A Phase III, Open-label, Multicentre, Single Arm Study to Assess the Efficacy and Safety of the Triptorelin 6-month Formulation in Chinese Paediatric Participants With Central Precocious Puberty.
Phase: PHASE3
Conditions: Central Precocious Puberty
Sponsor: Ipsen

D-CN-52014-244
CONFIDENTIAL
PROTOCOL VERSION 2.0: 29 APRIL 2022
PAGE 1/63
Protocol Title: A phase III, open-label, multicentre, single arm study to assess the efficacy and 
safety of the triptorelin 6-month formulation in Chinese paediatric participants with central 
precocious puberty
Protocol Number: D-CN-52014-244
Compound: Triptorelin pamoate (embonate) salt (IPN52014)
Short Title: A study to assess the efficacy and safety of the triptorelin 6-month formulation in 
paediatric participants with central precocious puberty.
Study Phase: Phase III
Sponsor Name: Ipsen Pharma
Legal Registered Address: 65, Quai Georges Gorse, 92100 Boulogne Billancourt, France
Regulatory Authority Identifier Numbers 
Not applicable
Date: 29 April 2022
Version number: 2.0
Persons supplied with this information must understand that it is strictly confidential.
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation.
  Protocol Protocol-V2.0-20220429-EN 2.0 EN 29 Apr 2022 | 
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D-CN-52014-244
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PROTOCOL VERSION 2.0: 29 APRIL 2022
PAGE 3/63
Principal Investigator Signature Page
I have read and agree to Protocol D-CN-52014-244, entitled ‘A phase III, open-label, 
multicentre, single arm study to assess the efficacy and safety of the triptorelin 6-month 
formulation in Chinese paediatric participants with central precocious puberty’. I am aware of 
my responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), 
local regulations (as applicable) and the study protocol. I agree to conduct the study according 
to these guidelines and to appropriately direct and assist the staff under my control, who will 
be involved in the study.
NAME: 
[ ]
TITLE:
[PRINCIPAL]
SIGNATURE:
INVESTIGATOR
DATE:
OFFICE:
[ ]
[ ]
[ ]
[ ]
[ ]
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D-CN-52014-244
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PROTOCOL VERSION 2.0: 29 APRIL 2022
PAGE 4/63
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
29 April 2022 (Version 2.0)
Original Protocol 
21 January 2021 (Version 1.0)
Amendment 1 (29 April 2022, Version 2.0)
Summary of change table from previous version of the protocol
Any new or amended text in the protocol is indicated in bold. Deletions are marked in strikeout 
text. Minor formatting and editing are not included.
Section 
WAS 
(Version 1.0, 21 January 2021)
IS
(Version 2.0, 29 April 2022)
Rationale
Sponsor 
Signatory
Update the 
information of 
the sponsor 
representative.
1.3 Schedule of 
Activities
(Table 2)
Add 
X[W]” to row “Clinical 
laboratory tests [p]”, column “Day 
1”.
w.
If 
the 
screening 
tests 
performed within 1 week 
prior to Day 1, clinical 
laboratory assessment will 
not be repeated on Day 1.
Clarify the 
time of 
clinical 
laboratory 
examination.
1.3 Schedule of 
Activities
(Table 2)
Add “X” to row “Body weight 
[m]”, column “Day 1”and “Month 
9”.
Add 
footnote 
“[v]” 
to 
row 
“Auxological 
parameters 
[j]”, 
column “Month 9”.
v.
BMI will not be collected at 
Month 9.
Clarify BMI 
measurement 
time.
1.3 Schedule of 
Activities
(Table 2 footnote)
d
Head MRI for all subjects to 
confirm CPP and check for 
tumours at screening, unless 
they have available brain MRI 
scans within 6 months for site 
to verify.
p
Clinical laboratory tests
including chemistry, 
haematology and urinalysis. In 
case of abnormal blood 
glucose as per investigator’s 
judgement, repetition of these 
tests will be performed before 
the injection and fasting status 
might be required. If the 
intervention injection is 
performed within 1 week of 
Screening tests, clinical 
laboratory assessment will not 
be repeated.
d
Head (Pituitary) MRI for all 
subjects to confirm CPP and 
check for tumours at 
screening, unless they have 
available MRI scans within 6 
months for site to verify.
p
Clinical laboratory tests 
including chemistry, 
haematology and urinalysis. In
case of abnormal blood 
glucose as per investigator’s 
judgement, repetition of these 
tests will be performed before 
the injection and fasting status 
might be required. 
Update 
according to 
the actual 
situation.
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rsion 2.0, 
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PAGE 5/63
Section 
WAS 
(Version 1.0, 21 January 2021)
IS
(Version 2.0, 29 April 2022)
Rationale
2.3 Benefit/Risk 
Assessment 
Detailed information about the 
known and expected benefits and 
risks and reasonably expected AEs 
of triptorelin may be found in the 
IB.
Detailed information about the 
known and expected benefits and 
risks and reasonably expected 
AEs of triptorelin may be found 
in the IB and development safety 
update report.
As per new 
template 
version.
4.2 Scientific 
Rationale for 
Study Design
The total blood volume (116 mL) 
to be collected during this study is 
considered to be an acceptable 
amount of blood to be collected 
over this time period from the 
population in this study based 
upon the standard reported in Ni 
[Ni 2017].
The total blood volume (114 mL) 
to be collected during this study is 
considered to be an acceptable 
amount of blood to be collected 
over this time period from the 
population in this study based 
upon the standard reported in Ni 
[Ni 20 7].
Update the 
total blood 
volume 
according to 
the actual 
situation.
5.1 Inclusion 
Criteria
-Girls with Tanner staging ≥2 for 
breast development and who have 
enlarged uterine length and/or 
ovarian 
volume 
and 
several 
follicles with diameter >4 mm in 
the ovary observed by pelvic type 
B ultrasound at the Screening visit; 
boys who have testicular volume 
≥4 mL observed by testicular 
orchidometer at the Screening 
visit.
-Girls with T nner staging ≥2 for 
breast d velopment and who have 
enlarged uterine length and/or 
ovarian volume and at least 2 
follicles with diameter >4 mm in 
the ovary observed by pelvic type 
B ultrasound at the Screening visit; 
boys who have testicular volume 
≥4 mL observed by testicular 
orchidometer at the Screening 
visit.
Clarify the 
minimum 
number of 
follicles larger 
than 4 mm in 
diameter.
8 STUDY 
ASSESSMENTS 
AND 
PROCEDURES
•
The maximum amount of 
blood 
collected 
from 
each 
participant over the dur tion of the 
study, 
including 
any 
extra 
assessments that may e required, 
will not exceed 1 6 mL. (see [Ni 
2017])
•
The maximum amount of 
blood 
collected 
from 
each 
participant over the duration of the 
study, 
including 
any 
extra 
assessments that may be required, 
will not exceed 114 mL. (see [Ni 
2017])
Update the 
total blood 
volume 
according to 
the actual 
situation.
8.4 
Pharmacokinetics
•
Approximately 4 mL of 
blood samples will be collected 
for measurement of triptorelin 6-
month formulation plasma 
concentrations of as specified in 
the SoA (Section 1.3) to be 
analysed at a bionalytics Service 
Provider (Covance). These blood 
samples will also be used to 
derive serum for bioanalytical 
cross-validation purposes.
•
Approximately 2 mL of 
blood samples will be collected 
for measurement of triptorelin 6-
month formulation plasma 
concentrations of as specified in 
the SoA (Section 1.3) to be 
analysed at a bionalytics Service 
Provider (Labcorp). 
•
Approximately 2 mL of 
blood samples will be collected 
to derive serum for bioanalytical 
cross-validation purposes.
Update 
according to 
the actual 
situation.
  Protocol Protocol-V2.0-20220429-EN 2.0 EN 29 Apr 2022 | 
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the
d
the
20 7
d
20 7].
d
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v
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ro
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he Screening
ro
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Girls with T nner
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Girls with T nne
breast d velopment 
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breast d velopme
enlarged uterine 
ed
enlarged uterine
ovarian volume
ve
ovarian volume
follicles with 
ve
follicles with 
the ovary ob
v
the ovary ob
B ultrasou
ov
B ultrasou
boys wh
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boys wh
≥4 m
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orch
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maximum amount of 
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PROTOCOL VERSION 2.0: 29 APRIL 2022
PAGE 6/63
Section 
WAS 
(Version 1.0, 21 January 2021)
IS
(Version 2.0, 29 April 2022)
Rationale
9.4.3.1
Pharmacokinetic 
Analyses 
Individual listings of triptorelin 
concentrations and descriptive 
summary statistics (n, mean, 
standard error of mean (SEM), 
SD, coefficient of variance 
(%CV), geomean, geomean SD, 
geomean %CV, median, min, 
max, 90% CI) will be presented 
by timepoint/visit following each 
administration. If required and 
warranted by the data, an attempt 
to build a model to characterize 
the PK in the population will be 
made. This will be described in a 
separate analysis plan and the 
outcomes summarised in a 
standalone report.
Individual listings of triptorelin 
concentrations and descriptive 
summary statistics (n, mean, 
standard error of mean (SEM), 
SD, coefficient of variance 
(%CV), geomean, geomean SD, 
geomean %CV, median, min, 
max, 95% CI) will be presented 
by timepoint/visit following each 
administration. If required and 
warranted by the data, an attempt 
to build a model to characterize 
the PK in the population will be 
made. An analysis to look at the 
relationship between 
concentrations versus efficacy 
and/
 safety may be performed 
if warranted by the data. This 
will be described in a separate 
analysis plan and the outcomes 
summarised in a standalone 
report.
Typo
corrected and 
relevant 
description 
added.
10.2 Appendix 2: 
Clinical 
Laboratory Tests
(Table 6)
a
If the intervention injection is 
performed within 1 week of 
Screening 
tests, 
clinical 
laboratory 
assessments 
(uri
lysis, biochemistry and 
haematology) will not be 
repeated on Day 1. 
Add “[a]” to row “Haematology” 
and “Routine Urinalysis”.
Add 
“X” 
to 
row 
“Alkaline 
Phosphatase”, 
column 
“Screening”.
a
If 
the 
screening 
tests 
performed within 1 week 
prior to Day 1, clinical 
laboratory 
assessments
(haematology, 
clinical 
chemistry and urinalysis) 
will not be repeated on Day 1
Update 
according to 
the actual 
situation.
10.3.2 Definition 
of Serious 
Adverse Events
A 
suspected 
or 
confirmed 
coronavirus COVID-19 (SARS-
CoV-2) infection must be reported 
as serious (seriousness criteria 
should 
be 
“other 
medically 
significant” if no other seriousness 
criteria 
are 
present 
(e.g. 
hospitalisation)).
A 
suspected 
or 
confirmed 
coronavirus COVID-19 (SARS-
CoV-2) 
infection 
should
be 
seriousness assessed based on 
the 
reported 
seriousness 
criteria. If no seriousness criteria 
is reported by the investigator, 
the COVID-19 infection will be 
collected and recorded as “non 
serious”.
Update to 
conform to 
new protocol 
template.
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d
K in
e.
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An ana
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and/
 safety may
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 safety ma
if warranted by 
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if warranted by 
will be describe
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will be describe
analysis plan
ve
analysis plan
summarise
ov
summarise
report.
ov
report.
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ervention injection is 
pp
ervention injection is 
p
med within 1 week
pp
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p
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p
ening 
tests
App
ening 
tests, 
clini
pp
, 
clini
App
oratory 
assessm
Ap
oratory 
assessm
uri
lysis, biochemis
Ap
uri
lysis, biochemis
Ap
haematology
Ap
haematology) will 
Ap
) will 
A
repeated on Day 1
A
repeated on Day 1
o
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Ad
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PAGE 8/63
Section 
WAS 
(Version 1.0, 21 January 2021)
IS
(Version 2.0, 29 April 2022)
Rationale
collection 
tool 
is 
unavailable. It must be 
retrospectively 
recorded as soon as the 
electronic 
data 
collection tool becomes 
available. 
•
Contacts 
for 
SAE 
reporting can be found 
on the SAE form and 
the cover sheet.
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PAGE 9/63
TABLE OF CONTENTS
LIST OF ABBREVIATIONS................................................................................................ 13
1
PROTOCOL SUMMARY ........................................................................................... 15
1.1
Synopsis.......................................................................................................................... 15
1.2
Schema ........................................................................................................................... 18
1.3
Schedule of Activities.................................................................................................... 19
1.4
Brief Summary.............................................................................................................. 21
2
INTRODUCTION ........................................................................................................ 22
2.1
Study Rationale............................................................................................................. 22
2.2
Background ................................................................................................................... 22
2.3
Benefit/Risk Assessment......................................... .................................................... 23
2.3.1
Risk Assessment .................................. ......... ............................................. 24
2.3.2
Benefit Assessment........................ ... ... ..................................................... 24
2.3.3
Overall Benefit: Risk Conclusion..
..................................................... 24
3
OBJECTIVES AND ENDPOINTS ....... ................................................................... 25
4
STUDY DESIGN..................................
..................................................................... 27
4.1
Overall Design................................... ........................................................................... 27
4.2
Scientific Rationale for Study Design.......................................................................... 27
4.3
Justification for Dose.............. .... .............................................................................. 28
4.4
End of Study Definition........... ..... ............................................................................. 28
5
STUDY POPULATION .......... ....... ........................................................................... 29
5.1
Inclusion Criteria................ . ..................................................................................... 29
5.2
Exclusion Criteria.........
......................................................................................... 29
5.3
Lifestyle Considerations............................................................................................... 30
5.3.1
Meals and Dietary Restrictions................................................................... 30
5.4
Screen Failures.............................................................................................................. 30
5.5
Criteria for Temporarily Delaying.............................................................................. 30
6
STUDY INTERVENTION AND CONCOMITANT THERAPY............................ 31
6.1
Study Intervention(s) Administered............................................................................ 31
6.2
Preparation, Handling, Storage and Accountability ................................................. 31
6.3
Measures to Minimize Bias: Randomisation and Blinding....................................... 32
6.3.1
Randomisation ............................................................................................ 32
6.3.2
Maintenance of blinding............................................................................. 32
6.4
Study Intervention Compliance................................................................................... 33
6.5
Dose Modification ......................................................................................................... 33
6.6
Continued Access to Study Intervention after the End of the Study ....................... 33
6.7
Treatment of Overdose................................................................................................. 33
6.8
Concomitant Therapy................................................................................................... 33
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6.8.1
Rescue Medicine ......................................................................................... 34
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 35
7.1
Discontinuation of the Study Intervention ................................................................. 35
7.1.1
Pregnancy.................................................................................................... 35
7.1.2
Temporary Discontinuation........................................................................ 35
7.2
Participant Discontinuation/Withdrawal from the Study ........................................ 35
7.3
Lost to Follow-up .......................................................................................................... 35
8
STUDY ASSESSMENTS AND PROCEDURES....................................................... 37
8.1
Efficacy Assessments .................................................................................................... 37
8.1.1
Luteinising Hormone and Follicle-stimulating Hormone Serum 
Concentrations .................................. ........................................................ 37
8.1.2
Gonadotropin-Releasing Hormone Stimulation Test................................ 37
8.1.3
Sex Steroids (Oestradiol and Testosterone Serum Concentrations)......... 37
8.1.4
Pubertal Stage Using the Tanner Method ................................................. 37
8.1.5
Auxological 
Parameters, 
Bone 
Age 
and 
Chronological 
Age 
Measurements and Gonad D velopment ................................................... 38
8.2
Safety Assessments.................................. ................................................................... 38
8.2.1
Physical Examinations .. ..... .................................................................. 38
8.2.2
Vital Signs ................. .
............................................................................ 38
8.2.3
Electrocardiograms...... ............................................................................. 38
8.2.4
Clinical Safety Laboratory Assessments .................................................... 38
8.2.5
Local Tolerability ... ...... ............................................................................ 39
8.2.6
Pregnancy Testing ..................................................................................... 39
8.3
Adverse Events, Serious Adverse Events and Other Safety Reporting................... 39
8.3.1
Time Period and Frequency for Collecting AE and SAE Information.... 39
8.3.2
Method of Detecting AEs and SAEs........................................................... 40
8.3.3
Follow-up of AEs and SAEs....................................................................... 40
8.3.4
Regulatory Reporting Requirements for SAEs.......................................... 40
8.3.5
Pregnancy.................................................................................................... 41
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs......................................................................... 41
8.3.7
Adverse Events of Special Interest ............................................................. 41
8.3.8
Reporting of Study Intervention Errors Including Misuse/Abuse............ 41
8.4
Pharmacokinetics.......................................................................................................... 42
8.5
Genetics and/or Pharmacogenomics ........................................................................... 42
8.6
Biomarkers .................................................................................................................... 42
8.7
Immunogenicity Assessments ...................................................................................... 43
8.8
Health Economics OR Medical Resource Utilization and Health Economics ........ 43
9
STATISTICAL CONSIDERATIONS ........................................................................ 44
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PAGE 11/63
9.1
Statistical Hypotheses................................................................................................... 44
9.2
Sample Size Determination.......................................................................................... 44
9.3
Analysis Sets .................................................................................................................. 44
9.4
Statistical Analyses ....................................................................................................... 45
9.4.1
General Considerations .............................................................................. 45
9.4.1.1
Reasons for Exclusion from the Analyses .................................................... 45
9.4.1.2
Significance Testing and Estimations .......................................................... 45
9.4.1.3
Statistical/Analytical Methods ..................................................................... 45
9.4.2
Analysis of Primary Endpoint .................................................................... 45
9.4.3
Analysis of Secondary Endpoints............................................................... 46
9.4.3.1
Pharmacokinetic Analyses........................................................................... 47
9.4.4
Safety Analyses................................. .. ..................................................... 47
9.4.5
Subgroups Analyses........................... ........ ............................................. 48
9.4.6
Other Analyses ...............................
.... ................................................. 48
9.5
Interim Analyses ............................................. ....... ..................................................... 48
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS....................................... ............................................................ 49
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations................. 49
10.1.1
Regulatory and Ethical Considerations ..................................................... 49
10.1.2
Financial Disclosure ....
......................................................................... 49
10.1.3
Legal Guardian Consent and Paediatric Participant Assent Processes:.. 49
10.1.4
Data Protection
.... .............................................................................. 50
10.1.5
Dissemination of Clinical Study Data........................................................ 51
10.1.6
Data Quality Assurance.............................................................................. 51
10.1.7
Source Documents ...................................................................................... 51
10.1.8
Study and Site Start and Closure................................................................ 52
10.1.9
Publication Policy ....................................................................................... 52
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 54
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ......................... 55
10.3.1
Definition of Adverse Events ...................................................................... 55
10.3.2
Definition of Serious Adverse Events......................................................... 56
10.3.3
Recording and Follow-Up of AE and/or SAE ........................................... 57
10.3.4
Reporting of SAEs....................................................................................... 58
10.4 Appendix 4: Contraceptive and Barrier Guidance ................................................... 58
10.4.1
Definitions................................................................................................... 58
10.4.2
Contraception Guidance............................................................................. 59
10.5 Appendix 6: Pubertal Stages According to Tanner Method..................................... 61
10.6 Appendix 7: Temporary Measures and Procedures Related to COVID-19 
Pandemic........................................................................................................................ 62
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11
REFERENCES.............................................................................................................. 63
LIST OF TABLES
Table 1
Objectives and Endpoints................................................................................... 15
Table 2
Schedule of Activities .......................................................................................... 19
Table 3
Triptorelin Risk Assessment............................................................................... 24
Table 4
Objectives and Endpoints................................................................................... 25
Table 5
Study Intervention Administered ...................................................................... 31
Table 6
Protocol-Required Safety Laboratory Tests..................................................... 54
LIST OF FIGURES
Figure 1 
Study Design ......................................... .............................................................. 18
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LIST OF ABBREVIATIONS
ABBREVIATION
Wording Definition 
AE(s)
Adverse Event(s)
BA
Bone Age
BMI
Body Mass Index
CA
Chronological Age
CI
Confidence Interval
CIOMS
Council for International Organisations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CPP
Central Precocious Puberty
CTFG
Clinical Trial Facilitation Group
CTCAE
Common Terminology Criteria for Adverse Events
eCRF
Electronic Case Report Form
%CV
Coefficient of variance
EU
European Union 
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Pr ctice
GLP
Good Lab ratory Practice
GnRH
Gonadotropin-releasing Hormone
GnRHa(s)
GnRH Agonist(s)
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IGF-1
Insulin-like Growth Factor 1
i.m.
Intramuscular
IMP
Investigational medicinal product
IRB
Institutional Review Board
ITT
Intention-to-treat
i.v.
Intravenous
IWRS
Interactive Web Response System
LAM
Lactational amenorrhoea method
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n Group
d
n Group
y Criteria for Adv
ed
y Criteria for Ad
port Form
ve
port Form
arianc
v
ariance
v
e
Appro
ion
o
ion
imulating Hormon
ro
imulating Hormon
linical Pr ctice
pr
linical Pr ctice
d Lab ratory Prac
p
d Lab ratory Prac
Gonadotropin
App
Gonadotropin-
pp
-relea
pp
relea
Ap
GnRH Agonist(s
Ap
GnRH Agonist(s
H
A
Hormone repl
Ap
ormone repl
A
Investigato
A
Investigato
rme
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ABBREVIATION
Wording Definition 
LH
Luteinising hormone
LHRH
Luteinising Hormone-releasing Hormone
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intention-to-treat
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for 
Adverse Events
PASS
Power Analysis and Sample Size
PK
Pharmacokinetic
PP
Per protocol 
PR
Prolonged Release
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS®
Statistical Analysis System®
SD(s)
Standard Deviation(s)
SEM
Standard error of the mean
SoA
Schedule of activities
SOC
System Organ Class
SUSAR
Suspect d unexpected serious adverse reaction
TEAE(s)
Treatment-emergent Adverse Event(s)
ULN
Upper Limit of Normal
USA
United States of America
WHO-DD
World Health Organization Drug Dictionary
WOCBP
Woman of childbearing potential
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Analysis System
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Analysis System®
d Deviation(s)
pro
d Deviation(s)
dard error of the m
pr
dard error of the m
chedule of activitie
pp
chedule of activitie
Ap
System Organ Cl
Ap
System Organ Cl
Suspect d 
Ap
Suspect d une
p
une
Treatment
A
Treatment
per L
A
L
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Objectives
Endpoints

To assess height (Z-score [height for age] and 
percentile for height for age) growth velocity and 
BA (Greulich and Pyle method) at Months 6 
and 12

Change in height (Z-score [height for age] and 
percentile for height for age) and growth velocity 
at Months 6 and 12 compared to baseline

Proportion of children in whom the BA/CA ratio 
did not rise at Month 6 and 12 relative to baseline 
(X ray)

Change in the ratio BA/CA at Months 6 and 12 
compared to baseline

To assess sexual maturation at Months 6 and 12

Proportion of children with stabilised pubertal 
(Tanner method) stage at Months 6 and 12.

To assess uterine length in girls and testis 
volumes in boys at Months 6 and 12

Proportion of girls with regression of uterine 
length at Months 6 and 12 (transabdominal 
ultrasound)

Proportion of boys with absence of progression 
of testis volumes at Months 6 and 12 (clinical 
assessment with orchidometer)

To assess the change of body weight and BMI at 
Months 6 and 12

Change in BMI and weight compared to baseline 
at Months 6 and 12

To assess the safety profile

To evaluate local tolerability at the injection site 
immediately and 2 hours after triptorelin injection

Incidence of TEAEs throughout the study, 
including local tolerability at the injection site 
immediately and 2 hours after triptorelin injection 

Change in clinical safety laboratory (blood 
biochemistry, haematology and urinalysis) 
parameters at Month 3, 6, 9 and 12 compared to 
baseline.

Change in physical examination and vital signs 
(blood pressure and heart rate) measurements at 
each visit compared to baseline

To assess the PK of plasma triptorelin 

Sparse plasma triptorelin concentrations at Day 1, 
Months 3, 6 and 12
BA=bone age; BMI=body mass index; CA=chronological age; CPP=central precocious puberty; FSH=follicle-
stimulant hormone; GnRH=gonadotropin-releasing hormone; i.v.=intravenous; IU=international unit; 
LH=luteinising hormone; PK=pharmacokinetics; PR=prolonged release; TEAEs=treatment-emergent adverse 
events
Overall Design:
•
This is an open-label, multicentre, single arm interventional study to evaluate the efficacy 
and safety of triptorelin 6-month formulation in Chinese paediatric participants with CPP 
over a period of 12 months.
•
This study aims to demonstrate that triptorelin 6-month formulation is efficacious in 
suppressing luteinizing hormone (LH) to prepuberal levels in children with CPP (defined 
as a peak LH ≤5 IU/L after intravenous (i.v.) gonadotropin-releasing hormone (GnRH) 
stimulation) at Month 6.
•
This study will enrol Chinese participants with CPP in girls less than 9 years old and 
boys less than 10 years old at initiation of triptorelin treatment. 
•
Approximately a total of 66 participants (including at least three boys) will be enrolled 
to be administered intramuscular (i.m.) injections of triptorelin on Day 1 and Month 6 of 
the study. The triptorelin injection dose will not be adapted based on body weight.
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oportio
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d
f testis volu
assessment with 
d
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
Change in BMI a
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Change in BMI
at Months 6 an
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at Months 6 an
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
Chan
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Chan
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Ap
sma triptorelin 
Ap
A
mass index; CA=
A
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•
The study consists of a Screening period (the Screening visit will take place up to 28 days 
before enrolment), during which participants with CPP will be screened for eligibility. 
Participants will receive triptorelin injections on Day 1 and Month 6 of the study. 
Participants will have study visits at Screening, Day 1 and at Months 3, 6, 9 and 12 
(Figure 1).
•
Each participant is expected to be enrolled in this study for a minimum of 12 months and 
up to 13 months (including Screening period).
•
Participants who complete the study will perform final procedures and assessments at the 
final visit (Month 12). Participants who withdraw from the study before the completion 
of the evaluation period will be invited to attend an Early Withdrawal visit to perform 
early discontinuation procedures and assessments.
Condition/Disease: Central precocious puberty
Study Hypothesis: Triptorelin 6-month formulation is safe and efficacious in children with 
CPP as confirmed by a suppressed peak-stimulated LH a  Month 6 (defined as peak of 
LH≤5 IU/L after i.v. GnRH stimulation).
Intervention Groups and Duration:
•
The study will consist of a Screening period (the Screening visit will take place up to 
28 days before enrolment), during which participants with CPP will be screened for 
eligibility before receiving the triptorelin injection (Day 1 of the study) and will visit the 
study centre at Month 3, 6, 9 and 12 (See Section 1.3). Participants will receive 
two injections during the study period before they attend the End of Study (EOS) visit at 
Month 12.
•
Participants who complete the study will perform final procedures and assessments at the 
final visit (Month 12). Parti ipants who withdraw from the study before the completion 
of the evaluation pe iod will be invited to attend an Early Withdrawal visit to perform 
early discontinuation procedures and assessments. 
Study Participant Duration: approximately 13 months; i.e. screening and two injections of 
the study intervention.
Intervention Duration: approximately 12 months; i.e. two injections of the study intervention.
Number of Participants: Approximately 66 participants will be enrolled in the study, 
including at least three boys. 
Statistical Methods: 
Sample Size determination
The sample size of this study is estimated based on following assumptions according to global 
pivotal study DEBIO 8206-CPP-301 [Klein 2016].
•
Expected outcome for the proportion of children with a suppressed LH response to the 
GnRH stimulation test (stimulated peak serum LH ≤5 IU/L) at Month 6 is 93%;
•
Null proportion is 80%; 
•
An exact binomial test of a proportion with a one-sided nominal significance level of 
0.025 and power =85%;
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•
Expected common dropout rate =5%. 
Under these assumptions, approximately 66 participants (Power Analysis and Sample Size 
(PASS) software) are planned to be enrolled into the study to ensure there are 62 treated 
participants to confirm the efficacy of the triptorelin 6-month formulation by the proportion of 
children with a suppressed LH response to the GnRH stimulation test at Month 6.
Primary Analysis 
For the primary efficacy endpoint, the summary statistics of number and percentage of 
participants and the exact two-sided 95% confidence interval (CI) for a binomial proportion 
will be computed by Statistical Analysis System® (SAS®) using the exact binomial distributions 
on the intention-to-treat (ITT) population (primary population of analysis), modified (m)ITT 
and per protocol (PP) sets.
Secondary Analyses 
For secondary efficacy endpoints related to a change at Months 3, 6, 9 and 12 compared to 
baseline, the descriptive summary statistics (n, mean, standard deviation (SD), median, 
minimum, maximum) will be calculated on the ITT population. In addition, secondary efficacy 
endpoints will be performed on the PP set. Exact two sided 95% CIs will also be constructed 
for all secondary endpoints expressed as percentages
1.2
Schema
The study design is shown in Figure 1.
Figu e 1
Study Design
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1.4
Brief Summary 
The purpose of this study is to assess the safety and efficacy of the triptorelin 6-month 
formulation in Chinese children with CPP. Efficacy will be defined by peak (LH levels ≤5 IU/L) 
after i.v. GnRH stimulation at Month 6. 
Study Participant Duration: approximately 13 months; i.e. screening and two injections of the 
study intervention.
Intervention Duration: approximately 12 months; i.e. two injections of the study intervention.
Visit Frequency: Screening, Day 1, Months 3, 6, 9 and 12.
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2
INTRODUCTION
Triptorelin is an agonist analogue of natural GnRH. The principal modification consists of 
substitution of natural glycine in position 6 by a D-amino acid (D tryptophan). Clinical and 
animal studies have provided positive results of triptorelin’s action in hormone-dependent 
disorders such as CPP, prostate cancer, endometriosis, uterine fibromyomas, in vitro 
fertilisation and breast cancer. 
2.1
Study Rationale
Currently marketed in China there is a triptorelin 1-month formulation indicated for the 
treatment of children with CPP.
A global pivotal study, DEBIO 8206-CPP-301, demonstrated the efficacy and safety of the 
6-month formulation over a period of 12 months and led to registration in the EU and USA. 
This current study is intended to document the efficacy, safety and PK of triptorelin 
6-month formulation in Chinese children with CPP over a period of 12 months. 
Henceforth in this protocol, triptorelin pamoate 22.5 mg 6-month formulation will be referred 
to as ‘triptorelin 6-month formulation’.
2.2
Background
Precocious puberty is a condition that causes early sexual development in girls and boys. While 
the chronological age (CA) limit for the onset of puberty is 8 years in girls and 9 years in boys 
for children in North America and Western European countries [Carel 2008], children with 
precocious puberty exhibit precocious pubertal development that can be 2.5 to 3 SDs earlier
than the current estimated average. The prevalence of precocious puberty is 10 times higher in 
girls than in boys [Carel 2008].
In a minority of children, precocio s puberty can occur due to an organic lesion (cerebral 
tumour); in most children, this condition is caused by the early release of GnRH (also known 
as luteinising hormone-releasing hormone (LHRH)) by the hypothalamus. In healthy children, 
GnRH stimulates the release of pitui ary gonadotropins follicle-stimulating hormone (FSH) and 
LH, which is then followed by pr longed suppression of these hormones, contributing to normal 
pubertal development. The form of precocious puberty caused by early GnRH stimulation is 
termed CPP. In children with CPP, early GnRH release leads to the precocious secretion of LH 
and FSH which, in turn, activate the early secretion of gonadal hormones by the ovaries or 
testes. 
Signs of puberty include pubic and axillary hair growth and changes in the child’s body shape 
and behaviour. Boys develop facial hair and their penis lengthens and girls develop breasts and 
may have menstrual periods. In children with CPP, these signs prematurely appear before the 
age of 8 years in girls and 9 years in boys, respectively. Furthermore, growth velocity 
accelerates, initially inducing a rapid height increase, which stops at an early age. Accelerated 
bone maturation leads to premature epiphyseal closure and a final height below the target height 
that was otherwise expected for the child’s age. These premature changes may also lead to 
psychological disorders in children with CPP. 
There is currently no nationwide epidemiology study of CPP data in China. Only two studies 
have been published about the incidence of precocious puberty in two cities: Jiu Jiang (study 
with 3,312 children investigated and an incidence of 0.68%, 1.25% in girls and 0.11% in boys) 
[Hu 2012] and Zhengzhou (study with 8,750 children investigated and an incidence of 0.74%, 
1.37% in girls and 0.26% in boys) [Wei 2010]. In coastal areas of China, precocious puberty 
has an incidence rate of 0.38%; the incidence in girls is higher at 0.67%. The prevalence of 
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precocious puberty in Shanghai is 100/10,000 [Lin 2004]. These data refer to precocious 
puberty without GnRH-dependent stimulation, which is not specific for CPP and are probably 
lower than numbers described above.
As reported by Carel and Léger [Carel 2008], the assessment of gonadotropin levels (based on 
ultrasensitive assays) is central to the diagnosis of CPP. The gold standard for evaluation is the 
measurement of gonadotropin levels after stimulation with GnRH or a GnRH agonist (GnRHa). 
Peak LH levels of 5 to 8 IU/L suggest progressive CPP but there is an overlap between 
prepubertal and early pubertal values [Carel 2008, Resende 2007]. Caution should be taken 
when interpreting gonadotropin levels in children younger than 2 to 3 years old as gonadotropin 
levels are normally high in this age group [Carel 2008].
In CPP (i.e. with no other identified cause such as a cerebral tumour), there is no surgical 
therapy available and no effective alternative therapeutic option other than taking a prolonged 
release (PR) formulation of synthetic GnRH. In severe cases, untreated CPP causes physical 
and psychological problems for the child. 
Treatment with GnRH analogues, which act by downregulating pituitary GnRH receptors
[Carel 2009, Comite 1981 Crowley 1981, Bertelloni 2013]  represent the standard of care for 
the treatment of CPP [Carel 2009]. Their efficacy to stop precocious development has been 
demonstrated and their use involves only minor adverse events (AEs). A review of CPP 
treatment by Krishna et al confirmed that treatment with PR formulations of GnRHas is safe, 
with relatively minor side effects, and supported that the outcome in terms of final height is 
favourable in most patients [Krishna 2019]. 
Diphereline® (international non-proprietary name (INN): triptorelin) is a synthetic GnRH 
analogue that is mainly characterised by th  replacement of the L-glycine in the 6th position by 
a D-tryptophan. This structural modification increases both the resistance to enzymatic 
degradation and the affinity to the pituitary receptor, thus prolonging the plasma half-life (t1/2) 
and increasing the potency of the drug
In China, Diphereline® is availabl  as a 1-month formulation, which is approved for use in 
patients with CPP, prostate c ncer  end metriosis, fibromyomas and female infertility.
Study DEBIO 8206-CPP-301 was the first 6-month triptorelin clinical trial in the treatment of 
CPP sponsored by Debiopharm International SA [Klein 2016]. This was an international, 
multicentre, nonrandomised, open-label, noncomparative phase III study of two i.m. injections 
of triptorelin 6-month formulation administered twice over 12 months in a group of 44 children 
with CPP comprising 39 girls and 5 boys. The 6-month formulation was safe and effective in 
suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval 
may improve compliance and increase comfort in the management of CPP.
The worldwide marketing status of all triptorelin formulations of which Ipsen and Debiopharm 
are the marketing authorisation holders (marketed by Ipsen under Debiopharm/Ipsen agreement) 
can be found in the Investigator’s Brochure (IB). Further details/additional information 
regarding risks and benefits to participants may also be found in the IB.
A more detailed description of the product, including further details on administration 
procedures and dosage are provided in Section 6.
2.3
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of triptorelin may be found in the IB and development safety update report.
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Objectives
Endpoints

To assess the safety profile

To evaluate local tolerability at the injection site 
immediately and 2 hours after triptorelin injection

Incidence of TEAEs throughout the study, 
including local tolerability at the injection site 
immediately and 2 hours after triptorelin injection 

Change in clinical safety laboratory (blood 
biochemistry, haematology and urinalysis) 
parameters at Month 3, 6, 9 and 12 compared to 
baseline.

Change in physical examination and vital signs 
(blood pressure and heart rate) measurements at 
each visit compared to baseline

To assess the PK of plasma triptorelin 

Sparse plasma triptorelin concentrations at Day 1,
Months 3, 6 and 12
BA=bone age; BMI=body mass index; CA=chronological age; CPP=central precocious puberty; FSH=follicle-
stimulant hormone; GnRH=gonadotropin-releasing hormone; i.v.=intravenous; IU=international unit; 
LH=luteinising hormone; PK=pharmacokinetics; PR=prolonged re ase; TEAEs=treatment-emergent adverse 
events
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4
STUDY DESIGN
4.1
Overall Design
•
This is an open-label, multicentre, single arm interventional study to evaluate the efficacy 
and safety of triptorelin 6-month formulation in Chinese paediatric participants with CPP 
over a period of 12 months.
•
This study aims to demonstrate that triptorelin 6-month formulation is efficacious 
suppressing LH to prepuberal levels in children with CPP (defined as a peak LH ≤5 IU/L 
after i.v. GnRH stimulation) at Month 6.
•
This study will enrol Chinese participants with CPP in girls less than 9 years old and in 
boys less than 10 years old at initiation of triptorelin treatment. 
•
Approximately a total 66 participants (including at least three boys) will be enrolled to 
be administered i.m. injections of triptorelin on Day 1 and Month 6 of the study. The 
triptorelin injection does not have to be adapted based on body weight.
•
The study consists of a Screening period (the Screening visit will take place up to 28 days 
before enrolment), during which participants with CPP will be screened for eligibility. 
Participants will receive triptorelin injections on Day 1 and Month 6 of the study. 
Participants will have study visits at Screening  Day 1 and Months 3, 6, 9 and 12
(Figure 1). 
•
Each participant is expected to be enrolled in this study for a minimum of 12 months and 
up to 13 months (including Screening period).
•
Participants who complete the study will perform final procedures and assessments at the 
final visit (Month 12). Participants who withdraw from the study before the completion 
of the evaluation period will be invited to attend an Early Withdrawal visit to perform 
early discontinuation procedures and assessments.
The study design is illustrated in Figure 1.
4.2
Scientific Rationale for Study Design
This uncontrolled phase III study will investigate the efficacy, safety and PK of triptorelin 
6-month formulation in children with CPP over 12 months.
For CPP, a non-comparative, open clinical trial design is acceptable as the efficacy of triptorelin 
will be assessed by the percentage of children achieving LH suppression to pre-pubertal levels, 
defined as LH ≤5 IU/L, after GnRH stimulation at Month 6 (primary endpoint).
As the efficacy of the drug is based on the suppression of the pituitary receptors responsible for 
LH (and FSH) production, no studies in this field with any GnRHa have had a comparative 
design. The recent approved leuprolide 3 months formulation in China is one of the examples 
of single arm, non-comparative design.
The LH response after the GnRH stimulation test, associated with clinical data and within a 
context of CPP, constitutes a reliable and feasible resource and can assist in monitoring the 
effectiveness of treatment.
The primary objective of the study is to assess the percentage of children with LH level 
suppression to prepubertal levels (serum LH ≤5 IU/L after GnRH stimulation) at Month 6. 
Participants would receive two injections of triptorelin (Day 1 and Month 6) and be followed 
for a total of 12 months. The objective of this study is to exclude any ethnicity factor that may 
lead to a different response. The serum LH ≤5 IU/L cut-off for primary endpoint definition of 
prepubertal levels is consistent with the global pivotal DEBIO 8206-CPP-301 study.
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d based 
d
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Screening visit
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Measures to safeguard the development and maturation of the child including assessment of 
physical growth, neuropsychiatric development, sexual maturation will be implemented and 
subject to close monitoring.
The total blood volume (114 mL) to be collected during this study is considered to be an 
acceptable amount of blood to be collected over this time period from the population in this 
study based upon the standard reported in Ni [Ni 2017].
This study will evaluate the PK profile of triptorelin 6-month formulation given to paediatric 
participants with CPP. The blood sample collection scheme was designed to collect the 
minimum number of blood samples to help provide useful information on the PK of the 
triptorelin 6-month formulation in paediatric Chinese population.
As with all clinical and PK studies, there are risks associated with venipuncture and multiple 
blood sample collection. To avoid multiple venipunctures, which cause additional discomfort 
and other potentially toxic effects, the use of i.v. indwelling catheters is permitted in this study. 
This minimises the number of venipunctures and the total volume of blood collected from each 
participant during the study.
4.3
Justification for Dose
For this intervention, the term “dose” refers to the i.m  injection of a triptorelin 22.5 mg created 
to guarantee the release of a monthly dose of 3.75 mg over a 169-day period. For more 
information see Section 6.5. This formulation has been made available in different countries 
(such as USA, Europe, South-East Asia) for th  treatment of CPP since 2009 and has been 
tested in the phase III Study DEBIO 8206-CPP-301 (see Section 2.2).
4.4
End of Study Definition
The EOS is defined as the date of the last visit of the last participant in the study as shown in 
the schedule of activities (SoA) (Table 2)
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit.
Criteria for study intervention di
ontinuation and participant discontinuation/withdrawal from 
the study are described in Section 7.1 and Section 7.2, respectively. Loss to follow-up is 
described in Section 7.3.
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llin
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total volu
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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
(1)
Participant is less than 9 years old for girls and less than 10 years old for boys at initiation 
of triptorelin treatment or at the time of signing the informed consent. 
Type of Participant and Disease Characteristics
(2)
Participant must present evidence of CPP documented by:
-
Onset of development of secondary sex characteristics (breast development in girls 
or testicular enlargement in boys according to the Tanner method: Stage II) before 
the age of 8 years in girls and 9 years in boys
-
Pubertal response of LH to GnRH stimulation test (stimulated peak LH ≥6 IU/L) 
in both sexes.
-
Difference between bone age (BA) and CA >1 year.
-
Girls with Tanner staging ≥2 for breast development and who have enlarged 
uterine length and/or ovarian volume and at least 2 follicles with diameter >4 mm 
in the ovary observed by pelvic type B ultrasound at the Screening visit; boys who 
have testicular volume ≥4 mL observed by testicular orchidometer at the 
Screening visit.
Sex and Contraception/Barrier Requirements
(3)
Girls who have already had menophania/menarche must have a negative highly sensitive 
(urine) pregnancy test as required by local regulations within 24 hours before the first 
dose of study intervention (see Section 8.2.6) and should not be at risk of pregnancy 
throughout the study period.
•
Additional requirements for pregnancy testing during and after study intervention 
are located in Section 8.2.6.
•
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a female participant 
with an early undetected pregnancy.
Informed Consent and Assent
(4)
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant’s legal guardian (as defined in Appendix 10.1.3) and the 
participant’s assent, in case determined by local requirements before any study-specific 
activity is performed. All legal guardians should be fully informed, and participants 
should be informed to the fullest extent possible, about the study in language and terms 
they are able to understand.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 
(1)
Major medical or psychiatric illness that could interfere with study visits.
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ng to t
d
ng to t
n boys
d
n boys
timulation test (st
ed
timulation test (
A
v
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and CA >1 ye
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2 for breast deve
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v
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pelvic type B ultra
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pelvic type B ultra
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r
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(2)
Gonadotropin-independent (peripheral) precocious puberty: extrapituitary secretion of 
gonadotropins or gonadotropin-independent gonadal or adrenal sex steroid secretion.
(3)
Non-progressing isolated premature thelarche.
(4)
Presence of an unstable intracranial tumour or an intracranial tumour requiring 
neurosurgery or cerebral irradiation. Participants with hamartomas not requiring surgery 
are eligible.
(5)
Any other condition or chronic illness or treatment possibly interfering with growth or 
other study endpoints (e.g. chronic steroid use except topical steroids, renal failure, 
diabetes, moderate to severe scoliosis).
Prior/Concomitant Therapy
(6)
Prior or current therapy with a GnRHa, medroxyprogesterone acetate, growth hormone 
or insulin-like growth factor 1 (IGF-1).
(7)
Use of anticoagulants (heparin and coumarin derivatives) within the 2 weeks prior to the 
Screening visit.
Prior/Concurrent Clinical Study Experience
Not applicable
Diagnostic Assessments
(8)
Evidence of renal (creatinine >1.5 x upper limit of normal (ULN)) or hepatic impairment 
(bilirubin >1.5 x ULN or alanine aminotransferase or aspartate transaminase >3 x ULN)
Other Exclusions
(9)
Diagnosis of short stature, i.e. >2.25 SD below the mean height for age
(10)
Known hypersensitivity to any of the test materials or related compounds.
5.3
Lifestyle Considerati ns
5.3.1
Meals and Dieta y Restrictions
Participants will refrain from poppy seed consumption from 48 hours prior to Day 1 and until 
the EOS visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is required
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes date of informed consent, demography, 
reason for screen failure, eligibility criteria and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) will not 
be rescreened.
5.5
Criteria for Temporarily Delaying
Not applicable. For information about temporarily delaying during the COVID-19 pandemic, 
please see the Appendix 7 in Section 10.6.
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erivativ
d
erivativ
x upper limit of no
ov
upper limit of no
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Ap
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poppy see
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6
STUDY INTERVENTION AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
Study intervention is described in Table 5.
Table 5
Study Intervention Administered
Arm Name
Triptorelin 6-month
Intervention Name
Triptorelin pamoate (embonate) salt
Intervention Description
A PR formulation of triptorelin pamoate 6-month formulation 
in D,L lactide co glycolide polymers for single i.m. injection
Type 
Drug
Dose Formulation
A yellow freeze-dried cake or powder supplied in a single 6 
mL glass vial
Unit Dose Strength(s)
22.5 mg (with release of  monthly dose of 3.75 mg over a 
169-day period)
Dosage Level(s)
Single dose delivered on Day 1 and Month 6
Route of Administration
i m. injection
Use
Experimental
IMP and AMP/NIMP
IMP
Sourcing
Manufactured by Debiopharm and provided centrally by the 
sponsor 
Packaging and Labelling
Study Intervention will be provided in a box containing one 
vial, one ampoule and one blister containing one injection 
syringe and two injection needles. Each box will be labelled as 
required per country requirement
Storage Requirements
To be stored in the outer carton at a temperature below 25°C in 
a dry place, protected from freezing
Current Name
Diphereline®
i.m.=intramuscular; IMP=investigational medicinal product; PR=prolonged release
6.2
Preparation, Handling, Storage and Accountability
The investigator or an approved representative (e.g. pharmacist) will ensure that triptorelin is 
reconstituted and dispensed by a member of staff specifically authorised by the investigator and 
trained for triptorelin reconstitution and administration.
The suspension for injection must be reconstituted using an aseptic technique and using the 
ampoule of solvent supplied for injection.
The instructions for reconstitution hereafter and in the leaflet provided with triptorelin must be 
strictly followed.
The solvent should be drawn into the syringe provided using the reconstitution needle (20G, 
without safety device) and transferred to the vial containing the powder. The suspension should 
be reconstituted by swirling the vial in a gentle circular motion until a homogeneous, milky 
suspension is formed. Do not invert the vial.
It is important to check there is no unsuspended powder in the vial. The suspension obtained 
should then be drawn back into the syringe, without inverting the vial. The reconstitution needle 
should then be changed and the injection needle (20G) used to administer the product.
As the product is a suspension, the injection should be administered for a single use immediately
after reconstitution to prevent sedimentation.
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dried
d
dried
h release of  mon
d
h release of  mo
riod)
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syringe and tw
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The excipients used in the paediatric formulation are safe for administration in the paediatric 
population participating in the study. 
Further guidance and information for the receipt, preparation, management and disposal/return
of the study intervention are provided in the “Investigational Medicinal Product Handling 
Manual”.
•
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
•
Only participants screened in the study and who meet the eligibility criteria may receive 
study intervention and only authorised site staff may supply or administer study 
intervention. All study intervention must be stored in a secure, environmentally 
controlled and monitored (manual or automated) area in accordance with the labelled 
storage conditions with access limited to the investigator and authorised site staff.
•
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition reco ds).
•
The sponsor will provide guidance on the destruction of unused study intervention. If 
destruction is authorised to take place at the investigational site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy and any special instructions provided by the sponsor. All 
destruction must be adequately documented.
•
The excipients used in the formulation are safe for administration in the paediatric 
population participating in the st dy. 
At each treatment dispensation (Day 1 and Month 6), a treatment number will be assigned by 
the Interactive Web Response System (IWRS). The IWRS will also manage all logistical 
aspects of the study treatment (e.g. replacement, drug supplies and expiry dates) and the 
recording of drug accountability/destruction. This service provides the investigator, 
investigational site coordinato s nd project team members with a service that is available 
24 hours a day, 7 days a week. Additional details may be found in the IWRS reference manual 
provided to each investigational site. In case of technical or dispensation queries, a 24-hour 
helpline is available. If a participant discontinues the study before any intake of study treatment, 
his/her assigned treatment number will not be reused.
In addition to the information provided in the IWRS, drug accountability paper records will be 
maintained by the investigator.
6.3
Measures to Minimize Bias: Randomisation and Blinding
6.3.1
Randomisation
This is a non-randomised, open-label study.
6.3.2
Maintenance of blinding
This is an open-label study therefore no procedures for blinding are applicable.
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esti
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6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the site will be recorded in the source documents and in the electronic case 
report form (eCRF). The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention.
6.5
Dose Modification
Not applicable. No dose modifications are to be performed in the study.
6.6
Continued Access to Study Intervention after the End of the Study
The participants will not receive any additional study intervention following the end of the 
study.
6.7
Treatment of Overdose 
The pharmaceutical properties of triptorelin 6-month formulation and its mode of 
administration make accidental or intentional overdose unlikely. There is no experience of 
overdose from clinical trials (for more information see the summary of package characteristics). 
If overdose occurs, this should be managed symptomatically.
In the event of an overdose, the investigator should:
•
Contact the medical monitor immediately.
•
Closely monitor the participant for any AE/SAE and laboratory abnormalities (at least 
up to the Month 12 visit). 
•
Document the quantity of the excess dose as well as the duration of the overdose. See 
Section 10.3.1 for reporting requirements concerning overdose.
6.8
Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant receives within 2 months before 
triptorelin administration or during triptorelin administration must be recorded on the eCRF 
along with:
•
Generic or trade name
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
The following concomitant medications are not permitted during this study:
•
Any treatment or procedure with an effect on the metabolism or secretion of 
gonadotropins (LH or FSH) or sex steroids (oestradiol and/or testosterone) will be 
considered as a protocol violation
•
All drugs mentioned as prohibited in the non-inclusion criteria remain prohibited during 
the study period: GnRH analogues (other than triptorelin 6-month formulation), 
medroxyprogesterone acetate, growth hormone or IGF-1, systemic or inhaled steroids 
(mild topical steroids are permitted) or anticoagulants.
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6
ed
6-
d
-month formu
ed
month form
overdose unlikely
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o
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f the excess dose 
pr
f the excess dose 
rting requirements
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Ap
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Ap
herapy
ine (including ove
Ap
ine (including ove
r herbal supplemen
Ap
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A
on or during tr
A
on or during tr
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•
Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce 
the level of GnRH receptors in the pituitary. When triptorelin is co-administered with 
drugs affecting pituitary secretion of gonadotropins, caution should be taken, and it is 
recommended that the participant’s hormonal status be supervised.
6.8.1
Rescue Medicine
Not applicable
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of the Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to be evaluated for efficacy, safety and PK, with assessments described in the SoA. 
See the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed.
7.1.1
Pregnancy
See Section 8.3.5.
7.1.2
Temporary Discontinuation
In case of suspected or confirmed COVID-19 (SARS-CoV-2) infection, the intervention 
administration may be temporarily discontinued depending on the participant clinical 
presentation. In some cases, the investigator may request a participant be retested before the 
intervention administration is resumed.
7.2
Participant Discontinuation/Withdrawal from the Study
The legal guardian and the paediatric participant have the right to withdraw permission (consent 
or assent, respectively) at any time during the study. If the study staff identify any reluctance in 
the legal guardian or paediatric participant (e.g  signs of verbal or physical dissent) about 
continued participation in the study, the pa di tric participant’s continuation in the study should 
be re-evaluated. The same principles that govern permission/assent/consent also govern its 
withdrawal. 
A participant may be withdrawn from the study for any of the following reasons:
•
Withdrawal of consent or assent if applicable (a paediatric participant’s dissent should 
be respected.)
•
Drug-related AE
•
Non-drug related AE
•
Non-drug related reason, e.g. participant relocates
•
Lack of efficacy.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such withdrawal of consent.
If the participant withdraws consent, it should be explained in detail in the medical records by 
the investigator as to whether the withdrawal is only from further receipt of study intervention 
or also from study procedures and/or posttreatment study follow-up. This information must be 
entered in the CRF. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if they fail to return for scheduled visits and 
is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
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ARS
d
ARS
depending
d
depending
request a partic
ed
request a part
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App
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App
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A
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•
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible. The site should counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
•
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
•
Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants enrolled, including those who did not receive study 
intervention. Public sources may be searched for vital status information. If vital status 
is determined as deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information.
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 10.1.
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nclu
d
nclu
for vital s
d
for vital s
ocumented, and 
d
ocumented, an
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Approve
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarised in the SoA (Table 2). Protocol waivers 
and exemptions are not allowed.
•
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
•
Adherence to the study design requirements, including those specified in the SoA 
(Table 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA (Table 2).
•
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 114 mL. 
(see [Ni 2017])
•
Repeat or unscheduled samples may be taken for safety reasons or in case of technical 
issues with the samples.
8.1
Efficacy Assessments
Efficacy and PK measurements will be performed centrally. The timing of efficacy assessments 
is summarised in the SoA (Table 2)  Procedures for recording efficacy data are discussed in this 
section and methods of analyses are discussed in Section 9.4. 
8.1.1
Luteinising Hormone and Follicle-stimulating Hormone Serum Concentrations
These parameters will be analysed centrally. The preparation and storage of samples are 
described separately in the Laboratory Manual.
8.1.2
Gonadotropin-Releasing Hormone Stimulation Test
Gonadorelin, a synthetic GnRH (manufacturer to be defined), will be used for gonadotrophin 
stimulation. Clinical sites will be supplied with gonadorelin to use in the GnRH stimulation test.
Blood samples will be collected prior to gonadorelin injection (timepoint T0) and at 30 minutes 
(T30), 60 minutes (T60) and 90 minutes (T90) after a single i.v. injection of gonadorelin with 
2.5 μg/kg (maximum 100 μg). 
A suppressed LH response to GnRH stimulation test is defined as peak serum LH ≤5 IU/L 
among the four timepoints (T0, T30, T60 and T90).
The FSH response to GnRH stimulation will be the peak serum FSH level among the four 
timepoints (T0, T30, T60 and T90).
8.1.3
Sex Steroids (Oestradiol and Testosterone Serum Concentrations)
These parameters will be analysed centrally. The preparation and storage of samples are 
described separately in the Laboratory Manual.
8.1.4
Pubertal Stage Using the Tanner Method
See Pubertal Stages According to the Tanner Method (Appendix 10.5 ) for details.
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8.1.5
Auxological Parameters, Bone Age and Chronological Age Measurements and 
Gonad Development
Target height and percentile height-for-age will be obtained from Tanner tables [Tanner 1966].
Bone age determination (in years and months) will be performed by X-rays of the hand and 
wrist and estimated by the Greulich and Pyle method [Greulich 1959]. 
Gonad development (uterine length or testis volume) will be determined by type B ultrasound 
or orchidometer respectively.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 2).
8.2.1
Physical Examinations
•
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight 
will also be measured and recorded. Body weight will be measured in underwear and 
without shoes.
•
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
•
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
•
Any clinically significant physical examina ion findings (abnormalities) observed during 
the study will be reported as AEs. Any physical examination findings (abnormalities) 
persisting at the end of the study will be followed by the Investigator until resolution or 
until reaching a clinically stable endpoint.
8.2.2
Vital Signs
Blood pressure and heart rate wil  be assessed with an automated device so that measurements 
are independent of the observer. Blood pressure and heart rate will be recorded in sitting 
position after 5 minutes of rest (seated). Absolute values and change from baseline will be 
analysed. Blood pressure will be measured using an appropriate cuff size.
8.2.3
Electrocardiograms
Not applicable
8.2.4
Clinical Safety Laboratory Assessments
•
Clinical safety laboratory tests (haematology and serum chemistry) and urinalysis will 
be performed by the study site or local laboratory as outlined in the SoA (Table 2).
•
See Appendix 10.2 for the list of clinical laboratory tests to be performed and for the 
timing and frequency.
•
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
•
Abnormal laboratory findings associated with the underlying disease, are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the participant's condition.
•
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 168 days after the last dose of study intervention 
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should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
•
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the aetiology should be identified and 
the sponsor notified.
•
All protocol-required laboratory tests, as defined in Appendix 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).
•
If laboratory values from non-protocol specified laboratory tests performed at the 
study site laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g. SAE or AE or dose modification), 
then the results must be recorded in the eCRF.
8.2.5
Local Tolerability
Assessment of local tolerability will be conducted as described in this section.
After each triptorelin injection, the injection site will be examined by a physician or medical 
staff (e.g. paediatric nurse) and assessed for characteristics such as but not limited to tenderness, 
redness, bruising, erythema, swelling, rash, pain, itching, induration, haematoma, ulceration or 
necrosis. If present, the extent of erythema, haematoma, rash, ulceration or necrosis will be 
described and assessed quantitatively; this will at least include measurement of maximum 
length and maximum width. 
Any reaction deemed clinically significant by the investigator meets the definition of a TEAE, 
thus it needs to be reported in the eCRF as such  as indicated in Appendix 10.3.3.
8.2.6
Pregnancy Testing
•
Pregnancy tests for female participants of childbearing potential will be performed as 
outlined in the SoA (Table 2).
•
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria.
•
Pregnancy testing (urine) will be repeated at the end of the study (see SoA Table 2).
•
Additional serum or urine pregnancy tests may be performed, as determined necessary 
by the investigator, to establish the absence of pregnancy at any time during the 
participant’s participation in the study.
8.3
Adverse Events, Serious Adverse Events and Other Safety Reporting.
The definitions of AEs and SAEs can be found in Appendix 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs or SAEs, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or the study (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the EOS visit at the time 
points specified in the SoA (Section 1.3).
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Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the eCRF.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of awareness of the event, as indicated in 
Appendix 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
Clinical Presentation of Adverse Events
Study-site staff should instruct the legal guardians and caregivers on how to report signs and 
symptoms (e.g. crying and pain) as well as viral signs of infections (eg nasopharyngitis, sinusitis, 
influenza) in the individual paediatric participant. They will be instructed to report both specific 
and nonspecific symptoms (including vomiting, diarrhoea, sleepiness, variation in the intensity 
and pattern of crying, etc). These nonspecific symptoms may be the only manifestations of 
some adverse reactions observed in childr n. Care should be taken that the clinical presentation 
of adverse reactions is not misinterpreted as the manifestation of a pre-existing or unrelated 
condition.
Moreover, symptoms that are dependent on participant communication ability (e.g. nausea, pain, 
mood alterations) in younger or mentally disabled children could potentially be at risk for 
under- or misreporting.
These events may or may not have been noted in the participant diary.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in Appendix 10.3.
8.3.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met.
•
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs and IECs and investigators.
•
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
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•
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
8.3.5
Pregnancy
The occurrence of pregnancy is very unlikely in this study population. In case a participant 
becomes pregnant, this information will be shared with the participant’s legal guardian as 
required by local regulations. 
•
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate forms (SAE form in the eCRF and Drug Exposure Form – paper form) and 
submit it to the sponsor within 24 hours
•
If pregnancy occurs during the study, the outcome of the pregnancy will be collected 
following completion of the study. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy using the Standard Drug 
Exposure for Pregnancy Form.
•
The investigator must instruct all female participants who have already had 
menophania/menarche to inform them immediately should they become pregnant during 
the study. The Investigator should counsel the participant, discuss the risks of continuing 
with the pregnancy and the possible effects on the foetus. Monitoring of the participant 
should continue until conclusion of the pregnancy, which may involve follow-up after 
the participant’s involvement in the study has ended. 
•
Pregnancies with a conception date within 6 months after the participant’s last dose of 
study medication must also be rep rted to the investigator for onward reporting to the 
sponsor.
•
If the Investigator becomes aware of a pregnancy occurring in the partner of a participant 
participating in the study, this should be reported to the sponsor as described above. 
Pregnancies in the partner with a conception date until 6 months after participant’s last 
dose of study medication should be reported after the partner has given written consent 
and the partner should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy.
Any participant becoming pregnant during the study will be withdrawn.
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable.
8.3.7
Adverse Events of Special Interest 
Not applicable
8.3.8
Reporting of Study Intervention Errors Including Misuse/Abuse
•
Medication errors are unintentional errors in the prescribing, dispensing, administration 
or monitoring of a study intervention (medicinal product) while under the control of a 
healthcare professional, participant or consumer (European Medicines Agency 
definition).
•
Misuse refers to situations where the study intervention is intentionally and 
inappropriately used not in accordance with the protocol.
•
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
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•
Study intervention errors and uses outside of what is foreseen in the protocol will be 
recorded in the eCRF irrespective of whether associated with an AE/SAE or not. It will 
also be documented in the AE section of the eCRF if associated with an AE. It will be 
reported in the safety database only if associated with an SAE. 
•
Misuse or abuse will be collected and reported in the safety database, whether associated 
or not with an AE/SAE, within 24 hours of investigator’s awareness.
8.4
Pharmacokinetics
•
Approximately 2 mL of blood samples will be collected for measurement of triptorelin 
6-month formulation plasma concentrations of as specified in the SoA (Section 1.3) to 
be analysed at a bionalytics Service Provider (Labcorp).
•
Approximately 2 mL of blood samples will be collected to derive serum for bioanalytical 
cross-validation purposes.
•
Instructions for the collection, handling, shipment methodology and reference ranges 
will be provided in the laboratory manual. The accurate date and time (24-hour clock 
time) of each sample collection must be recorded.
•
Plasma samples will be used to evaluate the PK of triptorelin 6-month formulation. Each
plasma sample will be divided into two aliquots (both for triptorelin level determination: 
a primary and a back-up aliquot). Samples collected for analyses of triptorelin 
concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study.
•
On predetermined dates, plasma samples will be shipped to the bioanalytical Service 
Provider under frozen conditions. For security reasons, aliquots of each sample will be 
shipped separately. The batch containing the second aliquot will not be shipped until the 
first one has arrived. Upon receipt at the bioanalytical Service Provider, samples will be 
checked and stored until analysis.
•
The concentration of triptorelin will be analysed using a validated specific and sensitive 
method, and in accord nce with Good Laboratory Practice (GLP). 
•
Serum samples will be used for the bioanalytical method cross-validation (two aliquots 
– a primary and a backup).
•
On predetermined dates, serum samples will be shipped to the bioanalytical Service 
Provider in charge of the cross-validation under frozen conditions. For security reasons, 
aliquots of each sample will be shipped separately. The batch containing the second 
aliquot will not be shipped until the first one has arrived. Upon receipt, samples will be 
checked and stored until analysis. 
•
Residual plasma/serum samples remaining from the analyses may also be retained by the 
sponsor for additional investigations. This could include using leftover plasma/serum 
samples for long-term stability, reproducibility, or other bioanalytical assessments. 
8.5
Genetics and/or Pharmacogenomics
Genetics are not evaluated in this study.
8.6
Biomarkers
Biomarkers are not evaluated in this study.
Note that a description of primary and secondary efficacy biomarkers can be found in 
Section 8.1.
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8.7
Immunogenicity Assessments
Immunogenicity assessments are not evaluated in this study.
8.8
Health Economics OR Medical Resource Utilization and Health Economics
This section is not applicable for this study.
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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The null hypothesis H0: P≤80% versus the alternative hypothesis H1: P>80%, where P is the 
proportion of children with LH suppression defined as stimulated peak LH ≤5 IU/L after GnRH 
stimulation at Month 6.
9.2
Sample Size Determination
The sample size of this study is estimated based on following assumptions according to global 
pivotal study DEBIO 8206-CPP-301 [Klein 2016].
•
Expected outcome for the proportion of children with a suppressed LH response to the 
GnRH stimulation test (stimulated peak serum LH ≤5 IU/L) at Month 6 is 93%;
•
Null proportion is 80%; 
•
An exact binomial test of a proportion with a one-sided nominal significance level of 
0.025 and power =85%;
•
Expected common dropout rate =5%. 
Under these assumptions, approximately 66 participants (including at least three boys) (PASS 
software) are planned to be enrolled into the study to ensure there are 62 treated participants to 
confirm the efficacy of the triptorelin 6-month formulation by the proportion of children with a 
suppressed LH response to the GnRH stimulation test at Month 6.
9.3
Analysis Sets
For the purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Screened population
All participants screened (i.e. who signed the ICF)
Safety population
All participants who received at least one dose of study intervention and have 
at least one postb seline safety assessment;
ITT/mITT population
The ITT population will include all participants who received at least one 
dose of study intervention;
The modified intention-to-treat (mITT) population will contain all treated 
participants having a Month 6 post-baseline assessment of the primary 
efficacy endpoint
PP population
The PP population will contain all participants in the mITT after exclusion 
of the participants who had major protocol deviations that could potentially 
affect the primary efficacy endpoint outcome for the participants
PK population 
All participants who received at least one dose of study intervention and 
have at least one valid triptorelin concentration
ICF=informed consent form; ITT=intention-to-treat; mITT=modified ITT; PK=pharmacokinetics; PP=per 
protocol.
The primary efficacy analysis will be performed on the ITT population. Supportive analysis of 
the primary efficacy endpoint will be based on the modified intention-to-treat (mITT) and the 
PP populations.
The secondary efficacy analyses will be based on the ITT population. Supportive analysis of 
the secondary analyses may be performed on the PP population.
The analyses of safety data will be performed based on the Safety population.
The analyses of PK data will be performed based on the PK population.
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9.4
Statistical Analyses
The statistical analysis plan (SAP) will be finalised before the first participant enters the study
and it will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
Other endpoints as well as demographic, baseline characteristics and disposition will be detailed 
in the SAP.
Statistical evaluation will be performed using Statistical Analysis System (SAS®) Version 9.4 
(or higher if available).
9.4.1
General Considerations
9.4.1.1
Reasons for Exclusion from the Analyses
Any major protocol deviation will be described and listed and its impact on the inclusion of any 
participant in each analysis population will be specified. The final list of protocol deviations 
impacting each analysis population will be reviewed prior to database lock. The list may be 
updated, up to the point of database lock, to include any dditional protocol deviations which 
may impact the analysis of each population.
9.4.1.2
Significance Testing and Estimations
For the primary efficacy endpoint, the summary statistics of number and percentage of 
participants and the exact two-sided 95% CI for a binomial proportion will be computed by 
SAS® using the exact binomial distributions on the ITT population (primary population of 
analysis), mITT and PP sets.
For secondary efficacy endpoints related to a change at Months 3, 6, 9 and 12 compared to 
baseline, the descriptive summary statistics (n, mean, SD, median, minimum, maximum) will 
be calculated on the ITT populati n. In addition, secondary efficacy endpoints may be 
performed on the PP set. Exact two-sided 95% CIs will also be constructed for all secondary 
endpoints expressed as percentages.
9.4.1.3
Statistical/Analytical Methods
Statistical analyses will be performed by an external Service Provider, managed by the 
Sponsor’s Biometry department.
Demographic and Other Baseline Characteristics
Descriptive summary statistics (n, mean, SD, median, minimum, maximum) and frequency 
counts of demographic and baseline data (medical history, concomitant disease, predosing AEs 
and ongoing medical history, prior and concomitant medications and therapies) will be 
presented for the ITT, mITT and PP sets, as well as the Safety population.
Participant Disposition and Withdrawals
The numbers and percentages of participants screened and included in each of the analysis 
populations will be tabulated overall and by centre. The reasons for participant exclusions from 
each of the populations and primary reasons for study discontinuation will be tabulated. 
Adjustment for Country/Centre Effect
Descriptive analysis will be carried out to evaluate any possible centre effect.
9.4.2
Analysis of Primary Endpoint 
The primary endpoint in this study is the proportion of children with LH suppression defined 
as stimulated peak LH ≤5 IU/L after GnRH stimulation at Month 6. The number and percentage 
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ed a
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of participants with LH suppression (stimulated peak LH ≤5 IU/L after GnRH stimulation) will 
be presented and its two-sided 95% CI using Clopper-Pearson method will be presented and 
calculated. A test to the null hypothesis (P≤80%) will be performed with a (one-sided) type I 
error as 2.5%.
9.4.3
Analysis of Secondary Endpoints 
•
Proportion of children with LH suppression defined as stimulated peak LH ≤5 IU/L after 
GnRH stimulation at Months 3 and 12:
The number and percentage of participants with LH suppression (stimulated peak LH 
≤5 IU/L after GnRH stimulation) will be presented at Months 3 and 12 and its two-sided 
95% CI will be presented and calculated using the same method as primary efficacy 
endpoint.
•
Change in basal serum LH and FSH levels at Months 3, 6, 9 and 12 compared to baseline:
A summary table for the basal serum LH and FSH levels will be provided with 
descriptive statistics (n, mean, SD, median, minimum and maximum) at Baseline, 
Months 3, 6, 9 and 12 and for absolute changes from Baseline.
•
Change in peak serum LH and FSH level after the GnRH stimulation test at Months 3, 6 
and 12 compared to baseline:
A summary table for the peak LH and FSH levels after the GnRH stimulation test will 
be provided with descriptive statistics (n  mean, SD, median, minimum and maximum) 
at Baseline, Months 3, 6 and 12 and for absolute changes from Baseline.
•
Proportion of children with pre-pubertal levels of sex steroids (defined as oestradiol 
≤20 pg/mL [<73 pmol/L] in girls or testosterone ≤30 ng/dL [<0.8 nmol/L] in boys) at 
Months 3, 6, 9 and 12:
The number and percentage of participants with pre-pubertal levels of sex steroids 
(defined as oestradiol ≤ 20 pg/mL in girls or testosterone ≤ 30 ng/dL in boys) will be 
presented at Months 3, 6, 9 and 12. The two-sided 95% CIs will be presented and 
calculated using the same method as primary efficacy endpoint.
•
Change in height (Z-score [height for age] and percentile for height for age) and growth 
velocity at Months 6 and 12 compared to baseline:
A summary table for the change in height (Z-score [height for age] and percentile for 
height for age) and growth velocity will be provided with descriptive statistics (n, mean, 
SD, median, minimum and maximum) at Months 6 and 12. In addition to the study 
endpoint on the change in height (Z-score and percentile) at Months 6 and 12, a summary 
table for the height absolute Z-scores and percentiles will be provided with descriptive 
statistics (n, mean, SD, median, minimum and maximum) at Baseline, Month 3, 6, 9 and 
12.
•
Proportion of children in whom the BA (Greulich and Pyle method):CA ratio did not rise 
at Months 6 and 12 relative to baseline (X‑ray):
The number and percentage of participants without increase of bone age (Greulich and 
Pyle method)/chronological age ratio from Baseline to Months 6 and 12 will be presented 
and its two-sided 95% CI will be presented and calculated using the same method as 
primary efficacy endpoint.
•
Change in difference between BA and CA and ratio BA:CA at Months 6 and 12 
compared to baseline:
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and FS
d
and FS
n, minimum 
d
n, minimum 
nges from Baselin
ed
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l after the GnRH s
ed
l after the GnRH s
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and FSH levels aft
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and FSH levels aft
stics (n  mean, SD
ov
stics (n  mean, SD
and for absolute c
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and for absolute c
pre
pre-
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-pubertal level
ro
pubertal level
ro
n girls or testoster
pr
n girls or testoster
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entage of particip
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ol ≤ 20 pg/mL in g
App
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ths 3, 6, 9 and 12
Ap
ths 3, 6, 9 and 12
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ht (Z
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A summary table for the difference between BA and CA and ratio BA:CA will be 
provided with descriptive statistics (n, mean, SD, median, minimum and maximum) at 
Baseline, Month 6 and Month 12 and for absolute changes from Baseline.
•
Proportion of children who achieve stabilisation of sexual maturation compared to 
baseline stage using Tanner method at Months 6 and 12:
The number and percentage of participants with no increase in Tanner puberty staging 
from Baseline to Months 6 and 12 will be presented and its two-sided 95% CI will be 
presented and calculated using the same method as primary efficacy endpoint.
•
Proportion of girls with regression of uterine length at Months 6 and 12 (transabdominal 
ultrasound): 
The number and percentage of girls with regression of uterine length at Months 6 and 12 
will be presented and its two-sided 95% CI will be presented and calculated using the 
same method as primary efficacy endpoint.
•
Proportion of boys with absence of progression of testis volumes at Month 6 and 12 
(clinical assessment with orchidometer):
The number and percentage of boys with absence of progression of testis volumes at 
Months 6 and 12 will be presented and its two-sided 95% CI will be presented and 
calculated using the same method as primary efficacy endpoint.
•
Change in body weight and BMI at Month 6 and 12:
A summary table for the body weight and BMI will be provided with descriptive statistics 
(n, mean, SD, median, minimum and maximum) at Baseline and Months 6 and 12 and 
for absolute changes from Baseline.
9.4.3.1
Pharmacokinetic Analyses 
Individual listings of triptorelin co cent ations and descriptive summary statistics (n, mean, 
standard error of mean (SEM), SD, coefficient of variance (%CV), geomean, geomean SD, 
geomean %CV, median, min, max, 95% CI) will be presented by timepoint/visit following each 
administration. If required and w rranted by the data, an attempt to build a model to characterize 
the PK in the population will be made. An analysis to look at the relationship between 
concentrations versus efficacy and/or safety may be performed if warranted by the data. This 
will be described in a separate analysis plan and the outcomes summarised in a standalone 
report.
9.4.4
Safety Analyses
Safety endpoints are indicated in Section 3.
All safety data will be included in the participant data listings. Analyses and summary tables 
will be based on the Safety population.
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version (version in use before database lock) and will be classified by MedDRA preferred term 
(PT) and system organ class (SOC). 
The incidence of all reported TEAEs, TEAEs associated with early withdrawal and SAEs will 
be tabulated overall. In addition, summary tables will be presented by maximum intensity and 
drug relationship. 
A TEAE is defined as any AE that occurs during the active phase of the study if: 
•
It was not present prior to receiving the dose of triptorelin, or
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d
sion of testi
d
th absence of prog
ed
th absence of pro
nd its two
ve
nd its two-
ve
-sided 
e
sided 
primary efficacy e
ve
primary efficacy e
at Month 6 and 12:
ov
at Month 6 and 12:
ov
eight and BMI wil
ov
eight and BMI wil
mum and maximum
ro
mum and maximum
Baseline.
pr
Baseline.
lyses 
p
lyses 
elin co cent ation
pp
elin co cent ation
EM), SD, coeffici
App
EM), SD, coeffici
min, max, 9
Ap
min, max, 95
p
5
A
% CI
p
% CI
red and w rranted 
Ap
red and w rranted 
ation will be ma
A
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A
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•
It was present prior to receiving the dose of triptorelin but the grade increased or became 
serious during the active phase of the study, or
•
It was present prior to receiving the dose of triptorelin, the grade/seriousness is the same, 
but the causality changed to “related” during the active phase of the study.
All TEAEs will be flagged in the AE listings. 
Summary incidence tables will be provided, classified by SOC, PT and associated National 
Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) worst 
grade. In the event of multiple occurrences of the same AEs being reported for the same 
participant, 
the 
maximum 
intensity 
(Grade 5 >Grade 4 >Grade 3 >Grade 2 >Grade 1 >missing >not applicable) will be chosen. All 
AEs will be collected up to the EOS visit (see Table 2 for SoA).
Concomitant medication will be coded by using World Health Organization Drug Dictionary 
(WHO-DD) version (version in use before database lock) and will be summarised with the 
number and percentage of participants receiving concomitant medication by drug class and 
preferred drug name.
Haematological and biochemical toxicities will be record d and graded according to the NCI-
CTCAE criteria, where available. The NCI-CTCAE Grades 3 and 4 haematology and 
biochemistry variables will be listed by participant and by visit.
Actual values and changes from baseline in clinic l laboratory tests, physical examinations and 
vital signs will be summarised using descriptive statistics at each visit. For laboratory data, 
abnormal values will be flagged in the da a listings and a list of clinically significant abnormal 
values will be presented. Shift tables using the worst on-treatment grade will be presented for 
the number and percentage of participants with NCI-CTCAE grades.
9.4.5
Subgroups Analyses
No subgroup analysis will be performed.
9.4.6
Other Analyses 
Not applicable
9.5
Interim Analyses 
No interim analysis will be performed. If an unplanned interim analysis is deemed necessary, 
the appropriate sponsor medical director, or designee, will be consulted to determine whether 
it is necessary to amend the protocol.
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ld He
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ld He
se lock) and
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se lock) and
concomitant me
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ill be record d and
NCI
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articipant and by v
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participants with N
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ses
A
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A
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10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
•
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines
•
Applicable International Council for Harmonisation
(ICH) of Technical 
Requirements for Pharmaceuticals for Human Use Good Clinical Practice (GCP)
Guidelines
•
Applicable laws and regulations
•
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g. any 
participant recruitment materials) must be approved by the IRB/IEC before the study is 
initiated.
•
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.
•
The protocol and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants.
•
The investigator will be responsibl  for the following:
•
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
•
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
•
Providing oversight of the conduct of the study at the site and adherence to 
applicable 
local 
regulations, 
ICH 
guidelines 
and 
the 
IRB/IEC 
requirements/procedures.
•
The investigator will be responsible for reporting cases of suspected child abuse and/or 
neglect according to local regulations including local medical association (e.g., American 
Academy of Pediatrics, EU Academy of Pediatrics) or Health Department guidelines.
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for one year after completion of the study.
10.1.3
Legal Guardian Consent and Paediatric Participant Assent Processes:
•
The informed consent/assent and any participant recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, 
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, and other
d
, and other
approved by the I
ed
approved by th
require IRB/IEC ap
ve
require IRB/IEC ap
gn, except for cha
ve
gn, except for cha
ants.
o
ants.
amendments to the
ov
amendments to the
Appro
xcept for changes
ro
xcept for changes
esponsibl  for the
pr
esponsibl  for the f
n summaries of the
pp
n summaries of the
y in accordance w
App
y in accordance w
y the IRB/IEC
App
y the IRB/IEC
Ap
the IRB/IEC of SA
Ap
the IRB/IEC of SA
procedures
Ap
procedures
versight of 
A
versight of 
al 
A
al
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including applicable privacy laws. They must be approved before use, as described in 
Appendix 10.1.1.
•
The investigator, or his/her authorised representative, will provide the legal guardian 
with the written ICF and the participant with the assent form, if applicable. They must 
be informed that participation is voluntary. The legal guardian will be required to sign 
written consent, and the participant, if applicable, will be required to sign written assent 
after the nature of the study has been fully explained and before performance of any 
study-related activity.
•
Assent requirements for paediatric participants may vary across regions and countries; 
local regulations should be followed as appropriate.
•
The medical record must include a statement that written informed consent from the legal 
guardian and assent from the paediatric participant (if deemed appropriate by local ethics 
review or local regulations) were obtained before the participant was enrolled in the study 
and the date the written consent and assent were btained. The medical record should 
describe how the investigator determined that the person signing the ICF was the 
participant’s legal guardian. The authorised person obtaining the informed consent must 
also sign the ICF and assent form attesting that the paediatric participant did not show 
signs of dissent particularly in those studies including toddlers and small children; it 
should be written in language appropriate to the child’s developmental and functional 
status.
•
Minor participants who assent to a s udy and later withdraw that assent should not be 
maintained in the study against their will, even if their legal guardian still wants them to 
participate.
•
A copy of the informed consent and assent forms must be provided to the participant and 
the participant’s legal guardian.
•
As appropriate, participants may be given the opportunity to meet privately with a 
member of the study site staff to ask confidential questions and to decline assent for 
confidential reasons  which  at their request, would not be shared with their legal 
guardian, unless required by local law.
•
If an ICF amendment is not applicable to all participants, this will be communicated to 
the IEC/IRB with a rationale. A participant and the legal guardian must be re-consented 
and re-assented to the most current version of the ICF(s) during their participation in the 
study if the change has an impact on this participant.
10.1.4
Data Protection
•
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
•
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent. 
•
The participant must be informed that his/her medical records may be examined by the 
sponsor’s auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
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d
 the
ere bta
d
ere bta
that the person
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that the pers
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ed
d person obtaini
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studies including 
ve
studies including 
opriate to the chil
ve
opriate to the chil
Appro
to a s udy and lat
ro
to a s udy and lat
st their will, even 
ro
st their will, even 
onsent and assent 
pr
onsent and assent 
guardian.
pp
guardian.
ticipants may be 
App
ticipants may be 
udy site staff to as
Ap
udy site staff to as
sons  which  at th
Ap
sons  which  at th
A
s required by loca
A
s required by loca
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A
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onal
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10.1.5
Dissemination of Clinical Study Data
•
The sponsor seeks to publish the results of its clinical trials in biomedical journals, 
whatever the outcome. Clinical trial results may also be presented at international 
congresses as posters or oral presentations.
•
Protocol and result summary will be made publicly available in the US Clinical Trials 
Registry (ClinicalTrials.gov) and the EU/EEA on the EU Clinical Trials Register 
(www.clinicaltrialsregister.eu) if required. The sponsor also provides clinical trial 
information to other national clinical trial registries or databases according to local 
requirements/legislation; in the case of this protocol the China Clinical Trials Registry 
(www.chinadrugtrials.org.cn/index.html). 
•
A clinical study report will be prepared if at least one participant has signed informed 
consent and received intervention, regardless of whether the study is completed or 
prematurely terminated. The clinical study report may be disclosed according to 
regulatory requirements. 
10.1.6
Data Quality Assurance
•
All participant data relating to the study will be recorded in the eCRF unless transmitted 
to the sponsor or designee electronically (e g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by signing the eCRF.
•
Guidance on completion of the eCRF will be provided in eCRF completion guidelines.
•
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections, make ll documents available for audit and inspection 
and provide direct access to source data documents.
•
Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
•
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
•
The sponsor assumes accountability for actions delegated to other individuals (e.g. 
Service Providers).
•
Records and documents, including signed ICFs, pertaining to the conduct of this study 
should be retained by the investigator according to the ICH-GCP guidelines, to local 
regulations, or as specified in the study agreement, whichever is longer. No records may 
be destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
10.1.7
Source Documents
•
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
•
Data reported in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
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epo
d
epo
will be recorded in
ed
will be recorded i
cally (e g. laborat
ve
cally (e g. laborat
tries are accurate a
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tries are accurate a
RF will be provid
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RF will be provid
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o
study-
o
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related mon
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ro
ns, make ll docum
source data docum
pro
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ribing strategy (e
pr
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anagement and M
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ds, responsibilitie
App
ds, responsibilitie
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A
ues and monitoring
App
and monitoring
he
A
he Monitoring Plan
Ap
Monitoring Plan
designee is respo
A
designee is respo
f the data.
A
f the data.
acco
A
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•
The investigator must maintain accurate documentation that supports the information 
entered in the eCRF. Source data must be attributable, legible, contemporaneous, original, 
accurate and complete.
•
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
10.1.8
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure t any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:
•
Discontinuation of further study intervention development
For site termination:
•
Failure of the investigator t  comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator
•
Total number of participants included earlier than expected
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Service Providers used in the 
study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.9
Publication Policy
•
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.
•
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.
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proved
the study site 
d
the study site
ponsor. Study site
ed
ponsor. Study s
when all required d
ed
when all required 
visit has been perf
ve
visit has been perf
osure t any time, p
ve
osure t any time, p
of the intended te
ov
of the intended te
dy site by the spon
ro
dy site by the spon
App
er study interventi
p
er study interventi
tigator t  comply w
App
tigator t  comply w
thorities, the spon
Ap
thorities, the spon
A
no recruitment 
Ap
no recruitment 
investigator
A
investigator
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A
pants
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•
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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•
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
-
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-oestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrolment.
•
Permanent sterilization methods (for the purpose of this study) include:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
-
For individuals with permanent infertility d e to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry.
•
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Notes: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
10.4.2
Contraception Guidance
Note: Pregnancy is highly unlikely in this study population and the guidance is listed for 
completeness 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly.

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or due to a to medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant)
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and orrectly. Typical use failure rates differ from those 
when used consistently and correctly.
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelin
, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode f action.
Note: Periodic abstinence (calendar, symptoth rmal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrh ea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction)
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10.5
Appendix 6: Pubertal Stages According to Tanner Method
STAGES OF DEVELOPMENT OF SECONDARY SEXUAL CHARACTERISTICS
BOYS: Genital (penis) development
Stage 1. Prepubertal: testes, scrotum, and penis of about same size and proportion as in early 
childhood.
Stage 2. Enlargement of scrotum and testes. Skin of scrotum reddens and changes in texture.
Stage 3. Enlargement of penis, at first mainly in length. Further growth of testes and scrotum.
Stage 4. Increased size of penis with growth in breadth and development of glans. Testes and
scrotum larger; scrotal skin darkened.
Stage 5. Genitalia adult in size and shape.
GIRLS: Breast development
Stage 1. Prepubertal: elevation of papilla only.
Stage 2. Breast bud stage: elevation of breast and papilla as small mound. Enlargement of areola
diameter.
Stage 3. Further enlargement and elevation of breast and areola, with no separation of their 
contours.
Stage 4. Projection of areola and papilla to form a secondary mound above level of breast.
Stage 5. Mature stage: projection of papilla only, related to recession of areola to general 
contour of breast.
BOTH SEXES: Pubic hair
Stage 1. Prepubertal: vellus over pubes is not further developed than over abdominal wall.
Stage 2. Sparse growth of l ng  sligh ly pigmented, downy hair, straight or slightly curled, 
chiefly at base of penis or along labia.
Stage 3. Considerably darker, coarser, and more curled hair. Hair spreads sparsely over junction 
of pubes.
Stage 4. Hair now adult in type but area covered is still considerably smaller than in adult. No 
spread to medial surface of thighs.
Stage 5. Adult in quantity and type with distribution of horizontal (or classically “feminine”) 
pattern.
Stage 6. Spread up linea alba (male-type pattern).
Modified from Tanner JM. Growth at Adolescence. 2nd ed. Oxford: Blackwell Scientific 
Publications, 1962.
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nd papilla as small m
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nd papilla as small 
on of breast and a
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A
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Ap
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ker, coarser
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10.6
Appendix 7: Temporary Measures and Procedures Related to COVID-19 
Pandemic
This appendix serves as notification of the temporary measures put in place for the conduct of 
the study during the COVID-19 pandemic and until such time as the situation resolves, at which 
point the protocol assessments will return to those specified in the current approved protocol 
effective at that time. The timing of when the pandemic is declared over may vary on a country 
by country basis as well as between sites in the same country, and as such the temporary 
measures may remain in place for differing periods of time per country/site. Investigators will 
determine the feasibility of starting or continuing study treatment on a patient by patient basis, 
depending on the ability to conduct safety monitoring and providing patients an adequate supply 
of study treatment, in accordance with local requirements.
Any temporary measure will be reported as a protocol deviation related to COVID-19.
Withdrawal from Study
Participants who are suspected or confirmed to have COVID-19 infection after enrolment will 
withdraw from the study (see also Section 7.1.2 for temporary withdrawal).
Telemedicine Visit
If the COVID-19 pandemic prevents participants from coming to the site for the Month 9 visit, 
the investigator will perform a telemedicine visit to collect all important medical information 
and safety event(s) occurring since the last visit. Besides the Month 9 visit, the participants may 
delay other visits no more than 2 weeks and preferably within 1 week or be withdrawn from the 
study as appropriate, as judged by the investigator and agreed with the sponsor.
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11
REFERENCES
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1959: 231
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Epidemiolog
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et al.
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et al. Efficacy and
pr
Efficacy and
precocious pubert
pr
precocious pubert
Rogol A et al. Use
App
Rogol A et al. Use
by An Internationa
Ap
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, Pan L et l. Inve
Ap
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iatr
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