An Observational, Retrospective Study to Evaluate the Long Term Safety and Effectiveness of Leuprorelin in the Treatment of Central Precocious Puberty
Conditions: Central Precocious Puberty
Sponsor: Takeda



•
Title: An Observational, Retrospective Study to Evaluate the Long Term Safety and Effectiveness 
of Leuprorelin in the Treatment of Central Precocious Puberty
NCT Number: NCT02993926
Protocol Approve Date: 26 January 2018
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.

TITLE PAGE
CONFIDENTIAL
NON-INTERVENTIONAL SAFETY STUDY
PROTOCOL

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1.0
TITLE
An Observational, Retrospective Study to Evaluate the Long Term Safety and Effectiveness of 
Leuprorelin in the Treatment of Central Precocious Puberty
Study Number: Leuprorelin-5001
Version Number: Amendment no. 01, 26 January 2018

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Approval
1.1
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also 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, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
PPD

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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 12.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix A– Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix B 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)

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TABLE OF CONTENTS
1.0
TITLE .............................................................................................................................2
Approval....................................................................................................................3
1.1
TABLE OF CONTENTS............................................................................................................5
2.0
LIST OF ABBREVIATIONS..........................................................................................7
3.0
MARKETING AUTHORIZATION HOLDER / SPONSOR ...........................................8
4.0
RESPONSIBLE PARTIES..............................................................................................9
5.0
ABSTRACT..................................................................................................................10
6.0
AMENDMENTS AND UPDATES ...............................................................................13
7.0
MILESTONES..............................................................................................................15
8.0
RATIONALE AND BACKGROUND...........................................................................16
9.0
RESEARCH QUESTION AND OBJECTIVES.............................................................17
10.0
RESEARCH METHODS ..............................................................................................18
Study Design ...........................................................................................................18
10.1
10.1.1 Study Population and Design .............................................................................18
10.1.2 Exposure............................................................................................................19
Variables .................................................................................................................19
10.2
10.2.1 Outcomes...........................................................................................................19
10.2.2 Variables to be Collected ...................................................................................20
10.2.3 Variables Collected During Each Study Phase....................................................24
Data Sources............................................................................................................26
10.3
Study Population......................................................................................................26
10.4
10.4.1 Inclusion Criteria ...............................................................................................26
10.4.2 Exclusion criteria ...............................................................................................27
Study Size................................................................................................................27
10.5
Data Handling and Recordkeeping...........................................................................27
10.6
10.6.1 Case Report Forms (Paper) ................................................................................27
10.6.2 Record Retention ...............................................................................................28
Data Analysis ..........................................................................................................29
10.7
10.7.1 Analysis Sets......................................................................................................29
10.7.2 Analysis of Demographics and Other Baseline Characteristics ...........................29
10.7.3 Effectiveness Analysis .......................................................................................29
10.7.4 Safety Analysis ..................................................................................................30
Quality Control and Quality Assurance ....................................................................31
10.8
10.8.1 Study-Site Monitoring Visits..............................................................................31

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10.8.2 Protocol Deviations............................................................................................31
10.8.3 Quality Assurance Audits and Regulatory Agency Inspections...........................32
Limitations of the Research Methods .......................................................................32
10.9
11.0
PROTECTION OF HUMAN SUBJECTS .....................................................................33
IRB and/or IEC Approval ........................................................................................33
11.1
Subject Information, Informed Consent, and Subject Authorization .........................34
11.2
Subject Confidentiality ............................................................................................35
11.3
Publication and Disclosure.......................................................................................35
11.4
12.0
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ................................................................................................................36
Definitions...............................................................................................................36
12.1
Collection and Recording of Adverse Events ...........................................................37
12.2
Reporting of Adverse Reactions to Regulatory Authorities/Ethics Committee ..........37
12.3
Other Safety Information .........................................................................................37
12.4
13.0
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS.......39
14.0
REFERENCES..............................................................................................................40
15.0
APPENDICES...............................................................................................................41

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2.0
LIST OF ABBREVIATIONS 
AE
adverse event
ADR
adverse drug reaction
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BA/CA
bone age/chronological age
BMD
bone mineral density
BMI
body mass index
CFDA
China Food and Drug Administration
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPP
central precocious puberty
CRF
case report form 
CRO
contract research organization
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 analogs
GPP
Good Pharmacoepidemiology Practices
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ISPE
International Society for Pharmacoepidemiology
LH
luteinizing hormone
MedDRA
Medical Dictionary for Regulatory Activities
PMDA
Pharmaceuticals and Medical Devices Agency
QTc
corrected QT interval
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SOC
system organ class
WBC
white blood cell
WHODRUG
World Health Organization Drug Dictionary

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3.0
MARKETING AUTHORIZATION HOLDER / SPONSOR
Marketing Authorization holder:
Takeda Pharmaceutical Company Limited,
1-1, Doshomachi 4-chome, Chuo-ku, Osaka Japan
Sponsor:
Takeda Development Center Asia,
Pte. Ltd 21 Biopolis Road Nucleos North Tower, Level 4 Singapore 138567

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4.0
RESPONSIBLE PARTIES
Contact Type/Role
China Contact
Serious Adverse Event Reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer
(carries overall responsibility for the conduct of the 
study)
Leading Principal Investigator
PPD

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5.0
ABSTRACT
Title
An Observational, Retrospective Study to Evaluate Long Term Safety and Effectiveness of 
Leuprorelin in the Treatment of Central Precocious Puberty
Rationale and Background
Precocious puberty refers to appearance of secondary sexual characteristics in boys before 9 
years and girls before 8 years [1]. 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]. Treatment 
goals include hormonal suppression, cessation of development of secondary sex characteristics, 
halting or preventing menarche, and preservation of adult height [1][2]. If left untreated, children 
with CPP can also face psychological challenge resulting from premature physical maturation 
that contrasts with their immature emotional development [2].
GnRH analogs (GnRHa) have been the standard of care for CPP [1]. Continuous exposure to 
GnRHa desensitizes pituitary gonadotropin receptors and suppresses luteinizing hormone (LH) 
and follicle stimulating hormone (FSH) secretion [2].
Leuprorelin acetate (trade name: ENANTONE) is a GnRHa widely used in the treatment of CPP. 
It was approved for CPP indication in China in 1998 at the dose of 30-90 μg/kg body weight 
subcutaneously administration every 4 weeks. However, recent clinical studies demonstrated that 
administration of leuprorelin acetate at lower than 90 μg/kg body weight cannot achieve optimal 
pituitary desensitization in many patients. If incomplete suppression is operative during 
treatment, GnRHa administration may exacerbate disease progression and bone age increase, 
impairing long-term outcome [3]. The dose greater than 90 μg/kg body weight was 
recommended in CPP treatment guideline issued in 2010 by the Ministry of Health of China and
Consensus on Diagnosis and Treatment of Central Precocious Puberty (2015) [4][5].
In 2013, China Food and Drug Administration (CFDA) approved the new dose of leuprorelin 
acetate at 30-180 μg/kg body weight, subcutaneous (SC), every 4 weeks [6]. The approval was 
based on results from the clinical trials of leuprorelin acetate conducted in US and Europe and a 
retrospective study in Japan [7][8]. There is a lack of safety and effectiveness data of leuprorelin 
acetate long term use in China. This retrospective, medical chart review study is designed to 
evaluate and compare descriptively the effectiveness and safety of high dose (≥90 μg/kg up to 
180 μg/kg) and low dose (<90 μg/kg down to 30 μg/kg) leuprorelin acetate in China.

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Research Question and Objectives
The goal of this study is to evaluate the safety and effectiveness of leuprorelin acetate in CPP 
treatment in China.
Objective 1: To describe the safety of high dose leuprorelin acetate (≥90 μg/kg up to 180 μg/kg) 
and low dose leuprorelin acetate (<90 μg/kg down to 30 μg/kg) in CPP treatment of at least 9 
continuous months of ENANTONE
Objective 2: To describe the long term effectiveness of high dose leuprorelin acetate (≥90 μg/kg
up to 180 μg/kg) and low dose leuprorelin acetate (<90 μg/kg down to 30 μg/kg) in CPP 
treatment of at least 9 continuous months of ENANTONE
Study Design
Observational retrospective medical chart review study.
Population
Patients with central precocious puberty treated with ENANTONE for at least 9 continuous 
months duration, initiated and received the last dose of ENANTONE treatment during the index 
period from 1 September 1998 to 30 September 2018 in multiple centers across China. Patients 
who were treated with other GnRHa (including generic leuprorelin acetate) after the 9-months 
treatment with ENANTONE can be enrolled into the study.
Outcomes
Primary Outcomes
1) Safety - Adverse events (AEs) and serious adverse events (SAEs) reported by physicians 
in the medical records (eg, incidence of any injection site reaction) during and after
treatment with ENANTONE
2) Effectiveness - Regression or no progression in Tanner staging during and after treatment 
with ENANTONE
Secondary Outcomes
1) LH and FSH suppression to prepubertal level during and after treatment with 
ENANTONE
2) Estradiol or testosterone level suppression during treatment with ENANTONE
3) Decrease in the ratio of bone age to chronological age (BA/CA ratio) during treatment 
with ENANTONE

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Additional Outcomes
1) Increase in predicted adult height during and after treatment with ENANTONE
2) Change from baseline in standard laboratory tests during and after treatment with 
ENANTONE
3) Incidence rate of polycystic ovarian syndrome during and after treatment with 
ENANTONE
4) Evaluation of the long term effect on reproduction
5) Change from baseline in bone mineral density (BMD) during and after treatment with 
ENANTONE
6) Change from baseline in body mass index (BMI) during and after treatment with 
ENANTONE
Data Sources
The retrospective study will be undertaken in China using the medical records of CPP patients 
from geographically distributed hospitals in both northern and southern China.
Study Size
Approximately 300 subjects (planned)
Data Analyses
A statistical analysis plan (SAP) will be prepared and finalized prior to completion of the data 
collection period. This document will provide further details regarding the definition of analysis 
variables and methodology to address all study objectives.

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6.0
AMENDMENTS AND UPDATES
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 01.
The primary purpose of this amendment is to revise the objectives, outcomes and 
inclusion/exclusion criteria to allow patients who were treated with GnRHa other than 
ENANTONE after the ENANTONE treatment to be enrolled into the study, provided that they 
have been treated with at least 9 continuous months of ENANTONE during the index period. 
Also, the index period is extended by 1 year from the original plan to enable further enrollment 
of patients.
Number
Section of study 
protocol
Amendment or update
Reason
1
Section 1.1
Approval
Updated the signatories.
To reflect the latest team membership.
2
Section 4.0
Responsible Parties
Updated the contact information.
To reflect the latest team membership.
3
Section 7.0
Milestones
Updated the actual dates for start 
of data collection and public 
disclosure.
To reflect the latest study progression.
4
Section 9.0
Research Question and 
Objectives (a)
Revised the wording for 
Objectives 1 and 2.
To reflect the change in study 
population (as described in row #5 of 
this table).
5
Section 10.1
Study Design (a)
Revised the study population 
requirement.
To allow patients who were treated with 
GnRHa other than ENANTONE after 
the ENANTONE treatment to be 
enrolled into the study provided that 
they have been treated with at least 9 
continuous months of ENANTONE 
during the index period.
6
Section 10.1
Study Design (a)
Added detailed description and 
diagram on the study design.
To clarify the definition of each study 
phase and time points.
7
Section 10.1
Study Design (a)
Extended the end of the index 
period from 30 September 2017 to 
30 September 2018.
To allow further enrollment of patients 
into the study.
8
Section 10.1
Study Design (a)
Added detailed description on 
dose groups.
To clarify how the patients will be 
categorized into each dose group.
9
Section 10.2.1
Outcomes (a)
Redefined the Secondary 
Outcomes by re-categorizing 
Secondary Outcomes #4 to #9 in 
the original protocol into 
Additional Outcomes #1 to #6.
To clarify the priority of the outcomes.
10
Section 10.2.1
Outcomes (a)
Removed the Secondary Outcome 
# 10 (Injection site reaction during 
the treatment phase) in the original 
protocol.
The assessment of injection site 
reaction is included in the Primary 
Outcome #1 (Safety).
(a) Section 5.0 (Abstract) also revised accordingly.

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Number
Section of study 
protocol
Amendment or update
Reason
11
Section 10.2.2
Variables to be 
Collected
New section created.
To clarify the types of variables to be 
collected.
12
Section 10.2.3
Variables Collected 
During Each Study 
Phase
New section created.
To clarify the variables to be collected 
during each study phase.
13
Section 10.4.1
Inclusion Criteria
Revised inclusion criteria #2, #3, 
#4 and #5.
To reflect the change in study 
population and index period (as 
described in rows #5 and #7 of this 
table).
14
Section 10.4.2
Exclusion Criteria
Revised exclusion criteria #1 and 
#2.
To reflect the change in study 
population (as described in row #5 of 
this table).
15
Section 10.7
Data Analysis
Revised the description of data 
analysis plan.
To reflect the change in study 
population (as described in row #5 of 
this table), and for clarification.
16
Section 10.7.1
Analysis Sets
Revised the definition of Per 
Protocol Set.
To reflect the change in study 
population (as described in row #5 of 
this table).
17
Section 10.7.3
Effectiveness Analysis
Revised the description of 
covariates on BMI analysis.
To revise typo.
18
Section 10.8.2
Protocol Deviations
Added description on protocol 
deviation rule.
To clarify that missing data for non-
mandatory variables will not be handled 
as protocol deviation.
19
Throughout the 
protocol
Revised/edited texts (including 
grammatical and editorial 
changes).
For clarification purposes.
(a) Section 5.0 (Abstract) also revised accordingly.

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7.0
MILESTONES
Milestone
Planned Date
Actual Date
Comments
Draft protocol to PRC
07 July 2016
07 July 2016
NA
Protocol approval 
30 Sep 2016
10 Oct 2016
NA
Start of data collection
31 Dec 2016
24 Jun 2017
NA
End of data collection
30 Jun 2018
To be determined
NA
Public Disclosure
31 Oct 2016
13 Dec 2016
NA
Final study results
30 Sep 2018
To be determined
NA
Final report of study results
31 Dec 2018
To be determined
NA

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8.0
RATIONALE AND BACKGROUND
Precocious puberty refers to appearance of secondary sexual characteristics in boys before 9 
years and girls before 8 years [1]. Children with CPP have premature secretion and release of 
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]. 
Treatment goals include hormonal suppression, cessation of development of secondary sex 
characteristics, halting or preventing menarche, and preservation of adult height [1][2]. If left 
untreated, children with CPP can also face psychological challenge resulting from premature 
physical maturation that contrasts with their immature emotional development [2].
GnRHa have been the standard of care for CPP [1]. Continuous exposure to GnRHa desensitizes 
pituitary gonadotropin receptors and suppresses LH and FSH secretion [2].
ENANTONE is a GnRHa widely used in the treatment of CPP. It was approved for CPP 
indication in China in 1998 at the dose of 30-90 μg/kg body weight subcutaneously 
administration every 4 weeks. However, recent clinical studies demonstrated that administration 
of leuprorelin acetate at lower than 90 μg/kg body weight cannot achieve optimal pituitary 
desensitization in many patients. If incomplete suppression is operative during treatment, GnRHa 
administration may exacerbate disease progression and bone age increase, impairing long-term 
outcome [3]. The dose greater than 90 μg/kg body weight was recommended in CPP treatment 
guideline issued in 2010 by the Ministry of Health of China and Consensus on Diagnosis and 
Treatment of Central Precocious Puberty (2015) [4][5].
In 2013, CFDA approved the new dose of leuprorelin acetate at 30-180 μg/kg body weight, SC, 
every 4 weeks [6]. The approval was based on results from the clinical trials of leuprorelin 
acetate conducted in US and Europe and a retrospective study in Japan [7][8]. There is a lack of 
safety and effectiveness data of leuprorelin acetate long term use in China. This retrospective, 
medical chart review study is designed to evaluate and compare descriptively the effectiveness 
and safety of high dose (≥90 μg/kg up to 180 μg/kg) and low dose (<90 μg/kg down to 30 μg/kg)
leuprorelin acetate in China.

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9.0
RESEARCH QUESTION AND OBJECTIVES
The goal of this study is to evaluate the safety and effectiveness of leuprorelin acetate in CPP 
treatment in China.
Objective 1: To describe the safety of high dose leuprorelin acetate (≥ 90 μg/kg up to 180 μg/kg) 
and low dose leuprorelin acetate (<90 μg/kg down to 30 μg/kg) in CPP treatment of at least 9 
continuous months of ENANTONE
Objective 2: To describe the long term effectiveness of high dose leuprorelin acetate (≥ 90 μg/kg 
up to 180 μg/kg) and low dose leuprorelin acetate (<90 μg/kg down to 30 μg/kg) in CPP 
treatment of at least 9 continuous months of ENANTONE

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10.0
RESEARCH METHODS
Study Design
10.1
10.1.1 Study Population and Design
This is an observational, retrospective study to evaluate long term safety and effectiveness of 
ENANTONE (leuprorelin acetate) in the treatment of CPP.
Approximately 300 patients with CPP, who were treated with ENANTONE for at least 9 
continuous months, who initiated and received the last dose of treatment during the index period 
from 1 September 1998 to 30 September 2018, will be enrolled into the study. Patients who were 
treated with other GnRHa (including generic leuprorelin acetate) after the 9-months treatment 
with ENANTONE can be enrolled into the study. Within each site, sequential eligible patients 
will be enrolled until the site’s patient quota has been reached. Medical records will be collected 
and reviewed.
Prior to ENANTONE treatment initiation, all relevant data (specified in Section 10.2.3.1), 
including data pertaining to the diagnosis of CPP will be collected at all available time points.
The ENANTONE Treatment Phase is the period during which patients were treated with at 
least 9 continuous months of ENANTONE. All relevant data (specified in Section 10.2.3.2) will 
be collected at all available time points.
The Follow-up Phase is the period after the ENANTONE Treatment Phase up to the day of last 
available follow-up data for the subject. All relevant data (specified in Section 10.2.3.2) will be 
collected at all available time points after the ENANTONE Treatment Phase. At a minimum, the 
data from the most recent time point available in the medical record should be included so as to 
include data on long term follow up of the subject. During the Follow-up Phase, a GnRHa 
Treatment Interval may apply to those patients who were treated with a GnRHa other than 
ENANTONE (either generic leuprorelin acetate or other GnRHa) for CPP; in this case, the dates 
of therapy with this other GnRHa should be noted in the case report form (CRF).
The study design is shown in Figure 10.a.

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Figure 10.a
Overview of Study Design
(a) Baseline: First day of administration of ENANTONE.
(b) End of Follow-up: The day of last available follow-up data for the subject.
10.1.2 Exposure
During the ENANTONE Treatment Phase, patients should have received at least 9 continuous 
months treatment with ENANTONE. According to the dose of ENANTONE the patient first 
received at Baseline and the weight of the patient at Baseline, each patient will be categorized to 
either one of the following dose groups:

Low dose group: subcutaneous injection of ENANTONE <90 μg/kg down to 30 μg/kg

High dose group: subcutaneous injection of ENANTONE ≥90 μg/kg up to 180 μg/kg
Variables
10.2
10.2.1 Outcomes
Primary Outcomes
1) Safety –Adverse events (AEs) and serious adverse events (SAEs) reported by physicians 
in the medical records (eg, incidence of any injection site reaction) during and after 
treatment with ENANTONE
2) Effectiveness - Regression or no progression in Tanner staging during and after treatment 
with ENANTONE
Secondary Outcomes
1) LH and FSH suppression to prepubertal level during and after with ENANTONE
2) Estradiol or testosterone level suppression to prepubertal level during and after treatment 
with ENANTONE

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3) Decrease in the ratio of bone age to chronological age (BA/CA ratio) during treatment 
with ENANTONE
Additional Outcomes
1) Increase in predicted adult height during and after treatment with ENANTONE
2) Change from baseline in standard laboratory tests during and after treatment with 
ENANTONE
3) Incidence rate of polycystic ovarian syndrome during and after treatment with 
ENANTONE
4) Evaluation of long term effect on reproduction
5) Change from baseline in BMD during and after treatment with ENANTONE
6) Change from baseline in BMI during and after treatment with ENANTONE
10.2.2 Variables to be Collected
The following variables may be collected and recorded on the CRF as are available in the 
subject's chart. At a minimum, data related to the primary and secondary endpoints should be 
collected. This includes data at time of diagnosis of CPP, at the beginning of the ENANTONE
Treatment Phase, at the end of the ENANTONE Treatment Phase and at the most recent time in 
the Follow-up Phase.
10.2.2.1 Informed Consent
Each patient or, when applicable, the subject’s legally acceptable representative must provide 
written informed consent before any study-required data are collected.
10.2.2.2 Patient Demographics
The date of birth, gender and family origin (North China/South China) of the patient will be 
recorded.
10.2.2.3 Disease History
The onset date of appearance of secondary characteristics and the CPP diagnosis date will be 
recorded.
10.2.2.4 BMD
The z-score for BMD and the anatomical site of measurement will be recorded. The BMD is 
typically determined using dual-energy X-ray absorptiometry, but BMD determined with any 
apparatus/mode is acceptable for collection. 
10.2.2.5 Bone Age, Growth Rate and BA/CA Ratio
Bone age (years and presence of any abnormalities) and growth rate will be recorded.

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BA/CA ratio will be calculated by the sponsor from the bone age and chronological age (derived 
from the date of birth, date when the X-ray was performed to assess bone age and the radiologic 
evaluation of bone age as available in the subject’s chart all of which will be recorded in the 
CRF). The calculated BA/CA results will not be recorded in the CRF.
10.2.2.6 Height, Predicted Adult Height, Weight and BMI
Height, predicted adult height and weight will be recorded.
The predicted adult height is preferably derived by the Tanner-Whitehouse 3 method; where not 
possible, Bayley-Pinneau method or other methods are also acceptable.
The BMI will be calculated by the sponsor from the patient’s weight and height recorded in the 
CRF. The calculated BMI results will not be recorded in the CRF.
10.2.2.7 Medical History and Comorbidities
The start/stop date of any medical history and/or comorbidities and whether any medication was 
given for the condition will be recorded. Medical history to be obtained will include determining 
whether the subject has any significant conditions or diseases relevant to the disease throughout 
the duration of the study and also prior to signing of informed consent.
10.2.2.8 Prior and Concomitant Medications
The dose and route of administration, start/stop date (including information on whether or not the 
start date was before the first dose of ENANTONE), and indication name of any medications 
used by the patient will be recorded.
10.2.2.9 Evaluation of Long Term Effect on Reproduction
The long term effect of GnRH agonist therapy on reproduction will be evaluated by the change 
in several parameters related to sexual maturity and if available fertility. These measures will be 
collected and qualitatively evaluated as available. These parameters include but may not be 
limited to measures such as changes in ovarian volume, follicle counts, presence and regularity 
of menstrual cycle in females, testicular volume in males, changes in the sex hormones in both 
sexes (LH, FSH, estradiol [female], testosterone [male]), and or elevated human chorionic 
gonadotropin beta subunit (β-HCG) in females and pregnancy and live births for both sexes.
Pelvic Measurement
The following data will be recorded:

Female patients: uterus length, ovarian volume, maximum follicle size, follicles number 
(left/right)

Male patients: testicular volume (left/right)

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Menstruation Cycles (Females)
For female patients, the age of menarche, rhythm of menstrual cycle (days) and menstrual 
quantity (normal/more than normal/less than normal) will be recorded.
Sexual Characteristic Examination
The following data will be recorded:

Female patients: pubic hair (Tanner staging), breast (Tanner staging)

Male patients: pubic hair (Tanner staging), beard, prominent Adam’s apple, voice change
Hormonal Measurements
The following data will be recorded:
LH, FSH, estradiol (female), testosterone (male)
β-HCG (Females)
Results of either serum or urine β-HCG will be recorded.
Pregnancy
If there is record of patient’s or the partner of the patient’s pregnancy, the following data will be 
recorded: date of last menstrual period before pregnancy, confirmation date of the pregnancy, 
estimated date of delivery (if applicable), outcome (live birth/therapeutic abortion/spontaneous 
abortion/stillbirth/neonatal death), number of births (and past birth dates if applicable).
10.2.2.10
Tanner Staging
Tanner staging data (breast [female], genitals [male], pubic hair [female/male]) will be recorded.
10.2.2.11
Cranial CT/MRI
Cranial CT/MRI results will be recorded.
10.2.2.12
Clinical Laboratory Test
Results of the parameters shown in Table 10.a will be recorded for urine analysis, hematology, 
and serum chemistry.

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Table 10.a
Clinical Hematology, Chemistry, and Urinalysis
Hematology
Chemistry
Urinalysis
Hematocrit
Hemoglobin
Platelets
RBC
WBC
Albumin
ALP
ALT
AST
Bicarbonate
BUN
Calcium
Creatinine kinase
Creatinine
Chloride
GGT
Glucose
Magnesium
Potassium
Sodium
Total bilirubin
Total protein
Glucose
Nitrite
Occult blood
pH
Protein
Specific gravity
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea 
nitrogen, GGT=gamma glutamyl transferase, RBC=red blood cell, WBC=white blood cell
10.2.2.13
Serum Markers of Bone Metabolism
Results of serum markers of bone metabolism (ie, crosslaps, osteocalcin, phosphorus, 
25-hydroxy vitamin D) will be recorded.
10.2.2.14
GnRH Stimulation Test
Results of GnRH stimulation tests (concentrations of LH and FSH at 0/30/60/90/120 min after 
injection) will be recorded.
10.2.2.15
Vaginal Bleeding (Females)
Any data of vaginal bleeding incidence (start/end dates and frequency) will be recorded.
10.2.2.16
Physical Examination
Any data of physical examination (ie, examination of the eyes, ears, nose, throat, cardiovascular 
system, respiratory system, gastrointestinal system, dermatologic system, extremities, 
musculoskeletal system, nervous system, lymph nodes, other) will be recorded.
10.2.2.17
ECG
12-lead ECG results (QT interval, corrected QTc interval [QTc], presence of any abnormalities) 
will be recorded.
10.2.2.18
Date of Visits and/or Hospitalizations
Date of visits and/or hospitalizations to the site will be recorded.
10.2.2.19
Drug Administration for CPP Treatment
The first date and dose of administration of ENANTONE, and the last date and dose of recorded 
administration of ENANTONE, and any other available data during the Treatment Phase will be 

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recorded. The dates of the first and last dose of ENANTONE need to be during the index period 
from 1 September 1998 to 30 September 2018.
If another GnRH agonist, such as generic leuprorelin, was administered for the treatment of CPP 
after 9 months of continuous ENANTONE, the first date and dose of administration of the GnRH 
agonist, and the last date and dose of recorded administration of the GnRH agonist, the 
medication name, and any other available data during the GnRHa Treatment Intervals will be 
recorded.
10.2.2.20
Adverse Events
Data on any AEs and SAEs (refer to Section 12.1 for definitions) will be recorded.
10.2.2.21
Study Completion
The reason for the completion of treatment with ENANTONE will be recorded.
10.2.3 Variables Collected During Each Study Phase
All data on the study-related variables described in Section 10.2.2 can be collected as available. 
Required variables to be collected during each study phase are described in the following 
Sections 10.2.3.1 and 10.2.3.2.
When the subject meets the protocol’s eligibility criteria (inclusion criteria) and henceforth 
enrolled into the study, the subject’s missing data – despite not satisfactory to fulfil a complete 
analysis for primary and secondary endpoints– will not be regarded as protocol deviation.
10.2.3.1 Variables Collected Prior to ENANTONE Treatment Initiation

Informed consent

Patient demographics

Disease history

BMD (z-scores)

Bone age and growth rate

Height, predicted adult height, and weight

Medical history and comorbidities

Prior and concomitant medications

Evaluation of long term effect on reproduction
–
Menstruation cycles (females)
–
Pelvic measurement
–
Sexual characteristic examination

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–
Hormonal measurements
–
β-HCG (females)
–
Pregnancy

Tanner staging

Cranial CT/MRI

Clinical laboratory test

Serum markers of bone metabolism

GnRH stimulation test

Physical examination

Date of visits and/or hospitalizations

Adverse events
10.2.3.2 Variables Collected During ENANTONE Treatment Phase, Follow-up Phase and 
GnRHa Treatment Intervals

Vaginal bleeding (females)

BMD (z-scores)

Bone age and growth rate

Height, predicted adult height and weight

Medical history and comorbidities

Prior and concomitant medications

Evaluation of long term effect on reproduction
–
Menstruation cycles (females)
–
Pelvic measurement
–
Sexual characteristic examination
–
Hormonal measurements
–
β-HCG (females)
–
Pregnancy

Tanner staging

Cranial CT/MRI

Clinical laboratory test

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
Serum markers of bone metabolism

GnRH stimulation test

Physical examination

ECG

Drug administration for CPP treatment (refer to Section 10.2.2.19)

Adverse events

Study Completion
Data Sources
10.3
This retrospective study will analyze data from medical records of CPP subjects (from 
approximately 300 subjects), from multiple centers across China. Approximately 6 medical 
facilities in China, from both northern and southern region of China will be selected for this 
study. The medical results of subjects from these medical facilities should provide reliable data 
on variables during the specified study phases as described in Section 10.2.2 and 10.2.3. The data 
collected between index period from 1 September 1998 to 30 September 2018 will be analyzed 
in this study. All data collected from patient’s medical chart can be reported as available. 
Patients from Leuprorelin-4001 Study can also be considered for Leuprorelin-5001 Study, with 
emphasis placed on analysis of data during the follow-up after the end of treatment with 
ENANTONE, considering this data will be lacking from these patients in the Leuprorelin-4001 
Study.
This study is observational and data will be collected as part of routine clinical practice and the 
outcomes will be reported based on available data. No imputation of missing data will be 
conducted.
Study Population
10.4
10.4.1 Inclusion Criteria
1)
Subjects with diagnosis of idiopathic CPP
2)
Subjects treated with leuprorelin acetate (ENANTONE) for at least 9 continuous months of 
therapy with either a stable dose of high dose (≥90 μg/kg up to 180 μg/kg) or low dose 
(<90 μg/kg down to 30 μg/kg).
3)
Subjects initiated and completed treatment during the index period from 1 September 1998 
to 30 September 2018
4)
Subjects who have the following information prior to initiation of ENANTONE and at least 
one record of each of the following parameters at the end of ENANTONE treatment in the 
medical records: Tanner staging, estradiol or testosterone level, and FSH and LH level. The 
subject should have at least one record of bone age prior to the initiation GnRHa therapy 

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with ENANTONE to support the diagnosis of CPP. In addition, the subject should have at 
least one record of bone age during treatment with ENANTONE.
5)
The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written informed consent form and any required privacy authorization prior to the 
initiation of any study procedure
10.4.2 Exclusion criteria
1)
Subjects treated with leuprorelin acetate or any other GnRHa for conditions other than CPP
2)
Subjects used any other GnRHa products for CPP treatment prior to initiation of 
ENANTONE therapy
3)
CPP patients with identified etiology, such as brain tumor or cranial irradiation
Study Size
10.5
Approximately 300 subjects will be enrolled into the study from multiple centers across China, 
as required by the CFDA. Within each site, eligible subjects will be enrolled until the site’s 
subject quota has been reached. The above sample size, if evenly split between low dose and 
high dose, will provide 95% confidence intervals (CIs) for the primary effectiveness variable 
with margins of error of approximately 7% and 6% if the observed effectiveness rates are 75% 
and 85%, respectively for low and high doses. Furthermore under these same assumptions a 95% 
CI for the odds ratio would have a lower bound >1.0, suggesting greater effectiveness for 
subjects treated with the high dose.
Data Handling and Recordkeeping 
10.6
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, 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).
10.6.1 Case Report Forms (Paper)
Completed case report forms (CRFs) are required for each subject who signs an informed 
consent.
The sponsor or its designee will supply investigative sites with paper CRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the CRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. CRFs must be completed in English. All paper CRFs must be filled out legibly in 
black or blue ballpoint ink (use of black ink is preferred).
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, and missing or unclear data. Queries may be issued by Takeda personnel 
(or designees) and will be answered by the site. 

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Corrections to paper CRFs are to be made by making a single-line strikeout of the incorrect 
information and writing in the revisions. All corrections must be initialed and dated. Reasons for 
significant corrections should additionally be included. All new additions are to be made with the 
date and signature or seal affixed.
The principal investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After submission of the CRFs to the sponsor, any change of, modification of or addition to the 
data on CRFs should be made by the investigator with use of change and modification records of 
CRFs (Data Clarification Form) provided by the sponsor. The principal investigator must review 
the Data Clarification Form for completeness and accuracy, and must sign, or sign and seal, and 
date the form.
CRFs 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 CRFs. The completed CRFs 
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.
10.6.2 Record Retention
The investigator agrees to keep the records stipulated in Section 10.6.1 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), 
copies of all paper CRFs and query responses, 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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Data Analysis
10.7
The clinical effective therapeutic dose as well as safety and effectiveness data of leuprorelin 
acetate used for the treatment of CPP will be summarized primarily using descriptive statistics; 
however inferential methods may be used to provide covariate adjustment as well as an indicator 
of data strength. To support the study objectives the primary data summaries will be focused on 
the ENANTONE treatment phase and the follow-up phase. The definition of each of these 
phases will be developed in the SAP. If more than 5% of subjects have CPP treatment with a 
generic GnRHa after ENANTONE then complimentary safety summary tables will be presented 
on those data from that therapy.
10.7.1 Analysis Sets
A statistical analysis plan (SAP) will be developed prior to releasing the study data to 
statisticians for analysis. Unless otherwise specified, statistical analyses will be performed using 
SAS © version 9.2, or later. Unless otherwise specified, data analyses and tabulations will be by 
dose level (high or low) and all subjects combined; with supportive analyses stratified by sex. 
Additional stratification variables may be identified in the SAP.
All enrolled subjects who are enrolled will be included in the Safety Analysis Set and the Full 
Analysis Set (FAS).
If 5% or more of the FAS set are found to have violated some of the following study criteria then 
repeat analysis will be performed on the Per Protocol Set, defined as subjects as follows:

Duration of treatment of at least 9 continuous months of leuprorelin acetate (ENANTONE), 
with evaluation
10.7.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for each of the dose level groups 
(high, low dose). Descriptive statistics (eg, N, mean, standard deviation, median, minimum, and 
maximum) will be generated for continuous variables (eg, age, height, weight, etc.) and the 
number and percentage of subjects within each category will be presented for categorical 
variables (eg, sex). Additional categories (eg, BMI intervals) maybe specified in the SAP. 
Medical history, concurrent medical conditions and concomitant medications will be tabulated. 
Descriptive statistics will also be determined for duration of time on treatment and follow up by 
dose level and by demographic categories (eg, male, female) within dose level.
10.7.3 Effectiveness Analysis
Any inferential statistical analysis resulting in p-values will be reported for the purpose of 
identifying notable findings rather than any formal test of statistical significance. Unless 
specified otherwise, all point estimates will be estimated alongside a companion 95% CI.
The primary effectiveness outcome, percentage of subjects who have regression or no 
progression (ie, response to treatment) in Tanner staging at the end of the ENANTONE
Treatment Phase will be analyzed using a Cochran-Mantel-Haenszel (CMH) test with sex as 

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strata variable and dose (high, low) as independent variable. The adjusted odds ratio and 95% CI
will be provided from the CMH test along with two-sided p-value. The 95% CI for the percent 
will also be determined using Clopper-Pearson exact method, unadjusted for sex, will be 
provided for overall responder and for each sub-response (regression/ no progression) for all 
subjects and by sex. If the final data are incompatible with the above analyses, then another 
method, such as ordinary percentages with 95% CIs (example using Wald type CIs), may be 
used.
Additional CMH analyses with adjustment by other demographic variables may be performed 
where necessary. If the data in the treatment period permits, similar analysis as described above 
will be performed at year intervals from the initiation of treatment, ie, Year 1, Year 2, etc.
The above analyses methodology will be also applied to the following effectiveness outcomes, at 
the end of the treatment phase and at year intervals, if appropriate:

Percentage of patients with LH suppression

Percentage of patients with FSH suppression

Percentage of patients with estradiol or testosterone level suppression to prepubertal level

Percentage of patients with a decrease from baseline in the ratio of bone age to chronological 
age

Percentage of patients with an increase from baseline in predicted adult height
Change from baseline for BMI at end of treatment phase will be analyzed. This analysis will also 
be performed at each year interval, as permitted by available data and where applicable, of the 
treatment phase.
The above analysis will be used for the following quantitative variables, with associated baseline 
value as covariate:

Change from baseline in BMI during the follow up phase, at yearly intervals, with end of 
treatment phase BMI as baseline

Change from baseline in BMD, at end of treatment phase and at yearly intervals

Change from baseline in BMD during the follow up phase, at yearly intervals with the end of 
treatment phase bone density as baseline

Change from baseline in patient height, at end of treatment phase and at yearly intervals

Change from baseline in patient height during the follow up phase, at yearly intervals with 
end of treatment phase height as baseline
10.7.4 Safety Analysis
Safety outcomes will be analyzed by treatment (high, low dose) and overall, and unless specified 
otherwise, will not be stratified by sex. Separate summaries will be performed for the treatment 
phase and the follow up phase, both overall and at year intervals.

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The primary safety outcome is the incidence per 100 person years (with 95% CIs) of AE and 
SAEs. All AEs and SAEs will be coded using the MedDRA coding dictionary. AEs and SAEs 
will be summarized together and separately at both MedDRA levels system organ class (SOC) 
and preferred term by tabulating the numbers of events, person years at risk and incidence per 
100 person years. Furthermore, overall total number of events, person years at risk, and 
incidence per 100 person years (ie, any AE/SOC at any time) will be provided.
Incidence rates per 100 person years (95% CI) for polycystic ovarian syndrome will be 
determined for female subjects, by treatment group.  Incidence rates per 100 person years for 
injection site reaction will be determined by treatment group. 
If the data permit, changes in standard laboratory tests will be summarized using descriptive 
statistics.
Quality Control and Quality Assurance
10.8
The study will be conducted in accordance with the International Society for
Pharmacoepidemiology (ISPE)Guidelines for Good Pharmacoepidemiology Practices (GPP)
(http://www.pharmacoepi.org/resources/guidelines_08027. cfm).
10.8.1 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 CRFs. 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 (contract research organization; CRO) and by the institutional review board (IRB) or 
independent ethics committee (IEC).
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee , including but not limited to the Investigator’s Binder, 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 CRFs 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.
10.8.2 Protocol Deviations
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, 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.
Note that missing data – despite not satisfactory to fulfil a complete analysis for primary and 
secondary endpoints– will not be regarded as protocol deviation.

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10.8.3 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 [PMDA]). 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 10.8.1.
Limitations of the Research Methods
10.9
This is an observational study, where the assignment to the dose level of leuprorelin acetate is at 
the discretion of the treating physician, which may also vary according to the patient’s body 
mass. Unlike clinical trials where treatment assignment is randomized to reduce physician bias, 
no randomization is used in the dose selection, and certain biases and confounding influences are 
inevitably present in the data to be analyzed. Subgroup analysis to evaluate the effect of dose on 
study outcomes will be performed for selected parameters.
This study is not statistically powered for any hypothesis testing, and all outcomes will be 
summarized using descriptive statistics. Since this study is observational and data will be 
collected as part of routine clinical practice and outcomes will be reported on the available data. 
No imputation of missing data will be conducted.

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11.0
PROTECTION OF HUMAN SUBJECTS
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 Good Clinical Practice (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 A. The principles of Helsinki are addressed through the 
protocol and through appendices containing requirements for informed consent and investigator 
responsibilities.
IRB and/or IEC Approval
11.1
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.
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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Subject Information, Informed Consent, and Subject Authorization
11.2
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.
Subject Confidentiality
11.3
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, PMDA), 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 dis charge 
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 11.2).
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 CRF).
Publication and Disclosure
11.4
The investigator is obliged to provide the sponsor with complete test results as required by 
protocol, 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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12.0
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
Definitions
12.1
Adverse Events
An AE is any untoward medical occurrence in a subject administered a medicinal product and 
which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, a new disease or worsening in severity or frequency of a concomitant disease, 
temporally associated with the use of a medicinal product, whether or not the event is considered 
causally related to the use of the product.
Adverse Reactions
An adverse reaction is an AE for which there is at least a reasonable suspicion of a causal 
relationship between an AE and a suspected medicinal product.
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:

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 12.a).

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Table 12.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
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered 
as “Important Medical Events” satisfying SAE reporting requirements.
Collection and Recording of Adverse Events
12.2
Reports of adverse events/reactions which are study outcomes or study covariates should be 
summarized as part of any interim safety analysis and in the final study report. SAE/adverse drug 
reaction (ADR) should be reported according to the following procedure:
A Takeda SAE/ADR 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/related.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE/ADR form should be transmitted within 24 hours to the attention of the contact listed 
in Section 4.0. The investigator should make sure the success of the reporting transmission.
Reporting of Adverse Reactions to Regulatory Authorities/Ethics Committee
12.3
Reporting will be in accordance with national regulations in China.
Other Safety Information
12.4
Where any of the following are study outcomes or covariates, they will be summarized in the 
study report and any interim reports:

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
Use during pregnancy

Overdose: This refers to the administration of a quantity of a drug given per administration 
or cumulatively, which is above the maximum recommended dose according to the 
authorised product information. Clinical judgement should always be applied.

Off-label use: This relates to situations where the drug is intentionally used for a medical 
purpose not in accordance with the authorised product information.

Misuse: This refers to situations where the drug is intentionally and inappropriately used not 
in accordance with the authorised product information.

Abuse: This corresponds to the persistent or sporadic, intentional excessive use of a drug, 
which is accompanied by harmful physical or psychological effects.

Medication error: This refers to any unintentional error in the prescribing, dispensing, or 
administration of a drug while in the control of the healthcare professional or patient.

Accidental occupational exposure: This refers to exposure to a drug, as a result of one’s 
professional or non-professional occupation.

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13.0
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
It is intended that study results will be presented to CFDA, as part of regulatory commitment 
study, to justify leuprorelin acetate long term use in China. Publication in peer-reviewed journals 
and presentation at scientific conferences may also be considered.

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14.0
REFERENCES
[1] Bertelloni S, Baroncelli GI. Current pharmacotherapy of central precocious puberty by 
GnRH analogs: certainties and uncertainties. Expert Opin Pharmacother. 2013;14(12):1627-
39.
[2] Mul D, Hughes IA. The use of GnRH agonists in precocious puberty. Eur J Endocrinol. 
2008;159 Suppl 1:S3-8.
[3] Partsch CJ, Hümmelink R, Peter M, Sippell WG, Oostdijk W, Odink RJ, Drop SL.
Comparison of Incomplete suppression of Pituitary-Gonadal activity in Girls with Central 
Precocious Puberty: Influence on growth and Predicted Final Height. Horm Res. 1993;39(3-
4):111-7.
[4] Chinese precocious puberty treatment guideline (2010).
[5] Consensus on Diagnosis and Treatment of Central Precocious Puberty (2015).
[6] Enantone prescription information (2013).
[7] T Tanaka, Y Naiki, R Horikawa. Evaluation of the dosage of LHRH analog in children with 
central precocious puberty. Japan Journal of Human Growth and Development Research. 
2010;16(2):85-92.
[8] Lee PA, Klein K, Mauras N, Neely EK, Bloch CA, Larsen L, et al. Efficacy and safety of 
leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of 
central precocious puberty. J Clin Endocrinol Metab. 2012;97(5):1572-80.

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15.0
APPENDICES
Annex 1
List of Stand-Alone Documents
Number
Document Reference 
Number
Date
Title
1
Appendix A
NA
Responsibilities of the Investigator
2
Appendix B
NA
Investigator Consent to Use of Personal 
Information

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Appendix A
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 
CRFs, 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.
11. Report adverse reactions to the sponsor promptly.

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Appendix B
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

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