually after the last dose until stable puberty is reached. 
Primary Objective: 
To evaluate the safety of leuprorelin in subjects with CPP 
Secondary Objective: 
To evaluate the efficacy of leuprorelin in subjects with CPP 
Subject Population: 
Subjects with appearance of secondary sexual characteristics before 8.0 years in girls and before 9.0 years in boys, 
with confirmed diagnosis of CPP. 
Number of Subjects: 
Estimated total: 300 
Number of Sites:  
Approximately 10-15 sites in China 
Dose Level(s): 
CPP subjects with body weight ≥20 kg will receive the 
recommended dose of leuprorelin 3.75 mg subcutaneous 
administration (SC) every 4 weeks. Subjects with body 
weight <20 kg will receive recommended dose of 1.88 mg 
SC every 4 weeks. It is not recommended to exceed 180 
μg/kg. 
Route of Administration:
Subcutaneous 
Duration of Treatment: 
96 weeks 
Period of Evaluation:
4 weeks Screening Period 
96 weeks Treatment Period  
4 weeks Safety Follow-up Period  
Observational Follow-up until stable puberty is 
reached 
Main Criteria for Inclusion: 
 In the opinion of the investigator, the subject and/or parent(s) or legal guardian are capable of understanding and 
complying with protocol requirements. 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 11 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
 The subject or the subject’s parent(s) or legally acceptable representative signs and dates a written informed 
consent form and any required privacy authorization prior to the initiation of any study procedures.  
 The subject has onset of appearance of secondary sexual characteristic earlier than age 8.0 years in girls or earlier 
than 9.0 years in boys and the symptom is persistent, and has confirmed diagnosis of CPP. 
 The subject has basal LH level >5.0 IU/L or peak LH>5.0 IU/L in stimulation test OR peak LH>3.3 IU/L with 
LH/follicle-stimulating hormone (FSH) >0.6 in stimulating test The subject has evidence of gonadal development 
evaluated by ultrasonography: multiple ovarian follicles ≥4 mm in any ovary OR uterine enlargement in females 
or testicular volume ≥4 mL in males. 
 The subject has advanced bone age (BA) ≥1 year and BA is ≤11.5 years in females or ≤12.5 years in males or 
predicted adult height <150 cm in females or <160 cm in males OR SDS<-2 standard deviations (SD) OR rapid 
growth defined as growth of BA/growth of chronologic age >1. BA is determined by Greulich and Pyle standards 
or Tanner-Whitehouse 3 (TW3) standards. 
 The subject has anticipated treatment duration of at least 2 year in investigator’s judgment. 
Main Criteria for Exclusion: 
 The subject has received any investigational compound within 30 days prior to screening. 
 The subject has received gonadotropin-releasing hormone analog (GnRHa) treatment in a previous clinical study 
or as a therapeutic agent. 
 The subject is an immediate family member, study site employee, or is in a dependant relationship with a study 
site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent 
under duress.  
 The subject has any findings in his/her medical history, physical examination, or safety clinical laboratory tests 
giving reasonable suspicion of underlying disease that might interfere with the conduct of the trial. 
 The subject has any concomitant medical condition that, in the opinion of the investigator, may expose a subject 
to an unacceptable level of safety risk or that affects subject compliance. 
 The subject has any screening abnormal laboratory value that suggests a clinically significant underlying disease 
or condition that may prevent the subject from entering the study; or the subject has: creatinine ≥1.5 mg/dL, 
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of normal, or 
total bilirubin >2.0 mg/dL, with AST/ALT elevated above the limits of normal values. 
 The subject has a history or clinical manifestations of significant adrenal or thyroid diseases or intracranial tumor 
OR has a history of malignant disease. 
 The subject has a history of hypersensitivity or allergies to leuprorelin, or related compounds including any 
excipients of the compound. 
 The subject has a diagnosis of peripheral precocious puberty. 
 The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year 
prior to the Screening Visit. 
 Subject or parent(s), at the discretion of the investigator, is unlikely to comply with the protocol or is unsuitable 
for any of other reason. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is subject incidence of treatment-emergent adverse events (TEAE).  
The secondary endpoint for this study is the percentage of subjects who have regression or no progression in Tanner 
staging at Week 96 compared with Baseline.  
The other endpoints for this study are: 
 Percentage of subjects with suppression of peak LH and FSH to pre-pubertal levels in stimulation test at Week 96 
 Percentage of subjects with suppression of basal estradiol level in female subjects or testosterone level in male 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 12 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
subjects to pre-pubertal level at Week 96 
 Percentage of subjects with improvement in predicted adult height at Week 96 compared with Baseline 
 Percentage of subjects with a decrease in the ratio of BA to chronological age at Week 96 compared with Baseline 
 Change in body mass index (BMI) 
 Change in bone mineral density 
 Incidence of polycystic ovarian syndrome in female subjects 
Statistical Considerations:
 Analysis Sets 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who are enrolled and received at least 1 dose of study drug. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects who are enrolled and received at least 1 dose of study drug. 
 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized. Summary statistics (N, mean, SD, median, minimum, 
and maximum) will be generated for continuous variables (eg, age and weight) and the number and percentage of 
subjects within each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristics data will be listed. 
 Efficacy Analysis 
The number and percentage of subjects who have regression or no progression in Tanner staging at Week 96 will be 
summarized. The number and percentage of subjects with suppression of peak LH and FSH after stimulation to 
pre-pubertal level at Week 96 compared with Baseline will be summarized. The number and percentage of subjects 
with suppression of basal estradiol level in female subjects or testosterone level in males subjects to pre-pubertal level 
at week 96 will be summarized. The number and percentage of subjects with improvement in predicted adult height at 
Week 96 compared with baseline will be summarized. The number and percentage of subjects with a decrease in the 
ratio of BA to chronological age at Week 96 compared with Baseline will be summarized. 
Individual data will be listed. 
 Safety Analysis 
All adverse events (AEs) will be coded by system organ class (SOC), high level term, and preferred term (PT) using 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment Emergent Adverse Events (TEAEs) are defined 
as AEs with onset occurring within 30 days (onset date – last date of dose +1≤ 30) after study drug administration. will 
be listed, and included in the summary tables. TEAEs will be summarized by treatment group by system organ class 
and preferred term.  The following summary tables will be included in the report: summary of TEAEs and drug-related 
TEAEs, relationship of TEAEs to study drug (related vs. not-related), severity of TEAEs and related TEAEs.  Data 
listings will be provided for all AEs including pretreatment event (PTE), TEAEs, AEs leading to study drug 
discontinuation, and serious adverse events serious adverse events (SAEs). 
Incidence of polycystic ovarian syndrome in female subjects will be summarized. 
 Other Variables 
Safety laboratory data, vital signs, height, weight, BMI and electrocardiograms will be summarized along with other 
data collected in the case report form (eCRF). 
Data collected during the observational follow-up period will be summarised and individual data will be listed. 


Leuprorelin 
 
Study No. Leuprorelin-4001 
Page 13 of 73 
Protocol Amendment #1 
16 Dec 2015 
 
CONFIDENTIAL 
Sample Size Justification:  
This study is not statistically powered for any hypothesis testing. Approximately 300 subjects will be enrolled into the 
study from multiple centers across China. The sample size of 300 subjects is considered to be sufficient to fulfill the 
study objectives of the evaluation of safety and efficacy of Leuprorelin in the treatment of CPP as required by the 
China Food and Drug Administration (CFDA). 


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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study. 


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3.3 
List of Abbreviations 
 
AE 
adverse event 
AFP 
alpha-fetoprotein 
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
β-HCG 
beta human chorionic gonadotropin 
BA 
bone age 
bpm 
beats per minute 
BMI 
body mass index 
CEA 
carcino-embryonic antigen 
CFDA 
China Food and Drug Administration 
CPP 
central precocious puberty 
eCRF 
electronic case report form 
CRO 
contract research organization
ECG 
electrocardiogram
FAS 
full analysis set 
FDA 
Food and Drug Administration
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice
GGT 
-glutamyl transferase
GnRH 
gonadotropin-releasing hormone 
GnRHa 
gonadotropin-releasing hormone analog 
hCG 
human chorionic gonadotropin
ICH 
International Conference on Harmonisation
IEC 
independent ethics committee
IND 
Investigational New Drug 
INR 
international normalized ratio
IRB 
institutional review board
IUD 
intrauterine device 
LFT 
liver function test 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities
MRI 
magnetic resonance imaging 
PP 
perprotocol 
PT 
preferred term 
PTE 
pretreatment event
QTc 
corrected QT interval 
SAE 
serious adverse event


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SAP 
statistical analysis plan
SC 
subcutaneous 
SAS 
safety analysis set 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse events 
TW3 
Tanner-Whitehouse 3 
ULN 
upper limit of normal
WHODRUG 
World Health Organization Drug Dictionary
 
 
3.4 
Corporate Identification 
TDC Japan 
Takeda Development Center Japan
TDC Asia 
Takeda Development Center Asia, Pte Ltd
TDC Europe 
Takeda Development Centre Europe Ltd.
TDC Americas 
Takeda Development Center Americas, Inc.
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Precocious puberty refers to appearance of secondary sexual characteristics in boys before 9 years 
and girls before 8 years. Children with central precocious puberty (CPP) have premature secretion 
and release of gonadotropin releasing hormone (GnRH) in the hypothalamus, activating secretion 
of gonadotropin by the pituitary gland, promoting development of the gonads and secretion of sex 
hormones, resulting in development of internal and external genital organs and appearance of 
secondary sexual characteristics [1]. 
The early onset of secondary characteristics can be psychologically and emotionally difficult for a 
young child. The young child does not understand the changes in his/her body and the emotional 
changes he or she is experiencing. The large size of the child due to the puberty growth spurt often 
causes further stress because of the greater expectations of parents and teachers because he/she 
seems older. Although intelligence and social skills do not advance with the child’s size, he/she 
may be pushed ahead in school or in social situations because of this. The child is no longer like 
his/her peers, but rather a child’s mind in a small adult body [2]. In China, the incidence of CPP is 
increasing. Epidemiology studies showed that the incidence of CPP in children aged 6-9 years in 
Zhejiang province is about 0.38% [3] and 1% in Shanghai [4]. The ratio of girls to boys is about 
4-5 to 1 [4]. 
CPP is controlled by the hypothalamic-pituitary-gonadal axis, the same mechanism that controls 
normal puberty. If the reproductive hormonal cycle can be interrupted, the child can be returned to 
a prepubertal state. Halting this process means suppressing the pituitary so that gonadotropins will 
decrease to prepubertal levels. Due to the negative feedback mechanism, the gonads will follow 
suit, then, suppression of gonadotropins and sex steroids will trigger decreases in growth and bone 
maturation and will also halt the development of secondary sexual characteristics. GnRH analogs 
(GnRHa) have been the standard of care for CPP. Continuous exposure to GnRHa desensitizes 
pituitary gonadotroph receptors and suppresses luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH) secretion [1]. 
Leuprorelin (Enantone) is a GnRHa widely used in the treatment of CPP worldwide including 
China. It is a potent inhibitor of ganodotropin secretion by downregulation of the GnRH receptors 
in the pituitary gland when administered continuously in therapeutic dose. First administration 
results in an initial transient increase (hormonal flare), then a decrease in LH and FSH, leading to a 
reduction in serum testosterone and estradiol to prepubertal levels usually within 2 to 4 weeks after 
initiation of treatment. The reduction of gonadotropins and sex steroids during treatment with 
GnRH agonist in children with CPP allows for normal physical and psychological growth and 
development. The effects of GnRH agonists treatment are entirely reversible upon discontinuation 
of treatment and natural maturation occurs when gonadotropins return to pubertal levels following 
discontinuation of leuprolide acetate [5,6,7,8]. 
 


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Two phase 3 studies were conducted in the United States to evaluate the efficacy and safety of 
leuprorelin in the treatment of CPP. The first study was an open label noncomparative study that 
utilized both the daily subcutaneous (SC) formulation and the depot formulation under the 
guidance of the individual investigator’s Investigational New Drug (IND) and protocol [9]. The 
second study was also a phase 3, open, noncomparative study, but conducted under the sponsor’s 
protocol and IND [9]. The studies were conducted at a total of 39 investigational sites. Two 
hundered twenty six (226) children were evaluated for efficacy and 365 for safety in these studies. 
In these investigations, children with CPP have been treated with leuprorelin injection or 
leuprorelin depot for periods of up to 4.9 and 2.7 years, respectively. The longest duration of 
treatment was 5.3 years, in a child who received both formulations. An initial dose of 50 ug/kg/day 
or 300 ug/kg/day once a month was recommended in the studies. In both studies, leuprorelin have 
been shown to be safe and effective in the suppression of gonadotropins and sex steroids in 
children with CPP who are properly diagnosed, aggressively treated and accurately monitored. 
4.2 
Rationale for the Proposed Study 
The administration dose of leuprorelin differs in various countries, ranging from 10 to 350 μg/kg 
body weight [10,11]. It was approved for CPP indication in China in 1998 at the dose of 
30-90 μg/kg body weight every 4 weeks SC administration . However, recent clinical studies 
demonstrated that administration of leuprorelin at lower than 90 μg/kg body weight cannot 
achieve optimal pituitary desensitization in many patients. If incomplete suppression occurs 
during treatment, GnRHa administration may exacerbate disease progression and bone age (BA) 
increase, impairing long-term outcome. The dose greater than 90 μg/kg body weight was 
recommended in CPP treatment guideline issued by China Ministry of Health [12]. In 2013, China 
Food and Drug Administration (CFDA) approved the new dose of Leuprorelin at 30-180 μg/kg 
body weight SC every 4 weeks [13]. The approval was based on the results from the clinical trials 
conducted in the United States, Europe and a retrospective study in Japan [14]. There is a lack of 
long term safety and efficacy  data of leuprorelin use in China. The main objective of this study is 
to collect the safety data in 300 CPP patients treated with leuprorelin after the approval of the new 
dose in China. Efficacy data will also be collected and evaluated. 
 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
To evaluate the safety of leuprorelin in subjects with CPP. 
5.1.2 Secondary Objective 
To evaluate the efficacy of leuprorelin in subjects with CPP. 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
Subject incidence of treatment-emergent adverse events (TEAE). 
5.2.2 Secondary Endpoint 
Percentage of subjects who have regression or no progression in Tanner staging at Week 96 
compared with Baseline. 
5.2.3 Additional Endpoints 
 Percentage of subjects with suppression of peak LH and FSH to pre-pubertal levels in 
stimulation test at Week 96. 
 Percentage of subjects with suppression of basal estradiol level in female subjects or 
testosterone level in male subjects to pre-pubertal level at Week 96. 
 Percentage of subjects with improvement in predicted adult height at Week 96 compared  with 
Baseline. 
 Percentage of subjects with a decrease in the ratio of BA to chronological age at Week 96 
compared with Baseline. 
 Change in laboratory values including changes in chemistry, hematology and bone metabolism 
biomarkers. 
 Change in body mass index (BMI). 
 Change in bone mineral density. 
 Incidence of polycystic ovarian syndrome in female subjects. 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 4, open label study to be conducted in China, to assess long-term safety and 
efficacy of leuprorelin in the treatment of CPP. Approximately 300 subjects will be enrolled. The 
treatment duration is 96 weeks. The study will consist of 3 periods including a 4-week Screening 
Period, a 96-week Treatment Period and a 4-week Safety Follow-up Period.  Followed by an 
observational follow-up period where subjects who remain on treatment will be observed at least 
every 24 weeks and after last dose all subjects will be followed up annually until stable puberty is 
reached. 
Eligible CPP subjects with body weight ≥20 kg will receive the recommended dose of leuprorelin 
3.75 mg SC every 4 weeks. Subjects with body weight <20 kg will receive recommended dose of 
1.88 mg SC every 4 weeks. It is not recommended to exceed 180 µg/kg. The dose can be adjusted 
based on subject’s condition and investigator’s judgment. Study visits, procedures, and evaluation 
are summarized in the Schedule of Study Procedures (Appendix A). Subjects will be followed 
until the end of the study, during which time they will be assessed by their treating physicians. 
serious adverse events (SAEs) and adverse events (AEs) will be recorded in the case report form 
(eCRF). Efficacy will be evaluated every 12 Weeks. The efficacy and safety data will be evaluated 
and submitted to CFDA. 
Subjects will be given the first dose of study drug in the clinic at Day 1 (Visit 2, Week 0). The last 
dose of study drug will be given on the day of Week 96 (Visit 10). All dosing of study drug will 
take place in the clinic by appropriate site staff. End of study assessment will be conducted at 
Week 96 (Visit 10). All subjects who receive study drug will be required to have a Final Safety 
Visit (Visit 11) at approximately 4 weeks after the last dose. 
After the end of the study, subjects will participate in a long term observational follow-up. During 
the observation follow-up period, the patient visits to the referring physician are not pre-specified 
by the study protocol, but will follow usual clinical practice. It is anticipated that the CPP patients 
will visit the site for check up at least every 24 weeks. All patient-care decisions, including 
diagnostic and therapeutic interventions, will be made by and conducted at the discretion of the 
participating  study physicians according to their clinical judgement and the local standard of 
medical care. It is recommended to monitor patients every 12 to 24 weeks in the treatment 
guideline issued by China Ministry of Health [4]. The procedures are summarized in the Schedule 
of Study Procedures (Appendix A). All subjects will be followed up annually after the last dose of 
leuprorelin until stable puberty is reached. Stable puberty is defined as 96 weeks after menarche 
for girls, or secondary sexual characteristics development of Tanner staging V for boys. At each 
visit, the following data will be collect if it is reported in the patients medical record: Tanner 
staging evaluation, height and weight measurement, menstrual history assessment and pelvic 
ultrasonography for girls.  
 
 


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Figure 6.a 
Schematic of Study Design 
                                                             
 
 
 
 
 
 
 
V=visit, D=day, Wk=week, SV=Screening Visit, EOS= End of Study, ET=Early Termination. 
A schedule of assessments is listed in Appendix A 错误!未找到引用源。. 
6.2 
Justification for Study Design, Dose, and Endpoints 
The design proposed in this study is acceptable to evaluate the long term safety and efficacy of 
leuprorelin. 
The dose of leuprorelin used in clinical practice varies in China. The label dose is 30-180 μg/kg 
body weight. The initial dose of 80-100 μg/kg body weight up to 3.75 mg was recommended in the 
treatment guideline issued by China Ministry of Health. It is also recommended to adjust the dose 
during the maintenance period depending on suppression of gonadal axis function. Leuprorelin is 
available in two strengths (3.75 mg and 1.88mg) for monthly administration in China. In many 
medical centers, it is administered at 3.75 mg every 4 weeks for patients with body weight ≥20 kg 
or 1.88 mg every 4 weeks for patients with body weight <20 kg. In a phase 3 trial conducted in 25 
centers in Germany, a favorable efficacy and safety profile was demonstrated with this treatment 
regimen. Therefore, the recommended leuprorelin dose in this study is 3.75 mg every 4 weeks for 
patients with body weight ≥20 kg or 1.88 mg every 4 weeks for patients with body weight <20 kg, 
not exceeding 180 μg/kg. The dose can be adjusted based on physician’s judgment. The 
inclusion/exclusion criteria are in alignment with Chinese and United States/European treatment 
guideline to ensure the treatment is given to the appropriate subjects.  
The safety and efficacy measurements and the clinical and routine laboratory procedures used in 
this study are standard and generally accepted. 
 
D -28 to D -1 
Wk 100 
Wk 0, 12, 24, 36, 48, 60, 72, 84, 96 
At least every 24 Wks 
Screening 
Period 
4 Wks 
Treatment Period 
96 Wks 
V 11/ET Visit/ 
Final Safety Visit
Long term observational 
follow up 
 
V 10/EOS/ 
Last dose
Follow up 
Period 
4 Wks
V 2/D 1 
First dose 
V 1/ 
SV 
Visit 2, 3, 4, 5, 6, 7, 8, 9, 10


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6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
 New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound/product, such that 
the risk/benefit is no longer acceptable for subjects participating in the study. 
 Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization or first dose or 
other.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
 
1. In the opinion of the investigator, the subject and/or parent(s) or legal guardian are capable of 
understanding and complying with protocol requirements. 
2. The subject or the subject’s parent(s) or legally acceptable representative signs and dates a 
written, informed consent form and any required privacy authorization prior to the initiation of 
any study procedures.  
3. The subject has age of onset of appearance of secondary sexual characteristic earlier than age 
8.0 years in girls or earlier than 9.0 years in boys and the symptom is persistent, and has 
confirmed diagnosis of CPP. 
4. The subject has basal LH level >5.0 IU/L or peak LH>5.0 IU/L in stimulation test OR peak 
LH>3.3 IU/L with LH/follicle-stimulating hormone (FSH) >0.6 in stimulating test.The subject 
has evidence of gonadal development evaluated by ultrasonography: multiple ovarian follicles 
≥4 mm in any ovary or uterine enlargement in females or testicular volume ≥ 4 mL in males. 
5. The subject has advanced BA ≥ 1 year and BA is ≤ 11.5 years in females or ≤ 12.5 years in 
males OR predicted adult height <150cm in females or < 160 cm in males OR SDS<-2SD OR 
rapid growth defined as growth of BA /growth of chronologic age >1. BA is determined by 
Greulich and Pyle standards or Tanner-Whitehouse 3 (TW3) standards at screening. 
6. The subject has anticipated treatment duration of at least 2 year in investigator’s judgment. 
7. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 90 days after last dose.  
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 90 days after last dose of study medication.  
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
 
9. The female subject who, at the discretion of the investigator, is deemed to be of child bearing 
potential must provide negative urine pregnancy test at test Day –1 or Day 1 prior to receiving 


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any dose of study medication drug administration and negative serum hCG pregnancy test at 
Screening. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
 
1. The subject has received any investigational compound within 30 days prior to Screening. 
2. The subject has received GnRHa treatment in a previous clinical study or as a therapeutic 
agent. 
3. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in the conduct of this study (eg, 
spouse, parent, child, sibling) or may consent under duress.  
4. The subject has any findings in his/her medical history, physical examination, or safety clinical 
laboratory tests giving reasonable suspicion of underlying disease that might interfere with the 
conduct of the trial.  
5. The subject has any concomitant medical condition that, in the opinion of the investigator, may 
expose a subject to an unacceptable level of safety risk or that affects subject compliance. 
6. The subject has any screening abnormal laboratory value that suggests a clinically significant 
underlying disease or condition that may prevent the subject from entering the study; or the 
subject has: creatinine ≥1.5 mg/dL, alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >2 times the upper limit of normal (ULN), or total bilirubin >2.0 
mg/dL, with AST/ALT elevated above the limits of normal values. 
7. The subject has a history or clinical manifestations of significant adrenal or thyroid diseases or 
intracranial tumor OR has a history of malignant disease. 
8. The subject has a history of hypersensitivity or allergies to leuprorelin, or related compounds 
including any excipients of the compound. 
9. The subject has a diagnosis of peripheral precocious puberty. 
10. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to the Screening Visit. 
11. Subject or parent(s), at the discretion of the investigator, is unlikely to comply with the 
protocol or is unsuitable for any of other reason. 
12. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period.  
13. If male, the subject intends to donate sperm during the course of this study or for 90 days  
thereafter.  


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7.3 
Excluded Medication, Procedures and Treatments  
The subjects should follow physician’s instruction on Medication, Procedures and Treatments. 
Any concomitant medications, procedures and treatments should be recorded. 
Hormonal contraceptives should be avoided during the study. In addition, all growth hormones 
need to be avoided for this study. 
7.4 
Diet, Fluid, Activity Control  
The subjects should follow physician’s instruction on diet, fluid and activity. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.16. 
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE. 
 Liver function test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment: 
– ALT or AST >8 × ULN, or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or clinical features of jaundice 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.  


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4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject.  
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 0. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
 
Leuprorelin 3.75 mg, 1 vial per box (attached with 1 ampule of 1 ml vehicle for suspension per 
vial). 
Leuprorelin 1.88 mg, 1 vial per box (attached with 1 ampule of 1 ml vehicle for suspension per 
vial). 
8.1.1.1 Investigational drug 
Leuprorelin 3.75 mg and 1.88 mg study medication are manufactured by Tianjin Takeda 
Pharmaceutical Company, Co., LTD. Tianjin, China. 
Each box label will be compliant with requirements of the CFDA. 
8.1.1.2 Sponsor-Supplied Drug 
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
Leuprorelin 3.75 mg, 1 vial per box (attached with 1 ampule of 1 ml vehicle for suspension per 
vial). 
Leuprorelin 1.88 mg, 1 vial per box (attached with 1 ampule of 1 ml vehicle for suspension per 
vial). 
8.1.2 Storage 
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 
8.1.3 Dose and Regimen 
This is a phase 4, open label study. The study will consist of 3 periods including a 4-week 
Screening Period, a 96-week Treatment Period and a 4-week Safety Follow-up Period.  


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During the Treatment Period, subjects with body weight ≥20 kg will receive the recommended 
dose of leuprorelin 3.75 mg SC every 4 weeks. Subjects with body weight <20 kg will receive 
recommended dose of 1.88 mg SC every 4 weeks. It is not recommended to exceed 180 ug/kg 
every 4 weeks. The dose can be adjusted based on physician’s judgment. 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Investigational drug Dispensing Procedures 
The investigator or investigator’s designee will inject the investigational drug to eligible subject at 
Day 1 (Visit 2). At subsequent visits, the investigator or designee will again inject investigational 
drug to the subject. 
 Subjects will receive treatment according to study schedule. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (Leuprorelin 3.75 mg and 1.88 mg), the investigator or designee must 
maintain records of all sponsor-supplied drug delivery to the site, site inventory, dispensation and 
use by each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment. If there are any discrepancies between the 
packing list versus the actual product received, the sponsor must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 


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The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
(Leuprorelin 3.75 mg and 1.88 mg) received and dispensed during his or her entire participation in 
the study. Proper drug accountability includes, but is not limited to: 
 Continuously monitoring expiration dates if expiry date it is provided to the investigator or 
designee.  
 Frequently verifying that actual inventory matches documented inventory. 
 Verifying that the log is completed for the drug accountability used to prepare each dose. 
 Verifying that all containers used are documented accurately on the log. 
 Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(Leuprorelin 3.75 mg and 1.88 mg), on a sponsor-approved drug accountability log. The following 
information will be recorded at a minimum: protocol number and title, name of investigator, site 
identifier and number, description of sponsor-supplied drugs, expiry date and amount dispensed 
including initials of the person dispensing the drug. The log should include all required 
information as a separate entry for each subject to whom sponsor-supplied drug is dispensed.  
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex and race as described by the 
subject of the subject at Screening (Visit 1).  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 28 days prior to signing of informed 
consent. 
9.1.3 Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination. 
9.1.4 Weight and Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off.  


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9.1.5 Vital Sign Procedure 
Vital signs will include body temperature infra-axillary measurement, respiratory rate, sitting 
blood pressure (resting more than 5 minutes), and pulse (beat per minute [bpm]). 
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained preferably within 0.5 hour before or after the scheduled blood 
draw. The most important consideration is for patient to be in a calm and stable state, when taking 
vital signs, as deemed suitable at the discretion of the investigator.   
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. 
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at screening examination. The condition (ie, 
diagnosis) should be described and recorded in the eCRF. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 40 mL, and the approximate total volume of 
blood for the study is 200 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Clinical Chemistry
Urinalysis 
RBC 
WBC 
Hemoglobin 
Hematocrit 
Platelets 
 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
 
Microscopic Analysis 
(only if positive dipstick 
results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc 
Other: 
GnRH stimulation test 
LH and FSH  
Estradiol or testosterone 
Serum bone metabolism biomarkers- phosphorus, 25-hydroxy vitamin D, osteocalcin, crosslaps 
Other Screening/Safety 
Urine
AFP, CEA, β-HCG 
Urine pregnancy test * 
 
AFP= alpha-fetoprotein, β-HCG= beta human chorionic gonadotropin, CEA=carcino-embryonic antigen, GGT= glutamyl transferase, RBC=red 
blood cells, WBC=white blood cells. 
*The female subject who, at the discretion of the investigator, is deemed to be of child bearing potential must provide negative urine pregnancy test 
at Day –1 or Day 1 prior to drug administration. 
 
The local laboratory will perform laboratory tests for hematology, serum chemistries, urinalysis, 
estradiol, testosterone, bone metabolism markers, LH, FSH, AFP, CEA, and β-HCG . The results 
of laboratory tests will be returned to the investigator, who is responsible for reviewing and filing 
these results. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted. 
(Please refer to Section 0 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.) 


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements). 
The investigator or designee is responsible for transcribing or attaching laboratory results to the 
eCRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 90 days after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. 
From signing of informed consent, throughout the duration of the study, and for 90 days after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who are pre-menarche with no ovulation 
ability or have been surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) . 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are:  
Barrier methods (each time the 
subject has intercourse): 
Intrauterine devices 
(IUDs): 
 
 Male condom PLUS 
spermicide. 
 Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide. 
 Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide. 
 Copper T PLUS 
condom or spermicide. 
 #Progesterone T PLUS 
condom or spermicide. 
 


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Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular serum/urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for female of childbearing potential and subjects will 
receive continued guidance with respect to the avoidance of pregnancy and sperm donation as part 
of the study procedures (Appendix A). In addition to a negative serum hCG pregnancy test at 
Screening, subjects also must have a negative urine hCG pregnancy at test Day –1 or Day 1 prior to 
receiving any dose of study medication drug administration. 
9.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug Leuprorelin should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study or for 90 days after the last dose, 
should also be recorded following authorization from the subject’s partner.  
If the pregnancy occurs during administration of active study medication, eg, after within 30 days 
of the last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received. 
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant.  
 
9.1.12 Bone Age 
Bone age will be evaluated by investigators at each site using TW3 standards or Greulich-Pyle 
standards, and the result will be recorded in the eCRF. All BA x-ray will be sent for central reading 
before the end of the study. If BA x-ray result is already available – whether in the same hospital or 


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other hospital -  within 28 days prior to first dose, the result be used for screening, under the 
condition that the Site retain a copy of the data/image in file notes as source documents.  
9.1.13 Bone Mineral Density 
Bone mineral density will be evaluated by dual energy x-ray bone densitometry at selected sites 
only. Throughout the study, the same apparatus should be used and operated in the same scan 
mode for all scans for an individual subject. The results will be recorded in the eCRF. 
9.1.14 Cranial MRI 
Cranial magnetic resonance imaging MRI will be performed at Screening Visit only. Investigators 
will assess the presence of any intracranial tumor. The results will be recorded in the eCRF. If  
Cranial MRI result is already available – whether in the same hospital or other hospital -  within 28 
days prior to first dose, the result can be used for screening, under the condition that the Site retain 
a copy of the data/image in file notes as source documents. Cranial MRI can consist of only 
pituitary scan, including saddle region.  
9.1.15 Pelvic/Testicular Ultrasonography 
Pelvic ultrasonography will be performed for females to measure ovarian volume, uterus size and 
volume and number of follicles. For males, ultrasonography will be performed to measure the 
testicular volume. The results will be recorded in the eCRF. 
9.1.16 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
 PTE/AE. 
 Did not meet inclusion criteria or did meet exclusion criteria.  
 Significant protocol deviation. 
 Lost to follow-up. 
 Voluntary withdrawal. 
 Study termination. 
 Other. 
Subject numbers assigned to subjects who fail screening should not be reused. 


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9.1.17 Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase. 
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be injected the study medication Leuprorelin 3.75 mg or 1.88 mg on site by 
investigator or investigator’s designee. All supplies used to administer study medication to the 
subject will be recorded on the eCRFs. 
If a subject is persistently noncompliant, defined as missing two consecutively scheduled drug 
injections against what is stipulated in the protocol’s schedule of study procedures,  with the study 
medication Leuprorelin 3.75 mg and 1.88 mg, it may be appropriate to withdraw the subject from 
the study. All subjects should be reinstructed about the dosing requirement during study contacts. 
The authorized study personnel conducting the re-education must document the process in the 
subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit. 
9.3.1 Screening - Visit 1 
Subjects will be screened within 28 days prior to first dose (Week 0, Visit 2). Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 7.0. See Section 9.1.16 for procedures for documenting screening failures. 
Procedures to be completed at Screening (Visit 1) include: 
 Informed consent. 
 Inclusion/exclusion criteria. 
 Demographics, medical history, and medication history. 
 Physical examination. 
 Vital signs. 
 Weight, height 
 Concomitant medications.  
 Concurrent medical conditions. 
 Predicted adult height. 


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 Tanner staging evaluation. 
 Bone age. 
 Hematology, Urine analysis, clinical chemistry laboratoty tests. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential. 
 ECG. 
 Pelvic/testicular ultrasonography. 
 Stimulation test. 
 Cranial MRI. 
 CEA, AFP, β-HCG. 
 PTE assessment. 
 Assign subject number. 
9.3.2 Study Entrance - Visit 2 (Week 0, first dose) 
Study entrance will take place on Day 1 (Visit 2). The following procedures will be performed and 
documented during Study Entrance: 
 Vital signs. 
 Weight, height 
 Concomitant medications.  
 Tanner staging evaluation. 
 Urine Pregnancy test. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential.  
 Estradiol or testosterone. 
 Bone mineral density. 
 Serum bone metabolism biomarker. 
 Injection of investigational drug by investigator or investigator’s designee. 
 PTE assessment. 
 AE assessment. 


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If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for study 
entrance, the subject should be assigned a subject number. Subjects will be instructed on when to 
take the first dose of investigational drug as described in Section 6.1. The procedure for 
documenting Screening failures is provided in Section 9.1.16. 
9.3.3 Treatment Phase - Visit 3 (Week 12) 
Visit 3 will take place on Week 12. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential. 
 ECG. 
 Estradiol or testosterone. 
 Stimulation test. 
 Injection of Investigational Drug by investigator or investigator’s designee. 
 AE assessment. 
9.3.4 Treatment Phase - Visit 4 (Week 24) 
Visit 4 will take place on Week 24. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Bone age. 
 Hematology. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential  


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 Clinical chemistry 
 Pelvic/Testicular ultrasonography  
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee 
 AE assessment 
9.3.5 Treatment Phase - Visit 5 (Week 36) 
Visit 5 will take place on Week 36. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential. 
 ECG. 
 LH and FSH. 
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee 
 AE assessment. 
9.3.6 Treatment Phase - Visit 6 (Week 48) 
Visit 6 will take place on Week 48. The following procedures will be performed and documented 
during this visit: 
 Physical examination. 
 Vital signs. 
 Weight, height. 
 Concomitant medications. 
 Predicted adult height. 
 Tanner staging evaluation. 


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 Bone age. 
 Hematology. 
 Urine analysis 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential  
 Clinical chemistry 
 Pelvic/testicular ultrasonography. 
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee 
 AE assessment 
9.3.7 Treatment Phase - Visit 7 (Week 60) 
Visit 7 will take place on Week 60. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential  
 ECG. 
 LH and FSH 
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee. 
 AE assessment. 
9.3.8 Treatment Phase - Visit 8 (Week 72) 
Visit 8 will take place on Week 72. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 


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 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Bone age. 
 Hematology. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential. 
 Clinical chemistry. 
 Pelvic/testicular ultrasonography. 
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee. 
 AE assessment. 
9.3.9 Treatment Phase - Visit 9 (Week 84) 
Visit 9 will take place on Week 84. The following procedures will be performed and documented 
during this visit: 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential. 
 LH and FSH. 
 Estradiol or testosterone. 
 Injection of investigational drug by investigator or investigator’s designee. 
 AE assessment. 
9.3.10 Treatment Phase - Visit 10 (Week 96, last dose) 
Visit 10 will take place on Week 96. The following procedures will be performed and documented 
during this visit: 


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 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Predicted adult height. 
 Tanner staging evaluation. 
 Bone age. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential.  
 ECG. 
 Pelvic/testicular ultrasonography. 
 Estradiol or testosterone. 
 Stimulation test. 
 Injection of investigational drug by investigator or investigator’s designee. 
 AE assessment. 
9.3.11 Final Safety Visit or Early Termination - Visit 11 (Week 100) 
Visit 11 will take place on Week 100. The following procedures will be performed and 
documented during this visit: 
 Physical examination. 
 Vital signs. 
 Weight, height. 
 Concomitant medications.  
 Tanner staging evaluation. 
 Hematology. 
 Urine analysis. 
 Pregnancy avoidance counseling, for female subject who, at the discretion of the investigator, 
is deemed to be of childbearing potential or , the male subject who is nonsterilized and sexually 
active with a female partner of childbearing potential.  
 Clinical chemistry. 
 Pelvic/testicular ultrasonography.  


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 Estradiol or testosterone. 
 Bone mineral density. 
 Serum bone metabolism biomarker. 
 AE assessment. 
The Final Visit will be performed on Week 100 or at the Early Termination Visit. The following 
procedures will be performed and documented: 
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page. 
9.3.12 Observational Follow-up  
Observational Follow-up will begin the first day after the Final safety Visit. 
During the observation follow-up the patient visits to the referring physician are not pre-specified 
by the study protocol, but will follow usual clinical practice. It is anticipated that the CPP patients 
will visit the site for check up at least every 24 weeks. All patient-care decisions, including 
diagnostic and therapeutic interventions, will be made by and conducted at the discretion of the 
participating study physicians according to their clinical judgement and the local standard of 
medical care.  
Data should be entered into the database, at the patients’ visits (at least every 24 weeks) and at the 
end of data collection. However, no patients will be excluded based on different reporting 
frequencies. The source of the data is the patient medical record. 
The following data will be recorded if it is collected as part of routine clinical practice: 
 Physical examination. 
 Vital signs. 
 Weight, height. 
 Predicted adult height. 
 Tanner staging evaluation. 
 Bone age. 
 Hematology. 
 Clinical chemistry. 
 ECG. 
 Pelvic/testicular ultrasonography. 
 Estradiol or testosterone. 


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 AE assessment. 
After the last dose of leuprorelin treatment, subjects will be followed up annually and conduct the 
following procedure until stable puberty is reached. 
The following data will be recorded when it is collected as part of routine clinical practice: 
 Tanner staging. 
 Height and weight. 
 Menstrual history for girls. 
 Pelvic ultrasongraphy for girls. 
 
The observational follow-up is not included in this study. The requirement has not been determined as yet. If 
long term observational follow-up is performed then the patients will undergo  a further Consent process, 
including new Parent/Patient Information sheet. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant medication. 
 Be considered unfavorable by the investigator for any reason. 
 PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE. 
Diagnoses vs signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention. 
 If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE. 
Preexisting conditions: 
 Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG etc.) should NOT be recorded as PTEs unless related to 
study procedures. However, if the subject experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded appropriately as a 
PTE (worsening or complication occurs before start of study medication) or an AE (worsening 
or complication occurs after start of study medication). Investigators should ensure that the 
event term recorded captures the change in the condition (eg, “worsening of…”). 
 If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”). 
 If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 


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Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
 Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. 
Overdose: 
 Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF. 
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 


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 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Takeda Medically Significant AE List  
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure
Anaphylactic shock
Malignant hypertension 
Acute renal failure
Convulsive seizure 
Pulmonary hypertension
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product 
 
Neuroleptic malignant syndrome / malignant hyperthermia
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs/AEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject.
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 


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Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.  
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
 Drug withdrawn – a study medication is stopped due to the particular AE. 
 Dose not changed – the particular AE did not require stopping a study medication. 
 Unknown – only to be used if it has not been possible to determine what action has been taken. 
 Not Applicable – a study medication was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE. 
 Dose Reduced – the dose was reduced due to the particular AE. 
 Dose Increased – the dose was increased due to the particular AE. 
 Dose Interrupted – the dose was interrupted due to the particular AE. 
10.1.12 Outcome 
 Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 


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 Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
 Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”. 
 Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis. 
 Fatal – the AEs/PTEs which are considered as the cause of death.  
 Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication (Visit 
2) or until screen failure. For subjects who discontinue prior to study medication administration, 
PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
medication (Visit 2). Routine collection of AEs will continue until 28 days after study visit 10, 
which will be Visit 11.  
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 


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laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Severity. 
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs). 
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure. 
6. Action concerning study medication (not applicable for PTEs). 
7. Outcome of event. 
8. Seriousness. 
Reporting of unexpected non-serious adverse drug reactions (ADRs): 
For the non-serious AE which is not listed in the labeling, if it is potentially related to the study 
medication or study procedure, or if the causality is unknown/missed, the investigator should 
report this unexpected non-serious ADR to Takeda within 7 calendar days of fist notification of the 
event. The the AE page of the eCRF should be transmitted within 7 calendar days to the attention 
of the contact listed in Section 1.1. The investigator should make sure the success of the reporting 
transmission. 
If the follow-up information of the unexpected non-serious ADR is received, the reporting of the 
follow-up information will follow the same reporting procedure of the initial report. 
 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 


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 Name of the study medication(s) 
 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1. The investigator should make sure the success of the reporting transmission. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests  
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed. 
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2). 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately or within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs which occurred in this study to regulatory authorities, 
investigators and IECs, as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further provision to 
the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 


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expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IEC in accordance 
with national regulations 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data monitoring committee or clinical endpoint committee will be used in 
this study. 
  
 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary (WHODRUG). 
12.1 
Electronic CRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs . 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs arerecorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change..Reasons for significant corrections should additionally be included.  
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date.  
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 


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electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
A blinded data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. 
A SAP will be prepared for the observational follow-up period. 
13.1.1 Analysis Sets 
Safety Analysis Set 
The Safety Analysis Set (SAS) will consist of all subjects who are enrolled and received at least 1 
dose of study drug. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects who are enrolled and received at least 1 
dose of study drug. 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will consist of subjects who are in the FAS and have no major 
protocol violations. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized. Summary statistics (N, mean, SD, 
median, minimum, and maximum) will be generated for continuous variables (eg, age and weight) 
and the number and percentage of subjects within each category will be presented for categorical 
variables (eg, sex, ethnicity, and race). Individual subject demographic and baseline characteristics 
data will be listed. 
Medical history, concurrent medical conditions and concomitant medications will be summarized 
and listed. 
13.1.3 Efficacy Analysis 
The number and percentage of subjects who have regression or no progression in Tanner staging at 
Week 96 will be summarized, individual data will be listed. The number and percentage of 
subjects with suppression of peak LH and FSH after stimulation to pre-pubertal level at Week 96 
will be summarized, individual data will be listed. The number and percentage of subjects with 
suppression of basal estradiol level in female subjects or testosterone level in male subjects to 


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pre-pubertal level at Week 96 will be summarized, individual data will be listed. The number and 
percentage of subjects with improvement in predicted adult height at Week 96 compared with 
Baseline will be summarized, individual data will be listed. The number and percentage of subjects 
with a decrease in the ratio of bone age to chronological age at Week 96 compared with Baseline 
will be summarized, individual data will be listed. For binary data where appropriate 95% 
confidence intervals will be presented.  
13.1.4 Safety Analysis 
For all safety endpoints, Baseline is defined as the last non-missing measurement prior to first dose 
of study drug. Safety data will be summarized using the safety analysis set.  
13.1.4.1 Adverse Events 
All AEs will be coded by system organ class (SOC), high level term, and preferred term (PT) using 
MedDRA. TEAEs are defined as AEs with onset occurring within 30 days (onset date – last date of 
dose +1≤ 30) after study drug administration. will be listed, and included in the summary tables. 
TEAEs will be summarized by treatment group by system organ class and preferred term.  The 
following summary tables will be included in the report: summary of TEAEs and drug-related 
TEAEs, relationship of TEAEs to study drug (related vs. not-related), severity of TEAEs and 
related TEAEs.  Data listings will be provided for all AEs including PTE, TEAEs, AEs leading to 
study drug discontinuation, and SAEs. 
Incidence of polycystic ovarian syndrome in female subjects will be summarized. 
13.1.4.2 Safety Laboratory Evaluation 
Individual results of safety laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be summarized and listed. Baseline, postdose, and 
change from Baseline to postdose laboratory data will be summarized. All clinical laboratory data 
will be listed. 
13.1.4.3 Vital Signs 
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be summarized 
and listed. Baseline, postdose, and changes from Baseline in vital sign measurements will be 
summarized. All vital sign data will be provided in the data listings. 
13.1.4.4 Height, Weight and BMI 
Baseline, postdose, and changes from Baseline in height, weight and BMI measurements will be 
summarized. All data for height, weight, BMI will be provided in the data listings. 
13.1.4.5 ECG 
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet TDC’s 
markedly abnormal criteria will be summarized and listed. Baseline, postdose, and changes from 


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Baseline in quantitative ECG parameters will be summarized. Shift tables will be generated for the 
investigator’s ECG interpretations that changed from Baseline to the postdose collections by 
above groups. Analysis of central tendency for QT/corrected QT interval (QTc) and categorical 
analysis of QT/QTc will be performed. All ECG data will be provided in the data listings.  
13.1.5 Other Analysis 
The serum bone metabolism biomarkers including phosphorus, 25-hydroxy vitamin D, osteocalcin, 
crosslaps will be summarized by Baseline, postdose and changes from Baseline, individual data 
will be listed. 
Baseline, postdose, and changes from Baseline in bone mineral density measurements will be 
summarized. All bone mineral density data will be provided in the data listings. 
Pelvic and testicular ultrasonography will be summarised and data will be provided in listings. 
Other Variables: 
The physical examination findings will be presented in data listings. 
The urine pregnancy test, cranial MRI, CEA, AFP and β-HCG at Screening will be summarised 
and listed. 
Data collected during the observational follow-up phase will be summarised and individual data 
will be listed. 
13.2 
Interim Analysis and Criteria for Early Termination 
One interim analysis will be performed after Week 100 visit. All available efficacy and safety data 
will be evaluated and reported to CFDA. The study will be continued to the observational safety 
follow-up phase. 
13.3 
Determination of Sample Size 
This study is not statistically powered for any hypothesis testing. Approximately 300 subjects will 
be enrolled into the study from multiple centers across China. The sample size of 300 subjects is 
considered to be sufficient to fulfill the study objectives of the evaluation of safety and efficacy of 
Leuprorelin in the treatment of CPP as required by the CFDA. 
 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.  
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those Americas sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives notification no 
protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 


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15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject. 


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with China GCP, ICH Guidelines for GCP and to verify compliance with this protocol, 
the sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, CFDA, FDA, Medicines and Healthcare products Regulatory 
Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and 
the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 


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15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.  
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.  
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee. 


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16.0 
REFERENCES 
1. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR, Antoniazzi F, et al. Consensus 
statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009; 
123: e752-62. 
2. Wheeler MD, Syne DM. The treatment of precocious puberty. Endcrinol Metab Clin North 
Am. 1991; 20: 183-90. 
3. Lin F, Zheng CH, Li H, et al. [Investigation and research about precocious puberty in eastern 
coast of Zhejiang Province.] Shiyong Erke Linchuan Zazhi. 2004; 19: 640–2. (In Chinese). 
4. CAI Depei, Precocious puberty and pubertal delay; Shanghai, China: Fudan University Press; 
June 1 2003, 16-23. 
5. Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing 
hormone agonist treatment of central precocious puberty: Final height, body proportions, body 
composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab. 1999; 
84: 4583-90. 
6. Hummelink R, Oostdijk W, Partsch CJ, Odink RJH, Drop SLS, Sippell WG. Growth, bone 
maturation and height prediction after three years of therapy withthe slow release 
GnRH-agonist decapeptyl-depot in children with central precocious puberty. Horm Metab Res. 
1992; 24: 122-6. 
7. Manasco PK, Pescovitz OH, Feuillan PP, Hench K, Barnes KM, Jones J, et al. Resumption of 
puberty after long term luteinizing hormone-releasing hormone agonist treatment of central 
precocious puberty. J Clin Endocrin Metabol.1988; 67: 368-72. 
8. Oostdijk W, Partsch DJ, Drop SLS, Sippell WG. Hormonal evaluation during and after 
long-term treatment with a slow-release GnRH agonist of children withcentral precocious 
puberty; effect on final height. In: Plant TM and Lee PA eds. The Neurobiology of Puberty. 
Bristol, UK: 1995: 319-25. 
9. Data on file. Overview of the study of leuprolide acetate in the treatment of central precocious 
puberty. Abbot-43838. 
10. Mul D, Hughes IA. The use of GnRH agonists in precocious puberty. Eur J Endocrinol. 2008; 
159: S3-8. 
11. Bertelloni S, Baroncelli GI. Current pharmacotherapy of central precocious puberty by GnRH 
analogs: certainties and uncertainties. Expert Opin Pharmacother. 2013; 14: 1627-38. 
12. Chinese precocious puberty treatment guideline 2010 and Concensus on Diagnosis and 
Treatment of Central Precocious Puberty (2015).  
13. Enantone prescription information 2013. 
14. Tanaka T, Naiki Y, Horikawa R. Evaluation of the dosage of LHRH analog in children with 
central precocious puberty. J Jpn Ass Hum Auxo. 2010; 16: 85-92. 


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Appendix A Schedule of Study Procedures 
 
Screening 
Treatment 
 
 
Study Day/Week: 
Days 
 -28 to -1 
Wk 0/ 
Day 
1/first 
dose 
(a) 
Wk 
12 
Wk 
24 
Wk 
36 
Wk 
48 
Wk 
60 
Wk 
72 
Wk 
84 
Wk 96/
last 
dose 
Final safety Visit/ 
Early 
Termination Visit 
Week 100 (b) 
Observational 
Follow-up visit
(c) 
Visit Windows (Days): 
NA
NA 
±5d
±5d
±5d
±5d
±5d
±5d
±5d
±5d
±5d 
Visit Number: 
1
2 
3 
4
5
6
7
8
9
10
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X
 
 
 
Demographics and medical 
history 
X
 
 
 
Medication history 
X
 
 
 
Physical examination 
X
 
 
X
X 
X
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and height 
X
X 
X
X
X
X
X
X
X
X
X 
X
Concomitant medications 
X
X 
X
X
X
X
X
X
X
X
X 
Concurrent medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Predicted adult height (d) 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Tanner staging evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone age (e) 
X
 
 
X
X
X
X
 
X
Hematology 
X
 
 
X
X
X
X 
X
Urine analysis 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Urine Pregnancy test (f) 
X 
 
 
Pregnancy avoidance 
counseling  
X
X 
X
X
X
X
X
X
X
X
X 
Clinical chemistry  
X
 
 
X
X
X
X 
X
ECG 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Pelvic/Testicular 
ultrasonography (g) 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
LH and FSH 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Estradiol or  Testosterone 
X(j) 
X
X
X
X
X
X
X
X
X 
X
Stimulation test (h) 
X
 
X
X
 
Cranial MRI (i) 
X 
 
 
 
 
 
 
 
 
 
 
 
CEA, AFP, β-HCG 
X
 
 
 
Bone mineral density (j) 
X (j) 
 
X 
Serum bone metabolism 
biomarker (k) 
 
X(j) 
 
 
 
 
 
 
 
 
X 
 
Injection investigational 
drug (l) 
X 
 
X
 
PTE assessment 
X
X 
 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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NA=not applicable. 
(a) The day of first investigational drug administration for Treatment period is Day 1. The day before first investigational drug 
administration for Treatment period is Day -1. 
(b) Conduct Final Visit procedures for subjects discontinued early per Section 7.6. The end of study is defined as the date of the last 
visit (Week 100) of the last subject undergoing the study unless the study is stopped earlier by sponsor  due to futility or for safety 
reasons.  Subjects who discontinued from the study for any reason will complete the Early Termination Visit/Final Safety Visit , 4 
weeks after the last dose of leuprorelin. 
(c) During the observational follow- up period, it is recommended to monitor the subjects who remain on treatment at least every 6 
months or at a schedule based on the investigator's judgments until drug discontinuation to collect the following: height and weight, 
secondary sexual characteristics, hematology, clinical chemistry, ultrasonography, LH and FSH, estradiol or testosterone and ECG. 
ECG will also be performed 4 weeks after the last administration of leuprorelin.  All subjects will be followed up annually after the 
last dose of leuprorelin until stable puberty is reached. At each visit, the following will be performed: Tanner staging, height and 
weight, BMI, menstrual history, and pelvic ultrasonography for girls. Stable puberty is defined as 2 years after menarche for girls or 
Tanner staging V of secondary sexual characteristics development for boys.  
(d) Predicted adult height will be evaluated using Bayley-Pinneau method. 
(e) Bone age will be evaluated by investigators at each site using TW3 standards or Greulich-Pyle standards at Screening. All bone 
age x-ray will be sent for central reading before the end of the study 
(f) The female subject who, at the discretion of the investigator, is deemed to be of child bearing potential must provide negative 
urine pregnancy test at Day –1 or Day 1 prior to drug administration. 
(g) Pelvic ultrasonography will be performed for females to measure, uterus size and number/size of follicles. For males, 
ultrasonography will be performed to measure the testicular volume. These results if available already can be used as part of 
screening. If result is already available – whether at same site or hospital – within 28 days prior to first dose, the result can be used 
for screening, under the condition that the Site retains a copy of the data in file notes as source documents.   
(h) Stimulation test:  Blood samples will be collected at 0, 30, and 60, minutes after the injection of GnRH.  It is acceptable to  use 
both GnRH and GnRHa in stimulation test; however, it is preferable to use GnRH as priority. These results if available already can 
be used as part of screening. If stimulation test result is already available – whether at same site or hospital – within 28 days prior to 
first dose, the result can be used for screening, under the condition that the Site retains a copy of the data in file notes as source 
documents.  (i) Cranial MRI can consist of only pituitary scan, including saddle region. 
(j) Bone mineral density will be evaluated by dual energy x-ray bone densitometry at selected sites, which can done at any time 
prior to the first dose after the Screening. Estradiol or Testosterone and Serum bone metabolim biomark also can be done at any 
time prior to first dose as part of screening visit. (k) Serum bone metabolism biomarker included phosphorus, 25-hydroxy vitamin 
D, osteocalcin, crosslaps. These 4 tests can be performed as per what is available at the given Site. These tests can done at any time 
prior to the first dose after the Screening. 
(l) Subcutaneous injection Leuprorelin every 4 weeks. For the dosing visits between Visits 2-3, between Visits 3-4,  between Visits 
4-5, between visits 5-6, between visits 6-7, between 7-8, between 8-9, between visits 9-10: these  visit window is +/- 2 days; in 
addition, the between gap between dosing cannot be less than 3 weeks (21 days).  
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.  
The investigator agrees to assume the following responsibilities  
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to  
ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.  
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 


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Appendix C Elements of the Subject Informed Consent  
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated. 
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 


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e) that the subject’s identity will remain confidential in the event that study results are 
published. 
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information. 
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 


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Appendix D Investigator Consent to Use of Personal Information  
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
 Takeda, its affiliates, and licensing partners. 
 Business partners assisting Takeda, its affiliates, and licensing partners. 
 Regulatory agencies and other health authorities. 
 IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
 Assessment of the suitability of investigator for the study and/or other clinical studies. 
 Management, monitoring, inspection, and audit of the study. 
 Analysis, review, and verification of the study results. 
 Safety reporting and pharmacovigilance relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication. 
 Inspections and investigations by regulatory authorities relating to the study. 
 Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
 Archiving and audit of study records. 
 Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above. 
 

SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open label, Multicenter Study to Assess the Safety and Efficacy of Leuprorelin in the 
Treatment of Central Precocious Puberty
NCT Number: NCT02427958
SAP Approve Date: 01 June 2017 
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


Takeda 
Statistical Analysis Plan 
Leuprorelin-4001 
Version: 1.0 
1 
An Open label, Multicenter Study to Assess the Safety and Efficacy of 
Leuprorelin in the Treatment of Central Precocious Puberty 
Leuprorelin-4001, Leuprorelin in the Treatment of Central Precocious 
Puberty 
Statistical Analysis Plan 
Version: 1.0 
Date: 01 June 2017 


PPD


PPD


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Statistical Analysis Plan 
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Version: 1.0 
 
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TABLE OF CONTENTS 
 
 
ABBREVIATIONS ........................................................................................................................ 6 
1. 
INTRODUCTION ................................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 8 
2.1. 
Objectives ....................................................................................................................... 8 
2.1.1.  Primary Objective ..................................................................................................... 8 
2.1.2.  Secondary Objective ................................................................................................. 8 
2.2. 
Endpoints ........................................................................................................................ 8 
2.2.1.  Primary Endpoint ..................................................................................................... 8 
2.2.2.  Secondary Endpoint.................................................................................................. 8 
2.2.3.  Additional Endpoints ................................................................................................ 8 
3. 
STUDY DESIGN ................................................................................................................. 9 
4. 
SAMPLE SIZE CONSIDERATION .................................................................................. 10 
5. 
ANALYSIS SETS .............................................................................................................. 10 
6. 
STATISTICAL ANALYSIS .............................................................................................. 11 
6.1. 
General Statistical Considerations ............................................................................... 11 
6.2. 
Data Handling Conventions ......................................................................................... 11 
6.2.1.  Premature Withdrawal and Missing Data ........................................................... 11 
6.2.2.  Definition of Baseline and Change from Baseline ................................................ 11 
6.2.3.  Definition of Study Day .......................................................................................... 11 
6.3. 
Study Subjects .............................................................................................................. 12 
6.3.1.  Disposition of Subjects ............................................................................................ 12 
6.3.2.  Protocol Deviation ................................................................................................... 13 
6.3.3.  Demographic and Baseline Characteristics .......................................................... 13 
6.3.4.  Medical History and Concurrent medical conditions .......................................... 14 
6.3.5.  Concomitant Medications ...................................................................................... 15 
6.4. 
Efficacy Analyses ......................................................................................................... 15 
6.5. 
Safety Analyses ............................................................................................................ 16 
6.5.1.  Adverse Events ........................................................................................................ 16 


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6.5.2.  Safety Laboratory Evaluation ............................................................................... 19 
6.5.3.  Vital Signs ................................................................................................................ 20 
6.5.4.  Height, Weight and BMI ........................................................................................ 20 
6.5.5.  ECG .......................................................................................................................... 21 
6.6. 
Other Analyses ............................................................................................................. 21 
6.7. 
Interim Analyses .......................................................................................................... 22 
7. 
REFERENCES ................................................................................................................... 22 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AFP 
alpha-fetoprotein 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-HCG 
beta human chorionic gonadotropin 
BA 
bone age 
BMI 
body mass index 
CEA 
carcino-embryonic antigen 
CFDA 
China Food and Drug Administration 
CPP 
central precocious puberty 
eCRF 
electronic case report form  
CRO 
contract research organization 
ECG 
electrocardiogram 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
-glutamyl transferase 
GnRH 
gonadotropin-releasing hormone 
GnRHa 
gonadotropin-releasing hormone analog 
hCG 
human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
LFT 
liver function test 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PPS 
per protocol analysis set 
PT 
preferred term 
PTE 
pretreatment event 
QTc 
corrected QT interval 
SAE 
serious adverse event 


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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SS 
safety analysis set 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TW3 
Tanner-Whitehouse 3 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives for 
Protocol Leuprorelin-4001. 
All decisions regarding final analysis, as defined in this SAP document, have been made prior to 
Database Lock (DBL) of the study data.   
2. 
 STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To evaluate the safety of leuprorelin in subjects with central precocious puberty (CPP). 
2.1.2. 
Secondary Objective 
To evaluate the efficacy of leuprorelin in subjects with CPP. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
 Subject incidence of treatment-emergent adverse events (TEAEs). 
2.2.2. 
Secondary Endpoint 
 Percentage of subjects who have regression or no progression in Tanner staging at Week 96 
compared with Baseline. 
2.2.3. 
Additional Endpoints 
 Percentage of subjects with suppression of peak luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) to pre-pubertal levels in stimulation test at Week 96. 
 Percentage of subjects with suppression of basal estradiol level in female subjects or 
testosterone level in male subjects to pre-pubertal level at Week 96. 
 Percentage of subjects with improvement in predicted adult height at Week 96 compared with 
Baseline. 
 Percentage of subjects with a decrease in the ratio of bone age (BA) to chronological age at 
Week 96 compared with Baseline. 


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 Change in laboratory values including changes in chemistry, hematology and bone 
metabolism biomarkers. 
 Change in body mass index (BMI). 
 Change in bone mineral density. 
 Incidence of polycystic ovarian syndrome in female subjects. 
3. 
STUDY DESIGN 
This is a phase 4, open label study to be conducted in China, to assess long-term safety and 
efficacy of leuprorelin in the treatment of CPP. Approximately 300 subjects will be enrolled. The 
treatment duration is 96 weeks. The study will consist of 3 periods including a 4-week Screening 
Period, a 96-week Treatment Period and a 4-week Safety Follow-up Period.  Followed by an 
observational follow-up period where subjects who remain on treatment will be observed at least 
every 24 weeks and after last dose all subjects will be followed up annually until stable puberty 
is reached. 
 Eligible CPP subjects with body weight ≥20 kg will receive the recommended dose of 
leuprorelin 3.75 mg SC every 4 weeks.  
 Eligible CPP subjects with body weight <20 kg will receive recommended dose of 1.88 mg 
SC every 4 weeks.  
It is not recommended to exceed 180 µg/kg. The dose can be adjusted based on subject’s 
condition and investigator’s judgment. Study visits, procedures, and evaluation are summarized 
in the Schedule of Study Procedures (Appendix A). Subjects will be followed until the end of the 
study, during which time they will be assessed by their treating physicians. serious adverse 
events (SAEs) and adverse events (AEs) will be recorded in the case report form (eCRF). 
Efficacy will be evaluated every 12 Weeks.  
Subjects will be given the first dose of study drug in the clinic at Day 1 (Visit 2, Week 0). The 
last dose of study drug will be given on the day of Week 96 (Visit 10). All dosing of study drug 
will take place in the clinic by appropriate site staff. End of study assessment will be conducted 
at Week 96 (Visit 10). All subjects who receive study drug will be required to have a Final Safety 
Visit (Visit 11) at approximately 4 weeks after the last dose. 
After the end of the study, subjects will participate in a long term observational follow-up. 
During the observation follow-up period, the patient visits to the referring physician are not pre-
specified by the study protocol, but will follow usual clinical practice. It is anticipated that the 
CPP patients will visit the site for check up at least every 24 weeks. All patient-care decisions, 


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including diagnostic and therapeutic interventions, will be made by and conducted at the 
discretion of the participating  study physicians according to their clinical judgement and the 
local standard of medical care. It is recommended to monitor patients every 12 to 24 weeks in the 
treatment guideline issued by China Ministry of Health [1]. The procedures are summarized in 
the Schedule of Study Procedures (Appendix A). All subjects will be followed up annually after 
the last dose of leuprorelin until stable puberty is reached. Stable puberty is defined as 96 weeks 
after menarche for girls, or secondary sexual characteristics development of Tanner staging V for 
boys. At each visit, the following data will be collect if it is reported in the patients medical 
record: Tanner staging evaluation, height and weight measurement, menstrual history assessment 
and pelvic ultrasonography for girls.  
Figure 3.a Schematic of Study Design 
                                                            
 
7.  
 
 
 
 
 
V=visit, D=day, Wk=week, SV=Screening Visit, EOS= End of Study, ET=Early Termination. 
A schedule of assessments is listed in Appendix AError! Reference source not found.. 
4. 
SAMPLE SIZE CONSIDERATION 
This study is not statistically powered for any hypothesis testing. Approximately 300 subjects 
will be enrolled into the study from multiple centers across China. The sample size of 300 
subjects is considered to be sufficient to fulfill the study objectives of the evaluation of safety 
and efficacy of Leuprorelin in the treatment of CPP as required by the China Food and Drug 
Administration (CFDA). 
5. 
ANALYSIS SETS 
 Safety Analysis Set (SS): The SS consists of all subjects who are enrolled and received at 
least 1 dose of study drug. 
 Full Analysis Set (FAS): The FAS consists of all subjects who are enrolled and received at 
least 1 dose of study drug. 
Wk 100 
D -28 to D -1 
Wk 0, 12, 24, 36, 48, 60, 72, 84, 96 
At least every 24 Wks 
Screening 
Period 
4 Wks 
Treatment Period 
96 Wks 
V 11/ET Visit/ 
Final Safety Visit 
Long term observational 
follow up 
V 10/EOS/ 
Last dose
Follow up 
Period 
4 Wks
V 2/D 1 
First dose 
V 1/ 
SV 
Visit 2, 3, 4, 5, 6, 7, 8, 9, 10 


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 Per Protocol Analysis Set (PPS): The PPS consists of all subjects who are in the FAS and 
have none of the following major protocol violations: 
o 
Subject doesn’t complete the Week 96 visit; 
o 
Subject has less than 90% treatment compliance; 
o 
Subject fails to meet inclusion criteria  No.s: 3, 4 and 6; 
o 
Subject meets exclusion criteria No.s: 1, 2, 4, 5, 6, and 8. 
6. 
STATISTICAL ANALYSIS 
6.1. 
General Statistical Considerations 
Statistical analysis will be performed using SAS® software (SAS Institute, Inc., Cary, North 
Carolina) Version 9.2, or later.  
Unless otherswise specified, all data summaries will be performed for the following groups: 
Males, Females, and All Subjects. Also, where applicable, separate tables will be provided for 
the Treatment period (upto including Week 100 visit) and the Follow-up period. Continuous 
variables will be summarized including the number, the mean, the standard deviation, median, 
minimum and maximum. Categorical variables will be summarized including the number and 
percentage of subjects. 
6.2. 
Data Handling Conventions 
6.2.1. Premature Withdrawal and Missing Data 
No imputation will be used for Missing data. 
6.2.2. Definition of Baseline and Change from Baseline 
Baseline is defined as the last non-missing measurement prior to first dose of study drug. 
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-baseline values. If either the baseline or post-baseline value is missing, the 
change from baseline is set to missing as well. 
6.2.3. Definition of Study Day 
For Screening and Treatment periods, the study day number will be calculated with respect to the  
treatment start date, and for the Follow-up period it will be calculated with respect to the date of 
the Week 100 Visit. Study Day is missing when target date is missing, and it is equal to target date – 
reference date when target date less than reference date, and it is equal to target date – reference date+1 


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when target date equal to or more than reference date. Therefore the day of first investigational drug 
administration for Treatment period is Day 1 and the day before first investigational drug 
administration for Treatment period is Day -1. The windows for mapping study days to study 
visit, for anlaysis purposes, is listed as table 6.a.Table 6.a 
Mapping study days to study visit 
Period 
Week/Study Day 
Visit Windows(Day) 
Visit Number 
Screening 
Day -28 to -1 
NA 
1 
Treatment 
Week 0/Day 1 
NA 
2 
Week 12/Day 84 
±14d 
3 
Week 24/Day 168 
±14d 
4 
Week 36/Day 252 
±14d 
5 
Week 48/Day 336 
±14d 
6 
Week 60/Day 420 
±14d 
7 
Week 72/Day 504 
±14d 
8 
Week 84/Day 588 
±14d 
9 
Week 96/Day 672 
±14d 
10 
Final safety Visit/ 
Early Termination Visit  
Week 100/Day 700 
±14d 
11 
Follow up 
 At 24 week intervals  
±28d 
  
 
6.3. 
Study Subjects 
6.3.1. Disposition of Subjects 
The number and percentage of subjects, that complete the study, or prematurely withdraw from 
the study will be summarized using safety analysis set. The number and percentage of subject 
that complete the treatment phase will also be tallied as well as the disposition of the subjects 
that discontinued prior to the follow-up period. In addition, the number and percentage of 
subjects who discontinuation from the study will be summarized by primary reason. In addition, 
individual reasons for discontinuation will be listed.  
The following category for primary discontinuation reason will be presented for this study. 
o Pretreatment Event (PTE) or AE 
o Significant Protocol Deviation 
o Lost to Follow-up 


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o Voluntary Withdrawal 
o Study Termination 
o Pregnancy 
o Lack of Efficacy 
o Investigator Judgment 
o Screen Failure 
o Other 
6.3.2. Protocol Deviation 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and institutional 
review board [IRB] or ethics committee [EC], as required). Significant deviations include, but 
are not limited to, those that involve fraud or misconduct, increase the health risk to the subject, 
or confound interpretation of primary study assessment. 
 The following category for deviation will be presented for this study. 
o Entry Criteria 
o Concomitant Medication 
o Procedure Not Performed per protocol (Primary Endpoint or Safety Related) 
o Study Medication 
o Withdrawal Criteria 
o Specify Deviation (Description, include date of site awareness if relevant) 
A summary of the number and percentage of patients with an significant protocol deviation by 
type of deviation will be provided using safety analysis set. Individual subject listings of 
significant protocol deviations will be provided. 
6.3.3. Demographic and Baseline Characteristics 
Patient demographics will be summarized using the safety analysis set.. The following 
demographic information will be presented for this study: 
o Sex; 
o Age; 
o Race;  


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o Height 
o Weight (as continuous variable) 
o Weight categories (i.e. <20 kg, ≥20 kg) 
o Age at date of diagnosis of CPP (derived determining number of days between date of 
birth and date of diagnosis divided by 365.25 to obtain age in years). 
Patient baseline characteristics will be summarized using the safety analysis set. The following 
baseline characteristics information will be presented for this study: 
o Tanner staging evaluation; 
o LH and FSH; 
o Estradiol or Testosterone; 
o Predicted adult height; 
o Bone age; 
o BMI; 
o Bone mineral density; 
 
Individual subject demographic and baseline characteristics data will be listed. 
6.3.4. Medical History and Concurrent medical conditions 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions. 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 28 days prior to signing of informed 
consent. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at screening examination. 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA),  and will be tabulated for the number and percent of 
patients by decreasing frequency based on safety analysis set.. 


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Individual medical history and concurrent medical conditions data will be listed. 
6.3.5.   Concomitant Medications 
Medication start and stop dates will be compared to the date of first dose of treatment to be 
classified as prior medications and concomitant medications.   
Prior medications are those medications that start and stop prior to the date of first dose of study 
treatment. Concomitant medications is any drug given in addition to the study medication and 
defines as those medications that start before, on or after the first day of study treatment of the 
defined treatment period and continue into the treatment period and/or continue into 30 days 
after last dose or after the week 100 visit.   
Concomitant therapy will be classified according to the World Health Organization Drug 
Dictionary (WHODRUG) and tabulated by WHO drug Anatomical Therapeutic Chemical (ATC) 
classification sorted by decreasing frequency and dose level based on safety analysis set. 
Individual subject concomitant medication data will be listed. 
6.4. 
Efficacy Analyses 
Efficacy analyses will be summarized using the FAS analysis set. Unless otherwise specified 
each summary of the efficacy variables will be presented for the primary time point (Week 96) as 
well as each planned visit. Only observed data will be summarized, and missing data will not be 
imputed. However, a visit called Final Visit will also be summarized; Final Value is defined as 
the last treatment phase value (ie. post-baseline and ≤ Week 100). 
A Pre-pubertal level will be any value less than (<) the upper limit of normal for the local 
laboratory, which value may be dependent on sex and/or age. If laboratory values are coverted to 
a common unit the normal ranges should also converted, however all comparisons to the pre-
pudertal level should be performed on the original unit. 
The related variables for efficacy analyses will be presented for this study. 
o Tanner staging 
o peak LH and FSH 
o basal estradiol (female) or testosterone level (male) 
o predicted adult height 
o the ratio of bone age to chronological age 


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The number and percentage of subjects who have regression or no progression in Tanner staging 
at Week 96 will be summarized, individual data will be listed.  
The number and percentage of subjects with suppression of peak LH and FSH, i.e. 
simultaneously,  after stimulation to pre-pubertal level at Week 96 (Visit 10) will be summarized, 
individual data will be listed. For each subject at each visit the peak value (i.e. largest value of 
the 0, 30, 60, 90 min samples) from the stimulation tests will be used,  
The number and percentage of subjects with suppression of basal estradiol level in female 
subjects or testosterone level in male subjects to pre-pubertal level at Week 96 (Visit 10) will be 
summarized, individual data will be listed.  
The number and percentage of subjects with improvement in predicted adult height at Week 96 
(Visit 10) compared with Baseline will be summarized, individual data will be listed.  
The number and percentage of subjects with a decrease in the ratio of bone age to chronological 
age at Week 96 (Visit 10) compared with Baseline will be summarized, individual data will be 
listed. Chronological age is determined using birthdate and date of the procedure to obtain age in 
days and then deviding by 365.25 to obtain age in years, not truncated to an integer. 
For above binary data, 95% confidence intervals will be presented with exact (Clopper-Pearson) 
method. 
6.5. 
Safety Analyses 
For all safety endpoints, Baseline is defined as the last non-missing measurement prior to first 
dose of study drug. Safety data will be summarized using the safety analysis set.  
6.5.1. Adverse Events 
Adverse events, including SAEs, are recorded in the eCRFs. AEs observed during the treatment 
period will be classified as treatment emergent adverse events (TEAEs) while those recorded 
during the follow-up period will be classified as clinical events.   Each AE will be coded to 
system organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
TEAEs are defined as AEs with onset occurring during the treatment phase and/or within 30 days 
(onset date – last date of dose +1≤ 30) after last study drug administration. However, for subjects 
that continue into the follow-up period, TEAEs will include all AEs up to the Week 100 visit. 
Clinical events will be any AE with onset after the Week 100 visit. 


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In general, AEs may be analyzed one of two ways. First method (subject count) is to report the 
count and percent of subjects reporting the AE. In this analysis a subject is only counted 1 time 
for the specific AE, and the percentage is with respect to the number of subjects in that safety set. 
For the treatment period the safety set is all subjects who receive at least 1 dose of study drug. 
For the follow-up period the safety set will be all subjects with at least 1 follow-up visit after the 
Week 100 visit. Second method (event count) is to count all events, for the specific AE, and 
calculate the rate per 100 patient years. Patient years (no. of days/365.25) for the treatment 
period will be determined from Day 1 to date of the Week 100 visit; patient years in follow-up 
period will be determined, at the subject level, from date of the Week 100 visit to date of last 
contact. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. 
Results in DEATH. 
2. 
Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
3. 
Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. 
Results in persistent or significant DISABILITY/INCAPACITY. 
5. 
 Lead to a CONGENITAL ANOMALY/BIRTH DEFECT.  
6. 
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
a. May require intervention to prevent items 1 through 5 above. 
b. May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
c. Includes any event or synonym described in the Takeda Medically Significant AE 
List (Table 6.b). 


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Table 6.b 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/Acute respiratory distress 
syndrome (ARDS) 
Hepatic necrosis 
Torsade de pointes/Ventricular fibrillation/Ventricular 
tachycardia 
Acute liver failure 
Malignant hypertension 
Anaphylactic shock 
Convulsive seizure 
Acute renal failure 
Agranulocytosis 
Pulmonary hypertension 
Aplastic anaemia 
Pulmonary fibrosis 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Confirmed or suspected endotoxin shock 
 
Confirmed or suspected transmission of infection 
agent by a medicinal product 
 
Neuroleptic malignant syndrome/malignant 
hyperthermia 
 
Spontaneous abortion/stillbirth and fetal death 
 
A PTE is defined as any untoward medical experience which occurs in a  subject who has signed 
an informed consent to participate in the study but prior to the administration of any study 
medication; it does not necessarily have to have a causal relationship with study medication or 
study procedures. 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE, if a subject is noted to have ALT or AST >3 ×ULN and 
total bilirubin >2 ×ULN for which an alternative etiology has not been identified, the event 
should be recorded as an SAE. In addition, an abnormal Liver Function Tests (LFT) Increases 
eCRF must be completed. 
For each study period AEs will be analyzed using the subject count method and the event count 
method, as described above. In each AE summary table, AEs will be presented at the MedDRA 
PT  and  SOC level. In these tables SOC levels will be listed alphabetically and under each SOC 
the PTs will be listed in order of decreasing frequency. Below is a list of different AE 
classifications to be analyzed; additional classifications may be identified later. Where 
appropriate, similar analyses will be produced for clinical events (i.e. those events reported 
during the follow up period). 
  all TEAEs 
 SAEs  


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o 
Repeat this analysis using all AE results for both the treatment phase and follow up 
phase pooled together. 
 Non serious AEs only at the PT level, overall and only those AEs meeting a minimum rate 
(eg. 5%) 
o 
Repeat this analysis using all AE results for both the treatment phase and follow up 
phase pooled together.  
 drug-related TEAEs 
 relationship of TEAEs to study drug (related vs. not-related) 
 severity of TEAEs (Mild, Moderate, Severe) 
 polycystic ovarian syndrome in female subjects 
Data listings will be provided for all AEs including PTE, TEAEs, AEs leading to study drug 
discontinuation, and SAEs. 
6.5.2. Safety Laboratory Evaluation 
Individual results of safety laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be summarized and listed.  
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized at 
each scheduled visit (Table 6.c). 
All clinical laboratory data (Table 6.c) will be listed. 
Table 6.c 
Safety laboratory test 
Laboratory Test 
Sample 
Visit 
Hematology 
RBC 
Visit1, 4, 6, 8, 11 
Follow-up visit 
Unscheduled Visit 
WBC 
Hemoglobin 
Hematocrit 
Platelets 
Clinical Chemistry 
ALT 
Visit1, 4, 6, 8, 11 
Follow-up visit 
Unscheduled Visit 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Total protein 
Creatinine 


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Statistical Analysis Plan 
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Version: 1.0 
 
20 
 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Urinalysis 
pH 
Visit1, 6, 11 
Unscheduled Visit 
Protein 
Glucose 
Blood 
Nitrite 
Microscopic Analysis (only if 
positive dipstick results): RBC/high 
power field WBC/high power field 
Epithelial cells, casts etc 
 
6.5.3. Vital Signs 
Vital signs include body temperature, respiratory rate, systolic blood pressure, diastolic blood 
pressure and pulse at each visit including scheduled visit (visit 1, 2, 3, 4, 5, 6, 7 8, 9, 10, 11, 
follow-up visit) and unscheduled visit. 
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be 
summarized and listed. 
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized at 
each scheduled visit.  
All vital sign data will be provided in the data listings. 
6.5.4. Height, Weight and BMI 
Baseline, postdose, and changes from Baseline in height, weight and BMI measurements will be 
summarize at each scheduled visit.  
All data for height, weight, BMI will be provided in the data listings. 


Takeda 
Statistical Analysis Plan 
Leuprorelin-4001 
Version: 1.0 
 
21 
 
6.5.5. ECG 
A standard 12-lead ECG will be recorded at each scheduled visit (visit 1, 3, 5, 7, 10, follow-up 
visit) and unscheduled visit. The investigator (or a qualified observer at the investigational site) 
will interpret the ECG within normal limits (Normal), abnormal but not clinically significant 
(Abnormal, NCS), or abnormal and clinically significant (Abnormal, CS). 
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet TDC’s 
markedly abnormal criteria will be summarized and listed. Analysis of central tendency for 
QT/corrected QT interval (QTc) and categorical analysis of QT/QTc will be performed. 
Baseline, postdose, and changes from Baseline for QT/corrected QT interval (QTc) will be 
summarized at each scheduled visit (visit 1, 3, 5, 7, 10, follow-up visit).  
Shift tables will be generated for the investigator’s ECG interpretations(Normal, Abnormal and  
NCS, Abnormal and CS) that changed from Baseline to the postdose collections by above groups 
at each scheduled visit (visit 1, 3, 5, 7, 10, follow-up visit).  
All ECG data will be provided in the data listings. 
6.6. 
Other Analyses 
The serum bone metabolism biomarkers including phosphorus, 25-hydroxy vitamin D, 
osteocalcin, crosslaps will be summarized at each scheduled visit (visit 2, 11) by Baseline, 
postdose and changes from Baseline, individual data will be listed. 
Baseline, postdose, and changes from Baseline in bone mineral density measurements will be 
summarized at each scheduled visit (visit 2, 11). All bone mineral density data will be provided 
in the data listings. 
Pelvic and testicular ultrasonography will be summarized at each scheduled visit (visit 1, 4, 6, 8, 
10, 11, follow-up visit) and data will be provided in listings. 
Other Variables: 
The physical examination findings will be presented in data listings. 
The urine pregnancy test, cranial magnetic resonance imaging (MRI), carcino-embryonic antigen 
(CEA), alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (β-HCG) at Screening 
will be summarized and listed. 


Takeda 
Statistical Analysis Plan 
Leuprorelin-4001 
Version: 1.0 
 
22 
 
Data collected during the observational follow-up phase will be summarized and individual data 
will be listed. 
6.7. 
Interim Analyses 
One interim analysis will be performed after Week 100(visit 11). All available efficacy and safety 
data will be evaluated and reported to CFDA. The study will be continued to the observational 
safety follow-up phase.  
 
7. REFERENCES 
1. CAI Depei, Precocious puberty and pubertal delay; Shanghai, China: Fudan University Press; 
June 1 2003, 16-23. 


Takeda 
Statistical Analysis Plan 
Leuprorelin-4001 
Version: 1.0 
 
23 
 
Appendix A Schedule of Study Procedures 
 
Screening 
Treatment 
 
 
Study Day/Week: 
Days 
 -28 to -1 
Wk 0/ 
Day 
1/first 
dose 
(a) 
Wk 
12 
Wk 
24 
Wk 
36 
Wk 
48 
Wk 
60 
Wk 
72 
Wk 
84 
Wk 96/
last 
dose 
Final safety Visit/ 
Early 
Termination Visit
Week 100 (b) 
Observational 
Follow-up 
visit 
(c) 
Visit Windows (Days): 
NA 
NA 
±5d
±5d
±5d
±5d
±5d
±5d
±5d
±5d
±5d 
Visit Number: 
1 
2 
3
4
5
6
7
8
9
10
11 
Informed consent 
X
 
 
Inclusion/exclusion criteria 
X
 
 
Demographics and medical 
history 
X
 
 
Medication history 
X
 
 
Physical examination 
X
 
X
X 
X
Vital signs 
X
X 
X
X
X
X
X
X
X
X
X 
X
Weight and height 
X
X 
X
X
X
X
X
X
X
X
X 
X
Concomitant medications 
X
X 
X
X
X
X
X
X
X
X
X 
Concurrent medical 
conditions 
X
 
 
Predicted adult height (d) 
X
 
X
X
 
X
Tanner staging evaluation 
X
X 
X
X
X
X
X
X
X
X
X 
X
Bone age (e) 
X
 
X
X
X
X
 
X
Hematology 
X
 
X
X
X
X 
X
Urine analysis 
X
 
X
X 
Urine Pregnancy test (f) 
 
X 
 
Pregnancy avoidance 
counseling  
X
X 
X
X
X
X
X
X
X
X
X 
Clinical chemistry  
X
 
X
X
X
X 
X
ECG 
X
 
X
X
X
X
 
X
Pelvic/Testicular 
ultrasonography (g) 
X
 
X
X
X
X
X 
X
LH and FSH 
 
 
X
X
X
 
Estradiol or  Testosterone 
 
X(j) 
X
X
X
X
X
X
X
X
X 
X
Stimulation test (h) 
X
 
X
X
 
Cranial MRI (i) 
X
 
 
CEA, AFP, β-HCG 
X
 
 
Bone mineral density (j) 
 
X (j) 
X 
Serum bone metabolism 
biomarker (k) 
 
X(j) 
X 
Injection investigational 
drug (l) 
 
X 
X
 
PTE assessment 
X
X 
 


Takeda 
Statistical Analysis Plan 
Leuprorelin-4001 
Version: 1.0 
 
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AE assessment 
 
X 
X
X
X
X
X
X
X
X
X 
X
NA=not applicable. 
(a) The day of first investigational drug administration for Treatment period is Day 1. The day before first investigational drug 
administration for Treatment period is Day -1. 
(b) Conduct Final Visit procedures for subjects discontinued early per Section Error! Reference source not found.. The end 
of study is defined as the date of the last visit (Week 100) of the last subject undergoing the study unless the study is stopped 
earlier by sponsor due to futility or for safety reasons.  Subjects who discontinued from the study for any reason will complete the 
Early Termination Visit/Final Safety Visit, 4 weeks after the last dose of leuprorelin. 
(c) During the observational follow- up period, it is recommended to monitor the subjects who remain on treatment at least every 
6 months or at a schedule based on the investigator's judgments until drug discontinuation to collect the following: height and 
weight, secondary sexual characteristics, hematology, clinical chemistry, ultrasonography, LH and FSH, estradiol or testosterone 
and ECG. ECG will also be performed 4 weeks after the last administration of leuprorelin.  All subjects will be followed up 
annually after the last dose of leuprorelin until stable puberty is reached. At each visit, the following will be performed: Tanner 
staging, height and weight, BMI, menstrual history, and pelvic ultrasonography for girls. Stable puberty is defined as 2 years after 
menarche for girls or Tanner staging V of secondary sexual characteristics development for boys.  
(d) Predicted adult height will be evaluated using Bayley-Pinneau method. 
(e) Bone age will be evaluated by investigators at each site using TW3 standards or Greulich-Pyle standards at Screening. All 
bone age x-ray will be sent for central reading before the end of the study 
(f) The female subject who, at the discretion of the investigator, is deemed to be of child bearing potential must provide negative 
urine pregnancy test at Day –1 or Day 1 prior to drug administration. 
(g) Pelvic ultrasonography will be performed for females to measure, uterus size and number/size of follicles. For males, 
ultrasonography will be performed to measure the testicular volume. These results if available already can be used as part of 
screening. If result is already available – whether at same site or hospital – within 28 days prior to first dose, the result can be 
used for screening, under the condition that the Site retains a copy of the data in file notes as source documents.   
(h) F test:  Blood samples will be collected at 0, 30, and 60, minutes after the injection of GnRH.  It is acceptable to use both 
GnRH and GnRHa in stimulation test; however, it is preferable to use GnRH as priority. These results if available already can be 
used as part of screening. If stimulation test result is already available – whether at same site or hospital – within 28 days prior to 
first dose, the result can be used for screening, under the condition that the Site retains a copy of the data in file notes as source 
documents.  (i) Cranial MRI can consist of only pituitary scan, including saddle region. 
(j) Bone mineral density will be evaluated by dual energy x-ray bone densitometry at selected sites, which can done at any time 
prior to the first dose after the Screening. Estradiol or Testosterone and Serum bone metabolim biomark also can be done at any 
time prior to first dose as part of screening visit. (k) Serum bone metabolism biomarker included phosphorus, 25-hydroxy vitamin 
D, osteocalcin, crosslaps. These 4 tests can be performed as per what is available at the given Site. These tests can done at any 
time prior to the first dose after the Screening. 
(l) Subcutaneous injection Leuprorelin every 4 weeks. For the dosing visits between Visits 2-3, between Visits 3-4,  between 
Visits 4-5, between visits 5-6, between visits 6-7, between 7-8, between 8-9, between visits 9-10: these  visit window is +/- 2 
days; in addition, the between gap between dosing cannot be less than 3 weeks (21 days).