Clinical trial NCT03296527
Conditions: Controlled Ovarian Simulation
Sponsor: Ferring Pharmaceuticals
Start date: 2017-12-01; Completion date: 2020-07-26
Enrollment: 1011 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian stimulation.

Detailed description:

Arms: arm 1: Recombinant follicle-stimulating hormone (rFSH). Follitropin delta for subcutaneous injection arm 2: rFSH. Follitropin alfa for subcutaneous injection
Interventions: intervention 1: Follitropin alfa intervention 2: Follitropin delta
Intervention descriptions: intervention 1: GONAL-F dose was fixed for the first 5 stimulation days. intervention 2: REKOVELLE (FE 999049) was fixed throughout the stimulation period.

Protocol documents:
SAP_002.pdf: 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
Title of trial:  
A randomised, controlled, assessor-blind, parallel groups, multicentre, 
Pan-Asian trial comparing the efficacy and safety of FE 999049 with 
follitropin alfa (GONAL-F) in controlled ovarian stimulation in women 
undergoing an assisted reproductive technology programme 
NCT number: 
NCT03296527 
Sponsor trial code: 
000145 
Date:  
08 December 2017 
 
 
 
 
 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 1 of 36 
STATISTICAL ANALYSIS PLAN 
A randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian trial comparing 
the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian 
stimulation in women undergoing an assisted reproductive technology programme 
lnvestigational Product: 
Indication: 
Phase: 
Author: 
Date: 
Version: 
Trial Code: 000145 
FE 999049, human recombinant follicle-stimulating hormone, 
solution for subcutaneous injection 
Controlled ovarian stimulation for the development of multiple 
follicles in women undergoing assisted reproductive technologies 
(ART) such as an in vitro fertilisation (IVF) or intracytoplasmic 
sperm injection (ICSI) cycle 
3 
08DEC2017 
1.0 
The information in this document is confidential and is proprieta,y to Ferring Pharmaceuticals AIS or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals AIS or 
another company within the Ferring Group 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Version 
No. 
Date 
1.0 
08DEC2017 
Ferring Phannaceuticals 
Change log 
Reason for the Change / Revision 
New document 
CONFIDENTIAL 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 2 of36 
Supersedes 
None 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 3 of36 
Signed Agreement on Statistical Analysis Plan 
Author:
Review:
Approval:
Project Statistician, Global Biometrics 
Ferring Pharmaceuticals A/S 
Vice President, Therapeutic Area, Reproductive Health 
Ferring Pharmaceuticals A/S 
Medical Director, Therapeutic Area, Reproductive Health 
Perring Pharmaceuticals A/S 
Pharmacovigilance Physician, Global Pharmacovigilance 
Perring Pharmaceuticals A/S 
Medical Writer, Medical Writing 
Ferring Pharmaceuticals A/S 
Global Regulatory Project Lead, Global Regulatory Affairs 
Ferring Pharmaceuticals A/S 
Lead Statistical Programmer, Global Biometrics 
Ferring Pharmaceuticals A/S 
l!!!ostatistician, China Clinical Development
Ferring International Pharma-Science Centre (China) Company Limited 
Senior Director, Global Biometrics 
Perring Pharmaceuticals A/S 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
TABLE OF CONTENTS 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
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TABLE OF CONTENTS ............................................................................................................................... 4 
1 
Introduction .......................................................................................................................................... 6 
1.1 
Defrni tions/ Abbreviations ........................................................................................................ 6 
1.1.l 
Definitionof Terms .................................................................................................. 6 
1.1.2 
Abbreviations ............................................................................................................ 6 
2 
Trial Objectives and Endpoints .......................................................................................................... 8 
2.1 
Objectives ................................................................................................................................. 8 
2.2 
Endpoints .................................................................................................................................. 8 
3 
Trial Design ........................................................................................................................................ 10 
3.1 
General Design Considerations ............................................................................................... JO 
3 .2 
Determination of Sample Size ................................................................................................ 10 
4 
Subject Disposition ............................................................................................................................ 11 
5 
Protocol Deviiations ............................................................................................................................ 12 
6 
Analysis Sets ....................................................................................................................................... 12 
6.1 
Intentiion-to-Treat Analysis Set ............................................................................................... 12 
6.2 
Full Analysis Set ..................................................................................................................... 12 
6.3 
Per Protocol Analysis Set. ....................................................................................................... 12 
6.4 
Safety Analysis Set ................................................................................................................. 13 
6.5 
Subgroups ............................................................................................................................... 13 
7 
Trial Population ................................................................................................................................. 13 
7 .1 
Demographics and Other Baseline Characteristics ................................................................. 13 
7. 1.1
Demographics ......................................................................................................... 13 
7.1.2
Infertility History, Menstrual History and Reproductive History ........................... 13 
7.2 
Medical History ....................................................................................................................... 14 
7 .3 
Prior and Concomitant Medication ......................................................................................... 14 
7.4 
Physical Examination and Gynaecological Examination ........................................................ 14 
8 
Exposure and Treatment Compliance ............................................................................................. 14 
8.1 
Extent of Exposure .................................................................................................................. 14 
8.2 
Treatment Compliance ............................................................................................................ 15 
9 
Efficacy ............................................................................................................................................... 15 
9 .1 
General Considerations ........................................................................................................... 15 
9.2 
Primary Endpoint .................................................................................................................... 17 
9.2. l 
Primary Variable Analysis ...................................................................................... 17 
9.2.2 
Sensitivity Analyses ............................................................................................... 18 
9.2.3 
Supplementary Descriptions ................................................................................... 19 
9.3 
Secondary Endpoints ............................................................................................................... 19 
9.4 
Other Endpoints ...................................................................................................................... 24 
10 
Safety ................................................................................................................................................... 24 
10.1 
General Considerations ........................................................................................................... 24 
10.2 
Adverse Events ....................................................................................................................... 24 
10.2.1 
Overview of Treatment-emergent Adverse Events ................................................ 25 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 5 of36 
I 0.2.2 
[ncidence of Adverse Events .................................................................................. 25 
10.3 
OHSS ...................................................................................................................................... 26 
10.4 
Safety Laboratory Variables ................................................................................................... 27 
10.5 
Injection Site Reactions .......................................................................................................... 28 
10.6 
Treatment-induced Anti-FSH Antibodies ............................................................................... 28 
10.7 
Immune-related Adverse Events ............................................................................................. 28 
10.8 
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen .................................... 28 
10.9 
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins ............................................................................................. 28 
10.10 
Pen Malfunction ...................................................................................................................... 29 
10.11 
Additional Safety Evaluations ................................................................................................ 29 
10.11.1 
Physical Examinations ............................................................................................ 29 
10.11.2 
Gynaecological Examination .................................................................................. 29 
10.1 l.3 
Changes in Body Weight ........................................................................................ 29 
l 0.11.4 
Vital Signs .............................................................................................................. 29 
10.12 
Pregnancy Follow-up .............................................................................................................. 29 
11 
Interim Analyses ................................................................................................................................ 31 
12 
Changes Compared to the Analyses Described in the Trial Protocol ........................................... 31 
13 
References ........................................................................................................................................... 32 
14 
Tables, Listings and Figures ............................................................................................................. 33 
Appendix 1 
Markedly Abnormal Laboratory Safety Values and Vital Signs ..................... 34 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
1 
Introduction 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
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This document describes the planned statistical analyses for 000145 and is based on the final 
protocol. The protocol is amended in China to have the option of a different NIMP sourcing 
process. The protocol for South Korea, Taiwan and Vietnam is E-Study Protocol-19954 version 1.0 
dated 18 Nov 2016. The consolidated protocol for China (including the changes introduced with the 
amendment) is E-Study Protocol-21768 version 1.0 dated 11 Sep 2017. 
1.1 
Definitions/ Abbreviations 
1.1.1 
Definition of Terms 
Term 
Assessor-blind 
ESTHER-I trial 
Pan-Asia 
Primary infertility 
Randomised 
Screened 
1.1.2 
Abbreviations 
Definition 
Assessor-blind means that all investigators, embryologists and 
central laboratory personnel will be blinded to treatment 
allocation 
Phase 3 trial, ESTHER-I (Evidence based Stimu1ation Trial with 
Human rFSH in Europe and Rest of World), conducted in 
11 countries overseas including Europe, North America and Latin 
America. Ferring trial ID: 000004 
Pan-Asia refers to China and other Asian countries, potentially 
Taiwan, South Korea and Vietnam 
No previous clinical pregnancy 
Subject who was randomised to trial treatment 
Subject who signed informed consent 
Abbreviation 
Meaning of abbreviation in document 
AE 
Adverse event 
AMH 
Anti-Mtillerian hormone 
ANCOV A 
Analysis of covariance 
ART 
Assisted reproductive technologies 
hCG 
Beta unit of human chorionic gonadotropin 
EMA 
European Medicines Agency 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
GnRH 
Gonadotropin-releasing hormone 
hCG 
Human chorionic gonadotropin 
ICD-10 
International Statistical Classification of Diseases and Related 
ICSI 
IMP 
ITT 
IVF 
LH 
LLOQ 
Fening Phannaceuticals 
Health Problems, 10th revision 
Intracytoplasmic sperm injection 
Investigational Medicinal Product 
Intention-to-treat 
In vitro fertilisation 
Luteinising hormone 
Lower limit of quantiification 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Abbreviation 
MedDRA 
NIMP 
OHSS 
pp 
PT 
SAE 
SAP 
soc 
ULN 
ULOQ 
Ferring Phannaceuticals 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
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Meaning of abbreviation in document 
Medical Dictionary for Regulatory Activities 
Non-investigational medicinal product 
Ovarian hyperstimulation syndrome 
Per protocol 
Preferred term 
Serious adverse event 
Statistical analysis plan 
System organ class 
Upper limit of normal 
Upper limit of quantification 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
2 
Trial Objectives and Endpoints 
2.1 
Objectives 
Primary Objective 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 8 of36 
•
To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to
ongoing pregnancy rate in women undergoing controUed ovarian stimulation
Secondary Objectives 
•
To compare the clinical benefits of FE 999049 in its dosing regimen to those ofGONAL-F
with respect to efficacy and safety
•
To compare FE 999049 with GONAL-F with respect to ovarian response including
follicular development and endocrine profile, as well as with respect to embryo
development
•
To assess the population pharmacokinetics of FE 999049
•
To compare FE 999049 with GONAL-F with respect to treatment efficiency
•
To compare FE 999049 with GONAL-F with respect to safety profile, including adverse
events, routine safety laboratory parameters and local tolerability
•
To evaluate the immunogenicity of FE 999049 after one treatment cycle
•
To perform a health economic analysis comparing FE 999049 with GONAL-F
2.2 
Endpoints 
Primary Endpoint 
•
Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)
Secondary Endpoints 
•
Positive hCG rate (positive serum hCG test 13-15 days after transfer)
•
Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
•
Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks
after transfer)
•
Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of
embryos transferred)
•
Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks aner transfer
divided by number of embryos transferred)
•
Proportion of subjects with extreme ovarian responses, defined as <4, 2'.: 15 or 2'.:20 oocytes
retrieved
•
Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or
preventive interventions for early OHSS
Fening Phannaceuticals 
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Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 9 of36 
•
Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or
embryo transfer cancellation due to excessive ovarian response / OHSS risk
•
Number and size of follicles on stimulation day 6 and end-of-stimulation
•
Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and ::::20
oocytes retrieved
•
Percentage of metaphase II oocytes ( only applicable for those inseminated using ICSI),
fertilisation rate as well as number and quality of embryos on day 3 after oocyte retrieval
•
Circulating concentrations of LH, estradiol, progesterone, inhibin A and inhibin Bon
stimulation day 6 and end-of-stimulation
•
Circulating concentrations of FSH on stimulation day 6, end-of-stimulation and oocyte
retrieval as well as FSH population phannacokinetic parameters
•
Total gonadotropin dose and number of stimulation days
•
Proportion of subjects with investigator-requested gonadotropin dose adjustments
•
Frequency and intensity of adverse events
•
Changes in circulating levels of clinical chemistry and haematology parameters and
proportion of subjects with markedly abnormal changes
•
Frequency and intensity of injection site reactions (redness, pain, itching, swelling and
bruising) assessed by the subject during the stimulation period
•
Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with
neutralising capacity
•
Frequency and intensity of immune-related adverse events
•
Proportion of subjects with cycle cancellations due to an adverse event, including immune­
related adverse events, or due to technical malfunctions of the administration pen
•
Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)
•
Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic
pregnancy (with and without medical/surgical intervention) and vanishing twins
•
Technical malfunctions of the administration pen
Post-trial Information 
•
Live birth rate and neonatal health, including minor/major congenital anomalies, at birth and
at 4 weeks after birth
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
3 
Trial Design 
3.1 
General Design Considerations 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 10 of36 
This is a randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian non­
inferiority trial comparing the efficacy and safety of two rFSH preparations, FE 999049 and 
follitropin alfa (GONAL-F), in first cycle subjects aged 20-40 years undergoing controlled ovarian 
stimulation for IVF/ICSI following a GnRH antagonist protocol. 
The trial has been d!esigned to demonstrate non-inferiority of FE 999049, a human cell line-derived 
rFSH preparation, versus an approved CHO-derived rFSH preparation, i.e. GONAL-F, with 
ongoing pregnancy rate as the primary endpoint. 
Eligible subjects will be randomised in a I: I ratio to controlled ovarian stimulation with FE 999049 
or GONAL-F. Randomisation will be stratified by trial site and age (<35, 35-37 and 38-40 years). 
The last scheduled visit in the main part of the trial is the ongoing pregnancy visit ( end-of-trial). 
The end-of-trial form should be filled out at the subject's last visit, irrespective of whether the 
subject completed the trial or not. 
Subjects with an ongoing pregnancy will be followed for pregnancy outcome as well as neonatal 
health at birth and at 4 weeks after birth. 
3.2 
Determination of Sample Size 
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation. The non-inferiority limit for the difference between treatments (FE 999049 versus 
GONAL-F) is -10.0% (absolute) for the primary endpoint. 
Since this is a non-inferiority trial, the full analysis set (FAS) and the per-protocol (PP) analyses are 
equally important, i.e. non-inferiority should be established for both analysis sets in order to have a 
robust conclusionP]_ Therefore, the expected proportion of Sll!bjects with major protocol deviations 
should be taken into account when setting the total sample size for the trial. The proportion of 
subjects with major protocol deviations is assumed to be at most 8%. 
The trial is designed to have 90% power of achieving the primary objective for the overall 
Pan-Asian trial population and 80% power in the Chinese population. The number of subjects 
needed to achieve 90% power depends on the assumptions regarding the ongoing pregnancy rate. 
Based on an assumed ongoing pregnancy rate of 32.2% observed in the PP population of the 
ESTHER 1 trial, N=9 l 8 subjects are required in the PP population to obtain a power of 90%. 
Anticipating at most 8% major protocol deviations this results in N=lOOO subjects to be 
randomised. The power is reasonably robust against deviations from the ongoing pregnancy rate 
assumption of 32.2%: a 35% ongoing pregnancy rate would still result in a 88.9% power, while 
lower rates will only increase the power (e.g. 30% yields 91.1 % power). Recruiting at least 740 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 11 of 36 
subjects in China is expected to secure that consistency can be established between the results from 
the overall Pan-Asian trial population and the Chinese trial population. In addition, to obtain 
approval in other Asian countries at least 260 subjects are needed. Thus a total sample size of 1,000 
subjects will be recruited for this trial. 
A blinded sample size reassessment will take p[ace when data on the primary endpoint are available 
for 70% of the planned subjects or when 800 subjects are randomised, whichever comes first. The 
sampEe size reassessment will be done without breaking the blind and without inflating the type I 
error of the trial[2l, in line with the current regulatory guidelines for non-inferiority trials by FDA[3l 
and in general by EMA [41 _ 
A restricted recalculation rule for the sample size reassessment will be used. Accordingly 1,000 
subjects should be randomised to achieve sufficient power if the ongoing pregnancy rate is 32.2%. 
If the ongoing pregnancy rate is above the expected 32.2%, the sample size can be adjusted up to a 
maximum of 1,144 (572 per treatment group), corresponding to an ongoing pregnancy rate of 50%. 
If the rate is below the expected 32.2% the sample size will not be decreased below the planned 
1,000 subjects. 
4 
Subject Disposition 
All screened subjects will be accounted for. 
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening 
failures. Number of screened subjects and their primary reason for screening failure will be 
summarised. Screening failures will not otherwise be accounted for. 
Subject disposition will be summarised by treatment group (FE 999049, GONAL-F, Total) and age 
stratum (All age strata, <35, 35-37, 38-40 years) for all randomised subjects. Separate tables will be 
produced by country. 
Subject disposition with respect to analysis sets will include the number of subjects that completed 
the trial and discontinued the triafl, including reason for trial discontinuation. 
Subject disposition with respect to analysis sets and age stratum will be summarised in a separate 
table by trial site. 
The number of subjects completing the procedures (including the reasons for not completing) will 
be summarised for the following trial parts: stimulation, triggering of final follicular maturation, 
oocyte retrieval, transfer, and pregnancy monitoring. 
Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation from the trial for non-completers. 
Subjects who discontinued from the trial will also be listed separately. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
5 
Protocol Deviations 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
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Major protocol deviations, such as significant non-compliance or other serious unforeseen 
deviations deemed to invalidate the data and affect the conclusions of the trial, will lead to 
exclusion of data from the PP analysis set. Data will not be excluded from the PP analysis set in 
case of minor protocol deviations. The list of major protocol deviations include, but is not restricted 
to: 
•
Unblinding of assessor
•
Treatment not in accordance with randomisation
•
Non-compliance with IMP for two or more days
•
Administration of hCG for triggering of final follicular maturation was not given despite the
triggering criterion for hCG administration was met
•
GnRH agonist criterion met but hCG used for triggering of final follicular maturation
•
GnRH agonist criterion not met but GnRH agonist used for triggering of final follicular
maturation
•
Non-compliance with the number of embryos transferred
The rating of protocol deviations in 'minor' and 'major' will be decided by the Ferring clinical 
team on the basis of a blinded review of data before declaration of clean file and lock of database. If 
the bljnded review identifies serious unforeseen deviations deemed to impact the primary endpoint 
and affect the conclusions of the trial these will also be rated as major deviations. 
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be tabulated and listed by subject for all 
randomised subjects. 
6 
Analysis Sets 
6.1 
Intention-to-Treat Analysis Set 
The intention-to-treat (ITT) analysis set is defined as all randomised subjects. Subjects will be 
analysed according to randomised (planned) treatment. 
6.2 
Full Analysis Set 
The FAS is defined as all randomised and exposed subjects. Subjects will be analysed according to 
randomised (planned) treatment. 
6.3 
Per Protocol Analysis Set 
The PP analysis set is defined as all randomised and exposed subjects except those excluded as a 
result of major protocol deviations as described in Section 5. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
6.4 
Safety Analysis Set 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 13 of36 
The safety analysis set is defined as all randomised and exposed subjects. Subjects will be analysed 
according to actual treatment received. 
6.5 
Subgroups 
Data will in some cases be reported using the following subgroups: 
•
Subjects grouped according to AMR at screening (<15 pmol/L, 15 pmol/L)
•
Subjects with at least I oocyte retrieved
•
Subjects with transfer
•
Subjects grouped according to number of embryos transferred (single, double)
•
Subjects grouped according to ongoing pregnancy type (single, twin, triplet)
•
Subjects grouped according to insemination method
•
Subjects grouped according to primary reason for infertility
•
Subjects grouped according to primary infertility
•
Subjects grouped according to smoking status
7 
Trial Population 
All relevant baseline data will be summarised by treatment group (FE 999049, GONAL-F, Total) 
and age stratum (All age strata, <35, 35-37, 38-40 years) for both the FAS and the PP analysis sets. 
Separate tables will be produced by country. The purpose of these tabulations is to characterise the 
treatment groups and assess the degree of similarity achieved by the randomisation. Baseline data 
will not be compared using statistical tests. Continuous variables will be presented with number of 
subjects, mean, standard deviation, median, inter-quartile range, minimum, and maximum. 
Categorical variables will be presented with number and percentage of subjects within each specific 
category. 
Listings will be produced for the ITT analysis set. 
7.1 
.Demographics and Other Baseline Characteristics 
7.1.1 
Demographics 
Demographics and other baseline characteristics (smoking and alcohol habits, body measurements, 
ultrasound parameters, vital signs, and endocrine parameters) obtained before first exposure to IMP 
will be listed and presented in summary tables. 
7.1.2 
Infertility History, Menstrual History and Reproductive History 
Infertility history (including previous fertility treatment), menstrual history and reproductive history 
will be listed and presented in summary tables. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
7 .2 
Medical History 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 14 of36 
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed and summarised for each medical item. This summary table will be 
produced overall (i.e. not by age stratum) and by country for the FAS. 
7.3 
Prior and Concomitant Medication 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference List. Prior and concomitant medication will be summarised by A TC classification 1 st 
level (alphabetically) and ATC classification 2nd level (in decreasing order of frequency). These 
medications will be tabulated separately for: 
•
Prior medication, i.e. medication taken exclusively prior to treatment (i.e. with stop
date/time before date/time of 1st IMP administration)
•
Concomitant medication, i.e. medication taken during the treatment period (i.e. medication
that was not stopped before date/time of 1st IMP administration and not started after the
end-of-trial visit)
These tables will be produced overall (i.e. not by age stratum) and by country for the FAS. 
If the timing of the dose of a medication cannot be established in relation to the administration of 
IMP, it will be considered as concomitant medication. 
Medications will be listed. 
7.4 
Physical Examination and Gynaecological Examination 
Physical examination and gynaecological examination performed during screening will be 
summarised per category. These tables will be produced overall (i.e. not by age stratum) and by 
country for the FAS. 
8 
Exposure and Treatment Compliance 
8.1 
Extent of Exposure 
Duration of treatment (days) is defined as the number of days from first exposure to the day of last 
exposure (both inclusive). If a subject misses an intermediate dose she will still be considered as 
being under treatment. 
Exposure will be summarised by treatment group (FE 999049, GONAL-F, Total) and age stratum 
(All age strata, <35, 35-37, 38-40 years) for the safety analysis set. Separate tables will be produced 
by country. Treatment comparisons will be produced for the overall Pan-Asian trial population and 
for the Chinese population. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Total Gonadotropin Dose and Number of Stimulation Days 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 15 of36 
Exposure to gonadotropins will be summarised as the total gonadotropin dose and the number of 
stimulation days. The total dose will be reported in µg for FE 999049 and both in IU and µg for 
GONAL-F. For subjects in the FE 999049 group the dose on stimulation day I will be summarised. 
The total gonadotropin dose and the number of stimulation days will be compared between 
treatments using van Elteren test stratified for age and within each age stratum using the 
Wilcoxon's test. 
Gonadotropin Dose Adjustments 
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. The requested dose change ( decrease I increase / no change) on stimulation 
day 6 will be tabulated. Further, the number of dose increase requests and number of dose decrease 
requests per subject will be tabulated. The requested dose change on stimulation day 6 will be 
compared between treatments using chi-square tests overall and within age stratum. 
GnRH Antagonist 
Exposure to GnRH antagonist will be summarised as the total dose administered (mg) and duration 
of treatment (days). 
Triggering with hCG or GnRH agonist 
Triggering criteria met (hCG, GnRH agonist or none) and drug used for triggering (hCG or GnRH 
agonist) will be summarised. 
Progesterone 
Exposure to progesterone will be summarised as the total dose administered (mg) and duration of 
treatment (days). 
8.2 
Treatment Compliance 
Treatment non-compliance will be presented in listings as non-compliance is expected to be 
limited. 
9 
Efficacy 
9.1 
General Considerations 
Primary and Secondary Endpoints 
The results of the analyses of the primary endpoint (ongoing pregnancy rate) based on the overall 
Pan-Asian trial population are essential for the non-inferiority claim. The results obtained for the 
Chinese trial population is considered supportive of the overall conclusion. If the results for the 
Chinese trial population are markedly different from those obtained based on the overall Pan-Asian 
trial population the reasons for this difference will be examined. The secondary endpoints positive 
hCG rate, clinical pregnancy rate, vital pregnancy rate, implantation rate and ongoing implantation
rate are considered supportive of the primary endpoint. However, non-inferiority does not need to
be established for these secondary endpoints.
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 16 of36 
The remaining secondary endpoints are intended to provide additional characterisation of the safety 
and efficacy of FE 999049. 
Analysis and Presentation of Primary and Secondary Endpoints 
Treatment comparisons will be produced for the overall Pan-Asian trial population and for the 
Chinese population. Summary tables for the primary endpoint and supportive pregnancy endpoints 
will be prepared by treatment group and age stratum, and by treatment group and AMH group for 
both the FAS and PP analysis sets. Separate tables will be produced by country. For the remaining 
secondary endpoints, summary tables will be prepared by treatment group and age stratum for the 
FAS. 
All talbulations will present the treatment groups and include a total column. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category. 
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will 
be listed for the FAS. 
Multiplicity 
No adjustments for multiplicity are required since there is only one primary endpoint and 
non-inferiority has to be established for both the FAS and the PP analysis sets. In addition, the 
testing for superiority based on the FAS will be made in a sequential manner, only if non-inferiority 
is established_l5l The evaluation of the subjects recruited in China will be regarded as supportive. 
Concerning the secondary endpoints no formal adjustment for multiplicity will be utilised. 
Missing Data 
For the primary endpoint, ongoing pregnancy rate, occurrence of missing data is unlikely but may 
occur in case the assessment was not done. For this endpoint, a subject's response is considered as 
'negative' unless recorded as 'positive'. Missing observations for the supportive secondary 
endpoints positive J3hCG rate, clinical pregnancy rate and vital pregnancy rate will be considered as 
'negative' unless recorded as 'positive'. An exception to this is if a later observation confirms that a 
previous missing observation was in fact positive. For example, if the phCG test result is missing 
but clinical pregnancy is recorded as 'positive' then the phCG test result wall be regarded as 
'positive'. 
For subjects with transfer but missing information on the number of viable fetuses 10-11 weeks 
after transfer, the number of viable fetuses will be imputed as zero irrespective of why data are not 
recorded. For subjects with transfer but missing information on the number of gestational sacs 5-6 
weeks after transfer, the number of gestational sacs will be imputed as the number of viable fetuses 
at 10-11 weeks after transfer. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
9.2 
Primary Endpoint 
9.2.1 
Primary Variable Analysis 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 17 of36 
This trial has one primary endpoint: Ongoing pregnancy rate. Ongoing pregnancy is defined as at 
least one intrauterine viable fetus 10-11 weeks after transfer. 
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to the primary endpoint in women undergoing controlled ovarian 
stimulation. The non-inferiority limit for the difference between treatments (FE 999049 versus 
GONAL-F) is -10.0% (absolute). 
The non-inferiority hypothesis to be tested for the primary endpoint is 
Ho: 7tFE - 7tGF  -10.0% against the alternative HA: 7tFE - 7tGF > -10.0%, 
where 7tFE and 7tGF denote the ongoing pregnancy rate after treatment with FE 999049 and 
GONAL-F, respectively. Non-inferiority will be evaluated based on the overall Pan-Asian trial 
population. 
The primary analyses will be adjusted for the stratification factor (age group) by using the Mantel­
Haenszel method to combine results across age strata. In brief, this corresponds to deriving a 
weighted average across age strata where the weight depends on the number of observations in each 
treatment group in each age stratum. 
For the primary endpoint the null hypothesis (Ho) will be tested against the alternative (HA) by 
constructing a two-sided 95% confidence interval for the difference in ongoing pregnancy rates. If 
the lower-limit of the two-sided 95% confidence interval is greater than the non-inferiority limit 
(-10.0%) for both the FAS and the PP analysis set, the null hypothesis will be rejected. In that case 
it will be claimed that FE 999049 is non-inferior to GONAL-F with respect to ongoing pregnancy 
rate in women undergoing controlled ovarian stimulation. 
If the lower-limit of the two-sided 95% confidence interval for the treatment difference based on 
the FAS not only lies above the non-inferiority limit (-10.0%) but also above zero then there is 
evidence of superiority in terms of statistical significance at the 5% level. In this case, the p-value 
from the test for superiority will be reported and it will be claimed that FE 999049 is superior to 
GONAL-F for the primary endpoint. The result based on the PP analysis set is not essential for the 
superiority claim but should lead to a comparable result for a robust interpretation. 
There is no need for a multiplicity adjustment when switching from non-inferiority to superiority 
since it is a simple sequential test procedure. This interpretation is in line with the Food and Drug 
Administration (FDA) draft guidance on "Multiplicity"[5J and EMA's "Points to consider on 
switching between superiority and non-inferiority"[ 1J. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 18 of36 
The two-sided 95% confidence intervals will be constructed based on the asymptotic normal 
distribution as 
where the sums are over the three age strata (i.e. i = l to 3), RD; = ii F£.i -frGF.i is the observed 
difference in rates (FE 999049 - GONAL-F) within stratum i, 
1[F,, · (1 - 1[FE · ) 
1[GF · (1 - 1[GF · ) 
SE(RD;) = 
"'•' 
,, + 
·,, 
,, is the standard error of the observed difference in 
nFE,i 
nGF,i 
rates within stratum i, 
nFE,i nGF,i 
w; = 
is the weight assigned to stratum i, 
nFE,; +ncF,; 
ic F£.;, ft GF.i are the observed rates for each treatment group and stratum, and 
n FE,;, n aF ,; are the number of observations in each treatment group and stratum. 
A supportive evaluation of the subjects recruited in China will be made and it is expected that the 
findings among the Chinese trial population will be consistent with the overall findings in the trial. 
If the results based on the Chinese trial population are markedly different from those obtained 
based on the overall Pan-Asian trial population the reasons for this difference will be examined. 
9.2.2 
Sensitivity Analyses 
Besides stratification by age the randomisation is also stratified by trial site. However, as detailed 
above, the primary analysis will be based on all data pooled across sites assuming homogeneity of 
the risk differences across sites. This assumption will be tested using the approach described by 
Lipsitz et al. (1998). [GJ Sites were all subjects have a positive outcome and sites where all subjects 
have a negative outcome will be excluded from this analysis. In addition sites with at most one 
subject in any treatment group will be excluded from this sensitivity analysis. If there is statistically 
significant heterogeneity across sites the implications for the interpretation of the primary result 
will be discussed. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 19 of36 
To evaluate the robustness of the conclusions, the following factors potentially impacting ongoing 
pregnancy will be evaluated one by one: 
•
Insemination method
•
Primary reason for infertility
•
Primary infertility
•
Smoking status
For each factor, the primary analysis will be repeated using the factor levels as strata instead of the 
age stratification. The outcomes of these analyses are considered supportive and should lead to 
similar results as the primary analysis to ensure robustness of the conclusion. 
9.2.3 
Supplementary Descriptions 
The ongoing pregnancy rate will be summarised for subjects with at least one oocyte retrieved and 
for subjects with transfer. The purpose of this is purely descriptive. 
As described in the protocol Section 6.5.1, transfer of one or two embryo(s) is to be performed on 
day 3 after oocyte retrieval. The decision to transfer either one or two embryo(s) is based on the 
subject's age and the quality and availability of embryo(s) on the day of transfer. Since this 
decision is based on observations performed after randomisation it can be affected by the treatment 
allocation. It is therefore not planned to perform a formal statistical analysis of the ongoing 
pregnancy rate adjU1sting for number of embryos transferred. The rationale for not including these 
adjustments in the primary analysis is that such an adjustment may hide or exaggerate the 
differences between treatments.(71 Instead the ongoing pregnancy rate will be presented by number 
of embryos transferred. Further, a frequency table will be produced to compare treatments with 
respect to number of embryos transferred. 
9.3 
Secondary Endpoints 
For each secondary endpoint the analysis based on the FAS will be used to assess the statistical 
significance of differences between treatments. The analysis based on the PP analysis set will be 
considered supportive and should lead to a similar but not necessarily statistically significant result 
in ord!er to have a robust interpretation. 
Statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of 'equal effect' against the alternative of 
'different effect'. 
Positive l}hCG Rate 
Positive PhCG is defined as posi6ve serum PhCG test 13-15 days after transfer. The positive PhCG 
rate is considered supportive to the primary endpoint and will therefore be analysed in a similar 
manner as the primary endpoint. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Clinical Pregnancy Rate 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 20 of36 
Clinical pregnancy is defined as at least one gestational sac 5-6 weeks after transfer. The clinical 
pregnancy rate is considered supportive to the primary endpoint and will therefore be analysed in a 
similar manner as the primary endpoint. For subjects with clinical pregnancy, the type of clinical 
pregnancy (intrauterine or ectopic) will be tabulated. 
Vital Pregnancy Rate 
Vital pregnancy is defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer. The vital pregnancy rate is considered supportive to the primary endpoint and will 
therefore be analysed in a similar manner as the primary endpoint. For subjects with a vital 
pregnancy, the number of intrauterine gestational sacs with fetal heart beat and the number of 
fetuses with fetal heart beat will be tabulated. 
Implantation Rate 
Implantation rate is defined as the number of gestational sacs 5-6 weeks after transfer divided by 
number of embryos transferred. For implantation rate, the experimental unit will be the transferred 
embryos, i.e., the analysis will compare the proportions of embryos transferred that results in 
gestational sacs 5-6 weeks after transfer. The implantation rate will be analysed in a similar manner 
as the primary endpoint. Note tha.t this endpoint is less relevant than the pregnancy endpoints since 
it is only defined in the subgroup of subjects that had an embryo transfer, and hence does not 
adhere to the randomisation principle. 
Ongoing Implantation Rate 
Ongoing implantation rate is defined as the number of intrauterine viable fetuses 10-11 weeks after 
transfer divided by number of embryos transferred. For ongoing implantation rate, the experimental 
unit will be the transferred embryos, i.e., the analysis will compare the proportions of embryos 
transferred that results in intrauterine viable fetuses 10-11 weeks after transfer. The ongoing 
implantation rate will be analysed in a similar manner as the primary endpoint. 
Ovarian Response and Extreme Ovarian Response 
The ovarian response will be defined based on the number of oocytes retrieved, and if the cycle was 
cancelled, the reason for cycle cancellation. Subjects will be grouped according to ovarian response 
as: 
•
Low response ( <4 oocytes retrieved or cancellation of cycle due to poor ovarian response)
•
Moderate response ( 4-7 oocytes retrieved)
•
Targeted response (8-14 oocytes retrieved)
•
Hyperresponse (15-19 oocytes retrieved)
•
Severe hyperresponse (20 oocytes retrieved or cancellation of cycle due to excessive
ovarian response)
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Extreme ovarian response will be defined as: 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 21 of36 
•
<4 oocytes retrieved or cancellation of cycle due to poor ovarian response
•
x15 oocytes retrieved or cancellation of cycle due to excessive ovarian response
•
x20 oocytes retrieved or cancellation of cycle due to excessive ovarian response
•
<4 or x 15 oocytes retrieved or cancellation of cycle due to poor or excessive ovarian
response
•
<4 or x20 oocytes retrieved or cancellation of cycle due to poor or excessive ovarian
response
For each definition of ovarian response and extreme ovarian response the proportion of subjects 
will be tabulated. Treatments win be compared using a logistic regression model with treatment and 
age stratum as factors. The difference between treatments will be reported as an odds ratio 
including 95% confidence interval and p-value for test of no treatment difference. If the expected 
number of observations is less than five in any of the cells in the contingency table then Fisher's 
exact test will be used as alternative. The possibility of a treatment-by-age interaction will be 
investigated. 
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo Tran sf er 
Cancellation due to Excessive Ovarian Response/ OHSS Risk 
The number of subjects with cycle cancellation or embryo transfer cancellation including the 
reasons for cancellation will be summarised. 
The following endpoints will be defined: 
•
Cycle cancellation or embryo transfer cancellation
•
Cycle cancellation due to poor or excessive response, or transfer cancellation due to
excessive ovarian response/OHSS risk
•
Cycle cancellation due to poor ovarian response
•
Cycle cancellation due to excessive ovarian response
•
Cycle cancellation due to poor or excessive ovarian response
•
Transfer cancellation due to excessive ovarian response/OHSS risk
•
Cycle cancellations due to excessive response or transfer cancellation due to excessive
ovarian response/OHSS risk
These endpoints will be tabulated and analysed in a similar manner as extreme ovarian response. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Number and Size of Follicles during Stimulation 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 22 of36 
Based on the transvaginal ultrasound on stimulation day 6 and at end-of-stimulation the following 
endpoints are defined: 
•
Total number of follicles
•
Size of the largest follicle (mm)
•
Average follicle size (mm)
•
Average size of three largest follicles (mm)
•
Number of :follicles 2:8 mm, 2:10 mm, 2: 12 mm, 2:15 mm and 2:17 mm
Number and size of follicles will be compared between treatments using the van Elteren test 
stratified for age and within each age stratum using the Wilcoxon's test. 
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised on the follicle 
level (number of follicles 2-7 mm, 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and¦ 17 mm). 
Number of Oocytes Retrieved 
The number of oocytes retrieved will be compared between treatments using the van Elteren test 
stratified for age and within each age stratum using the Wilcoxon's test. 
Additional summarises will be made for subjects with at least one oocyte retrieved. The purpose of 
this is purely descriptive. 
Metaphase II Oocytes 
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The 
percentage of MII oocytes to oocytes retrieved for subjects where all oocytes are inseminated using 
ICSI will be tabulated. In the subgroup of subjects where all oocytes are inseminated using ICSI the 
number of MII oocytes will be compared between treatments using the van Elteren test stratified for 
age and within each age stratum using the Wilcoxon's test. Subjects will be grouped according to 
number of MII oocytes as: §6, 6-12, ¦13 and the corresponding frequencies tabulated. 
Fertilisation Rate 
An oocyte is defined as fertilised if it is scored as 2 pronuclei. on day I after oocyte retrieval. For 
subjects with oocytes retrieved, the rate of fertilised oocytes to oocytes retrieved (and also the rate 
of fertilised oocytes to metaphase II oocytes for those inseminated using ICSI) will be tabulated. 
The number of fertilised oocytes and the fertilisation rate will be compared between treatment 
groups using the van Elteren test stratified for age and within each age stratum using the 
Wilcoxon's test. Subjects will be grouped according to number of fertilised oocytes as: <4, 4-7, 8-
14, 15-19, ¦20 and the corresponding frequencies tabulated. Note that the analysis of fertilisation 
rates excludes subjects without oocytes retrieved and do therefore not adhere to the randomisation 
principle. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Number and Quality of Embryos on Day 3 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 23 of36 
Based on the embryo assessment day 3 the following endpoints are defined: 
•
Number of embryos
•
Number of good-quality embryos
•
Subjects with at least one embryo
•
Subjects with at least one good-quality embryo
•
Rate of embryos to oocytes retrieved
•
Rate of good-quality embryos to oocytes retrieved
•
Rate of embryos to MIi oocytes
•
Rate of good-quality embryos to MIi oocytes
•
Number of cryopreserved embryos
•
Subjects with at least one cryopreserved embryo
Numbers and rates will be compared between treatments using the van Elteren test stratified for age 
and within each age stratum using the Wilcoxon's test. For each definition of 'subjects with at least 
one' the proportion of subjects will be tabulated and analysed in a similar manner as extreme 
ovanan response. 
Embryo quality will be summarised including a breakdown by selected quality parameters ( degree 
of fragmentation, embryo stage, blastomere uniformity, visual sign of multi-nucleation) and 
insemination method. Separate summaries will be made for the transferred embryos and for the 
cryopreserved embryos. 
Circulating Levels. of Endocrine Parameters 
Blood samples drawn at stimulation days 1 and 6 and end-of-stimulation are analysed for FSH, LH, 
estradiol, progesterone, inhibin A and inhibin B. Furthermore, blood samples drawn at the oocyte 
retrieval visit are also analysed for FSH. Values below the lower limit of quantification (LLOQ) 
will be included as LLOQ/2. Values above the upper limit of quantification (ULOQ) will be 
included as ULOQ. 
Each endocrine parameter and the change from baseline for post-baseline measurements will be 
tabulated for stimulation day l (baseline), stimulation day 6 and end-of-stimulation (and also the 
oocyte retrieval visit for FSH). For each parameter the change from baseline will be compared 
between treatments using an analysis of covariance model (ANCOV A). The ANCOV A will be 
fitted to the relative change from baseline in In-transformed measurements with treatment and age 
stratum as fixed factors and the ln-transformed baseline measurement as covariate. The estimated 
treatment difference with 95% confidence interval will be presented on the scale of measurement 
(i.e. back-transformed using base e) and accompanied by the p-value for test of no treatment 
difference. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 24 of36 
Summary tables will be prepared for LH and/or progesterone displaying the proportion of subjects 
who have a markedly abnormal value. These tables will also include a break-down by classification 
of the baseline value. The markedly abnormal criteria is specified in Appendix 1. 
9.4 
Other Endpoints 
FSH Population Pharmacokinetics 
A population pharmacokinetic model describing FSH concentrations following repeated dosing of 
FE 999049 will be prepared under the responsibility of the Ferring Translational Medicine 
Department. 
These results will be reported separately. 
10 
Safety 
10.1 
General Considerations 
Safety endpoints will be summarised by treatment group for the safety analysis set. Separate tables 
will be produced by country. 
Missing Data 
For adverse events a worst-case approach will be used to impute missing values for causality, 
intensity and seriousness of the event. 
10.2 
Adverse Events 
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events are grouped according to start of IMP as follows: 
•
Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent
and before start of IMP, or a pre-existing medical condition that worsens in intensity after
signed informed consent but before start of IMP.
•
Treatment-emergent adverse event, i.e. any adverse event occurring after start ofIMP and
before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical
condition that worsens in intensity after start of IMP and before the end-of-trial visit.
If the timing of an AE cannot be established in relation to the administration ofIMP, it will be 
considered as a treatment emergent AE. 
In addition to the grouping of adverse events described in the protocol, adverse events will be 
categorised as 'other significant adverse events ,[SJ and 'unexpected non-serious adverse drug 
reactions'. These events will be identified in a blinded review of the data before declaration of clean 
file and lock of database. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 25 of36 
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in listings only. 
10.2.1 
Overview of Treatment-emergent Adverse Events 
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: 
•
All adverse events
•
Severe adverse events
•
Adverse drug reactions
•
Adverse events leading to discontinuation
•
Serious adverse events
•
Adverse events leading to death
An adverse drug reaction is an adverse event judged by the investigator to be related to IMP with a 
reasonable possibility. 
10.2.2 
Incidence of Adverse Events 
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported. 
Summary tables will be produced for the following: 
•
All adverse events
•
Adverse events by causality (reasonable possibility/ no reasonable possibility)
•
Adverse events leading to death
•
Adverse events by intensity (mild / moderate / severe)
•
Adverse drug reactions by intensity (mild/ moderate/ severe)
•
Serious adverse events
•
Adverse events leading to discontinuation
•
Other significant adverse events[8l
•
Unexpected non-serious adverse drug reactions
•
Adverse events with an incidence of2.5% in any treatment group
•
Non-serious adverse events with an incidence of 2:5% in any treatment group
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
10.3 
OHSS 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 26 of36 
OHSS will be tabulated by classification (mild, moderate, severe) and grade (1, 2, 3, 4, 5). 
Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Pr·eventive Interventions 
for Early OHSS 
Early OHSS is defined as OHSS with onset :S9 days after triggering of final follicular maturation. 
Note that this includes OHSS with onset before triggering and ORSS with onset during stimulation 
where triggering is not performed. 
The following endpoints are defined: 
•
Subjects with early OHSS
•
Subjects with early ORSS of moderate or severe grade
•
Subjects with preventive interventions for early ORSS
•
Subjects with early ORSS and/or preventive interventions for early ORSS
•
Subjects with early ORSS of moderate or severe grade and/or preventive interventions for
early ORSS
For each definition the proportion of subjects will be tabulated. Treatments will be compared using 
a logistic regression model with treatment and age stratum as factors. Treatment comparisons will 
be produced for the overall Pan-Asian trial population and for the Chinese population. 
The risk of preventiive interventions for early ORSS and/or early ORSS is related to the ovarian 
response potential. AMH is a well-established predictor of ovarian response to gonadotropin 
treatment and was confomed to be the best endocrine marker of ovarian response to FE 999049 
treatment in the phase 2 trial. Since FE 999049 is dosed based on AMR it is likely that the 
relationship between AMR and the risk of experiencing preventive interventions for early ORSS 
and/or early ORSS differs between FE 999049 and GONAL-F. To further explore this for each of 
the endpoints above, two different logistic regression models will be fitted assuming an increasing 
risk with increasing AMR with two nested models as follows: 
Model 1: LOGIT(n) = ®o + ®dn(AMH), 
where 1t denotes the risk and the ®' s denotes the regression coefficients. 
Model 2: LOGIT(n) = ®o + ®dn(AMR) + 2,i + 3,i ln(AMR), 
where i=I, 2 indicates the two treatments. This is model 1 with addition of treatment and 
treatrnent-by-ln(AMR) interaction terms. 
The two models will be compared using the likelihood ratio test. Adjusted odds ratio estimates 
(comparing FE 999049 to GONAL-F) and associated 95% Wald confidence interval will be 
provided. A statistically significant improvement with model 2 compared to model I should be 
interpreted as a treatment difference in that the relationship between AMR and the risk of 
experiencing preventive interventions for early ORSS and/or early ORSS. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 27 of36 
The estimated risks based on the models will be plotted as a function of AMH, i.e. overall and for 
each treatment group. The plots will include observed incidences for AMH-based subgroups of 
subjects. The adequacy of the model fits will be evaluated using the Hosmer-Lemeshow 
goodness-of-fit test and by examining how weH the model fit describes the data in the plot. 
It should be noted that the likelihood ratio test using two nested models above corresponds to a test 
of the contrast P2,1 = P2,2 = p3,1 = f33,2 = 0 in model 2 above. 
Late OHSS (Including OHSS of Moderate/Severe Grade) 
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
The following endpoints are defined: 
•
Subjects with late OHSS
•
Subjects with late OHSS of moderate or severe grade
These endpoints will be tabulated and analysed in a similar manner as the endpoints defined for 
early OHSS. 
OHSS (Early and/or Late) and/or Preventive Interventions for Early OHSS 
The following endpoints are defined: 
•
Subjects with early and/or late OHSS
•
Subjects with early and/or late OHSS of moderate or severe grade
•
Subjects with early and/or late OHSS and/or preventive interventions for early OHSS
•
Subjects with early and/or late OHSS of moderate or severe grade and/or preventive
interventions for early OHSS
These endpoints will be tabulated and analysed in a similar manner as the endpoints defined for 
early OHSS. 
10.4 
Safety Laboratory Variiables 
Safety laboratory variables will be grouped under "Haematology" and "Clinical Chemistry". 
The baseline is based on the blood sample drawn at stimulation day 1. Treatment-emergent 
laboratory data will be obtained at end-of-stimulation and end-of-trial. 
The circulating levels of clinical chemistry and haematology parameters including change from 
baseline will be tabulated for each time-point for each laboratory variable. 
Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-trial 
values, using a categorisation of low, normal and high values at each visit. Low, normal and high 
will be defined according to the reference ranges provided by the central laboratory. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 28 of36 
Summary tables by visit will be prepared displaying the proportion of subjects who have a 
markedly abnormal value. These tables will also include a break-down by classification of the 
baseline value. Markedly abnormal criteria for the safety laboratory variables is specified in 
Appendix 1. 
All laboratory values will be listed by subject and time point. Values outside the reference range 
and markedly abnonnal values will be flagged. 
10.5 
Injection Site Reactions 
Injection site reactions will be tabulated by symptom (redness, pain, itching, swelling, bruising), 
time after injection (immediately after, 30 minutes after, 24 hours after) and intensity (none, mild, 
moderate, severe, moderate/severe). 
10.6 
Treatment-induced Anti-FSH Antibodies 
The proportion of subjects with treatment-induced anti-FSH antibodies as well as the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralising capacity will be tabulated. 
Furthermore, for subjects with treatment-induced anti-FSH antibodies, all antibody assessments 
will be listed. 
10.7 
Immune-related Adverse Events 
Potential immune-related adverse events will be tabulated by SOC and PT using the SMQs for: 
anaphylactic reaction, angioedema, hypersensitivity reactions and severe cutaneous reactions and 
the Ferring defined PTs including: asthenia, pyrexia, body temperature increased, chills, influenza­
like illness, musculoskeletal pain, syncope and pre-syncope. 
10.8 
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen 
Adverse events leading to cycle cancellation will be listed. 
10.9 
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins 
The incidence of biochemical pregnancy, spontaneous abortion, ectopic pregnancy and vanishing 
twins will be reported as part of the adverse events summaries described in Section 10.2.2 . 
Early pregnancy loss is defined as pregnancy loss occurring before ongoing pregnancy (hCG to 
ongoing pregnancy). The incidence of early pregnancy loss will be tabulated. The denominator will 
be the subjects at risk for early pregnancy loss, i.e. number of subjects with a positive PhCG. Early 
pregnancy losses will also be grouped as: 'PhCG to vital pregnancy' and 'vital pregnancy to 
ongoing pregnancy'. Summaries will be made overall, by vital pregnancy type and by ongoing 
pregnancy type. The pregnancy types are defined as 'singleton', 'twin', 'triplets' and 'higher-order 
multiples' based on number of intrauterine viable fetus( es) at the respective assessment. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
10.10 
Pen Malfunction 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 29 of36 
Number of subjects reporting technical malfunctions of the administration pen and the type of 
malfunction will be tabulated. 
I 0.11 
Additional Safety Evaluations 
10.11.1 
Physical Examinations 
Physical examination at end-of-trial compared to baseline (screening) will be summarised in shift 
tables. Subjects with any abnormal finding will be listed. The list will include both baseline and 
end-of-trial assessment for comparison. 
10.11.2 
Gynaecological Examination 
Gynaecological examination at end-of-trial compared to baseline (screening) will be summarised in 
shift tables. Subjects with any abnormal finding will be listed. The list will include both baseline 
and end-of-trial assessment for comparison. 
10.11.3 
Changes in Body Weiight 
Body weight will be measured at screening, on stimulation day 1 (baseline) and at end-of-trial. The 
actual measurements and tbe change from baseline will be tabulated. 
10.11.4 
Vital Signs 
Vital signs and their change from stimulation day 1 (baseline) to end-of-trial will be summarised. 
Shift tables will be prepared to compare the baseline values with the end-of-trial values using the 
categorisation of low, normal and! high reference values. Low, normal and high reference values is 
specified in the Appendix 1. 
For systolic and diastolic blood pressure, a summary table will be prepared displaying the 
proportion of subjects with a markedly abnormal value at end-of-trial. A break-down of the 
classification at baseline will be included. The markedly abnormal criteria is specified in 
Appendix 1. Vital signs will be listed and values categorised as low, high or markedly abnormal 
will be flagged. 
10.12 
Pregnancy Follow-up 
Pregnancy follow-up information will be collected for all subjects with ongoing pregnancy. All 
intrauterine viable fetuses at the ongoing pregnancy visits will be accounted for. Neonatal health 
data will be collected at birth and at 4 weeks after birth for all children born. 
All data captured during the pregnancy follow-up will be listed. 
Live Birth 
Live birth is defined as the birth of at least one live baby. For all live births the type of pregnancy 
(singleton, twin, triplets and higher-order multiples) will be summarised. Subjects with no 
information ona live birth will be regarded as not having live birth. 
Fening Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 30 of36 
The live birth rate is considered supportive to the primary endpoint and will therefore be analysed 
in a SEmilar manner as the primary endpoint. Treatment comparisons will be produced for the 
overall Pan-Asian trial population and for the Chinese population. Summary tables will be prepared 
by treatment group and age stratum for both the FAS and PP analysis sets. Separate tables will be 
produced by country. In addition, live birth will be summarised based on the subgroups defined in 
Section 6.5. 
Live Rate at 4 Weeks after Birth 
The live rate is defined as all subjects with a live neonate at 4 weeks after birth. The live rate at 4 
weeks after birth will be analysed in a similar manner as the primary endpoint. Treatment 
comparisons will be produced for the overall Pan-Asian trial population and for the Chinese 
population. Summary tables will be prepared by treatment group and age stratum for both the FAS 
and PP analysis sets. Separate tables will be produced by country. 
Late Pregnancy Loss 
A late pregnancy loss is defined as an ongoing pregnancy not followed by live birth. The incidence 
of late pregnancy losses will be tabulated by treatment group and age stratum for the safety analysis 
set. Separate tables will be produced by country. The denominator will be the subjects at risk of a 
late pregnancy loss, i.e. number of subjects with an ongoing pregnancy. 
The reason for no live birth (still birth, miscarriage, elective termination) will be tabulated at the 
fetus/neonate level. In case of elective termination the reason (social circumstances, fetal anomaly, 
other) will be included. Further, the table will summarise if an autopsy was taken (yes/no). In case 
the reason for electiive termination is 'other' the listing will include the specification as reported by 
the investigator in the eCRF. 
Neonatal Health at Birth and at 4 Weeks after Birth 
Neonatal health at birth and at 4 weeks after birth, including minor/major congenital anomalies, 
will be summaries for all live-born neonates. Summaries includes delivery details, gestational age, 
gender, birth weight and birth length. Admission to neonatal intensive care unit and/or neonatal 
care unit will be summaries at birth and at 4 weeks after birth, including the reasons for admissions. 
The Apgar score at I, 5 and 10 minutes after birth will be summarised. Neonates will be grouped 
according to the Apgar score for each assessment time as: 0-3, 4-6, 7-10 and the corresponding 
frequencies tabulated. These data will be summarised by the treatment group and age stratum, and 
by treatment group and pregnancy type (singletons, twins), for the safety analysis set. Separate 
tables will be produced by country. 
Incidence of Serious Adverse Events 
All serious adverse events will be coded using Med.ORA. In addition, congenital anomalies on the 
fetus/neonates will lbe coded using ICD-10 and these events will be classified as minor or major in 
accordance with the EMA guideline. 
All serious adverse events will be listed. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Summary tables will be produced for the following: 
•
Maternal serious adverse events by SOC and PT
•
Neonatal serious adverse events by SOC and PT
•
Congenital anomalies on the fetus/neonates by ICD-10
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 31 of36 
•
Congenital anomalies on the fetus/neonates classification as major by ICD-10
•
Congenital anomalies on the fetus/neonates classification as minor by ICD-10
11 
Interim Analyses 
No interim analysis intended to compare treatments with respect to efficacy or safety is planned. 
A sample size re-assessment is planned and will be done without breaking the blind and without 
inflatiing the type I error of the trial, in line with the current regulatory guidelines (see Section 3.2). 
12 
Changes Compared to the Analyses Described in the Trial Protocol 
There are no changes to the primary analysis planned in the protocol for the primary endpoint. The 
sensitivity analyses planned on subgroups of subjects (subjects with oocytes retrieved and subjects 
with transfer) have been excluded since these analyses do not adhere to the randomisation principle. 
Descriptive statistics will be used to present the results in the subgroups. 
For the secondary endpoints, details and context of the analyses described in the protocol have been 
clarified and some additional analyses have been included to make the result description more 
complete. The proposed analyses for ordinal data have been excluded since there are no ordinal 
endpoints. For example a grouping based on increasing number of oocytes retrieved is ordinal, 
however, the corresponding ovarian response (low response, moderate response, target response, 
hyperresponse, severe hyperresponse) is not ordinal. The treatment comparisons will be carried out 
as planned based on the ungrouped data. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
13 
References 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 32 of36 
[ 1]
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee
for Proprietary Medicinal Products (CPMP). Points to consider on switching !between
superiority and non-inferiority. CPMP/EWP/482/99.
[2]
Friede T, Mitchell C, MUiier-Velten G. Blinded Sample Size Reestimation in Non­
Inferiority Trials with Binary Endpoints. Biometriical Journal 2007; 6, 903-916.
[3]
U.S. Department of Health and Human Services Food and Drug Administration, Center
for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and
Research (CBER), Draft guidance March 2010, Non-inferiority Clinical Trials.
[4]
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee
for Proprietary Medicinal Products (CPMP), ICH E9, Statistical Principles for Clinical
Trials, CPMP/ICH/363/96.
[5]
U.S. Department of Health and Human Services Food and Drug Administration, Center
for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and
Research (CBER), Draft guidance January 2017, Multiple Endpoints in Clinical Trials.
[6]
Lipsitz SR, Dear KGB, Laird NM, Molenberghs G. Tests for Homogeneity of the Risk
Difference When Data Are Sparse. Biometrics 1998; 54: 148-160.
[7]
The European Agency for the EvalU1ation of Medicinal Products (EMEA), Committee
for Proprietary Medicinal Products (CPMP). Points to consider on adjustments for
baseline covariates. CPMP/EWP/2863/99.
[8]
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee
for Proprietary Medicinal Products (CPMP), ICH E3, Structure and Contents of Clinical
Study Reports. CPMP/ICH/137/95.
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
14 
Tables, Listings and Figures 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 33 of36 
Shells for tables, figures and listings will be presented in a separate document. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 34 of36 
Appendix 1 
Markedly Abnormal Laboratory Safety Values and Vital 
Signs 
The markedly abnormal laboratory safety values and vital signs presented in this Appendix are 
FE 999049 project standards. The same criteria were applied to the data captured in the ESTHER 
trial. 
Table 1: 
Markedly Abnormal Criteria for Haematology 
Markedly abnormal criteria 
Variable 
Units 
Low 
High 
Haemoglobin 
g/L 
:=;; 115 
Not applicable 
Haematocrit 
Ratio 
:=;; 0.37 
q 0.56 
Total WBC 
109/L 
:=;; 2.8 
q 16.0 
Eosinophils 
% 
Not applicable 
q 10 
Neutrophils 
% 
:=;; 15 
q 90 
Lymphocytes 
% 
:=;; 10 
q 80 
Mooocytes 
% 
Not applicable 
q 20 
Basophils 
% 
Not applicable 
q5 
Bands 
% 
Not applicable 
q 20 
Platelets 
109/L 
:=;; 75 
q 700 
Total RBC 
1012/L 
:=;; 3.5 
Not applicable 
RBC: Red blood cells, WBC: White blood cells. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 35 of 36 
Table 2: 
Markedly Abnormal Criteria for Clinical Chemistry 
Markedly abnormal criteria 
Variable 
Units 
Low 
High 
Albumin 
g/L 
< 20 
Not applicable 
ALT 
IU/L 
Not applicable 
> 3xULN
Alkaline phosphatase 
IU/L 
Not applicable 
> 3xULN
AST 
IU/L 
Not applicable 
> 3xULN
Bicarbonate 
mmol/L 
< 15.1 
> 34.9
Bilirubiu direct 
umol/L 
Not applicable 
> 2xULN
Bilirubin total 
umol/L 
Not applicable 
>2xULN
Blood urea nitrogen 
mmol/L 
Not applicable 
> 12.5
Calcium 
mmol/L 
< 1.75 
> 2.74
Chloride 
mmol/L 
Not applicable 
Not applicable 
Cholesterol (30-40Y) 
mmol/L 
Not applicable 
> 10.34
Creatinine 
umol/L 
Not applicable 
> 3xULN
GGT 
IU/L 
Not applicable 
> 3xULN
Glucos.e 
mmol/L 
< 2.5 
> 16.7
LDH 
IU/L 
Not applicable 
> 3xULN
Phosphate 
mmol/L 
< 0.6 
Not applicable 
Potassium 
mrnol/L 
< 3.0 
> 5.8
Sodium 
mmol/L 
< 125 
> 155
Total protein 
g/L 
< 20 
> 90
Uric acid 
umol/L 
Not applicable 
> 595
ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, GGT: Gamma Glutamyl Transferase, 
LDH: Lactate Dehydrogeuase. 
Table 3: 
Markedly Abnormal Criteria for Endocrine Parameters 
Variable 
Unit 
Markedly abnormal criteria (high) 
LH 
IU/L 
> 10
Progesterone 
nmol/L 
> 3.18
LH and progesterone 
Not applicable 
LH > IO IU/L and progesterone> 3.18 nmol/L on the same 
day 
LH: Luteinising Hormone. 
Ferring Phannaceuticals 
CONFIDENTIAL 


Follitropin Delta, FE 999049 
Trial Code: 000145 
Statistical Analysis Plan 
Date: 08DEC2017 
E-Statisticai Analysis Plan-21980; Ver.1.0
Supersedes: None 
Pa e 36 of36 
Table 4: 
Reference Ranges and Markedly Abnormal Criteria for Vital Signs 
Variable 
Reference range 
Markedly abnormal criteria 
Low 
High 
Low 
High 
Systolic blood 
<90 
>140
< 80 and decrease of2'.: 20 
> 155 and increase of2'.:20
pressure (mmHg) 
from baseline 
from baseline
Diastolic blood 
<60 
>90
< 50 and decrease of 2'.: 15 
> I 00 and increase of 2'.: 15
pressure (mmHg) 
from baseline 
from baseline
Pulse rate (bmp) 
<50 
>100
< 45 and decrease of2'.: 15 
> 130 and increase of
from baseline 
2'.:150 from baseline
Ferring Phannaceuticals 
CONFIDENTIAL 

Prot_001.pdf: 
 
 
 
 
 
 
 
Protocol (consolidated protocol incorporating amendment 02) 
Sites in mainland China 
 
 
Title of trial: 
A randomised, controlled, assessor-blind, parallel groups, multicentre, 
Pan-Asian trial comparing the efficacy and safety of FE 999049 with 
follitropin alfa (GONAL-F) in controlled ovarian stimulation in women 
undergoing an assisted reproductive technology programme 
NCT number: 
NCT03296527 
Sponsor trial code: 
000145 
Date: 
27 September 2018 
 
 
 
 
 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 1 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian trial comparing 
the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian 
stimulation in women undergoing an assisted reproductive technology programme
Trial Code: 000145
US IND Number:
103,040
Investigational Medicinal 
Product:
FE 999049, human recombinant follicle-stimulating 
hormone (rFSH), solution for subcutaneous injection
Indication:
Controlled ovarian stimulation for the development of 
multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro
fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle
Phase:
3
Sponsor:
Ferring Pharmaceuticals A/S
Global Clinical and Non-Clinical R&D
Science and Medicine, Reproductive Health
International PharmaScience Center
Kay Fiskers Plads 11
2300 Copenhagen S
Denmark
Tel: (+45) 88 33 88 34 
Version:
3.0 Mainland China (consolidated protocol; changes 
introduced with country specific amendment #02
version 1.0 and 2.0 for mainland China implemented)
GCP Statement:
This trial will be performed in compliance with GCP
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 2 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian trial comparing 
the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian 
stimulation in women undergoing an assisted reproductive technology programme
SIGNATORY INVESTIGATOR
 
TRIAL SITES
A total of 15-30 trial sites in mainland China and other Asian countries and regions, potentially 
Taiwan, South Korea and Vietnam.
PLANNED TRIAL PERIOD
First patient first visit (FPFV):
Q2 2017
Last patient first visit (LPFV):
Q4 2018
Last patient last visit (LPLV):
Q1 2019
Post-trial follow-up completed:
Q1 2020
CLINICAL PHASE
3
BACKGROUND / RATIONALE
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) belonging to the 
pharmaceutical class of gonadotropins. It is intended for the following indication: “Controlled 
ovarian stimulation for the development of multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm 
injection (ICSI) cycle”. FE 999049 will be delivered as a solution for injection for subcutaneous 
self-administration by an injection pen.
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6®
cell line is well-characterised, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound 
polypeptide chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues
with 5 intrachain-disulphide bonds. The β-subunit contains 111 amino acid residues with 
6 intrachain-disulphide bonds. Each subunit is N-glycosylated at two positions, and about 40% of 
the total mass is carbohydrates.
There are no commercially available rFSH products derived from human cell lines, but Ferring has 
recently submitted a Marketing Authorisation Application to the European Medicines Agency 
(EMA) for FE 999049 (October 2015) and received positive opinion from the Committee for 
Medicinal Products for Human Use (October 2016). Currently-approved rFSH products for the 
proposed indication, such as follitropin alfa (GONAL-F, Merck Serono) and follitropin beta 
(PUREGON, MSD), are derived from a Chinese hamster ovary (CHO) cell line. The amino acid 
sequence of FE 999049 is identical to the endogenous human FSH sequence and to that in existing 
CHO-derived rFSH products. Manufacturing from different cell systems leads to glycosylation 
heterogeneity between rFSH preparations. The glycosylation profile of recombinant proteins is 
dependent on the expressing cell line and the cell culture conditions. Differences in glycosylation


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 3 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
profile, sialic acid pattern and isoform profile, have been documented between FE 999049 and
existing rFSH products from a CHO cell line. Comparison between the FE 999049 and the 
GONAL-F and PUREGON profiles indicate differences in acidity and carbohydrate side chains. As 
CHO cells lack enzymatic functions to construct more complex carbohydrate structures found in 
humans, the glycosylation profile of FE 999049 is more complex. In addition, RE 999049 contains 
both α2,3 and α2,6 sialylation patterns, while CHO-derived rFSH products exclusively carry 
2,3 linked sialic acid; this difference further contributes to the observed differences in glycosylation 
profiles between FE 999049 and CHO-derived rFSH products.
Before the current trial, Ferring has completed four phase 1 trials, two phase 2 dose-response trials
(one conducted in EU and one in Japan) and two phase 3 trials as part of the clinical development 
programme for FE 999049. A total of 1,927 subjects have been included in the completed clinical 
trials, of whom 1,112 subjects were exposed to FE 999049.
The two phase 2 trials were randomised, controlled, assessor-blind, multi-centre dose-response 
trials in which randomisation was stratified according to the subject’s anti-Müllerian hormone 
(AMH) level at screening. In both trials, a statistically significant dose-response relationship for 
FE 999049 with respect to the number of oocytes retrieved was observed for the overall population 
and for each AMH strata. Furthermore, the dose-response profile observed in Japanese and 
European subjects was similar. An individualised FE 999049 dosing regimen based on subject’s 
AMH level and body weight was designed by modelling and simulation and prospectively tested in 
the phase 3 trials.
During the phase 3 trials, 665 IVF/ICSI subjects were treated with FE 999049 in 1,012 treatment 
cycles. The two phase 3 trials supported the efficacy and safety of FE 999049 in the proposed 
indication. ESTHER-1 (trial 000004, Evidence-based Stimulation Trial with Human rFSH in 
Europe and Rest of World, ESTHER) was an efficacy trial designed to demonstrate non-inferiority 
of FE 999049 versus an approved recombinant FSH preparation with ongoing pregnancy rate and 
ongoing implantation rate as co-primary endpoints (as agreed with the EMA during Scientific 
Advice) and also to prospectively evaluate the outcome of the stratified medicine approach with the 
individualised FE 999049 dosing regimen based on the AMH level (measured by Elecsys® AMH 
Immunoassay, Roche Diagnostics) and body weight. ESTHER-2 (trial 000071) was a safety 
immunogenicity trial with up to two repeated treatment cycles in subjects who did not achieve an
ongoing pregnancy in ESTHER-1. Both trials have been completed with respect to their 
intervention part.
The ESTHER-1 trial demonstrated non-inferiority of FE 999049 to GONAL-F for the two co-
primary endpoints, ongoing pregnancy rate and ongoing implantation rate, for both the per-protocol 
(PP) and modified intention-to-treat (mITT) populations. Across treatment groups and analysis 
populations, the ongoing pregnancy rate was in the range 31-33% and the ongoing implantation rate 
in the range 35-37%. 
The AMH dosing regimen for FE 999049 in controlled ovarian stimulation cycles led to a 
statistically significantly lower proportion of subjects with extreme ovarian response (<4 or ≥15 
oocytes retrieved or <4 or ≥20 oocytes retrieved) compared to the GONAL-F group, when adjusted 
for AMH. Furthermore, the value of the individualised FE 999049 dosing regimen was reflected in 
statistically significant and clinically relevant reductions in ovarian hyperstimulation syndrome 
(OHSS) risk management compared to GONAL-F. Overall, the incidence of preventive 
interventions for early OHSS among subjects treated with FE 999049 was half of that observed 
with GONAL-F, which was a statistically significant reduction. The combined incidence of early 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 4 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
OHSS (all and those of moderate/severe grade) and/or preventive interventions for early OHSS was 
also statistically significantly reduced with FE 999049 in comparison to GONAL-F. Overall, there 
was a statistically significantly lower incidence of total OHSS and/or preventive interventions for 
early OHSS, and of total moderate/severe OHSS and/or preventive interventions for early OHSS 
with FE 999049 compared to GONAL-F.
A design similar to the phase 3 trial ESTHER-1 is being proposed for the present trial to be 
conducted in mainland China and other Asian countries and regions, with some modifications 
according to local practice. The primary objective of this trial is to demonstrate non-inferiority of 
FE 999049 compared with GONAL-F with respect to ongoing pregnancy rate in women 
undergoing controlled ovarian stimulation.
OBJECTIVES
Primary Objective

To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to 
ongoing pregnancy rate in women undergoing controlled ovarian stimulation
Secondary Objectives

To compare the clinical benefits of FE 999049 in its dosing regimen to those of GONAL-F 
with respect to efficacy and safety

To compare FE 999049 with GONAL-F with respect to ovarian response including 
follicular development and endocrine profile, as well as with respect to embryo 
development

To assess the population pharmacokinetics of FE 999049

To compare FE 999049 with GONAL-F with respect to treatment efficiency 

To compare FE 999049 with GONAL-F with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To evaluate the immunogenicity of FE 999049 after one treatment cycle

To perform a health economic analysis comparing FE 999049 with GONAL-F
ENDPOINTS
Primary Endpoint

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 5 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
embryos transferred)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer
divided by number of embryos transferred)

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes
retrieved

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
embryo transfer cancellation due to excessive ovarian response / OHSS risk

Number and size of follicles on stimulation day 6 and end-of-stimulation

Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 
oocytes retrieved

Percentage of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 after oocyte retrieval

Circulating concentrations of LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Circulating concentrations of FSH on stimulation day 6, end-of-stimulation and oocyte 
retrieval as well as FSH population pharmacokinetic parameters

Total gonadotropin dose and number of stimulation days

Proportion of subjects with investigator-requested gonadotropin dose adjustments

Frequency and intensity of adverse events

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralising capacity

Frequency and intensity of immune-related adverse events

Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical intervention) and vanishing twins

Technical malfunctions of the administration pen


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 6 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
POST-TRIAL INFORMATION

Live birth rate and neonatal health, including minor/major congenital anomalies, at birth and 
at 4 weeks after birth
METHODOLOGY
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian non-
inferiority trial comparing the efficacy and safety of two rFSH preparations, FE 999049 and 
follitropin alfa (GONAL-F), in first cycle subjects aged 20-40 years undergoing controlled ovarian 
stimulation for IVF/ICSI following a gonadotropin-releasing hormone (GnRH) antagonist protocol. 
The trial has been designed to demonstrate non-inferiority of FE 999049, a human cell line-derived 
rFSH preparation, versus an approved CHO-derived rFSH preparation, i.e. GONAL-F, with 
ongoing pregnancy rate as the primary endpoint. Secondary endpoints include pharmacokinetic 
profile of FE 999049, pharmacodynamic parameters of FSH action as well as efficacy and safety 
parameters related to controlled ovarian stimulation. The assessor-blind design ensures that the 
investigators and other assessors such as embryologists and central laboratory personnel are blinded 
to individual treatment allocation. The sponsor will break the blind when all subjects have 
completed the end-of-trial visit, in order to evaluate efficacy and safety up to the ongoing 
pregnancy visit.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio 
to treatment with either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation 
will be stratified by centre and according to age (<35, 35-37 and 38-40 years). Subjects randomised 
to FE 999049 will have their individual dose determined on the basis of their AMH level at 
screening and their body weight at randomisation. The daily FE 999049 dose will be fixed
throughout the stimulation period. For subjects with low AMH (<15 pmol/L) the daily FE 999049 
dose is 12 μg, irrespective of body weight. For subjects with high AMH (≥15 pmol/L) the daily 
FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on actual 
AMH and body weight (note: the minimum and maximum allowed daily doses are 6 µg and 12 µg, 
respectively). Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is 
not allowed. For subjects randomised to GONAL-F, the dosing regimen is within labelling. The 
starting daily dose of GONAL-F is 150 IU and fixed for the first five stimulation days after which it 
may be adjusted by 75 IU per day based on the individual response. The maximum daily GONAL-
F dose allowed is 450 IU. Subjects can be treated with GONAL-F for a maximum of 20 days, and 
coasting is not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When the leading follicle reaches ≥15 mm, visits must be 
performed daily. To prevent a premature LH surge, a GnRH antagonist will be initiated on 
stimulation day 6 and continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥3 follicles with a diameter ≥17 mm are observed. If there are 
<25 follicles with a diameter ≥12 mm, human chorionic gonadotropin (hCG) will be administered. 
If there are 25-35 follicles with a diameter ≥12 mm, a GnRH agonist can be administered or the 
cycle can be cancelled. In case of excessive follicular development, defined as >35 follicles with a 
diameter ≥12 mm, the cycle is to be cancelled. If it is judged by the investigator that ≥3 follicles 
with a diameter ≥17 mm cannot be reached, but 1 or 2 follicles with a diameter ≥17 mm are 
observed, the cycle may either be cancelled due to poor follicular development or triggering of final 
follicular maturation is to be induced, as judged by the investigator.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 7 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Rescue ICSI is not allowed. Fertilisation and embryo 
development will be assessed from oocyte retrieval to the day of transfer. For subjects who 
underwent triggering of final follicular maturation with hCG, transfer is performed on day 3
(embryo stage) after oocyte retrieval. Subjects <35 years at randomisation will have single embryo 
transfer if a good-quality embryo is available; otherwise, double embryo transfer will be performed 
(and single transfer if two embryos are not available). Subjects ≥35 years at randomisation will 
have double embryo transfer (and single transfer if two embryos are not available). Remaining 
embryos may be cryopreserved in accordance with local guidelines and/or regulations. For subjects 
who underwent triggering of final follicular maturation with GnRH agonist, no transfer will take 
place in the current fresh cycle and the embryos available will be cryopreserved on day 3, 5 or 6, 
according to local practice. All cryopreserved embryos can be used by the subject after completion 
of the trial, in accordance with local guidelines and/or regulations. 
Vaginal progesterone will be provided for luteal phase support from the day of oocyte retrieval or 
the day after and at least until clinical pregnancy. Thereafter the investigator may decide to 
continue up to the ongoing pregnancy visit, according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs. A serum βhCG test will be
performed 13-15 days after transfer, clinical pregnancy will be confirmed by transvaginal 
ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be confirmed by transvaginal or 
abdominal ultrasound 10-11 weeks after transfer.
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and haematology parameters as well as anti-FSH antibodies. Endocrine 
parameters are assessed at screening, stimulation day 1, stimulation day 6 and end-of-stimulation, 
furthermore FSH is also assessed at oocyte retrieval. Clinical chemistry and haematology 
parameters are assessed at screening, stimulation day 1, end-of-stimulation and end-of-trial. Anti-
FSH antibodies are collected at four occasions. The first blood sample is taken at the screening visit 
and is exclusively used as back-up samples for the anti-drug antibody assay development. The 
subsequent three samples are used for analysis of anti-FSH antibodies in the individual subjects in 
the trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-dosing: 5-10 
days after the last FE 999049 or GONAL-F dose (it may coincide with the transfer visit) and 19-28 
days after the last FE 999049 or GONAL-F dose (it may coincide with the βhCG test visit). 
Subjects with a treatment-induced anti-FSH antibody response will be followed until the response 
has become negative or returned to the pre-dosing level, with a maximum follow-up period of one 
year. 
Local tolerability of FE 999049 and GONAL-F following subcutaneous administration will be 
assessed by the subject three times daily: immediately, 30 minutes and 24 hours after each 
injection. The assessment of injection site reactions will be made throughout the stimulation period 
and recorded by the subjects in a diary. 
Post-Trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up. All subjects with an ongoing 
pregnancy will be followed till delivery to gather information on live birth rate. Furthermore, data 
will be gathered on neonatal health, including any congenital anomalies, at birth and at 4 weeks 
after birth. These data will be reported separately.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 8 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
NUMBER OF SUBJECTS
It is planned to randomise 1,000 subjects from 15-30 sites in mainland China and other Asian 
countries and regions. Of the 1,000 subjects it is expected that 740 subjects will be recruited in 
mainland China (i.e. possessing a Chinese identification card and having native Chinese parents)
and the rest from other Asian countries and regions, potentially Taiwan, South Korea and Vietnam. 
It is estimated that approximately 1,200 subjects should be screened to achieve 1,000 subjects 
eligible for randomisation.
CRITERIA FOR INCLUSION / EXCLUSION
This trial will include Asian women aged 20-40 years undergoing their first IVF/ICSI cycle. They 
have been diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have 
partners diagnosed with male factor infertility, and are considered eligible for IVF or ICSI. The 
allowed body mass index (BMI) is 17.5-32.0 kg/m2, thus including underweight, normal weight, 
overweight and obese subjects. The exclusion criteria incorporate the contraindications for the use 
of gonadotropins.
The complete list of inclusion and exclusion criteria is provided below.
Inclusion Criteria
1. Informed Consent Documents signed prior to screening evaluations.
2. In good physical and mental health in the judgement of the investigator.
3. Asian pre-menopausal females between the ages of 20 and 40 years. The subjects must be at 
least 20 years (including the 20th birthday) when they sign the informed consent and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised ASRM classification, 1996) or with partners diagnosed with 
male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm 
injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
5. Infertility for at least one year before randomisation for subjects <35 years or for at least 
6 months for subjects ≥35 years (not applicable in case of tubal or severe male factor 
infertility).
6. The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
7. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no polyps and no congenital structural abnormalities which are
associated with a reduced chance of pregnancy) within 1 year prior to randomisation. 
9. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would 
contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 
1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 9 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
10. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 2 years prior to randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. Willing to accept transfer of 1-2 embryos.
Exclusion Criteria
1. Known endometriosis stage III-IV (defined by the revised ASRM classification, 1996).
2. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
3. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 
4. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
5. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
6. Known inherited or acquired thrombophilia disease.
7. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
8. Known porphyria.
9. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
10. Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records; i.e. not based on the anti-FSH antibody analyses conducted in the trial). 
11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
12. Known moderate or severe impairment of renal or hepatic function.
13. Any abnormal finding of clinical chemistry, haematology or vital signs at screening which 
is clinically significant as judged by the investigator.
14. Currently breast-feeding.
15. Undiagnosed vaginal bleeding.
16. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
17. Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine 
abnormalities or retained intrauterine device.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 10 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
18. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomisation) or contraindication to pregnancy.
19. Known current active pelvic inflammatory disease.
20. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral 
contraceptives, progestogen or estrogen preparations.
21. Use of hormonal preparations (except for thyroid medication) during the last menstrual
cycle before randomisation.
22. Known history of chemotherapy (except for gestational conditions) or radiotherapy. 
23. Current or past (1 year prior to randomisation) abuse of alcohol or drugs.
24. Current (last month) intake of more than 14 units of alcohol per week.
25. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
26. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
27. Previous participation in the trial.
28. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 11 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
MEDICINAL PRODUCTS
Investigational Medicinal Products (IMPs)
IMP name
Drug type
Active ingredient, route of 
administration and 
concentration
Daily dose
FE 999049
rFSH
FE 999049 in solution for 
subcutaneous injection; 
72 µg FSH in 2.16 mL
AMH <15 pmol/L: 12 μg. 
AMH ≥15 pmol/L: ranging from 
0.19 to 0.10 μg/kg, i.e. depending 
on actual AMH. The minimum and 
maximum allowed doses are 6 µg
per day and 12 µg per day, 
respectively.
The dose is fixed throughout 
stimulation
GONAL-F
rFSH
Follitropin alfa in solution 
for subcutaneous injection; 
900 IU (66 μg) FSH in 1.5 
mL
Starting dose of 150 IU fixed for 
the first five stimulation days, 
followed by potential adjustments
of 75 IU per day with a maximum 
dose of 450 IU per day
Concomitant Fertility Medication / Non-investigational Medicinal Products (NIMPs)
NIMP name
Drug type
Active ingredient and route 
of administration 
Dose
CETROTIDE
GnRH 
antagonist
Cetrorelix acetate powder 
and solvent for solution for 
subcutaneous injection
0.25 mg, daily dose
OVITRELLE
hCG
Choriogonadotropin alfa in 
solution for subcutaneous 
injection
250 µg, single dose
GONAPEPTYL GnRH agonist Triptorelin acetate in 
solution for subcutaneous 
injection
0.2 mg, single dose
CRINONE
Progesterone
Progesterone gel for 
vaginal administration
90 mg, daily dose


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 12 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
DURATION OF TREATMENT
The maximum period of exposure to FE 999049 or GONAL-F is 20 days.
STATISTICAL METHODS
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation. Ongoing pregnancy is defined as at least one intrauterine viable fetus 10-11 weeks 
after transfer. The non-inferiority limit for the difference between treatments (FE 999049 versus 
GONAL-F) is -10.0% (absolute) for the primary endpoint. 
The trial is designed to have 90% power of achieving the primary objective for the overall trial 
population and to have 80% power in the mainland Chinese population. Assuming an ongoing 
pregnancy rate of 32.2% in both treatment groups, a total of 918 subjects are needed in the PP 
analysis set. To account for major protocol deviations a total of 1,000 subjects should be 
randomised. To secure that consistency can be established between the results from the overall trial
population and the mainland Chinese trial population at least 740 subjects will be recruited in 
mainland China. The remaining subjects will be recruited from other Asian countries and regions.
Sample Size Monitoring
The overall ongoing pregnancy rate will be monitored in a blinded manner, as the number of 
subjects to be randomised may need to be increased beyond the planned 1,000, if the overall 
ongoing pregnancy rate observed in the trial is above the estimated 32.2% used for the sample size 
calculation. The expected maximum number of subjects to be randomised would then be 
approximately 1,144 (572 per treatment group), corresponding to an observed rate of 50%. Blinded 
monitoring of the assumptions underlying the sample size is recommended specifically for non-
inferiority trials by Food and Drug Administration (FDA) and in general by EMA.
Primary Endpoint: Ongoing Pregnancy Rate
The non-inferiority hypothesis to be tested for the primary endpoint is
H0: FE - GF -10.0% against the alternative HA: FE - GF > -10.0%,
where FE and GF denote the ongoing pregnancy rate after treatment with FE 999049 and 
GONAL-F, respectively. Non-inferiority will be evaluated based on the overall trial population.
The null hypothesis (H0) will be tested against the alternative (HA) by constructing a two-sided 95% 
confidence interval for the difference in ongoing pregnancy rates. The primary analysis will be 
adjusted for the stratification factor (age group) by using the Mantel-Haenszel method to combine 
results across age groups. In brief, this corresponds to deriving a weighted average across age 
groups where the weight depends on the number of observations in each treatment group in each 
age stratum.
Evaluation of the Primary Objective
If the lower limit of the two-sided 95% confidence interval based on the overall population is
greater than the non-inferiority limit (-10.0%) for both the full analysis set (FAS) and the PP 
analysis set, the null hypotheses will be rejected. In that case it will be claimed that FE 999049 is 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 13 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
non-inferior to GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled 
ovarian stimulation.
If the lower limit of the two-sided 95% confidence interval for the treatment difference based on the 
FAS not only lies above the non-inferiority limit (-10.0%) but also above zero then there is 
evidence of superiority in terms of statistical significance at the 5% level. The result based on the 
PP analysis set is not essential for the superiority claim but should lead to a comparable result for a 
robust interpretation.
A supportive evaluation of the subjects recruited in mainland China will be conducted, and it is 
expected that the findings among the mainland Chinese trial population will be consistent with the 
overall findings in the trial. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 14 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
TABLE OF CONTENTS
Page
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 19
LIST OF FIGURES...................................................................................................................................... 20
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 21
1
INTRODUCTION ............................................................................................................................. 24
1.1
Background............................................................................................................................. 24
1.2
Scientific Justification for Conducting the Trial..................................................................... 25
1.3
Benefit / Risk Aspects............................................................................................................. 26
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 29
2.1
Objectives ............................................................................................................................... 29
2.2
Endpoints ................................................................................................................................ 29
3
INVESTIGATIONAL PLAN ........................................................................................................... 31
3.1
Overall Trial Design................................................................................................................ 31
3.1.1
Trial Design Diagram................................................................................................. 31
3.1.2
Overall Design and Control Methods ........................................................................ 32
3.1.3
Trial Schedule............................................................................................................ 34
3.2
Planned Number of Trial Sites and Subjects........................................................................... 34
3.3
Interim Analysis and Administrative Review......................................................................... 34
3.4
Data Monitoring Committee ................................................................................................... 34
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 34
3.5.1
Trial Design ............................................................................................................... 34
3.5.2
Selection of Endpoints ............................................................................................... 36
3.5.3
Blinding...................................................................................................................... 37
3.5.4
Selection of Doses in the Trial................................................................................... 38
3.5.5
Selection of the Trial Population ............................................................................... 39
3.5.6
Follow-up Procedures ................................................................................................ 39
4
SELECTION OF TRIAL POPULATION ...................................................................................... 40
4.1
Trial Population....................................................................................................................... 40
4.1.1
Inclusion Criteria ....................................................................................................... 40
4.1.2
Exclusion Criteria ...................................................................................................... 41
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 42
4.2.1
Recruitment................................................................................................................ 42
4.2.2
Randomisation ........................................................................................................... 42
4.3
Restrictions ............................................................................................................................. 43
4.3.1
Prior and Concomitant Therapies .............................................................................. 43
4.3.2
Prohibited Therapy..................................................................................................... 43
4.4
Withdrawal Criteria................................................................................................................. 43
4.5
Subject Replacement............................................................................................................... 43
5
TREATMENTS ................................................................................................................................. 44
5.1
Investigational Medicinal Products (IMPs) ............................................................................ 44
5.1.1
FE 999049 Dosing Regimen...................................................................................... 44


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 15 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
5.1.2
GONAL-F Dosing Regimen...................................................................................... 46
5.2
Non-Investigational Medicinal Products (NIMPs) ................................................................. 46
5.3
Characteristics and Source of Supply ..................................................................................... 47
5.4
Packaging and Labelling......................................................................................................... 48
5.5
Conditions for Storage and Use .............................................................................................. 49
5.6
Blinding / Unblinding ............................................................................................................. 49
5.6.1
Blinding...................................................................................................................... 49
5.6.2
Unblinding of Individual Subject Treatment ............................................................. 50
5.7
Dispensing and Accountability, Return and Destruction........................................................ 50
5.8
Auxiliary Supplies................................................................................................................... 51
6
TRIAL PROCEDURES .................................................................................................................... 52
6.1
Screening................................................................................................................................. 53
6.2
Stimulation.............................................................................................................................. 54
6.2.1
Stimulation Day 1 ...................................................................................................... 54
6.2.2
Stimulation Day 6 ...................................................................................................... 55
6.2.3
Stimulation Days ≥7 to ≤20 ....................................................................................... 56
6.2.4
End-of-stimulation..................................................................................................... 56
6.3
Oocyte Retrieval ..................................................................................................................... 58
6.4
Oocyte / Embryo Evaluation................................................................................................... 59
6.5
Transfer................................................................................................................................... 60
6.5.1
Embryo Transfer........................................................................................................ 60
6.5.2
First Post-dosing Anti-FSH Antibody Assessment (5-10 Days after Last IMP 
Dose).......................................................................................................................... 61
6.6
βhCG Test............................................................................................................................... 61
6.6.1
βhCG Test.................................................................................................................. 61
6.6.2
Second Post-dosing Anti-FSH Antibody Assessment (19-28 Days after Last IMP 
Dose).......................................................................................................................... 62
6.7
Clinical Pregnancy.................................................................................................................. 62
6.8
Ongoing Pregnancy................................................................................................................. 62
6.9
End-of-trial.............................................................................................................................. 63
6.10
Post-trial Activities ................................................................................................................. 63
7
TRIAL ASSESSMENTS ................................................................................................................... 64
7.1
Assessment Related to Primary Endpoint............................................................................... 64
7.1.1
Ongoing Pregnancy.................................................................................................... 64
7.2
Assessments Related to Secondary Endpoints........................................................................ 64
7.2.1
βhCG Test.................................................................................................................. 64
7.2.2
Clinical Pregnancy..................................................................................................... 64
7.2.3
Vital Pregnancy.......................................................................................................... 64
7.2.4
Implantation............................................................................................................... 64
7.2.5
Ongoing Implantation ................................................................................................ 64
7.2.6
Extreme Ovarian Response........................................................................................ 65
7.2.7
Early OHSS (including OHSS of Moderate/Severe Grade) and/or Preventive 
Interventions for Early OHSS.................................................................................... 65
7.2.8
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo 
Transfer Cancellation due to Excessive Ovarian Response / OHSS Risk ................. 65
7.2.9
Number and Size of Follicles during Stimulation...................................................... 65
7.2.10 Number and Distribution of Oocytes Retrieved......................................................... 65


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 16 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
7.2.11 Metaphase II Oocytes................................................................................................. 65
7.2.12 Fertilisation Rate........................................................................................................ 66
7.2.13 Number and Quality of Embryos on Day 3 ............................................................... 66
7.2.14 Circulating Levels of Endocrine Parameters.............................................................. 66
7.2.15 FSH Population Pharmacokinetics............................................................................. 66
7.2.16 Total Gonadotropin Dose and Number of Stimulation Days..................................... 67
7.2.17 Gonadotropin Dose Adjustments............................................................................... 67
7.2.18 Adverse Events .......................................................................................................... 67
7.2.19 Clinical Chemistry and Haematology Parameters ..................................................... 67
7.2.20 Injection Site Reactions ............................................................................................. 67
7.2.21 Anti-FSH Antibodies ................................................................................................. 68
7.2.22 Immune-related Adverse Events................................................................................ 69
7.2.23 Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen....................... 69
7.2.24 Late OHSS (including OHSS of Moderate/Severe Grade)........................................ 70
7.2.25 Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins................................................................................ 70
7.2.26 Pen Malfunction......................................................................................................... 70
7.3
Other Assessments.................................................................................................................. 70
7.3.1
Demographics ............................................................................................................ 70
7.3.2
Medical History ......................................................................................................... 70
7.3.3
Infertility History ....................................................................................................... 70
7.3.4
Menstrual History ...................................................................................................... 70
7.3.5
Reproductive History................................................................................................. 71
7.3.6
Smoking and Alcohol Habits..................................................................................... 71
7.3.7
Body Weight and Height............................................................................................ 71
7.3.8
Physical Examination................................................................................................. 71
7.3.9
Gynaecological Examination..................................................................................... 71
7.3.10 Endocrine Parameters at Screening............................................................................ 72
7.3.11 Vital Signs.................................................................................................................. 72
7.3.12 Ovarian Volume......................................................................................................... 72
7.3.13 Endometrial Status..................................................................................................... 72
7.3.14 Embryo Transfer Procedure....................................................................................... 73
7.3.15 Concomitant Medication............................................................................................ 73
7.3.16 Drug Dispensing and Accountability......................................................................... 73
7.3.17 End-of-trial Form....................................................................................................... 73
7.4
Assessments Related to Post-trial Information ....................................................................... 73
7.4.1
Pregnancy Follow-up................................................................................................. 73
7.5
Handling of Biological Samples ............................................................................................. 73
8
ADVERSE EVENTS ......................................................................................................................... 75
8.1
Adverse Event Definition........................................................................................................ 75
8.2
Collection and Recording of Adverse Events......................................................................... 75
8.2.1
Collection of Adverse Events .................................................................................... 75
8.2.2
Recording of Adverse Events .................................................................................... 75
8.3
Adverse Events of Special Interest and/or Requiring Special Handling................................. 78
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)........................................................... 78
8.3.2
Local Tolerability....................................................................................................... 80
8.3.3
Treatment-induced Anti-FSH Antibodies.................................................................. 80


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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8.3.4
Menstrual Bleeding.................................................................................................... 81
8.3.5
Ovarian Torsion ......................................................................................................... 81
8.3.6
Pregnancy Losses....................................................................................................... 81
8.3.7
Multiple Pregnancies ................................................................................................. 81
8.4
Serious Adverse Events .......................................................................................................... 82
8.4.1
Serious Adverse Event Definition.............................................................................. 82
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 83
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 84
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 84
8.5.2
Collection of Serious Adverse Events with Onset after End-of-trial......................... 84
8.5.3
Follow-up of Serious Adverse Events with Onset during the Post-Trial................... 85
9
STATISTICAL METHODS ............................................................................................................. 86
9.1
Determination of Sample Size ................................................................................................ 86
9.2
Subject Disposition ................................................................................................................. 88
9.3
Protocol Deviations................................................................................................................. 89
9.4
Analysis Sets........................................................................................................................... 89
9.5
Trial Population....................................................................................................................... 90
9.5.1
General Considerations.............................................................................................. 90
9.5.2
Trial Population Parameters....................................................................................... 90
9.6
Treatment Compliance............................................................................................................ 91
9.7
Endpoint Assessments............................................................................................................. 92
9.7.1
General Considerations.............................................................................................. 92
9.7.2
Primary Endpoint....................................................................................................... 93
9.7.3
Secondary Endpoints ................................................................................................. 95
9.8
Additional Safety Evaluations .............................................................................................. 101
9.9
Post-trial Activities ............................................................................................................... 102
9.10
Interim Analyses and Administrative Review ...................................................................... 102
10
DATA HANDLING ......................................................................................................................... 103
10.1
Source Data and Source Documents..................................................................................... 103
10.2
e-CRF.................................................................................................................................... 104
10.3
Data Management ................................................................................................................. 105
10.4
Provision of Additional Information..................................................................................... 105
11
MONITORING PROCEDURES ................................................................................................... 106
11.1
Periodic Monitoring.............................................................................................................. 106
11.2
Audit and Inspection............................................................................................................. 106
11.3
Confidentiality of Subject Data............................................................................................. 106
12
CHANGES IN THE CONDUCT OF THE TRIAL...................................................................... 107
12.1
Protocol Amendments........................................................................................................... 107
12.2
Deviations from the Protocol ................................................................................................ 107
12.3
Premature Trial Termination................................................................................................. 107
13
REPORTING AND PUBLICATION ............................................................................................ 108
13.1
Clinical Trial Report ............................................................................................................. 108
13.2
Confidentiality and Ownership of Trial Data........................................................................ 108
13.3
Publications and Public Disclosure....................................................................................... 108
13.3.1 Publication Policy.................................................................................................... 108
13.3.2 Public Disclosure Policy.......................................................................................... 109


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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14
ETHICAL AND REGULATORY ASPECTS............................................................................... 110
14.1
Ethics Committee.................................................................................................................. 110
14.2
Regulatory Authorities Notification...................................................................................... 110
14.3
End-of-trial and End-of-trial Notification............................................................................. 110
14.4
Ethical Conduct of the Trial.................................................................................................. 110
14.5
Subject Information and Consent.......................................................................................... 111
14.6
Trial Participation Card......................................................................................................... 112
14.7
Delivery Data Checklist........................................................................................................ 112
14.8
Compliance Reference Documents....................................................................................... 113
15
LIABILITIES AND INSURANCE ................................................................................................ 114
15.1
ICH-GCP Responsibilities.................................................................................................... 114
15.2
Liabilities and Insurance....................................................................................................... 114
16
ARCHIVING.................................................................................................................................... 115
16.1
Investigator File .................................................................................................................... 115
16.2
Trial Master File.................................................................................................................... 115
17
REFERENCES................................................................................................................................. 116
APPENDIX 1
Master Informed Consent Documentation
APPENDIX 2
Contact List
ATTACHMENT 1
Agreement on the Protocol


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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LIST OF TABLES 
Page
Table 5-1
FE 999049 Dosing Regimen...........................................................................................45
Table 5-2
GONAL-F Dosing Regimen...........................................................................................46
Table 5-3
Non-Investigational Medicinal Products (NIMPs) .........................................................47
Table 5-4
Characteristics and Source of Supply of Medicinal Products.........................................48
Table 6-1
Trial Flow Chart – Subject Procedures...........................................................................52
Table 6-2
Triggering and Cycle Cancellation Criteria related to Follicular Development.............57
Table 6-3 Trial Flow Chart – Oocyte / Embryo Procedures ...........................................................59
Table 8-1
Classification of Mild, Moderate and Severe OHSS (Golan’s Classification 
System)............................................................................................................................79
Table 9-1
Implications of Choice on Non-inferiority Margin on Sample Size, Precision and 
Difference in Observed Rates .........................................................................................87
Table 9-2
Sample Size by Ongoing Pregnancy Rate for the PP Analysis Set ................................88


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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LIST OF FIGURES
Page
Figure 3-1 Trial Diagram – Trial Period...........................................................................................31


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
α
alfa
AMH
anti-Müllerian hormone
ART
assisted reproductive technologies
ATC
Anatomical Therapeutic Chemical classification system 
β
beta
βhCG
beta unit of human chorionic gonadotropin
BMI
body mass index
CBC
complete blood count 
CHO
Chinese hamster ovary
CHEM-20
a blood test to measure the level of 20 different proteins, lipids and electrolytes
DHEA
dehydroepiandrosterone
e-CRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FDA
Food and Drug Administration
FPFV
first patient first visit
FSH 
follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH 
gonadotropin-releasing hormone
GPV
Global Pharmacovigilance Department
h
hour(s)
HBsAg 
Hepatitis B Surface Antigen
hCG
human chorionic gonadotropin 
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HLT
high level term
ICD-10
International Statistical Classification of Diseases and Related Health Problems, 10th
revision
ICH
International Conference on Harmonisation
ICMART
International Committee Monitoring Assisted Reproductive Technologies
ICMJE
International Committee of Medical Journal Editors
ICSI
intracytoplasmic sperm injection
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
investigational medicinal product
IND
investigational new drug 
ITT
intention-to-treat
IU
international units
IVF
in vitro fertilisation
L
litre
LH
luteinising hormone
LLOQ 
lower limit of quantification
LPFV
last patient first visit


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
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LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalent(s)
mg
milligram
mITT
modified intention-to-treat
MSR
minimum significant ratio
mL
millilitre
NCU
neonatal care unit
ng
nanogram
NIMP
non-investigational medicinal product
NICU
neonatal intensive care unit 
OHSS
ovarian hyperstimulation syndrome
PER.C6®
host cell line of human fetal retinal origin
PGD
preimplantation genetic diagnosis
PGS
preimplantation genetic screening
pmol
picomol
PP
per-protocol
PT
preferred term
rFSH
recombinant follicle-stimulating hormone
rhCG
recombinant human chorionic gonadotropin 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SMQ
Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries 
SUSAR
suspected unexpected serious adverse reaction
TSH
thyroid-stimulating hormone
μg
microgram
ULOQ 
upper limit of quantification
US
ultrasound
WHO 
World Health Organization 
AMH Unit Conversion Factors 
1 pmol/L = 0.140 ng/mL
1 ng/mL = 7.143 pmol/L


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Definition of Terms
Major congenital anomaly 
A life threatening structural anomaly or one likely to cause significant 
impairment of health or functional capacity and which needs medical 
or surgical treatment.1,2
Minor congenital anomaly 
Relatively frequent structural anomaly not likely to cause any 
medical or cosmetic problems.1,2
Medicinal Product Names 
Product
Trade name used 
in the protocol
Trade name in the 
participating 
countries
Company name 
used in the protocol
Company name in the 
participating countries
Follitropin alfa
GONAL-F
GONAL-F 
(CH, KR, TW, VN)
Merck Serono
Merck Serono, Merck
Cetrorelix acetate
CETROTIDE
CETROTIDE 
(CH, KR, TW, VN)
Merck Serono
Merck Serono, Merck
Choriogonadotropin 
alfa
OVITRELLE
(Trade name in EU 
where the product 
is sourced)
OVIDREL 
(CH, KR, TW) 
OVITRELLE (VN)
Merck Serono
Merck Serono, Merck
Triptorelin acetate
GONAPEPTYL
(Trade name in EU 
where the product 
is sourced)
DECAPEPTYL 
(CH, KR, TW)
FERTIPEPTIL (VN)
Ferring 
Pharmaceuticals
Ferring 
Pharmaceuticals
Progesterone
CRINONE
CRINONE 
(KR, TW, VN)
Progesterone 
Sustained-release 
vaginal gel (CH)
Merck Serono
Merck Serono, Merck
CH: Mainland China; KR: South Korea; TW: Taiwan, VN: Vietnam
(Throughout this document, all trade names are written in capitals to comply with Ferring standard operating 
procedures)


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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1
INTRODUCTION
1.1
Background
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) belonging to the 
pharmaceutical class of gonadotropins. It is intended for the following indication: “Controlled 
ovarian stimulation for the development of multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm 
injection (ICSI) cycle”. FE 999049 will be delivered as a solution for injection for subcutaneous 
self-administration by an injection pen.
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6®
cell line is well-characterised, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound 
polypeptide chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues 
with 5 intrachain-disulphide bonds. The β-subunit contains 111 amino acid residues with 
6 intrachain-disulphide bonds. Each subunit is N-glycosylated at two positions, and about 40% of 
the total mass is carbohydrates.
There are no commercially available rFSH products derived from human cell lines, but Ferring has 
recently submitted a Marketing Authorisation Application to the European Medicines Agency 
(EMA) for FE 999049 (October 2015) and received positive opinion from the Committee for 
Medicinal Products for Human Use (October 2016). Currently-approved rFSH products for the 
proposed indication, such as follitropin alfa (GONAL-F, Merck Serono) and follitropin beta 
(PUREGON, MSD), are derived from a Chinese hamster ovary (CHO) cell line. The amino acid 
sequence of FE 999049 is identical to the endogenous human FSH sequence and to that in existing 
CHO-derived rFSH products. Manufacturing from different cell systems leads to glycosylation 
heterogeneity between rFSH preparations. The glycosylation profile of recombinant proteins is 
dependent on the expressing cell line and the cell culture conditions. Differences in glycosylation
profile, sialic acid pattern and isoform profile, have been documented between FE 999049 and 
existing rFSH products from a CHO cell line. Comparison between the FE 999049 and the
GONAL-F and PUREGON profiles indicate differences in acidity and carbohydrate side chains. As 
CHO cells lack enzymatic functions to construct more complex carbohydrate structures found in 
humans, the glycosylation profile of FE 999049 is more complex. In addition, FE 999049 contains 
both α2,3 and α2,6 sialylation patterns, while CHO-derived rFSH products exclusively carry 
2,3 linked sialic acid; this difference further contributes to the observed differences in glycosylation 
profiles between FE 999049 and CHO-derived rFSH products.
Before the current trial, Ferring has completed four phase 1 trials, two phase 2 dose-response trials
(one conducted in EU and one in Japan) and two phase 3 trials as part of the clinical development 
programme for FE 999049. A total of 1,927 subjects have been included in the completed clinical 
trials, of whom 1,112 subjects were exposed to FE 999049. 
The two phase 2 trials were randomised, controlled, assessor-blind, multi-centre dose-response 
trials in which randomisation was stratified according to the subject’s anti-Müllerian hormone 
(AMH) level at screening. In both trials, a statistically significant dose-response relationship for 
FE 999049 with respect to the number of oocytes retrieved was observed for the overall population 
and for each AMH strata. Furthermore, the dose-response profile observed in Japanese and 
European subjects was similar. An individualised FE 999049 dosing regimen based on subject’s 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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AMH level and body weight was designed by modelling and simulation and prospectively tested in 
the phase 3 trials.  
During the phase 3 trials, 665 IVF/ICSI subjects were treated with FE 999049 in 1,012 treatment 
cycles. The two phase 3 trials supported the efficacy and safety of FE 999049 in the proposed 
indication. ESTHER-1 (trial 000004, Evidence-based Stimulation Trial with Human rFSH in 
Europe and Rest of World, ESTHER) was an efficacy trial designed to demonstrate non-inferiority 
of FE 999049 versus an approved recombinant FSH preparation with ongoing pregnancy rate and 
ongoing implantation rate as co-primary endpoints (as agreed with the EMA during Scientific 
Advice) and also to prospectively evaluate the outcome of the stratified medicine approach with the 
individualised FE 999049 dosing regimen based on the AMH level (measured by Elecsys® AMH 
Immunoassay, Roche Diagnostics) and body weight. ESTHER-2 (trial 000071) was a safety 
immunogenicity trial with up to two repeated treatment cycles in subjects who did not achieve an 
ongoing pregnancy in ESTHER-1. Both trials have been completed with respect to their 
intervention part.
The ESTHER-1 trial demonstrated non-inferiority of FE 999049 to GONAL-F for the two co-
primary endpoints, ongoing pregnancy rate and ongoing implantation rate, for both the per-protocol 
(PP) and modified intention-to-treat (mITT) populations. Across treatment groups and analysis 
populations, the ongoing pregnancy rate was in the range 31-33% and the ongoing implantation rate 
in the range 35-37%. 
The AMH dosing regimen for FE 999049 in controlled ovarian stimulation cycles led to a 
statistically significantly lower proportion of subjects with extreme ovarian response (<4 or ≥15 
oocytes retrieved or <4 or ≥20 oocytes retrieved) compared to the GONAL-F group, when adjusted 
for AMH. Furthermore, the value of the individualised FE 999049 dosing regimen was reflected in 
statistically significant and clinically relevant reductions in ovarian hyperstimulation syndrome 
(OHSS) risk management compared to GONAL-F. Overall, the incidence of preventive 
interventions for early OHSS among subjects treated with FE 999049 was half of that observed 
with GONAL-F, which was a statistically significant reduction. The combined incidence of early 
OHSS (all and those of moderate/severe grade) and/or preventive interventions for early OHSS was 
also statistically significantly reduced with FE 999049 in comparison to GONAL-F. Overall, there 
was a statistically significantly lower incidence of total OHSS and/or preventive interventions for 
early OHSS, and of total moderate/severe OHSS and/or preventive interventions for early OHSS 
with FE 999049 compared to GONAL-F.
A design similar to the phase 3 trial ESTHER-1 is being proposed for the present trial to be 
conducted in mainland China and other Asian countries and regions, with some modifications 
according to local practice. The primary objective of this trial is to demonstrate non-inferiority of 
FE 999049 compared with GONAL-F with respect to ongoing pregnancy rate in women 
undergoing controlled ovarian stimulation.
For further information regarding FE 999049, please refer to the current edition of Investigator’s 
Brochure.
1.2
Scientific Justification for Conducting the Trial
The present trial is a phase 3 trial designed to assess the efficacy and safety of the human-derived 
rFSH preparation FE 999049 in women undergoing controlled ovarian stimulation for the 
development of multiple follicles for ART. FE 999049 is the first rFSH preparation derived from a 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
human cell line. The dosing regimen for FE 999049 will be individualised for each woman based 
on her AMH level and body weight. The trial will support the registration of FE 999049 in 
mainland China and other Asian countries and regions.
1.3
Benefit / Risk Aspects
Benefits
The treatment cycle is provided to the participating subjects free of charge, as Ferring compensates 
the investigational sites for their expenses. Subjects participating in this trial may benefit by
achieving pregnancy. Subjects will be closely monitored, and they will have either the same or 
more frequent visits to the clinic compared to routine treatment, depending on local practice. In 
addition, the data obtained from the treatment cycle may provide useful information for optimising 
the ovarian response and for clinical planning of subsequent treatment cycles.
Risks
The risks associated with ART treatment, including the risks associated with controlled ovarian 
stimulation and clinical and laboratory procedures, are explained to the subjects as part of the
counselling prior to starting treatment.
Gonadotropins
In this trial, controlled ovarian stimulation will be performed either with the individualised 
FE 999049 dosing regimen or with GONAL-F, a widely available recombinant FSH preparation 
used in line with its approved labelling. Both preparations will be administered subcutaneously.
To date, a total of 1,112 women have been exposed to FE 999049 in completed phase 1, 2 and 3
trials. The overall adverse event profile of the individualised FE 999049 dosing regimen appeared 
to be comparable to that of GONAL-F with the exception of fewer OHSS and/or preventive 
interventions with FE 999049. The most frequently reported adverse drug reactions during 1,012 
treatment cycles with FE 999049 in the phase 3 programme were headache, pelvic discomfort,
OHSS, pelvic pain, adnexa uteri pain, nausea and fatigue (all reported as common, i.e. 1% to 
< 10%). Uncommon adverse drug reactions reported with FE 999049 were diarrhoea, dizziness, 
mood swings, constipation, vomiting, abdominal discomfort, breast pain, breast tenderness, vaginal 
haemorrhage and somnolence. FE 999049 administered with the injection pen was well-tolerated 
with a low incidence of local injection site reactions. The severity of local injection site reactions 
was in general mild and comparable to that reported for GONAL-F administrated with the pre-filled 
pen.
The FE 999049 dosing regimen used in this trial is an individualised dosing regimen based on the 
subject’s AMH and body weight. AMH is a well-established predictor of ovarian response to 
gonadotropin treatment and was confirmed to be the best endocrine marker of ovarian response to 
FE 999049 treatment in the phase 2 trial. The FE 999049 dosing is based on the Elecsys® AMH 
assay from Roche Diagnostics which displays better performance with less variability than other 
AMH assays.3
GONAL-F is a commercially available CHO-derived rFSH preparation with established safety and 
efficacy4. The most frequent adverse events in relation to use of GONAL-F are as follows: 
headache, ovarian cysts and injection site reactions (all reported as very common, i.e. ≥10%) and 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea and mild 
or moderate OHSS including associated symptomatology (all reported as common, i.e. 1% to 
<10%)4. The GONAL-F dosing regimen used in this trial is in line with labelling recommendations.
Concerning well-known risks associated with the use of gonadotropin products for ovarian 
stimulation, subjects are closely monitored throughout the trial. The most serious risk associated 
with gonadotropin treatment is OHSS. OHSS manifests itself with increasing degrees of severity. 
Moderate/severe OHSS is associated with marked ovarian enlargement, fluid accumulation and 
other complications. Early OHSS can potentially be prevented by withholding gonadotropins, 
withholding human chorionic gonadotropin (hCG) or administering gonadotropin-releasing 
hormone (GnRH) agonist for triggering of final follicular maturation. Very rare cases of serious 
allergic reactions have been reported after injection of gonadotropins. Concerning immunogenicity, 
the risk of treatment-induced anti-drug-antibodies for gonadotropin products is very low (estimated 
to be 0-2%5,6,7,8,9,10,11) and no safety or efficacy concern has been identified with regards to 
immunogenicity with FE 999049 or with the available rFSH preparations.
Procedures and Concomitant Fertility Medications
Subjects will undergo standard ART treatment procedures (e.g. transvaginal ultrasound, blood 
sampling, oocyte retrieval and transfer) and also receive concomitant fertility medication as part of 
the treatment cycle in this trial. The transvaginal ultrasound examinations may be associated with 
mild discomfort and a very rare risk of infection. The blood sampling might be associated with mild 
discomfort, bruising and a very rare risk of infection. The oocyte retrieval procedure is associated 
with discomfort and very rarely infections and bleeding. The transfer procedure is associated with 
mild discomfort and very rarely infections and mild bleeding. The concomitant fertility medications 
are approved products and are considered generally well-tolerated. The most frequently reported
adverse events with these concomitant medication products are similar to those reported for FSH 
preparations, such as headache, injection site reactions, pelvic pain, abdominal pain, abdominal 
distension and allergic reactions. Furthermore, the vaginal progesterone has been associated with 
vulvovaginal disorders and uterine spasms (at a frequency of 1-2%).
Pregnancy-related Events
A serious concern associated with ART cycles is the frequency of multiple pregnancies / births and 
the related neonatal health problems. To minimise the risk of multiple gestations, subjects will have 
transfer of 1 or 2 embryos of the highest quality available. The incidence of miscarriage and ectopic 
pregnancy is higher in women undergoing controlled ovarian stimulation than in women conceiving 
spontaneously, though the risk of ectopic pregnancy is mainly higher in patients with a history of 
tubal infertility. Furthermore, the prevalence of congenital malformations after ART may be 
slightly higher than after spontaneous conceptions; this is thought to be due to differences in 
parental characteristics (e.g. maternal age and sperm characteristics) and multiple pregnancies.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Clinical Trial Protocol 
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Benefits / Risks
Participation in this trial is not expected to have a negative influence on the subject’s likelihood of 
conceiving compared to normal clinical practice. Furthermore, participation does not imply extra 
risks for the subjects in comparison to routine controlled ovarian stimulation. In conclusion, the 
evaluation of benefits and risks indicate that participation in this trial is associated with a
favourable benefit-risk ratio.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to 
ongoing pregnancy rate in women undergoing controlled ovarian stimulation
Secondary Objectives

To compare the clinical benefits of FE 999049 in its dosing regimen to those of GONAL-F 
with respect to efficacy and safety

To compare FE 999049 with GONAL-F with respect to ovarian response including 
follicular development and endocrine profile, as well as with respect to embryo 
development

To assess the population pharmacokinetics of FE 999049

To compare FE 999049 with GONAL-F with respect to treatment efficiency

To compare FE 999049 with GONAL-F with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To evaluate the immunogenicity of FE 999049 after one treatment cycle

To perform a health economic analysis comparing FE 999049 with GONAL-F
2.2
Endpoints
Primary Endpoint

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
embryos transferred)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer
divided by number of embryos transferred)

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes
retrieved


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
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
Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
embryo transfer cancellation due to excessive ovarian response / OHSS risk

Number and size of follicles on stimulation day 6 and end-of-stimulation

Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 
oocytes retrieved

Percentage of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 after oocyte retrieval

Circulating concentrations of LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Circulating concentrations of FSH on stimulation day 6, end-of-stimulation and oocyte 
retrieval as well as FSH population pharmacokinetic parameters

Total gonadotropin dose and number of stimulation days

Proportion of subjects with investigator-requested gonadotropin dose adjustments

Frequency and intensity of adverse events

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralising capacity

Frequency and intensity of immune-related adverse events

Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical intervention) and vanishing twins

Technical malfunctions of the administration pen
Post-trial Information

Live birth rate and neonatal health, including minor/major congenital anomalies, at birth and 
at 4 weeks after birth


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A diagram illustrating the trial period is shown in Figure 3-1.
Figure 3-1
Trial Diagram – Trial Period


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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3.1.2
Overall Design and Control Methods
Trial Design 
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian non-
inferiority trial comparing the efficacy and safety of two rFSH preparations, FE 999049 and 
follitropin alfa (GONAL-F), in first cycle subjects aged 20-40 years undergoing controlled ovarian 
stimulation for IVF/ICSI following a GnRH antagonist protocol. The trial has been designed to 
demonstrate non-inferiority of FE 999049, a human cell line-derived rFSH preparation, versus an 
approved CHO-derived rFSH preparation, i.e. GONAL-F, with ongoing pregnancy rate as the 
primary endpoint. Secondary endpoints include pharmacokinetic profile of FE 999049, 
pharmacodynamic parameters of FSH action as well as efficacy and safety parameters related to 
controlled ovarian stimulation. The assessor-blind design ensures that the investigators and other 
assessors such as embryologists and central laboratory personnel are blinded to individual treatment 
allocation. The sponsor will break the blind when all subjects have completed the end-of-trial visit, 
in order to evaluate efficacy and safety up to the ongoing pregnancy visit.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio 
to treatment with either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation 
will be stratified by centre and according to age (<35, 35-37 and 38-40 years). Subjects randomised 
to FE 999049 will have their individual dose determined on the basis of their AMH level at 
screening and their body weight at randomisation. The daily FE 999049 dose will be fixed 
throughout the stimulation period. For subjects with low AMH (<15 pmol/L) the daily FE 999049 
dose is 12 μg, irrespective of body weight. For subjects with high AMH (≥15 pmol/L) the daily 
FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on actual 
AMH and body weight (note, the minimum and maximum allowed daily doses are 6 µg and 12 µg, 
respectively). Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is 
not allowed. For subjects randomised to GONAL-F, the dosing regimen is within labelling. The 
starting daily dose of GONAL-F is 150 IU and fixed for the first five stimulation days after which it 
may be adjusted by 75 IU per day based on the individual response. The maximum daily 
GONAL-F dose allowed is 450 IU. Subjects can be treated with GONAL-F for a maximum of 
20 days, and coasting is not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When the leading follicle reaches ≥15 mm, visits must be 
performed daily. To prevent a premature LH surge, a GnRH antagonist will be initiated on 
stimulation day 6 and continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥3 follicles with a diameter ≥17 mm are observed. If there are 
<25 follicles with a diameter ≥12 mm, hCG will be administered. If there are 25-35 follicles with a 
diameter ≥12 mm, a GnRH agonist can be administered or the cycle can be cancelled. In case of 
excessive follicular development, defined as >35 follicles with a diameter ≥12 mm, the cycle is to 
be cancelled. If it is judged by the investigator that ≥3 follicles with a diameter ≥17 mm cannot be 
reached, but 1 or 2 follicles with a diameter ≥17 mm are observed, the cycle may either be 
cancelled due to poor follicular development or triggering of final follicular maturation is to be 
induced, as judged by the investigator.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Rescue ICSI is not allowed. Fertilisation and embryo 
development will be assessed from oocyte retrieval to the day of transfer. For subjects who 
underwent triggering of final follicular maturation with hCG, transfer is performed on day 3 
(embryo stage) after oocyte retrieval. Subjects <35 years at randomisation will have single embryo 
transfer if a good-quality embryo is available; otherwise, double embryo transfer will be performed 
(and single transfer if two embryos are not available). Subjects ≥35 years at randomisation will 
have double embryo transfer (and single transfer if two embryos are not available). Remaining 
embryos may be cryopreserved in accordance with local guidelines and/or regulations. For subjects 
who underwent triggering of final follicular maturation with GnRH agonist, no transfer will take 
place in the current fresh cycle and the embryos available will be cryopreserved on day 3, 5 or 6,
according to local practice. All cryopreserved embryos can be used by the subject after completion 
of the trial, in accordance with local guidelines and/or regulations. 
Vaginal progesterone will be provided for luteal phase support from the day of oocyte retrieval or 
the day after and at least until clinical pregnancy. Thereafter the investigator may decide to 
continue up to the ongoing pregnancy visit, according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs. A serum βhCG test will be
performed 13-15 days after transfer, clinical pregnancy will be confirmed by transvaginal 
ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be confirmed by transvaginal or 
abdominal ultrasound 10-11 weeks after transfer. 
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and haematology parameters as well as anti-FSH antibodies. Endocrine 
parameters are assessed at screening, stimulation day 1, stimulation day 6 and end-of-stimulation, 
and furthermore FSH is also assessed at oocyte retrieval. Clinical chemistry and haematology 
parameters are assessed at screening, stimulation day 1, end-of-stimulation and end-of-trial. Anti-
FSH antibodies are collected at four occasions. The first blood sample is taken at the screening visit 
and is exclusively used as back-up samples for the anti-drug antibody assay development. The 
subsequent three samples are used for analysis of anti-FSH antibodies in the individual subjects in 
the trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-dosing: 5-10 
days after the last FE 999049 or GONAL-F dose (it may coincide with the transfer visit) and 19-28 
days after the last FE 999049 or GONAL-F dose (it may coincide with the βhCG test visit). 
Subjects with a treatment-induced anti-FSH antibody response will be followed until the response 
has become negative or returned to the pre-dosing level, with a maximum follow-up period of one 
year. 
Local tolerability of FE 999049 and GONAL-F following subcutaneous administration will be 
assessed by the subject three times daily: immediately, 30 minutes and 24 hours after each 
injection. The assessment of injection site reactions will be made throughout the stimulation period 
and recorded by the subjects in a diary. 
Post-Trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up. All subjects with an ongoing 
pregnancy will be followed till delivery to gather information on live birth rate. Furthermore, data 
will be gathered on neonatal health, including any congenital anomalies, at birth and at 4 weeks 
after birth. These data will be reported separately.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
3.1.3
Trial Schedule
First patient first visit (FPFV):
Q2 2017
Last patient first visit (LPFV):
Q4 2018
Last patient last visit (LPLV):
Q1 2019
Post-trial follow-up completed:
Q1 2020
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise 1,000 subjects from 15-30 sites in mainland China and other Asian 
countries and regions. Of the 1,000 subjects it is expected that 740 subjects will be recruited in 
mainland China (i.e. possessing a Chinese identification card and having native Chinese parents)
and the rest from other Asian countries and regions, potentially Taiwan, South Korea and Vietnam.
It is estimated that approximately 1,200 subjects should be screened to achieve 1,000 subjects 
eligible for randomisation. 
The assumptions underlying the sample size calculations will be monitored in a blinded manner 
(see sections 3.3, 9.1 and 9.10), and the number of randomised subjects may be adjusted up to a 
maximum of approximately 1,144 subjects, corresponding to an observed ongoing pregnancy rate 
of 50%.
3.3
Interim Analysis and Administrative Review
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned. 
The overall ongoing pregnancy rate will be monitored in a blinded manner. This monitoring will be 
performed by the project statistician who will evaluate the overall ongoing pregnancy rate in 
relation to the assumptions underlying the sample size.
3.4
Data Monitoring Committee
No Data Monitoring Committee will be established for this trial.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
The primary objective of the trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation.
Strict criteria have been incorporated in the design of this comparative trial to properly assess the 
effect of the interventions on treatment outcome. In general, standardisation of criteria, timing of 
assessments, procedures and interventions have to a great extent been incorporated in the design of 
this trial to minimise variation12,13,14.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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This is a randomised controlled trial using an approved gonadotropin preparation as active 
comparator. It is a parallel group design restricted to a single treatment cycle, as this design is 
preferred over a cross-over design in fertility trials. The trial will be open-label but assessor-blind. 
A double-blind design is not considered feasible for the present trial for various practical reasons, 
which are described in detail in section 3.5.3. The assessor-blinding will ensure blinding and 
thereby unbiased evaluation by the investigators, embryologists and central laboratory personnel. 
Similarly, Ferring staff will also remain blinded to individual subject treatment allocation during 
the conduct of the trial. The trial will be a multi-centre Pan-Asian trial. This set-up ensures that the 
required number of subjects can be recruited within a reasonable time and also has the advantage 
that it should facilitate subsequent generalisation of the results.
The trial is designed to demonstrate non-inferiority of FE 999049 versus GONAL-F with respect to 
ongoing pregnancy rate. The non-inferiority margin for the primary endpoint has been set at -10.0% 
(absolute) in line with other recent large randomised controlled trials in ART15,16,17 and the power is 
90% for the overall trial population and 80% power for the mainland Chinese population. A non-
inferiority margin of -8.0% (and a power of 80%) has been implemented in the pivotal phase 3 trial 
(ESTHER-1). However, the present phase 3 trial to be conducted in mainland China and other 
Asian countries and regions will not be a stand-alone trial but will be supported by the ESTHER-1 
trial conducted in Europe and the Rest of World, arguing for a less strict non-inferiority limit in the 
present trial. Furthermore, narrowing the non-inferiority margin with 2% points (i.e. from -10.0% to
-8.0%) would increase the sample size by 516 subjects but would only reduce the maximum 
allowed difference in the point estimates for the ongoing pregnancy rate for FE 999049 required to 
demonstrate non-inferiority versus the comparator, by 0.8% (further details are provided in 
section 9.1), which is not clinically relevant.
Subjects will undergo controlled ovarian stimulation with an individualised dosing regimen of 
FE 999049 based on the subject’s AMH level and body weight, or with a labelling recommended 
dosing regimen of GONAL-F, following a GnRH antagonist protocol. The daily FE 999049 dose is 
fixed throughout the stimulation period in this trial. The daily GONAL-F dose is fixed for the first 
five stimulation days after which it may be adjusted by 75 IU per day based on the individual 
response, which is within the recommendations in the labelling. The selection of doses is described 
in detail in section 3.5.4. Monitoring of ovarian response by transvaginal ultrasound and blood 
sampling for assessment of several endocrine parameters will be performed regularly during 
stimulation.
Oocytes will be inseminated by either IVF or ICSI reflecting the procedures used in the target 
population for the proposed indication. Embryos will be cultured for 3 days and embryo 
development will be assessed from oocyte retrieval till the day of transfer, allowing evaluation of 
embryo development until cleavage stage. The duration of culture in this trial is adapted to clinical 
practice in Asia where transfer on day 3 after oocyte retrieval is the most common. In contrast, 
culture to blastocyst stage and transfer on day 5 after oocyte retrieval are incorporated in the 
phase 3 trial ESTHER-1, reflecting clinical practice in the participating countries in that trial.
The present protocol requires single or double embryo transfer on day 3 for all women, depending 
on age, with at least one good-quality embryo available. The scientific justification for 
incorporating these features is that it will ensure that the data obtained in this trial are in line with 
the current clinical directions taken for maintaining efficacy (i.e. ongoing pregnancy rates) and 
minimising risks (i.e. multiple pregnancies)18,19,20. The embryo transfer policy in this trial has been 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Ferring Pharmaceuticals
CONFIDENTIAL
adapted to clinical practice in Asia, and is not identical to the policy in the ESTHER-1 trial where 
single embryo (blastocyst) transfer is more strictly enforced.
Luteal phase support of the endometrium will be provided via vaginal progesterone. The 
progesterone product used in ESTHER-1 is not approved in all Asian countries and regions and 
therefore another progesterone product which is approved in mainland China and the other 
participating Asian countries and regions will be used in the present trial. Furthermore, luteal phase 
support in this trial continues to at least the clinical pregnancy visit while it was stopped at the
βhCG visit in ESTHER-1; this is a reflection of differences in local clinical practice.
Subjects who achieve a pregnancy will be followed till live birth to collect information on 
pregnancy outcome. In addition, neonatal health data will be gathered at birth and at 4 weeks after 
birth. These data will be reported separately.
3.5.2
Selection of Endpoints
The ultimate objective of fertility treatment is live birth. Ongoing pregnancy is considered an 
appropriate primary endpoint for efficacy trials, as ongoing pregnancy is the best predictor of live 
birth and it is definable within a time period in which other potential confounding factors are more 
easily controlled14.
One of the secondary objectives is to compare the clinical benefits of FE 999049 in its dosing 
regimen to those of GONAL-F with respect to efficacy and safety. This objective is addressed by 
multiple endpoints to address it from several angles; i.e. proportion of subjects with extreme 
ovarian response, early OHSS (including moderate/severe grade), preventive interventions for early 
OHSS, cycle cancellations due to poor ovarian response development and cycle cancellation due to 
excessive ovarian response.
Additional secondary endpoints include pharmacodynamic parameters, such as ovarian response in 
terms of follicular development, endocrine profile and oocytes retrieved, and also oocyte / embryo 
quality. Follicular development and endocrine profile will be evaluated after the initial 5 days (i.e. 
before any potential dose adjustments in the GONAL-F group and before start of the GnRH 
antagonist) as well as at the end of stimulation. The endocrine profile consists of FSH, luteinising 
hormone (LH), estradiol, progesterone, inhibin A and inhibin B. Serum FSH levels will be used to 
assess the population pharmacokinetics associated with repeated dosing of FE 999049, which is 
also a secondary endpoint. 
Clinical safety endpoints cover adverse events, early and late OHSS, preventive interventions for 
early OHSS, local tolerability, clinical chemistry and haematology parameters, immunogenicity and 
pregnancy-related events (i.e. multi-fetal gestations, biochemical pregnancies, spontaneous 
abortions, ectopic pregnancies and vanishing twins). Pre-defined local tolerability reactions, i.e. 
redness, pain, itching, swelling and bruising, will be assessed by the subjects on three occasions 
spanning from immediately after the subcutaneous injection till 24 hours after. Presence of anti-
FSH antibodies will be evaluated 5-10 and 19-28 days after the last administration of FE 999049 or 
GONAL-F for assessment of a potential immunoglobulin M (IgM) response and a fully mounted 
immunoglobulin G (IgG) immune response, respectively21,22,23. Technical malfunction of the pens 
used for administration of the gonadotropin preparations will also be monitored.
Post-trial activities cover follow-up of ongoing pregnancies up to live birth. Neonatal health data at 
birth and at 4 weeks after birth will be gathered. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 37 of 119
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CONFIDENTIAL
In conclusion, the list of primary and secondary endpoints is appropriate for an efficacy trial and 
furthermore includes items of special interest considering the profile of FE 999049 and specific
recommendations from EMA.
3.5.3
Blinding
The two investigational medicinal products (IMPs) differ in presentation as FE 999049 is provided 
as a liquid in a cartridge to be administered via an injection pen whereas GONAL-F is provided as a 
liquid in a pre-filled pen. Furthermore, GONAL-F is manufactured by Merck Serono and bought 
commercially for use in this phase 3 trial. Therefore, a double-blind, double-dummy design is not 
feasible. The trial, however, is assessor-blind, ensuring unbiased evaluation by the investigators, 
embryologists and central laboratory personnel. 
One or more trial medication delegate(s) will be identified at each site. The trial medication 
delegate will be responsible for all trial medication related issues, both practically at the clinic and
in interactions with the subject. To maintain the assessor-blinding, the trial medication delegate is 
not allowed to perform any assessments in the trial. Information on treatment allocation is only 
available to the trial medication delegate. The investigator does not have access to these modules in 
the electronic case report form (e-CRF). Thus, only the trial medication delegate at the site, the 
monitors and the participating subjects will know the treatment allocation once the subjects are 
randomised. Precaution will be taken to ensure that the treatment allocations are not available to the 
investigators or other assessors throughout the trial. Subjects will be clearly instructed to only 
discuss their treatment allocation with the trial medication delegate, and to not mention it to the 
investigator.
Drug accountability forms and other forms identifying treatment allocation are kept unavailable to 
the investigator. The subject will during the informed consent process be informed, both verbally 
and in writing, to not disclose her treatment allocation to the investigator. Trial staff is provided 
training in the importance of maintaining blinding, and trial medication delegates are also helped to 
set up systems at the clinic.
The trial medication delegate will dispense the trial medication to the subject (and may also do the 
actual administration at the clinic, if required). The investigator will, based on the follicular 
development, judge if dose adjustments are recommended and state his/her directions on a form 
developed for that purpose, which will be used to inform the trial medication delegate. Depending 
on whether the subject is being treated with FE 999049 or GONAL-F, the trial medication delegate
will provide detailed instructions to the subject in line with the dosing regimen for each preparation
as outlined in the protocol. In other words, if the investigator recommends a dose adjustment, the 
trial medication delegate will implement a decrease or increase of 75 IU per day as applicable if the 
subject is in the GONAL-F group, while no dose adjustments will be implemented if the subject is 
in the FE 999049 group. Requests for cycle cancellation due to inappropriate response or other 
medical reasons are followed, irrespective of treatment group.
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and sponsor’s responsible medical officer) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when all subjects have completed 
the end-of-trial visit and the trial database is declared clean and locked.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 38 of 119
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CONFIDENTIAL
3.5.4
Selection of Doses in the Trial
FE 999049
Modelling and simulation based on the efficacy and safety data obtained in the European phase 2 
trial have been used to establish the overall dosing regimen for FE 999049 in the phase 3 trials. 
This is the same dosing regimen that was used in the phase 3 trial 000004 (ESTHER-1), where it 
has been shown to reduce the risk of extreme ovarian response, the risk of cycle cancellation due to 
excessive ovarian response, and the risk of early moderate/severe OHSS and/or prevention 
interventions for early OHSS, while obtaining a pregnancy rate that is non-inferior to GONAL-F.
AMH and body weight were found to influence the dose-response with regard to obtaining the aim 
of the model of the FE 999049 dosing regimen. The impact of body weight on ovarian response is 
clinically relevant for low dose levels of FE 999049, while the effect is only minor at dose levels of 
12 μg and above. The individualised dosing regimen of FE 999049 in the present trial is described 
in detail in section 5.1.1 and is summarised as follows: For subjects with low AMH (<15 pmol/L)
the daily FE 999049 dose is 12 μg, irrespective of body weight, and for subjects with high AMH
(≥15 pmol/L) the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, 
depending on the baseline AMH level. The minimum and maximum allowed daily doses are 6 µg 
and 12 µg, respectively.
GONAL-F
Subjects randomised to GONAL-F will be dosed according to the approved labelling. The starting 
dose of GONAL-F in this trial is 150 IU, which is the same starting dose as used in the ESTHER-1
trial. The European4, mainland Chinese24, Taiwanese25, South Korean26 and Vietnamese27
labelling’s for GONAL-F state a starting dose of 150-225 IU, but provide no recommendation for 
when to use 150 IU and when to use 225 IU. In the absence of a recommendation from the 
manufacturer, the lowest effective dose has been selected as this would be a reasonable approach in 
clinical practice, especially as this trial will include subjects with no previous controlled ovarian 
stimulation for IVF/ICSI. This choice is also in line with the US labelling of GONAL-F28 which 
recommends a starting dose of 150 IU in patients where the endogenous gonadotropin levels are not 
suppressed (such as the GnRH antagonist cycle, where prevention of premature LH surge is only 
initiated after 5 days of stimulation). The GONAL-F starting dose is fixed for the first five 
stimulation days after which it may be adjusted by 75 IU per day based on the individual response. 
For GONAL-F, the maximum daily dose allowed is 450 IU. 
Concomitant Fertility Medication 
The doses and overall treatment regimens for the GnRH antagonist, hCG and progesterone products 
are in line with the recommendations in the respective products’ labelling for the indication of ART
and/or standard clinical practice. The GnRH agonist is included as an option for triggering of final 
follicular maturation in subjects with 25-35 follicles with a diameter ≥12 mm, as this approach is 
associated with almost an elimination of the risk of early moderate/severe OHSS despite high 
ovarian response. The use of a GnRH agonist for triggering of final follicular maturation in a GnRH 
antagonist protocol is well-described in the literature and considered an acceptable alternative to 
cycle cancellation29,30,31,32,33.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 39 of 119
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CONFIDENTIAL
3.5.5
Selection of the Trial Population
This trial will include women undergoing their first IVF/ICSI cycle, as this group of subjects is 
considered the most appropriate population for a trial comparing the efficacy between 
gonadotropins and furthermore when using different dosing regimens. The subjects have been
diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have partners 
diagnosed with male factor infertility, and are considered eligible for IVF or ICSI. The trial will 
include women up to 40 years of age and will thereby cover the patient age span in which most 
ART treatments are performed. The allowed body mass index (BMI) is 17.5-32.0 kg/m2, thus 
including underweight, normal weight, overweight and obese subjects.
The exclusion criteria incorporate the contraindications for the use of gonadotropins.
Altogether, the population selected for this trial would be expected to be representative for patients 
undergoing controlled ovarian stimulation in IVF/ICSI cycles.
3.5.6
Follow-up Procedures
Post-trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up at birth and at 4 weeks after 
birth as described in section 7.4.1. 
Safety Follow-up
As a safety precaution, subjects with treatment-induced anti-FSH antibody response will be 
followed until the response has become negative or returned to the pre-dosing level for at least 2 
consecutive measurements with a maximum follow-up period of one year .The assessments will 
also be terminated if the subject commences a new treatment cycle with any gonadotropin 
preparation. Safety follow-up also includes follow-up on adverse events (with onset during the trial 
and classified as serious or related to IMP) until it is resolved or until the medical condition of the 
subject is stable.
Access to Therapy after End-of-trial
Concerning access to therapy after completion of the trial, FE 999049 is currently under clinical 
development and cannot be offered to subjects after participation in this clinical trial. However, 
several gonadotropin preparations are approved for controlled ovarian stimulation and are 
commercially available.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 40 of 119
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CONFIDENTIAL
4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects must meet all of the criteria listed below to be eligible for participation in the trial.
1. Informed Consent Documents signed prior to screening evaluations.
2. In good physical and mental health in the judgement of the investigator.
3. Asian pre-menopausal females between the ages of 20 and 40 years. The subjects must be at 
least 20 years (including the 20th birthday) when they sign the informed consent and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised ASRM classification, 1996) or with partners diagnosed with 
male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm 
injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
5. Infertility for at least one year before randomisation for subjects <35 years or for at least 
6 months for subjects ≥35 years (not applicable in case of tubal or severe male factor 
infertility).
6. The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
7. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no polyps and no congenital structural abnormalities which are
associated with a reduced chance of pregnancy) within 1 year prior to randomisation. 
9. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would 
contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 
1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.
10. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 2 years prior to randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. Willing to accept transfer of 1-2 embryos.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
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4.1.2
Exclusion Criteria
Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.
1. Known endometriosis stage III-IV (defined by the revised ASRM classification, 1996).
2. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
3. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 
4. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
5. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
6. Known inherited or acquired thrombophilia disease.
7. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
8. Known porphyria.
9. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
10. Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records; i.e. not based on the anti-FSH antibody analyses conducted in the trial). 
11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
12. Known moderate or severe impairment of renal or hepatic function.
13. Any abnormal finding of clinical chemistry, haematology or vital signs at screening which 
is clinically significant as judged by the investigator.
14. Currently breast-feeding.
15. Undiagnosed vaginal bleeding.
16. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
17. Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine 
abnormalities or retained intrauterine device.
18. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomisation) or contraindication to pregnancy.
19. Known current active pelvic inflammatory disease.
20. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral 
contraceptives, progestogen or estrogen preparations.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 42 of 119
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CONFIDENTIAL
21. Use of hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomisation.
22. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
23. Current or past (1 year prior to randomisation) abuse of alcohol or drugs.
24. Current (last month) intake of more than 14 units of alcohol per week.
25. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
26. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
27. Previous participation in the trial.
28. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The participating subjects will be recruited among the patients attending the clinics included in the 
trial. Advertisements may be used if approved by the local ethics committee and regulatory 
authorities, as applicable according to local regulations.
A screening number is allocated to each subject who has given written informed consent to 
participate in the trial. A subject must always be assigned to the lowest available screening number 
at each site. A subject screening / enrolment log for all screened subjects must be maintained by the 
investigator.
4.2.2
Randomisation
On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to treatment with 
either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation is performed 
centrally through the e-CRF and will be stratified according to age (<35, 35-37 and 38-40 years).
The randomisation number will be allocated to the subject together with the treatment allocation 
and starting dose. When a subject is randomised to the trial, she will always be assigned to the 
lowest available randomisation number. An independent statistician at the Ferring Global 
Biometrics Department will prepare a computer-generated randomisation list and randomisation is 
performed in blocks. Blocks will be maintained within trial sites, i.e. the randomisation will be 
stratified by trial site. The block size will only be revealed when the trial database is declared clean 
and locked. An overview of recruitment will be recorded on a subject identification code list for all 
randomised subjects kept by the investigator. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 43 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
The subjects must not have used fertility modifiers, including DHEA, metformin or cycle 
programming with oral contraceptives, progestogen or estrogen preparations, or hormonal 
preparations (except for thyroid medication) during the last menstrual cycle before randomisation.
The subject must also not use metformin as ongoing treatment during the trial.
During the trial it is prohibited to administer any other fertility medications, than the ones provided 
as part of the trial regimen.
Dopamine agonist for preventive intervention of OHSS is not allowed.
4.3.2
Prohibited Therapy
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial.
4.4
Withdrawal Criteria
Withdrawal from Trial
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. 
If, at the time of discontinuation, a dose of the IMP has already been administered, the subject must 
be advised to participate in the follow-up safety investigations, which will include all post-dosing 
antibody assessments and all procedures outlined in the end-of-trial visit.
The investigator also has the right to withdraw subjects. For any discontinuation, the investigator 
will obtain all the required details and document the date of the premature termination and the main 
reason in the e-CRF.
Withdrawal of Consent
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analysed. This will be described in the Informed Consent Documents. The subject 
can request destruction of samples which would otherwise have been kept in storage.
4.5
Subject Replacement
A subject can only be assigned one screening number and one randomisation number.
Subjects who discontinue prematurely from the trial after randomisation are not to be replaced, i.e. 
randomisation numbers are uniquely linked to each subject and cannot be re-used.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 44 of 119
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CONFIDENTIAL
5
TREATMENTS
5.1
Investigational Medicinal Products (IMPs)
Subjects will be randomised to the following IMPs in a 1:1 ratio in the trial:

FE 999049 manufactured by Ferring will be provided as a cartridge and an injection pen. 
One subcutaneous injection will be administered daily, starting on day 2-3 of the subject’s 
menstrual cycle and continued throughout the stimulation period. 

GONAL-F (follitropin alfa for injection) manufactured by Merck Serono is provided as a 
pre-filled pen containing a liquid formulation for injection. One subcutaneous injection will 
be administered daily, starting on day 2-3 of the subject’s menstrual cycle and continued 
throughout the stimulation period.
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for FE 999049 and the Prescribing Information for GONAL-F.
5.1.1
FE 999049 Dosing Regimen
Subjects randomised to FE 999049 will have their individual dose determined on the basis of their 
AMH level at screening and their body weight at randomisation. For subjects with low AMH 
(<15 pmol/L) the daily FE 999049 dose is 12 μg, irrespective of body weight. For subjects with 
high AMH (≥15 pmol/L) the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 
0.10 μg/kg, i.e. dependent on actual AMH and body weight. The minimum and maximum allowed 
daily doses are 6 µg and 12 µg, respectively. 
The daily FE 999049 dose will be fixed throughout the stimulation period. Dosing will continue 
until the criterion for triggering of final follicular maturation has been met. Subjects can be treated 
with FE 999049 for a maximum of 20 days. Coasting is not allowed. Overdose and medication 
errors of IMP with and without clinical consequences will be tracked in the e-CRF and reviewed 
ongoing by Ferring GPV.
The complete FE 999049 dosing regimen is tabulated in detail in Table 5-1.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 45 of 119
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CONFIDENTIAL
Table 5-1
FE 999049 Dosing Regimen
Treatment 
group
AMH 
concentration 
(pmol/L)
Daily dose fixed throughout 
stimulation
Minimum 
daily dose
Maximum 
daily dose
FE 999049        <15
12 μg 
12 μg
15-16
0.19 μg/kg
6 µg
12 μg
17
0.18 μg/kg
6 µg
12 μg
18
0.17 μg/kg
6 µg
12 μg
19-20
0.16 μg/kg
6 µg
12 μg
21-22
0.15 μg/kg
6 µg
12 μg
23-24
0.14 μg/kg
6 µg
12 μg
25-27
0.13 μg/kg
6 µg
12 μg
28-32 
0.12 μg/kg
6 µg
12 μg
33-39 
0.11 μg/kg
6 µg
12 μg
≥40 
0.10 μg/kg
6 µg
12 μg
AMH concentration will be rounded off to integers.
Subjects can be treated for a maximum of 20 days.
The FE 999049 preparation is administered as a single daily subcutaneous injection in the 
abdomen. The dose must not be split into two injections. To minimise local injection site reactions, 
it is advisable to change injection site regularly.
The first FE 999049 injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer FE 999049.
Calculation of the FE 999049 Dose and Setting the Dose on the FE 999049 Pen
The subject’s serum AMH concentration will be available from the blood sample taken at screening 
and analysed by a central laboratory using a qualified assay. The AMH concentration will be 
provided from the central laboratory directly to the e-CRF. The subject’s body weight will be 
measured at randomisation using a calibrated scale and performed without shoes and overcoat. The 
body weight result will be entered into the e-CRF. The FE 999049 dosing algorithm has been 
programmed in the e-CRF, which calculates the FE 999049 dose based on the subject’s AMH and 
body weight. 
The FE 999049 injection pen has a dosing scale numbered from 0 to 24 μg. Each number is 
separated by two lines, each representing 0.33 μg. Thus, the pen can be set to supply doses rounded 
to the nearest 0.33 μg. Rounding off of the calculated dose may be needed, as in this example of a 
subject weighing 60.0 kg with an AMH level of 30 pmol/L for whom the calculated dose is 7.2 μg 
(0.12 μg/kg * 60.0 kg) which will then be rounded to 7.33 μg, i.e. 7 μg + 1 line on the pen. The 
minimum daily dose of 6 µg will be administered in cases like this example: a subject weighing 
40.0 kg and with an AMH level of 40 pmol/L will have a calculated dose of 4.0 µg (0.10 µg/kg * 
40.0 kg) which will then be rounded up to 6 µg. The e-CRF will provide the calculated dose in an 
output that matches the numbers and lines on the injection pen; i.e. any rounding off will be done 
automatically prior to providing the subject’s calculated dose.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 46 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
The trial medication delegate will be instructed and trained in the correct use of the pen, so that 
correct instructions can be provided to the subjects.
5.1.2
GONAL-F Dosing Regimen
For subjects randomised to GONAL-F, the dosing regimen is within labelling. The starting dose of 
GONAL-F is 150 IU per day and fixed for the first five stimulation days, after which it may be 
adjusted by 75 IU per day based on the individual response. The maximum daily GONAL-F dose 
allowed is 450 IU. Dosing will continue until the criterion for triggering of final follicular 
maturation has been met. Subjects can be treated with GONAL-F for a maximum of 20 days.
Coasting is not allowed. Overdose and medication errors of IMP with and without clinical 
consequences will be tracked in the e-CRF and reviewed ongoing by Ferring GPV.
The GONAL-F dosing regimen is shown in detail in Table 5-2.
Table 5-2
GONAL-F Dosing Regimen
Treatment 
group
Starting dose 
stimulation day 1-5
Daily dose stimulation day 6 and 
onwards
Maximum 
daily dose
GONAL-F
150 IU
Adjustments of 75 IU per day allowed 
according to the individual response.
450 IU
Subjects can be treated for a maximum of 20 days.
The GONAL-F preparation is administered as a single daily subcutaneous injection in the abdomen. 
The dose must not be split into two injections. To minimise local injection site reactions, it is 
advisable to change injection site regularly.
The first GONAL-F injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer GONAL-F.
Setting the Dose on the GONAL-F Pen
The GONAL-F pen has a dosing scale applicable for the starting dose and subsequent potential 
dose adjustments. 
The trial medication delegate will be instructed and trained in the correct use of the pen, so that 
correct instructions can be provided to the subjects.
5.2
Non-Investigational Medicinal Products (NIMPs)
As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the following 
non-investigational medicinal products (NIMPs) as illustrated in Table 5-3.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 47 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
Table 5-3
Non-Investigational Medicinal Products (NIMPs)
NIMP
Trade name
Timing
GnRH 
antagonist
CETROTIDE
0.25 mg subcutaneous injection once daily, starting on 
stimulation day 6 and continued throughout the stimulation 
period.
hCG
OVITRELLE
A single 250 µg subcutaneous injection as soon as reaching 
the criterion for triggering of final follicular maturation with 
hCG (≥3 follicles with a diameter ≥17 mm and <25 follicles 
with a diameter ≥12 mm).
GnRH agonist
GONAPEPTYL
Two consecutive injections of 0.1 mg, i.e. a total of 0.2 mg,
as soon as reaching the criterion for triggering of final 
follicular maturation with GnRH agonist (≥3 follicles with a 
diameter ≥17 mm and 25-35 follicles with a diameter 
≥12 mm), unless the cycle is cancelled.
Progesterone
CRINONE
90 mg vaginal gel (8%) once daily, starting on the day of 
oocyte retrieval or the day after and continued at least until 
clinical pregnancy. Progesterone support will be terminated 
earlier in case of no transfer, menses, negative βhCG or 
pregnancy loss.
(Note: not required for subjects who undergo triggering of 
final follicular maturation with GnRH agonist)
All NIMPs are used in line with the recommendations in the respective products’ labelling for the 
indication of ART and/or standard clinical practice supported by literature.
5.3
Characteristics and Source of Supply
All medicinal products that are centrally sourced (i.e. provided by Ferring) will be handled 
according to the principles of Good Manufacturing Practice (GMP). Table 5-4 provides an 
overview of the presentation and manufacturer of each medicinal product.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 48 of 119
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CONFIDENTIAL
Table 5-4
Characteristics and Source of Supply of Medicinal Products
IMP / NIMP
Presentation
Manufacturer
FE 999049
(rFSH)
FE 999049 is provided as a cartridge and 
an administration pen. Each cartridge 
contains a solution for injection 
delivering 72 µg FSH in 2.16 mL
Ferring Pharmaceuticals
GONAL-F
(rFSH)
GONAL-F (follitropin alfa) is provided 
as a pre-filled pen containing a liquid 
formulation for injection. Each pen 
delivers 900 IU (66 µg) FSH in 1.5 mL
Merck Serono
CETROTIDE
(GnRH antagonist)
CETROTIDE (cetrorelix acetate) is 
provided as powder and solvent for 
solution for injection. After 
reconstitution, 1 mL solvent contains 
0.25 mg cetrorelix
Merck Serono
OVITRELLE
(rhCG)
OVITRELLE (choriogonadotropin alfa) 
is provided as a pre-filled syringe
(0.5 mL) for single use delivering 250 µg 
choriogonadotropin alfa
Merck Serono
GONAPEPTYL
(GnRH agonist)
GONAPEPTYL (triptorelin acetate) is 
provided as a pre-filled syringe (1 mL) 
delivering 0.1 mg triptorelin acetate
Ferring Pharmaceuticals
CRINONE
(progesterone)
CRINONE is provided as sustained-
release vaginal gel 8% (90 mg) in 
prefilled applicators delivering 90 mg of 
progesterone
Merck Serono / Watson / 
Columbia / Actavis
5.4
Packaging and Labelling
Packaging and labelling of the centrally sourced medicinal products will be performed under the 
responsibility of the IMP department at Ferring in accordance with GMP and national regulatory 
requirements.
GONAL-F as well as all NIMPs are commercially available. No modification from the usual 
commercial state of GONAL-F will be made, except for trial-specific labelling. All centrally 
sourced medicinal products will be labelled with trial-specific labels, which contain a self-adhesive 
tear-off portion to be affixed to the drug label accountability form maintained at the trial site.
In mainland China, commercially available CETROTIDE may be provided to the subjects on 
prescription, if agreed between the trial site and Ferring, and no packaging and labelling will be 
performed by Ferring in this case.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
5.5
Conditions for Storage and Use
The trial medication delegate will ensure that the centrally sourced medicinal products will be 
stored in appropriate conditions as stated in the IMP Handling guideline and in a secure location 
with controlled access. The storage compartment shall be monitored regularly and the temperature 
shall be documented.
Deviations in storage temperature must be reported without delay and the centrally sourced 
medicinal products must not be used until further instructions from Ferring are received.
Storage and deviations in storage temperature before dispensing of prescribed CETROTIDE will be 
handled according to standard practice at the hospital / clinic pharmacy and local regulations.
In case of technical malfunction of an administration pen, all relevant details (including time, date, 
a description of the malfunction and whether dosing was affected) of the incidence should be 
reported, the pen should be replaced and the treatment continued.
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for FE 999049 and the Product Information for GONAL-F as well as for 
OVITRELLE, GONAPEPTYL, CETROTIDE and CRINONE.
5.6
Blinding / Unblinding
5.6.1
Blinding
The trial is assessor-blind, and all investigators, embryologists and central laboratory personnel will 
be blinded to treatment allocation throughout the trial. The trial medication delegate at site (person 
responsible for IMP/NIMP), the trial coordinator at site (person entering data into e-CRF), the 
monitors and the participating subjects will know the treatment allocation once the subjects are 
randomised. Precaution must be taken to ensure that the treatment allocations are not available to 
the investigators or other assessors throughout the trial. Subjects must be clearly instructed to only 
discuss their treatment allocation with the trial medication delegate, and to not mention it to the 
investigator.
The trial medication delegate will dispense the trial medication to the subject (and may also do the 
actual administration at the clinic, if required). The investigator will, based on the follicular 
development, judge if dose adjustments are recommended and state his/her directions on a form 
developed for that purpose, which will be used to inform the trial medication delegate. Depending 
on whether the subject is being treated with FE 999049 or GONAL-F, the trial medication delegate
will provide detailed instructions to the subject in line with the dosing regimen for each preparation
as outlined in the protocol. In other words, if the investigator recommends a dose adjustment, the 
trial medication delegate will implement a decrease or increase of 75 IU per day as applicable if the 
subject is in the GONAL-F group, while no dose adjustments will be implemented if the subject is
in the FE 999049 group. Requests for cycle cancellation due to inappropriate response or other 
medical reasons are followed, irrespective of treatment group.
The randomisation list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information in the e-CRF will not be accessible to assessors or the Ferring clinical trial team or 
laboratory personnel during the trial.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and sponsor’s responsible medical officer) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when the trial database is declared 
clean and locked.
5.6.2
Unblinding of Individual Subject Treatment
An emergency unblinding solution will be available to the investigator and designated persons at 
the sponsor. Breaking of the blind for individual subjects in emergency situations is only permitted 
in case of a suspected unexpected serious adverse reaction (SUSAR) or in case of an important 
adverse event where the knowledge of the IMP in question is required for therapeutic decisions for 
the management of the subject.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
the sponsor. It should be recorded in the e-CRF that the code is broken, why, when and by whom. 
The investigator must record the event of unblinding in the subject’s medical record, including the 
reason for unblinding.
In case of accidental unblinding (e.g. the subject tells the investigator), the same documentation as 
for emergency unblinding must be obtained, i.e. why, when and by whom must be recorded in the 
e-CRF, and the event must also be recorded in the subject’s medical record.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the authorities and/or ethics committees. In that situation, every effort will be made to 
maintain blinding of sponsor personnel involved in data analysis and interpretation. Other 
personnel may be unblinded for SUSARs, including trial site staff as well as staff acting on behalf 
of Ferring.
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and locked.
5.7
Dispensing and Accountability, Return and Destruction
All handling of centrally sourced medicinal products (both IMP and NIMP) will be done by a trial 
medication delegate(s) at the site. Prescribed CETROTIDE will be dispensed to the subject by a 
trial medication delegate or a pharmacist / pharmacist assistant, while all subsequent handling of 
prescribed CETROTIDE will be performed by the trial medication delegate. The trial medication 
delegate will maintain subject dispensing logs, detailing the dates, quantities and batch numbers of 
dispensed and returned IMP and NIMP for each subject. The trial medication delegate will also 
manage the overall drug accountability at the site.
The monitor will verify drug accountability of IMP and NIMP throughout the trial and will 
document any discrepancies.
Concerning destruction, the trial medication delegate at the site must ensure destruction of 
dispensed IMP and NIMP in accordance with local legislation after drug accountability has been 
verified by the monitor and signed off by the trial medication delegate, while non-dispensed IMP 
and NIMP will be returned for destruction as instructed by the Ferring IMP Department.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 51 of 119
Ferring Pharmaceuticals
CONFIDENTIAL
5.8
Auxiliary Supplies
Ferring will be responsible for the supply of safety containers for collection of used cartridges, 
pens, syringes and needles.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 52 of 119
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CONFIDENTIAL
6
TRIAL PROCEDURES
The flow of the trial procedures for subjects is shown in Table 6-1.
Table 6-1
Trial Flow Chart – Subject Procedures
Scree-
ning
Stimulation
Oocyte 
retrieval
Transfer
Pregnancy monitoring
End
During stimulation
End-of-
stimula-
tion
OR
Transfer
βhCG
Clinical
Ongoing
End-of-
trial
Timing
<90 days 
before 
random-
isation
Day 1
Day 6 
Day ≥7 
to <20 a)
End
36h ±2h 
after 
triggering
Day 3
after OR
13-15 
days 
after 
transfer
5-6 
weeks 
after 
transfer
10-11 
weeks 
after 
transfer
b)
Written informed consent
X
Inclusion/exclusion criteria
X
   X c)
Demographics
X
Medical history 
X
Infertility history
X
Menstrual history
X
Reproductive history
X
Smoking and alcohol habits
X
Body weight and height
X
   X c),d)
   X d)
Physical examination
X
X
Gynaecological examination
X
X
Pregnancy test
X
   X c)
Ultrasound
   X c)
X
X
X
X
X
Randomisation
X
Vital signs
X
   X e)
X
Blood collection, clin chem / haem
X
   X e)
X
X
Blood collection, endocrine f)
X
   X e)
   X g)
   X g)
X h)
Blood collection, antibodies i)
   X j)
   X e)
  
   X k)
X l)
   X l)
IMP dispensing
X
   X m)
   X m)
NIMP dispensing
   X n)
X
X
X
X
X
Xo
Local tolerability (diary) 
X
X
X
X
Oocyte retrieval
X
Embryo transfer
X
βhCG test (local laboratory)
X
Drug accountability
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
End-of-trial form
X
a) Visits must be scheduled at least every second day; when the leading follicle reaches ≥15 mm visits must be scheduled daily. 
b) End-of-trial assessments must be performed at the subject’s last scheduled visit: at the earliest 19-28 days after the last IMP dose. 
c) Performed before randomisation.
d)   Only body weight.
e) Performed before the first IMP dose. 
f)
Endocrine parameters consist of a screening panel, a treatment panel, and FSH.
g) Performed at least 8 h after IMP administration.
h) FSH only.
i)
All subjects with a treatment-induced antibody response must be followed until the response is negative or has returned to pre-dosing level, with a 
maximum follow-up period of one year.  
j)
Sample exclusively used as back-up samples for the anti-drug antibody assay development.
k) Blood sampling for antibody assessment must be done 5-10 days after the last IMP dose (this may coincide with the transfer visit; alternatively, 
a separate visit must be scheduled).
l)
Blood sampling for antibody assessment must be done 19-28 days after the last IMP dose (this may coincide with the βhCG visit; alternatively, 
a separate visit must be scheduled).
m) The daily dose of FE 999049 is fixed throughout stimulation. The dose of GONAL-F is fixed for the first 5 days, after which it may be adjusted by 
75 IU per day based on the individual response.
n)  The trial medication delegate (or another qualified trial staff) should observe the general health of the subject, with emphasis on symptoms of an 
acute allergic reaction, for 30 min after the GnRH antagonist dosing.
o)  Luteal phase support can be continued until the ongoing pregnancy visit, if applicable according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs.
IMP: investigational medicinal product; NIMP: non-investigational medicinal product


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
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6.1
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before stimulation day 1 (randomisation). 
The following must take place during the screening period:

Signed and dated written informed consent, obtained prior to any trial-related procedures

Allocation of a screening number

Check of inclusion and exclusion criteria (those which are possible to check at screening)

Demographics (age, ethnicity, race)

Collection of the following data:
-
Medical history (including any cysts)
-
Infertility history
-
Menstrual history
-
Reproductive history
-
Smoking and alcohol habits

Body weight and height [note: these are used for calculation of BMI]

Physical examination

Vital signs

Gynaecological examination

Pregnancy test – must be negative

Blood collection for central laboratory analysis of:
-
Clinical chemistry and haematology parameters [note: the results must be available 
before randomisation]
-
Endocrine parameters (screening panel: AMH, thyroid-stimulating hormone (TSH) and 
prolactin) [note: the results must be available prior to randomisation]
-
Anti-FSH antibodies [exclusively used as back-up samples for the anti-drug antibody 
assay development]

Recording of use of any concomitant medication (within the last 3 months prior to signed 
informed consent for participation in the trial)

Recording of adverse events (from the date of signed informed consent for participation in 
the trial)
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit, scheduled on day 2-3 of the menstrual cycle.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
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6.2
Stimulation 
6.2.1
Stimulation Day 1 
Subjects will attend the stimulation day 1 visit on day 2-3 of the menstrual cycle.
The following must take place prior to randomisation:

Ensure that the subject is still eligible for participation in the trial

Check those inclusion and exclusion criteria that were not possible during screening 

Body weight [note: this body weight result is used for dose calculation in the FE 999049 
group and should be measured on a trial specific calibrated scale]

Pregnancy test – must be negative

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, ovarian volume, 
number and size of follicles). If a cyst ≥10 mm is observed (functional or not), it should be 
punctured before treatment is initiateda. If the cyst was present at the screening visit, it 
should have been recorded on the medical history form. If the cyst presented between 
screening and stimulation day 1, it should be recorded on the adverse event form.
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation:

Randomisation, i.e. assignment to the lowest available subject number and thereby 
allocation to either FE 999049 or GONAL-F
The following must take place after randomisation but before administration of the first dose of 
IMP (FE 999049 or GONAL-F):

Vital signs (systolic blood pressure, diastolic blood pressure, pulse)

Blood collection for central laboratory analysis of:
-
Clinical chemistry and haematology parameters
-
Endocrine parameters (AMH and treatment panel: FSH, LH, estradiol, progesterone, 
inhibin A and inhibin B)
-
Anti-FSH antibodies
Once the above has been completed, the following must be performed by the trial medication 
delegate. Care must be taken to ensure blinding of the investigator and other assessors.

Dispense IMP according to randomisation and instruct the subject on how to administer the
IMP 

Administer the 1st dose of IMP according to randomisation [administration of IMP takes 
place at the clinic and can be done by either the trial medication delegate or the subject
under supervision by the trial medication delegate]:
                                                                                                                                                
a Treatment can be initiated the same day. If puncture is not possible, randomisation may be postponed to the next 
menstrual cycles, assuming that the cyst will disappear and that the subject fulfils the inclusion criteria. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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-
If randomised to FE 999049; daily dose according to AMH level at screening and body 
weight at randomisation (see Table 5-1 for detailed instructions)
-
If randomised to GONAL-F; starting dose for the first 5 days is fixed at 150 IU

Hand out the diary to the subject. The subject must be instructed to assess and record local 
tolerability immediately, 30 min and 24 hours after each IMP administration throughout the 
entire stimulation period.
After the first administration of FE 999049 or GONAL-F, the subject must do the following: 

Assessment of local tolerability (recorded in a diary) – the first evaluation of local 
tolerability reactions at the injection site is done immediately after the subcutaneous 
injection of IMP, followed by the second evaluation 30 min after injection of IMP and the 
third evaluation 24 hours after injection of IMP (before the next day’s injection of IMP).
Finally, this must be done before the subject leaves the clinic:

Take precautions in the event that the subject experiences an acute allergic reaction. In the 
first 30 min following the IMP administration, the trial medication delegate (or another 
qualified trial staff) must observe the subject’s general health with emphasis on symptoms 
of an acute allergic reaction. The trial sites are requested to have facilities (i.e. medication, 
equipment and trained staff) and procedures in place for diagnosis and treatment of acute 
allergic reactions.

Recording of use of any concomitant medication

Recording of adverse events
The next visit must be scheduled for stimulation day 6.
6.2.2
Stimulation Day 6 
The following must take place at stimulation day 6:

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, number and size of follicles)

Blood collection for central laboratory analysis of:
-
endocrine parameters (treatment panel: FSH, LH, estradiol, progesterone, inhibin A 
and inhibin B) – the blood sample must be drawn at least 8 hours after the latest IMP 
administration

Dispensing of IMP and potential dose adjustment
-
FE 999049: the daily dose is fixed throughout stimulation
-
GONAL-F: from stimulation day 6 and onwards, the daily dose may be adjusted by 
75 IU per day based on the individual response

Dispensing and administration of GnRH antagonist [the first administration of GnRH 
antagonist takes place at the clinic and can be done by either the trial medication delegate or 
the subject under supervision by the trial medication delegate]

Collection of local tolerability data (diary pages)


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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
Drug accountability of IMP

Recording of use of any concomitant medication

Recording of adverse events
Finally, this must be done before the subject leaves the clinic:

In the first 30 min following the GnRH antagonist administration, the trial medication 
delegate (or another qualified trial staff) must observe the subject’s general health with 
emphasis on symptoms of an acute allergic reaction. Note: it is important that the subject 
does not mix up the injection sites for IMP and GnRH antagonist

Instruct the subject to administer the GnRH antagonist at a daily dose of 0.25 mg throughout 
the stimulation period.
After the stimulation day 6 visit, the next visits must be scheduled at least every second day 
throughout the remaining stimulation period. When the leading follicle reaches ≥15 mm, visits must 
be performed daily.
6.2.3
Stimulation Days ≥7 to ≤20
These visits will take place at least every second day throughout the remaining stimulation period. 
When the leading follicle reaches ≥15 mm, visits must be performed daily. Coasting is not allowed. 
The maximum period of stimulation is 20 days.
The following must take place at all visits throughout the remainder of the stimulation period (with 
the exception of the end-of-stimulation visit, which is described in section 6.2.4):

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, number and size of follicles)

Dispensing of IMP, as applicable

Dispensing of GnRH antagonist, as applicable

Collection of local tolerability data (diary pages)

Drug accountability of IMP and GnRH antagonist

Recording of use of any concomitant medication

Recording of adverse events
6.2.4
End-of-stimulation
The end-of-stimulation visit takes place when the subject reaches the criterion for triggering of final 
follicular maturation or any of the cycle cancellation criteria because of poor or excessive follicular
development as specified in Table 6-2. Administration of hCG or GnRH agonist must take place as 
soon as reaching the criterion for triggering of final follicular maturation.
If triggering as soon as reaching the criterion would lead to oocyte retrieval or embryo transfer on a 
day the clinic is closed e.g. Sunday or a public holiday, stimulation may be continued for one 
additional day, meaning triggering is delayed for a maximum of one day.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
If the GnRH antagonist is administered in the morning it should also be administered on the day of 
triggering. If the GnRH antagonist is administered in the evening, no GnRH antagonist is to be 
given on the day of triggering.
Table 6-2
Triggering and Cycle Cancellation Criteria related to Follicular Development
Poor follicular development 
Triggering criterion 
Excessive follicular development
If it is judged by the investigator 
that ≥3 follicles with a diameter 
≥17 mm cannot be reached, but 
1 or 2 follicles with a diameter 
≥17 mm are observed, the cycle 
may either be cancelled due to 
poor follicular development or 
triggering of final follicular 
maturation is to be induced, as 
judged by the investigator.
Criterion for triggering of final 
follicular maturation:

≥3 follicles with a diameter 
≥17 mm
If <25 follicles with a diameter 
≥12 mm are observed, hCG is 
administered.
In case of >35 follicles with a 
diameter ≥12 mm, the cycle is to
be cancelled.
If 25-35 follicles with a diameter 
≥12 mm are observed, GnRH 
agonist can be administered; 
alternatively the cycle can be 
cancelled.
If 25-35 follicles with a diameter 
≥12 mm are observed, the cycle 
can be cancelled; alternatively 
GnRH agonist can be
administered.
Triggering drug must be 
administered the day the criterion 
is met.
The investigator also has the option of cancelling the cycle for other relevant medical reasons, 
including adverse events and technical malfunctions of the administration pen.
The following must take place at end-of-stimulation visit:

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, ovarian volume, number and size of 
follicles)

Blood collection for central laboratory analysis of:
-
clinical chemistry and haematology parameters
-
endocrine parameters (treatment panel: FSH, LH, estradiol, progesterone, inhibin A 
and inhibin B) – the blood sample must be drawn at least 8 hours after the latest 
administration of IMP and GnRH antagonist

Dispensing of hCG or GnRH agonist, as applicable

Dispensing of GnRH antagonist

Collection of local tolerability data (diary pages)

Drug accountability of IMP and GnRH antagonist

Recording of use of any concomitant medication


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL

Recording of adverse events
For subjects who receive a triggering drug, the next visit is the oocyte retrieval visit which must be 
scheduled 36h (±2h) after the administration of hCG or GnRH agonist.
For subjects with cycle cancellation, the next visit is the first post-dosing anti-FSH antibody blood 
sampling visit 5-10 days after the last FE 999049 or GONAL-F dose (section 6.5.2).
6.3
Oocyte Retrieval
Oocyte retrieval must take place 36h (±2h) after hCG or GnRH agonist administration. All oocytes 
from follicles with an estimated diameter ≥12 mm should be retrieved. Below are listed the 
procedures related to the subjects attending the oocyte retrieval visit, while procedures related to 
the oocytes are described in section 6.4.
The following must take place at the oocyte retrieval visit:

Blood collection for central laboratory analysis of:
-
endocrine parameter (FSH only)

Oocyte retrieval

Dispensing of progesterone for luteal phase support – must be started on the day of oocyte 
retrieval or the day after and continued at least until clinical pregnancy [note: only 
applicable for subjects who underwent triggering of final follicular maturation with hCG 
and who had oocytes retrieved]

Drug accountability of hCG or GnRH agonist, as applicable

Collection of diary pages

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with oocytes retrieved following hCG administration, the next visit is the transfer visit 
3 days after oocyte retrieval (section 6.5.1). 
For subjects with oocytes retrieved following GnRH agonist administration, the oocytes will 
undergo the procedures described in section 6.4 and embryos will be cryopreserved on day 3, 5 or 6
after oocyte retrieval, according to local practice. The next visit for these subjects is the first post-
dosing anti-FSH antibody assessment visit which must be scheduled 5-10 days after the last 
FE 999049 or GONAL-F dose (section 6.5.2).
For subjects with no oocytes retrieved, the next visit is the first post-dosing anti-FSH antibody 
assessment visit which must be scheduled 5-10 days after the last FE 999049 or GONAL-F dose 
(section 6.5.2).


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
Page 59 of 119
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CONFIDENTIAL
6.4
Oocyte / Embryo Evaluation
The laboratory procedures regarding handling and evaluations of oocytes and embryos are 
described in a trial-specific manual. This section provides an overview of the procedures and 
assessments to be made from oocyte retrieval till transfer at the embryo stage. The flow of the trial 
procedures for oocytes is shown in Table 6-3.
Table 6-3
Trial Flow Chart – Oocyte / Embryo Procedures
Day 0 (OR)
Day 1 after OR
Day 3 after OR
Oocyte retrieval (OR)
X
Assessment of maturity stage (applicable for oocytes 
undergoing ICSI)
X
Insemination by IVF or ICSIb
X
Assessment of oocyte fertilisation
X
Assessment of embryo quality
X
Transfer of 1 or 2 embryos of the highest quality 
available:
– Subjects <35 years at randomisation: 

single embryo transfer if a good-quality embryo is 
available 

double embryo transfer if a good-quality embryo is 
not available (and if two embryos are available)
– Subjects ≥35 years at randomisation: 

double embryo transfer (if two embryos are 
available)
X
Cryopreservation of embryos, as applicablec
Xc
Assisted hatching and pre-implantation genetic diagnosis (PGD) / pre-implantation genetic 
screening (PGS) are prohibited.
Day 0 (Oocyte Retrieval)

Assessment of maturity stage (applicable for oocytes undergoing ICSI)

Insemination at 0h using IVF or ICSI using ejaculated sperm (fresh or frozen) from partner 
or donor
Day 1 after Oocyte Retrieval

Assessment of fertilisation (number of pronuclei)
                                                                                                                                                
b Rescue ICSI is not allowed.
c Cryopreservation of surplus embryos can be postponed to day 5 or 6, according to local practice.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Day 3 after Oocyte Retrieval

Assessment of embryo quality:

Number of cells

Compaction status

Fragmentation (either 0%, 1-10%, 11-20%, 21-50% or >50% fragmentation, or 
totally fragmented (no blastomeres recognised))

Blastomere uniformity (equally or unequally)

Visual signs of multinucleation (yes/no)
Good quality embryo is defined as an embryo with ≥6 blastomeres and ≤20% fragmentation, 
without signs of multinucleation

Transfer of embryo (section 6.5)
Cryopreservation of surplus embryos should be performed on day 3 after oocyte retrieval.
Cryopreservation can be postponed to day 5 or day 6 after oocyte retrieval, as applicable and 
according to local practice.
6.5
Transfer
6.5.1
Embryo Transfer
Transfer is performed on day 3 (embryo stage) after oocyte retrieval. The subject-related 
procedures are described below.

Blood collection for central laboratory analysis of anti-FSH antibodies (first post-dosing 
assessment)

Transfer of 1 or 2 embryo(s) of the highest quality available according to this policy:
-
Subjects <35 years at randomisation: 

single embryo transfer if a good quality embryo is available

double embryo transfer if a good-quality embryo is not available (and single 
transfer if two embryos are not available). 
-
Subjects ≥35 years at randomisation:

double embryo transfer (and single transfer if two embryos are not available).
(note: transfer is only applicable for subjects who underwent triggering of final follicular 
maturation with hCG. Subjects who were administered GnRH agonist will not undergo transfer
in the current fresh cycle).

Dispensing of progesterone for luteal phase support 

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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For subjects with embryo transfer, the next visit is the βhCG test visit which must be scheduled 
13-15 days after transfer (section 6.6).
6.5.2
First Post-dosing Anti-FSH Antibody Assessment (5-10 Days after Last IMP Dose)
Subjects who have been exposed to FE 999049 or GONAL-F must have the first post-dosing anti-
FSH antibody assessment performed 5-10 days after the last FE 999049 or GONAL-F dose. This 
may coincide with the transfer visit (section 6.5.1). 
For subjects who do not attend the transfer visit, a separate visit must be scheduled, at which the 
following must take place:

Blood collection for central laboratory analysis of anti-FSH antibodies

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events
6.6
βhCG Test
6.6.1
βhCG Test
Subjects who have undergone transfer must attend a visit 13-15 days after transfer. 
The following must take place:

Blood collection for local laboratory analysis of hCG

Blood collection for central laboratory analysis of anti-FSH antibodies (second post-dosing 
assessment)

Dispensing of progesterone for luteal phase support, if applicable

Drug accountability of progesterone

Recording of use of any concomitant medication 

Recording of adverse events
The blood sample for βhCG will be analysed by the local laboratory and evaluated according to the 
laboratory’s reference ranges. In case of a borderline hCG result, the test should be repeated. 
Subjects with a positive hCG test must attend a clinical pregnancy visit 5-6 weeks after transfer 
(section 6.7). Subjects with a negative hCG test must proceed to the end-of-trial assessments 
(section 6.9).


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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CONFIDENTIAL
6.6.2
Second Post-dosing Anti-FSH Antibody Assessment (19-28 Days after Last IMP 
Dose)
Subjects who have been exposed to FE 999049 or GONAL-F must have the second post-dosing 
anti-FSH antibody assessment performed 19-28 days after the last FE 999049 or GONAL-F dose. 
This may coincide with the βhCG test visit (section 6.6.1). 
For subjects who do not attend the βhCG test visit, a separate visit must be scheduled, at which the 
following must take place:

Blood collection for central laboratory analysis of anti-FSH antibodies

Dispensing of progesterone for luteal phase support, if applicable

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events
For subjects who do not attend the βhCG test visit, this second post-dosing anti-FSH antibody 
assessment may be done in connection with the end-of-trial visit (section 6.9).
6.7
Clinical Pregnancy
Subjects with a positive hCG test must attend a visit 5-6 weeks after transfer. 
The following must take place:

Transvaginal ultrasound of uterus to assess any clinical pregnancy 

Drug accountability of progesterone

Dispensing of progesterone for luteal phase support, if continued according to local practice

Recording of use of any concomitant medication 

Recording of adverse events
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms 
a vital pregnancy. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit
10-11 weeks after transfer (section 6.8). Subjects with no vital pregnancy must undergo end-of-trial 
assessments (section 6.9).
6.8
Ongoing Pregnancy
If a vital pregnancy has been documented, the subject must attend a visit 10-11 weeks after transfer. 
The following procedures / assessments must take place:

Ultrasound (transvaginal or abdominal) of uterus to assess any intrauterine viable fetus

Drug accountability of progesterone, if applicable

Recording of use of any concomitant medication 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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
Recording of adverse events
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy.
6.9
End-of-trial
If a subject attends the scheduled trial visits, the end-of-trial assessments should take place at the 
last scheduled trial visit, i.e. for subjects with a confirmed vital pregnancy, the ongoing pregnancy 
visit would be the last scheduled trial visit and thus the visit where the end-of-trial assessments 
should be done.
Due to the timing of the mandatory anti-FSH antibody assessments, the end-of-trial assessments 
can at the earliest be 19-28 days after the last FE 999049 or GONAL-F dose. This may coincide 
with the βhCG visit for subjects with a negative βhCG test.
The following procedures / assessments must take place at the end-of-trial visit, irrespective of 
whether the subject discontinues the trial prematurely or completes it:

Body weight

Physical examination

Gynaecological examination

Vital signs 

Blood collection for central laboratory analysis of
-
clinical chemistry and haematology parameters
-
anti-FSH antibodies (second post-dosing assessment) [note: only applicable for 
subjects who have not already had a blood sample taken for the second post-dosing 
anti-FSH antibodies assessment as described in sections 6.6.1 and 6.6.2]

Drug accountability, if applicable

Recording of use of any concomitant medication

Recording of adverse events

Completion of end-of-trial form 
These assessments serve to document the subject’s physical health at the end of the trial.
6.10
Post-trial Activities
Pregnancy Follow-up
All subjects with an ongoing pregnancy will be followed till delivery to gather information on live 
birth rate. Furthermore, data will be gathered on neonatal health, including any congenital
anomalies, at birth and at 4 weeks after birth as described in section 7.4.1.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Supersedes: Ver. 2.0
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7
TRIAL ASSESSMENTS
7.1
Assessment Related to Primary Endpoint
7.1.1
Ongoing Pregnancy
A transvaginal or abdominal ultrasound of the uterus will be performed 10-11 weeks after transfer. 
Ongoing pregnancy will be defined as at least one intrauterine viable fetus. For ongoing 
pregnancies, the number of intrauterine viable fetuses will be recorded.
7.2
Assessments Related to Secondary Endpoints
7.2.1
βhCG Test
A blood hCG test must be obtained 13-15 days after transfer. If the test is positive according to the 
local laboratory’s reference ranges, this confirms a positive hCG.
7.2.2
Clinical Pregnancy
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Clinical 
pregnancy will be defined as at least one gestational sac, either intrauterine or ectopic. The 
inclusion of ectopic pregnancies and the lack of specification of heart beat in the definition of 
clinical pregnancy is in line with the current International Committee Monitoring Assisted 
Reproductive Technologies (ICMART) and World Health Organization (WHO) glossary on ART 
terminology.d,34 For intrauterine and ectopic pregnancies, the number of gestational sacs with fetal 
heart beat as well as without fetal heart beat will be recorded. 
7.2.3
Vital Pregnancy
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Vital pregnancy 
will be defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after 
transfer. 
7.2.4
Implantation
Implantation is determined based on the transvaginal ultrasound performed at the clinical 
pregnancy visit. Implantation rate will be defined as the number of gestational sacs 5-6 weeks after 
transfer divided by number of embryos transferred.
7.2.5
Ongoing Implantation
Ongoing implantation is determined based on the ultrasound performed at the ongoing pregnancy 
visit. Ongoing implantation rate will be defined as the number of intrauterine viable fetuses 
                                                                                                                                                
d
ICMART and WHO glossary on ART terminology: Clinical pregnancy – a pregnancy diagnosed by 
ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes 
ectopic pregnancy.


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10-11 weeks after transfer divided by number of embryos transferred.
7.2.6
Extreme Ovarian Response
The number of oocytes retrieved will be counted at the oocyte retrieval visit. Extreme ovarian 
response will be defined as retrieval of <4, ≥15 or ≥20 oocytes.
7.2.7
Early OHSS (including OHSS of Moderate/Severe Grade) and/or Preventive 
Interventions for Early OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3 for details) and 
all OHSS cases will be graded as mild, moderate or severe. Preventive interventions for early 
OHSS cover cycle cancellation due to excessive ovarian response or triggering of final follicular 
maturation with GnRH agonist.
7.2.8
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo Transfer 
Cancellation due to Excessive Ovarian Response / OHSS Risk
The reason for each cycle cancellation will be recorded. Cycle cancellations related to inappropriate 
ovarian response will include poor and excessive follicular development. Cycle cancellation due to 
poor follicular development is implemented when the investigator judges that ≥3 follicles with a 
diameter ≥17 mm cannot be reached by stimulation day 20. Cycle cancellation due to excessive 
follicular development is implemented when >35 follicles with a diameter ≥12 mm are observed
(can also be implemented if there are 25-35 follicles with a diameter ≥12 mm). The reason for each 
embryo transfer cancellation will be recorded. Transfer cancellation due to adverse events such as 
the Medical Dictionary for Regulatory Activities preferred terms (MedDRA PTs) "ovarian 
hyperfunction" and "ovarian hyperstimulation syndrome" and "high progesterone" in subjects with 
embryos available for transfer will be considered as transfer cancellations due to excessive response 
/ OHSS risk.
7.2.9
Number and Size of Follicles during Stimulation
Transvaginal ultrasound will be performed at all visits during the stimulation period to count the 
number of follicles and measure the size of the follicles. Data will be recorded separately for the 
right and left ovary.
7.2.10
Number and Distribution of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit. The proportion of 
subjects with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted 
response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) will be 
calculated.
7.2.11
Metaphase II Oocytes
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity 


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stage will be categorised as germinal vesicle, metaphase I, metaphase II, degenerated or other.
7.2.12
Fertilisation Rate 
The number of pronuclei will be counted on day 1 after oocyte retrieval and recorded as 0, 1, 2 or 
>2. Fertilised oocytes with 2 pronuclei will be regarded as correctly fertilised.
7.2.13
Number and Quality of Embryos on Day 3
Each embryo will be followed closely and formally evaluated on day 3 after oocyte retrieval. The 
quality evaluation will consist of assessment of cleavage stage and embryo morphology parameters 
(number of cells, degree of fragmentation, blastomere uniformity and visual signs of 
multinucleation). 
Cleavage stage will be defined by the number of blastomeres: 1, 2, 3, 4, 5, 6, 7, 8, …. On day 3, it 
will also be possible to indicate the compaction status instead of number of blastomeres.
Degree of fragmentation will be classified as one of the following: 0%, 1-10%, 11-20%, 21-50%, or 
>50% fragmentation, or totally fragmented (no blastomeres recognised).
Blastomere uniformity will be classified as equally sized blastomeres or unequally sized 
blastomeres (largest blastomere >25% larger in average diameter compared to the smallest 
blastomere). 
Visual sign of multinucleation will be evaluated as yes or no.
A good quality embryo is defined as an embryo with ≥6 blastomeres and ≤20% fragmentation, 
without signs of multinucleation.
7.2.14
Circulating Levels of Endocrine Parameters
During treatment, the following panel of endocrine parameters will be evaluated (treatment panel): 
FSH, LH, estradiol, progesterone, inhibin A and inhibin B. 
Blood samples will be drawn at stimulation day 1e, stimulation day 6 and the end-of-stimulation
visit. The sample on stimulation day 1 (baseline) will be collected prior to the first dose of 
FE 999049 or GONAL-F, and samples drawn at stimulation day 6 and the end-of-stimulation visit 
will be collected at least 8 hours after the previous FE 999049, GONAL-F or GnRH antagonist
administration. The samples will be analysed at a central laboratory. The investigator will review 
and evaluate the laboratory results. The Laboratory Report will be signed and dated by the 
investigator.
7.2.15
FSH Population Pharmacokinetics
In addition to the sampling time points mentioned in section 7.2.14, blood samples will also be 
drawn at the oocyte retrieval visit for analysis of FSH. 
Based on the serum FSH samples obtained during the trial, a population pharmacokinetic model 
will be developed to assess the pharmacokinetics of FE 999049 and confirm predictors for FSH 
                                                                                                                                                
e
AMH will also be included in the stimulation day 1 analyses.


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concentration levels, such as body weight.
7.2.16
Total Gonadotropin Dose and Number of Stimulation Days
The start and end dates as well as daily dose of IMP will be recorded and used to calculate the total 
FE 999049 or GONAL-F dose administered and the number of stimulation days.
7.2.17
Gonadotropin Dose Adjustments
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. 
7.2.18
Adverse Events
Adverse events will be recorded from the signed informed consent for participation in the trial until 
the end-of-trial visit. For each adverse event the following parameters are recorded by the 
investigator on the Adverse Event Log: description of event, date and time of onset, intensity, 
causal relation to IMP, action taken to IMP, other actions taken, seriousness of the adverse event, 
date and time of outcome, and outcome. Furthermore, the pattern (e.g. the frequency, time of onset, 
intensity, seriousness and outcome) of the most frequent / relevant adverse events will be tabulated. 
7.2.19 Clinical Chemistry and Haematology Parameters
The following clinical chemistry and haematology parameters will be analysed at a central 
laboratory: 
CHEM-20: alanine transaminase, albumin, alkaline phosphatase, aspartate aminotransferase, 
bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, 
creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus,
potassium, sodium, total protein, uric acid.
Complete Blood Count (CBC): red blood cells, red blood cell morphology, white blood cells, white 
blood cell morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular 
haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Blood samples will be drawn at screening, on stimulation day 1, end-of-stimulation and end-of-
trial. The samples from the screening visit will be used for safety and eligibility evaluation of the 
subject before randomisation. The sample at stimulation day 1 (baseline) must be drawn before the 
first FE 999049 or GONAL-F injection. The investigator will review the laboratory results and 
evaluate and document whether the abnormal results are non-clinically or clinically significant. The 
Laboratory Report will be signed and dated by the investigator.
7.2.20 Injection Site Reactions
Every day throughout the stimulation period, the subjects will assess the local tolerability of 
subcutaneous injections of FE 999049 or GONAL-F at three time points relative to the daily 
administration: immediately after the injection, 30 minutes after the injection and 24 hours after the 
injection. The following injection site reactions will be assessed: redness, pain, itching, swelling 


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and bruising. The presence and intensity of each injection site reaction will be rated as one of the 
following: none, mild, moderate or severe.
The subject will record the assessments in a diary and the diary data will subsequently be 
transcribed to the e-CRF.
7.2.21 Anti-FSH Antibodies
Blood samples for assessment of anti-FSH antibodies in the individual subjects in the trial will be 
drawn pre-dosing and post-dosing: 

Screening [note: this sample is exclusively used as back-up sample for the anti-drug 
antibody assay development]

Stimulation day 1, prior to dosing (baseline; pre-dosing sample)

5-10 days after the last FE 999049 or GONAL-F dose
This may coincide with the transfer visit. Subjects not reaching transfer must be called in for 
this extra visit.

19-28 days after the last FE 999049 or GONAL-F dose
This may coincide with the βhCG visit. In case of discontinuation before the βhCG visit, 
this assessment should be done at the end-of-trial visit scheduled 19-28 days after the last 
FE 999049 or GONAL-F dose.
Ferring has developed the following assays for evaluating the immunogenicity of FE 999049 or 
GONAL-F:
Assay 1)
A screening immunoassay, assessing the presence in serum of anti-FSH antibodies, 
using a parametric cut-point approach with a 5% false positive rate. 
Assay 2)
A confirmatory immunoassay, confirming or disconfirming the specificity of any 
positive results in assay 1), using a parametric cut-point approach with a 0.1% false 
positive rate.
Assay 3)
A titre immunoassay determining the antibody response titre of any anti-FSH 
antibodies confirmed in assay 2).
Assay 4)
A cell-based assay qualitatively assessing the neutralising capacity of any anti-FSH 
antibodies confirmed in assay 2), using a parametric cut-point approach with a 1% 
false positive rate.
Assay 5)
A cell-based assay determining the neutralising antibody response titre of any 
positive result in assay 4).
Assay 6)
A confirmatory assay based on native FSH, in order to assess cross-reactivity with 
native FSH of any anti-FSH antibodies confirmed to be specific towards exogenous 
FSH in assay 2), using a parametric cut-point approach with a 0.1% false positive 
rate.
In subjects with a negative pre-dosing sample, a treatment-induced anti-FSH antibody response will 
be defined as any post-dosing sample being positive in the confirmatory assay; Assay 2).


Follitropin Delta, FE 999049
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In subjects with a positive pre-dosing sample, a treatment-induced anti-FSH antibody response will 
be defined as a statistically determined fold increase in titres from the pre-dosing assessment to a 
post-dosing assessment.f
All positive samples in the confirmatory Assay 2) will be further characterised for titre, neutralising 
capacity (qualitatively and titre) and cross-reactivity. A subject is defined to have treatment-
induced anti-FSH antibodies with neutralising capacity if the subject has a positive outcome of 
assay 4) after IMP administration compared to pre-dose.
The proportion of subjects with treatment-induced anti-FSH antibodies and the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralising capacity are secondary 
endpoints.
Subjects with a treatment-induced anti-FSH antibody response (both with and without neutralising 
capacity) will be followed until the response becomes negative or has returned to pre-dosing level.
These subjects will be called in for monthly assessments for a period of 3 months after the last post-
dosing anti-FSH antibody sampling. If required, further assessments will be made quarterly, i.e. 6, 9
and 12 months after the last post-dosing anti-FSH antibody sampling. The assessments will be 
terminated when two consecutive assessments are negative or indicate that the pre-dosing level has 
been reached, with a maximum follow-up period of one year. The assessments will also be 
terminated if the subject commences a new treatment cycle with a gonadotropin preparation.
7.2.22
Immune-related Adverse Events
All adverse events reported in the trial will be analysed to identify those that potentially are 
immune-related. To identify all possible cases, a broad-scope search on Standardised Medical 
Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), including ‘Hypersensitivity’,
‘Anaphylactic reactions’, ‘Angioedema’ and ‘Severe cutaneous adverse reactions’ will be 
considered. Moreover, to identify the potential cases manifested by non-specific symptoms and not 
covered by these SMQs, other MedDRA PTs like ‘Musculoskeletal pain’, ‘Asthenia’, ‘Pyrexia’, 
‘Chills’, ‘Body temperature increased’, ‘Influenza like illness’, ‘Injection related reaction’, ‘Pre-
syncope'’ and ‘Syncope’ will also be taken into account. Hypersensitivity reactions manifested by 
local symptoms will be identified using the MedDRA high level term (HLT) ‘injection site 
reactions’. The SMQs may include very specific as well as less specific terms; hence a narrow-
scope search on these SMQs will be carried out to identify those cases that are highly likely to 
represent an immune-related aetiology.
7.2.23
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen
The reason for each cycle cancellation will be recorded. Among the options are adverse events, 
including immune-related adverse events, and technical malfunctions of the administration pen.
                                                                                                                                                
f
The fold increase in titres will be determined by minimum significant ratio (MSR) experiments during assay 
validation. The clinical trial report will clearly state the MSR used in the data evaluation.


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Trial Code: 000145
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7.2.24
Late OHSS (including OHSS of Moderate/Severe Grade)
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3 for details) and 
all OHSS cases will be graded as mild, moderate or severe.
7.2.25
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins
Data related to multi-fetal gestation defined as a pregnancy with more than one fetus will be 
recorded. Furthermore, data related to the occurrence of biochemical pregnancy, spontaneous 
abortion, ectopic pregnancy (with and without medical/surgical interventions) and vanishing twins 
will also be recorded.
7.2.26
Pen Malfunction
Incidences of technical malfunctions of the administration pen will be recorded.
7.3
Other Assessments
7.3.1
Demographics
Demographic information will be obtained during the screening period, including date of birth and 
confirmation of the subject’s race and nationality. Mainland Chinese subjects must possess a 
Chinese identification card and have native Chinese parents. 
7.3.2
Medical History
Any relevant medical history will be recorded at screening. This includes diagnoses / symptoms 
and whether it is a past or ongoing occurrence.
7.3.3
Infertility History
Information about the reasons of infertility will be obtained during the screening period. Duration 
of infertility will be recorded at the randomisation visit. This will also cover information about any 
previous treatment for infertility, including type of treatment and gonadotropin preparations used. 
7.3.4
Menstrual History
Information about the menstrual history (average cycle length) will be obtained during the 
screening period.


Follitropin Delta, FE 999049
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7.3.5
Reproductive History
Information about the reproductive history will be obtained during the screening period. This will 
include number of clinical pregnancies, number of fetuses and outcome. Information on primary 
versus secondary infertility will be derived.
7.3.6
Smoking and Alcohol Habits
Information about smoking and alcohol habits will be obtained during the screening period. 
Smoking will be categorised as 0, 1-5 or 6-10 cigarettes per day. Alcohol will be categorised as 0, 
1-7 or 8-14 units per week.
7.3.7
Body Weight and Height
Body weight will be measured at screening, stimulation day 1 and at end-of-trial. Body weight will 
be measured without shoes and overcoat and using a calibrated scale. The body weight at 
randomisation will be used for dose calculation in the FE 999049 group.
Height will only be measured at screening and will be used to calculate BMI.
7.3.8
Physical Examination
A complete physical examination will be performed at screening and end-of-trial. Information will 
be recorded for general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth and throat), respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system and skin.
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events.
7.3.9
Gynaecological Examination
A complete gynaecological examination will be performed at screening and end-of-trial. 
Information will be recorded for breast, external genitalia, vagina, cervix, uterus, ovaries and
fallopian tubes.
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported as medical history or as reason for infertility on the Infertility History form, as applicable, 
and evaluated in accordance with inclusion criteria 8 and 9 (section 4.1.1).
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 


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abnormal clinically significant. Abnormal clinically significant changes from screening to 
end-of-trial must be recorded as adverse events.
7.3.10 Endocrine Parameters at Screening
At screening, the following panel of endocrine parameters will be evaluated (screening panel): 
AMH, TSH and prolactin. The sample will be analysed at a central laboratory.
The results of the screening panel must be available prior to randomisation. The investigator will 
review and evaluate the laboratory results (with the exception of AMH, which will not be made 
available to the investigator). The Laboratory Report will be signed and dated by the investigator.
The AMH samples collected at screening may be used for correlation analysis of Elecsys® AMH
immunoassay results determined at provincial local laboratories versus the central laboratory.
7.3.11 Vital Signs
Systolic and diastolic blood pressure as well as pulse will be measured at screening, stimulation 
day 1 and end-of-trial. All assessments of vital signs will be done while the subject is in supine 
position after resting for 3 minutes. 
7.3.12 Ovarian Volume
As part of the transvaginal ultrasounds performed at stimulation day 1 and end-of-stimulation, the 
size – length, width and depth (recorded in mm) – of each ovary is measured and used for 
subsequent calculation of ovarian volume. 
7.3.13 Endometrial Status
Transvaginal ultrasound of the uterus to assess the endometrial status will be conducted at all visits 
during the stimulation period. The endometrial status assessments consist of the following 
parameters: endometrial thickness, endometrial triple-layer structure and endometrial echogenicity 
pattern (note: the latter two are not assessed on stimulation day 1).
Endometrial thickness (composed of both layers of the endometrium) will be measured in the 
sagittal view of the uterus from the proximal and distal interfaces between the echogenic 
endometrium and the hypoechoic inner layer of the myometrium. Care should be taken not to 
include the hypoechoic subendometrial halo and to account for the presence of any fluid in the 
uterine cavity (not to be included in the endometrial thickness value). Endometrial thickness will be 
recorded in mm.
Endometrial triple-layer structure will be recorded as observed or not.
Endometrial echogenicity pattern will be recorded as hypoechogenic, isoechogenic, 
hyperechogenic, or not possible to evaluate.


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7.3.14 Embryo Transfer Procedure
Any difficulty or eventuality (e.g. greater resistance is met, the procedure is time-consuming, there 
is a need to change to a harder catheter, uterine sounding or cervical dilation is carried out, or there 
is blood in any part of the catheter), during the transfer procedure will be noted.
7.3.15 Concomitant Medication
The use of any concomitant medication within the last 3 months prior to informed consent for 
participation in the trial (except medication used in previous infertility treatment cycles) and 
throughout the trial will be recorded. Recording of concomitant medication will be performed at all 
visits. Any changes in concomitant medications or treatments must be recorded at each visit. 
7.3.16 Drug Dispensing and Accountability
For all medicinal products, dates of administration and dose administered will be recorded. 
Furthermore, time of administration will also be recorded for IMP, GnRH antagonist, hCG and 
GnRH agonist. Details on drug dispensing and accountability are provided in section 5.7.
7.3.17 End-of-trial Form
An end-of-trial form must be filled in at the subject’s last visit, irrespective of whether the subject 
completes the trial or not. Completion / discontinuation status will be recorded, as well as date and 
reason for discontinuation in case the subject did not complete the trial.
7.4
Assessments Related to Post-trial Information
7.4.1
Pregnancy Follow-up
For subjects with an ongoing pregnancy, information on the pregnancy period, including any 
relevant interventions performed and incidence of second or third trimester losses, as well as the 
pregnancy outcome, e.g. live birth, will be gathered. Further, neonatal health data will be collected 
at birth and at 4 weeks after birth for all children born. At birth, the data collected will include 
gender, birth weight and length, way of delivery, position of neonate and Apgar score as well as 
information on any congenital anomalies and admission to neonatal intensive care unit (NICU) or 
neonatal care unit (NCU). At 4 weeks after birth, the data collected will include any congenital 
anomalies, hospitalisations, death of neonate and any other relevant medical conditions. These
follow-up data can be obtained from the subject, unless medical judgement is required.
These data will be reported separately.
7.5
Handling of Biological Samples
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. All biological 
samples will be analysed at central laboratories and will be maintained in storage after the end of 
the trial. Destruction will take place within 2 years after reporting of the trial or when methods / 


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results have been adequately validated. For all biological samples collected in the trial, it applies 
that analyses beyond those described in the protocol can only be performed after obtaining the 
required approvals. The processes related to handling of biological samples will be described in the 
informed consent documents, and biobank / data protection legislation including local legislation 
will be adhered to.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes:

Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP.

Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP.

Any laboratory abnormality, vital sign or finding from physical or gynaecological
examination assessed as clinically significant by the investigator [note: pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or during 
the screening period are not adverse events, but are recorded as medical history.]

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures.
All adverse events will be coded by Ferring Global Pharmacovigilance using MedDRA (the version 
effective at trial start).
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the end-of-trial visit.
The sources of adverse events cover:

The subject’s response to questions about her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit).

Symptoms spontaneously reported by the subject.

Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities.

Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalisation).
8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s e-CRF with information about:

Adverse event

Date and time of onset


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
Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome

Outcome

Seriousness
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Event
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis / symptom should be entered per record.
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event.g
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event).
Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
date is the date the sample was taken or the examination was performed. 
                                                                                                                                                
g
Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
changes in intensity after the administration of the IMP, this must be recorded as two separate events. The initial 
adverse event should be recorded with outcome “not yet recovered” and the date and time of outcome is when the 
intensity changed. The second adverse event should be recorded with date and time of onset when the intensity 
changed. 


Follitropin Delta, FE 999049
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Intensity
The intensity of an adverse event must be classified using the following 3-point scale:
Mild:
Awareness of signs or symptoms, but no disruption of usual activity.
Moderate:
Event sufficient to affect usual activity (disturbing).
Severe:
Inability to work or perform usual activities (unacceptable).
Causal Relationship to IMP
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship 
between the IMP and the adverse event. The adverse event may occur 
as part of the pharmacological action of the IMP or may be 
unpredictable in its occurrence.
Examples: 

Adverse events that are uncommon but are known to be strongly 
associated with IMP exposure.

Adverse events that are not commonly associated with IMP 
exposure, but the event occurs in association with other factors 
strongly suggesting causation, such as a strong temporal 
association with the IMP or the event recurs on rechallenge with 
the IMP.
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the adverse event.
Examples:

Known consequences of the underlying disease or condition 
under investigation.

Adverse events common in the trial population, which are also 
anticipated to occur with some frequency during the course of the 
trial, regardless of IMP exposure.
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:

No change (medication schedule maintained or no action taken)

Discontinued

Interrupted


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
Dose reduced

Dose increased
Other Action Taken
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date and time the subject recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment)

Recovered with sequelae (resulted in persistent or significant disability / incapacity)

Recovering

Not recovered

Fatal
8.3
Adverse Events of Special Interest and/or Requiring Special Handling
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)
Symptoms and Classification
OHSS is an adverse event of special interest during controlled ovarian stimulation. Investigators 
will record OHSS symptoms and use these symptoms directly to grade (1, 2, 3, 4 or 5) each OHSS 
case into Golan’s classification system35 as shown in Table 8-1.


Follitropin Delta, FE 999049
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Table 8-1
Classification of Mild, Moderate and Severe OHSS (Golan’s Classification 
System)
Mild OHSS
Grade 1
Abdominal distension and discomfort 
Grade 2 
Features of grade 1 plus nausea/vomiting and/or diarrhoea. Ovaries enlarged to 
5-12 cm.a)
Moderate OHSS
Grade 3 
Features of mild OHSS plus ultrasonic evidence of ascites.b)
Severe OHSS
Grade 4 
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax (or 
breathing difficulties). Paracentesis due to OHSS symptoms. c)
Grade 5 
All of the above plus change in blood volume, increased blood viscosity due to 
haemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d) Hospitalisation due to OHSS symptoms.
a) For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded. 
b) For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis. 
c) In case of paracentesis, the volume of fluid drained should be measured.
d) Heaemoconcentration is defined as haematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded.
All cases of OHSS must be reported as adverse events. Those that fall under the category serious 
adverse events must be reported as such. Note that the classification ‘mild OHSS’, ‘moderate 
OHSS’ and ‘severe OHSS’ does not refer to the classification of an adverse event’s intensity (also 
rated mild, moderate, or severe).
Subject narratives will be prepared for all moderate and severe OHSS cases.
Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of 
final follicular maturation and late OHSS will be defined as OHSS with onset >9 days after 
triggering of final follicular maturation.
In addition to early OHSS and late OHSS overall, emphasis will be placed on OHSS of 
moderate/severe grade.
Preventive Interventions of Early OHSS
Preventive interventions of early OHSS include the following:

Cycle cancellation due to excessive ovarian response


Follitropin Delta, FE 999049
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
Triggering of final follicular maturation with GnRH agonist 
Investigations to be Conducted in Subjects where OHSS Symptoms are Observed
The following investigations must be conducted when OHSS symptoms are first observed and 
repeated when there are clinically relevant changes in the OHSS presentation: 

Body weight and maximum abdominal circumference (for all OHSS)

Vital signs (for all OHSS)

Blood sample for central laboratory analysis of the following (for moderate/severe OHSS):

Progesterone and estradiol

CBC (red blood cells, red blood cell morphology, white blood cells, white blood cell 
morphology, haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets)

CHEM-20 (alanine transaminase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, 
calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric 
acid)

Coagulation parameters (prothrombin time, activated partial thrombin time)
Any treatments of OHSS, e.g. intravenous administration of volume expanders, paracentesis, use of 
low-molecular-weight heparin and intravenous administration of albumin, must be recorded as 
concomitant medication.
8.3.2
Local Tolerability
Injection site reactions after administration of IMP (FE 999049 and GONAL-F) are only to be 
reported as adverse events if they require active management, i.e. discontinuation of IMP, 
additional investigations or treatment of the injection site reaction. Local tolerability of IMP 
constitutes a secondary endpoint and will be evaluated in detail based on the subjects’ recordings in 
the diary. 
Local tolerability reactions after administration of NIMP are to be reported as adverse events if they 
fulfil the definition of an adverse event.
8.3.3
Treatment-induced Anti-FSH Antibodies
Presence of treatment-induced anti-FSH antibodies is not to be reported as an adverse event. These 
data will be described as part of the secondary endpoints.


Follitropin Delta, FE 999049
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8.3.4
Menstrual Bleeding
Menstrual bleeding is only to be reported as an adverse event in case it is excessive, painful, 
delayed or in any other way deviating from the subject’s normal menstruation. Menstrual bleeding 
associated with lack of pregnancy will be reported as part of the efficacy evaluation.
8.3.5
Ovarian Torsion
Any case of ovarian torsion will be reported as an adverse event and it will be specified whether it 
is associated with any signs or symptoms of OHSS.
8.3.6
Pregnancy Losses
The following terminology should be used for reporting of pregnancy losses during the trial:
Biochemical pregnancy: 
Positive βhCG test but no gestational sac is observed on later 
transvaginal ultrasound, or menstruation is reported
Spontaneous abortion: 
Positive βhCG test but all intrauterine gestational sacs are 
without fetal heart beat as documented by ultrasound, or there 
are no viable fetuses observed by ultrasound
Vanishing twin:
Spontaneous disappearance of an intrauterine gestational sac 
with or without heart beat in a pregnancy where one viable 
fetus remains as documented by ultrasound
Ectopic pregnancy:
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery
Concerning timing, a pregnancy loss occurring before ongoing pregnancy (i.e. during 1st trimester) 
will be defined as an early pregnancy loss, while a pregnancy loss occurring after ongoing 
pregnancy (i.e. during 2nd or 3rd trimester) during the post-trial follow-up will be defined as a late 
pregnancy loss.
8.3.7
Multiple Pregnancies
Multi-fetal gestations are not to be reported as adverse events. These data will be described as part 
of the secondary endpoints.


Follitropin Delta, FE 999049
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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious Adverse Events during the Trial
An event is defined a serious 
adverse event if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a subject 
enrolled in a trial is per se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe.
requires in-patient
hospitalisation or prolongation 
of existing hospitalisation
The term hospitalisation means that the subject was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation 
describes a period of at least 24 hours. Over-night stay for observation, stay 
at emergency room or treatment on an out-patient basis do not constitute a 
hospitalisation. However, medical judgement must always be exercised and 
when in doubt the case should be considered serious (i.e. if case fulfils the 
criterion for a medically important event). Hospitalisations for administrative 
or social purposes do not constitute a serious adverse event. Hospital 
admissions and/or surgical operations planned before trial inclusion are not 
considered adverse events, if the illness or disease existed before the subject 
was enrolled in the trial, provided that the condition did not deteriorate during 
the trial.
results in persistent or 
significant disability /
incapacity
Disability / incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgement by the investigator.
is an important medical event
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalisation 
but might jeopardise the patient or might require intervention to prevent one of 
the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse.
Serious Adverse Events during Post-trial Follow-up
The following untoward medical occurrences reported as part of the pregnancy outcome and 
neonatal health data collection will be recorded as serious adverse events. Data will be collected at 
birth and at 4 weeks after birth.

Death of mother in connection with pregnancy or labour

Death of neonate


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
Stillbirth (≥ gestational age 24 weeks + 0 days, calculated from the day of transfer + 17 
days34)

Neonate admitted to the NICU regardless of duration or NCU for more than 2 hours

Congenital anomaly / birth defect

Medically important event
In case of admission to NICU or NCU, the reason for admission must be reported as a serious 
adverse event, rather than just the act of hospitalisation. 
Congenital anomalies will be coded by Ferring using both MedDRA and ICD-10 and classified as 
minor or majorh in accordance with the EMA guideline1.
8.4.2
Collection, Recording and Reporting of Serious Adverse Events
Serious Adverse Event Reporting by the Investigator
All serious adverse events must be reported immediately to Ferring Global Pharmacovigilance as 
soon as it becomes known to the investigator and not later than within 24 hours of their knowledge 
of the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed Serious Adverse Event (SAE) Report 
Form with the fullest possible details within 3 calendar days of his/her knowledge of the serious 
adverse event.
Serious Adverse Event (SAE) Report Form
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Global Pharmacovigilance using the contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: safety.mailbox@ferring.com
Fax: 
Information to be Entered / Updated in the e-CRF
Completion of the Demographics, Adverse Event form, Medical History form and Concomitant 
Medication form are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Global Pharmacovigilance to access the information.
                                                                                                                                                
h
Major abnormalities: a life threatening structural anomaly or one likely to cause significant impairment of health or 
functional capacity and which needs medical or surgical treatment. 
Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems.


Follitropin Delta, FE 999049
Trial Code: 000145
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Additional information relevant to the serious adverse event such as hospital records, results from 
investigations, e.g. laboratory parameters (that are not already uploaded in the e-CRF), invasive 
procedures, scans and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 
Global Pharmacovigilance using the contact details in the section above. In any case this 
information must be supplied by the investigator upon request from Ferring. On any copies 
provided, such details such as subject’s name, address, and hospital ID number should be concealed 
and instead subject number should be provided.
The investigator will supply Ferring and the ethics committee with any additional requested 
information such as results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.
The expectedness is assessed by Ferring according to the current edition of the Investigator’s 
Brochure for FE 999049 and the Product Information for GONAL-F.4
Serious adverse events will be considered reportable regardless of whether or not the IMP was used 
in accordance with the provisions in the protocol, Investigator’s Brochure and labelling.
8.5
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow-up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. If the event is a chronic condition, the investigator and Ferring may agree that 
further follow-up is not required.
8.5.2
Collection of Serious Adverse Events with Onset after End-of-trial
If an investigator becomes aware of a serious adverse event after the end of the trial, and he/she 
assesses the serious adverse event to have a reasonable possible causality to the IMP (FE 999049 or 
GONAL-F) or a NIMP where Ferring is Marketing Authorisation Holder (i.e. GONAPEPTYL) the 
case will have to be reported to Ferring, regardless how long after the end of the trial this takes 
place.


Follitropin Delta, FE 999049
Trial Code: 000145
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8.5.3
Follow-up of Serious Adverse Events with Onset during the Post-Trial
For post-trial serious adverse events in neonates, where the neonate has not recovered at the 4-
weeks follow-up assessment, the investigator must follow up until SAE has resolved. If the SAE is 
a chronic condition or the medical condition of the neonate is stable, the investigator and Ferring 
may agree that further follow-up is not required.


Follitropin Delta, FE 999049
Trial Code: 000145
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9
STATISTICAL METHODS
The Ferring Global Biometrics Department will be responsible for the statistical analyses of the 
primary and secondary endpoints. This section details the planned statistical analyses for the 
primary endpoint and outlines the planned statistical analyses for the secondary endpoints. All 
analyses and further descriptions of the statistical methodology for the primary and secondary 
endpoints will be included in the Statistical Analysis Plan (SAP) available before the first subject is 
randomised. A separate SAP will be prepared to cover the post-trial information.
The Ferring Health Economics & Outcome Research department will perform a health economic 
analysis of FE 999049 in comparison with GONAL-F utilising relevant data recorded in this trial. 
The details of this analysis will be described in a separate health economic analysis plan.
9.1
Determination of Sample Size
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation. The non-inferiority limit for the difference between treatments (FE 999049 versus
GONAL-F) is -10.0% (absolute) for the primary endpoint.
The trial is designed to have 90% power of achieving the primary objective for the overall trial 
population and 80% power in the mainland Chinese population. The number of subjects needed to 
achieve 90% power depends on the assumptions regarding the ongoing pregnancy rate. The 
ongoing pregnancy rate is defined as the number of subjects with at least one intrauterine viable 
fetus 10-11 weeks after transfer divided by the number of randomised and exposed subjects. 
Considerations for Choice of Non-inferiority Margin
Assuming that the ongoing pregnancy rate is 32.2% in both treatment groups, then the total number 
of subjects needed to achieve 90% power is governed by the choice of non-inferiority margin. In 
order to establish non-inferiority, the two-sided 95% confidence interval must lie entirely above the 
chosen non-inferiority margin. Therefore, the power of the test is directly related to the width of the 
two-sided 95% confidence interval. The width of this confidence interval is inversely related to the 
square root of the sample size, i.e. a quadrupling of the sample size will lead to a halving of the 
width of the confidence interval. In fact, increasing the sample size with 500 subjects from 100 to 
600 reduces the width of the confidence band with 59%, while the impact of a similar increase in 
number of subjects from 1,000 to 1,500 only reduces the width of the confidence band with 18%.
The sample sizes for three different non-inferiority margins are shown in Table 9-1. As shown,
changing the non-inferiority margin from -12.0% to -10.0% requires 280 additional subjects, while 
tightening the margin with an additional 2.0% requires 516 additional subjects. To further illustrate 
the difference between these three non-inferiority margins, the width of the two-sided 95% 
confidence intervals and the precision quantified as ±1 standard error are also included in 
Table 9-1. As can be seen, increasing the sample size from 918 to 1,434 subjects reduces the 
standard error with 0.6 percentage points (from 3.1% to 2.5%).


Follitropin Delta, FE 999049
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The relation between the choice of non-inferiority margin and the maximum allowed difference in 
ongoing pregnancy rates leading to non-inferiority can also be derived. Assuming the observed rate 
for the GONAL-F group is 32.2% the minimum observed rate in the FE 999049 group that still 
leads to non-inferiority is shown in Table 9-1. For example, if the non-inferiority margin is -10.0% 
and the observed ongoing pregnancy rate in the GONAL-F group is 32.2%, then non-inferiority 
will only be established if the observed ongoing pregnancy rate in the FE 999049 group is at least 
28.2%, i.e. the observed ongoing pregnancy rates must not differ with more than 4.0 percentage 
points. Tightening the margin to -8.0%, (i.e. adding 516 subjects) will require a minimum ongoing 
pregnancy rate of 29.0% in the FE 999049 in order to claim non-inferiority, i.e. a maximum 
difference of 3.2 percentage points. Hence, increasing the sample size from 918 to 1,436 subjects 
reduces the maximum allowable observed difference between treatments by 0.8 percentage points 
(from 4.0% to 3.2%).
Taking the above into account a non-inferiority margin of -10.0% (absolute) seems appropriate 
since further tightening of the non-inferiority margin will lead to an increase in sample size with 
only limited impact on the precision of the estimate and the maximum difference in observed rates 
leading to non-inferiority.
Table 9-1
Implications of Choice on Non-inferiority Margin on Sample Size, Precision and 
Difference in Observed Rates
Non-inferiority margin (absolute)
-12.0%
-10.0%
-8.0%
Subjects needed to achieve 90% power in the PP population*
638
918
1434
Expected width of two-sided 95% confidence interval
14.5%
12.1%
9.7%
Expected precision of estimate (± 1 standard error)
± 3.7%
± 3.1%
± 2.5%
Minimum ongoing pregnancy rate with FE 999049 needed to 
claim non-inferiority if the observed rate with GONAL-F is 32.2%
27.3%
28.2%
29.0%
Maximum difference that can be observed (GONAL-F minus 
FE 999049) leading to non-inferiority if the observed rate with 
GONAL-F is 32.2%
4.9%
4.0%
3.2%
* Assuming 8% major protocol deviations
Considerations for Sample Size
Table 9-2 summarises the required sample size to obtain 80% and 90% power for various rates 
(assumed equal in the two treatment groups) and assuming a non-inferiority margin of -10.0% 
(absolute).
Since this is a non-inferiority trial, the full analysis set (FAS) and the per-protocol (PP) analyses are 
equally important, i.e. non-inferiority should be established for both analysis sets in order to have a 
robust conclusion36,37. Therefore, the expected proportion of subjects with major protocol deviations 
should be taken into account when setting the total sample size for the trial. The proportion of 
subjects with major protocol deviations is assumed to be at most 8%.


Follitropin Delta, FE 999049
Trial Code: 000145
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Table 9-2
Sample Size by Ongoing Pregnancy Rate for the PP Analysis Set
Ongoing pregnancy rate
(Assumed equal in the two 
treatment groups)
Assuming 80% power and -10.0% 
(absolute) non-inferiority margin
Assuming 90% power and -10.0% 
(absolute) non-inferiority margin
Number of subjects
Number of subjects
Per group
Total
Per group
Total
PP*
PP*
PP*
PP*
25%
295
590
395
790
30%
330
660
442
884
32.2%
343
686
459
918
35%
358
716
479
958
40%
377
754
505
1010
45%
389
778
521
1042
50%
393
786
526
1052
* Assuming 8% major protocol deviations
Based on an assumed ongoing pregnancy rate of 32.2 % observed in the PP population of the 
ESTHER 1 trial, N=918 subjects are required in the PP population to obtain a power of 90%. 
Anticipating at most 8% major protocol deviations this results in N=1000 subjects to be 
randomised. The power is reasonably robust against deviations from the ongoing pregnancy rate 
assumption of 32.2%: a 35% ongoing pregnancy rate would still result in a 88.9% power, while 
lower rates will only increase the power (e.g. 30% yields 91.1% power). Recruiting at least 
740 subjects in mainland China is expected to secure that consistency can be established between 
the results from the overall trial population and the mainland Chinese trial population. In addition, 
to obtain approval in other Asian countries and regions at least 260 subjects are needed. Thus a total 
sample size of 1,000 subjects will be recruited for this trial.
A sample size re-assessment is planned and will be done without breaking the blind and without 
inflating the type 1 error of the trial, in line with the current regulatory guidelines (see section 9.10). 
The expected maximum number of subjects to be randomised would then be approximately 1,144
(572 per treatment group), corresponding to an observed rate of 50%. 
9.2
Subject Disposition
All screened subjects will be accounted for. 
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening 
failures.
Subject disposition with respect to analysis sets will be tabulated by treatment group overall, by age 
stratum and country for all randomised subjects. This table will include the number of completed 
and discontinued subjects including reason for discontinuation. Screening failures and their primary 
reason for screening failure will also be included. Screening failures will not otherwise be 
accounted for. 
A separate table will summarise the subject disposition with respect to analysis sets by trial site 
overall and by age stratum. 


Follitropin Delta, FE 999049
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Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately.
9.3
Protocol Deviations
Major protocol deviations, such as significant non-compliance or other serious unforeseen
deviations deemed to invalidate the data and affect the conclusions of the trial, will lead to
exclusion of data from the PP analysis set. Data will not be excluded from the PP analysis set in
case of minor protocol deviations. The list of major protocol deviations include, but is not restricted 
to:

Unblinding of assessor

Treatment not in accordance with randomisation

Non-compliance with IMP for two or more days

Administration of hCG for triggering of final follicular maturation was not given despite the
triggering criterion for hCG administration was met

GnRH agonist criterion met but hCG used for triggering of final follicular maturation

GnRH agonist criterion not met but GnRH agonist used for triggering of final follicular 
maturation

Non-compliance with the number of embryos transferred
The rating of protocol deviations in ‘minor’ and ‘major’ will be decided by the Ferring clinical
team on the basis of a blinded review of data before declaration of clean file and lock of database. If 
the blinded review identifies serious unforeseen deviations deemed to impact the primary endpoint 
and affect the conclusions of the trial these will also be rated as major deviations. 
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be tabulated and listed by subject for the 
FAS analysis set.
9.4
Analysis Sets
Intention-to-Treat (ITT) Analysis Set
The intention-to-treat (ITT) analysis set is defined as all randomised subjects. Subjects will be 
analysed according to randomised treatment.
Full Analysis Set (FAS)
The FAS is defined as all randomised and exposed subjects. Subjects will be analysed according to 
randomised treatment.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Per-Protocol (PP) Analysis Set
The PP analysis set is defined as all randomised and exposed subjects except those excluded as a 
result of major protocol deviations as described in section 9.3. 
Safety Analysis Set
The safety analysis set is defined as all randomised and exposed subjects. Subjects will be analysed 
according to actual treatment received. 
9.5
Trial Population
9.5.1
General Considerations
All relevant baseline data will be summarised in tables including both treatment groups and a total 
column. The purpose of these tabulations is to characterise the treatment groups and assess the 
degree of similarity achieved by the randomisation. Baseline data will not be compared using 
statistical tests. Unless otherwise noted, tabulations will be produced overall and by age stratum for 
both the FAS and the PP analysis set. Continuous variables will be presented with number of 
subjects, mean, standard deviation, median, inter-quartile range, minimum, and maximum. 
Categorical variables will be presented with number and percentage of subjects within each specific 
category. 
Listings will be produced for the FAS. 
Unless otherwise noted, missing data will not be imputed.
9.5.2
Trial Population Parameters
Demographics and other Baseline Characteristics
Demographics and other baseline characteristics (smoking and alcohol habits, body measurements, 
ultrasound parameters, vital signs, and endocrine parameters) obtained before first exposure to IMP 
will be listed by subject and tabulated.
Medical History
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarised for each medical item. This summary 
table will be produced overall (i.e. not by age stratum) for the FAS.
Infertility History, Menstrual History and Reproductive History
Infertility history, menstrual history and reproductive history will be listed by subject and presented 
in summary tables.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Physical Examination and Gynaecological Examination
Physical examination and gynaecological examination performed during screening will be 
summarised per category. These tables will be produced overall (i.e. not by age stratum) for the 
FAS.
Concomitant Medication
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference List. Prior and concomitant medication will be summarised by ATC classification 1st
level (alphabetically) and ATC classification 2nd level (in decreasing order of frequency). These 
medications will be tabulated separately for:

Prior medication, i.e. medication taken exclusively prior to treatment (i.e. with stop 
date/time before date/time of 1st IMP administration)  

Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date/time of 1st IMP administration and not started after the end-
of-trial visit)
These tables will be produced overall (i.e. not by age stratum) for the FAS.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
Concomitant medications will be listed by subject.
9.6
Treatment Compliance
Treatment non-compliance will be presented in listings as non-compliance is expected to be 
limited.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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9.7
Endpoint Assessments
9.7.1
General Considerations
Primary and Secondary Endpoints
The results of the analyses of the primary endpoint (ongoing pregnancy rate) based on the overall 
trial population are essential for the non-inferiority claim. The results obtained for the mainland 
Chinese trial population is considered supportive of the overall conclusion. If the results for the 
mainland Chinese trial population are markedly different from those obtained based on the overall 
trial population the reasons for this difference will be examined. The secondary endpoints positive 
βhCG rate, clinical pregnancy rate, vital pregnancy rate, implantation rate and ongoing implantation 
rate are considered supportive of the primary endpoint. However, non-inferiority does not need to 
be established for these secondary endpoints.
The remainder of the secondary endpoints are intended to provide additional characterisation of the 
treatments. 
Analysis and Presentation of Primary and Secondary Endpoints
Summary tables and treatment comparisons for the primary endpoint and supportive secondary 
endpoints will be presented overall, by age stratum and country for both the FAS and PP analysis 
sets. Treatment comparisons will be produced for the overall trial population and for the mainland 
Chinese population. As applicable for the remaining secondary endpoints, summary tables and 
treatment comparisons may be presented overall and by age stratum for the FAS and PP analysis 
sets. 
All tabulations will present the treatment groups and include a total column. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category. 
All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of ‘equal effect’ against the alternative of 
‘different effect’.
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will 
be listed for the FAS.
Multiplicity 
No adjustments for multiplicity are required since there is only one primary endpoint and non-
inferiority has to be established for both the FAS and the PP analysis sets. In addition, the testing 
for superiority will be made in a sequential manner, only if non-inferiority is established. The 
evaluation of the subjects recruited in mainland China will be regarded as supportive. Concerning 
the secondary endpoints no formal adjustment for multiplicity will be utilised. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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Missing Data
Missing observations for the primary endpoint ongoing pregnancy rate will be imputed as 
‘negative’ irrespective of the reason why data are not recorded.
Missing observations for the supportive secondary endpoints positive βhCG rate, clinical pregnancy 
rate and vital pregnancy rate will be imputed as ‘negative’ unless a positive result is observed at a 
later pregnancy assessment. For example, if the outcome of βhCG is missing but clinical pregnancy 
is positive then βhCG will be imputed as ‘positive’.
For subjects with transfer but missing information on the number of viable fetuses 10-11 weeks 
after transfer, the number of viable fetuses will be imputed as zero irrespective of why data are not 
recorded. For subjects with transfer but missing information on the number of gestational sacs 
5-6 weeks after transfer, the number of gestational sacs will be imputed as the number of viable 
fetuses at 10-11 weeks after transfer.
For adverse events, missing values will be treated as missing, except for causality, intensity and
seriousness of adverse events, where a worst-case approach will be used.
Missing values will not be imputed for any of the other secondary endpoints.
9.7.2
Primary Endpoint
This trial has one primary endpoint: Ongoing pregnancy rate. The primary objective of this trial is 
to demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to the primary 
endpoint in women undergoing controlled ovarian stimulation. The non-inferiority limit for the 
difference between treatments (FE 999049 versus GONAL-F) is -10.0% (absolute).
The non-inferiority hypothesis to be tested for the primary endpoint is
H0: FE - GF -10.0% against the alternative HA: FE - GF > -10.0%,
where FE and GF denote the ongoing pregnancy rate after treatment with FE 999049 and 
GONAL-F, respectively. Non-inferiority will be evaluated based on the overall trial population.
The primary analyses will be adjusted for the stratification factor (age group) by using the Mantel-
Haenszel method to combine results across age groups. In brief, this corresponds to deriving a 
weighted average across age groups where the weight depends on the number of observations in 
each treatment group in each age stratum.
For the primary endpoint the null hypothesis (H0) will be tested against the alternative (HA) by 
constructing a two-sided 95% confidence interval for the difference in ongoing pregnancy rates. If 
the lower-limit of the two-sided 95% confidence interval is greater than the non-inferiority limit 
(-10.0%) for both the FAS and the PP analysis set, the null hypothesis will be rejected. In that case 
it will be claimed that FE 999049 is non-inferior to GONAL-F with respect to ongoing pregnancy 
rate in women undergoing controlled ovarian stimulation.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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If the lower-limit of the two-sided 95% confidence interval for the treatment difference based on 
the FAS not only lies above the non-inferiority limit (-10.0%) but also above zero then there is 
evidence of superiority in terms of statistical significance at the 5% level. In this case, the p-value 
from the test for superiority will be reported and it will be claimed that FE 999049 is superior to 
GONAL-F for the primary endpoint analysed. The result based on the PP analysis set is not 
essential for the superiority claim but should lead to a comparable result for a robust interpretation. 
There is no need for a multiplicity adjustment when switching from non-inferiority to superiority 
since it is a simple sequential test procedure. This interpretation is in line with the Food and Drug 
Administration (FDA) draft guidance on “Non-inferiority Clinical Trials”36 and EMA’s “Points to 
consider on switching between superiority and non-inferiority”38.
Due to the large sample size the two-sided 95% confidence intervals will be established based on 
the asymptotic normal distribution as follows


2
2
2
)
(
96
.1





i
i
i
i
i
i
w
RD
SE
w
w
RD
w
,
where all sums are over the three strata (i.e. i = 1 to 3) and
i
GF
i
FE
i
RD
,
,
ˆ
ˆ




is the observed difference in rates within age stratum i
i
GF
i
GF
i
GF
i
FE
i
FE
i
FE
i
n
n
RD
SE
,
,
,
,
,
,
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
(








is the standard error of the observed 
difference in rates within age stratum i
i
GF
i
FE
i
GF
i
FE
i
n
n
n
n
w
,
,
,
,


is the weight assigned to age stratum i
i
FE
,
ˆ
is the observed rate in age stratum i in the FE 999049 group
i
GF
,
ˆ
is the observed rate in age stratum i in the GONAL-F group
i
FE
n
, is the number of observations in the FE 999049 group in age stratum i
i
GF
n
, is the number of observations in the GONAL-F group in age stratum i
A supportive evaluation of the subjects recruited in mainland China will be conducted, and it is 
expected that the findings among the mainland Chinese trial population will be consistent with the 
overall findings in the trial. If the results based on the mainland Chinese trial population are 
markedly different from those obtained based on the overall trial population the implications for the 
overall conclusion of the trial will be evaluated.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Additional Analyses, including Sensitivity Analysis
The primary analyses described above will be repeated restricted to subjects with oocytes retrieved 
and to subjects with embryo(s) transferred. Since the trial is not powered to establish non-inferiority 
for these subgroups, the outcomes of these analyses are considered supportive of the primary 
analysis.
Besides stratification by age group the randomisation is also stratified by trial site. However, as 
detailed above, the primary analysis will be based on all data pooled across sites assuming 
homogeneity of the risk differences across sites. This assumption will be tested using the approach 
described by Lipsitz et al. (1998).39 If there is statistically significant heterogeneity across sites the 
implications for the interpretation of the primary result will be discussed.
To evaluate the robustness of the conclusions, the following factors potentially impacting ongoing 
pregnancy will be evaluated one by one:

Insemination method

Primary reason for infertility

Primary infertility

Smoking status
For each factor, subjects will be grouped according to the levels of the factor and the primary 
analysis will be repeated using this grouping. The outcomes of these analyses are considered 
supportive and should lead to similar results as the primary analysis to ensure robustness of the 
conclusion.
As described in Section 6.5.1, transfer of one or two embryo(s) is to be performed on day 3 after 
oocyte retrieval. The decision to transfer either one or two embryo(s) is based on the subject’s age 
and the quality and availability of embryo(s) on the day of transfer. Since this decision is based on 
observations performed after randomisation it can be affected by the treatment allocation. It is 
therefore not planned to perform a formal statistical analysis of the ongoing pregnancy rate
adjusting for number of embryos transferred. The rationale for not including these adjustments in 
the primary analysis is that such an adjustment may hide or exaggerate the differences between 
treatments.40 Instead the ongoing pregnancy rate will be presented by number of embryos
transferred. Further, a frequency table will be produced to compare the treatment groups with 
respect to number of embryos transferred.
9.7.3
Secondary Endpoints
For each secondary endpoint the analysis based on the FAS will be used to assess the statistical 
significance of differences between treatments. The analysis based on the PP analysis set will be 
considered supportive and should lead to a similar but not necessarily statistically significant result 
in order to have a robust interpretation.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Supersedes: Ver. 2.0
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Positive βhCG Rate
The positive βhCG rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner.
Clinical Pregnancy Rate
The clinical pregnancy rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner. For subjects with clinical pregnancy, the type of clinical pregnancy 
(intrauterine or ectopic) will be tabulated.
Vital Pregnancy Rate
The vital pregnancy rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner. For subjects with a vital pregnancy, the number of intrauterine 
gestational sacs with fetal heart beat and the number of fetuses with fetal heart beat will be 
tabulated.
Implantation Rate
For implantation rate, the experimental unit will be the transferred embryos, i.e. the analysis will 
compare the proportions of embryos transferred that results in gestational sacs 5-6 weeks after 
transfer.
Ongoing Implantation Rate
For ongoing implantation rate, the experimental unit will be the transferred embryos, i.e. the 
analysis will compare the proportions of embryos transferred that results in intrauterine viable 
fetuses 10-11 weeks after transfer.
Extreme Ovarian Response
The analyses of extreme ovarian response will be performed using the following definitions of 
extreme ovarian response: <4 oocytes retrieved, ≥15 oocytes retrieved, ≥20 oocytes retrieved, <4 or 
≥15 oocytes retrieved and <4 or ≥20 oocytes retrieved. Subjects with cycle cancellation due to poor 
ovarian response will be included as <4 oocytes retrieved. Subjects with cycle cancellation due to 
excessive ovarian response will be included as ≥15 and ≥20 oocytes retrieved.
For each definition the proportion of subjects with extreme ovarian response will be tabulated. 
Treatment groups will be compared using a logistic regression model with treatment and age group 
as factors. The possibility of an interaction will be tested. The difference between treatments will be 
reported as an odds ratio including 95% confidence interval and p-value for test of no treatment 
difference. If the expected number of observations is less than five in any of the cells in the 
contingency table then Fisher’s exact test within strata will be used as alternative.


Follitropin Delta, FE 999049
Trial Code: 000145
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Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions 
for Early OHSS
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). Early OHSS is defined as OHSS with onset ≤9 days after triggering of final 
follicular maturation. Note that this includes OHSS with onset before triggering and OHSS with 
onset during stimulation where triggering is not performed.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
extreme ovarian response. The analysis will be performed for the proportion of subjects with early 
OHSS, the proportion of subjects with early OHSS of moderate or severe grade, the proportion of 
subjects with preventive interventions for early OHSS, the proportion of subjects with early OHSS 
and/or preventive interventions for early OHSS, and the proportion of subjects with early OHSS of 
moderate or severe grade and/or preventive interventions for early OHSS.
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo Transfer 
Cancellation due to Excessive Ovarian Response / OHSS Risk
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
extreme ovarian response. The analysis will be performed for the following: the proportion of 
subjects with cycle cancellation due to poor ovarian response, the proportion of subjects with cycle 
cancellation due to excessive ovarian response, the proportion of subjects with cycle cancellation 
due to poor or excessive ovarian response, the proportion of subjects with embryo transfer 
cancellation due to excessive ovarian response / OHSS risk.
Number and Size of Follicles during Stimulation 
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised by treatment on 
the follicle level (number of follicles 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and ≥17 mm) and 
on the subject level (total number of follicles, size of largest follicle, average follicle size, average 
size of three largest follicles, and number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and 
≥17 mm). Continuous data will be compared between treatment groups using the van Elteren test 
stratified for age-group. Ordinal data will be compared using the Cochran-Mantel-Haenszel test for 
ordinal data stratified for age-group. Within strata comparisons will be based on Wilcoxon’s test.
Number and Size Distribution of Oocytes Retrieved
The number of oocytes retrieved will be tabulated including both summary statistics and a 
frequency table with subjects grouped according to number of oocytes retrieved [<4 (low response), 
4-7 (moderate response), 8-14 (targeted response), 15-19 (hyperresponse) and ≥20 (severe 
hyperresponse)]. Subjects with cycle cancellation due to poor ovarian response will be included in 
the <4 oocytes group. Subjects with cycle cancellation due to excessive ovarian response will be 
included in the ≥20 oocytes group. Continuous data will be compared between treatment groups 
using the van Elteren test stratified for age-group. Ordinal data will be compared using the 
Cochran-Mantel-Haenszel test for ordinal data stratified for age-group. Within strata comparisons 
will be based on Wilcoxon’s test.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Metaphase II Oocytes
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The 
percentage of MII oocytes to oocytes retrieved for subjects where all oocytes are inseminated using 
ICSI will be tabulated. Further, the number of MII oocytes per subject will be tabulated including 
both summary statistics and a frequency table. Continuous data will be compared between 
treatment groups using the van Elteren test stratified for age-group. Ordinal data will be compared 
using the Cochran-Mantel-Haenszel test for ordinal data stratified for age-group. Within strata 
comparisons will be based on Wilcoxon’s test.
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei on day 1 after oocyte retrieval. For
subjects with oocytes retrieved, the rate of fertilised oocytes to oocytes retrieved (and also the rate 
of fertilised oocytes to metaphase II oocytes for those inseminated using ICSI) will be tabulated. 
Further, the number of fertilised oocytes per subject will be tabulated including both summary 
statistics and a frequency table. Continuous data will be compared between treatment groups using
the van Elteren test stratified for age-group. Ordinal data will be compared using the Cochran-
Mantel-Haenszel test for ordinal data stratified for age-group. Within strata comparisons will be 
based on Wilcoxon’s test.
Number and Quality of Embryos on Day 3
The number of embryos on day 3 including a breakdown by selected quality parameters will be 
tabulated including both summary statistics and frequency tables. Further, for subjects with oocytes 
retrieved, the rate of embryos to oocytes retrieved will be summarised overall and by selected 
quality parameters. Continuous data will be compared between treatment groups using the van 
Elteren test stratified for age-group. Ordinal data will be compared using the Cochran-Mantel-
Haenszel test for ordinal data stratified for age-group. Within strata comparisons will be based on 
Wilcoxon’s test.
Circulating Levels of Endocrine Parameters
Blood samples drawn at stimulation days 1 and 6 and end-of-stimulation are analysed for FSH, LH, 
estradiol, progesterone, inhibin A and inhibin B. Furthermore, blood samples drawn at the oocyte 
retrieval visit are also analysed for FSH. Values below the lower limit of quantification (LLOQ) 
will be included as LLOQ/2. Values above the upper limit of quantification (ULOQ) will be 
included as ULOQ. 


Follitropin Delta, FE 999049
Trial Code: 000145
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Each endocrine parameter and the change from baseline for post-baseline measurements will be 
tabulated for stimulation day 1 (baseline), stimulation day 6 and end-of-stimulation (and also the 
oocyte retrieval visit for FSH). For each parameter the change from baseline will be compared 
between treatment groups using an analysis of covariance model (ANCOVA). The ANCOVA will 
be fitted to the relative change from baseline in log-transformed measurements with treatment and 
age strata as fixed factors and the log-transformed baseline measurement as covariate. The 
estimated treatment difference with 95% confidence interval will be presented on the scale of 
measurement (i.e. back-transformed using base e) and accompanied by the p-value for test of no 
treatment difference.
FSH Population Pharmacokinetics
A population pharmacokinetic model describing FSH concentrations following repeated dosing of 
FE 999049 will be prepared under the responsibility of the Ferring Experimental Medicine 
Department.
The results will be reported separately. 
Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose and the number of stimulation days will be tabulated and compared 
between treatment groups. These endpoints will be compared between treatments using Wilcoxon’s 
test.
Gonadotropin Dose Adjustments
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. The requested dose change (decrease / increase / no change) on stimulation 
day 6 will be tabulated. Further, the number of dose increase requests and number of dose decrease 
requests per subject will be tabulated. Treatment groups will be compared using chi-square tests.
Adverse Events
Adverse Events – General 
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events are grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before start of IMP, or a pre-existing medical condition that worsens in intensity after 
signed informed consent but before start of IMP.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of IMP and 
before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of IMP and before the end-of-trial visit.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
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Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only.
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: all adverse events, severe adverse events, 
adverse reactions, adverse events leading to discontinuation, serious adverse events and deaths. An 
adverse reaction is an adverse event judged by the investigator to be related to IMP with a 
reasonable possibility.
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported.
Summary tables will be produced for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate / severe), adverse reactions by intensity (mild / moderate / severe), 
serious adverse events, adverse events leading to discontinuation, adverse events with an incidence 
of ≥5% in any treatment group, and non-serious adverse events with an incidence of ≥5% in any 
treatment group.
Clinical Chemistry and Haematology Parameters
Safety laboratory variables will be grouped under “Haematology” and “Clinical Chemistry”.
The baseline is based on the blood sample drawn at stimulation day 1. Treatment-emergent 
laboratory data will be obtained at end-of-stimulation and end-of-trial.
The circulating levels of clinical chemistry and haematology parameters including change from 
baseline will be tabulated for each time-point for each laboratory variable. 
Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-trial 
values, using a categorisation of low, normal and high values at each visit. Low, normal and high 
will be defined according to the reference ranges provided by the central laboratory.
For each laboratory variable, a summary table will be prepared displaying the proportion of 
subjects who have at least one markedly abnormal value. The table will also include a break-down 
by classification of the baseline value. Markedly abnormal criteria for the safety laboratory 
variables will be specified in the SAP.
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged.
Injection Site Reactions
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
and number of subjects experiencing those events will be tabulated by time (immediately, 
30 minutes, 24 hours), reaction and intensity (none, mild, moderate and severe).


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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E-Study Protocol-21768;Ver. 3.0 Mainland China
Clinical Trial Protocol 
Supersedes: Ver. 2.0
Country Specific - Mainland China
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Treatment-Induced Anti-FSH Antibodies
The proportion of subjects with treatment-induced anti-FSH antibodies as well as the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralising capacity will be tabulated. 
Furthermore, all assessments of anti-FSH antibodies will be listed for subjects with a positive 
results in assay 1). 
Immune-related Adverse Events
Potential immune-related adverse events will be tabulated using the SMQs, PTs and HLTs 
mentioned in section 7.2.22.
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse Events, or 
due to Technical Malfunctions of the Administration Pen
A summary table will be prepared showing the proportion of subjects with cycle cancellations 
including reason for cancellation.
Late OHSS (Including OHSS of Moderate/Severe Grade)
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days after triggering of final 
follicular maturation.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS. The analysis will be performed for the proportion of subjects with late OHSS and the 
proportion of subjects with late OHSS of moderate or severe grade.
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy and 
Vanishing Twins
Frequency tables will be prepared for these endpoints.
Pen Malfunction
The frequency of technical malfunctions of the administration pen will be tabulated.
9.8
Additional Safety Evaluations
Physical Examination
Physical examination at end-of-trial compared to baseline will be summarised in shift tables and all 
subjects with any abnormal finding will be listed per subject. The list will include both baseline and 
end-of-trial assessment for comparison.


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Gynaecological Examination
Gynaecological examination at end-of-trial compared to baseline will be summarised in shift tables 
and all subjects with any abnormal finding will be listed by subject. The list will include both 
baseline and end-of-trial assessment for comparison.
Changes in Body Weight 
Body weight will be measured at screening, on stimulation day 1 (baseline) and at end-of-trial. The 
actual measurements and the change from baseline will be tabulated.
Vital Signs
Vital signs and their change from stimulation day 1 (baseline) to end-of-trial will be summarised. 
Shift tables will be prepared to compare the baseline values with the end-of-trial values using the 
categorisation of low, normal and high values. Low, normal and high values will be specified in the 
SAP. All vital signs values will be listed per subject. Values outside the reference range will be 
flagged.
9.9
Post-trial Activities
A separate SAP will be prepared to cover the post-trial information.
The number and percentage of subjects with live birth will be presented by treatment group. 
Subjects with no information on live birth will be defaulted to a negative response.
Neonatal health, including minor/major congenital anomalies, at birth and at 4 weeks after birth 
will be presented by treatment group.
9.10
Interim Analyses and Administrative Review
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned.
A blinded sample size reassessment will take place when data on the primary endpoint are available 
for 70% of the planned subjects or when 800 subjects are randomised, whichever comes first. The 
sample size reassessment will be done without breaking the blind and without inflating the type I 
error of the trial, in line with the current regulatory guidelines for non-inferiority trials by FDA36
and in general by EMA.37
A restricted recalculation rule for the sample size reassessment will be used. Accordingly 1,000 
subjects should be randomised to achieve sufficient power if the ongoing pregnancy rate is 32.2%. 
If the ongoing pregnancy rate is above the expected 32.2%, the sample size can be adjusted up to a 
maximum of 1,144 (572 per treatment group), corresponding to an ongoing pregnancy rate of 50%. 
If the rate is below the expected 32.2% the sample size will not be decreased below the planned 
1,000 subjects.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data - ICH Definition
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial).
Trial-specific Source Data Requirements - Ferring
Source documents need to be preserved for the maximum period of time permitted by local 
requirements. For each subject enrolled, the investigator will indicate in the source documents that 
the subject participates in this trial, and will record at least the following information, if applicable: 

Existence of subject (initials, date of birth) 

Confirmation of participation in trial (trial ID, subject ID)

Informed consent(s) (date and time of oral information, date and time of handing out 
Informed Consent Documents, date and time of obtaining written informed consent(s))

Eligibility for participation in the trial (documenting all inclusion / exclusion criteria)

Relevant medical history, infertility history, menstrual history and reproductive history

Body weight measurements

Visit dates

Any assessment performed, i.e. vital signs, physical examination, TVU, etc.

Dates of administration of IMP 

Dates and daily doses of NIMP

Dates and daily doses of concomitant medication 

Date of oocyte retrieval and number of oocytes retrieved

Date of transfer and number and quality of embryos transferred

Results of βhCG test and ultrasound at clinical and ongoing pregnancy visits


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
Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth and 
4 weeks after birth

Local tolerability reactions after IMP administration – diary 

Adverse events (description as well as start/stop date and time)

OHSS symptoms, preventive interventions, investigations and treatments

Reason for discontinuation

Event of unblinding, including the reason for unblinding
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record.
If the trial sites use electronic subject record systems, the sponsor will decide if the electronic 
subject records qualify for the trial and document the decision. If the electronic subject records 
system does not qualify for the trial, it may be considered to utilise certified printouts of the data in 
the electronic subject records system for source data as an exception.
The source data for the endocrine parameters, clinical chemistry and haematology parameters will 
be available at the central laboratory. Laboratory reports will be available at the sites.
10.2
e-CRF
An e-CRF system provided by an independent third-party contract research organisation, Target 
Health Inc., will be used for data capture. The system is validated and access at all levels to the 
system is granted / revoked following sponsor and vendor procedures, in accordance with 
regulatory requirements and system requirements.
Data should be entered into the system within a reasonable time after the subject has attended a 
visit or after the data become available, as applicable.
The investigator will approve / authorise the e-CRF entries for each subject, with the exception of 
the treatment allocation module which is un-accessible to the investigator to maintain the assessor-
blinding, with an electronic signature which is equivalent to a handwritten signature.
The e-CRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and locked, a final copy of the database will be stored at Ferring. The investigator 
will also receive a copy of the trial site’s final and locked data (including audit trail, electronic 
signature and queries) as write-protected pdf-files produced by Target Health Inc. The pdf-files will 
be stored in an electronic format and will be provided to the investigator before access to the e-CRF 
is revoked. 
Errors occurring in the e-CRF will be corrected electronically. Such corrections / modifications will 
be automatically tracked by an audit trail detailing the date and time of the correction and the name 
of the person making the correction.


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10.3
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
department, Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection, cleaning and validation.
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions. The investigator will permit the 
monitor direct access to all source data, including electronic medical records, and/or documents in 
order to facilitate data verification. The investigator will co-operate with the monitor to ensure that 
any discrepancies that may be identified are resolved. The investigator is expected to be able to 
meet the monitor during these visits. When the first subject is randomised at the trial site a 
monitoring visit will take place shortly afterwards. For this trial, the frequency of the monitoring 
visits is intended to be approximately every second week (it can be adjusted depending on 
recruitment rate).
11.2
Audit and Inspection
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic / foreign regulatory inspectors or 
representatives from ethics committees who may audit / inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki41 and all other relevant regulations.
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorised Ferring representatives and representatives from regulatory authorities and ethics 
committees may wish to inspect their medical records. During audits / inspections the auditors / 
inspectors may copy relevant parts of the medical records. No personal identification apart from the 
screening / randomisation number will appear on these copies.
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or ethics committees.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
e-CRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Documents, will be maintained by the investigator in strict 
confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving ethics committees and regulatory authorities, in 
accordance with local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial 
subjects may be implemented prior to ethics committee approval or favourable opinion.
12.2
Deviations from the Protocol
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
monitor, and the implications of the deviation must be reviewed and discussed. Any deviation must 
be documented in the e-CRF. A log of protocol deviation reports will be available in the e-CRF. 
Protocol deviation reports and supporting documentation must be kept in the Investigator’s File and 
filed in the Trial Master File at the end of the trial.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and ethics committees will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator. 
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial.
Authorship is granted based on the criteria established by the International Committee of Medical 
Journal Editors (ICMJE).42 The total number of authors is based on the guideline from the relevant 
journal or congress. In the event of any disagreement in the content of a publication, both the 
investigator’s and Ferring’s opinion will be fairly and sufficiently represented in the publication.
Any external contract research organisation or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial.
If the investigator wishes to independently publish / present any results from the trial, the draft 
manuscript / presentation must be submitted in writing to Ferring for comment prior to submission. 
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published. Under such conditions the publication will be modified or delayed at the investigator’s 
discretion, to allow sufficient time for Ferring to seek patent protection of the invention.


Follitropin Delta, FE 999049
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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate registry, i.e. 
www.ClinicalTrials.gov a website maintained by the National Library of Medicine (NLM) at the 
U.S. National Institutes of Health (NIH). Trial registration may occur in other registries in 
accordance with local regulatory requirements. A summary of the trial results is made publicly 
available in accordance with applicable regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Ethics Committee
An ethics committee will review the protocol, any potential protocol amendments and potential 
advertisements used for recruitment. The ethics committee will review the Subject Information 
Sheet and the Informed Consent Form, their updates (if any), and any written materials given to the 
subjects. All ethics committee approvals relevant for the clinic must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. A list of all ethics 
committees to which the protocol has been submitted and the name of the chairmen will be 
included in the Clinical Trial Report.
14.2
Regulatory Authorities Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All national regulatory approvals must be available in the relevant country 
before a subject is exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-trial and End-of-trial Notification
The end of main trial is defined as LPLV and the end of post-trial follow-up is defined as the last 
assessment performed in the pregnancy follow-up period.
End-of-trial notification will be reported according to local regulations.
In the case of early termination, Ferring must notify the end of the trial to the national regulatory
authorities and the concerned ethics committees immediately and at the latest within 15 days after 
the trial is halted, clearly explaining the reasons, and describe follow-up measures, if any, taken for 
safety reasons. 
Upon completion of the trial Ferring shall send the results of the clinical trial to the national 
regulatory authorities and the concerned ethics committees, according to local regulation.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements.


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14.5
Subject Information and Consent
Informed Consent Documents regarding Participation in the Trial – Subject 
The investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects of 
the trial which are relevant to the subject’s decision to participate. The trial subject must be given 
ample time to consider participation in the trial, before the consent is obtained. The Informed 
Consent Documents (consisting of the Subject Information and the Informed Consent Form) must 
be signed and dated by the subject and the investigator who has provided information to the subject 
regarding the trial before the subject is exposed to any trial-related procedure, including screening 
tests for eligibility.
The investigator will explain that the subject is completely free to refuse to enter the trial or to 
withdraw from it at any time, without any consequences for her further care and without the need to 
justify her decision.
The subject will receive a copy of the Informed Consent Documents.
If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new Subject Information and Informed Consent Form will be 
forwarded to the ethics committee(s) (and regulatory authorities, if required). The trial subjects will 
be informed about this new information and re-consent will be obtained.
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by 
Ferring, ethics committee representatives or regulatory authority inspector(s), in accordance with 
applicable regulatory requirements, may review her source records and data. Data protection will be 
handled in compliance with national / local regulations.
Informed Consent Documents regarding Data Collection on the Neonate – Parental
For countries where a separate information and informed consent form is required to collect 
pregnancy outcome data on the neonate, the investigator will obtain a freely given written consent 
from the child-custody holders, i.e. the subject and the subject’s partner in case of joint custody. 
The child-custody holders must be given ample time before the consent is obtained. The Informed 
Consent Documents must be signed and dated by the child-custody holders and the investigator 
who has provided information to the child-custody holders. Written consent by the child-custody 
holders regarding collection of pregnancy outcome data on the neonate must be obtained before the 
subject is randomised and preferably at the time of obtaining written consent by the subject 
regarding participation in the trial. 
The investigator will explain that the child-custody holders are completely free to refuse to consent 
to this data collection or to withdraw consent at any time, without any consequences and without 
the need to justify their decision.
The child-custody holders will receive a copy of the Informed Consent Documents.


Follitropin Delta, FE 999049
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The child-custody holders will be informed that the monitor(s), quality assurance auditor(s) 
mandated by Ferring, ethics committee representatives or regulatory authority inspector(s), in 
accordance with applicable regulatory requirements, may review the neonate’s source records and 
data. Data protection will be handled in compliance with national / local regulations.
14.6
Trial Participation Card
The subject will be provided with a Trial Participation Card bearing the following information:

That she is participating in a clinical trial

That the trial involves controlled ovarian stimulation with recombinant FSH (either an FSH 
preparation under clinical development or an approved FSH product)

The name and phone number of the investigator

Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark 
[note: this statement is only to be included on the Subject Information Card if required by 
local regulations]
The subject will be asked to return the Trial Participation Card at the end-of-trial visit. 
Each subject’s primary care physician will be notified of their participation in the trial by the 
investigator, if the subject agrees and if applicable.
14.7
Delivery Data Checklist
Subjects with a positive ongoing pregnancy will be provided with a checklist for pregnancy follow-
up, where the subject will be reminded to report the following information to the investigator:
At delivery:

Date of delivery 

Way of delivery (vaginal / vacuum extraction / forceps / caesarean section)

Position of neonate (head / breech / transverse / other – please specify)

Gender

Birth weight (kg)

Birth length (cm)

Apgar score after 1, 5 and 10 minutes 

Admission to NICU/NCU (reason and duration)

Neonatal death

Malformation / congenital anomaly


Follitropin Delta, FE 999049
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4 weeks after delivery (any new information since birth):

Admission to NICU/NCU (reason and duration)

Neonatal death

Malformation / congenital anomaly

Any relevant medical condition
14.8
Compliance Reference Documents
The Declaration of Helsinki, the consolidated ICH-GCP and other national law(s) in the countries
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing the IMP in accordance with the approved protocol or an approved amendment, and 
for its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the investigator for at least 15 years after the 
completion or discontinuation of the trial, if no further instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous e-CRF data for Ferring. The investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Documents for at least 15 years after the 
completion or discontinuation of the trial.
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the Investigator File archived at an 
external archive.
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


Follitropin Delta, FE 999049
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17
REFERENCES
1
European Medicines Agency (EMA). Committee for medicinal products for human use 
(CHMP). Guideline on the exposure to medicinal products during pregnancy: need for post-
authorisation data. EMEA/CHMP/313666/2005.
2
Food and Drug Administration (FDA). Center for Drug Evaluation and Research (CDER) 
and Center for Biologics Evaluation and Research (CBER). Reviewer Guidance: Evaluating 
the risk of drug exposure in human pregnancies. April 2005.
3
Deeks ED. Elecsys® AMH assay: a review in anti-Müllerian hormone quantification and 
assessment of ovarian reserve. Mol Diagn Ther 2015; 19: 245-249.
4
GONAL-F Summary of Product Characteristics. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000071/WC500023748.pdf.
Downloaded November 18th 2016.
5
Coelingh Bennink HJT, Fauser BCJM, Out HJ. Recombinant follicle-stimulating hormone 
(FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene 
citrate-resistant, normogonadotropic, chronic anovulation: a prospective, multicenter, 
assessor-blind, randomized, clinical trial. Fertil Steril 1998; 69: 19-25.
6
Recombinant Human FSH Study Group. Clinical assessment of recombinant human 
follicle-stimulating hormone in stimulating ovarian follicular development before in vitro 
fertilization. Fertil Steril 1995; 63: 77-86.
7
Out HJ, Mannaerts BMJL, Driessen SGAJ, Coelingh Bennink HJT. A prospective, 
randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle 
stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization. Hum Reprod 1995; 
10: 2534-2540.
8
Wadhwa M, Thorpe R. Unwanted immunogenicity: implications for follow-on biologicals. 
Drug Information Journal 2007; 41: 1-9.
9
TNO. Determination of anti-FSH antibodies in patient serum samples using a validated 
bridging enzyme-linked immunosorbet assay (ELISA). FE999902 CS001. January 2009. 
(Report prepared for Ferring Pharmaceuticals)
10
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Assessment Report for Elonva (corifollitropin alfa). EMA/CHMP/802299/2009. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/001106/WC500074789.pdf 
Downloaded November 18th 2016.
11
Norman RJ, Zegers-Hochschild F, Salle BS, Elbers J, Heijnen E, Marintcheva-Petrova M, 
Mannaerts B on behalf of the Trust Investigators. Repeated ovarian stimulation with
corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for 
immunogenicity. Hum Reprod 2011; 26: 2200-2208.
12
Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility 
trials. Hum Reprod 2003; 18: 1000-1004.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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13
Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 
2003; 18: 1005-1009.
14
Arce J-C, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the 
design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 
2005; 20: 1757-1771.
15
Nyboe Andersen A, Devroey P and Arce J-C for the MERIT Group. Clinical outcome 
following stimulation with highly purified hMG or recombinant FSH in patients undergoing 
IVF: a randomized assessor-blind controlled trial. Hum Reprod 2006; 21: 3217-3227.
16
Doody KJ, Schnell VL, Foulk RA, Miller CE, Kolb BA, Blake EJ and Yankov VI. 
Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-
vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian 
hyperstimulation. Fertil Steril 2009; 91: 1012-1017.
17
Devroey P, Pellicer A, Nyboe Andersen A, Arce J-C on behalf of the Menopur in GnRH 
Antagonist Cycles with Single Embryo Transfer (MEGASET) Trial Group. A randomized 
assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH 
antagonist cycle with compulsory single-blastocyst transfer. Fertil Steril 2012; 97: 561-571.
18
Csokmay JM, Hill MJ, Chason RJ, Hennessy S, James AN, Cohen J, DeCherney AH, 
Segars JH, Payson MD. Experience with a patient-friendly, mandatory, single-blastocyst 
transfer policy: the power of one. Fertil Steril 2011; 96: 580-584.
19
Kresowik JD, Stegmann BJ, Sparks AE, Ryan GL, van Voorhis BJ. Five-years of a 
mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate 
without lowering pregnancy rates. Fertil Steril 2011; 96: 1367-1369.
20
Practice Committee of Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Elective single-embryo 
transfer. Fertil Steril 2012; 97: 835-842.
21
Murphy KP, Travers P, Walport M, Janeway C. Janeway’s Immunobiology. 7th edition. 
New York, Garland Science. 2008.
22
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on immunogenicity assessment of biotechnology-derived therapeutic 
proteins. EMEA/CHMP/BMWP/14327/2006 Rev 1.
23
Food and Drug Administration (FDA). Guidance for Industry: Assay Development for 
Immunogenicity Testing of Therapeutic Proteins. Draft, 2009.  
24
GONAL-F Prescribing Information China, Merck Serono, December 2014.
25
GONAL-F Prescribing Information Taiwan, Merck Serono, December 2013.
26
GONAL-F Prescribing Information South Korea, Merck Serono, January 2016.
27
GONAL-F Prescribing Information Vietnam, Merck Serono, November 2015.
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GONAL-F Prescribing Information.
http://www.emdserono.com/cmg.emdserono_us/en/images/Gona-
f_Multidose_tcm115_19349.pdf?Version
Downloaded November 18th 2016.


Follitropin Delta, FE 999049
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Griesinger G, von Otte S, Schroer A, Ludwig AK, Diedrich K, Al-Hasani S, Schultze-
Mosgau A. Elective cryopreservation of all pronuclear oocytes after GnRH agonist 
triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, 
observational proof-of-concept study. Hum Reprod 2007; 22: 1348-1352.
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Griesinger G, Kolibianakis EM, Papanikolaou EG, Diedrich K, Van Steirteghem A, 
Devroey P, Ejdrup Bredkjær H, Humaidan P. Triggering of final oocyte maturation with 
gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Live birth after 
frozen-thawed embryo replacement cycles. Fertil Steril 2007; 88: 616-621.
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Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of 
gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after 
cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization 
prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized 
controlled study. Fertil Steril 2008; 89: 84-91.
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Humaidan P, Papanikolaou EG, Tarlatzis BC. GnRHa to trigger final oocyte maturation: a 
time to reconsider. Hum Reprod 2009; 24: 2389-2394.
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Herrero L, Pareja S, Losada C, Cobo AC, Pellicer A, García-Velasco JA. Avoiding the use 
of human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist 
triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome. 
Fertil Steril 2011; 95: 1137-1140.
34
Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, 
Sullivan E, van der Poel S on behalf of ICMART and WHO. The International Committee 
for Monitoring Assisted Reproductive Technology (ICMART) and the World Health 
Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod 2009; 24: 
2683-2687.
35
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation 
syndrome: an update review. Obstet Gynecol Survey 1989; 44: 430-440.
36
U.S. Department of Health and Human Services Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), Draft guidance March 2010, Non-inferiority Clinical Trials.
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The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP), ICH E9, Statistical Principles for Clinical Trials, 
CPMP/ICH/363/96.
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The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP). Points to consider on switching between 
superiority and non-inferiority. CPMP/EWP/482/99.
39
Lipsitz SR, Dear KGB, Laird NM, Molenberghs G. Tests for Homogeneity of the Risk 
Difference When Data Are Sparse. Biometrics 1998; 54: 148-160. 
40
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP). Points to consider on adjustments for baseline 
covariates. CPMP/EWP/2863/99.


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41
World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. 59th WMA General Assembly, Seoul, October 2008.
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International Committee of Medical Journal Editors (ICMJE). Uniform requirements for 
manuscripts submitted to biomedical journals: ethical considerations in the conduct and 
reporting of research: authorship and contributorship. 
www.ICMJE.org. Downloaded November 18th 2016.

Prot_000.pdf: 
 
 
 
 
 
 
 
Protocol (consolidated protocol incorporating amendment 03) 
Sites in South Korea, Taiwan and Vietnam 
 
 
Title of trial: 
A randomised, controlled, assessor-blind, parallel groups, multicentre, 
Pan-Asian trial comparing the efficacy and safety of FE 999049 with 
follitropin alfa (GONAL-F) in controlled ovarian stimulation in women 
undergoing an assisted reproductive technology programme 
NCT number: 
NCT03296527 
Sponsor trial code: 
000145 
Date: 
27 September 2018 
 
 
 
 
 


Follitropin Delta, FE 999049
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CLINICAL TRIAL PROTOCOL
A randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian trial comparing 
the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian 
stimulation in women undergoing an assisted reproductive technology programme
Trial Code: 000145
US IND Number:
103,040
Investigational Medicinal 
Product:
FE 999049, human recombinant follicle-stimulating 
hormone (rFSH), solution for subcutaneous injection
Indication:
Controlled ovarian stimulation for the development of 
multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro
fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle
Phase:
3
Sponsor:
Ferring Pharmaceuticals A/S
Global Clinical and Non-Clinical R&D
Science and Medicine, Reproductive Health
International PharmaScience Center
Kay Fiskers Plads 11
2300 Copenhagen S
Denmark
Tel: (+45) 88 33 88 34 
Version:
3.0 (consolidated protocol; changes introduced with 
amendment #03 version 1.0 and 2.0 implemented)
GCP Statement:
This trial will be performed in compliance with GCP
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian trial comparing 
the efficacy and safety of FE 999049 with follitropin alfa (GONAL-F) in controlled ovarian 
stimulation in women undergoing an assisted reproductive technology programme
SIGNATORY INVESTIGATOR
 
TRIAL SITES
A total of 15-30 trial sites in mainland China and other Asian countries, potentially Taiwan, South 
Korea and Vietnam.
PLANNED TRIAL PERIOD
First patient first visit (FPFV):
Q2 2017
Last patient first visit (LPFV):
Q4 2018
Last patient last visit (LPLV):
Q1 2019
Post-trial follow-up completed:
Q1 2020
CLINICAL PHASE
3
BACKGROUND / RATIONALE
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) belonging to the 
pharmaceutical class of gonadotropins. It is intended for the following indication: “Controlled 
ovarian stimulation for the development of multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm 
injection (ICSI) cycle”. FE 999049 will be delivered as a solution for injection for subcutaneous 
self-administration by an injection pen.
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6®
cell line is well-characterised, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound 
polypeptide chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues 
with 5 intrachain-disulphide bonds. The β-subunit contains 111 amino acid residues with 
6 intrachain-disulphide bonds. Each subunit is N-glycosylated at two positions, and about 40% of 
the total mass is carbohydrates.
There are no commercially available rFSH products derived from human cell lines, but Ferring has 
recently submitted a Marketing Authorisation Application to the European Medicines Agency 
(EMA) for FE 999049 (October 2015) and received positive opinion from the Committee for 
Medicinal Products for Human Use (October 2016). Currently-approved rFSH products for the 
proposed indication, such as follitropin alfa (GONAL-F, Merck Serono) and follitropin beta 
(PUREGON, MSD), are derived from a Chinese hamster ovary (CHO) cell line. The amino acid 
sequence of FE 999049 is identical to the endogenous human FSH sequence and to that in existing 
CHO-derived rFSH products. Manufacturing from different cell systems leads to glycosylation 
heterogeneity between rFSH preparations. The glycosylation profile of recombinant proteins is 
dependent on the expressing cell line and the cell culture conditions. Differences in glycosylation


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profile, sialic acid pattern and isoform profile, have been documented between FE 999049 and
existing rFSH products from a CHO cell line. Comparison between the FE 999049 and the 
GONAL-F and PUREGON profiles indicate differences in acidity and carbohydrate side chains. As 
CHO cells lack enzymatic functions to construct more complex carbohydrate structures found in 
humans, the glycosylation profile of FE 999049 is more complex. In addition, RE 999049 contains 
both α2,3 and α2,6 sialylation patterns, while CHO-derived rFSH products exclusively carry 
2,3 linked sialic acid; this difference further contributes to the observed differences in glycosylation 
profiles between FE 999049 and CHO-derived rFSH products.
Before the current trial, Ferring has completed four phase 1 trials, two phase 2 dose-response trials
(one conducted in EU and one in Japan) and two phase 3 trials as part of the clinical development 
programme for FE 999049. A total of 1,927 subjects have been included in the completed clinical 
trials, of whom 1,112 subjects were exposed to FE 999049.
The two phase 2 trials were randomised, controlled, assessor-blind, multi-centre dose-response 
trials in which randomisation was stratified according to the subject’s anti-Müllerian hormone 
(AMH) level at screening. In both trials, a statistically significant dose-response relationship for 
FE 999049 with respect to the number of oocytes retrieved was observed for the overall population 
and for each AMH strata. Furthermore, the dose-response profile observed in Japanese and 
European subjects was similar. An individualised FE 999049 dosing regimen based on subject’s 
AMH level and body weight was designed by modelling and simulation and prospectively tested in 
the phase 3 trials.
During the phase 3 trials, 665 IVF/ICSI subjects were treated with FE 999049 in 1,012 treatment 
cycles. The two phase 3 trials supported the efficacy and safety of FE 999049 in the proposed 
indication. ESTHER-1 (trial 000004, Evidence-based Stimulation Trial with Human rFSH in 
Europe and Rest of World, ESTHER) was an efficacy trial designed to demonstrate non-inferiority 
of FE 999049 versus an approved recombinant FSH preparation with ongoing pregnancy rate and 
ongoing implantation rate as co-primary endpoints (as agreed with the EMA during Scientific 
Advice) and also to prospectively evaluate the outcome of the stratified medicine approach with the 
individualised FE 999049 dosing regimen based on the AMH level (measured by Elecsys® AMH 
Immunoassay, Roche Diagnostics) and body weight. ESTHER-2 (trial 000071) was a safety 
immunogenicity trial with up to two repeated treatment cycles in subjects who did not achieve an
ongoing pregnancy in ESTHER-1. Both trials have been completed with respect to their 
intervention part.
The ESTHER-1 trial demonstrated non-inferiority of FE 999049 to GONAL-F for the two co-
primary endpoints, ongoing pregnancy rate and ongoing implantation rate, for both the per-protocol 
(PP) and modified intention-to-treat (mITT) populations. Across treatment groups and analysis 
populations, the ongoing pregnancy rate was in the range 31-33% and the ongoing implantation rate 
in the range 35-37%. 
The AMH dosing regimen for FE 999049 in controlled ovarian stimulation cycles led to a 
statistically significantly lower proportion of subjects with extreme ovarian response (<4 or ≥15 
oocytes retrieved or <4 or ≥20 oocytes retrieved) compared to the GONAL-F group, when adjusted 
for AMH. Furthermore, the value of the individualised FE 999049 dosing regimen was reflected in 
statistically significant and clinically relevant reductions in ovarian hyperstimulation syndrome 
(OHSS) risk management compared to GONAL-F. Overall, the incidence of preventive 
interventions for early OHSS among subjects treated with FE 999049 was half of that observed 
with GONAL-F, which was a statistically significant reduction. The combined incidence of early 


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OHSS (all and those of moderate/severe grade) and/or preventive interventions for early OHSS was 
also statistically significantly reduced with FE 999049 in comparison to GONAL-F. Overall, there 
was a statistically significantly lower incidence of total OHSS and/or preventive interventions for 
early OHSS, and of total moderate/severe OHSS and/or preventive interventions for early OHSS 
with FE 999049 compared to GONAL-F.
A design similar to the phase 3 trial ESTHER-1 is being proposed for the present trial to be 
conducted in China and other Asian countries, with some modifications according to local practice. 
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation.
OBJECTIVES
Primary Objective

To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to 
ongoing pregnancy rate in women undergoing controlled ovarian stimulation
Secondary Objectives

To compare the clinical benefits of FE 999049 in its dosing regimen to those of GONAL-F 
with respect to efficacy and safety

To compare FE 999049 with GONAL-F with respect to ovarian response including 
follicular development and endocrine profile, as well as with respect to embryo 
development

To assess the population pharmacokinetics of FE 999049

To compare FE 999049 with GONAL-F with respect to treatment efficiency 

To compare FE 999049 with GONAL-F with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To evaluate the immunogenicity of FE 999049 after one treatment cycle

To perform a health economic analysis comparing FE 999049 with GONAL-F
ENDPOINTS
Primary Endpoint

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 


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embryos transferred)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer
divided by number of embryos transferred)

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes
retrieved

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
embryo transfer cancellation due to excessive ovarian response / OHSS risk

Number and size of follicles on stimulation day 6 and end-of-stimulation

Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 
oocytes retrieved

Percentage of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 after oocyte retrieval

Circulating concentrations of LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Circulating concentrations of FSH on stimulation day 6, end-of-stimulation and oocyte 
retrieval as well as FSH population pharmacokinetic parameters

Total gonadotropin dose and number of stimulation days

Proportion of subjects with investigator-requested gonadotropin dose adjustments

Frequency and intensity of adverse events

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralising capacity

Frequency and intensity of immune-related adverse events

Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical intervention) and vanishing twins

Technical malfunctions of the administration pen


Follitropin Delta, FE 999049
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POST-TRIAL INFORMATION

Live birth rate and neonatal health, including minor/major congenital anomalies, at birth and 
at 4 weeks after birth
METHODOLOGY
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian non-
inferiority trial comparing the efficacy and safety of two rFSH preparations, FE 999049 and 
follitropin alfa (GONAL-F), in first cycle subjects aged 20-40 years undergoing controlled ovarian 
stimulation for IVF/ICSI following a gonadotropin-releasing hormone (GnRH) antagonist protocol. 
The trial has been designed to demonstrate non-inferiority of FE 999049, a human cell line-derived 
rFSH preparation, versus an approved CHO-derived rFSH preparation, i.e. GONAL-F, with 
ongoing pregnancy rate as the primary endpoint. Secondary endpoints include pharmacokinetic 
profile of FE 999049, pharmacodynamic parameters of FSH action as well as efficacy and safety 
parameters related to controlled ovarian stimulation. The assessor-blind design ensures that the 
investigators and other assessors such as embryologists and central laboratory personnel are blinded 
to individual treatment allocation. The sponsor will break the blind when all subjects have 
completed the end-of-trial visit, in order to evaluate efficacy and safety up to the ongoing 
pregnancy visit.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio 
to treatment with either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation 
will be stratified by centre and according to age (<35, 35-37 and 38-40 years). Subjects randomised 
to FE 999049 will have their individual dose determined on the basis of their AMH level at 
screening and their body weight at randomisation. The daily FE 999049 dose will be fixed
throughout the stimulation period. For subjects with low AMH (<15 pmol/L) the daily FE 999049 
dose is 12 μg, irrespective of body weight. For subjects with high AMH (≥15 pmol/L) the daily 
FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on actual 
AMH and body weight (note: the minimum and maximum allowed daily doses are 6 µg and 12 µg, 
respectively). Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is 
not allowed. For subjects randomised to GONAL-F, the dosing regimen is within labelling. The 
starting daily dose of GONAL-F is 150 IU and fixed for the first five stimulation days after which it 
may be adjusted by 75 IU per day based on the individual response. The maximum daily GONAL-
F dose allowed is 450 IU. Subjects can be treated with GONAL-F for a maximum of 20 days, and 
coasting is not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When the leading follicle reaches ≥15 mm, visits must be 
performed daily. To prevent a premature LH surge, a GnRH antagonist will be initiated on 
stimulation day 6 and continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥3 follicles with a diameter ≥17 mm are observed. If there are 
<25 follicles with a diameter ≥12 mm, human chorionic gonadotropin (hCG) will be administered. 
If there are 25-35 follicles with a diameter ≥12 mm, a GnRH agonist can be administered or the 
cycle can be cancelled. In case of excessive follicular development, defined as >35 follicles with a 
diameter ≥12 mm, the cycle is to be cancelled. If it is judged by the investigator that ≥3 follicles 
with a diameter ≥17 mm cannot be reached, but 1 or 2 follicles with a diameter ≥17 mm are 
observed, the cycle may either be cancelled due to poor follicular development or triggering of final 


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follicular maturation is to be induced, as judged by the investigator.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Rescue ICSI is not allowed. Fertilisation and embryo 
development will be assessed from oocyte retrieval to the day of transfer. For subjects who 
underwent triggering of final follicular maturation with hCG, transfer is performed on day 3
(embryo stage) after oocyte retrieval. Subjects <35 years at randomisation will have single embryo 
transfer if a good-quality embryo is available; otherwise, double embryo transfer will be performed 
(and single transfer if two embryos are not available). Subjects ≥35 years at randomisation will 
have double embryo transfer (and single transfer if two embryos are not available). Remaining 
embryos may be cryopreserved in accordance with local guidelines and/or regulations. For subjects 
who underwent triggering of final follicular maturation with GnRH agonist, no transfer will take 
place in the current fresh cycle and the embryos available will be cryopreserved on day 3, 5 or 6, 
according to local practice. All cryopreserved embryos can be used by the subject after completion 
of the trial, in accordance with local guidelines and/or regulations. 
Vaginal progesterone will be provided for luteal phase support from the day of oocyte retrieval or 
the day after and at least until clinical pregnancy. Thereafter the investigator may decide to 
continue up to the ongoing pregnancy visit, according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs. A serum βhCG test will be
performed 13-15 days after transfer, clinical pregnancy will be confirmed by transvaginal 
ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be confirmed by transvaginal or 
abdominal ultrasound 10-11 weeks after transfer.
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and haematology parameters as well as anti-FSH antibodies. Endocrine 
parameters are assessed at screening, stimulation day 1, stimulation day 6 and end-of-stimulation, 
furthermore FSH is also assessed at oocyte retrieval. Clinical chemistry and haematology 
parameters are assessed at screening, stimulation day 1, end-of-stimulation and end-of-trial. Anti-
FSH antibodies are collected at four occasions. The first blood sample is taken at the screening visit 
and is exclusively used as back-up samples for the anti-drug antibody assay development. The 
subsequent three samples are used for analysis of anti-FSH antibodies in the individual subjects in 
the trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-dosing: 5-10 
days after the last FE 999049 or GONAL-F dose (it may coincide with the transfer visit) and 19-28 
days after the last FE 999049 or GONAL-F dose (it may coincide with the βhCG test visit). 
Subjects with a treatment-induced anti-FSH antibody response will be followed until the response 
has become negative or returned to the pre-dosing level, with a maximum follow-up period of one 
year. 
Local tolerability of FE 999049 and GONAL-F following subcutaneous administration will be 
assessed by the subject three times daily: immediately, 30 minutes and 24 hours after each 
injection. The assessment of injection site reactions will be made throughout the stimulation period 
and recorded by the subjects in a diary. 
Post-Trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up. All subjects with an ongoing 
pregnancy will be followed till delivery to gather information on live birth rate. Furthermore, data 
will be gathered on neonatal health, including any congenital anomalies, at birth and at 4 weeks 


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after birth. These data will be reported separately.
NUMBER OF SUBJECTS
It is planned to randomise 1,000 subjects from 15-30 sites in mainland China and other Asian 
countries. Of the 1,000 subjects it is expected that 740 subjects will be recruited in China (i.e.
possessing a Chinese identification card and having native Chinese parents) and the rest from other 
Asian countries, potentially Taiwan, South Korea and Vietnam. It is estimated that approximately
1,200 subjects should be screened to achieve 1,000 subjects eligible for randomisation.
CRITERIA FOR INCLUSION / EXCLUSION
This trial will include Asian women aged 20-40 years undergoing their first IVF/ICSI cycle. They 
have been diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have 
partners diagnosed with male factor infertility, and are considered eligible for IVF or ICSI. The 
allowed body mass index (BMI) is 17.5-32.0 kg/m2, thus including underweight, normal weight, 
overweight and obese subjects. The exclusion criteria incorporate the contraindications for the use 
of gonadotropins.
The complete list of inclusion and exclusion criteria is provided below.
Inclusion Criteria
1. Informed Consent Documents signed prior to screening evaluations.
2. In good physical and mental health in the judgement of the investigator.
3. Asian pre-menopausal females between the ages of 20 and 40 years. The subjects must be at 
least 20 years (including the 20th birthday) when they sign the informed consent and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised ASRM classification, 1996) or with partners diagnosed with 
male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm 
injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
5. Infertility for at least one year before randomisation for subjects <35 years or for at least 
6 months for subjects ≥35 years (not applicable in case of tubal or severe male factor 
infertility).
6. The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
7. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no polyps and no congenital structural abnormalities which are
associated with a reduced chance of pregnancy) within 1 year prior to randomisation. 
9. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would 
contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 
1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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CONFIDENTIAL
10. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 2 years prior to randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. Willing to accept transfer of 1-2 embryos.
Exclusion Criteria
1. Known endometriosis stage III-IV (defined by the revised ASRM classification, 1996).
2. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
3. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 
4. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
5. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
6. Known inherited or acquired thrombophilia disease.
7. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
8. Known porphyria.
9. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
10. Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records; i.e. not based on the anti-FSH antibody analyses conducted in the trial). 
11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
12. Known moderate or severe impairment of renal or hepatic function.
13. Any abnormal finding of clinical chemistry, haematology or vital signs at screening which 
is clinically significant as judged by the investigator.
14. Currently breast-feeding.
15. Undiagnosed vaginal bleeding.
16. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
17. Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine 
abnormalities or retained intrauterine device.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
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18. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomisation) or contraindication to pregnancy.
19. Known current active pelvic inflammatory disease.
20. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral 
contraceptives, progestogen or estrogen preparations.
21. Use of hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomisation.
22. Known history of chemotherapy (except for gestational conditions) or radiotherapy. 
23. Current or past (1 year prior to randomisation) abuse of alcohol or drugs.
24. Current (last month) intake of more than 14 units of alcohol per week.
25. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
26. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
27. Previous participation in the trial.
28. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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MEDICINAL PRODUCTS
Investigational Medicinal Products (IMPs)
IMP name
Drug type
Active ingredient, route of 
administration and 
concentration
Daily dose
FE 999049
rFSH
FE 999049 in solution for 
subcutaneous injection; 
72 µg FSH in 2.16 mL
AMH <15 pmol/L: 12 μg. 
AMH ≥15 pmol/L: ranging from 
0.19 to 0.10 μg/kg, i.e. depending 
on actual AMH. The minimum and 
maximum allowed doses are 6 µg
per day and 12 µg per day, 
respectively.
The dose is fixed throughout 
stimulation
GONAL-F
rFSH
Follitropin alfa in solution 
for subcutaneous injection; 
900 IU (66 μg) FSH in 1.5 
mL
Starting dose of 150 IU fixed for 
the first five stimulation days, 
followed by potential adjustments
of 75 IU per day with a maximum 
dose of 450 IU per day
Concomitant Fertility Medication / Non-investigational Medicinal Products (NIMPs)
NIMP name
Drug type
Active ingredient and route 
of administration 
Dose
CETROTIDE
GnRH 
antagonist
Cetrorelix acetate powder 
and solvent for solution for 
subcutaneous injection
0.25 mg, daily dose
OVITRELLE
hCG
Choriogonadotropin alfa in 
solution for subcutaneous 
injection
250 µg, single dose
GONAPEPTYL GnRH agonist Triptorelin acetate in 
solution for subcutaneous 
injection
0.2 mg, single dose
CRINONE
Progesterone
Progesterone gel for
vaginal administration
90 mg, daily dose


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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DURATION OF TREATMENT
The maximum period of exposure to FE 999049 or GONAL-F is 20 days.
STATISTICAL METHODS
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation. Ongoing pregnancy is defined as at least one intrauterine viable fetus 10-11 weeks 
after transfer. The non-inferiority limit for the difference between treatments (FE 999049 versus 
GONAL-F) is -10.0% (absolute) for the primary endpoint. 
The trial is designed to have 90% power of achieving the primary objective for the overall trial 
population and to have 80% power in the Chinese population. Assuming an ongoing pregnancy rate 
of 32.2% in both treatment groups, a total of 918 subjects are needed in the PP analysis set. To 
account for major protocol deviations a total of 1,000 subjects should be randomised. To secure that 
consistency can be established between the results from the overall trial population and the Chinese 
trial population at least 740 subjects will be recruited in China. The remaining subjects will be 
recruited from other Asian countries.
Sample Size Monitoring
The overall ongoing pregnancy rate will be monitored in a blinded manner, as the number of 
subjects to be randomised may need to be increased beyond the planned 1,000, if the overall 
ongoing pregnancy rate observed in the trial is above the estimated 32.2% used for the sample size 
calculation. The expected maximum number of subjects to be randomised would then be 
approximately 1,144 (572 per treatment group), corresponding to an observed rate of 50%. Blinded 
monitoring of the assumptions underlying the sample size is recommended specifically for non-
inferiority trials by Food and Drug Administration (FDA) and in general by EMA.
Primary Endpoint: Ongoing Pregnancy Rate
The non-inferiority hypothesis to be tested for the primary endpoint is
H0: FE - GF -10.0% against the alternative HA: FE - GF > -10.0%,
where FE and GF denote the ongoing pregnancy rate after treatment with FE 999049 and 
GONAL-F, respectively. Non-inferiority will be evaluated based on the overall trial population.
The null hypothesis (H0) will be tested against the alternative (HA) by constructing a two-sided 95% 
confidence interval for the difference in ongoing pregnancy rates. The primary analysis will be 
adjusted for the stratification factor (age group) by using the Mantel-Haenszel method to combine 
results across age groups. In brief, this corresponds to deriving a weighted average across age 
groups where the weight depends on the number of observations in each treatment group in each 
age stratum.
Evaluation of the Primary Objective
If the lower limit of the two-sided 95% confidence interval based on the overall population is
greater than the non-inferiority limit (-10.0%) for both the full analysis set (FAS) and the PP 
analysis set, the null hypotheses will be rejected. In that case it will be claimed that FE 999049 is 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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CONFIDENTIAL
non-inferior to GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled 
ovarian stimulation.
If the lower limit of the two-sided 95% confidence interval for the treatment difference based on the 
FAS not only lies above the non-inferiority limit (-10.0%) but also above zero then there is 
evidence of superiority in terms of statistical significance at the 5% level. The result based on the 
PP analysis set is not essential for the superiority claim but should lead to a comparable result for a 
robust interpretation.
A supportive evaluation of the subjects recruited in China will be conducted, and it is expected that 
the findings among the Chinese trial population will be consistent with the overall findings in the 
trial. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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CONFIDENTIAL
TABLE OF CONTENTS
Page
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 19
LIST OF FIGURES...................................................................................................................................... 20
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 21
1
INTRODUCTION ............................................................................................................................. 24
1.1
Background............................................................................................................................. 24
1.2
Scientific Justification for Conducting the Trial..................................................................... 25
1.3
Benefit / Risk Aspects............................................................................................................. 26
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 29
2.1
Objectives ............................................................................................................................... 29
2.2
Endpoints ................................................................................................................................ 29
3
INVESTIGATIONAL PLAN ........................................................................................................... 31
3.1
Overall Trial Design................................................................................................................ 31
3.1.1
Trial Design Diagram................................................................................................. 31
3.1.2
Overall Design and Control Methods ........................................................................ 32
3.1.3
Trial Schedule............................................................................................................ 34
3.2
Planned Number of Trial Sites and Subjects........................................................................... 34
3.3
Interim Analysis and Administrative Review......................................................................... 34
3.4
Data Monitoring Committee ................................................................................................... 34
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 34
3.5.1
Trial Design ............................................................................................................... 34
3.5.2
Selection of Endpoints ............................................................................................... 36
3.5.3
Blinding...................................................................................................................... 37
3.5.4
Selection of Doses in the Trial................................................................................... 38
3.5.5
Selection of the Trial Population ............................................................................... 39
3.5.6
Follow-up Procedures ................................................................................................ 39
4
SELECTION OF TRIAL POPULATION ...................................................................................... 40
4.1
Trial Population....................................................................................................................... 40
4.1.1
Inclusion Criteria ....................................................................................................... 40
4.1.2
Exclusion Criteria ...................................................................................................... 41
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 42
4.2.1
Recruitment................................................................................................................ 42
4.2.2
Randomisation ........................................................................................................... 42
4.3
Restrictions ............................................................................................................................. 43
4.3.1
Prior and Concomitant Therapies .............................................................................. 43
4.3.2
Prohibited Therapy..................................................................................................... 43
4.4
Withdrawal Criteria................................................................................................................. 43
4.5
Subject Replacement............................................................................................................... 43
5
TREATMENTS ................................................................................................................................. 44
5.1
Investigational Medicinal Products (IMPs) ............................................................................ 44
5.1.1
FE 999049 Dosing Regimen...................................................................................... 44


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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5.1.2
GONAL-F Dosing Regimen...................................................................................... 46
5.2
Non-Investigational Medicinal Products (NIMPs) ................................................................. 46
5.3
Characteristics and Source of Supply ..................................................................................... 47
5.4
Packaging and Labelling......................................................................................................... 48
5.5
Conditions for Storage and Use .............................................................................................. 48
5.6
Blinding / Unblinding ............................................................................................................. 49
5.6.1
Blinding...................................................................................................................... 49
5.6.2
Unblinding of Individual Subject Treatment ............................................................. 50
5.7
Dispensing and Accountability, Return and Destruction........................................................ 50
5.8
Auxiliary Supplies................................................................................................................... 50
6
TRIAL PROCEDURES .................................................................................................................... 51
6.1
Screening................................................................................................................................. 52
6.2
Stimulation.............................................................................................................................. 53
6.2.1
Stimulation Day 1 ...................................................................................................... 53
6.2.2
Stimulation Day 6 ...................................................................................................... 54
6.2.3
Stimulation Days ≥7 to ≤20 ....................................................................................... 55
6.2.4
End-of-stimulation..................................................................................................... 55
6.3
Oocyte Retrieval ..................................................................................................................... 57
6.4
Oocyte / Embryo Evaluation................................................................................................... 58
6.5
Transfer................................................................................................................................... 59
6.5.1
Embryo Transfer........................................................................................................ 59
6.5.2
First Post-dosing Anti-FSH Antibody Assessment (5-10 Days after Last IMP 
Dose).......................................................................................................................... 60
6.6
βhCG Test............................................................................................................................... 60
6.6.1
βhCG Test.................................................................................................................. 60
6.6.2
Second Post-dosing Anti-FSH Antibody Assessment (19-28 Days after Last IMP 
Dose).......................................................................................................................... 61
6.7
Clinical Pregnancy.................................................................................................................. 61
6.8
Ongoing Pregnancy................................................................................................................. 61
6.9
End-of-trial.............................................................................................................................. 62
6.10
Post-trial Activities ................................................................................................................. 62
7
TRIAL ASSESSMENTS ................................................................................................................... 63
7.1
Assessment Related to Primary Endpoint............................................................................... 63
7.1.1
Ongoing Pregnancy.................................................................................................... 63
7.2
Assessments Related to Secondary Endpoints........................................................................ 63
7.2.1
βhCG Test.................................................................................................................. 63
7.2.2
Clinical Pregnancy..................................................................................................... 63
7.2.3
Vital Pregnancy.......................................................................................................... 63
7.2.4
Implantation............................................................................................................... 63
7.2.5
Ongoing Implantation ................................................................................................ 63
7.2.6
Extreme Ovarian Response........................................................................................ 64
7.2.7
Early OHSS (including OHSS of Moderate/Severe Grade) and/or Preventive 
Interventions for Early OHSS.................................................................................... 64
7.2.8
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo 
Transfer Cancellation due to Excessive Ovarian Response / OHSS Risk ................. 64
7.2.9
Number and Size of Follicles during Stimulation...................................................... 64
7.2.10 Number and Distribution of Oocytes Retrieved......................................................... 64


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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Supersedes: Ver. 2.0
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7.2.11 Metaphase II Oocytes................................................................................................. 64
7.2.12 Fertilisation Rate........................................................................................................ 65
7.2.13 Number and Quality of Embryos on Day 3 ............................................................... 65
7.2.14 Circulating Levels of Endocrine Parameters.............................................................. 65
7.2.15 FSH Population Pharmacokinetics............................................................................. 65
7.2.16 Total Gonadotropin Dose and Number of Stimulation Days..................................... 66
7.2.17 Gonadotropin Dose Adjustments............................................................................... 66
7.2.18 Adverse Events .......................................................................................................... 66
7.2.19 Clinical Chemistry and Haematology Parameters ..................................................... 66
7.2.20 Injection Site Reactions ............................................................................................. 66
7.2.21 Anti-FSH Antibodies ................................................................................................. 67
7.2.22 Immune-related Adverse Events................................................................................ 68
7.2.23 Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen....................... 68
7.2.24 Late OHSS (including OHSS of Moderate/Severe Grade)........................................ 69
7.2.25 Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins................................................................................ 69
7.2.26 Pen Malfunction......................................................................................................... 69
7.3
Other Assessments.................................................................................................................. 69
7.3.1
Demographics ............................................................................................................ 69
7.3.2
Medical History ......................................................................................................... 69
7.3.3
Infertility History ....................................................................................................... 69
7.3.4
Menstrual History ...................................................................................................... 69
7.3.5
Reproductive History................................................................................................. 70
7.3.6
Smoking and Alcohol Habits..................................................................................... 70
7.3.7
Body Weight and Height............................................................................................ 70
7.3.8
Physical Examination................................................................................................. 70
7.3.9
Gynaecological Examination..................................................................................... 70
7.3.10 Endocrine Parameters at Screening............................................................................ 71
7.3.11 Vital Signs.................................................................................................................. 71
7.3.12 Ovarian Volume......................................................................................................... 71
7.3.13 Endometrial Status..................................................................................................... 71
7.3.14 Embryo Transfer Procedure....................................................................................... 72
7.3.15 Concomitant Medication............................................................................................ 72
7.3.16 Drug Dispensing and Accountability......................................................................... 72
7.3.17 End-of-trial Form....................................................................................................... 72
7.4
Assessments Related to Post-trial Information ....................................................................... 72
7.4.1
Pregnancy Follow-up................................................................................................. 72
7.5
Handling of Biological Samples ............................................................................................. 72
8
ADVERSE EVENTS ......................................................................................................................... 74
8.1
Adverse Event Definition........................................................................................................ 74
8.2
Collection and Recording of Adverse Events......................................................................... 74
8.2.1
Collection of Adverse Events .................................................................................... 74
8.2.2
Recording of Adverse Events .................................................................................... 74
8.3
Adverse Events of Special Interest and/or Requiring Special Handling................................. 77
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)........................................................... 77
8.3.2
Local Tolerability....................................................................................................... 79
8.3.3
Treatment-induced Anti-FSH Antibodies.................................................................. 79


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Supersedes: Ver. 2.0
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8.3.4
Menstrual Bleeding.................................................................................................... 80
8.3.5
Ovarian Torsion ......................................................................................................... 80
8.3.6
Pregnancy Losses....................................................................................................... 80
8.3.7
Multiple Pregnancies ................................................................................................. 80
8.4
Serious Adverse Events .......................................................................................................... 81
8.4.1
Serious Adverse Event Definition.............................................................................. 81
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 82
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 83
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 83
8.5.2
Collection of Serious Adverse Events with Onset after End-of-trial......................... 83
8.5.3
Follow-up of Serious Adverse Events with Onset during the Post-Trial................... 84
9
STATISTICAL METHODS ............................................................................................................. 85
9.1
Determination of Sample Size ................................................................................................ 85
9.2
Subject Disposition ................................................................................................................. 87
9.3
Protocol Deviations................................................................................................................. 88
9.4
Analysis Sets........................................................................................................................... 88
9.5
Trial Population....................................................................................................................... 89
9.5.1
General Considerations.............................................................................................. 89
9.5.2
Trial Population Parameters....................................................................................... 89
9.6
Treatment Compliance............................................................................................................ 90
9.7
Endpoint Assessments............................................................................................................. 91
9.7.1
General Considerations.............................................................................................. 91
9.7.2
Primary Endpoint....................................................................................................... 92
9.7.3
Secondary Endpoints ................................................................................................. 94
9.8
Additional Safety Evaluations .............................................................................................. 100
9.9
Post-trial Activities ............................................................................................................... 101
9.10
Interim Analyses and Administrative Review ...................................................................... 101
10
DATA HANDLING ......................................................................................................................... 102
10.1
Source Data and Source Documents..................................................................................... 102
10.2
e-CRF.................................................................................................................................... 103
10.3
Data Management ................................................................................................................. 104
10.4
Provision of Additional Information..................................................................................... 104
11
MONITORING PROCEDURES ................................................................................................... 105
11.1
Periodic Monitoring.............................................................................................................. 105
11.2
Audit and Inspection............................................................................................................. 105
11.3
Confidentiality of Subject Data............................................................................................. 105
12
CHANGES IN THE CONDUCT OF THE TRIAL...................................................................... 106
12.1
Protocol Amendments........................................................................................................... 106
12.2
Deviations from the Protocol ................................................................................................ 106
12.3
Premature Trial Termination................................................................................................. 106
13
REPORTING AND PUBLICATION ............................................................................................ 107
13.1
Clinical Trial Report ............................................................................................................. 107
13.2
Confidentiality and Ownership of Trial Data........................................................................ 107
13.3
Publications and Public Disclosure....................................................................................... 107
13.3.1 Publication Policy.................................................................................................... 107
13.3.2 Public Disclosure Policy.......................................................................................... 108


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
E-Study Protocol-19954;Ver. 3.0
Clinical Trial Protocol 
Supersedes: Ver. 2.0
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CONFIDENTIAL
14
ETHICAL AND REGULATORY ASPECTS............................................................................... 109
14.1
Ethics Committee.................................................................................................................. 109
14.2
Regulatory Authorities Notification...................................................................................... 109
14.3
End-of-trial and End-of-trial Notification............................................................................. 109
14.4
Ethical Conduct of the Trial.................................................................................................. 109
14.5
Subject Information and Consent.......................................................................................... 110
14.6
Trial Participation Card......................................................................................................... 111
14.7
Delivery Data Checklist........................................................................................................ 111
14.8
Compliance Reference Documents....................................................................................... 112
15
LIABILITIES AND INSURANCE ................................................................................................ 113
15.1
ICH-GCP Responsibilities.................................................................................................... 113
15.2
Liabilities and Insurance....................................................................................................... 113
16
ARCHIVING.................................................................................................................................... 114
16.1
Investigator File .................................................................................................................... 114
16.2
Trial Master File.................................................................................................................... 114
17
REFERENCES................................................................................................................................. 115
APPENDIX 1
Master Informed Consent Documentation
APPENDIX 2
Contact List
ATTACHMENT 1
Agreement on the Protocol


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Clinical Trial Protocol 
Supersedes: Ver. 2.0
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CONFIDENTIAL
LIST OF TABLES 
Page
Table 5-1
FE 999049 Dosing Regimen...........................................................................................45
Table 5-2
GONAL-F Dosing Regimen...........................................................................................46
Table 5-3
Non-Investigational Medicinal Products (NIMPs) .........................................................47
Table 5-4
Characteristics and Source of Supply of Medicinal Products.........................................48
Table 6-1
Trial Flow Chart – Subject Procedures...........................................................................51
Table 6-2
Triggering and Cycle Cancellation Criteria related to Follicular Development.............56
Table 6-3 Trial Flow Chart – Oocyte / Embryo Procedures ...........................................................58
Table 8-1
Classification of Mild, Moderate and Severe OHSS (Golan’s Classification 
System)............................................................................................................................78
Table 9-1
Implications of Choice on Non-inferiority Margin on Sample Size, Precision and 
Difference in Observed Rates .........................................................................................86
Table 9-2
Sample Size by Ongoing Pregnancy Rate for the PP Analysis Set ................................87


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Supersedes: Ver. 2.0
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LIST OF FIGURES
Page
Figure 3-1 Trial Diagram – Trial Period...........................................................................................31


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
α
alfa
AMH
anti-Müllerian hormone
ART
assisted reproductive technologies
ATC
Anatomical Therapeutic Chemical classification system 
β
beta
βhCG
beta unit of human chorionic gonadotropin
BMI
body mass index
CBC
complete blood count 
CHO
Chinese hamster ovary
CHEM-20
a blood test to measure the level of 20 different proteins, lipids and electrolytes
DHEA
dehydroepiandrosterone
e-CRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FDA
Food and Drug Administration
FPFV
first patient first visit
FSH 
follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH 
gonadotropin-releasing hormone
GPV
Global Pharmacovigilance Department
h
hour(s)
HBsAg 
Hepatitis B Surface Antigen
hCG
human chorionic gonadotropin 
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HLT
high level term
ICD-10
International Statistical Classification of Diseases and Related Health Problems, 10th
revision
ICH
International Conference on Harmonisation
ICMART
International Committee Monitoring Assisted Reproductive Technologies
ICMJE
International Committee of Medical Journal Editors
ICSI
intracytoplasmic sperm injection
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
investigational medicinal product
IND
investigational new drug 
ITT
intention-to-treat
IU
international units
IVF
in vitro fertilisation
L
litre
LH
luteinising hormone
LLOQ 
lower limit of quantification
LPFV
last patient first visit


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LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalent(s)
mg
milligram
mITT
modified intention-to-treat
MSR
minimum significant ratio
mL
millilitre
NCU
neonatal care unit
ng
nanogram
NIMP
non-investigational medicinal product
NICU
neonatal intensive care unit 
OHSS
ovarian hyperstimulation syndrome
PER.C6®
host cell line of human fetal retinal origin
PGD
preimplantation genetic diagnosis
PGS
preimplantation genetic screening
pmol
picomol
PP
per-protocol
PT
preferred term
rFSH
recombinant follicle-stimulating hormone
rhCG
recombinant human chorionic gonadotropin 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SMQ
Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries 
SUSAR
suspected unexpected serious adverse reaction
TSH
thyroid-stimulating hormone
μg
microgram
ULOQ 
upper limit of quantification
US
ultrasound
WHO 
World Health Organization 
AMH Unit Conversion Factors 
1 pmol/L = 0.140 ng/mL
1 ng/mL = 7.143 pmol/L


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Definition of Terms
Major congenital anomaly 
A life threatening structural anomaly or one likely to cause significant 
impairment of health or functional capacity and which needs medical 
or surgical treatment.1,2
Minor congenital anomaly 
Relatively frequent structural anomaly not likely to cause any 
medical or cosmetic problems.1,2
Medicinal Product Names 
Product
Trade name used 
in the protocol
Trade name in the 
participating 
countries
Company name 
used in the protocol
Company name in the 
participating countries
Follitropin alfa
GONAL-F
GONAL-F 
(CH, KR, TW, VN)
Merck Serono
Merck Serono, Merck
Cetrorelix acetate
CETROTIDE
CETROTIDE 
(CH, KR, TW, VN)
Merck Serono
Merck Serono, Merck
Choriogonadotropin 
alfa
OVITRELLE
(Trade name in EU 
where the product 
is sourced)
OVIDREL 
(CH, KR, TW) 
OVITRELLE (VN)
Merck Serono
Merck Serono, Merck
Triptorelin acetate
GONAPEPTYL
(Trade name in EU 
where the product 
is sourced)
DECAPEPTYL 
(CH, KR, TW)
FERTIPEPTIL (VN)
Ferring 
Pharmaceuticals
Ferring 
Pharmaceuticals
Progesterone
CRINONE
CRINONE 
(KR, TW, VN)
Progesterone 
Sustained-release 
vaginal gel (CH)
Merck Serono
Merck Serono, Merck
CH: China; KR: South Korea; TW: Taiwan, VN: Vietnam
(Throughout this document, all trade names are written in capitals to comply with Ferring standard operating 
procedures)


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1
INTRODUCTION
1.1
Background
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) belonging to the 
pharmaceutical class of gonadotropins. It is intended for the following indication: “Controlled 
ovarian stimulation for the development of multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm 
injection (ICSI) cycle”. FE 999049 will be delivered as a solution for injection for subcutaneous 
self-administration by an injection pen.
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6®
cell line is well-characterised, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound 
polypeptide chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues 
with 5 intrachain-disulphide bonds. The β-subunit contains 111 amino acid residues with 
6 intrachain-disulphide bonds. Each subunit is N-glycosylated at two positions, and about 40% of 
the total mass is carbohydrates.
There are no commercially available rFSH products derived from human cell lines, but Ferring has 
recently submitted a Marketing Authorisation Application to the European Medicines Agency 
(EMA) for FE 999049 (October 2015) and received positive opinion from the Committee for 
Medicinal Products for Human Use (October 2016). Currently-approved rFSH products for the 
proposed indication, such as follitropin alfa (GONAL-F, Merck Serono) and follitropin beta 
(PUREGON, MSD), are derived from a Chinese hamster ovary (CHO) cell line. The amino acid 
sequence of FE 999049 is identical to the endogenous human FSH sequence and to that in existing 
CHO-derived rFSH products. Manufacturing from different cell systems leads to glycosylation 
heterogeneity between rFSH preparations. The glycosylation profile of recombinant proteins is 
dependent on the expressing cell line and the cell culture conditions. Differences in glycosylation
profile, sialic acid pattern and isoform profile, have been documented between FE 999049 and 
existing rFSH products from a CHO cell line. Comparison between the FE 999049 and the
GONAL-F and PUREGON profiles indicate differences in acidity and carbohydrate side chains. As 
CHO cells lack enzymatic functions to construct more complex carbohydrate structures found in 
humans, the glycosylation profile of FE 999049 is more complex. In addition, FE 999049 contains 
both α2,3 and α2,6 sialylation patterns, while CHO-derived rFSH products exclusively carry 
2,3 linked sialic acid; this difference further contributes to the observed differences in glycosylation 
profiles between FE 999049 and CHO-derived rFSH products.
Before the current trial, Ferring has completed four phase 1 trials, two phase 2 dose-response trials
(one conducted in EU and one in Japan) and two phase 3 trials as part of the clinical development 
programme for FE 999049. A total of 1,927 subjects have been included in the completed clinical 
trials, of whom 1,112 subjects were exposed to FE 999049. 
The two phase 2 trials were randomised, controlled, assessor-blind, multi-centre dose-response 
trials in which randomisation was stratified according to the subject’s anti-Müllerian hormone 
(AMH) level at screening. In both trials, a statistically significant dose-response relationship for 
FE 999049 with respect to the number of oocytes retrieved was observed for the overall population 
and for each AMH strata. Furthermore, the dose-response profile observed in Japanese and 
European subjects was similar. An individualised FE 999049 dosing regimen based on subject’s 


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AMH level and body weight was designed by modelling and simulation and prospectively tested in 
the phase 3 trials.  
During the phase 3 trials, 665 IVF/ICSI subjects were treated with FE 999049 in 1,012 treatment 
cycles. The two phase 3 trials supported the efficacy and safety of FE 999049 in the proposed 
indication. ESTHER-1 (trial 000004, Evidence-based Stimulation Trial with Human rFSH in 
Europe and Rest of World, ESTHER) was an efficacy trial designed to demonstrate non-inferiority 
of FE 999049 versus an approved recombinant FSH preparation with ongoing pregnancy rate and 
ongoing implantation rate as co-primary endpoints (as agreed with the EMA during Scientific 
Advice) and also to prospectively evaluate the outcome of the stratified medicine approach with the 
individualised FE 999049 dosing regimen based on the AMH level (measured by Elecsys® AMH 
Immunoassay, Roche Diagnostics) and body weight. ESTHER-2 (trial 000071) was a safety 
immunogenicity trial with up to two repeated treatment cycles in subjects who did not achieve an 
ongoing pregnancy in ESTHER-1. Both trials have been completed with respect to their 
intervention part.
The ESTHER-1 trial demonstrated non-inferiority of FE 999049 to GONAL-F for the two co-
primary endpoints, ongoing pregnancy rate and ongoing implantation rate, for both the per-protocol 
(PP) and modified intention-to-treat (mITT) populations. Across treatment groups and analysis 
populations, the ongoing pregnancy rate was in the range 31-33% and the ongoing implantation rate 
in the range 35-37%. 
The AMH dosing regimen for FE 999049 in controlled ovarian stimulation cycles led to a 
statistically significantly lower proportion of subjects with extreme ovarian response (<4 or ≥15 
oocytes retrieved or <4 or ≥20 oocytes retrieved) compared to the GONAL-F group, when adjusted 
for AMH. Furthermore, the value of the individualised FE 999049 dosing regimen was reflected in 
statistically significant and clinically relevant reductions in ovarian hyperstimulation syndrome 
(OHSS) risk management compared to GONAL-F. Overall, the incidence of preventive 
interventions for early OHSS among subjects treated with FE 999049 was half of that observed 
with GONAL-F, which was a statistically significant reduction. The combined incidence of early 
OHSS (all and those of moderate/severe grade) and/or preventive interventions for early OHSS was 
also statistically significantly reduced with FE 999049 in comparison to GONAL-F. Overall, there 
was a statistically significantly lower incidence of total OHSS and/or preventive interventions for 
early OHSS, and of total moderate/severe OHSS and/or preventive interventions for early OHSS 
with FE 999049 compared to GONAL-F.
A design similar to the phase 3 trial ESTHER-1 is being proposed for the present trial to be 
conducted in China and other Asian countries, with some modifications according to local practice.
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation.
For further information regarding FE 999049, please refer to the current edition of Investigator’s 
Brochure.
1.2
Scientific Justification for Conducting the Trial
The present trial is a phase 3 trial designed to assess the efficacy and safety of the human-derived 
rFSH preparation FE 999049 in women undergoing controlled ovarian stimulation for the 
development of multiple follicles for ART. FE 999049 is the first rFSH preparation derived from a 


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human cell line. The dosing regimen for FE 999049 will be individualised for each woman based 
on her AMH level and body weight. The trial will support the registration of FE 999049 in China
and other Asian countries.
1.3
Benefit / Risk Aspects
Benefits
The treatment cycle is provided to the participating subjects free of charge, as Ferring compensates 
the investigational sites for their expenses. Subjects participating in this trial may benefit by
achieving pregnancy. Subjects will be closely monitored, and they will have either the same or 
more frequent visits to the clinic compared to routine treatment, depending on local practice. In 
addition, the data obtained from the treatment cycle may provide useful information for optimising 
the ovarian response and for clinical planning of subsequent treatment cycles.
Risks
The risks associated with ART treatment, including the risks associated with controlled ovarian 
stimulation and clinical and laboratory procedures, are explained to the subjects as part of the 
counselling prior to starting treatment.
Gonadotropins
In this trial, controlled ovarian stimulation will be performed either with the individualised 
FE 999049 dosing regimen or with GONAL-F, a widely available recombinant FSH preparation 
used in line with its approved labelling. Both preparations will be administered subcutaneously.
To date, a total of 1,112 women have been exposed to FE 999049 in completed phase 1, 2 and 3
trials. The overall adverse event profile of the individualised FE 999049 dosing regimen appeared 
to be comparable to that of GONAL-F with the exception of fewer OHSS and/or preventive 
interventions with FE 999049. The most frequently reported adverse drug reactions during 1,012 
treatment cycles with FE 999049 in the phase 3 programme were headache, pelvic discomfort,
OHSS, pelvic pain, adnexa uteri pain, nausea and fatigue (all reported as common, i.e. 1% to 
< 10%). Uncommon adverse drug reactions reported with FE 999049 were diarrhoea, dizziness, 
mood swings, constipation, vomiting, abdominal discomfort, breast pain, breast tenderness, vaginal 
haemorrhage and somnolence. FE 999049 administered with the injection pen was well-tolerated 
with a low incidence of local injection site reactions. The severity of local injection site reactions 
was in general mild and comparable to that reported for GONAL-F administrated with the pre-filled 
pen.
The FE 999049 dosing regimen used in this trial is an individualised dosing regimen based on the 
subject’s AMH and body weight. AMH is a well-established predictor of ovarian response to 
gonadotropin treatment and was confirmed to be the best endocrine marker of ovarian response to 
FE 999049 treatment in the phase 2 trial. The FE 999049 dosing is based on the Elecsys® AMH 
assay from Roche Diagnostics which displays better performance with less variability than other 
AMH assays.3
GONAL-F is a commercially available CHO-derived rFSH preparation with established safety and 
efficacy4. The most frequent adverse events in relation to use of GONAL-F are as follows: 
headache, ovarian cysts and injection site reactions (all reported as very common, i.e. ≥10%) and 


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abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea and mild 
or moderate OHSS including associated symptomatology (all reported as common, i.e. 1% to 
<10%)4. The GONAL-F dosing regimen used in this trial is in line with labelling recommendations.
Concerning well-known risks associated with the use of gonadotropin products for ovarian 
stimulation, subjects are closely monitored throughout the trial. The most serious risk associated 
with gonadotropin treatment is OHSS. OHSS manifests itself with increasing degrees of severity. 
Moderate/severe OHSS is associated with marked ovarian enlargement, fluid accumulation and 
other complications. Early OHSS can potentially be prevented by withholding gonadotropins, 
withholding human chorionic gonadotropin (hCG) or administering gonadotropin-releasing 
hormone (GnRH) agonist for triggering of final follicular maturation. Very rare cases of serious 
allergic reactions have been reported after injection of gonadotropins. Concerning immunogenicity, 
the risk of treatment-induced anti-drug-antibodies for gonadotropin products is very low (estimated 
to be 0-2%5,6,7,8,9,10,11) and no safety or efficacy concern has been identified with regards to 
immunogenicity with FE 999049 or with the available rFSH preparations.
Procedures and Concomitant Fertility Medications
Subjects will undergo standard ART treatment procedures (e.g. transvaginal ultrasound, blood 
sampling, oocyte retrieval and transfer) and also receive concomitant fertility medication as part of 
the treatment cycle in this trial. The transvaginal ultrasound examinations may be associated with 
mild discomfort and a very rare risk of infection. The blood sampling might be associated with mild 
discomfort, bruising and a very rare risk of infection. The oocyte retrieval procedure is associated 
with discomfort and very rarely infections and bleeding. The transfer procedure is associated with 
mild discomfort and very rarely infections and mild bleeding. The concomitant fertility medications 
are approved products and are considered generally well-tolerated. The most frequently reported
adverse events with these concomitant medication products are similar to those reported for FSH 
preparations, such as headache, injection site reactions, pelvic pain, abdominal pain, abdominal 
distension and allergic reactions. Furthermore, the vaginal progesterone has been associated with 
vulvovaginal disorders and uterine spasms (at a frequency of 1-2%).
Pregnancy-related Events
A serious concern associated with ART cycles is the frequency of multiple pregnancies / births and 
the related neonatal health problems. To minimise the risk of multiple gestations, subjects will have 
transfer of 1 or 2 embryos of the highest quality available. The incidence of miscarriage and ectopic 
pregnancy is higher in women undergoing controlled ovarian stimulation than in women conceiving 
spontaneously, though the risk of ectopic pregnancy is mainly higher in patients with a history of 
tubal infertility. Furthermore, the prevalence of congenital malformations after ART may be 
slightly higher than after spontaneous conceptions; this is thought to be due to differences in 
parental characteristics (e.g. maternal age and sperm characteristics) and multiple pregnancies.


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Benefits / Risks
Participation in this trial is not expected to have a negative influence on the subject’s likelihood of 
conceiving compared to normal clinical practice. Furthermore, participation does not imply extra 
risks for the subjects in comparison to routine controlled ovarian stimulation. In conclusion, the 
evaluation of benefits and risks indicate that participation in this trial is associated with a
favourable benefit-risk ratio.


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to 
ongoing pregnancy rate in women undergoing controlled ovarian stimulation
Secondary Objectives

To compare the clinical benefits of FE 999049 in its dosing regimen to those of GONAL-F 
with respect to efficacy and safety

To compare FE 999049 with GONAL-F with respect to ovarian response including 
follicular development and endocrine profile, as well as with respect to embryo 
development

To assess the population pharmacokinetics of FE 999049

To compare FE 999049 with GONAL-F with respect to treatment efficiency

To compare FE 999049 with GONAL-F with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To evaluate the immunogenicity of FE 999049 after one treatment cycle

To perform a health economic analysis comparing FE 999049 with GONAL-F
2.2
Endpoints
Primary Endpoint

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
embryos transferred)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer
divided by number of embryos transferred)

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes
retrieved


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
Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
embryo transfer cancellation due to excessive ovarian response / OHSS risk

Number and size of follicles on stimulation day 6 and end-of-stimulation

Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 
oocytes retrieved

Percentage of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 after oocyte retrieval

Circulating concentrations of LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Circulating concentrations of FSH on stimulation day 6, end-of-stimulation and oocyte 
retrieval as well as FSH population pharmacokinetic parameters

Total gonadotropin dose and number of stimulation days

Proportion of subjects with investigator-requested gonadotropin dose adjustments

Frequency and intensity of adverse events

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralising capacity

Frequency and intensity of immune-related adverse events

Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical intervention) and vanishing twins

Technical malfunctions of the administration pen
Post-trial Information

Live birth rate and neonatal health, including minor/major congenital anomalies, at birth and 
at 4 weeks after birth


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A diagram illustrating the trial period is shown in Figure 3-1.
Figure 3-1
Trial Diagram – Trial Period


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3.1.2
Overall Design and Control Methods
Trial Design 
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, Pan-Asian non-
inferiority trial comparing the efficacy and safety of two rFSH preparations, FE 999049 and 
follitropin alfa (GONAL-F), in first cycle subjects aged 20-40 years undergoing controlled ovarian 
stimulation for IVF/ICSI following a GnRH antagonist protocol. The trial has been designed to 
demonstrate non-inferiority of FE 999049, a human cell line-derived rFSH preparation, versus an 
approved CHO-derived rFSH preparation, i.e. GONAL-F, with ongoing pregnancy rate as the 
primary endpoint. Secondary endpoints include pharmacokinetic profile of FE 999049, 
pharmacodynamic parameters of FSH action as well as efficacy and safety parameters related to 
controlled ovarian stimulation. The assessor-blind design ensures that the investigators and other 
assessors such as embryologists and central laboratory personnel are blinded to individual treatment 
allocation. The sponsor will break the blind when all subjects have completed the end-of-trial visit, 
in order to evaluate efficacy and safety up to the ongoing pregnancy visit.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio 
to treatment with either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation 
will be stratified by centre and according to age (<35, 35-37 and 38-40 years). Subjects randomised 
to FE 999049 will have their individual dose determined on the basis of their AMH level at 
screening and their body weight at randomisation. The daily FE 999049 dose will be fixed 
throughout the stimulation period. For subjects with low AMH (<15 pmol/L) the daily FE 999049 
dose is 12 μg, irrespective of body weight. For subjects with high AMH (≥15 pmol/L) the daily
FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on actual 
AMH and body weight (note, the minimum and maximum allowed daily doses are 6 µg and 12 µg, 
respectively). Subjects can be treated with FE 999049 for a maximum of 20 days, and coasting is 
not allowed. For subjects randomised to GONAL-F, the dosing regimen is within labelling. The 
starting daily dose of GONAL-F is 150 IU and fixed for the first five stimulation days after which it 
may be adjusted by 75 IU per day based on the individual response. The maximum daily 
GONAL-F dose allowed is 450 IU. Subjects can be treated with GONAL-F for a maximum of 
20 days, and coasting is not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When the leading follicle reaches ≥15 mm, visits must be 
performed daily. To prevent a premature LH surge, a GnRH antagonist will be initiated on 
stimulation day 6 and continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥3 follicles with a diameter ≥17 mm are observed. If there are 
<25 follicles with a diameter ≥12 mm, hCG will be administered. If there are 25-35 follicles with a 
diameter ≥12 mm, a GnRH agonist can be administered or the cycle can be cancelled. In case of 
excessive follicular development, defined as >35 follicles with a diameter ≥12 mm, the cycle is to 
be cancelled. If it is judged by the investigator that ≥3 follicles with a diameter ≥17 mm cannot be 
reached, but 1 or 2 follicles with a diameter ≥17 mm are observed, the cycle may either be 
cancelled due to poor follicular development or triggering of final follicular maturation is to be 
induced, as judged by the investigator.


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Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Rescue ICSI is not allowed. Fertilisation and embryo 
development will be assessed from oocyte retrieval to the day of transfer. For subjects who 
underwent triggering of final follicular maturation with hCG, transfer is performed on day 3 
(embryo stage) after oocyte retrieval. Subjects <35 years at randomisation will have single embryo 
transfer if a good-quality embryo is available; otherwise, double embryo transfer will be performed 
(and single transfer if two embryos are not available). Subjects ≥35 years at randomisation will 
have double embryo transfer (and single transfer if two embryos are not available). Remaining 
embryos may be cryopreserved in accordance with local guidelines and/or regulations. For subjects 
who underwent triggering of final follicular maturation with GnRH agonist, no transfer will take 
place in the current fresh cycle and the embryos available will be cryopreserved on day 3, 5 or 6,
according to local practice. All cryopreserved embryos can be used by the subject after completion 
of the trial, in accordance with local guidelines and/or regulations. 
Vaginal progesterone will be provided for luteal phase support from the day of oocyte retrieval or 
the day after and at least until clinical pregnancy. Thereafter the investigator may decide to 
continue up to the ongoing pregnancy visit, according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs. A serum βhCG test will be
performed 13-15 days after transfer, clinical pregnancy will be confirmed by transvaginal 
ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be confirmed by transvaginal or 
abdominal ultrasound 10-11 weeks after transfer. 
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and haematology parameters as well as anti-FSH antibodies. Endocrine 
parameters are assessed at screening, stimulation day 1, stimulation day 6 and end-of-stimulation, 
and furthermore FSH is also assessed at oocyte retrieval. Clinical chemistry and haematology 
parameters are assessed at screening, stimulation day 1, end-of-stimulation and end-of-trial. Anti-
FSH antibodies are collected at four occasions. The first blood sample is taken at the screening visit 
and is exclusively used as back-up samples for the anti-drug antibody assay development. The 
subsequent three samples are used for analysis of anti-FSH antibodies in the individual subjects in 
the trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-dosing: 5-10 
days after the last FE 999049 or GONAL-F dose (it may coincide with the transfer visit) and 19-28 
days after the last FE 999049 or GONAL-F dose (it may coincide with the βhCG test visit). 
Subjects with a treatment-induced anti-FSH antibody response will be followed until the response 
has become negative or returned to the pre-dosing level, with a maximum follow-up period of one 
year. 
Local tolerability of FE 999049 and GONAL-F following subcutaneous administration will be 
assessed by the subject three times daily: immediately, 30 minutes and 24 hours after each 
injection. The assessment of injection site reactions will be made throughout the stimulation period 
and recorded by the subjects in a diary. 
Post-Trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up. All subjects with an ongoing 
pregnancy will be followed till delivery to gather information on live birth rate. Furthermore, data 
will be gathered on neonatal health, including any congenital anomalies, at birth and at 4 weeks 
after birth. These data will be reported separately.


Follitropin Delta, FE 999049
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3.1.3
Trial Schedule
First patient first visit (FPFV):
Q2 2017
Last patient first visit (LPFV):
Q4 2018
Last patient last visit (LPLV):
Q1 2019
Post-trial follow-up completed:
Q1 2020
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise 1,000 subjects from 15-30 sites in mainland China and other Asian 
countries. Of the 1,000 subjects it is expected that 740 subjects will be recruited in China (i.e.
possessing a Chinese identification card and having native Chinese parents) and the rest from other 
Asian countries, potentially Taiwan, South Korea and Vietnam. It is estimated that approximately 
1,200 subjects should be screened to achieve 1,000 subjects eligible for randomisation. 
The assumptions underlying the sample size calculations will be monitored in a blinded manner 
(see sections 3.3, 9.1 and 9.10), and the number of randomised subjects may be adjusted up to a 
maximum of approximately 1,144 subjects, corresponding to an observed ongoing pregnancy rate 
of 50%.
3.3
Interim Analysis and Administrative Review
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned. 
The overall ongoing pregnancy rate will be monitored in a blinded manner. This monitoring will be 
performed by the project statistician who will evaluate the overall ongoing pregnancy rate in 
relation to the assumptions underlying the sample size.
3.4
Data Monitoring Committee
No Data Monitoring Committee will be established for this trial.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
The primary objective of the trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation.
Strict criteria have been incorporated in the design of this comparative trial to properly assess the 
effect of the interventions on treatment outcome. In general, standardisation of criteria, timing of 
assessments, procedures and interventions have to a great extent been incorporated in the design of 
this trial to minimise variation12,13,14.


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This is a randomised controlled trial using an approved gonadotropin preparation as active 
comparator. It is a parallel group design restricted to a single treatment cycle, as this design is 
preferred over a cross-over design in fertility trials. The trial will be open-label but assessor-blind. 
A double-blind design is not considered feasible for the present trial for various practical reasons, 
which are described in detail in section 3.5.3. The assessor-blinding will ensure blinding and 
thereby unbiased evaluation by the investigators, embryologists and central laboratory personnel. 
Similarly, Ferring staff will also remain blinded to individual subject treatment allocation during 
the conduct of the trial. The trial will be a multi-centre Pan-Asian trial. This set-up ensures that the 
required number of subjects can be recruited within a reasonable time and also has the advantage 
that it should facilitate subsequent generalisation of the results.
The trial is designed to demonstrate non-inferiority of FE 999049 versus GONAL-F with respect to 
ongoing pregnancy rate. The non-inferiority margin for the primary endpoint has been set at -10.0% 
(absolute) in line with other recent large randomised controlled trials in ART15,16,17 and the power is 
90% for the overall trial population and 80% power for the Chinese population. A non-inferiority 
margin of -8.0% (and a power of 80%) has been implemented in the pivotal phase 3 trial 
(ESTHER-1). However, the present phase 3 trial to be conducted in China and other Asian 
countries will not be a stand-alone trial but will be supported by the ESTHER-1 trial conducted in 
Europe and the Rest of World, arguing for a less strict non-inferiority limit in the present trial.
Furthermore, narrowing the non-inferiority margin with 2% points (i.e. from -10.0% to -8.0%) 
would increase the sample size by 516 subjects but would only reduce the maximum allowed 
difference in the point estimates for the ongoing pregnancy rate for FE 999049 required to 
demonstrate non-inferiority versus the comparator, by 0.8% (further details are provided in 
section 9.1), which is not clinically relevant.
Subjects will undergo controlled ovarian stimulation with an individualised dosing regimen of 
FE 999049 based on the subject’s AMH level and body weight, or with a labelling recommended 
dosing regimen of GONAL-F, following a GnRH antagonist protocol. The daily FE 999049 dose is 
fixed throughout the stimulation period in this trial. The daily GONAL-F dose is fixed for the first 
five stimulation days after which it may be adjusted by 75 IU per day based on the individual 
response, which is within the recommendations in the labelling. The selection of doses is described 
in detail in section 3.5.4. Monitoring of ovarian response by transvaginal ultrasound and blood 
sampling for assessment of several endocrine parameters will be performed regularly during 
stimulation.
Oocytes will be inseminated by either IVF or ICSI reflecting the procedures used in the target 
population for the proposed indication. Embryos will be cultured for 3 days and embryo 
development will be assessed from oocyte retrieval till the day of transfer, allowing evaluation of 
embryo development until cleavage stage. The duration of culture in this trial is adapted to clinical 
practice in Asia where transfer on day 3 after oocyte retrieval is the most common. In contrast, 
culture to blastocyst stage and transfer on day 5 after oocyte retrieval are incorporated in the 
phase 3 trial ESTHER-1, reflecting clinical practice in the participating countries in that trial.
The present protocol requires single or double embryo transfer on day 3 for all women, depending 
on age, with at least one good-quality embryo available. The scientific justification for 
incorporating these features is that it will ensure that the data obtained in this trial are in line with 
the current clinical directions taken for maintaining efficacy (i.e. ongoing pregnancy rates) and 
minimising risks (i.e. multiple pregnancies)18,19,20. The embryo transfer policy in this trial has been 


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adapted to clinical practice in Asia, and is not identical to the policy in the ESTHER-1 trial where 
single embryo (blastocyst) transfer is more strictly enforced.
Luteal phase support of the endometrium will be provided via vaginal progesterone. The 
progesterone product used in ESTHER-1 is not approved in all Asian countries and therefore 
another progesterone product which is approved in China and the other participating Asian 
countries will be used in the present trial. Furthermore, luteal phase support in this trial continues to 
at least the clinical pregnancy visit while it was stopped at the βhCG visit in ESTHER-1; this is a 
reflection of differences in local clinical practice.
Subjects who achieve a pregnancy will be followed till live birth to collect information on 
pregnancy outcome. In addition, neonatal health data will be gathered at birth and at 4 weeks after 
birth. These data will be reported separately.
3.5.2
Selection of Endpoints
The ultimate objective of fertility treatment is live birth. Ongoing pregnancy is considered an 
appropriate primary endpoint for efficacy trials, as ongoing pregnancy is the best predictor of live 
birth and it is definable within a time period in which other potential confounding factors are more 
easily controlled14.
One of the secondary objectives is to compare the clinical benefits of FE 999049 in its dosing 
regimen to those of GONAL-F with respect to efficacy and safety. This objective is addressed by 
multiple endpoints to address it from several angles; i.e. proportion of subjects with extreme 
ovarian response, early OHSS (including moderate/severe grade), preventive interventions for early 
OHSS, cycle cancellations due to poor ovarian response development and cycle cancellation due to 
excessive ovarian response.
Additional secondary endpoints include pharmacodynamic parameters, such as ovarian response in 
terms of follicular development, endocrine profile and oocytes retrieved, and also oocyte / embryo 
quality. Follicular development and endocrine profile will be evaluated after the initial 5 days (i.e. 
before any potential dose adjustments in the GONAL-F group and before start of the GnRH 
antagonist) as well as at the end of stimulation. The endocrine profile consists of FSH, luteinising 
hormone (LH), estradiol, progesterone, inhibin A and inhibin B. Serum FSH levels will be used to 
assess the population pharmacokinetics associated with repeated dosing of FE 999049, which is 
also a secondary endpoint. 
Clinical safety endpoints cover adverse events, early and late OHSS, preventive interventions for 
early OHSS, local tolerability, clinical chemistry and haematology parameters, immunogenicity and 
pregnancy-related events (i.e. multi-fetal gestations, biochemical pregnancies, spontaneous 
abortions, ectopic pregnancies and vanishing twins). Pre-defined local tolerability reactions, i.e. 
redness, pain, itching, swelling and bruising, will be assessed by the subjects on three occasions 
spanning from immediately after the subcutaneous injection till 24 hours after. Presence of anti-
FSH antibodies will be evaluated 5-10 and 19-28 days after the last administration of FE 999049 or 
GONAL-F for assessment of a potential immunoglobulin M (IgM) response and a fully mounted 
immunoglobulin G (IgG) immune response, respectively21,22,23. Technical malfunction of the pens 
used for administration of the gonadotropin preparations will also be monitored.
Post-trial activities cover follow-up of ongoing pregnancies up to live birth. Neonatal health data at 
birth and at 4 weeks after birth will be gathered. 


Follitropin Delta, FE 999049
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In conclusion, the list of primary and secondary endpoints is appropriate for an efficacy trial and 
furthermore includes items of special interest considering the profile of FE 999049 and specific
recommendations from EMA.
3.5.3
Blinding
The two investigational medicinal products (IMPs) differ in presentation as FE 999049 is provided 
as a liquid in a cartridge to be administered via an injection pen whereas GONAL-F is provided as a 
liquid in a pre-filled pen. Furthermore, GONAL-F is manufactured by Merck Serono and bought 
commercially for use in this phase 3 trial. Therefore, a double-blind, double-dummy design is not 
feasible. The trial, however, is assessor-blind, ensuring unbiased evaluation by the investigators, 
embryologists and central laboratory personnel. 
One or more trial medication delegate(s) will be identified at each site. The trial medication 
delegate will be responsible for all trial medication related issues, both practically at the clinic and
in interactions with the subject. To maintain the assessor-blinding, the trial medication delegate is 
not allowed to perform any assessments in the trial. Information on treatment allocation is only 
available to the trial medication delegate. The investigator does not have access to these modules in 
the electronic case report form (e-CRF). Thus, only the trial medication delegate at the site, the 
monitors and the participating subjects will know the treatment allocation once the subjects are 
randomised. Precaution will be taken to ensure that the treatment allocations are not available to the 
investigators or other assessors throughout the trial. Subjects will be clearly instructed to only 
discuss their treatment allocation with the trial medication delegate, and to not mention it to the 
investigator.
Drug accountability forms and other forms identifying treatment allocation are kept unavailable to 
the investigator. The subject will during the informed consent process be informed, both verbally 
and in writing, to not disclose her treatment allocation to the investigator. Trial staff is provided 
training in the importance of maintaining blinding, and trial medication delegates are also helped to 
set up systems at the clinic.
The trial medication delegate will dispense the trial medication to the subject (and may also do the 
actual administration at the clinic, if required). The investigator will, based on the follicular 
development, judge if dose adjustments are recommended and state his/her directions on a form 
developed for that purpose, which will be used to inform the trial medication delegate. Depending 
on whether the subject is being treated with FE 999049 or GONAL-F, the trial medication delegate
will provide detailed instructions to the subject in line with the dosing regimen for each preparation
as outlined in the protocol. In other words, if the investigator recommends a dose adjustment, the 
trial medication delegate will implement a decrease or increase of 75 IU per day as applicable if the 
subject is in the GONAL-F group, while no dose adjustments will be implemented if the subject is 
in the FE 999049 group. Requests for cycle cancellation due to inappropriate response or other 
medical reasons are followed, irrespective of treatment group.
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and sponsor’s responsible medical officer) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when all subjects have completed 
the end-of-trial visit and the trial database is declared clean and locked.


Follitropin Delta, FE 999049
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3.5.4
Selection of Doses in the Trial
FE 999049
Modelling and simulation based on the efficacy and safety data obtained in the European phase 2 
trial have been used to establish the overall dosing regimen for FE 999049 in the phase 3 trials. 
This is the same dosing regimen that was used in the phase 3 trial 000004 (ESTHER-1), where it 
has been shown to reduce the risk of extreme ovarian response, the risk of cycle cancellation due to 
excessive ovarian response, and the risk of early moderate/severe OHSS and/or prevention 
interventions for early OHSS, while obtaining a pregnancy rate that is non-inferior to GONAL-F.
AMH and body weight were found to influence the dose-response with regard to obtaining the aim 
of the model of the FE 999049 dosing regimen. The impact of body weight on ovarian response is 
clinically relevant for low dose levels of FE 999049, while the effect is only minor at dose levels of 
12 μg and above. The individualised dosing regimen of FE 999049 in the present trial is described 
in detail in section 5.1.1 and is summarised as follows: For subjects with low AMH (<15 pmol/L)
the daily FE 999049 dose is 12 μg, irrespective of body weight, and for subjects with high AMH
(≥15 pmol/L) the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, 
depending on the baseline AMH level. The minimum and maximum allowed daily doses are 6 µg 
and 12 µg, respectively.
GONAL-F
Subjects randomised to GONAL-F will be dosed according to the approved labelling. The starting 
dose of GONAL-F in this trial is 150 IU, which is the same starting dose as used in the ESTHER-1
trial. The European4, Chinese24, Taiwanese25, South Korean26 and Vietnamese27 labelling’s for 
GONAL-F state a starting dose of 150-225 IU, but provide no recommendation for when to use 
150 IU and when to use 225 IU. In the absence of a recommendation from the manufacturer, the 
lowest effective dose has been selected as this would be a reasonable approach in clinical practice, 
especially as this trial will include subjects with no previous controlled ovarian stimulation for 
IVF/ICSI. This choice is also in line with the US labelling of GONAL-F28 which recommends a 
starting dose of 150 IU in patients where the endogenous gonadotropin levels are not suppressed 
(such as the GnRH antagonist cycle, where prevention of premature LH surge is only initiated after 
5 days of stimulation). The GONAL-F starting dose is fixed for the first five stimulation days after 
which it may be adjusted by 75 IU per day based on the individual response. For GONAL-F, the 
maximum daily dose allowed is 450 IU. 
Concomitant Fertility Medication 
The doses and overall treatment regimens for the GnRH antagonist, hCG and progesterone products 
are in line with the recommendations in the respective products’ labelling for the indication of ART
and/or standard clinical practice. The GnRH agonist is included as an option for triggering of final 
follicular maturation in subjects with 25-35 follicles with a diameter ≥12 mm, as this approach is 
associated with almost an elimination of the risk of early moderate/severe OHSS despite high 
ovarian response. The use of a GnRH agonist for triggering of final follicular maturation in a GnRH 
antagonist protocol is well-described in the literature and considered an acceptable alternative to 
cycle cancellation29,30,31,32,33.


Follitropin Delta, FE 999049
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3.5.5
Selection of the Trial Population
This trial will include women undergoing their first IVF/ICSI cycle, as this group of subjects is 
considered the most appropriate population for a trial comparing the efficacy between 
gonadotropins and furthermore when using different dosing regimens. The subjects have been
diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have partners 
diagnosed with male factor infertility, and are considered eligible for IVF or ICSI. The trial will 
include women up to 40 years of age and will thereby cover the patient age span in which most 
ART treatments are performed. The allowed body mass index (BMI) is 17.5-32.0 kg/m2, thus 
including underweight, normal weight, overweight and obese subjects.
The exclusion criteria incorporate the contraindications for the use of gonadotropins.
Altogether, the population selected for this trial would be expected to be representative for patients 
undergoing controlled ovarian stimulation in IVF/ICSI cycles.
3.5.6
Follow-up Procedures
Post-trial Activities
Post-trial activities cover pregnancy and neonatal health follow-up at birth and at 4 weeks after 
birth as described in section 7.4.1. 
Safety Follow-up
As a safety precaution, subjects with treatment-induced anti-FSH antibody response will be 
followed until the response has become negative or returned to the pre-dosing level for at least 2 
consecutive measurements with a maximum follow-up period of one year .The assessments will 
also be terminated if the subject commences a new treatment cycle with any gonadotropin 
preparation. Safety follow-up also includes follow-up on adverse events (with onset during the trial 
and classified as serious or related to IMP) until it is resolved or until the medical condition of the 
subject is stable.
Access to Therapy after End-of-trial
Concerning access to therapy after completion of the trial, FE 999049 is currently under clinical 
development and cannot be offered to subjects after participation in this clinical trial. However, 
several gonadotropin preparations are approved for controlled ovarian stimulation and are 
commercially available.


Follitropin Delta, FE 999049
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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects must meet all of the criteria listed below to be eligible for participation in the trial.
1. Informed Consent Documents signed prior to screening evaluations.
2. In good physical and mental health in the judgement of the investigator.
3. Asian pre-menopausal females between the ages of 20 and 40 years. The subjects must be at 
least 20 years (including the 20th birthday) when they sign the informed consent and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
4. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised ASRM classification, 1996) or with partners diagnosed with 
male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm 
injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
5. Infertility for at least one year before randomisation for subjects <35 years or for at least 
6 months for subjects ≥35 years (not applicable in case of tubal or severe male factor 
infertility).
6. The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
7. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no polyps and no congenital structural abnormalities which are
associated with a reduced chance of pregnancy) within 1 year prior to randomisation. 
9. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would 
contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 
1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.
10. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 2 years prior to randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. Willing to accept transfer of 1-2 embryos.


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4.1.2
Exclusion Criteria
Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.
1. Known endometriosis stage III-IV (defined by the revised ASRM classification, 1996).
2. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
3. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 
4. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
5. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
6. Known inherited or acquired thrombophilia disease.
7. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
8. Known porphyria.
9. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
10. Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records; i.e. not based on the anti-FSH antibody analyses conducted in the trial). 
11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
12. Known moderate or severe impairment of renal or hepatic function.
13. Any abnormal finding of clinical chemistry, haematology or vital signs at screening which 
is clinically significant as judged by the investigator.
14. Currently breast-feeding.
15. Undiagnosed vaginal bleeding.
16. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
17. Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine 
abnormalities or retained intrauterine device.
18. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomisation) or contraindication to pregnancy.
19. Known current active pelvic inflammatory disease.
20. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral 
contraceptives, progestogen or estrogen preparations.


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21. Use of hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomisation.
22. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
23. Current or past (1 year prior to randomisation) abuse of alcohol or drugs.
24. Current (last month) intake of more than 14 units of alcohol per week.
25. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
26. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
27. Previous participation in the trial.
28. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The participating subjects will be recruited among the patients attending the clinics included in the 
trial. Advertisements may be used if approved by the local ethics committee and regulatory 
authorities, as applicable according to local regulations.
A screening number is allocated to each subject who has given written informed consent to 
participate in the trial. A subject must always be assigned to the lowest available screening number 
at each site. A subject screening / enrolment log for all screened subjects must be maintained by the 
investigator.
4.2.2
Randomisation
On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to treatment with 
either FE 999049 or GONAL-F, and stimulation will be initiated. Randomisation is performed 
centrally through the e-CRF and will be stratified according to age (<35, 35-37 and 38-40 years).
The randomisation number will be allocated to the subject together with the treatment allocation 
and starting dose. When a subject is randomised to the trial, she will always be assigned to the 
lowest available randomisation number. An independent statistician at the Ferring Global 
Biometrics Department will prepare a computer-generated randomisation list and randomisation is 
performed in blocks. Blocks will be maintained within trial sites, i.e. the randomisation will be 
stratified by trial site. The block size will only be revealed when the trial database is declared clean 
and locked. An overview of recruitment will be recorded on a subject identification code list for all 
randomised subjects kept by the investigator. 


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4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
The subjects must not have used fertility modifiers, including DHEA, metformin or cycle 
programming with oral contraceptives, progestogen or estrogen preparations, or hormonal 
preparations (except for thyroid medication) during the last menstrual cycle before randomisation.
The subject must also not use metformin as ongoing treatment during the trial.
During the trial it is prohibited to administer any other fertility medications, than the ones provided 
as part of the trial regimen.
Dopamine agonist for preventive intervention of OHSS is not allowed.
4.3.2
Prohibited Therapy
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial.
4.4
Withdrawal Criteria
Withdrawal from Trial
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. 
If, at the time of discontinuation, a dose of the IMP has already been administered, the subject must 
be advised to participate in the follow-up safety investigations, which will include all post-dosing 
antibody assessments and all procedures outlined in the end-of-trial visit.
The investigator also has the right to withdraw subjects. For any discontinuation, the investigator 
will obtain all the required details and document the date of the premature termination and the main 
reason in the e-CRF.
Withdrawal of Consent
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analysed. This will be described in the Informed Consent Documents. The subject 
can request destruction of samples which would otherwise have been kept in storage.
4.5
Subject Replacement
A subject can only be assigned one screening number and one randomisation number.
Subjects who discontinue prematurely from the trial after randomisation are not to be replaced, i.e. 
randomisation numbers are uniquely linked to each subject and cannot be re-used.


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5
TREATMENTS
5.1
Investigational Medicinal Products (IMPs)
Subjects will be randomised to the following IMPs in a 1:1 ratio in the trial:

FE 999049 manufactured by Ferring will be provided as a cartridge and an injection pen. 
One subcutaneous injection will be administered daily, starting on day 2-3 of the subject’s 
menstrual cycle and continued throughout the stimulation period. 

GONAL-F (follitropin alfa for injection) manufactured by Merck Serono is provided as a 
pre-filled pen containing a liquid formulation for injection. One subcutaneous injection will 
be administered daily, starting on day 2-3 of the subject’s menstrual cycle and continued 
throughout the stimulation period.
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for FE 999049 and the Prescribing Information for GONAL-F.
5.1.1
FE 999049 Dosing Regimen
Subjects randomised to FE 999049 will have their individual dose determined on the basis of their 
AMH level at screening and their body weight at randomisation. For subjects with low AMH 
(<15 pmol/L) the daily FE 999049 dose is 12 μg, irrespective of body weight. For subjects with 
high AMH (≥15 pmol/L) the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 
0.10 μg/kg, i.e. dependent on actual AMH and body weight. The minimum and maximum allowed 
daily doses are 6 µg and 12 µg, respectively. 
The daily FE 999049 dose will be fixed throughout the stimulation period. Dosing will continue 
until the criterion for triggering of final follicular maturation has been met. Subjects can be treated 
with FE 999049 for a maximum of 20 days. Coasting is not allowed. Overdose and medication 
errors of IMP with and without clinical consequences will be tracked in the e-CRF and reviewed 
ongoing by Ferring GPV.
The complete FE 999049 dosing regimen is tabulated in detail in Table 5-1.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Table 5-1
FE 999049 Dosing Regimen
Treatment 
group
AMH 
concentration 
(pmol/L)
Daily dose fixed throughout 
stimulation
Minimum 
daily dose
Maximum 
daily dose
FE 999049        <15
12 μg 
12 μg
15-16
0.19 μg/kg
6 µg
12 μg
17
0.18 μg/kg
6 µg
12 μg
18
0.17 μg/kg
6 µg
12 μg
19-20
0.16 μg/kg
6 µg
12 μg
21-22
0.15 μg/kg
6 µg
12 μg
23-24
0.14 μg/kg
6 µg
12 μg
25-27
0.13 μg/kg
6 µg
12 μg
28-32 
0.12 μg/kg
6 µg
12 μg
33-39 
0.11 μg/kg
6 µg
12 μg
≥40 
0.10 μg/kg
6 µg
12 μg
AMH concentration will be rounded off to integers.
Subjects can be treated for a maximum of 20 days.
The FE 999049 preparation is administered as a single daily subcutaneous injection in the 
abdomen. The dose must not be split into two injections. To minimise local injection site reactions, 
it is advisable to change injection site regularly.
The first FE 999049 injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer FE 999049.
Calculation of the FE 999049 Dose and Setting the Dose on the FE 999049 Pen
The subject’s serum AMH concentration will be available from the blood sample taken at screening 
and analysed by a central laboratory using a qualified assay. The AMH concentration will be 
provided from the central laboratory directly to the e-CRF. The subject’s body weight will be 
measured at randomisation using a calibrated scale and performed without shoes and overcoat. The 
body weight result will be entered into the e-CRF. The FE 999049 dosing algorithm has been 
programmed in the e-CRF, which calculates the FE 999049 dose based on the subject’s AMH and 
body weight. 
The FE 999049 injection pen has a dosing scale numbered from 0 to 24 μg. Each number is 
separated by two lines, each representing 0.33 μg. Thus, the pen can be set to supply doses rounded 
to the nearest 0.33 μg. Rounding off of the calculated dose may be needed, as in this example of a 
subject weighing 60.0 kg with an AMH level of 30 pmol/L for whom the calculated dose is 7.2 μg 
(0.12 μg/kg * 60.0 kg) which will then be rounded to 7.33 μg, i.e. 7 μg + 1 line on the pen. The 
minimum daily dose of 6 µg will be administered in cases like this example: a subject weighing 
40.0 kg and with an AMH level of 40 pmol/L will have a calculated dose of 4.0 µg (0.10 µg/kg * 
40.0 kg) which will then be rounded up to 6 µg. The e-CRF will provide the calculated dose in an 
output that matches the numbers and lines on the injection pen; i.e. any rounding off will be done 
automatically prior to providing the subject’s calculated dose.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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The trial medication delegate will be instructed and trained in the correct use of the pen, so that 
correct instructions can be provided to the subjects.
5.1.2
GONAL-F Dosing Regimen
For subjects randomised to GONAL-F, the dosing regimen is within labelling. The starting dose of 
GONAL-F is 150 IU per day and fixed for the first five stimulation days, after which it may be 
adjusted by 75 IU per day based on the individual response. The maximum daily GONAL-F dose 
allowed is 450 IU. Dosing will continue until the criterion for triggering of final follicular 
maturation has been met. Subjects can be treated with GONAL-F for a maximum of 20 days.
Coasting is not allowed. Overdose and medication errors of IMP with and without clinical 
consequences will be tracked in the e-CRF and reviewed ongoing by Ferring GPV.
The GONAL-F dosing regimen is shown in detail in Table 5-2.
Table 5-2
GONAL-F Dosing Regimen
Treatment 
group
Starting dose 
stimulation day 1-5
Daily dose stimulation day 6 and 
onwards
Maximum 
daily dose
GONAL-F
150 IU
Adjustments of 75 IU per day allowed 
according to the individual response.
450 IU
Subjects can be treated for a maximum of 20 days.
The GONAL-F preparation is administered as a single daily subcutaneous injection in the abdomen. 
The dose must not be split into two injections. To minimise local injection site reactions, it is 
advisable to change injection site regularly.
The first GONAL-F injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer GONAL-F.
Setting the Dose on the GONAL-F Pen
The GONAL-F pen has a dosing scale applicable for the starting dose and subsequent potential 
dose adjustments. 
The trial medication delegate will be instructed and trained in the correct use of the pen, so that 
correct instructions can be provided to the subjects.
5.2
Non-Investigational Medicinal Products (NIMPs)
As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the following 
non-investigational medicinal products (NIMPs) as illustrated in Table 5-3.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Table 5-3
Non-Investigational Medicinal Products (NIMPs)
NIMP
Trade name
Timing
GnRH 
antagonist
CETROTIDE
0.25 mg subcutaneous injection once daily, starting on 
stimulation day 6 and continued throughout the stimulation 
period.
hCG
OVITRELLE
A single 250 µg subcutaneous injection as soon as reaching 
the criterion for triggering of final follicular maturation with 
hCG (≥3 follicles with a diameter ≥17 mm and <25 follicles 
with a diameter ≥12 mm).
GnRH agonist
GONAPEPTYL
Two consecutive injections of 0.1 mg, i.e. a total of 0.2 mg,
as soon as reaching the criterion for triggering of final 
follicular maturation with GnRH agonist (≥3 follicles with a 
diameter ≥17 mm and 25-35 follicles with a diameter 
≥12 mm), unless the cycle is cancelled.
Progesterone
CRINONE
90 mg vaginal gel (8%) once daily, starting on the day of 
oocyte retrieval or the day after and continued at least until 
clinical pregnancy. Progesterone support will be terminated 
earlier in case of no transfer, menses, negative βhCG or 
pregnancy loss.
(Note: not required for subjects who undergo triggering of 
final follicular maturation with GnRH agonist)
All NIMPs are used in line with the recommendations in the respective products’ labelling for the 
indication of ART and/or standard clinical practice supported by literature.
5.3
Characteristics and Source of Supply
All medicinal products are provided by Ferring and will be handled according to the principles of 
Good Manufacturing Practice (GMP). Table 5-4 provides an overview of the presentation and 
manufacturer of each medicinal product.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Table 5-4
Characteristics and Source of Supply of Medicinal Products
IMP / NIMP
Presentation
Manufacturer
FE 999049
(rFSH)
FE 999049 is provided as a cartridge and 
an administration pen. Each cartridge 
contains a solution for injection 
delivering 72 µg FSH in 2.16 mL
Ferring Pharmaceuticals
GONAL-F
(rFSH)
GONAL-F (follitropin alfa) is provided 
as a pre-filled pen containing a liquid 
formulation for injection. Each pen 
delivers 900 IU (66 µg) FSH in 1.5 mL
Merck Serono
CETROTIDE
(GnRH antagonist)
CETROTIDE (cetrorelix acetate) is 
provided as powder and solvent for 
solution for injection. After 
reconstitution, 1 mL solvent contains 
0.25 mg cetrorelix
Merck Serono
OVITRELLE
(rhCG)
OVITRELLE (choriogonadotropin alfa) 
is provided as a pre-filled syringe
(0.5 mL) for single use delivering 250 µg 
choriogonadotropin alfa
Merck Serono
GONAPEPTYL
(GnRH agonist)
GONAPEPTYL (triptorelin acetate) is 
provided as a pre-filled syringe (1 mL) 
delivering 0.1 mg triptorelin acetate
Ferring Pharmaceuticals
CRINONE
(progesterone)
CRINONE is provided as sustained-
release vaginal gel 8% (90 mg) in 
prefilled applicators delivering 90 mg of 
progesterone
Merck Serono / Watson / 
Columbia / Actavis
5.4
Packaging and Labelling
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
IMP department at Ferring in accordance with GMP and national regulatory requirements.
GONAL-F as well as all NIMPs are commercially available. No modification from the usual 
commercial state of GONAL-F will be made, except for trial-specific labelling. All medicinal
products will be labelled with trial-specific labels, which contain a self-adhesive tear-off portion to 
be affixed to the drug label accountability form maintained at the trial site.
5.5
Conditions for Storage and Use
The trial medication delegate will ensure that the medicinal products will be stored in appropriate 
conditions as stated in the IMP Handling guideline and in a secure location with controlled access. 
The storage compartment shall be monitored regularly and the temperature shall be documented.
Deviations in storage temperature must be reported without delay and the medicinal products must 
not be used until further instructions from Ferring are received.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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In case of technical malfunction of an administration pen, all relevant details (including time, date, 
a description of the malfunction and whether dosing was affected) of the incidence should be 
reported, the pen should be replaced and the treatment continued.
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for FE 999049 and the Product Information for GONAL-F as well as for 
OVITRELLE, GONAPEPTYL, CETROTIDE and CRINONE.
5.6
Blinding / Unblinding
5.6.1
Blinding
The trial is assessor-blind, and all investigators, embryologists and central laboratory personnel will 
be blinded to treatment allocation throughout the trial. The trial medication delegate at site (person 
responsible for IMP/NIMP), the trial coordinator at site (person entering data into e-CRF), the 
monitors and the participating subjects will know the treatment allocation once the subjects are 
randomised. Precaution must be taken to ensure that the treatment allocations are not available to 
the investigators or other assessors throughout the trial. Subjects must be clearly instructed to only 
discuss their treatment allocation with the trial medication delegate, and to not mention it to the 
investigator.
The trial medication delegate will dispense the trial medication to the subject (and may also do the 
actual administration at the clinic, if required). The investigator will, based on the follicular 
development, judge if dose adjustments are recommended and state his/her directions on a form 
developed for that purpose, which will be used to inform the trial medication delegate. Depending 
on whether the subject is being treated with FE 999049 or GONAL-F, the trial medication delegate
will provide detailed instructions to the subject in line with the dosing regimen for each preparation
as outlined in the protocol. In other words, if the investigator recommends a dose adjustment, the 
trial medication delegate will implement a decrease or increase of 75 IU per day as applicable if the 
subject is in the GONAL-F group, while no dose adjustments will be implemented if the subject is
in the FE 999049 group. Requests for cycle cancellation due to inappropriate response or other 
medical reasons are followed, irrespective of treatment group.
The randomisation list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information in the e-CRF will not be accessible to assessors or the Ferring clinical trial team or 
laboratory personnel during the trial.
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and sponsor’s responsible medical officer) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when the trial database is declared 
clean and locked.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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5.6.2
Unblinding of Individual Subject Treatment
An emergency unblinding solution will be available to the investigator and designated persons at 
the sponsor. Breaking of the blind for individual subjects in emergency situations is only permitted 
in case of a suspected unexpected serious adverse reaction (SUSAR) or in case of an important 
adverse event where the knowledge of the IMP in question is required for therapeutic decisions for 
the management of the subject.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
the sponsor. It should be recorded in the e-CRF that the code is broken, why, when and by whom. 
The investigator must record the event of unblinding in the subject’s medical record, including the 
reason for unblinding.
In case of accidental unblinding (e.g. the subject tells the investigator), the same documentation as 
for emergency unblinding must be obtained, i.e. why, when and by whom must be recorded in the 
e-CRF, and the event must also be recorded in the subject’s medical record.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the authorities and/or ethics committees. In that situation, every effort will be made to 
maintain blinding of sponsor personnel involved in data analysis and interpretation. Other 
personnel may be unblinded for SUSARs, including trial site staff as well as staff acting on behalf 
of Ferring.
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and locked.
5.7
Dispensing and Accountability, Return and Destruction
All handling of medicinal products (both IMP and NIMP) will be done by a trial medication 
delegate(s) at the site. The trial medication delegate will maintain subject dispensing logs, detailing 
the dates, quantities and batch numbers of dispensed and returned IMP and NIMP for each subject. 
The trial medication delegate will also manage the overall drug accountability at the site.
The monitor will verify drug accountability of IMP and NIMP throughout the trial and will 
document any discrepancies.
Concerning destruction, the trial medication delegate at the site must ensure destruction of 
dispensed IMP and NIMP in accordance with local legislation after drug accountability has been 
verified by the monitor and signed off by the trial medication delegate, while non-dispensed IMP 
and NIMP will be returned for destruction as instructed by the Ferring IMP Department.
5.8
Auxiliary Supplies
Ferring will be responsible for the supply of safety containers for collection of used cartridges, 
pens, syringes and needles.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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Supersedes: Ver. 2.0
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6
TRIAL PROCEDURES
The flow of the trial procedures for subjects is shown in Table 6-1.
Table 6-1
Trial Flow Chart – Subject Procedures
Scree-
ning
Stimulation
Oocyte 
retrieval
Transfer
Pregnancy monitoring
End
During stimulation
End-of-
stimula-
tion
OR
Transfer
βhCG
Clinical
Ongoing
End-of-
trial
Timing
<90 days 
before 
random-
isation
Day 1
Day 6 
Day ≥7 
to <20 a)
End
36h ±2h 
after 
triggering
Day 3
after OR
13-15 
days 
after 
transfer
5-6 
weeks 
after 
transfer
10-11 
weeks 
after 
transfer
b)
Written informed consent
X
Inclusion/exclusion criteria
X
   X c)
Demographics
X
Medical history 
X
Infertility history
X
Menstrual history
X
Reproductive history
X
Smoking and alcohol habits
X
Body weight and height
X
   X c),d)
   X d)
Physical examination
X
X
Gynaecological examination
X
X
Pregnancy test
X
   X c)
Ultrasound
   X c)
X
X
X
X
X
Randomisation
X
Vital signs
X
   X e)
X
Blood collection, clin chem / haem
X
   X e)
X
X
Blood collection, endocrine f)
X
   X e)
   X g)
   X g)
X h)
Blood collection, antibodies i)
   X j)
   X e)
  
   X k)
X l)
   X l)
IMP dispensing
X
   X m)
   X m)
NIMP dispensing
   X n)
X
X
X
X
X
Xo
Local tolerability (diary) 
X
X
X
X
Oocyte retrieval
X
Embryo transfer
X
βhCG test (local laboratory)
X
Drug accountability
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
End-of-trial form
X
a) Visits must be scheduled at least every second day; when the leading follicle reaches ≥15 mm visits must be scheduled daily. 
b) End-of-trial assessments must be performed at the subject’s last scheduled visit: at the earliest 19-28 days after the last IMP dose. 
c) Performed before randomisation.
d)   Only body weight.
e) Performed before the first IMP dose. 
f)
Endocrine parameters consist of a screening panel, a treatment panel, and FSH.
g) Performed at least 8 h after IMP administration.
h) FSH only.
i)
All subjects with a treatment-induced antibody response must be followed until the response is negative or has returned to pre-dosing level, with a 
maximum follow-up period of one year.  
j)
Sample exclusively used as back-up samples for the anti-drug antibody assay development.
k) Blood sampling for antibody assessment must be done 5-10 days after the last IMP dose (this may coincide with the transfer visit; alternatively, 
a separate visit must be scheduled).
l)
Blood sampling for antibody assessment must be done 19-28 days after the last IMP dose (this may coincide with the βhCG visit; alternatively, 
a separate visit must be scheduled).
m) The daily dose of FE 999049 is fixed throughout stimulation. The dose of GONAL-F is fixed for the first 5 days, after which it may be adjusted by 
75 IU per day based on the individual response.
n)  The trial medication delegate (or another qualified trial staff) should observe the general health of the subject, with emphasis on symptoms of an 
acute allergic reaction, for 30 min after the GnRH antagonist dosing.
o)  Luteal phase support can be continued until the ongoing pregnancy visit, if applicable according to local practice. Progesterone administration 
should not continue if menses, negative βhCG or pregnancy loss occurs.
IMP: investigational medicinal product; NIMP: non-investigational medicinal product


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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6.1
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before stimulation day 1 (randomisation). 
The following must take place during the screening period:

Signed and dated written informed consent, obtained prior to any trial-related procedures

Allocation of a screening number

Check of inclusion and exclusion criteria (those which are possible to check at screening)

Demographics (age, ethnicity, race)

Collection of the following data:
-
Medical history (including any cysts)
-
Infertility history
-
Menstrual history
-
Reproductive history
-
Smoking and alcohol habits

Body weight and height [note: these are used for calculation of BMI]

Physical examination

Vital signs

Gynaecological examination

Pregnancy test – must be negative

Blood collection for central laboratory analysis of:
-
Clinical chemistry and haematology parameters [note: the results must be available 
before randomisation]
-
Endocrine parameters (screening panel: AMH, thyroid-stimulating hormone (TSH) and 
prolactin) [note: the results must be available prior to randomisation]
-
Anti-FSH antibodies [exclusively used as back-up samples for the anti-drug antibody 
assay development]

Recording of use of any concomitant medication (within the last 3 months prior to signed 
informed consent for participation in the trial)

Recording of adverse events (from the date of signed informed consent for participation in 
the trial)
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit, scheduled on day 2-3 of the menstrual cycle.


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
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6.2
Stimulation 
6.2.1
Stimulation Day 1 
Subjects will attend the stimulation day 1 visit on day 2-3 of the menstrual cycle.
The following must take place prior to randomisation:

Ensure that the subject is still eligible for participation in the trial

Check those inclusion and exclusion criteria that were not possible during screening 

Body weight [note: this body weight result is used for dose calculation in the FE 999049 
group and should be measured on a trial specific calibrated scale]

Pregnancy test – must be negative

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, ovarian volume, 
number and size of follicles). If a cyst ≥10 mm is observed (functional or not), it should be 
punctured before treatment is initiateda. If the cyst was present at the screening visit, it 
should have been recorded on the medical history form. If the cyst presented between 
screening and stimulation day 1, it should be recorded on the adverse event form.
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation:

Randomisation, i.e. assignment to the lowest available subject number and thereby 
allocation to either FE 999049 or GONAL-F
The following must take place after randomisation but before administration of the first dose of 
IMP (FE 999049 or GONAL-F):

Vital signs (systolic blood pressure, diastolic blood pressure, pulse)

Blood collection for central laboratory analysis of:
-
Clinical chemistry and haematology parameters
-
Endocrine parameters (AMH and treatment panel: FSH, LH, estradiol, progesterone, 
inhibin A and inhibin B)
-
Anti-FSH antibodies
Once the above has been completed, the following must be performed by the trial medication 
delegate. Care must be taken to ensure blinding of the investigator and other assessors.

Dispense IMP according to randomisation and instruct the subject on how to administer the
IMP 

Administer the 1st dose of IMP according to randomisation [administration of IMP takes 
place at the clinic and can be done by either the trial medication delegate or the subject
under supervision by the trial medication delegate]:
                                                                                                                                                
a Treatment can be initiated the same day. If puncture is not possible, randomisation may be postponed to the next 
menstrual cycles, assuming that the cyst will disappear and that the subject fulfils the inclusion criteria. 


Follitropin Delta, FE 999049
Trial Code: 000145
Date: 27 Sep 2018
Solution for Injection
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-
If randomised to FE 999049; daily dose according to AMH level at screening and body 
weight at randomisation (see Table 5-1 for detailed instructions)
-
If randomised to GONAL-F; starting dose for the first 5 days is fixed at 150 IU

Hand out the diary to the subject. The subject must be instructed to assess and record local 
tolerability immediately, 30 min and 24 hours after each IMP administration throughout the 
entire stimulation period.
After the first administration of FE 999049 or GONAL-F, the subject must do the following: 

Assessment of local tolerability (recorded in a diary) – the first evaluation of local 
tolerability reactions at the injection site is done immediately after the subcutaneous 
injection of IMP, followed by the second evaluation 30 min after injection of IMP and the 
third evaluation 24 hours after injection of IMP (before the next day’s injection of IMP).
Finally, this must be done before the subject leaves the clinic:

Take precautions in the event that the subject experiences an acute allergic reaction. In the 
first 30 min following the IMP administration, the trial medication delegate (or another 
qualified trial staff) must observe the subject’s general health with emphasis on symptoms 
of an acute allergic reaction. The trial sites are requested to have facilities (i.e. medication, 
equipment and trained staff) and procedures in place for diagnosis and treatment of acute 
allergic reactions.

Recording of use of any concomitant medication

Recording of adverse events
The next visit must be scheduled for stimulation day 6.
6.2.2
Stimulation Day 6 
The following must take place at stimulation day 6:

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, number and size of follicles)

Blood collection for central laboratory analysis of:
-
endocrine parameters (treatment panel: FSH, LH, estradiol, progesterone, inhibin A 
and inhibin B) – the blood sample must be drawn at least 8 hours after the latest IMP 
administration

Dispensing of IMP and potential dose adjustment
-
FE 999049: the daily dose is fixed throughout stimulation
-
GONAL-F: from stimulation day 6 and onwards, the daily dose may be adjusted by 
75 IU per day based on the individual response

Dispensing and administration of GnRH antagonist [the first administration of GnRH 
antagonist takes place at the clinic and can be done by either the trial medication delegate or 
the subject under supervision by the trial medication delegate]

Collection of local tolerability data (diary pages)


Follitropin Delta, FE 999049
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
Drug accountability of IMP

Recording of use of any concomitant medication

Recording of adverse events
Finally, this must be done before the subject leaves the clinic:

In the first 30 min following the GnRH antagonist administration, the trial medication 
delegate (or another qualified trial staff) must observe the subject’s general health with 
emphasis on symptoms of an acute allergic reaction. Note: it is important that the subject 
does not mix up the injection sites for IMP and GnRH antagonist

Instruct the subject to administer the GnRH antagonist at a daily dose of 0.25 mg throughout 
the stimulation period.
After the stimulation day 6 visit, the next visits must be scheduled at least every second day 
throughout the remaining stimulation period. When the leading follicle reaches ≥15 mm, visits must 
be performed daily.
6.2.3
Stimulation Days ≥7 to ≤20
These visits will take place at least every second day throughout the remaining stimulation period. 
When the leading follicle reaches ≥15 mm, visits must be performed daily. Coasting is not allowed. 
The maximum period of stimulation is 20 days.
The following must take place at all visits throughout the remainder of the stimulation period (with 
the exception of the end-of-stimulation visit, which is described in section 6.2.4):

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, number and size of follicles)

Dispensing of IMP, as applicable

Dispensing of GnRH antagonist, as applicable

Collection of local tolerability data (diary pages)

Drug accountability of IMP and GnRH antagonist

Recording of use of any concomitant medication

Recording of adverse events
6.2.4
End-of-stimulation
The end-of-stimulation visit takes place when the subject reaches the criterion for triggering of final 
follicular maturation or any of the cycle cancellation criteria because of poor or excessive follicular
development as specified in Table 6-2. Administration of hCG or GnRH agonist must take place as 
soon as reaching the criterion for triggering of final follicular maturation.
If triggering as soon as reaching the criterion would lead to oocyte retrieval or embryo transfer on a 
day the clinic is closed e.g. Sunday or a public holiday, stimulation may be continued for one 
additional day, meaning triggering is delayed for a maximum of one day.


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If the GnRH antagonist is administered in the morning it should also be administered on the day of 
triggering. If the GnRH antagonist is administered in the evening, no GnRH antagonist is to be 
given on the day of triggering.
Table 6-2
Triggering and Cycle Cancellation Criteria related to Follicular Development
Poor follicular development 
Triggering criterion 
Excessive follicular development
If it is judged by the investigator 
that ≥3 follicles with a diameter 
≥17 mm cannot be reached, but 
1 or 2 follicles with a diameter 
≥17 mm are observed, the cycle 
may either be cancelled due to 
poor follicular development or 
triggering of final follicular 
maturation is to be induced, as 
judged by the investigator.
Criterion for triggering of final 
follicular maturation:

≥3 follicles with a diameter 
≥17 mm
If <25 follicles with a diameter 
≥12 mm are observed, hCG is 
administered.
In case of >35 follicles with a 
diameter ≥12 mm, the cycle is to
be cancelled.
If 25-35 follicles with a diameter 
≥12 mm are observed, GnRH 
agonist can be administered; 
alternatively the cycle can be 
cancelled.
If 25-35 follicles with a diameter 
≥12 mm are observed, the cycle 
can be cancelled; alternatively 
GnRH agonist can be
administered.
Triggering drug must be 
administered the day the criterion 
is met.
The investigator also has the option of cancelling the cycle for other relevant medical reasons, 
including adverse events and technical malfunctions of the administration pen.
The following must take place at end-of-stimulation visit:

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, ovarian volume, number and size of 
follicles)

Blood collection for central laboratory analysis of:
-
clinical chemistry and haematology parameters
-
endocrine parameters (treatment panel: FSH, LH, estradiol, progesterone, inhibin A 
and inhibin B) – the blood sample must be drawn at least 8 hours after the latest 
administration of IMP and GnRH antagonist

Dispensing of hCG or GnRH agonist, as applicable

Dispensing of GnRH antagonist

Collection of local tolerability data (diary pages)

Drug accountability of IMP and GnRH antagonist

Recording of use of any concomitant medication


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
Recording of adverse events
For subjects who receive a triggering drug, the next visit is the oocyte retrieval visit which must be 
scheduled 36h (±2h) after the administration of hCG or GnRH agonist.
For subjects with cycle cancellation, the next visit is the first post-dosing anti-FSH antibody blood 
sampling visit 5-10 days after the last FE 999049 or GONAL-F dose (section 6.5.2).
6.3
Oocyte Retrieval
Oocyte retrieval must take place 36h (±2h) after hCG or GnRH agonist administration. All oocytes 
from follicles with an estimated diameter ≥12 mm should be retrieved. Below are listed the 
procedures related to the subjects attending the oocyte retrieval visit, while procedures related to 
the oocytes are described in section 6.4.
The following must take place at the oocyte retrieval visit:

Blood collection for central laboratory analysis of:
-
endocrine parameter (FSH only)

Oocyte retrieval

Dispensing of progesterone for luteal phase support – must be started on the day of oocyte 
retrieval or the day after and continued at least until clinical pregnancy [note: only 
applicable for subjects who underwent triggering of final follicular maturation with hCG 
and who had oocytes retrieved]

Drug accountability of hCG or GnRH agonist, as applicable

Collection of diary pages

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with oocytes retrieved following hCG administration, the next visit is the transfer visit 
3 days after oocyte retrieval (section 6.5.1). 
For subjects with oocytes retrieved following GnRH agonist administration, the oocytes will 
undergo the procedures described in section 6.4 and embryos will be cryopreserved on day 3, 5 or 6
after oocyte retrieval, according to local practice. The next visit for these subjects is the first post-
dosing anti-FSH antibody assessment visit which must be scheduled 5-10 days after the last 
FE 999049 or GONAL-F dose (section 6.5.2).
For subjects with no oocytes retrieved, the next visit is the first post-dosing anti-FSH antibody 
assessment visit which must be scheduled 5-10 days after the last FE 999049 or GONAL-F dose
(section 6.5.2).


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6.4
Oocyte / Embryo Evaluation
The laboratory procedures regarding handling and evaluations of oocytes and embryos are 
described in a trial-specific manual. This section provides an overview of the procedures and 
assessments to be made from oocyte retrieval till transfer at the embryo stage. The flow of the trial 
procedures for oocytes is shown in Table 6-3.
Table 6-3
Trial Flow Chart – Oocyte / Embryo Procedures
Day 0 (OR)
Day 1 after OR
Day 3 after OR
Oocyte retrieval (OR)
X
Assessment of maturity stage (applicable for oocytes 
undergoing ICSI)
X
Insemination by IVF or ICSIb
X
Assessment of oocyte fertilisation
X
Assessment of embryo quality
X
Transfer of 1 or 2 embryos of the highest quality 
available:
– Subjects <35 years at randomisation: 

single embryo transfer if a good-quality embryo is 
available 

double embryo transfer if a good-quality embryo is 
not available (and if two embryos are available)
– Subjects ≥35 years at randomisation: 

double embryo transfer (if two embryos are 
available)
X
Cryopreservation of embryos, as applicablec
Xc
Assisted hatching and pre-implantation genetic diagnosis (PGD) / pre-implantation genetic 
screening (PGS) are prohibited.
Day 0 (Oocyte Retrieval)

Assessment of maturity stage (applicable for oocytes undergoing ICSI)

Insemination at 0h using IVF or ICSI using ejaculated sperm (fresh or frozen) from partner 
or donor
Day 1 after Oocyte Retrieval

Assessment of fertilisation (number of pronuclei)
                                                                                                                                                
b Rescue ICSI is not allowed.
c Cryopreservation of surplus embryos can be postponed to day 5 or 6, according to local practice.


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Day 3 after Oocyte Retrieval

Assessment of embryo quality:

Number of cells

Compaction status

Fragmentation (either 0%, 1-10%, 11-20%, 21-50% or >50% fragmentation, or 
totally fragmented (no blastomeres recognised))

Blastomere uniformity (equally or unequally)

Visual signs of multinucleation (yes/no)
Good quality embryo is defined as an embryo with ≥6 blastomeres and ≤20% fragmentation, 
without signs of multinucleation

Transfer of embryo (section 6.5)
Cryopreservation of surplus embryos should be performed on day 3 after oocyte retrieval.
Cryopreservation can be postponed to day 5 or day 6 after oocyte retrieval, as applicable and 
according to local practice.
6.5
Transfer
6.5.1
Embryo Transfer
Transfer is performed on day 3 (embryo stage) after oocyte retrieval. The subject-related 
procedures are described below.

Blood collection for central laboratory analysis of anti-FSH antibodies (first post-dosing 
assessment)

Transfer of 1 or 2 embryo(s) of the highest quality available according to this policy:
-
Subjects <35 years at randomisation: 

single embryo transfer if a good quality embryo is available

double embryo transfer if a good-quality embryo is not available (and single 
transfer if two embryos are not available). 
-
Subjects ≥35 years at randomisation:

double embryo transfer (and single transfer if two embryos are not available).
(note: transfer is only applicable for subjects who underwent triggering of final follicular 
maturation with hCG. Subjects who were administered GnRH agonist will not undergo transfer
in the current fresh cycle).

Dispensing of progesterone for luteal phase support 

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events


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For subjects with embryo transfer, the next visit is the βhCG test visit which must be scheduled 
13-15 days after transfer (section 6.6).
6.5.2
First Post-dosing Anti-FSH Antibody Assessment (5-10 Days after Last IMP Dose)
Subjects who have been exposed to FE 999049 or GONAL-F must have the first post-dosing anti-
FSH antibody assessment performed 5-10 days after the last FE 999049 or GONAL-F dose. This 
may coincide with the transfer visit (section 6.5.1). 
For subjects who do not attend the transfer visit, a separate visit must be scheduled, at which the 
following must take place:

Blood collection for central laboratory analysis of anti-FSH antibodies

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events
6.6
βhCG Test
6.6.1
βhCG Test
Subjects who have undergone transfer must attend a visit 13-15 days after transfer. 
The following must take place:

Blood collection for local laboratory analysis of hCG

Blood collection for central laboratory analysis of anti-FSH antibodies (second post-dosing 
assessment)

Dispensing of progesterone for luteal phase support, if applicable

Drug accountability of progesterone

Recording of use of any concomitant medication 

Recording of adverse events
The blood sample for βhCG will be analysed by the local laboratory and evaluated according to the 
laboratory’s reference ranges. In case of a borderline hCG result, the test should be repeated. 
Subjects with a positive hCG test must attend a clinical pregnancy visit 5-6 weeks after transfer 
(section 6.7). Subjects with a negative hCG test must proceed to the end-of-trial assessments 
(section 6.9).


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6.6.2
Second Post-dosing Anti-FSH Antibody Assessment (19-28 Days after Last IMP 
Dose)
Subjects who have been exposed to FE 999049 or GONAL-F must have the second post-dosing 
anti-FSH antibody assessment performed 19-28 days after the last FE 999049 or GONAL-F dose. 
This may coincide with the βhCG test visit (section 6.6.1). 
For subjects who do not attend the βhCG test visit, a separate visit must be scheduled, at which the 
following must take place:

Blood collection for central laboratory analysis of anti-FSH antibodies

Dispensing of progesterone for luteal phase support, if applicable

Drug accountability of progesterone

Recording of use of any concomitant medication

Recording of adverse events
For subjects who do not attend the βhCG test visit, this second post-dosing anti-FSH antibody 
assessment may be done in connection with the end-of-trial visit (section 6.9).
6.7
Clinical Pregnancy
Subjects with a positive hCG test must attend a visit 5-6 weeks after transfer. 
The following must take place:

Transvaginal ultrasound of uterus to assess any clinical pregnancy 

Drug accountability of progesterone

Dispensing of progesterone for luteal phase support, if continued according to local practice

Recording of use of any concomitant medication 

Recording of adverse events
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms 
a vital pregnancy. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit
10-11 weeks after transfer (section 6.8). Subjects with no vital pregnancy must undergo end-of-trial 
assessments (section 6.9).
6.8
Ongoing Pregnancy
If a vital pregnancy has been documented, the subject must attend a visit 10-11 weeks after transfer. 
The following procedures / assessments must take place:

Ultrasound (transvaginal or abdominal) of uterus to assess any intrauterine viable fetus

Drug accountability of progesterone, if applicable

Recording of use of any concomitant medication 


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
Recording of adverse events
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy.
6.9
End-of-trial
If a subject attends the scheduled trial visits, the end-of-trial assessments should take place at the 
last scheduled trial visit, i.e. for subjects with a confirmed vital pregnancy, the ongoing pregnancy 
visit would be the last scheduled trial visit and thus the visit where the end-of-trial assessments 
should be done.
Due to the timing of the mandatory anti-FSH antibody assessments, the end-of-trial assessments 
can at the earliest be 19-28 days after the last FE 999049 or GONAL-F dose. This may coincide 
with the βhCG visit for subjects with a negative βhCG test.
The following procedures / assessments must take place at the end-of-trial visit, irrespective of 
whether the subject discontinues the trial prematurely or completes it:

Body weight

Physical examination

Gynaecological examination

Vital signs 

Blood collection for central laboratory analysis of
-
clinical chemistry and haematology parameters
-
anti-FSH antibodies (second post-dosing assessment) [note: only applicable for 
subjects who have not already had a blood sample taken for the second post-dosing 
anti-FSH antibodies assessment as described in sections 6.6.1 and 6.6.2]

Drug accountability, if applicable

Recording of use of any concomitant medication

Recording of adverse events

Completion of end-of-trial form 
These assessments serve to document the subject’s physical health at the end of the trial.
6.10
Post-trial Activities
Pregnancy Follow-up
All subjects with an ongoing pregnancy will be followed till delivery to gather information on live 
birth rate. Furthermore, data will be gathered on neonatal health, including any congenital
anomalies, at birth and at 4 weeks after birth as described in section 7.4.1.


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7
TRIAL ASSESSMENTS
7.1
Assessment Related to Primary Endpoint
7.1.1
Ongoing Pregnancy
A transvaginal or abdominal ultrasound of the uterus will be performed 10-11 weeks after transfer. 
Ongoing pregnancy will be defined as at least one intrauterine viable fetus. For ongoing 
pregnancies, the number of intrauterine viable fetuses will be recorded.
7.2
Assessments Related to Secondary Endpoints
7.2.1
βhCG Test
A blood hCG test must be obtained 13-15 days after transfer. If the test is positive according to the 
local laboratory’s reference ranges, this confirms a positive hCG.
7.2.2
Clinical Pregnancy
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Clinical 
pregnancy will be defined as at least one gestational sac, either intrauterine or ectopic. The 
inclusion of ectopic pregnancies and the lack of specification of heart beat in the definition of 
clinical pregnancy is in line with the current International Committee Monitoring Assisted 
Reproductive Technologies (ICMART) and World Health Organization (WHO) glossary on ART 
terminology.d,34 For intrauterine and ectopic pregnancies, the number of gestational sacs with fetal 
heart beat as well as without fetal heart beat will be recorded. 
7.2.3
Vital Pregnancy
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Vital pregnancy 
will be defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after 
transfer. 
7.2.4
Implantation
Implantation is determined based on the transvaginal ultrasound performed at the clinical 
pregnancy visit. Implantation rate will be defined as the number of gestational sacs 5-6 weeks after 
transfer divided by number of embryos transferred.
7.2.5
Ongoing Implantation
Ongoing implantation is determined based on the ultrasound performed at the ongoing pregnancy 
visit. Ongoing implantation rate will be defined as the number of intrauterine viable fetuses 
                                                                                                                                                
d
ICMART and WHO glossary on ART terminology: Clinical pregnancy – a pregnancy diagnosed by 
ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes 
ectopic pregnancy.


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10-11 weeks after transfer divided by number of embryos transferred.
7.2.6
Extreme Ovarian Response
The number of oocytes retrieved will be counted at the oocyte retrieval visit. Extreme ovarian 
response will be defined as retrieval of <4, ≥15 or ≥20 oocytes.
7.2.7
Early OHSS (including OHSS of Moderate/Severe Grade) and/or Preventive 
Interventions for Early OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3 for details) and 
all OHSS cases will be graded as mild, moderate or severe. Preventive interventions for early 
OHSS cover cycle cancellation due to excessive ovarian response or triggering of final follicular 
maturation with GnRH agonist.
7.2.8
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo Transfer 
Cancellation due to Excessive Ovarian Response / OHSS Risk
The reason for each cycle cancellation will be recorded. Cycle cancellations related to inappropriate 
ovarian response will include poor and excessive follicular development. Cycle cancellation due to 
poor follicular development is implemented when the investigator judges that ≥3 follicles with a 
diameter ≥17 mm cannot be reached by stimulation day 20. Cycle cancellation due to excessive 
follicular development is implemented when >35 follicles with a diameter ≥12 mm are observed
(can also be implemented if there are 25-35 follicles with a diameter ≥12 mm). The reason for each 
embryo transfer cancellation will be recorded. Transfer cancellation due to adverse events such as 
the Medical Dictionary for Regulatory Activities preferred terms (MedDRA PTs) "ovarian 
hyperfunction" and "ovarian hyperstimulation syndrome" and "high progesterone" in subjects with 
embryos available for transfer will be considered as transfer cancellations due to excessive response 
/ OHSS risk.
7.2.9
Number and Size of Follicles during Stimulation
Transvaginal ultrasound will be performed at all visits during the stimulation period to count the 
number of follicles and measure the size of the follicles. Data will be recorded separately for the 
right and left ovary.
7.2.10
Number and Distribution of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit. The proportion of 
subjects with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted 
response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) will be 
calculated.
7.2.11
Metaphase II Oocytes
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity 


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stage will be categorised as germinal vesicle, metaphase I, metaphase II, degenerated or other.
7.2.12
Fertilisation Rate 
The number of pronuclei will be counted on day 1 after oocyte retrieval and recorded as 0, 1, 2 or 
>2. Fertilised oocytes with 2 pronuclei will be regarded as correctly fertilised.
7.2.13
Number and Quality of Embryos on Day 3
Each embryo will be followed closely and formally evaluated on day 3 after oocyte retrieval. The 
quality evaluation will consist of assessment of cleavage stage and embryo morphology parameters 
(number of cells, degree of fragmentation, blastomere uniformity and visual signs of 
multinucleation). 
Cleavage stage will be defined by the number of blastomeres: 1, 2, 3, 4, 5, 6, 7, 8, …. On day 3, it 
will also be possible to indicate the compaction status instead of number of blastomeres.
Degree of fragmentation will be classified as one of the following: 0%, 1-10%, 11-20%, 21-50%, or 
>50% fragmentation, or totally fragmented (no blastomeres recognised).
Blastomere uniformity will be classified as equally sized blastomeres or unequally sized 
blastomeres (largest blastomere >25% larger in average diameter compared to the smallest 
blastomere). 
Visual sign of multinucleation will be evaluated as yes or no.
A good quality embryo is defined as an embryo with ≥6 blastomeres and ≤20% fragmentation, 
without signs of multinucleation.
7.2.14
Circulating Levels of Endocrine Parameters
During treatment, the following panel of endocrine parameters will be evaluated (treatment panel): 
FSH, LH, estradiol, progesterone, inhibin A and inhibin B. 
Blood samples will be drawn at stimulation day 1e, stimulation day 6 and the end-of-stimulation
visit. The sample on stimulation day 1 (baseline) will be collected prior to the first dose of 
FE 999049 or GONAL-F, and samples drawn at stimulation day 6 and the end-of-stimulation visit 
will be collected at least 8 hours after the previous FE 999049, GONAL-F or GnRH antagonist
administration. The samples will be analysed at a central laboratory. The investigator will review 
and evaluate the laboratory results. The Laboratory Report will be signed and dated by the 
investigator.
7.2.15
FSH Population Pharmacokinetics
In addition to the sampling time points mentioned in section 7.2.14, blood samples will also be 
drawn at the oocyte retrieval visit for analysis of FSH. 
Based on the serum FSH samples obtained during the trial, a population pharmacokinetic model 
will be developed to assess the pharmacokinetics of FE 999049 and confirm predictors for FSH 
                                                                                                                                                
e
AMH will also be included in the stimulation day 1 analyses.


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concentration levels, such as body weight.
7.2.16
Total Gonadotropin Dose and Number of Stimulation Days
The start and end dates as well as daily dose of IMP will be recorded and used to calculate the total 
FE 999049 or GONAL-F dose administered and the number of stimulation days.
7.2.17
Gonadotropin Dose Adjustments
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. 
7.2.18
Adverse Events
Adverse events will be recorded from the signed informed consent for participation in the trial until 
the end-of-trial visit. For each adverse event the following parameters are recorded by the 
investigator on the Adverse Event Log: description of event, date and time of onset, intensity, 
causal relation to IMP, action taken to IMP, other actions taken, seriousness of the adverse event, 
date and time of outcome, and outcome. Furthermore, the pattern (e.g. the frequency, time of onset, 
intensity, seriousness and outcome) of the most frequent / relevant adverse events will be tabulated. 
7.2.19 Clinical Chemistry and Haematology Parameters
The following clinical chemistry and haematology parameters will be analysed at a central 
laboratory: 
CHEM-20: alanine transaminase, albumin, alkaline phosphatase, aspartate aminotransferase, 
bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, 
creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus,
potassium, sodium, total protein, uric acid.
Complete Blood Count (CBC): red blood cells, red blood cell morphology, white blood cells, white 
blood cell morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular 
haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Blood samples will be drawn at screening, on stimulation day 1, end-of-stimulation and end-of-
trial. The samples from the screening visit will be used for safety and eligibility evaluation of the 
subject before randomisation. The sample at stimulation day 1 (baseline) must be drawn before the 
first FE 999049 or GONAL-F injection. The investigator will review the laboratory results and 
evaluate and document whether the abnormal results are non-clinically or clinically significant. The 
Laboratory Report will be signed and dated by the investigator.
7.2.20 Injection Site Reactions
Every day throughout the stimulation period, the subjects will assess the local tolerability of 
subcutaneous injections of FE 999049 or GONAL-F at three time points relative to the daily 
administration: immediately after the injection, 30 minutes after the injection and 24 hours after the 
injection. The following injection site reactions will be assessed: redness, pain, itching, swelling 


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and bruising. The presence and intensity of each injection site reaction will be rated as one of the 
following: none, mild, moderate or severe.
The subject will record the assessments in a diary and the diary data will subsequently be 
transcribed to the e-CRF.
7.2.21 Anti-FSH Antibodies
Blood samples for assessment of anti-FSH antibodies in the individual subjects in the trial will be 
drawn pre-dosing and post-dosing: 

Screening [note: this sample is exclusively used as back-up sample for the anti-drug 
antibody assay development]

Stimulation day 1, prior to dosing (baseline; pre-dosing sample)

5-10 days after the last FE 999049 or GONAL-F dose
This may coincide with the transfer visit. Subjects not reaching transfer must be called in for 
this extra visit.

19-28 days after the last FE 999049 or GONAL-F dose
This may coincide with the βhCG visit. In case of discontinuation before the βhCG visit, 
this assessment should be done at the end-of-trial visit scheduled 19-28 days after the last 
FE 999049 or GONAL-F dose.
Ferring has developed the following assays for evaluating the immunogenicity of FE 999049 or 
GONAL-F:
Assay 1)
A screening immunoassay, assessing the presence in serum of anti-FSH antibodies, 
using a parametric cut-point approach with a 5% false positive rate. 
Assay 2)
A confirmatory immunoassay, confirming or disconfirming the specificity of any 
positive results in assay 1), using a parametric cut-point approach with a 0.1% false 
positive rate.
Assay 3)
A titre immunoassay determining the antibody response titre of any anti-FSH 
antibodies confirmed in assay 2).
Assay 4)
A cell-based assay qualitatively assessing the neutralising capacity of any anti-FSH 
antibodies confirmed in assay 2), using a parametric cut-point approach with a 1% 
false positive rate.
Assay 5)
A cell-based assay determining the neutralising antibody response titre of any 
positive result in assay 4).
Assay 6)
A confirmatory assay based on native FSH, in order to assess cross-reactivity with 
native FSH of any anti-FSH antibodies confirmed to be specific towards exogenous 
FSH in assay 2), using a parametric cut-point approach with a 0.1% false positive 
rate.
In subjects with a negative pre-dosing sample, a treatment-induced anti-FSH antibody response will 
be defined as any post-dosing sample being positive in the confirmatory assay; Assay 2).


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In subjects with a positive pre-dosing sample, a treatment-induced anti-FSH antibody response will 
be defined as a statistically determined fold increase in titres from the pre-dosing assessment to a 
post-dosing assessment.f
All positive samples in the confirmatory Assay 2) will be further characterised for titre, neutralising 
capacity (qualitatively and titre) and cross-reactivity. A subject is defined to have treatment-
induced anti-FSH antibodies with neutralising capacity if the subject has a positive outcome of 
assay 4) after IMP administration compared to pre-dose.
The proportion of subjects with treatment-induced anti-FSH antibodies and the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralising capacity are secondary 
endpoints.
Subjects with a treatment-induced anti-FSH antibody response (both with and without neutralising 
capacity) will be followed until the response becomes negative or has returned to pre-dosing level.
These subjects will be called in for monthly assessments for a period of 3 months after the last post-
dosing anti-FSH antibody sampling. If required, further assessments will be made quarterly, i.e. 6, 9
and 12 months after the last post-dosing anti-FSH antibody sampling. The assessments will be 
terminated when two consecutive assessments are negative or indicate that the pre-dosing level has 
been reached, with a maximum follow-up period of one year. The assessments will also be 
terminated if the subject commences a new treatment cycle with a gonadotropin preparation.
7.2.22
Immune-related Adverse Events
All adverse events reported in the trial will be analysed to identify those that potentially are 
immune-related. To identify all possible cases, a broad-scope search on Standardised Medical 
Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), including ‘Hypersensitivity’,
‘Anaphylactic reactions’, ‘Angioedema’ and ‘Severe cutaneous adverse reactions’ will be 
considered. Moreover, to identify the potential cases manifested by non-specific symptoms and not 
covered by these SMQs, other MedDRA PTs like ‘Musculoskeletal pain’, ‘Asthenia’, ‘Pyrexia’, 
‘Chills’, ‘Body temperature increased’, ‘Influenza like illness’, ‘Injection related reaction’, ‘Pre-
syncope'’ and ‘Syncope’ will also be taken into account. Hypersensitivity reactions manifested by 
local symptoms will be identified using the MedDRA high level term (HLT) ‘injection site 
reactions’. The SMQs may include very specific as well as less specific terms; hence a narrow-
scope search on these SMQs will be carried out to identify those cases that are highly likely to 
represent an immune-related aetiology.
7.2.23
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen
The reason for each cycle cancellation will be recorded. Among the options are adverse events, 
including immune-related adverse events, and technical malfunctions of the administration pen.
                                                                                                                                                
f
The fold increase in titres will be determined by minimum significant ratio (MSR) experiments during assay 
validation. The clinical trial report will clearly state the MSR used in the data evaluation.


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7.2.24
Late OHSS (including OHSS of Moderate/Severe Grade)
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3 for details) and 
all OHSS cases will be graded as mild, moderate or severe.
7.2.25
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins
Data related to multi-fetal gestation defined as a pregnancy with more than one fetus will be 
recorded. Furthermore, data related to the occurrence of biochemical pregnancy, spontaneous 
abortion, ectopic pregnancy (with and without medical/surgical interventions) and vanishing twins 
will also be recorded.
7.2.26
Pen Malfunction
Incidences of technical malfunctions of the administration pen will be recorded.
7.3
Other Assessments
7.3.1
Demographics
Demographic information will be obtained during the screening period, including date of birth and 
confirmation of the subject’s race and nationality. Chinese subjects must possess a Chinese 
identification card and have native Chinese parents. 
7.3.2
Medical History
Any relevant medical history will be recorded at screening. This includes diagnoses / symptoms 
and whether it is a past or ongoing occurrence.
7.3.3
Infertility History
Information about the reasons of infertility will be obtained during the screening period. Duration 
of infertility will be recorded at the randomisation visit. This will also cover information about any 
previous treatment for infertility, including type of treatment and gonadotropin preparations used. 
7.3.4
Menstrual History
Information about the menstrual history (average cycle length) will be obtained during the 
screening period.


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7.3.5
Reproductive History
Information about the reproductive history will be obtained during the screening period. This will 
include number of clinical pregnancies, number of fetuses and outcome. Information on primary 
versus secondary infertility will be derived.
7.3.6
Smoking and Alcohol Habits
Information about smoking and alcohol habits will be obtained during the screening period. 
Smoking will be categorised as 0, 1-5 or 6-10 cigarettes per day. Alcohol will be categorised as 0, 
1-7 or 8-14 units per week.
7.3.7
Body Weight and Height
Body weight will be measured at screening, stimulation day 1 and at end-of-trial. Body weight will 
be measured without shoes and overcoat and using a calibrated scale. The body weight at 
randomisation will be used for dose calculation in the FE 999049 group.
Height will only be measured at screening and will be used to calculate BMI.
7.3.8
Physical Examination
A complete physical examination will be performed at screening and end-of-trial. Information will 
be recorded for general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth and throat), respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system and skin.
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events.
7.3.9
Gynaecological Examination
A complete gynaecological examination will be performed at screening and end-of-trial. 
Information will be recorded for breast, external genitalia, vagina, cervix, uterus, ovaries and
fallopian tubes.
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported as medical history or as reason for infertility on the Infertility History form, as applicable, 
and evaluated in accordance with inclusion criteria 8 and 9 (section 4.1.1).
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 


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abnormal clinically significant. Abnormal clinically significant changes from screening to 
end-of-trial must be recorded as adverse events.
7.3.10 Endocrine Parameters at Screening
At screening, the following panel of endocrine parameters will be evaluated (screening panel): 
AMH, TSH and prolactin. The sample will be analysed at a central laboratory.
The results of the screening panel must be available prior to randomisation. The investigator will 
review and evaluate the laboratory results (with the exception of AMH, which will not be made 
available to the investigator). The Laboratory Report will be signed and dated by the investigator.
The AMH samples collected at screening may be used for correlation analysis of Elecsys® AMH
immunoassay results determined at provincial local laboratories versus the central laboratory.
7.3.11 Vital Signs
Systolic and diastolic blood pressure as well as pulse will be measured at screening, stimulation 
day 1 and end-of-trial. All assessments of vital signs will be done while the subject is in supine 
position after resting for 3 minutes. 
7.3.12 Ovarian Volume
As part of the transvaginal ultrasounds performed at stimulation day 1 and end-of-stimulation, the 
size – length, width and depth (recorded in mm) – of each ovary is measured and used for 
subsequent calculation of ovarian volume. 
7.3.13 Endometrial Status
Transvaginal ultrasound of the uterus to assess the endometrial status will be conducted at all visits 
during the stimulation period. The endometrial status assessments consist of the following 
parameters: endometrial thickness, endometrial triple-layer structure and endometrial echogenicity 
pattern (note: the latter two are not assessed on stimulation day 1).
Endometrial thickness (composed of both layers of the endometrium) will be measured in the 
sagittal view of the uterus from the proximal and distal interfaces between the echogenic 
endometrium and the hypoechoic inner layer of the myometrium. Care should be taken not to 
include the hypoechoic subendometrial halo and to account for the presence of any fluid in the 
uterine cavity (not to be included in the endometrial thickness value). Endometrial thickness will be 
recorded in mm.
Endometrial triple-layer structure will be recorded as observed or not.
Endometrial echogenicity pattern will be recorded as hypoechogenic, isoechogenic, 
hyperechogenic, or not possible to evaluate.


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7.3.14 Embryo Transfer Procedure
Any difficulty or eventuality (e.g. greater resistance is met, the procedure is time-consuming, there 
is a need to change to a harder catheter, uterine sounding or cervical dilation is carried out, or there 
is blood in any part of the catheter), during the transfer procedure will be noted.
7.3.15 Concomitant Medication
The use of any concomitant medication within the last 3 months prior to informed consent for 
participation in the trial (except medication used in previous infertility treatment cycles) and 
throughout the trial will be recorded. Recording of concomitant medication will be performed at all 
visits. Any changes in concomitant medications or treatments must be recorded at each visit. 
7.3.16 Drug Dispensing and Accountability
For all medicinal products, dates of administration and dose administered will be recorded. 
Furthermore, time of administration will also be recorded for IMP, GnRH antagonist, hCG and 
GnRH agonist. Details on drug dispensing and accountability are provided in section 5.7.
7.3.17 End-of-trial Form
An end-of-trial form must be filled in at the subject’s last visit, irrespective of whether the subject 
completes the trial or not. Completion / discontinuation status will be recorded, as well as date and 
reason for discontinuation in case the subject did not complete the trial.
7.4
Assessments Related to Post-trial Information
7.4.1
Pregnancy Follow-up
For subjects with an ongoing pregnancy, information on the pregnancy period, including any 
relevant interventions performed and incidence of second or third trimester losses, as well as the 
pregnancy outcome, e.g. live birth, will be gathered. Further, neonatal health data will be collected 
at birth and at 4 weeks after birth for all children born. At birth, the data collected will include 
gender, birth weight and length, way of delivery, position of neonate and Apgar score as well as 
information on any congenital anomalies and admission to neonatal intensive care unit (NICU) or 
neonatal care unit (NCU). At 4 weeks after birth, the data collected will include any congenital 
anomalies, hospitalisations, death of neonate and any other relevant medical conditions. These
follow-up data can be obtained from the subject, unless medical judgement is required.
These data will be reported separately.
7.5
Handling of Biological Samples
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. All biological 
samples will be analysed at central laboratories and will be maintained in storage after the end of 
the trial. Destruction will take place within 2 years after reporting of the trial or when methods / 


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results have been adequately validated. For all biological samples collected in the trial, it applies 
that analyses beyond those described in the protocol can only be performed after obtaining the 
required approvals. The processes related to handling of biological samples will be described in the 
informed consent documents, and biobank / data protection legislation including local legislation 
will be adhered to.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes:

Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP.

Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP.

Any laboratory abnormality, vital sign or finding from physical or gynaecological
examination assessed as clinically significant by the investigator [note: pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or during 
the screening period are not adverse events, but are recorded as medical history.]

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures.
All adverse events will be coded by Ferring Global Pharmacovigilance using MedDRA (the version 
effective at trial start).
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the end-of-trial visit.
The sources of adverse events cover:

The subject’s response to questions about her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit).

Symptoms spontaneously reported by the subject.

Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities.

Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalisation).
8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s e-CRF with information about:

Adverse event

Date and time of onset


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
Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome

Outcome

Seriousness
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Event
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis / symptom should be entered per record.
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event.g
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event).
Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
date is the date the sample was taken or the examination was performed. 
                                                                                                                                                
g
Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
changes in intensity after the administration of the IMP, this must be recorded as two separate events. The initial 
adverse event should be recorded with outcome “not yet recovered” and the date and time of outcome is when the 
intensity changed. The second adverse event should be recorded with date and time of onset when the intensity 
changed. 


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Intensity
The intensity of an adverse event must be classified using the following 3-point scale:
Mild:
Awareness of signs or symptoms, but no disruption of usual activity.
Moderate:
Event sufficient to affect usual activity (disturbing).
Severe:
Inability to work or perform usual activities (unacceptable).
Causal Relationship to IMP
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship 
between the IMP and the adverse event. The adverse event may occur 
as part of the pharmacological action of the IMP or may be 
unpredictable in its occurrence.
Examples: 

Adverse events that are uncommon but are known to be strongly 
associated with IMP exposure.

Adverse events that are not commonly associated with IMP 
exposure, but the event occurs in association with other factors 
strongly suggesting causation, such as a strong temporal 
association with the IMP or the event recurs on rechallenge with 
the IMP.
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the adverse event.
Examples:

Known consequences of the underlying disease or condition 
under investigation.

Adverse events common in the trial population, which are also 
anticipated to occur with some frequency during the course of the 
trial, regardless of IMP exposure.
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:

No change (medication schedule maintained or no action taken)

Discontinued

Interrupted


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
Dose reduced

Dose increased
Other Action Taken
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date and time the subject recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment)

Recovered with sequelae (resulted in persistent or significant disability / incapacity)

Recovering

Not recovered

Fatal
8.3
Adverse Events of Special Interest and/or Requiring Special Handling
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)
Symptoms and Classification
OHSS is an adverse event of special interest during controlled ovarian stimulation. Investigators 
will record OHSS symptoms and use these symptoms directly to grade (1, 2, 3, 4 or 5) each OHSS 
case into Golan’s classification system35 as shown in Table 8-1.


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Table 8-1
Classification of Mild, Moderate and Severe OHSS (Golan’s Classification 
System)
Mild OHSS
Grade 1
Abdominal distension and discomfort 
Grade 2 
Features of grade 1 plus nausea/vomiting and/or diarrhoea. Ovaries enlarged to 
5-12 cm.a)
Moderate OHSS
Grade 3 
Features of mild OHSS plus ultrasonic evidence of ascites.b)
Severe OHSS
Grade 4 
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax (or 
breathing difficulties). Paracentesis due to OHSS symptoms. c)
Grade 5 
All of the above plus change in blood volume, increased blood viscosity due to 
haemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d) Hospitalisation due to OHSS symptoms.
a) For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded. 
b) For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis. 
c) In case of paracentesis, the volume of fluid drained should be measured.
d) Heaemoconcentration is defined as haematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded.
All cases of OHSS must be reported as adverse events. Those that fall under the category serious 
adverse events must be reported as such. Note that the classification ‘mild OHSS’, ‘moderate 
OHSS’ and ‘severe OHSS’ does not refer to the classification of an adverse event’s intensity (also 
rated mild, moderate, or severe).
Subject narratives will be prepared for all moderate and severe OHSS cases.
Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of 
final follicular maturation and late OHSS will be defined as OHSS with onset >9 days after 
triggering of final follicular maturation.
In addition to early OHSS and late OHSS overall, emphasis will be placed on OHSS of 
moderate/severe grade.
Preventive Interventions of Early OHSS
Preventive interventions of early OHSS include the following:

Cycle cancellation due to excessive ovarian response


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
Triggering of final follicular maturation with GnRH agonist 
Investigations to be Conducted in Subjects where OHSS Symptoms are Observed
The following investigations must be conducted when OHSS symptoms are first observed and 
repeated when there are clinically relevant changes in the OHSS presentation: 

Body weight and maximum abdominal circumference (for all OHSS)

Vital signs (for all OHSS)

Blood sample for central laboratory analysis of the following (for moderate/severe OHSS):

Progesterone and estradiol

CBC (red blood cells, red blood cell morphology, white blood cells, white blood cell 
morphology, haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets)

CHEM-20 (alanine transaminase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, 
calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric 
acid)

Coagulation parameters (prothrombin time, activated partial thrombin time)
Any treatments of OHSS, e.g. intravenous administration of volume expanders, paracentesis, use of 
low-molecular-weight heparin and intravenous administration of albumin, must be recorded as 
concomitant medication.
8.3.2
Local Tolerability
Injection site reactions after administration of IMP (FE 999049 and GONAL-F) are only to be 
reported as adverse events if they require active management, i.e. discontinuation of IMP, 
additional investigations or treatment of the injection site reaction. Local tolerability of IMP 
constitutes a secondary endpoint and will be evaluated in detail based on the subjects’ recordings in 
the diary. 
Local tolerability reactions after administration of NIMP are to be reported as adverse events if they 
fulfil the definition of an adverse event.
8.3.3
Treatment-induced Anti-FSH Antibodies
Presence of treatment-induced anti-FSH antibodies is not to be reported as an adverse event. These 
data will be described as part of the secondary endpoints.


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8.3.4
Menstrual Bleeding
Menstrual bleeding is only to be reported as an adverse event in case it is excessive, painful, 
delayed or in any other way deviating from the subject’s normal menstruation. Menstrual bleeding 
associated with lack of pregnancy will be reported as part of the efficacy evaluation.
8.3.5
Ovarian Torsion
Any case of ovarian torsion will be reported as an adverse event and it will be specified whether it 
is associated with any signs or symptoms of OHSS.
8.3.6
Pregnancy Losses
The following terminology should be used for reporting of pregnancy losses during the trial:
Biochemical pregnancy: 
Positive βhCG test but no gestational sac is observed on later 
transvaginal ultrasound, or menstruation is reported
Spontaneous abortion: 
Positive βhCG test but all intrauterine gestational sacs are 
without fetal heart beat as documented by ultrasound, or there 
are no viable fetuses observed by ultrasound
Vanishing twin:
Spontaneous disappearance of an intrauterine gestational sac 
with or without heart beat in a pregnancy where one viable 
fetus remains as documented by ultrasound
Ectopic pregnancy:
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery
Concerning timing, a pregnancy loss occurring before ongoing pregnancy (i.e. during 1st trimester) 
will be defined as an early pregnancy loss, while a pregnancy loss occurring after ongoing 
pregnancy (i.e. during 2nd or 3rd trimester) during the post-trial follow-up will be defined as a late 
pregnancy loss.
8.3.7
Multiple Pregnancies
Multi-fetal gestations are not to be reported as adverse events. These data will be described as part 
of the secondary endpoints.


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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious Adverse Events during the Trial
An event is defined a serious 
adverse event if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a subject 
enrolled in a trial is per se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe.
requires in-patient
hospitalisation or prolongation 
of existing hospitalisation
The term hospitalisation means that the subject was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation 
describes a period of at least 24 hours. Over-night stay for observation, stay 
at emergency room or treatment on an out-patient basis do not constitute a 
hospitalisation. However, medical judgement must always be exercised and 
when in doubt the case should be considered serious (i.e. if case fulfils the 
criterion for a medically important event). Hospitalisations for administrative 
or social purposes do not constitute a serious adverse event. Hospital 
admissions and/or surgical operations planned before trial inclusion are not 
considered adverse events, if the illness or disease existed before the subject 
was enrolled in the trial, provided that the condition did not deteriorate during 
the trial.
results in persistent or 
significant disability /
incapacity
Disability / incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgement by the investigator.
is an important medical event
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalisation 
but might jeopardise the patient or might require intervention to prevent one of 
the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse.
Serious Adverse Events during Post-trial Follow-up
The following untoward medical occurrences reported as part of the pregnancy outcome and 
neonatal health data collection will be recorded as serious adverse events. Data will be collected at 
birth and at 4 weeks after birth.

Death of mother in connection with pregnancy or labour

Death of neonate


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
Stillbirth (≥ gestational age 24 weeks + 0 days, calculated from the day of transfer + 17 
days34)

Neonate admitted to the NICU regardless of duration or NCU for more than 2 hours

Congenital anomaly / birth defect

Medically important event
In case of admission to NICU or NCU, the reason for admission must be reported as a serious 
adverse event, rather than just the act of hospitalisation. 
Congenital anomalies will be coded by Ferring using both MedDRA and ICD-10 and classified as 
minor or majorh in accordance with the EMA guideline1.
8.4.2
Collection, Recording and Reporting of Serious Adverse Events
Serious Adverse Event Reporting by the Investigator
All serious adverse events must be reported immediately to Ferring Global Pharmacovigilance as 
soon as it becomes known to the investigator and not later than within 24 hours of their knowledge 
of the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed Serious Adverse Event (SAE) Report 
Form with the fullest possible details within 3 calendar days of his/her knowledge of the serious 
adverse event.
Serious Adverse Event (SAE) Report Form
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Global Pharmacovigilance using the contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: safety.mailbox@ferring.com
Fax: 
Information to be Entered / Updated in the e-CRF
Completion of the Demographics, Adverse Event form, Medical History form and Concomitant 
Medication form are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Global Pharmacovigilance to access the information.
                                                                                                                                                
h
Major abnormalities: a life threatening structural anomaly or one likely to cause significant impairment of health or 
functional capacity and which needs medical or surgical treatment. 
Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems.


Follitropin Delta, FE 999049
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Additional information relevant to the serious adverse event such as hospital records, results from 
investigations, e.g. laboratory parameters (that are not already uploaded in the e-CRF), invasive 
procedures, scans and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 
Global Pharmacovigilance using the contact details in the section above. In any case this 
information must be supplied by the investigator upon request from Ferring. On any copies 
provided, such details such as subject’s name, address, and hospital ID number should be concealed 
and instead subject number should be provided.
The investigator will supply Ferring and the ethics committee with any additional requested 
information such as results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.
The expectedness is assessed by Ferring according to the current edition of the Investigator’s 
Brochure for FE 999049 and the Product Information for GONAL-F.4
Serious adverse events will be considered reportable regardless of whether or not the IMP was used 
in accordance with the provisions in the protocol, Investigator’s Brochure and labelling.
8.5
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow-up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. If the event is a chronic condition, the investigator and Ferring may agree that 
further follow-up is not required.
8.5.2
Collection of Serious Adverse Events with Onset after End-of-trial
If an investigator becomes aware of a serious adverse event after the end of the trial, and he/she 
assesses the serious adverse event to have a reasonable possible causality to the IMP (FE 999049 or 
GONAL-F) or a NIMP where Ferring is Marketing Authorisation Holder (i.e. GONAPEPTYL) the 
case will have to be reported to Ferring, regardless how long after the end of the trial this takes 
place.


Follitropin Delta, FE 999049
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8.5.3
Follow-up of Serious Adverse Events with Onset during the Post-Trial
For post-trial serious adverse events in neonates, where the neonate has not recovered at the 4-
weeks follow-up assessment, the investigator must follow up until SAE has resolved. If the SAE is 
a chronic condition or the medical condition of the neonate is stable, the investigator and Ferring 
may agree that further follow-up is not required.


Follitropin Delta, FE 999049
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9
STATISTICAL METHODS
The Ferring Global Biometrics Department will be responsible for the statistical analyses of the 
primary and secondary endpoints. This section details the planned statistical analyses for the 
primary endpoint and outlines the planned statistical analyses for the secondary endpoints. All 
analyses and further descriptions of the statistical methodology for the primary and secondary 
endpoints will be included in the Statistical Analysis Plan (SAP) available before the first subject is 
randomised. A separate SAP will be prepared to cover the post-trial information.
The Ferring Health Economics & Outcome Research department will perform a health economic 
analysis of FE 999049 in comparison with GONAL-F utilising relevant data recorded in this trial. 
The details of this analysis will be described in a separate health economic analysis plan.
9.1
Determination of Sample Size
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian 
stimulation. The non-inferiority limit for the difference between treatments (FE 999049 versus
GONAL-F) is -10.0% (absolute) for the primary endpoint.
The trial is designed to have 90% power of achieving the primary objective for the overall trial 
population and 80% power in the Chinese population. The number of subjects needed to achieve 
90% power depends on the assumptions regarding the ongoing pregnancy rate. The ongoing 
pregnancy rate is defined as the number of subjects with at least one intrauterine viable fetus 
10-11 weeks after transfer divided by the number of randomised and exposed subjects. 
Considerations for Choice of Non-inferiority Margin
Assuming that the ongoing pregnancy rate is 32.2% in both treatment groups, then the total number 
of subjects needed to achieve 90% power is governed by the choice of non-inferiority margin. In 
order to establish non-inferiority, the two-sided 95% confidence interval must lie entirely above the 
chosen non-inferiority margin. Therefore, the power of the test is directly related to the width of the 
two-sided 95% confidence interval. The width of this confidence interval is inversely related to the 
square root of the sample size, i.e. a quadrupling of the sample size will lead to a halving of the 
width of the confidence interval. In fact, increasing the sample size with 500 subjects from 100 to 
600 reduces the width of the confidence band with 59%, while the impact of a similar increase in 
number of subjects from 1,000 to 1,500 only reduces the width of the confidence band with 18%.
The sample sizes for three different non-inferiority margins are shown in Table 9-1. As shown,
changing the non-inferiority margin from -12.0% to -10.0% requires 280 additional subjects, while 
tightening the margin with an additional 2.0% requires 516 additional subjects. To further illustrate 
the difference between these three non-inferiority margins, the width of the two-sided 95% 
confidence intervals and the precision quantified as ±1 standard error are also included in 
Table 9-1. As can be seen, increasing the sample size from 918 to 1,434 subjects reduces the 
standard error with 0.6 percentage points (from 3.1% to 2.5%).


Follitropin Delta, FE 999049
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The relation between the choice of non-inferiority margin and the maximum allowed difference in 
ongoing pregnancy rates leading to non-inferiority can also be derived. Assuming the observed rate 
for the GONAL-F group is 32.2% the minimum observed rate in the FE 999049 group that still 
leads to non-inferiority is shown in Table 9-1. For example, if the non-inferiority margin is -10.0% 
and the observed ongoing pregnancy rate in the GONAL-F group is 32.2%, then non-inferiority 
will only be established if the observed ongoing pregnancy rate in the FE 999049 group is at least 
28.2%, i.e. the observed ongoing pregnancy rates must not differ with more than 4.0 percentage 
points. Tightening the margin to -8.0%, (i.e. adding 516 subjects) will require a minimum ongoing 
pregnancy rate of 29.0% in the FE 999049 in order to claim non-inferiority, i.e. a maximum 
difference of 3.2 percentage points. Hence, increasing the sample size from 918 to 1,436 subjects 
reduces the maximum allowable observed difference between treatments by 0.8 percentage points 
(from 4.0% to 3.2%).
Taking the above into account a non-inferiority margin of -10.0% (absolute) seems appropriate 
since further tightening of the non-inferiority margin will lead to an increase in sample size with 
only limited impact on the precision of the estimate and the maximum difference in observed rates 
leading to non-inferiority.
Table 9-1
Implications of Choice on Non-inferiority Margin on Sample Size, Precision and 
Difference in Observed Rates
Non-inferiority margin (absolute)
-12.0%
-10.0%
-8.0%
Subjects needed to achieve 90% power in the PP population*
638
918
1434
Expected width of two-sided 95% confidence interval
14.5%
12.1%
9.7%
Expected precision of estimate (± 1 standard error)
± 3.7%
± 3.1%
± 2.5%
Minimum ongoing pregnancy rate with FE 999049 needed to 
claim non-inferiority if the observed rate with GONAL-F is 32.2%
27.3%
28.2%
29.0%
Maximum difference that can be observed (GONAL-F minus 
FE 999049) leading to non-inferiority if the observed rate with 
GONAL-F is 32.2%
4.9%
4.0%
3.2%
* Assuming 8% major protocol deviations
Considerations for Sample Size
Table 9-2 summarises the required sample size to obtain 80% and 90% power for various rates 
(assumed equal in the two treatment groups) and assuming a non-inferiority margin of -10.0% 
(absolute).
Since this is a non-inferiority trial, the full analysis set (FAS) and the per-protocol (PP) analyses are 
equally important, i.e. non-inferiority should be established for both analysis sets in order to have a 
robust conclusion36,37. Therefore, the expected proportion of subjects with major protocol deviations 
should be taken into account when setting the total sample size for the trial. The proportion of 
subjects with major protocol deviations is assumed to be at most 8%.


Follitropin Delta, FE 999049
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Date: 27 Sep 2018
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Table 9-2
Sample Size by Ongoing Pregnancy Rate for the PP Analysis Set
Ongoing pregnancy rate
(Assumed equal in the two 
treatment groups)
Assuming 80% power and -10.0% 
(absolute) non-inferiority margin
Assuming 90% power and -10.0% 
(absolute) non-inferiority margin
Number of subjects
Number of subjects
Per group
Total
Per group
Total
PP*
PP*
PP*
PP*
25%
295
590
395
790
30%
330
660
442
884
32.2%
343
686
459
918
35%
358
716
479
958
40%
377
754
505
1010
45%
389
778
521
1042
50%
393
786
526
1052
* Assuming 8% major protocol deviations
Based on an assumed ongoing pregnancy rate of 32.2 % observed in the PP population of the 
ESTHER 1 trial, N=918 subjects are required in the PP population to obtain a power of 90%. 
Anticipating at most 8% major protocol deviations this results in N=1000 subjects to be 
randomised. The power is reasonably robust against deviations from the ongoing pregnancy rate 
assumption of 32.2%: a 35% ongoing pregnancy rate would still result in a 88.9% power, while 
lower rates will only increase the power (e.g. 30% yields 91.1% power). Recruiting at least 
740 subjects in China is expected to secure that consistency can be established between the results 
from the overall trial population and the Chinese trial population. In addition, to obtain approval in 
other Asian countries at least 260 subjects are needed. Thus a total sample size of 1,000 subjects 
will be recruited for this trial.
A sample size re-assessment is planned and will be done without breaking the blind and without 
inflating the type 1 error of the trial, in line with the current regulatory guidelines (see section 9.10). 
The expected maximum number of subjects to be randomised would then be approximately 1,144
(572 per treatment group), corresponding to an observed rate of 50%. 
9.2
Subject Disposition
All screened subjects will be accounted for. 
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening 
failures.
Subject disposition with respect to analysis sets will be tabulated by treatment group overall, by age 
stratum and country for all randomised subjects. This table will include the number of completed 
and discontinued subjects including reason for discontinuation. Screening failures and their primary 
reason for screening failure will also be included. Screening failures will not otherwise be 
accounted for. 
A separate table will summarise the subject disposition with respect to analysis sets by trial site 
overall and by age stratum. 


Follitropin Delta, FE 999049
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Date: 27 Sep 2018
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Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately.
9.3
Protocol Deviations
Major protocol deviations, such as significant non-compliance or other serious unforeseen
deviations deemed to invalidate the data and affect the conclusions of the trial, will lead to
exclusion of data from the PP analysis set. Data will not be excluded from the PP analysis set in
case of minor protocol deviations. The list of major protocol deviations include, but is not restricted 
to:

Unblinding of assessor

Treatment not in accordance with randomisation

Non-compliance with IMP for two or more days

Administration of hCG for triggering of final follicular maturation was not given despite the
triggering criterion for hCG administration was met

GnRH agonist criterion met but hCG used for triggering of final follicular maturation

GnRH agonist criterion not met but GnRH agonist used for triggering of final follicular 
maturation

Non-compliance with the number of embryos transferred
The rating of protocol deviations in ‘minor’ and ‘major’ will be decided by the Ferring clinical
team on the basis of a blinded review of data before declaration of clean file and lock of database. If 
the blinded review identifies serious unforeseen deviations deemed to impact the primary endpoint 
and affect the conclusions of the trial these will also be rated as major deviations. 
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be tabulated and listed by subject for the 
FAS analysis set.
9.4
Analysis Sets
Intention-to-Treat (ITT) Analysis Set
The intention-to-treat (ITT) analysis set is defined as all randomised subjects. Subjects will be 
analysed according to randomised treatment.
Full Analysis Set (FAS)
The FAS is defined as all randomised and exposed subjects. Subjects will be analysed according to 
randomised treatment.


Follitropin Delta, FE 999049
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Per-Protocol (PP) Analysis Set
The PP analysis set is defined as all randomised and exposed subjects except those excluded as a 
result of major protocol deviations as described in section 9.3. 
Safety Analysis Set
The safety analysis set is defined as all randomised and exposed subjects. Subjects will be analysed 
according to actual treatment received. 
9.5
Trial Population
9.5.1
General Considerations
All relevant baseline data will be summarised in tables including both treatment groups and a total 
column. The purpose of these tabulations is to characterise the treatment groups and assess the 
degree of similarity achieved by the randomisation. Baseline data will not be compared using 
statistical tests. Unless otherwise noted, tabulations will be produced overall and by age stratum for 
both the FAS and the PP analysis set. Continuous variables will be presented with number of 
subjects, mean, standard deviation, median, inter-quartile range, minimum, and maximum. 
Categorical variables will be presented with number and percentage of subjects within each specific 
category. 
Listings will be produced for the FAS. 
Unless otherwise noted, missing data will not be imputed.
9.5.2
Trial Population Parameters
Demographics and other Baseline Characteristics
Demographics and other baseline characteristics (smoking and alcohol habits, body measurements, 
ultrasound parameters, vital signs, and endocrine parameters) obtained before first exposure to IMP 
will be listed by subject and tabulated.
Medical History
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarised for each medical item. This summary 
table will be produced overall (i.e. not by age stratum) for the FAS.
Infertility History, Menstrual History and Reproductive History
Infertility history, menstrual history and reproductive history will be listed by subject and presented 
in summary tables.


Follitropin Delta, FE 999049
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Physical Examination and Gynaecological Examination
Physical examination and gynaecological examination performed during screening will be 
summarised per category. These tables will be produced overall (i.e. not by age stratum) for the 
FAS.
Concomitant Medication
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference List. Prior and concomitant medication will be summarised by ATC classification 1st
level (alphabetically) and ATC classification 2nd level (in decreasing order of frequency). These 
medications will be tabulated separately for:

Prior medication, i.e. medication taken exclusively prior to treatment (i.e. with stop 
date/time before date/time of 1st IMP administration)  

Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date/time of 1st IMP administration and not started after the end-
of-trial visit)
These tables will be produced overall (i.e. not by age stratum) for the FAS.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
Concomitant medications will be listed by subject.
9.6
Treatment Compliance
Treatment non-compliance will be presented in listings as non-compliance is expected to be 
limited.


Follitropin Delta, FE 999049
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9.7
Endpoint Assessments
9.7.1
General Considerations
Primary and Secondary Endpoints
The results of the analyses of the primary endpoint (ongoing pregnancy rate) based on the overall 
trial population are essential for the non-inferiority claim. The results obtained for the Chinese trial 
population is considered supportive of the overall conclusion. If the results for the Chinese trial
population are markedly different from those obtained based on the overall trial population the 
reasons for this difference will be examined. The secondary endpoints positive βhCG rate, clinical 
pregnancy rate, vital pregnancy rate, implantation rate and ongoing implantation rate are considered 
supportive of the primary endpoint. However, non-inferiority does not need to be established for 
these secondary endpoints.
The remainder of the secondary endpoints are intended to provide additional characterisation of the 
treatments. 
Analysis and Presentation of Primary and Secondary Endpoints
Summary tables and treatment comparisons for the primary endpoint and supportive secondary 
endpoints will be presented overall, by age stratum and country for both the FAS and PP analysis 
sets. Treatment comparisons will be produced for the overall trial population and for the Chinese 
population. As applicable for the remaining secondary endpoints, summary tables and treatment 
comparisons may be presented overall and by age stratum for the FAS and PP analysis sets. 
All tabulations will present the treatment groups and include a total column. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category. 
All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of ‘equal effect’ against the alternative of 
‘different effect’.
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will 
be listed for the FAS.
Multiplicity 
No adjustments for multiplicity are required since there is only one primary endpoint and non-
inferiority has to be established for both the FAS and the PP analysis sets. In addition, the testing 
for superiority will be made in a sequential manner, only if non-inferiority is established. The 
evaluation of the subjects recruited in China will be regarded as supportive. Concerning the 
secondary endpoints no formal adjustment for multiplicity will be utilised. 


Follitropin Delta, FE 999049
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Missing Data
Missing observations for the primary endpoint ongoing pregnancy rate will be imputed as 
‘negative’ irrespective of the reason why data are not recorded.
Missing observations for the supportive secondary endpoints positive βhCG rate, clinical pregnancy 
rate and vital pregnancy rate will be imputed as ‘negative’ unless a positive result is observed at a 
later pregnancy assessment. For example, if the outcome of βhCG is missing but clinical pregnancy 
is positive then βhCG will be imputed as ‘positive’.
For subjects with transfer but missing information on the number of viable fetuses 10-11 weeks 
after transfer, the number of viable fetuses will be imputed as zero irrespective of why data are not 
recorded. For subjects with transfer but missing information on the number of gestational sacs 
5-6 weeks after transfer, the number of gestational sacs will be imputed as the number of viable 
fetuses at 10-11 weeks after transfer.
For adverse events, missing values will be treated as missing, except for causality, intensity and
seriousness of adverse events, where a worst-case approach will be used.
Missing values will not be imputed for any of the other secondary endpoints.
9.7.2
Primary Endpoint
This trial has one primary endpoint: Ongoing pregnancy rate. The primary objective of this trial is 
to demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to the primary 
endpoint in women undergoing controlled ovarian stimulation. The non-inferiority limit for the 
difference between treatments (FE 999049 versus GONAL-F) is -10.0% (absolute).
The non-inferiority hypothesis to be tested for the primary endpoint is
H0: FE - GF -10.0% against the alternative HA: FE - GF > -10.0%,
where FE and GF denote the ongoing pregnancy rate after treatment with FE 999049 and 
GONAL-F, respectively. Non-inferiority will be evaluated based on the overall trial population.
The primary analyses will be adjusted for the stratification factor (age group) by using the Mantel-
Haenszel method to combine results across age groups. In brief, this corresponds to deriving a 
weighted average across age groups where the weight depends on the number of observations in 
each treatment group in each age stratum.
For the primary endpoint the null hypothesis (H0) will be tested against the alternative (HA) by 
constructing a two-sided 95% confidence interval for the difference in ongoing pregnancy rates. If 
the lower-limit of the two-sided 95% confidence interval is greater than the non-inferiority limit 
(-10.0%) for both the FAS and the PP analysis set, the null hypothesis will be rejected. In that case 
it will be claimed that FE 999049 is non-inferior to GONAL-F with respect to ongoing pregnancy 
rate in women undergoing controlled ovarian stimulation.


Follitropin Delta, FE 999049
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If the lower-limit of the two-sided 95% confidence interval for the treatment difference based on 
the FAS not only lies above the non-inferiority limit (-10.0%) but also above zero then there is 
evidence of superiority in terms of statistical significance at the 5% level. In this case, the p-value 
from the test for superiority will be reported and it will be claimed that FE 999049 is superior to 
GONAL-F for the primary endpoint analysed. The result based on the PP analysis set is not 
essential for the superiority claim but should lead to a comparable result for a robust interpretation. 
There is no need for a multiplicity adjustment when switching from non-inferiority to superiority 
since it is a simple sequential test procedure. This interpretation is in line with the Food and Drug 
Administration (FDA) draft guidance on “Non-inferiority Clinical Trials”36 and EMA’s “Points to 
consider on switching between superiority and non-inferiority”38.
Due to the large sample size the two-sided 95% confidence intervals will be established based on 
the asymptotic normal distribution as follows


2
2
2
)
(
96
.1





i
i
i
i
i
i
w
RD
SE
w
w
RD
w
,
where all sums are over the three strata (i.e. i = 1 to 3) and
i
GF
i
FE
i
RD
,
,
ˆ
ˆ




is the observed difference in rates within age stratum i
i
GF
i
GF
i
GF
i
FE
i
FE
i
FE
i
n
n
RD
SE
,
,
,
,
,
,
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
(








is the standard error of the observed 
difference in rates within age stratum i
i
GF
i
FE
i
GF
i
FE
i
n
n
n
n
w
,
,
,
,


is the weight assigned to age stratum i
i
FE
,
ˆ
is the observed rate in age stratum i in the FE 999049 group
i
GF
,
ˆ
is the observed rate in age stratum i in the GONAL-F group
i
FE
n
, is the number of observations in the FE 999049 group in age stratum i
i
GF
n
, is the number of observations in the GONAL-F group in age stratum i
A supportive evaluation of the subjects recruited in China will be conducted, and it is expected that 
the findings among the Chinese trial population will be consistent with the overall findings in the 
trial. If the results based on the Chinese trial population are markedly different from those obtained 
based on the overall trial population the implications for the overall conclusion of the trial will be 
evaluated.


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Additional Analyses, including Sensitivity Analysis
The primary analyses described above will be repeated restricted to subjects with oocytes retrieved 
and to subjects with embryo(s) transferred. Since the trial is not powered to establish non-inferiority 
for these subgroups, the outcomes of these analyses are considered supportive of the primary 
analysis.
Besides stratification by age group the randomisation is also stratified by trial site. However, as 
detailed above, the primary analysis will be based on all data pooled across sites assuming 
homogeneity of the risk differences across sites. This assumption will be tested using the approach 
described by Lipsitz et al. (1998).39 If there is statistically significant heterogeneity across sites the 
implications for the interpretation of the primary result will be discussed.
To evaluate the robustness of the conclusions, the following factors potentially impacting ongoing 
pregnancy will be evaluated one by one:

Insemination method

Primary reason for infertility

Primary infertility

Smoking status
For each factor, subjects will be grouped according to the levels of the factor and the primary 
analysis will be repeated using this grouping. The outcomes of these analyses are considered 
supportive and should lead to similar results as the primary analysis to ensure robustness of the 
conclusion.
As described in Section 6.5.1, transfer of one or two embryo(s) is to be performed on day 3 after 
oocyte retrieval. The decision to transfer either one or two embryo(s) is based on the subject’s age 
and the quality and availability of embryo(s) on the day of transfer. Since this decision is based on 
observations performed after randomisation it can be affected by the treatment allocation. It is 
therefore not planned to perform a formal statistical analysis of the ongoing pregnancy rate
adjusting for number of embryos transferred. The rationale for not including these adjustments in 
the primary analysis is that such an adjustment may hide or exaggerate the differences between 
treatments.40 Instead the ongoing pregnancy rate will be presented by number of embryos
transferred. Further, a frequency table will be produced to compare the treatment groups with 
respect to number of embryos transferred.
9.7.3
Secondary Endpoints
For each secondary endpoint the analysis based on the FAS will be used to assess the statistical 
significance of differences between treatments. The analysis based on the PP analysis set will be 
considered supportive and should lead to a similar but not necessarily statistically significant result 
in order to have a robust interpretation.


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Positive βhCG Rate
The positive βhCG rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner.
Clinical Pregnancy Rate
The clinical pregnancy rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner. For subjects with clinical pregnancy, the type of clinical pregnancy 
(intrauterine or ectopic) will be tabulated.
Vital Pregnancy Rate
The vital pregnancy rate is considered supportive of the primary endpoint and will therefore be 
analysed in a similar manner. For subjects with a vital pregnancy, the number of intrauterine 
gestational sacs with fetal heart beat and the number of fetuses with fetal heart beat will be 
tabulated.
Implantation Rate
For implantation rate, the experimental unit will be the transferred embryos, i.e. the analysis will 
compare the proportions of embryos transferred that results in gestational sacs 5-6 weeks after 
transfer.
Ongoing Implantation Rate
For ongoing implantation rate, the experimental unit will be the transferred embryos, i.e. the 
analysis will compare the proportions of embryos transferred that results in intrauterine viable 
fetuses 10-11 weeks after transfer.
Extreme Ovarian Response
The analyses of extreme ovarian response will be performed using the following definitions of 
extreme ovarian response: <4 oocytes retrieved, ≥15 oocytes retrieved, ≥20 oocytes retrieved, <4 or 
≥15 oocytes retrieved and <4 or ≥20 oocytes retrieved. Subjects with cycle cancellation due to poor 
ovarian response will be included as <4 oocytes retrieved. Subjects with cycle cancellation due to 
excessive ovarian response will be included as ≥15 and ≥20 oocytes retrieved.
For each definition the proportion of subjects with extreme ovarian response will be tabulated. 
Treatment groups will be compared using a logistic regression model with treatment and age group 
as factors. The possibility of an interaction will be tested. The difference between treatments will be 
reported as an odds ratio including 95% confidence interval and p-value for test of no treatment 
difference. If the expected number of observations is less than five in any of the cells in the 
contingency table then Fisher’s exact test within strata will be used as alternative.


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Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions 
for Early OHSS
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). Early OHSS is defined as OHSS with onset ≤9 days after triggering of final 
follicular maturation. Note that this includes OHSS with onset before triggering and OHSS with 
onset during stimulation where triggering is not performed.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
extreme ovarian response. The analysis will be performed for the proportion of subjects with early 
OHSS, the proportion of subjects with early OHSS of moderate or severe grade, the proportion of 
subjects with preventive interventions for early OHSS, the proportion of subjects with early OHSS 
and/or preventive interventions for early OHSS, and the proportion of subjects with early OHSS of 
moderate or severe grade and/or preventive interventions for early OHSS.
Cycle Cancellation due to Poor or Excessive Ovarian Response or Embryo Transfer 
Cancellation due to Excessive Ovarian Response / OHSS Risk
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
extreme ovarian response. The analysis will be performed for the following: the proportion of 
subjects with cycle cancellation due to poor ovarian response, the proportion of subjects with cycle 
cancellation due to excessive ovarian response, the proportion of subjects with cycle cancellation 
due to poor or excessive ovarian response, the proportion of subjects with embryo transfer 
cancellation due to excessive ovarian response / OHSS risk.
Number and Size of Follicles during Stimulation 
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised by treatment on 
the follicle level (number of follicles 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and ≥17 mm) and 
on the subject level (total number of follicles, size of largest follicle, average follicle size, average 
size of three largest follicles, and number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and 
≥17 mm). Continuous data will be compared between treatment groups using the van Elteren test 
stratified for age-group. Ordinal data will be compared using the Cochran-Mantel-Haenszel test for 
ordinal data stratified for age-group. Within strata comparisons will be based on Wilcoxon’s test.
Number and Size Distribution of Oocytes Retrieved
The number of oocytes retrieved will be tabulated including both summary statistics and a 
frequency table with subjects grouped according to number of oocytes retrieved [<4 (low response), 
4-7 (moderate response), 8-14 (targeted response), 15-19 (hyperresponse) and ≥20 (severe 
hyperresponse)]. Subjects with cycle cancellation due to poor ovarian response will be included in 
the <4 oocytes group. Subjects with cycle cancellation due to excessive ovarian response will be 
included in the ≥20 oocytes group. Continuous data will be compared between treatment groups 
using the van Elteren test stratified for age-group. Ordinal data will be compared using the 
Cochran-Mantel-Haenszel test for ordinal data stratified for age-group. Within strata comparisons 
will be based on Wilcoxon’s test.


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Metaphase II Oocytes
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The 
percentage of MII oocytes to oocytes retrieved for subjects where all oocytes are inseminated using 
ICSI will be tabulated. Further, the number of MII oocytes per subject will be tabulated including 
both summary statistics and a frequency table. Continuous data will be compared between 
treatment groups using the van Elteren test stratified for age-group. Ordinal data will be compared 
using the Cochran-Mantel-Haenszel test for ordinal data stratified for age-group. Within strata 
comparisons will be based on Wilcoxon’s test.
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei on day 1 after oocyte retrieval. For
subjects with oocytes retrieved, the rate of fertilised oocytes to oocytes retrieved (and also the rate 
of fertilised oocytes to metaphase II oocytes for those inseminated using ICSI) will be tabulated. 
Further, the number of fertilised oocytes per subject will be tabulated including both summary 
statistics and a frequency table. Continuous data will be compared between treatment groups using
the van Elteren test stratified for age-group. Ordinal data will be compared using the Cochran-
Mantel-Haenszel test for ordinal data stratified for age-group. Within strata comparisons will be 
based on Wilcoxon’s test.
Number and Quality of Embryos on Day 3
The number of embryos on day 3 including a breakdown by selected quality parameters will be 
tabulated including both summary statistics and frequency tables. Further, for subjects with oocytes 
retrieved, the rate of embryos to oocytes retrieved will be summarised overall and by selected 
quality parameters. Continuous data will be compared between treatment groups using the van 
Elteren test stratified for age-group. Ordinal data will be compared using the Cochran-Mantel-
Haenszel test for ordinal data stratified for age-group. Within strata comparisons will be based on 
Wilcoxon’s test.
Circulating Levels of Endocrine Parameters
Blood samples drawn at stimulation days 1 and 6 and end-of-stimulation are analysed for FSH, LH, 
estradiol, progesterone, inhibin A and inhibin B. Furthermore, blood samples drawn at the oocyte 
retrieval visit are also analysed for FSH. Values below the lower limit of quantification (LLOQ) 
will be included as LLOQ/2. Values above the upper limit of quantification (ULOQ) will be 
included as ULOQ. 


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Each endocrine parameter and the change from baseline for post-baseline measurements will be 
tabulated for stimulation day 1 (baseline), stimulation day 6 and end-of-stimulation (and also the 
oocyte retrieval visit for FSH). For each parameter the change from baseline will be compared 
between treatment groups using an analysis of covariance model (ANCOVA). The ANCOVA will 
be fitted to the relative change from baseline in log-transformed measurements with treatment and 
age strata as fixed factors and the log-transformed baseline measurement as covariate. The 
estimated treatment difference with 95% confidence interval will be presented on the scale of 
measurement (i.e. back-transformed using base e) and accompanied by the p-value for test of no 
treatment difference.
FSH Population Pharmacokinetics
A population pharmacokinetic model describing FSH concentrations following repeated dosing of 
FE 999049 will be prepared under the responsibility of the Ferring Experimental Medicine 
Department.
The results will be reported separately. 
Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose and the number of stimulation days will be tabulated and compared 
between treatment groups. These endpoints will be compared between treatments using Wilcoxon’s 
test.
Gonadotropin Dose Adjustments
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. The requested dose change (decrease / increase / no change) on stimulation 
day 6 will be tabulated. Further, the number of dose increase requests and number of dose decrease 
requests per subject will be tabulated. Treatment groups will be compared using chi-square tests.
Adverse Events
Adverse Events – General 
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events are grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before start of IMP, or a pre-existing medical condition that worsens in intensity after 
signed informed consent but before start of IMP.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of IMP and 
before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of IMP and before the end-of-trial visit.


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Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only.
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: all adverse events, severe adverse events, 
adverse reactions, adverse events leading to discontinuation, serious adverse events and deaths. An 
adverse reaction is an adverse event judged by the investigator to be related to IMP with a 
reasonable possibility.
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported.
Summary tables will be produced for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate / severe), adverse reactions by intensity (mild / moderate / severe), 
serious adverse events, adverse events leading to discontinuation, adverse events with an incidence 
of ≥5% in any treatment group, and non-serious adverse events with an incidence of ≥5% in any 
treatment group.
Clinical Chemistry and Haematology Parameters
Safety laboratory variables will be grouped under “Haematology” and “Clinical Chemistry”.
The baseline is based on the blood sample drawn at stimulation day 1. Treatment-emergent 
laboratory data will be obtained at end-of-stimulation and end-of-trial.
The circulating levels of clinical chemistry and haematology parameters including change from 
baseline will be tabulated for each time-point for each laboratory variable. 
Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-trial 
values, using a categorisation of low, normal and high values at each visit. Low, normal and high 
will be defined according to the reference ranges provided by the central laboratory.
For each laboratory variable, a summary table will be prepared displaying the proportion of 
subjects who have at least one markedly abnormal value. The table will also include a break-down 
by classification of the baseline value. Markedly abnormal criteria for the safety laboratory 
variables will be specified in the SAP.
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged.
Injection Site Reactions
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
and number of subjects experiencing those events will be tabulated by time (immediately, 
30 minutes, 24 hours), reaction and intensity (none, mild, moderate and severe).


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Treatment-Induced Anti-FSH Antibodies
The proportion of subjects with treatment-induced anti-FSH antibodies as well as the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralising capacity will be tabulated. 
Furthermore, all assessments of anti-FSH antibodies will be listed for subjects with a positive 
results in assay 1). 
Immune-related Adverse Events
Potential immune-related adverse events will be tabulated using the SMQs, PTs and HLTs 
mentioned in section 7.2.22.
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse Events, or 
due to Technical Malfunctions of the Administration Pen
A summary table will be prepared showing the proportion of subjects with cycle cancellations 
including reason for cancellation.
Late OHSS (Including OHSS of Moderate/Severe Grade)
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days after triggering of final 
follicular maturation.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS. The analysis will be performed for the proportion of subjects with late OHSS and the 
proportion of subjects with late OHSS of moderate or severe grade.
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy and 
Vanishing Twins
Frequency tables will be prepared for these endpoints.
Pen Malfunction
The frequency of technical malfunctions of the administration pen will be tabulated.
9.8
Additional Safety Evaluations
Physical Examination
Physical examination at end-of-trial compared to baseline will be summarised in shift tables and all 
subjects with any abnormal finding will be listed per subject. The list will include both baseline and 
end-of-trial assessment for comparison.


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Gynaecological Examination
Gynaecological examination at end-of-trial compared to baseline will be summarised in shift tables 
and all subjects with any abnormal finding will be listed by subject. The list will include both 
baseline and end-of-trial assessment for comparison.
Changes in Body Weight 
Body weight will be measured at screening, on stimulation day 1 (baseline) and at end-of-trial. The 
actual measurements and the change from baseline will be tabulated.
Vital Signs
Vital signs and their change from stimulation day 1 (baseline) to end-of-trial will be summarised. 
Shift tables will be prepared to compare the baseline values with the end-of-trial values using the 
categorisation of low, normal and high values. Low, normal and high values will be specified in the 
SAP. All vital signs values will be listed per subject. Values outside the reference range will be 
flagged.
9.9
Post-trial Activities
A separate SAP will be prepared to cover the post-trial information.
The number and percentage of subjects with live birth will be presented by treatment group. 
Subjects with no information on live birth will be defaulted to a negative response.
Neonatal health, including minor/major congenital anomalies, at birth and at 4 weeks after birth 
will be presented by treatment group.
9.10
Interim Analyses and Administrative Review
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned.
A blinded sample size reassessment will take place when data on the primary endpoint are available 
for 70% of the planned subjects or when 800 subjects are randomised, whichever comes first. The 
sample size reassessment will be done without breaking the blind and without inflating the type I 
error of the trial, in line with the current regulatory guidelines for non-inferiority trials by FDA36
and in general by EMA.37
A restricted recalculation rule for the sample size reassessment will be used. Accordingly 1,000 
subjects should be randomised to achieve sufficient power if the ongoing pregnancy rate is 32.2%. 
If the ongoing pregnancy rate is above the expected 32.2%, the sample size can be adjusted up to a 
maximum of 1,144 (572 per treatment group), corresponding to an ongoing pregnancy rate of 50%. 
If the rate is below the expected 32.2% the sample size will not be decreased below the planned 
1,000 subjects.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data - ICH Definition
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial).
Trial-specific Source Data Requirements - Ferring
Source documents need to be preserved for the maximum period of time permitted by local 
requirements. For each subject enrolled, the investigator will indicate in the source documents that 
the subject participates in this trial, and will record at least the following information, if applicable: 

Existence of subject (initials, date of birth) 

Confirmation of participation in trial (trial ID, subject ID)

Informed consent(s) (date and time of oral information, date and time of handing out 
Informed Consent Documents, date and time of obtaining written informed consent(s))

Eligibility for participation in the trial (documenting all inclusion / exclusion criteria)

Relevant medical history, infertility history, menstrual history and reproductive history

Body weight measurements

Visit dates

Any assessment performed, i.e. vital signs, physical examination, TVU, etc.

Dates of administration of IMP 

Dates and daily doses of NIMP

Dates and daily doses of concomitant medication 

Date of oocyte retrieval and number of oocytes retrieved

Date of transfer and number and quality of embryos transferred

Results of βhCG test and ultrasound at clinical and ongoing pregnancy visits


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
Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth and 
4 weeks after birth

Local tolerability reactions after IMP administration – diary 

Adverse events (description as well as start/stop date and time)

OHSS symptoms, preventive interventions, investigations and treatments

Reason for discontinuation

Event of unblinding, including the reason for unblinding
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record.
If the trial sites use electronic subject record systems, the sponsor will decide if the electronic 
subject records qualify for the trial and document the decision. If the electronic subject records 
system does not qualify for the trial, it may be considered to utilise certified printouts of the data in 
the electronic subject records system for source data as an exception.
The source data for the endocrine parameters, clinical chemistry and haematology parameters will 
be available at the central laboratory. Laboratory reports will be available at the sites.
10.2
e-CRF
An e-CRF system provided by an independent third-party contract research organisation, Target 
Health Inc., will be used for data capture. The system is validated and access at all levels to the 
system is granted / revoked following sponsor and vendor procedures, in accordance with 
regulatory requirements and system requirements.
Data should be entered into the system within a reasonable time after the subject has attended a 
visit or after the data become available, as applicable.
The investigator will approve / authorise the e-CRF entries for each subject, with the exception of 
the treatment allocation module which is un-accessible to the investigator to maintain the assessor-
blinding, with an electronic signature which is equivalent to a handwritten signature.
The e-CRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and locked, a final copy of the database will be stored at Ferring. The investigator 
will also receive a copy of the trial site’s final and locked data (including audit trail, electronic 
signature and queries) as write-protected pdf-files produced by Target Health Inc. The pdf-files will 
be stored in an electronic format and will be provided to the investigator before access to the e-CRF 
is revoked. 
Errors occurring in the e-CRF will be corrected electronically. Such corrections / modifications will 
be automatically tracked by an audit trail detailing the date and time of the correction and the name 
of the person making the correction.


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10.3
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
department, Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection, cleaning and validation.
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions. The investigator will permit the 
monitor direct access to all source data, including electronic medical records, and/or documents in 
order to facilitate data verification. The investigator will co-operate with the monitor to ensure that 
any discrepancies that may be identified are resolved. The investigator is expected to be able to 
meet the monitor during these visits. When the first subject is randomised at the trial site a 
monitoring visit will take place shortly afterwards. For this trial, the frequency of the monitoring 
visits is intended to be approximately every second week (it can be adjusted depending on 
recruitment rate).
11.2
Audit and Inspection
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic / foreign regulatory inspectors or 
representatives from ethics committees who may audit / inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki41 and all other relevant regulations.
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorised Ferring representatives and representatives from regulatory authorities and ethics 
committees may wish to inspect their medical records. During audits / inspections the auditors / 
inspectors may copy relevant parts of the medical records. No personal identification apart from the 
screening / randomisation number will appear on these copies.
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or ethics committees.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
e-CRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Documents, will be maintained by the investigator in strict 
confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving ethics committees and regulatory authorities, in 
accordance with local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial 
subjects may be implemented prior to ethics committee approval or favourable opinion.
12.2
Deviations from the Protocol
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
monitor, and the implications of the deviation must be reviewed and discussed. Any deviation must 
be documented in the e-CRF. A log of protocol deviation reports will be available in the e-CRF. 
Protocol deviation reports and supporting documentation must be kept in the Investigator’s File and 
filed in the Trial Master File at the end of the trial.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and ethics committees will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator. 
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial.
Authorship is granted based on the criteria established by the International Committee of Medical 
Journal Editors (ICMJE).42 The total number of authors is based on the guideline from the relevant 
journal or congress. In the event of any disagreement in the content of a publication, both the 
investigator’s and Ferring’s opinion will be fairly and sufficiently represented in the publication.
Any external contract research organisation or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial.
If the investigator wishes to independently publish / present any results from the trial, the draft 
manuscript / presentation must be submitted in writing to Ferring for comment prior to submission. 
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published. Under such conditions the publication will be modified or delayed at the investigator’s 
discretion, to allow sufficient time for Ferring to seek patent protection of the invention.


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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate registry, i.e. 
www.ClinicalTrials.gov a website maintained by the National Library of Medicine (NLM) at the 
U.S. National Institutes of Health (NIH). Trial registration may occur in other registries in 
accordance with local regulatory requirements. A summary of the trial results is made publicly 
available in accordance with applicable regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Ethics Committee
An ethics committee will review the protocol, any potential protocol amendments and potential 
advertisements used for recruitment. The ethics committee will review the Subject Information 
Sheet and the Informed Consent Form, their updates (if any), and any written materials given to the 
subjects. All ethics committee approvals relevant for the clinic must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. A list of all ethics 
committees to which the protocol has been submitted and the name of the chairmen will be 
included in the Clinical Trial Report.
14.2
Regulatory Authorities Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All national regulatory approvals must be available in the relevant country 
before a subject is exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-trial and End-of-trial Notification
The end of main trial is defined as LPLV and the end of post-trial follow-up is defined as the last 
assessment performed in the pregnancy follow-up period.
End-of-trial notification will be reported according to local regulations.
In the case of early termination, Ferring must notify the end of the trial to the national regulatory
authorities and the concerned ethics committees immediately and at the latest within 15 days after 
the trial is halted, clearly explaining the reasons, and describe follow-up measures, if any, taken for 
safety reasons. 
Upon completion of the trial Ferring shall send the results of the clinical trial to the national 
regulatory authorities and the concerned ethics committees, according to local regulation.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements.


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14.5
Subject Information and Consent
Informed Consent Documents regarding Participation in the Trial – Subject 
The investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects of 
the trial which are relevant to the subject’s decision to participate. The trial subject must be given 
ample time to consider participation in the trial, before the consent is obtained. The Informed 
Consent Documents (consisting of the Subject Information and the Informed Consent Form) must 
be signed and dated by the subject and the investigator who has provided information to the subject 
regarding the trial before the subject is exposed to any trial-related procedure, including screening 
tests for eligibility.
The investigator will explain that the subject is completely free to refuse to enter the trial or to 
withdraw from it at any time, without any consequences for her further care and without the need to 
justify her decision.
The subject will receive a copy of the Informed Consent Documents.
If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new Subject Information and Informed Consent Form will be 
forwarded to the ethics committee(s) (and regulatory authorities, if required). The trial subjects will 
be informed about this new information and re-consent will be obtained.
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by 
Ferring, ethics committee representatives or regulatory authority inspector(s), in accordance with 
applicable regulatory requirements, may review her source records and data. Data protection will be 
handled in compliance with national / local regulations.
Informed Consent Documents regarding Data Collection on the Neonate – Parental
For countries where a separate information and informed consent form is required to collect 
pregnancy outcome data on the neonate, the investigator will obtain a freely given written consent 
from the child-custody holders, i.e. the subject and the subject’s partner in case of joint custody. 
The child-custody holders must be given ample time before the consent is obtained. The Informed 
Consent Documents must be signed and dated by the child-custody holders and the investigator 
who has provided information to the child-custody holders. Written consent by the child-custody 
holders regarding collection of pregnancy outcome data on the neonate must be obtained before the 
subject is randomised and preferably at the time of obtaining written consent by the subject 
regarding participation in the trial. 
The investigator will explain that the child-custody holders are completely free to refuse to consent 
to this data collection or to withdraw consent at any time, without any consequences and without 
the need to justify their decision.
The child-custody holders will receive a copy of the Informed Consent Documents.


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The child-custody holders will be informed that the monitor(s), quality assurance auditor(s) 
mandated by Ferring, ethics committee representatives or regulatory authority inspector(s), in 
accordance with applicable regulatory requirements, may review the neonate’s source records and 
data. Data protection will be handled in compliance with national / local regulations.
14.6
Trial Participation Card
The subject will be provided with a Trial Participation Card bearing the following information:

That she is participating in a clinical trial

That the trial involves controlled ovarian stimulation with recombinant FSH (either an FSH 
preparation under clinical development or an approved FSH product)

The name and phone number of the investigator

Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark 
[note: this statement is only to be included on the Subject Information Card if required by 
local regulations]
The subject will be asked to return the Trial Participation Card at the end-of-trial visit. 
Each subject’s primary care physician will be notified of their participation in the trial by the 
investigator, if the subject agrees and if applicable.
14.7
Delivery Data Checklist
Subjects with a positive ongoing pregnancy will be provided with a checklist for pregnancy follow-
up, where the subject will be reminded to report the following information to the investigator:
At delivery:

Date of delivery 

Way of delivery (vaginal / vacuum extraction / forceps / caesarean section)

Position of neonate (head / breech / transverse / other – please specify)

Gender

Birth weight (kg)

Birth length (cm)

Apgar score after 1, 5 and 10 minutes 

Admission to NICU/NCU (reason and duration)

Neonatal death

Malformation / congenital anomaly


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4 weeks after delivery (any new information since birth):

Admission to NICU/NCU (reason and duration)

Neonatal death

Malformation / congenital anomaly

Any relevant medical condition
14.8
Compliance Reference Documents
The Declaration of Helsinki, the consolidated ICH-GCP and other national law(s) in the countries
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing the IMP in accordance with the approved protocol or an approved amendment, and 
for its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the investigator for at least 15 years after the 
completion or discontinuation of the trial, if no further instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous e-CRF data for Ferring. The investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Documents for at least 15 years after the 
completion or discontinuation of the trial.
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the Investigator File archived at an 
external archive.
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


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Lipsitz SR, Dear KGB, Laird NM, Molenberghs G. Tests for Homogeneity of the Risk 
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The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
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covariates. CPMP/EWP/2863/99.


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World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. 59th WMA General Assembly, Seoul, October 2008.
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