Conditions: Infertility, Female
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 437
Healthy volunteers: no

Brief summary:
To compare the efficacy and safety of FE 999049 (follitropin delta) and its personalized dosing algorithm in controlled ovarian stimulation for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using a long gonadotropin-releasing hormone (GnRH) agonist protocol versus a short GnRH antagonist protocol.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: FE 999049 + GnRH agonist (GONAPEPTYL) intervention 2: FE 999049 + GnRH antagonist (CETROTIDE)
Intervention descriptions: intervention 1: Pre-filled injection pen intervention 2: Powder and solvent for solution for injection

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Cover page for Protocol 
 
 
Sponsor name 
Ferring Pharmaceuticals A/S 
NCT Number: 
NCT03809429 
Sponsor trial ID: 
000304 
Official title of trial: 
A randomised, controlled, open label, parallel group, 
multicentre trial comparing the efficacy and safety of 
individualised FE 999049 (follitropin delta) dosing, using 
a long GnRH agonist protocol and a GnRH antagonist 
protocol in women undergoing controlled ovarian 
stimulation 
Document Date:  
09 Dec 2020 
 
 
 
 
 


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Follitropin Delta, FE 999049
Trial Code: 000304
Solution for Injection
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A randomised, controlled, open label, parallel group, multicentre trial comparing the efficacy 
and safety of individualised FE 999049 (follitropin delta) dosing, using a long GnRH agonist 
protocol and a GnRH antagonist protocol in women undergoing controlled ovarian 
stimulation
Trial 000304
BEYOND
EudraCT Number:
2017-002783-40
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:
3b
Name and Address of Sponsor:
Ferring Pharmaceuticals A/S
Global Clinical R&D
International PharmaScience Center
Kay Fiskers Plads 11
2300 Copenhagen S
Denmark
Version:
3.0 (Consolidated protocol; changes introduced with 
protocol amendment 02 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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Trial Code: 000304
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SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, open label, parallel group, multicentre trial comparing the efficacy and 
safety of individualised FE 999049 (follitropin delta) dosing, using a long GnRH agonist protocol 
and a GnRH antagonist protocol in women undergoing controlled ovarian stimulation 
SIGNATORY INVESTIGATOR
Professor Anja Pinborg, The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, 
Denmark
TRIAL SITES
Approximately 15 sites in 5-7 countries
PLANNED TRIAL PERIOD
First patient first visit (FPFV):
Q1 2019
Last patient first visit (LPFV):
Q3 2021
Last patient last visit (LPLV) / end-of-trial:   
Q1 2022
Post-trial follow-up completed:
   Q4 2022
CLINICAL PHASE
3b
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE 
TRIAL
FE 999049 (follitropin delta) is a novel human recombinant follicle-stimulating hormone (rFSH) 
under global development by Ferring Pharmaceuticals. FE 999049 is individually dosed based on 
the patient’s body weight and serum anti-Müllerian hormone (AMH) level. In December 2016, 
Ferring received Marketing Authorisation approval from the European Commission for 
FE 999049 under the trade name REKOVELLE. During 2017, FE 999049 was approved in 
Australia, Brazil, Israel and Switzerland, and in 2018, also in Canada and Mexico. The indication 
is: “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.”
All clinical phase 2 and 3 trials conducted with FE 999049 have applied the gonadotropin-
releasing hormone (GnRH) antagonist protocol and the FE 999049 dosing algorithm has not yet 
been studied in a long GnRH agonist protocol. Previous studies comparing the efficacy and 
safety of a GnRH antagonist protocol with a long GnRH agonist protocol using rFSH derived 
from Chinese hamster ovary (CHO) cell lines have consistently indicated that the cohort of 
recruited follicles is slightly smaller in GnRH antagonist cycles. The difference in the largest 


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CONFIDENTIAL
randomised controlled trial was -1.0 oocyte (95% confidence interval [CI] -1.8; -0.2) which is in 
agreement with the estimated difference of -1.07 oocyte (95% CI -1.52; -0.61) in a Cochrane 
review including 27 randomised controlled trials. The evidence available suggests that the long 
GnRH agonist protocol compared to the GnRH antagonist protocol is generally associated with 
one more oocyte retrieved, one more day of stimulation, and consequently a higher total dose of 
exogenous FSH equivalent to one more day of dosing.
The impact on ovarian response and efficacy when applying the long GnRH agonist protocol 
instead of the GnRH antagonist protocol with FE 999049 is hypothesised to be similar to those 
described in the literature for existing rFSH preparations. In the pivotal phase 3 trial ESTHER-1, 
the mean number of oocytes retrieved was 9.6± 5.8 in the FE 999049 group and 10.1 ± 6.6 in the 
GONAL-F group for all randomised subjects. For subjects with triggering of final follicular 
maturation the mean number of oocytes retrieved was 10.0 ± 5.6 in the FE 999049 group and 
10.4 ± 6.5 in the GONAL-F group. When analysed by AMH, the mean number of oocytes 
retrieved was 8.0 ± 4.3 in the FE 999049 group versus 7.0 ± 3.9 in the GONAL-F group among 
patients with AMH <15 pmol/L, and 11.6 ± 5.9 in the FE 999049 group versus 13.3 ± 6.9 oocytes 
in the GONAL-F group among patients with AMH ≥15 pmol/L. 
This prospective, comparative trial is designed to document the ovarian response following the 
application of the individualised FE 999049 dosing regimen in a long GnRH agonist protocol 
compared to a GnRH antagonist protocol. The trial will describe the impact of the protocol on the 
mean number of oocytes retrieved, the mean number of oocytes retrieved in patients with AMH 
<15 pmol/L and AMH ≥15 pmol/L as well as the distribution of the number of oocytes retrieved 
(<4, 4-7, 8-14, 15-19, ≥20 oocytes).  
OBJECTIVES
Primary objective

To evaluate the effect of individualised FE 999049 treatment on ovarian response in a 
long GnRH agonist protocol versus a GnRH antagonist protocol
Secondary objectives

To evaluate the effect of individualised FE 999049 treatment on other pharmacodynamic
parameters in a long GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the effect of individualised FE 999049 treatment on pregnancy rates in a long 
GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the safety of individualised FE 999049 treatment in a long GnRH agonist 
protocol versus a GnRH antagonist protocol


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ENDPOINTS
Primary endpoint

Number of oocytes retrieved 
Secondary endpoints

Proportion of subjects with cycle cancellation due to poor ovarian response or excessive 
ovarian response 

Proportion of subjects with blastocyst transfer cancellation after oocyte retrieval due to 
(risk of) ovarian hyperstimulation syndrome (OHSS)

Number and size of follicles on stimulation day 6 and end-of-stimulation

Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Number of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on 
day 5 after oocyte retrieval

Circulating concentrations of FSH, luteinising hormone (LH), estradiol, progesterone and 
inhibin B on stimulation day 6, end-of-stimulation and at oocyte retrieval

Total gonadotropin dose and number of stimulation days

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number 
of blastocysts transferred)

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) 

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after 
transfer divided by number of blastocysts transferred)

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) 

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Frequency and intensity of adverse events

Technical malfunctions of the prefilled injection 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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METHODOLOGY
This will be a randomised, controlled, open label, parallel group, multicentre trial comparing the 
efficacy and safety of individualised FE 999049 dosing in first cycle patients aged 18-40 years 
undergoing controlled ovarian stimulation for IVF/ICSI following either a long GnRH agonist 
protocol or a GnRH antagonist protocol. The trial has been designed to describe potential 
differences in the mean number of oocytes retrieved with adequate precision. 
Subjects will be screened within 90 days prior to randomisation for compliance with the 
inclusion and exclusion criteria. Randomisation may take place as soon as all eligibility criteria 
are met. Randomisation does not necessarily need to take place at a physical visit, but can be 
done by delegated trial staff without the subject being present at the clinic. However, the subject 
will be contacted prior to randomisation to confirm eligibility. Subjects will be randomised in a 
1:1 ratio to controlled ovarian stimulation with FE 999049 in a long GnRH agonist protocol or to 
controlled ovarian stimulation with FE 999049 in a GnRH antagonist protocol. Randomisation 
will be stratified by centre and according to age (<35, 35-37 and 38-40 years). The subject will 
be informed of treatment allocation and when to start treatment by the delegated trial staff.
Subjects randomised to treatment with FE 999049 in the long GnRH agonist protocol will start 
down-regulation with GnRH agonist (triptorelin acetate, GONAPEPTYL) 0.1 mg/day 
subcutaneously in the mid-luteal phase (i.e. cycle day 21-24) of their menstrual cycle. Ovarian 
stimulation with FE 999049 will start after 14 days (±1 day) if the subject has experienced 
withdrawal bleeding and the following down-regulation criteria are fulfilled: 1) a thin 
endometrium (<5 mm) is observed by transvaginal ultrasound, and 2) no ovarian follicles 
≥10 mm (including cysts that cannot be punctured prior to stimulation) are observed by 
transvaginal ultrasound. In case achievement of down-regulation is doubtful or it is deemed 
helpful, serum estradiol is to be measured (<50 pg/mL or 180 pmol/L; local laboratory). If down-
regulation is confirmed and ovarian stimulation is initiated, treatment with GnRH agonist is 
continued throughout the stimulation period. If the subject has not experienced withdrawal 
bleeding after 14 days (±1 day), a urinary pregnancy test is to be performed. If the subject is not 
pregnant and down-regulation is not confirmed, treatment with GnRH agonist will be continued 
and stimulation will be postponed until down-regulation is confirmed. Subsequent visit(s) for 
confirmation of down-regulation will be scheduled according to local practice. If down-
regulation is not achieved after 28 days, treatment with GnRH agonist will be stopped and the 
subject will be withdrawn from the trial. 
Subjects randomised to treatment with FE 999049 in the GnRH antagonist protocol will start 
stimulation with FE 999049 on day 2 or 3 of their menstrual cycle. To prevent a premature LH 
surge, a GnRH antagonist (cetrorelix acetate, CETROTIDE) 0.25 mg/day subcutaneously will be 
initiated on stimulation day 6 and continued throughout the stimulation period. 
Subjects will have their individual FE 999049 dose determined on the basis of their AMH level at 
screening and their body weight on stimulation day 1. The daily FE 999049 dose will be fixed 


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throughout the stimulation period. For subjects with AMH <15 pmol/L the daily FE 999049 dose 
is 12 μg, irrespective of body weight. For subjects with 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. AMH will be measured by Elecsys® AMH Plus Immunoassay (Roche Diagnostics). 
The maximum allowed daily FE 999049 dose is 12 µg. Subjects can be treated with FE 999049 
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. 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, a single dose of human chorionic gonadotropin (hCG) (OVITRELLE) 250 µg will be 
administered. If there are ≥25 follicles with a diameter ≥12 mm, the cycle will 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.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF and/or ICSI. Fertilisation and embryo development will be 
assessed from oocyte retrieval to the day of transfer. For all subjects blastocyst transfer is 
performed on day 5 after oocyte retrieval. Subjects <38 years at randomisation will have single 
blastocyst transfer. Subjects ≥38 years at randomisation will have single blastocyst transfer if 
they have a good-quality blastocyst available, i.e. a blastocyst of grade 3BB or higher; otherwise 
they may have double blastocyst transfer. Remaining blastocysts may be cryopreserved and used 
by the subject after completion of the trial, in accordance with local guidelines and/or 
regulations. All procedures and assessments related to cryopreserved cycles will take place 
outside this protocol and will not be paid for by Ferring.
Vaginal progesterone tablets (LUTINUS) 100 mg three times daily will be provided for luteal 
phase support from the day after oocyte retrieval and until the serum βhCG test. Luteal phase 
support may be continued after a positive βhCG is obtained if this is local practice. A serum 
βhCG test is 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 assessed at screening, stimulation day 1, stimulation day 6, end-of-stimulation and at 
oocyte retrieval. 


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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 minor/major congenital anomalies, at birth 
and at 4 weeks after birth. These data will be reported separately.
NUMBER OF SUBJECTS
It is planned to randomise approximately 400 subjects of whom approximately 200 will be 
randomised to the long GnRH agonist protocol and approximately 200 will be randomised to the 
GnRH antagonist protocol. It is estimated that up to 500 subjects should be screened to achieve 
400 randomised and treated subjects.
CRITERIA FOR INCLUSION / EXCLUSION
This trial applies similar inclusion/exclusion criteria as ESTHER-1. Women undergoing their 
first IVF/ICSI cycle and aged 18-40 years will be included. 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 
patients. The exclusion criteria incorporate the contraindications for the use of gonadotropins.
The complete list of inclusion, exclusion and withdrawal criteria is provided below.
Inclusion Criteria
1. Informed Consent Forms signed prior to screening evaluations.
2. In good physical and mental health. 
3. The subjects must be at least 18 years (including the 18th birthday) when they sign the 
Informed Consent Form 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 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 <38 years or for at least 
6 months for subjects ≥38 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.  


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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. no endometrioma greater than 
2 cm or 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 2-5) serum levels of FSH between 1 and 15 IU/L at 
screening.
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to 
randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. If <38 years willing to accept single blastocyst transfer. If ≥38 years willing to accept 
transfer of a single good-quality blastocyst (double blastocyst transfer may be performed 
if no good-quality blastocyst is available).
Exclusion Criteria
1. AMH >35 pmol/L at screening.
2. Strong preference of the subject for either treatment protocol. 
3. Known endometriosis stage III-IV (defined by the revised American Society for 
Reproductive Medicine [ASRM] classification, 1996).
4. Known history of recurrent miscarriage (defined as three consecutive losses after 
ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of 
pregnancy). 
5. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
6. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
7. Known inherited or acquired thrombophilia disease.
8. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of 
these events.
9. Known porphyria.
10. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.


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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. Currently breast-feeding.
14. Undiagnosed vaginal bleeding.
15. Known abnormal cervical cytology of clinical significance observed within 3 years prior 
to randomisation (unless the clinical significance has been resolved).
16. 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.
17. Pregnancy (negative pregnancy test must be documented at screening) or contraindication 
to pregnancy.
18. Known current active pelvic inflammatory disease.
19. 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.
20. Use of hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomisation.
21. Known history of chemotherapy (except for gestational conditions) or radiotherapy. 
22. Current or past (1 year prior to randomisation) abuse of alcohol or drugs and/or current 
(last month) intake of more than 14 units of alcohol per week.
23. Current or past (3 months prior to randomisation) smoking habit of more than 
10 cigarettes per day.
24. Hypersensitivity to any active ingredient or excipients in the medicinal products used in 
the trial.
25. Previous participation in the trial.
26. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
Withdrawal Criteria
1. One or more follicles ≥10 mm (including cysts that cannot be punctured prior to 
stimulation) observed on the transvaginal ultrasound on stimulation day 1 / day of 
confirmation of down-regulation.
2. Down-regulation not achieved within 28 days after the first GnRH agonist administration.
3. Pregnancy (positive pregnancy test) between screening and stimulation day 1.


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4. Use of fertility modifiers between randomisation and stimulation day 1, including DHEA, 
metformin or cycle programming with oral contraceptives, progestogen or estrogen 
preparations.
5. Use of hormonal preparations (except for thyroid medication and trial medication) 
between randomisation and stimulation day 1.


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MEDICINAL PRODUCTS
Investigational Medicinal Product (IMP)
IMP name
Drug type
Active ingredient, route of 
administration and 
concentration
Daily dose
FE 999049
REKOVELLE
(follitropin delta)
rFSH
FE 999049 in solution for 
subcutaneous injection; 
72 µg follitropin delta in 
2.16 mL
pre-filled injection pen 
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 
Dose is fixed throughout 
stimulation 
The maximum daily dose is 12 µg
FE 999049 Dosing Regimen
AMH (pmol/L)
<15
15-16
17
18
19-20
21-22
23-24
25-27
28-32
33-39
≥40 a
Fixed daily dose of 
FE 999049
12
0.19
0.18
0.17
0.16
0.15
0.14
0.13
0.12
0.11
0.10
µg
µg/kg b
a The cut-off limit for AMH in this trial is 35 pmol/L, i.e. only subjects with AMH level ≤35 pmol/L will be included 
in the trial. 
b The maximum daily FE 999049 dose is 12 µg.
Concomitant Fertility Medication / Non-investigational Medicinal Products (NIMPs)
NIMP name
Drug type
Active ingredient and route of 
administration 
Dose
GONAPEPTYL
GnRH agonist 
Triptorelin acetate in solution 
for subcutaneous injection 
0.1 mg, daily 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
LUTINUS
Progesterone
Progesterone tablet for 
vaginal administration
100 mg vaginal tablets three times 
daily 
DURATION OF TREATMENT
The maximum period of exposure to FE 999049 is 20 days.


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STATISTICAL METHODS
The primary analyses of the efficacy endpoints will be based on the full analysis set (FAS), 
including all randomised subjects, regardless of whether they started FE 999049 treatment or not.
However, subjects that discontinued before starting FE 999049 treatment due to the COVID-19 
pandemic (e.g. due to operational and/or societal issues) will be excluded from the FAS. Subjects 
will be analysed according to randomised protocol. Safety endpoints will be analysed using the 
safety analysis set, including all randomised subjects that were exposed to FE 999049.
The primary objective of this trial is to evaluate the effect of individualised FE 999049 treatment 
on ovarian response using a long GnRH agonist protocol versus a GnRH antagonist protocol. The 
primary endpoint is the number of oocytes retrieved. The estimand of interest is the difference 
between FE 999049 treatment in the long GnRH agonist protocol versus FE 999049 treatment in 
the GnRH antagonist protocol for all randomised subjects, assuming that all subjects start
treatment with FE 999049. In the statistical analyses, subjects that discontinue after 
randomisation but before start of FE 999049 treatment (except for subjects that never started 
treatment due to the COVID-19 pandemic) will have their endpoint data imputed from subjects 
who started FE 999049 treatment in the same protocol, using a multiple imputation method. The 
mean number of oocytes retrieved will be compared between the long GnRH agonist protocol 
and the GnRH antagonist protocol using a negative binomial regression model with protocol, age 
stratum, and AMH (<15 pmol/L or ≥15 pmol/L) at screening as factors. A logarithmic link 
function will be used for the mean in the model. From this model, the mean difference between 
the two protocols in number of oocytes retrieved will be estimated, and a 95% CI for the estimate 
will be calculated using the delta method. The same models (without AMH as factor) will be 
used to compare the mean number of oocytes retrieved between the two protocols in the two sub-
groups defined by AMH <15 pmol/L and AMH ≥15 pmol/L at screening.
The distribution of the number of oocytes retrieved will be further characterised and compared 
between the two protocols. The empirical distributions will be described with special focus on the 
proportion of subjects with <4, 4-7, 8-14, 15-19, and ≥20 oocytes retrieved. Additional 
descriptions will be made for the two subgroups defined by AMH level at screening.
Secondary endpoints will be described for the two protocols, both for the full group of subjects 
and for the subgroups defined by AMH level at screening.
Sample size calculation
The purpose of this trial is to gain clinical experience with the use of FE 999049 when applied in 
a long GnRH agonist protocol. The trial is descriptive and does not include any hypothesis 
testing. The sample size is based on achieving a reasonable precision in the estimate of the 
difference in mean number of oocytes retrieved between treatment with FE 999049 in a long 
GnRH agonist protocol versus treatment with FE 999049 in a GnRH antagonist protocol.
In the ESTHER-1 trial the standard deviation for the number of oocytes retrieved was 5.8 in the 


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CONFIDENTIAL
FE 999049 treatment group. Due to a potentially higher number of oocytes retrieved in the long 
GnRH agonist protocol the standard deviation in this trial may be slightly higher. Assuming a 
standard deviation of 7.0, a sample size of 400 subjects (200 subjects per group) will give a 
95% CI that ranges from -1.4 to +1.4 of the observed mean difference, i.e. the interval from the 
observed mean difference -1.4 to the observed mean difference +1.4 will with 95% probability 
include the true mean difference. This is regarded to be reasonably precise for describing the 
comparability of individualised FE 999049 dosing using the two protocols.


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES ....................................................................................................................................... 19
LIST OF FIGURES...................................................................................................................................... 19
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 20
1
INTRODUCTION ............................................................................................................................. 23
1.1
Background............................................................................................................................. 23
1.2
Scientific Justification for Conducting the Trial..................................................................... 25
1.3
Benefit / Risk Aspects............................................................................................................. 25
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...................................................................................................................... 35
3.4
Data Monitoring Committee ................................................................................................... 35
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 35
3.5.1
Trial Design ............................................................................................................... 35
3.5.2
Selection of Endpoints ............................................................................................... 36
3.5.3
Blinding...................................................................................................................... 37
3.5.4
Selection of Doses in the Trial................................................................................... 37
3.5.5
Selection and Timing of Dose for Each Subject........................................................ 38
3.5.6
Selection of the Trial Population ............................................................................... 38
3.5.7
Withdrawal Criteria ................................................................................................... 39
3.5.8
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............................................................................................................... 44
5
TREATMENTS ................................................................................................................................. 45
5.1
Treatments Administered........................................................................................................ 45
5.1.1
Investigational Medicinal Product ............................................................................. 45


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5.1.2
Non-Investigational Medicinal Product..................................................................... 47
5.2
Characteristics and Source of Supply ..................................................................................... 47
5.3
Packaging and Labelling......................................................................................................... 48
5.4
Conditions for Storage and Use .............................................................................................. 49
5.5
Blinding / Unblinding ............................................................................................................. 49
5.5.1
Blinding...................................................................................................................... 49
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 50
5.6
Treatment Compliance............................................................................................................ 50
5.6.1
Dispensing and Accountability.................................................................................. 50
5.6.2
Assessment of Compliance........................................................................................ 50
5.7
Auxiliary Supplies................................................................................................................... 50
5.8
Return and Destruction of Medicinal Products and Auxiliary Supplies................................. 50
6
TRIAL PROCEDURES .................................................................................................................... 51
6.1
Trial Flow Chart...................................................................................................................... 51
6.2
Screening................................................................................................................................. 52
6.3
Randomisation ........................................................................................................................ 53
6.4
Down-regulation ..................................................................................................................... 53
6.5
Confirmation of Down-regulation .......................................................................................... 54
6.6
Stimulation.............................................................................................................................. 55
6.6.1
Stimulation Day 1 ...................................................................................................... 55
6.6.2
Stimulation Day 6 ...................................................................................................... 56
6.6.3
Stimulation Days ≥7 to <20 ..................................................................................... 57
6.6.4
End-of-stimulation..................................................................................................... 57
6.7
Oocyte Retrieval ..................................................................................................................... 58
6.8
Oocyte / Embryo / Blastocyst Evaluation............................................................................... 59
6.9
Transfer................................................................................................................................... 60
6.10
βhCG Test............................................................................................................................... 61
6.11
Clinical Pregnancy.................................................................................................................. 61
6.12
Ongoing Pregnancy................................................................................................................. 62
6.13
End-of-trial.............................................................................................................................. 62
6.14
Post-trial Activities ................................................................................................................. 62
7
TRIAL ASSESSMENTS ................................................................................................................... 63
7.1
Assessment Related to Primary Endpoint............................................................................... 63
7.1.1
Number of Oocytes Retrieved.................................................................................... 63
7.2
Assessment Related to Secondary Endpoints ......................................................................... 63
7.2.1
Cycle Cancellation due to Poor Ovarian Response or Excessive Ovarian 
Response .................................................................................................................... 63
7.2.2
Transfer Cancellation due to (Risk of) OHSS............................................................ 63
7.2.3
Number and Size of Follicles during Stimulation...................................................... 63
7.2.4
Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved......... 63
7.2.5
Metaphase II Oocytes................................................................................................. 63
7.2.6
Fertilisation Rate........................................................................................................ 64
7.2.7
Number and Quality of Embryos on Day 3 ............................................................... 64
7.2.8
Number and Quality of Blastocysts on Day 5............................................................ 64
7.2.9
Circulating Levels of Endocrine Parameters.............................................................. 65
7.2.10 Total Gonadotropin Dose and Number of Stimulation Days..................................... 66


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7.2.11 βhCG Test.................................................................................................................. 66
7.2.12 Implantation............................................................................................................... 66
7.2.13 Clinical Pregnancy..................................................................................................... 66
7.2.14 Vital Pregnancy.......................................................................................................... 66
7.2.15 Ongoing Pregnancy.................................................................................................... 67
7.2.16 Ongoing Implantation ................................................................................................ 67
7.2.17 Early OHSS (including Moderate/Severe)................................................................. 67
7.2.18 Late OHSS (including Moderate/Severe) .................................................................. 67
7.2.19 Adverse Events .......................................................................................................... 67
7.2.20 Pen Malfunction......................................................................................................... 67
7.3
Other Assessments.................................................................................................................. 68
7.3.1
Demographics ............................................................................................................ 68
7.3.2
Medical History ......................................................................................................... 68
7.3.3
Infertility History ....................................................................................................... 68
7.3.4
Menstrual History ...................................................................................................... 68
7.3.5
Reproductive History................................................................................................. 68
7.3.6
Smoking and Alcohol Habits..................................................................................... 68
7.3.7
Body Measurements................................................................................................... 68
7.3.8
Physical Examination................................................................................................. 69
7.3.9
Gynaecological Examination..................................................................................... 69
7.3.10 Endocrine Parameters at Screening............................................................................ 69
7.3.11 Ovarian Volume......................................................................................................... 69
7.3.12 Endometrial Status..................................................................................................... 69
7.3.13 Blastocyst Transfer Procedure ................................................................................... 70
7.3.14 Concomitant Medication............................................................................................ 70
7.3.15 Drug Dispensing and Accountability......................................................................... 70
7.3.16 End-of-trial Form....................................................................................................... 70
7.4
Assessments related to Post-trial Information......................................................................... 71
7.4.1
Pregnancy Follow-up................................................................................................. 71
7.5
Handling of Biological Samples ............................................................................................. 71
8
ADVERSE EVENTS ......................................................................................................................... 72
8.1
Adverse Event Definition........................................................................................................ 72
8.2
Collection and Recording of Adverse Events......................................................................... 72
8.2.1
Collection of Adverse Events .................................................................................... 72
8.2.2
Recording of Adverse Events .................................................................................... 72
8.3
Adverse Events of Special Interest ......................................................................................... 75
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)........................................................... 75
8.3.2
Pregnancy Losses....................................................................................................... 77
8.4
Events Requiring Special Handling ........................................................................................ 78
8.4.1
Menstrual Bleeding.................................................................................................... 78
8.4.2
Multiple Pregnancies ................................................................................................. 78
8.5
Serious Adverse Events .......................................................................................................... 79
8.5.1
Serious Adverse Event Definition.............................................................................. 79
8.5.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 81
8.6
Follow-up of Adverse Events and Serious Adverse Events.................................................... 82
8.6.1
Follow-up of Adverse Events with Onset during the Trial........................................ 82
8.6.2
Collection of Serious Adverse Events with Onset after End-of-trial......................... 82


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8.6.3
Follow-up of Serious Adverse Events with Onset during Post-trial.......................... 82
8.6.4
Adverse Events on Non-investigational Medicinal Products..................................... 82
8.6.5
Pregnancy during Down-regulation........................................................................... 83
9
STATISTICAL METHODS ............................................................................................................. 84
9.1
Determination of Sample Size ................................................................................................ 84
9.2
Subject Disposition ................................................................................................................. 84
9.3
Protocol Deviations................................................................................................................. 84
9.4
Analysis Sets........................................................................................................................... 84
9.4.1
Full Analysis Set........................................................................................................ 84
9.4.2
Safety Analysis Set .................................................................................................... 85
9.5
Trial Population....................................................................................................................... 85
9.5.1
Demographics and other Baseline Characteristics..................................................... 85
9.5.2
Medical History and Concomitant Medication.......................................................... 85
9.6
Endpoint Assessments............................................................................................................. 85
9.6.1
General Considerations.............................................................................................. 85
9.6.2
Primary Endpoint....................................................................................................... 86
9.6.3
Secondary Endpoints ................................................................................................. 88
9.7
Interim Analyses ..................................................................................................................... 92
10
DATA HANDLING ........................................................................................................................... 93
10.1
Source Data and Source Documents....................................................................................... 93
10.2
e-CRF...................................................................................................................................... 94
10.3
Use of Patient Reported Outcome........................................................................................... 95
10.4
Health Economics ................................................................................................................... 95
10.5
Data Management ................................................................................................................... 95
10.6
Provision of Additional Information....................................................................................... 95
11
MONITORING PROCEDURES ..................................................................................................... 96
11.1
Periodic Monitoring................................................................................................................ 96
11.2
Audit and Inspection............................................................................................................... 96
11.3
Confidentiality of Subject Data............................................................................................... 97
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 98
12.1
Protocol Amendments............................................................................................................. 98
12.2
Deviations from the Protocol .................................................................................................. 98
12.3
Premature Trial Termination................................................................................................... 98
13
REPORTING AND PUBLICATION .............................................................................................. 99
13.1
Clinical Trial Report ............................................................................................................... 99
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 99
13.3
Publications and Public Disclosure......................................................................................... 99
13.3.1 Publication Policy...................................................................................................... 99
13.3.2 Public Disclosure Policy............................................................................................ 99
14
ETHICAL AND REGULATORY ASPECTS............................................................................... 101
14.1
Independent Ethics Committee ............................................................................................. 101
14.2
Regulatory Authorities Authorisation / Approval / Notification .......................................... 101
14.3
End-of-trial and End-of-trial Notification............................................................................. 101
14.4
Ethical Conduct of the Trial.................................................................................................. 101
14.5
Subject Information and Consent.......................................................................................... 102


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14.6
Subject Participation Card .................................................................................................... 103
14.7
Delivery Data Checklist........................................................................................................ 104
14.8
Compliance Reference Documents....................................................................................... 104
15
LIABILITIES AND INSURANCE ................................................................................................ 105
15.1
ICH-GCP Responsibilities.................................................................................................... 105
15.2
Liabilities and Insurance....................................................................................................... 105
16
ARCHIVING.................................................................................................................................... 106
16.1
Investigator File .................................................................................................................... 106
16.2
Trial Master File.................................................................................................................... 106
17
REFERENCES................................................................................................................................. 107


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LIST OF TABLES 
Table 5-1
FE 999049 Dosing Regimen...........................................................................................46
Table 5-2
Non-Investigational Medicinal Products ........................................................................47
Table 5-3
Characteristics and Source of Supply of Medicinal Products.........................................48
Table 5-4
Packaging of Medicinal Products ...................................................................................49
Table 6-1
Trial Flow Chart – Subject Procedures...........................................................................51
Table 6-2
Triggering and Cycle Cancellation Criteria related to Follicular Development.............58
Table 6-3
Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures........................................59
Table 8-1
Classification of Mild, Moderate and Severe OHSS ......................................................76
LIST OF FIGURES
Figure 3-1 Trial Diagram – Trial Period...........................................................................................31
Figure 3-2 Trial Diagram – Post-trial Activities...............................................................................32


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations

alfa
AMH
anti-Müllerian hormone
ART
assisted reproductive technologies
ASRM
American Society for Reproductive Medicine
ATC
Anatomical Therapeutic Chemical Classification System
β
beta
βhCG
beta unit of human chorionic gonadotropin
BMI
body mass index
CHO
Chinese hamster ovary
CI
confidence interval
CRO
contract research organisation
DHEA
dehydroepiandrosterone
e-CRF
electronic case report form
EMA
European Medicines Agency
EU
European Union
FAS
full analysis set
FPFV
first patient first visit
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH
gonadotropin-releasing hormone
h
hours
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
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


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ICMJE
International Committee of Medical Journal Editors
ICSI
intracytoplasmic sperm injection
IMP
investigational medicinal product
IEC
independent ethics committee
IU
international unit
IVF
in vitro fertilisation
kg
kilogram
L
litre
LH
luteinising hormone
LLOQ
lower limit of quantification
LPFV
last patient first visit
LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
millilitre
NCU
neonatal care unit
NIMP
non-investigational medicinal product
NICU
neonatal intensive care unit
NLM
National Library of Medicine
OHSS
ovarian hyperstimulation syndrome
PCU
pediatric care unit
PER.C6®
host cell line of human fetal retinal origin
PICU
pediatric intensive care unit
pmol
picomol
PT
preferred term
rFSH
recombinant follicle-stimulating hormone
SmPC
Summary of Product Charateristics
SOC
system organ class
TSH
thyroid-stimulating hormone
µg
microgram
WHO
World Health Organization


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Definition of Terms
Gestational age
Gestational age is calculated from the day of transfer + 19 days to the 
outcome of the pregnancy (e.g. delivery).
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 
protocol
Trade name in 
participating 
countries
Company name 
used in protocol
Company name in 
participating 
countries
FE 999049
Follitropin delta
REKOVELLE
REKOVELLE
Ferring 
Pharmaceuticals
Ferring 
Pharmaceuticals
Cetrorelix acetate 
CETROTIDE
CETROTIDE
Merck
Merck
Choriogonadotropin 
alfa
OVITRELLE
OVITRELLE
Merck
Merck
Triptorelin acetate
GONAPEPTYL
GONAPEPTYL / 
DECAPEPTYL /
FERTIPEPTIL
Ferring 
Pharmaceuticals
Ferring 
Pharmaceuticals
Progesterone
LUTINUS
LUTINUS a) 
Ferring 
Pharmaceuticals
Ferring 
Pharmaceuticals
a)
Other common tradename is ENDOMETRIN.
(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) under global development
by Ferring Pharmaceuticals. 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”. Ferring has received Marketing Authorisation approval from the European 
Commission for FE 999049 under the trade name REKOVELLE (December 2016). During 2017, 
FE 999049 was approved in Australia, Brazil, Israel and Switzerland, and in 2018, also in Canada 
and Mexico.
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 other commercially available rFSH products derived from human cell lines. Currently
approved rFSH products for the proposed indication, such as follitropin alfa (GONAL-F, Merck 
Serono) and follitropin beta (PUREGON, MSD), are derived from Chinese hamster ovary (CHO) 
cell lines. The amino acid sequence of FE 999049 is the native human FSH sequence and is 
identical to that in CHO-derived rFSH products. Differences in glycosylation, as shown by glycan 
and isoform profiles, have been documented between FE 999049 and rFSH products from CHO 
cell lines. 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 FE 999049 glycosylation 
profile is likely to be more similar to native human FSH as compared with CHO-derived rFSH 
products. In addition, sialic acid linkage in position 2,6 in FE 999049 is absent from CHO-derived 
rFSH products which 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. 
The clinical translation of the differential glycosylation profile of FE 999049 has been reflected in 
clinical trials. Thus, daily multiple-dose administration of identical international unit (IU) doses of 
FE 999049 and a CHO-derived rFSH product as determined in the rat in vivo Steelman-Pohley 
bioassay did not provide comparable pharmacokinetics and pharmacodynamics, with the 
differential glycosylation profile of FE 999049 being considered the most likely cause for this 
finding. Consequently, it was considered that the rat in vivo Steelman Pohley bioassay might not 
fully reflect the potency of FE 999049 in humans, as supported by biotransformation studies in 
mice and rats and that using the protein content (µg) in combination with a consistent drug 


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substance quality profile would be more appropriate for expressing doses of FE 999049 than the 
bioactivity (IU). Therefore, FE 999049 is dosed by mass (µg) rather than in IU.
The development of FE 999049 has prospectively incorporated the use of a biomarker of ovarian 
response to gonadotropins (anti-Müllerian hormone [AMH]) to identify patients at higher risk of 
reduced efficacy or increased safety concern, enabling stratification according to the patients’ 
potential to respond to FE 999049. Furthermore, body weight has been shown to influence the 
exposure to FE 999049. Therefore, the posology of FE 999049 is individualised for each patient 
based on her body weight and serum AMH to obtain an ovarian response with favourable 
safety/efficacy profile. The outcome is a fixed-dose regimen supporting individualised ovarian 
stimulation with safe and efficient use of FE 999049 founded on current scientific knowledge and 
prospectively confirmed data.
The efficacy and safety of the FE 999049 individualised dosing regimen based on the woman’s 
serum AMH and body weight has been confirmed in a large phase 3 trial, ESTHER-1 (Evidence-
based Stimulation Trial with Human rFSH in Europe and Rest of World)3, conducted in 
11 countries including Europe, North America and Latin America. The ESTHER-1 trial was 
conducted in 1,326 IVF/ICSI patients who were randomised 1:1 to controlled ovarian stimulation 
with one of the following treatments: 1) FE 999049 in its individualised dosing regimen with the 
daily dose fixed throughout simulation, or 2) an approved CHO-derived rFSH product (follitropin 
alfa, GONAL-F) at a standard starting dose of 150 IU/day followed by dose adjustments based on 
the subject’s follicular response during stimulation. FE 999049 in its individualised dosing regimen 
was demonstrated to be non-inferior to follitropin alfa with respect to ongoing pregnancy rate 
(30.7% versus 31.6%) and ongoing implantation rate (35.2% versus 35.8%). In subjects with 
triggering of final follicular maturation there was no statistically significant difference between 
treatment groups in terms of number of oocytes retrieved, with an average of 10.0 for FE 999049 
and 10.4 for follitropin alfa. Nevertheless, the individualised FE 999049 dosing regimen in 
comparison to follitropin alfa led to statistically significantly more oocytes retrieved among patients 
with AMH <15 pmol/L (population at risk of hyporesponse) with an average of 8.0 versus 7.0 and 
statistically significantly fewer oocytes among patients with AMH ≥15 pmol/L (population at risk 
of hyperresponse) with an average of 11.6 versus 13.3. The immediate clinical relevance of this 
shift in ovarian response with FE 999049 therapy was realised as statistically significantly fewer 
patients with extreme ovarian response compared to follitropin alfa, i.e. <4 oocytes among patients 
with AMH <15 pmol/L (12% versus 18%) and ≥15 or ≥20 oocytes among patients with 
AMH ≥15 pmol/L (28% versus 35%, and 10% versus 16%). Despite implementation of dose 
adjustments during stimulation for 37% of the patients in the follitropin alfa group, an appropriate 
ovarian response, defined as 8-14 oocytes, was reached by a higher proportion of patients treated 
with FE 999049 compared to follitropin alfa, i.e. 43% versus 38%. A statistically significantly 
lower total gonadotropin dose in the FE 999049 group compared to the follitropin alfa group was 
observed with an average of 90 µg and 104 µg, respectively. When data where analysed for all
subjects randomised, there was also no statistically significant difference between treatment groups 
in terms of number of oocytes retrieved, with an average of 9.6 for FE 999049 and 10.1 for 
follitropin alfa. In comparison to follitropin alfa, the individualised FE 999049 dosing regimen led 
to statistically significantly more oocytes retrieved among patients with AMH <15 pmol/L with an 
average of 7.5 versus 6.6 and statistically significantly fewer oocytes among patients with 
AMH ≥15 pmol/L) with an average of 11.2 versus 13.2. Fewer patients with extreme ovarian 


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response was observed for FE 999049 compared to follitropin alfa, i.e. <4 oocytes among patients 
with AMH <15 pmol/L (16% versus 22%) and ≥15 or ≥20 oocytes among patients with 
AMH ≥15 pmol/L (27% versus 35%, and 10% versus 16%). Implementation of dose adjustments 
during stimulation was performed for 37% of the patients in the follitropin alfa group, yet an 
appropriate ovarian response, defined as 8-14 oocytes, was reached by a higher proportion of 
patients treated with FE 999049 compared to follitropin alfa, i.e. 42% versus 37%.
For further information regarding FE 999049, please refer to the Summary of Product 
Characteristics (SmPC).4
1.2
Scientific Justification for Conducting the Trial
All clinical phase 2 and 3 trials conducted with FE 999049 have applied the gonadotropin-releasing 
hormone (GnRH) antagonist protocol and the FE 999049 dosing algorithm has not yet been studied 
in a long GnRH agonist protocol. Previous studies comparing the efficacy and safety of a GnRH 
antagonist protocol with a long GnRH agonist protocol using rFSH derived from CHO cell lines 
have consistently indicated that the cohort of recruited follicles is slightly smaller in GnRH 
antagonist cycles. The difference in the largest randomised controlled trial5 was -1.0 oocyte 
(95% CI 1.8; -0.2) which is in agreement with the estimated difference of -1.07 oocyte 
(95% CI -1.52; -0.61) in a Cochrane review including 27 randomised controlled trials.6 The 
evidence available suggests that the long GnRH agonist protocol compared to the GnRH antagonist 
protocol is generally associated with one more oocyte retrieved, one more day of stimulation, and 
consequently a higher total dose of exogenous FSH equivalent to one more day of dosing. 
This prospective, comparative trial is designed to document the ovarian response following the 
application of the individualised FE 999049 dosing regimen in a long GnRH agonist protocol 
compared to a GnRH antagonist protocol. The trial will describe the impact of the protocol on the 
overall number of oocytes retrieved, the number of oocytes retrieved in patients with AMH 
<15 pmol/L and AMH ≥15 pmol/L as well as the distribution of the number of oocytes retrieved 
(<4, 4-7, 8-14, 15-19, ≥20 oocytes). 
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 a pregnancy. Furthermore, subjects who do not achieve an ongoing pregnancy will also 
have the option of cryopreserved cycles. All procedures and assessments related to cryopreserved 
cycles will take place outside this protocol and will not be paid for by Ferring. Subjects in this trial 
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 


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planning of subsequent treatment cycles.
Risks
The risks associated with ART treatment, including the risk of controlled ovarian stimulation and 
clinical and laboratory procedures, are explained to the subjects as part of the counselling prior to 
starting treatment.
Gonadotropins
As part of the development programme for FE 999049, a total of 1,927 subjects have to date been 
included in four phase 1 trials, two phase 2 trials (one conducted in EU and one in Japan) and two 
phase 3 trials. Of these, 1,112 subjects were exposed to FE 999049 in a range from a single dose up 
to exposure in three consecutive stimulation cycles. During the phase 3 trials ESTHER-1 and 
ESTHER-2, 665 IVF/ICSI subjects were treated with FE 999049 in 1,012 treatment cycles. The 
overall adverse event profile of the individualised FE 999049 dosing regimen appeared to be 
comparable to that of the comparator GONAL-F with the exception of fewer cases of ovarian 
hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS 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 was administered with an injection pen containing a replaceable cartridge and 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 a
pre-filled pen. In the current trial, FE 999049 will be administered using the pre-filled FE 999049 
injection pen.
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. The incidence of early OHSS can be minimised by withholding gonadotropins, 
withholding human chorionic gonadotropin (hCG) or administering GnRH agonist for triggering of 
final follicular maturation. In this trial, administering GnRH agonist for triggering of final follicular 
maturation cannot be allowed as half the subjects are treated in a long GnRH agonist protocol and 
the main statistical analysis compares the number and distribution of oocytes for all subjects, i.e. 
the full analysis set (FAS). 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%7,8,9,10,11,12,13). In the phase 3 
trial ESTHER-1, the incidence of treatment-induced anti-FSH antibodies was 1.05% in the 


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FE 999049 group. None of the anti-FSH antibodies were of neutralising capacity. No safety or 
efficacy concern has been identified with regards to immunogenicity with FE 999049.
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, nausea and allergic reactions. Furthermore, the vaginal progesterone has been associated 
with vulvovaginal disorders and uterine spasms (at a frequency of 1-2%), and the GnRH agonist 
with vaginal bleeding/spotting (>10%). Ovarian cyst formation is also a recognised complication of 
GnRH agonist use.
Pregnancy-related Events
Oocytes will be inseminated using IVF or ICSI and subsequently cultured to day 5 (blastocyst 
stage) after oocyte retrieval. Although the frequency of cancellation of transfer is higher when 
culturing to blastocyst stage compared to culturing only to cleavage stage14, the pregnancy rates per 
started cycle are at least as good with blastocyst transfer as with cleavage embryo transfer14 and 
may even be higher.15 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, single blastocyst transfer is mandatory for women <38 years, as these women in general 
have a very good prognosis for obtaining pregnancy. In women ≥38 years, the transfer policy 
depends on the quality of the available blastocysts, i.e. single blastocyst transfer if they have at least 
one good-quality blastocyst, and double blastocyst transfer may be performed if they have no 
good-quality blastocysts. 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.
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 


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evaluation of benefits and risks indicate that participation is 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 evaluate the effect of individualised FE 999049 treatment on ovarian response in a long 
GnRH agonist protocol versus a GnRH antagonist protocol 
Secondary Objectives

To evaluate the effect of individualised FE 999049 treatment on other pharmacodynamic
parameters in a long GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the effect of individualised FE 999049 treatment on pregnancy rates in a long 
GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the safety of individualised FE 999049 treatment in a long GnRH agonist 
protocol versus a GnRH antagonist protocol
2.2
Endpoints
Primary Endpoint

Number of oocytes retrieved 
Secondary Endpoints

Proportion of subjects with cycle cancellation due to poor ovarian response or excessive 
ovarian response 

Proportion of subjects with blastocyst transfer cancellation after oocyte retrieval due to (risk 
of) OHSS

Number and size of follicles on stimulation day 6 and end-of-stimulation

Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Number of metaphase II oocytes (only applicable for those inseminated using ICSI), 
fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on day 5 
after oocyte retrieval

Circulating concentrations of FSH, luteinising hormone (LH), estradiol, progesterone and 
inhibin B on stimulation day 6, end-of-stimulation and at oocyte retrieval

Total gonadotropin dose and number of stimulation days

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred)

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)


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
Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after transfer
divided by number of blastocysts transferred)

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) 

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Frequency and intensity of adverse events

Technical malfunctions of the pre-filled injection 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
A diagram illustrating the post-trial activities is shown in Figure 3-2.
Antagonist:
Day 2-3 of
menstrual cycle
Long agonist:
When pituitary
down-regulation is 
established
Screening 
Triggering + 
36±2 h
Oocyte retrieval
Transfer
Transfer +
13-15 days
βhCG test
OR +
5 days
Triggering
of final follicular
maturation
Stimulation 
day 1
US 
Stimulation 
day 6
f
End-of-trial
visit
End of stimulation
GnRH agonist a
Transfer +
5-6 weeks
Clinical pregnancy 
Ongoing pregnancy 
Transfer +
10-11 weeks
GnRH antagonist c
Progesterone e
US
US
US
US
FE 999049 b
FE 999049 b
hCG d
hCG d
Progesterone e
Randomisation
Endocrine
Endocrine
Endocrine
Endocrine
Endocrine
a.
GnRH agonist (GONAPEPTYL 0.1 mg/day) from the mid-luteal phase (i.e. day 21-24) of the subject’s menstrual cycle and continued 
throughout the stimulation period.
b.
The FE 999049 dose is based on the subject’s AMH at screening and body weight on stimulation day 1. In the GnRH agonist protocol, 
stimulation with FE 999049 starts when down-regulation is established. In the GnRH antagonist protocol, stimulation with FE 999049 starts 
on day 2-3 of the subject’s menstrual cycle.
c.
GnRH antagonist (CETROTIDE 0.25 mg/day) from stimulation day 6 and continued throughout the stimulation period. 
d.
hCG (OVITRELLE 250 μg single dose) when triggering criterion is met.
e.
Progesterone (LUTINUS 3x100 mg/day) from the day after oocyte retrieval and continued until the day of the βhCG visit. Luteal phase 
support may be continued after a positive βhCG test is obtained if this is local practice.
f.
Stimulation day 1, 6 and hereafter at least every second day. When the leading follicle reaches ≥15 mm, visits will be scheduled daily.
OR: oocyte retrieval, US: ultrasound


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Figure 3-2 Trial Diagram – Post-trial Activities
3.1.2
Overall Design and Control Methods
Trial Design 
This will be a randomised, controlled, open label, parallel group, multicentre trial comparing the 
efficacy and safety of individualised FE 999049 dosing in first cycle patients aged 18-40 years 
undergoing controlled ovarian stimulation for IVF/ICSI following either a long GnRH agonist 
protocol or a GnRH antagonist protocol. The trial has been designed to describe potential 
differences in the mean number of oocytes retrieved with adequate precision. 
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. Randomisation may take place as soon as all eligibility criteria are met. 
Randomisation does not necessarily need to take place at a physical visit, but can be done by 
delegated trial staff without the subject being present at the clinic. However, the subject will be 
contacted prior to randomisation to confirm eligibility. Subjects will be randomised in a 1:1 ratio to 
controlled ovarian stimulation with FE 999049 in a long GnRH agonist protocol or to controlled 
ovarian stimulation with FE 999049 in a GnRH antagonist protocol. Randomisation will be 
stratified by centre and according to age (<35, 35-37 and 38-40 years). The subject will be informed 
of treatment allocation and when to start treatment by the delegated trial staff.
Subjects randomised to treatment with FE 999049 in the long GnRH agonist protocol will start 
down-regulation with GnRH agonist (triptorelin acetate, GONAPEPTYL) 0.1 mg/day 


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subcutaneously in the mid-luteal phase (i.e. cycle day 21-24) of their menstrual cycle. Ovarian 
stimulation with FE 999049 will start after 14 days (±1 day) if the subject has experienced 
withdrawal bleeding and the following down-regulation criteria are fulfilled: 1) a thin endometrium 
(<5 mm) is observed by transvaginal ultrasound, and 2) no ovarian follicles ≥10 mm (including 
cysts that cannot be punctured prior to stimulation) are observed by transvaginal ultrasound. In case 
achievement of down-regulation is doubtful or it is deemed helpful, serum estradiol is to be 
measured (<50 pg/mL or 180 pmol/L; local laboratory). If down-regulation is confirmed and 
ovarian stimulation is initiated, treatment with GnRH agonist is continued throughout the 
stimulation period. If the subject has not experienced withdrawal bleeding after 14 days (±1 day), a 
urinary pregnancy test is to be performed. If the subject is not pregnant and down-regulation is not 
confirmed, treatment with GnRH agonist will be continued and stimulation will be postponed until 
down-regulation is confirmed. Subsequent visit(s) for confirmation of down-regulation will be 
scheduled according to local practice. If down-regulation is not achieved after 28 days, treatment 
with GnRH agonist will be stopped and the subject will be withdrawn from the trial. 
Subjects randomised to treatment with FE 999049 in the GnRH antagonist protocol will start 
stimulation with FE 999049 on day 2 or 3 of their menstrual cycle. To prevent a premature LH 
surge, a GnRH antagonist (cetrorelix acetate, CETROTIDE) 0.25 mg/day subcutaneously will be 
initiated on stimulation day 6 and continued throughout the stimulation period.
Subjects will have their individual FE 999049 dose determined on the basis of their AMH level at 
screening and their body weight on stimulation day 1. The daily FE 999049 dose will be fixed 
throughout the stimulation period. For subjects with AMH <15 pmol/L the daily FE 999049 dose is 
12 μg, irrespective of body weight. For subjects with 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. AMH will be measured by Elecsys® AMH Plus Immunoassay (Roche Diagnostics). The 
maximum allowed daily FE 999049 dose is 12 µg. Subjects can be treated with FE 999049 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. 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, a single dose of 
hCG (OVITRELLE) 250 µg will be administered. If there are ≥25 follicles with a diameter 
≥12 mm, the cycle will 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.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF and/or ICSI. Fertilisation and embryo development will be 
assessed from oocyte retrieval to the day of transfer. For all subjects blastocyst transfer is 
performed on day 5 after oocyte retrieval. Subjects <38 years at randomisation will have single 


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blastocyst transfer. Subjects ≥38 years at randomisation will have single blastocyst transfer if they 
have a good-quality blastocyst available, i.e. a blastocyst of grade 3BB or higher; otherwise they 
may have double blastocyst transfer. Remaining blastocysts may be cryopreserved and used by the 
subject after completion of the trial, in accordance with local guidelines and/or regulations. All 
procedures and assessments related to cryopreserved cycles will take place outside this protocol and 
will not be paid for by Ferring.
Vaginal progesterone tablets (LUTINUS) 100 mg three times daily will be provided for luteal phase 
support from the day after oocyte retrieval and until the serum βhCG test. Luteal phase support may 
be continued after a positive βhCG is obtained if this is local practice. A serum βhCG test is 
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 assessed at screening, stimulation day 1, stimulation day 6, end-of-stimulation and at oocyte 
retrieval. 
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 minor/major congenital anomalies, at birth and at 
4 weeks after birth. These data will be reported separately.
3.1.3
Trial Schedule
First patient first visit (FPFV):
Q1 2019
Last patient first visit (LPFV):
Q3 2021
Last patient last visit (LPLV) / end-of-trial:
Q1 2022
Post-trial follow-up completed:
Q4 2022
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise approximately 400 subjects from approximately 15 sites. Approximately 
200 will be randomised to the long GnRH agonist protocol and approximately 200 will be 
randomised to the GnRH antagonist protocol. It is estimated that up to 500 subjects should be 
screened to achieve 400 randomised and treated subjects. 


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3.3
Interim Analysis
No interim analysis is planned. 
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 evaluate the effect of individualised FE 999049 treatment on 
ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocol.
This is a randomised controlled trial with a parallel group design which is preferred over a cross-
over design in fertility trials. The trial will be open label as a double–blind design is not feasible 
due to the required GnRH agonist treatment prior to start of stimulation in a long GnRH agonist 
protocol. In contrast, in a GnRH antagonist protocol, the GnRH antagonist is only started during the 
mid-follicular phase of the stimulation period. Prior to start of stimulation in a long GnRH agonist 
protocol, down-regulation needs to be confirmed based on ultrasound findings, thus neither patients 
nor the assessors in this trial can be blinded. The lack of blinding may result in different withdrawal 
patterns for the two protocols. To minimise this, only subjects without strong preference for one of 
the protocols will be included. The trial will be a multicentre, multinational 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.
Randomisation will be stratified by age group (<35, 35-37 and 38-40 years). Age is known to 
influence ovarian response, e.g. the primary endpoint, number of oocytes retrieved, as well as 
pregnancy endpoints such as clinical pregnancy rate and ongoing pregnancy rate. Stratification by 
age group will ensure that within each age group, a similar number of subjects is randomised to 
each protocol. This will increase the precision of the trial and facilitate separate presentations by 
age group. In addition, randomisation is stratified by centre as ovarian response and pregnancy 
outcome may differ between centres. 
Subjects will undergo controlled ovarian stimulation with an individualised dosing regimen of 
FE 999049 based on the subject’s AMH level and body weight, following either a long GnRH 
agonist protocol or a GnRH antagonist protocol. The daily FE 999049 dose is fixed throughout the 
stimulation period in this trial. 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.
In this trial, subjects with ≥25 follicles of ≥12 mm at end of stimulation will be cancelled, meaning 
that hCG will be withhold in both treatment groups. Subjects in the GnRH antagonist group with 


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such high ovarian response could in principle receive GnRH agonist for triggering of final follicular 
maturation, but this approach is not allowed as an identical cancellation policy for both treatment 
groups is essential for a valid comparative analysis of the primary endpoint. However, the 
anticipated number of subjects that needs to be cancelled in the current trial is anticipated to be low. 
In the previous phase 3 trial ESTHER-1, there was no upper cut-off level for AMH, and only 2.5% 
of all subjects had ≥25 follicles ≥12 mm at the end of stimulation. The incidence was only 1.2% for 
FE 999049 treated subjects with AMH ≤35 pmol/L. In this phase 3b trial, subjects with 
AMH >35 pmol/L will be excluded which will lower the frequency of potential high responders, 
such as subjects with polycystic ovarian syndrome (PCOS) who have an increased risk of 
developing OHSS. Based on the incidence of 1.2% in the ESTHER-1 trial, only 5 subjects of the 
planned 400 randomised subjects are expected to be cancelled due to this criterion. 
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 5 days and embryo 
development will be assessed from oocyte retrieval till the day of transfer, allowing evaluation of 
embryo development until blastocyst stage. 
The present protocol requires single blastocyst transfer on day 5 for all women <38 years and for 
women ≥38 years with at least one good-quality blastocyst available. Women ≥38 years with no 
good-quality blastocyst may have double blastocyst transfer. 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).16,17,18 Further, there is increasing evidence suggesting 
that late stages of embryo progression are better predictors of clinical pregnancy than early embryo 
development parameters.19 In good prognosis patients, the transfer of blastocysts yields a higher 
live birth rate than that achieved with transfer of the same number of cleavage stage embryos.15
Subjects who achieve an ongoing 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.
3.5.2
Selection of Endpoints
In the phase 3 trial ESTHER-1 it was demonstrated that individualised FE 999049 dosing based on 
the subjects AMH and body weight in comparison to conventional rFSH treatment increased the 
number of oocytes retrieved in subjects with low AMH (<15 pmol/L) and decreased the number of 
oocytes retrieved in subjects with high AMH (≥15 pmol/L), the latter reducing the occurrence of 
preventive interventions for early OHSS. 
The primary endpoint of this trial, the number of oocytes retrieved, is an endpoint reflecting the 
pharmacological effect of FSH on follicular development and growth, and it is associated with the 
risk of OHSS. Previous comparative trials with GnRH antagonist versus long GnRH agonist 
protocols, including meta-analyses, have demonstrated that following rFSH treatment in a GnRH 
antagonist protocol, less oocytes are retrieved and accordingly a lower risk of OHSS is observed.5,20


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The primary endpoint of this trial will allow the comparison of distribution of the number of 
oocytes retrieved following each GnRH analogue protocol, and more specifically in subjects with 
low AMH (<15 pmol/L) and high AMH (≥15 pmol/L). Based on current knowledge about the 
difference in ovarian response following treatment with CHO-derived rFSH in either protocol20 an 
overall treatment difference of at least 1 oocyte is to be anticipated, the difference being smaller in 
subjects with low AMH than in subjects with high AMH. This treatment difference, especially in 
subjects with high AMH, will indicate whether the FE 999049 dosing algorithm remains safe and 
effective when applied in a GnRH agonist protocol. 
Secondary endpoints include standard efficacy endpoints in fertility treatment such as pregnancy 
outcomes, e.g. clinical pregnancy rate and ongoing pregnancy rate. Cycle cancellation due to poor 
or excessive ovarian response, blastocyst transfer cancellation due to (risk of) OHSS, distribution of 
number of oocytes retrieved, total gonadotropin dose and number of stimulation days will also be 
assessed.
Secondary endpoints related to safety include adverse events, early OHSS and late OHSS. 
Technical malfunction of the pre-filled injection pen used for administration of FE 999049 will also 
be monitored. 
Other secondary endpoints include pharmacodynamic parameters such as ovarian response in terms 
of follicular development, endocrine profile and also embryo and blastocyst quality. Follicular 
development will be evaluated on day 6 as well as at end-of-stimulation. The endocrine profile 
consists of FSH, LH, estradiol, progesterone, and inhibin B and will be evaluated on stimulation 
day 6, end-of-stimulation and at oocyte retrieval.
Post-trial activities cover follow-up of ongoing pregnancies up to live birth and neonatal health data 
at birth and at 4 weeks after birth. Neonatal health data will be gathered to provide additional safety 
information.
3.5.3
Blinding
This trial is open label and unblinded due to the different protocols being compared and no 
measures are taken to prevent investigators, delegated trial staff or subjects from knowing the 
treatment allocation or dose of FE 999049 administered. It would be impractical to blind the 
protocols as they differ in respect to when treatment with GnRH agonist and GnRH antagonist, 
respectively, is initiated, and when the subject is to start stimulation with FE 999049. 
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 (000009) have been used to identify the overall dosing regimen for FE 999049. The objective 


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of the FE 999049 dosing regimen is to obtain an appropriate ovarian response of 8-14 oocytes in 
most subjects, to minimise the proportion of subjects with <4 oocytes due to risk of unavailability 
of blastocysts for transfer, and to minimise the proportion of subjects with 15 oocytes or more as 
well as 20 oocytes or more due to the risk of early moderate/severe OHSS. 
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 proposed individualised dosing regimen of FE 999049 is described in detail 
in section 5.1 and is summarised as follows: for subjects with AMH <15 pmol/L the daily 
FE 999049 dose is 12 μg, irrespective of body weight, and for subjects with 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 safety and efficacy of this dosing regimen has been confirmed 
in the phase 3 trial ESTHER-1, and the dosing regimen of FE 999049 in this trial will be the same 
dosing regimen that was evaluated in the phase 3 trial and according to the labelling.
Concomitant Fertility Medication 
The doses and overall treatment regimens for the GnRH agonist (GONAPEPTYL), GnRH 
antagonist (CETROTIDE), hCG (OVITRELLE) and progesterone (LUTINUS) products are in line 
with the recommendations in the respective products’ labelling for the indication of ART and/or 
standard clinical practice.
3.5.5
Selection and Timing of Dose for Each Subject
The proposed individualised dosing regimen of FE 999049 is described in detail in section 5.1.
3.5.6
Selection of the Trial Population
This trial applies similar inclusion/exclusion criteria as ESTHER-1 and will include women
undergoing their first IVF/ICSI cycle, as this group of patients is considered the most appropriate 
population for a trial using different treatment protocols. 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.21 The allowed body mass index (BMI) is 17.5-32.0 kg/m2, thus including underweight, 
normal weight, overweight and obese patients. 
Subjects with an AMH level > 35 pmol/L at screening will be excluded from the trial as these 
subjects are likely to have polycystic ovaries and may have an increased risk of OHSS. Subjects 
with a strong preference for either treatment protocol will also be excluded from the trial. For 
example, some subjects may prefer the short term GnRH antagonist protocol or suffer from needle 


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fobia which could cause more premature discontinuations among subjects randomised to the GnRH 
agonist protocol. Furthermore, 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.
3.5.7
Withdrawal Criteria
Description of specific withdrawal criteria for the individual subject is listed in section 4.4.
3.5.8
Follow-up Procedures
Post-trial Activities
Post-trial activities includes follow-up of ongoing pregnancies and neonatal health follow-up at 
birth and at 4 weeks after birth. 
Safety Follow-up
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 investigational medicinal 
product (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.
Access to Therapy after End-of-trial
In December 2016, Ferring received Marketing Authorisation approval from the European 
Commission for FE 999049 and the product is approved under the trade name REKOVELLE in all 
countries included in this trial. Commercial availability may vary across countries. 


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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 Forms signed prior to screening evaluations.
2. In good physical and mental health. 
3. The subjects must be at least 18 years (including the 18th birthday) when they sign the 
Informed Consent Form 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 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 <38 years or for at least 
6 months for subjects ≥38 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. no endometrioma greater than 2 cm or 
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 2-5) serum levels of FSH between 1 and 15 IU/L at 
screening.
11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to randomisation. 
12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
13. If <38 years willing to accept single blastocyst transfer. If ≥38 years willing to accept 
transfer of a single good-quality blastocyst (double blastocyst transfer may be performed if 
no good-quality blastocyst is available).


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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. AMH >35 pmol/L at screening.
2. Strong preference of the subject for either treatment protocol. 
3. Known endometriosis stage III-IV (defined by the revised ASRM classification, 199622).
4. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy). 
5. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial.
6. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
7. Known inherited or acquired thrombophilia disease.
8. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
9. Known porphyria.
10. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
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. Currently breast-feeding.
14. Undiagnosed vaginal bleeding.
15. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
16. 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.
17. Pregnancy (negative pregnancy test must be documented at screening) or contraindication to 
pregnancy.
18. Known current active pelvic inflammatory disease.
19. 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.
20. Use of hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomisation.
21. Known history of chemotherapy (except for gestational conditions) or radiotherapy. 


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22. Current or past (1 year prior to randomisation) abuse of alcohol or drugs and/or current (last 
month) intake of more than 14 units of alcohol per week.
23. Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
24. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
25. Previous participation in the trial.
26. 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. 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/enrollment log for all screened subjects must be maintained by the 
investigator.
4.2.2
Randomisation
Randomisation may take place as soon as all eligibility criteria are met. Subjects will be 
randomised in a 1:1 ratio to controlled ovarian stimulation with FE 999049 in a long GnRH agonist 
protocol or to controlled ovarian stimulation with FE 999049 in a GnRH antagonist protocol. 
Randomisation is performed centrally through the electronic case report form (e-CRF) and will be 
stratified by centre and according to age (<35, 35-37 and 38-40 years). The randomisation number 
will be allocated to the subject together with the treatment allocation. 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 centres, i.e. the randomisation will be stratified by centre. 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 use fertility modifiers, including DHEA, metformin or cycle programming 
with oral contraceptives, progestogen or estrogen preparations, or hormonal preparations (except 
for thyroid medication) from randomisation and until the end of the trial.
4.3.2
Prohibited Therapy
Additional to the medicinal products listed in section 4.3.1 it is prohibited to administer other 
gonadotropins than FE 999049 and concomitant fertility medication provided as part of the trial 
regimen.
It is prohibited to administer medication for prevention of OHSS to subjects not showing symptoms 
of OHSS. For subjects with symptoms of OHSS, medication can be administered according to local 
practice.
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. The investigator must withdraw subjects if one of the following criteria is 
met:
Withdrawal Criteria
1. One or more follicles ≥10 mm (including cysts that cannot be punctured prior to 
stimulation) observed on the transvaginal ultrasound on stimulation day 1 / day of 
confirmation of down-regulation.
2. Down-regulation not achieved within 28 days after the first GnRH agonist administration.
3. Pregnancy (positive pregnancy test) between screening and stimulation day 1.
4. Use of fertility modifiers between randomisation and stimulation day 1, including DHEA, 
metformin or cycle programming with oral contraceptives, progestogen or estrogen 
preparations.
5. Use of hormonal preparations (except for thyroid medication and trial medication) between
randomisation and stimulation day 1.


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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 Form. 
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. Withdrawn subjects will not be 
replaced.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Product
Subjects will be randomised in a 1:1 ratio to controlled ovarian stimulation with FE 999049 
(follitropin delta) in a long GnRH agonist protocol or to controlled ovarian stimulation with 
FE 999049 in a GnRH antagonist protocol. All subjects will be treated with FE 999049 in a 
pre-filled injection pen.
FE 999049 Dosing Regimen
Subjects will have their individual FE 999049 dose determined on the basis of their AMH level at 
screening and their body weight on stimulation day 1. 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 daily FE 999049 dose will be fixed throughout the stimulation period. The maximum allowed 
daily FE 999049 dose is 12 μg. 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 FE 999049 with and without 
clinical consequences will be tracked in the e-CRF and reviewed ongoing by Ferring Global
Pharmacovigilance.
The complete FE 999049 dosing regimen is tabulated in detail in Table 5-1.


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Table 5-1
FE 999049 Dosing Regimen
AMH concentration 
(pmol/L)
Daily dose fixed throughout stimulation
Maximum daily 
dose
<15
12 μg 
12 μg
15-16
0.19 μg/kg   
12 μg
17
0.18 μg/kg   
12 μg
18
0.17 μg/kg   
12 μg
19-20
0.16 μg/kg   
12 μg
21-22
0.15 μg/kg   
12 μg
23-24
0.14 μg/kg   
12 μg
25-27
0.13 μg/kg   
12 μg
28-32 
0.12 μg/kg                      
12 μg
33-39 
0.11 μg/kg                       
12 μg
≥40 
0.10 μg/kg                       
12 μg
AMH concentration will be rounded off to integers. The cut-off limit for AMH in this trial is 35 pmol/L, i.e. only subjects with AMH level ≤35 
pmol/L will be included in the trial.
Subjects can be treated for a maximum of 20 days.
The FE 999049 preparation is administered as daily subcutaneous injection(s) in the abdomen.a 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 
delegated trial staff or the subject under supervision by the delegated trial staff. Subsequent 
injections can be done at home or at the clinic. The delegated trial staff 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 Pre-filled Injection 
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 on stimulation day 1 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 pre-filled injection pen has a dosing scale numbered from 0 to 20 μg. Each number 
is separated by two lines, each representing 0.33 μg. Thus, the pre-filled injection pen can be set to 
supply doses rounded to the nearest 0.33 μg. Rounding off of the calculated dose may be needed, as 
                                                
a It will be allowed to split the dose if the pre-filled injection pen does not contain enough FE 999049 for the daily dose 
to be administered. The remaining part of the dose will then be administered using a new FE 999049 pre-filled 
injection pen.


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in this example of a subject weighing 75.0 kg with an AMH level of 24 pmol/L for whom the 
calculated dose is 10.5 μg (0.14 μg/kg * 75.0 kg) which will then be rounded to 10.66 μg, i.e. 
10 μg + 2 lines on the pen. The e-CRF will provide the calculated dose in an output that matches 
the numbers and lines on the pre-filled injection pen; i.e. any rounding off will be done 
automatically prior to providing the subject’s calculated dose.
The delegated trial staff will be instructed and trained in the correct use of the pre-filled injection 
pen, so that correct instructions can be provided to the subjects.
5.1.2
Non-Investigational Medicinal Product
As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the following 
non-investigational medicinal products (NIMPs) as illustrated in Table 5-2.
Table 5-2
Non-Investigational Medicinal Products
NIMP
Trade name
Dose
GnRH agonist
GONAPEPTYL
0.1 mg subcutaneous injection once daily, starting in 
the mid-luteal phase of the subject’s menstrual cycle 
(i.e. day 21-24) and continued throughout the 
stimulation period.
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 (≥3 follicles with a diameter ≥17 mm and 
<25 follicles with a diameter ≥12 mm).
Progesterone
LUTINUS
100 mg vaginal tablets three times daily, starting on 
the day after oocyte retrieval and continued until the 
day of the βhCG test. Progesterone will be terminated 
earlier in case of no transfer, menses, negative βhCG 
or pregnancy loss.
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.
5.2
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). It should be noted that Ferring will only provide 
progesterone for luteal phase support until the serum βhCG test. Table 5-3 provides an overview of 
the presentation and manufacturer of each medicinal product.


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Table 5-3
Characteristics and Source of Supply of Medicinal Products
IMP / NIMP
Presentation
Manufacturer
FE 999049
(rFSH)
FE 999049 is provided as a pre-filled 
injection pen for multiple use 
containing 72 µg of follitropin delta in 
2.16 mL solution.
Ferring Pharmaceuticals
GONAPEPTYL 
(GnRH agonist)
GONAPEPTYL (triptorelin acetate) is 
provided as a pre-filled syringe (1 mL) 
for single use delivering 0.1 mg
triptorelin acetate.
Ferring Pharmaceuticals
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 acetate.
Merck
OVITRELLE 
(hCG)
OVITRELLE (choriogonadotropin alfa) 
is provided as a pre-filled syringe 
(0.5 mL) for single use delivering 
250 µg choriogonadotropin alfa.
Merck
LUTINUS
(progesterone)
LUTINUS is provided as vaginal 
tablets, each containing 100 mg of 
progesterone.
Ferring Pharmaceuticals
5.3
Packaging and Labelling
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
Clinical Trial Supply Department at Ferring in accordance with GMP and national regulatory 
requirements. 
All medicinal products will be labelled with trial-specific labels containing a unique IMP number to 
ensure traceability.
Details on the packaging of each medicinal product are provided in Table 5-4.


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Table 5-4
Packaging of Medicinal Products
IMP / NIMP
Packaging
FE 999049 
FE 999049 is provided in boxes containing 1 pre-filled injection pen 
for multiple use and single-use disposable needles. 
GONAPEPTYL 
(GnRH agonist)
GONAPEPTYL is provided in boxes containing 7 pre-filled syringes
for single use.
CETROTIDE 
(GnRH antagonist)
CETROTIDE is provided in boxes with 1 vial with powder and
1 pre-filled syringe with 1 mL solvent.
OVITRELLE 
(hCG)
OVITRELLE is provided in boxes containing 1 pre-filled syringe for 
single use.
LUTINUS
(progesterone)
LUTINUS is provided in boxes containing 1 vaginal applicator and 
21 vaginal tablets, packed individually in a sealed foil pouch.
5.4
Conditions for Storage and Use
The delegated trial staff will ensure that the medicinal products will be stored in appropriate 
conditions as stated in the labelling and in a secure location with controlled access. The storage 
compartment shall be monitored regularly and the temperature shall be documented.
Excursions in storage temperature must be reported to the sponsor as instructed in a trial specific
guideline.
In case of technical malfunction of a pre-filled injection pen, all relevant details (including time, 
date, a description of the malfunction and whether dosing was affected) of the incidence should be 
reported to the sponsor in a timely manner according to instructions in a trial specific guideline. 
The pen should be replaced and the treatment continued.
For information on warnings, precautions and treatment of overdose, please refer to the SmPCs for 
FE 999049, GONAPEPTYL, CETROTIDE, OVITRELLE, and LUTINUS.
5.5
Blinding / Unblinding
5.5.1
Blinding
Not applicable as this is an open label trial.


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5.5.2
Unblinding of Individual Subject Treatment
Not applicable as this is an open label trial. 
5.6
Treatment Compliance
5.6.1
Dispensing and Accountability
All handling of medicinal products (both IMP and NIMP) will be done by delegated trial staff at the 
site. The delegated trial staff will maintain subject dispensing logs, detailing the dates, quantities 
and batch numbers of dispensed and returned IMP and NIMP for each subject. The delegated trial 
staff 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.
5.6.2
Assessment of Compliance
The IMP and NIMP will only be dispensed by authorised trial staff to subjects who meet the 
eligibility criteria and are randomised to a treatment group in the trial. All medication will be 
dispensed at the trial site and the subject will enter dates and time of IMP, GnRH antagonist and 
hCG administration, dose of IMP administered, and date of first and last GnRH agonist and 
progesterone administration in a trial specific diary. For each day between first and last GnRH 
agonist administration and between first and last progesterone administration, information about 
whether the drug was administered will also be entered in the trial specific diary. This will later be 
entered into the e-CRF by delegated and trained trial staff (for GnRH agonist and progesterone 
administration between first day and last day of administration, summary information will be 
entered into the e-CRF). In case the subject has taken an incorrect IMP dose, this will be captured 
in the e-CRF as a medication error. 
5.7
Auxiliary Supplies
Ferring will supply safety containers for the collection of used injection pens and needles.
5.8
Return and Destruction of Medicinal Products and Auxiliary Supplies
Used / dispensed IMP and NIMP can be destroyed at the site in accordance with local legislation 
after drug accountability has been verified by the monitor. 
Unused / non-dispensed IMP and NIMP will be returned for destruction as instructed by the Ferring 
Clinical Trial Supply Department after drug accountability has been verified by the monitor.


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6
TRIAL PROCEDURES
6.1
Trial Flow Chart
Table 6-1
Trial Flow Chart – Subject Procedures
Screening
Rando-
misation
GnRH 
agonist 
group
Stimulation
Oocyte 
retrieval
Transfer
Pregnancy monitoring
End
Down-
regulation
period
During stimulation
End-of-
stimu-
lation
OR
Transfer
βhCG
Clinical
Ongoing
End-of-
trial
Timing
<90 d 
before 
rando-
misation
a)
b)
SD 1
SD 6
SD ≥7 
to <20 
c)
End
36h ±2h 
after 
triggering
Day 5 after 
OR
13-15 
days 
after 
transfer
5-6 
weeks 
after 
transfer
10-11 
weeks after 
transfer
d)
Written informed consent
X
Inclusion/exclusion criteria
X
X
Withdrawal criteria
  X e
  X f
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 f,g
Physical exam
X
Gynaecological exam
X
Pregnancy test (local lab)
X
  X h
X f
Ultrasound
X
  X f,i
X
X
X
X
X
Randomisation
X
Blood collection, endocrine 
X j
  X f,k
  X k
  X k
  X k
Confirmation of down-reg
  X l
Serum E2 (local lab)
  X m
  
IMP dispensing
X
X
X
GnRH agonist dispensing
       X n ······························X
GnRH antagonist dispensing
    X o ········X
hCG dispensing
  X p
Oocyte retrieval
X
Progesterone dispensing
      X
X q
Blastocyst transfer
X
Serum βhCG test (local lab)
X
Drug accountability
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
End-of-trial form
X
a)
Randomisation does not necessarily need to take place at a physical visit by the subject, but can be done by the delegated trial staff without the subject being present at 
the clinic
b)
Subjects randomised to treatment with FE 999049 in the long GnRH agonist protocol will attend a mandatory visit where down-regulation will be initiated and a 
mandatory visit after 14 days (±1 day) for confirmation of down-regulation  The number of subsequent visits for subjects who are not down-regulated after 14 days 
(±1 day) will depend on local practice
c)
Visits must be scheduled at least every second day; when the leading follicle reaches ≥15 mm visits must be scheduled daily  
d)
End-of-trial is the subject’s last scheduled visit
e)
Withdrawal criteria will be checked at different time points during the down-regulation period
f)
Performed before the first IMP dose  
g)
Only body weight  
h)
A pregnancy test will be made at start of down-regulation and repeated after 14 days (±1 day) if the subject has not experienced withdrawal bleeding
i)
For subject randomised to treatment with FE 999049 in the long GnRH agonist protocol, the ultrasound assessments on stimulation day 1 can be combined with the 
ultrasound performed to confirm down-regulation if the subject fulfils the criteria for continuing to stimulation day 1
j)
Endocrine parameters consist of a screening panel (AMH, FSH, prolactin and TSH: central laboratory)
k)
Endocrine parameters consist of a treatment panel (estradiol, FSH, inhibin B, LH and progesterone: central laboratory) and AMH (at SD 1 only)
l)
Confirmation of down-regulation will be assessed after 14 days (±1 day)  If down-regulation is not confirmed and the subject is not pregnant, treatment with triptorelin 
acetate is continued and stimulation is postponed until down-regulation is confirmed  Subsequent visit(s) for confirmation of down-regulation will be scheduled according 
to local practice If down-regulation is not achieved after 28 days, the subject is withdrawn from the trial
m) In case achievement of down-regulation is doubtful or it is deemed helpful, serum estradiol is to be measured (<50 pg/mL or 180 pmol/L)
n)
Only applicable for subjects randomised to treatment with FE 999049 in the long GnRH agonist protocol
o)
Only applicable for subjects randomised to treatment with FE 999049 in the GnRH antagonist protocol
p)
Triggering of final follicular maturation will be done as soon as ≥3 follicles with a diameter of ≥17 mm are observed   
q)
Progesterone for luteal phase support will be administered from the day after oocyte retrieval and until the serum βhCG test Luteal phase support may be continued after 
a positive βhCG test is obtained if this is local practice


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6.2
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before 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) 
[note: if the results of the examinations for eligibility according to inclusion criteria 8, 9 and 
11 are older than required per protocol or not available, respective examinations should be 
performed during the screening period. Blood collection for Negative serum HBsAg, HCV
and HIV antibody tests will be performed at the local laboratory, if applicable]

Demographics (age, ethnicity, race)

Collection of the following data:
- Medical history
- Infertility history
- Menstrual history
- Reproductive history
- Smoking and alcohol habits

Body measurements (body weight, height) [note: these are used for calculation of BMI]

Physical examination

Gynaecological examination

Pregnancy test – must be negative

Blood collection for central laboratory analysis of endocrine parameters (screening panel; 
AMH, FSH, prolactin and thyroid-stimulating hormone [TSH]) [note: the results must be 
available prior to randomisation and reviewed by the investigator to assess the eligibility of 
the subject]

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 randomisation which may take place as soon as all eligibility criteria 
are met but within 90 days from the screening visit. 


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6.3
Randomisation
Randomisation does not necessarily need to take place at a physical visit, but can be done by 
delegated trial staff without the subject being present at the clinic. 
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

Recording of use of concomitant medication

Recording of adverse events
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 controlled ovarian stimulation with FE 999049 in either a long GnRH agonist 
protocol or a GnRH antagonist protocol

Provide the completed subject participation card to the subject (or at the next scheduled visit 
if randomisation is not performed at a physical visit)
The subject will be informed of treatment allocation by the delegated trial staff.
Subjects randomised to controlled ovarian stimulation with FE 999049 in a long GnRH agonist 
protocol will proceed to a down-regulation visit where down-regulation will be initiated. Subjects 
randomised to controlled ovarian stimulation with FE 999049 in a GnRH antagonist protocol will 
proceed to the stimulation day 1 visit (section 6.6.1).
6.4
Down-regulation
Subjects randomised to controlled ovarian stimulation with FE 999049 in a long GnRH agonist 
protocol will start down-regulation in the mid-luteal phase (i.e. cycle day 21-24) of their menstrual 
cycle.
The following must take place at the down-regulation visit prior to GnRH agonist administration:

Check withdrawal criteria and ensure that the subject is still eligible for participation in the 
trial

Urinary pregnancy test – must be negative
Once the above has been done, the subject will start down-regulation with GnRH agonist:

Dispensing and administration of GnRH agonist [the first administration of GnRH agonist 
takes place at the clinic and can be done by either delegated trial staff or the subject under 
supervision by the delegated trial staff]


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Finally, this must be done before the subject leaves the clinic:

In the first 30 min following the GnRH agonist administration, the delegated trial staff must 
observe the subject’s general health with emphasis on symptoms of an acute allergic 
reaction 

Instruct the subject to administer the GnRH agonist at a daily dose of 0.1 mg throughout the 
stimulation period

Recording of use of any concomitant medication

Recording of adverse events

Hand out the diary to the subject. The subject must be instructed to record administration of 
GnRH agonist
A new visit must be scheduled for confirmation of down-regulation after 14 days (±1 day) of GnRH 
agonist treatment.
6.5
Confirmation of Down-regulation 
Subjects randomised to controlled ovarian stimulation with FE 999049 in a long GnRH agonist 
protocol who have started down-regulation will attend a visit for confirmation of down-regulation
after 14 days (±1 day) of GnRH agonist treatment. The following criteria must be fulfilled before 
the subject can proceed to stimulation with FE 999049:

The subject must have experienced withdrawal bleeding

The subject must have a thin endometrium <5 mm visible on transvaginal ultrasound

The subject must not have any ovarian follicles ≥10 mm (including cysts that cannot be 
punctured prior to stimulation) visible on transvaginal ultrasound
The ultrasound performed to confirm down-regulation can be combined with the ultrasound 
assessments performed on stimulation day 1 if the subject fulfills the three criteria (see 
section 6.6.1). In case achievement of down-regulation is doubtful or it is deemed helpful, serum 
estradiol is to be measured (<50 pg/mL or 180 pmol/L; local laboratory). 
In case the subject has not experienced withdrawal bleeding after 14 days (±1 day), a urinary 
pregnancy test is to be performed. If the subject is not pregnant and down-regulation is not 
confirmed, treatment with GnRH agonist will be continued and stimulation will be postponed.
Subsequent visit(s) for confirmation of down-regulation will be scheduled according to local 
practice (note: only the data from the visit where down-regulation is confirmed will be reported in 
the e-CRF). If down-regulation is not achieved after 28 days, treatment with GnRH agonist will be
stopped and the subject will be withdrawn from the trial (note: in this case, the data from the last 
visit for confirmation of down-regulation will be reported in the e-CRF).


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If down-regulation is confirmed, the subject may proceed to controlled ovarian stimulation with 
FE 999049 and undergo the stimulation day 1 assessments on the same day as down-regulation is 
confirmed. A new visit must be scheduled for stimulation day 1 if the subject does not proceed 
directly to the stimulation day 1 assessments (note: this visit must take place within 2 days after 
down-regulation is confirmed).
6.6
Stimulation
6.6.1
Stimulation Day 1
Subjects randomised to controlled ovarian stimulation with FE 999049 in a long GnRH agonist 
protocol will attend the stimulation day 1 visit after down-regulation is confirmed (note: this can be 
on the same day as the visit for confirmation of down-regulation or within 2 days after down-
regulation is confirmed).
Subjects randomised to controlled ovarian stimulation with FE 999049 in a GnRH antagonist 
protocol will attend the stimulation day 1 visit on day 2-3 of the menstrual cycle.
The following must take place before administration of the first dose of FE 999049:

Check withdrawal criteria and ensure that the subject is still eligible for participation in the 
trial

Body measurements (body weight) [once the body weight has been entered into the e-CRF, 
the FE 999049 dose will be calculated and displayed within the system]

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 initiated.b 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.

Blood collection for central laboratory analysis of endocrine parameters (treatment panel; 
FSH, LH, inhibin B, progesterone and estradiol, and additionally AMH)
Once the above has been completed, the following must be performed by the delegated trial staff:

Dispense FE 999049 to the subject and instruct the subject on how to administer FE 999049
                                                
b Treatment can be initiated the same day. If puncture is not possible, stimulation may be postponed to the next 
menstrual cycle for subjects randomised to controlled ovarian stimulation with FE 999049 in the GnRH antagonist 
protocol, assuming that the cyst will disappear, that the subject fulfils the inclusion criteria and that stimulation day 1 
can take place within 90 days from screening. 


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
Administer the 1st dose of FE 999049 according to AMH level at screening and body weight 
at stimulation day 1 [administration of FE 999049 takes place at the clinic and can be done 
by either the delegated trial staff or the subject under supervision by the delegated trial staff]

Dispensing of GnRH agonist as needed [note: only applicable for subjects randomised to
controlled ovarian stimulation with FE 999049 in a long GnRH agonist protocol]

Recording of use of any concomitant medication

Recording of adverse events

Hand out the diary to the subjects randomised to controlled ovarian stimulation with 
FE 999049 in a GnRH antagonist protocol. 

All subjects must be instructed to record administration of FE 999049
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 FE 999049 administration, the delegated trial staff (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.
The next visit must be scheduled for stimulation day 6.
6.6.2
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) –
the blood sample must be drawn at least 8 hours after the latest administration of FE 999049
and, if applicable, prior to administration of GnRH antagonist

Dispensing of FE 999049 as needed

Dispensing of GnRH agonist as needed [note: only applicable for subjects randomised to 
controlled ovarian stimulation with FE 999049 in a long GnRH agonist protocol]

Dispensing and administration of GnRH antagonist [note: only applicable for subjects 
randomised to controlled ovarian stimulation with FE 999049 in a GnRH antagonist 
protocol; the first administration of GnRH antagonist takes place at the clinic and can be 
done by either the delegated trial staff or the subject under supervision by the delegated trial 
staff]

Drug accountability of FE 999049 and, if applicable, GnRH agonist 

Recording of use of any concomitant medication


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
Recording of adverse events

The subjects randomised to controlled ovarian stimulation with FE 999049 in a GnRH 
antagonist protocol must be instructed to record administration of GnRH antagonist
Finally, this must be done before the subject leaves the clinic [note: only applicable to subjects
randomised to controlled ovarian stimulation with FE 999049 in a GnRH antagonist protocol]:

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. 

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.
6.6.3
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 6.6.4): 

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial triple-
layer structure, endometrial echogenicity pattern, number and size of follicles)

Dispensing of FE 999049 as needed

Dispensing of GnRH agonist or GnRH antagonist, as applicable and as needed

Drug accountability of FE 999049 and GnRH agonist or GnRH antagonist, as applicable

Recording of use of any concomitant medication

Recording of adverse events
6.6.4
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 must take place as soon as reaching 
the criterion for triggering of final follicular maturation.


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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 ≥25 follicles with a 
diameter ≥12 mm, the cycle is to 
be cancelled.
hCG 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 pre-filled injection pen.
The following must take place at the 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 endocrine parameters (treatment panel)
– the blood sample must be drawn at least 8 hours after the latest administration of 
FE 999049 and GnRH agonist or GnRH antagonist, as applicable

Dispensing of hCG, if applicable

Drug accountability of FE 999049 and GnRH agonist or GnRH antagonist, as applicable

Recording of use of any concomitant medication

Recording of adverse events
For subjects who receive hCG, the next visit is the oocyte retrieval visit which must be scheduled 
36h (±2h) after the administration of hCG. 
Subjects with cycle cancellation will undergo end-of-trial assessments (section 6.13).
6.7
Oocyte Retrieval
Oocyte retrieval must take place 36h (±2h) after hCG 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 6.8.


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The following must take place at the oocyte retrieval visit:

Blood collection for central laboratory analysis of endocrine parameters (treatment panel)
preferably before oocyte retrieval procedure

Oocyte retrieval

Dispensing of progesterone for luteal support – must be started on the day after oocyte 
retrieval [note: only applicable for subjects who had oocytes retrieved]

Drug accountability of hCG

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with oocytes retrieved, the next visit is the transfer visit 5 days after oocyte retrieval 
(section 6.9). Subjects having no oocytes retrieved will undergo end-of-trial assessments 
(section 6.13).
6.8
Oocyte / Embryo / Blastocyst Evaluation
The laboratory procedures regarding handling and evaluations of oocytes, embryos and blastocysts 
are described in detail 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 blastocyst stage. 
The flow of the trial procedures for oocytes is shown in Table 6-3.
Table 6-3
Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures
Day 0 
(OR)
Day 1 
after OR
Day 3 
after OR
Day 5 
after OR
Oocyte retrieval (OR)
X
Assessment of maturity stage (applicable for oocytes 
undergoing ICSI)
X
Insemination by IVF and/or ICSI
X
Assessment of oocyte fertilisation
X
Assessment of embryo / blastocyst quality
X
X
Transfer of blastocyst(s)a of the highest quality available: 
– Subjects <38 years at randomisation: 

single blastocyst transfer
– Subjects ≥38 years at randomisation: 

single blastocyst transfer if a good-qualityb blastocyst 
is available

double blastocyst transfer may be performed if a 
good-qualityb blastocyst is not available
X
a 
In the absence of blastocysts, compacted (not compacting) morulas could take the place of blastocysts for transfer.
b
A good-quality blastocyst is defined as a grade 3BB or above.


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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 by IVF or ICSI using ejaculated sperm (fresh or frozen) from partner or donor
Day 1 after Oocyte Retrieval

Assessment of fertilisation (number of pronuclei)
Day 3 after Oocyte Retrieval

Assessment of embryo quality
From day 3 and onwards, embryos must be cultured separately to ensure individual assessment.
Day 5 after Oocyte Retrieval

Assessment of blastocyst quality 

Transfer of blastocyst(s) according to transfer policy (section 6.9)

Remaining blastocysts may be cryopreserved in accordance with local guidelines and/or 
regulations. All procedures and assessments related to cryopreserved cycles will take place 
outside this protocol
6.9
Transfer
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. The subject-related 
procedures are described below.

Transfer of blastocyst(s) of the highest quality available according to this policy: 
Subjects <38 years at randomisation:

single blastocyst transfer
Subjects ≥38 years at randomisation:

single blastocyst transfer if a good-quality 
blastocyst (i.e. grade 3BB or above) is 
available

double blastocyst transfer may be 
performed if a good-quality blastocyst (i.e. 
grade 3BB or above) is not available
Note: only blastocysts of acceptable quality as judged by the investigator or embryologist 
should be transferred. If only low-quality blastocysts are available, the investigator or 


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embryologist may decide not to transfer any blastocysts without this being a protocol 
violation. In the absence of viable blastocysts, compacted (not compacting) morulas could 
be used for transfer.

Dispensing of progesterone for luteal phase support 

Drug accountability of progesterone

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
13-15 days after transfer (section 6.10)
6.10
βhCG Test
Subjects who have undergone transfer must attend a visit 13-15 days after transfer. Subjects 
experiencing a full menstrual bleeding may have the hCG test performed as part of the end-of-trial 
assessments if this occurs 13-15 days after transfer.
The following must take place:

Blood collection for local laboratory analysis of hCG 

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 
local reference ranges. In case of a doubtful / inconclusive hCG result, the test should be repeated, 
preferably within 2 days. Subjects with a positive hCG test must attend a clinical pregnancy visit 
5-6 weeks after transfer (section 6.11). Subjects with a negative hCG test must proceed to the 
end-of-trial assessments (section 6.13).
6.11
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 

Recording of use of any concomitant medication 

Recording of adverse events


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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 
(section 6.12). Subjects with no vital pregnancy must undergo end-of-trial assessments 
(section 6.13).
6.12
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

Recording of use of any concomitant medication 

Recording of adverse events
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy.
6.13
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.
The following procedures / assessments must take place at the last scheduled trial visit, irrespective 
of whether the subject discontinues the trial prematurely or completes it: 

Drug accountability, if applicable

Recording of use of any concomitant medication

Recording of adverse events

Completion of end-of-trial form 
6.14
Post-trial Activities
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 minor/major congenital
anomalies, at birth and at 4 weeks after birth.


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7
TRIAL ASSESSMENTS
7.1
Assessment Related to Primary Endpoint
7.1.1
Number of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit.
7.2
Assessment Related to Secondary Endpoints
7.2.1
Cycle Cancellation due to Poor Ovarian Response or Excessive Ovarian Response
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 >25 follicles with a diameter ≥12 mm are observed.
7.2.2
Transfer Cancellation due to (Risk of) OHSS
The reason for each blastocyst 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”, “ovarian hyperstimulation syndrome” and “high progesterone” in 
subjects with blastocysts available for transfer will be considered as transfer cancellations due to 
excessive response / (risk of) OHSS.
7.2.3
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.
7.2.4
Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
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.
7.2.5
Metaphase II Oocytes
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity 
stage will be categorised as germinal vesicle, metaphase I, metaphase II, degenerated or other.


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7.2.6
Fertilisation Rate
The number of pronuclei will be counted on day 1 after insemination and recorded as 0, 1, 2 or >2. 
Fertilised oocytes with 2 pronuclei will be regarded as correctly fertilised.
7.2.7
Number and Quality of Embryos on Day 3
Each embryo will be evaluated on day 3 after oocyte retrieval. The quality evaluation will consist 
of assessment of cleavage stage and embryo morphology parameters (blastomere uniformity, 
degree of fragmentation 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.
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). 
Degree of fragmentation will be classified as one of the following: 0%, 1-10%, 11-25%, 26-50% or 
>50% fragmentation, or totally fragmented (no blastomeres recognised).
Visual sign of multinucleation will be evaluated as yes or no.
7.2.8
Number and Quality of Blastocysts on Day 5
Blastocyst Expansion and Hatching Status, Blastocyst Inner Cell Mass Grading and 
Trophectoderm Grading 
The quality evaluation of blastocysts on day 5 after oocyte retrieval will consist of assessment of 
three parameters: blastocyst expansion and hatching status, blastocyst inner cell mass grading and 
trophectoderm grading. The scoring is based on the classification system by Gardner & 
Schoolcraft23 with the addition of D-categories for inner cell mass and trophectoderm.
Blastocyst expansion and hatching status will be assessed as one of the following:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, that of the 
embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early embryo, with 
a thinning zona
5. A hatching blastocyst with the trophectoderm starting to herniate through the zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the zona


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For blastocysts with expansion and hatching status 3-6, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as one of the following:
A. Tightly packed, many cells
B. Loosely grouped, several cells
C. Very few cells
D. Degenerative or no inner cell mass visible
Trophectoderm grading will be assessed as one of the following:
A. Many cells forming a cohesive epithelium
B. Few cells forming a loose epithelium
C. Very few large cells 
D. Degenerative or very large cells
Blastocysts with expansion and hatching status 3-6 will have a score combining the three 
parameters (blastocyst expansion and hatching status, inner cell mass and trophectoderm); e.g. 4AB 
for a blastocyst with blastocyst expansion and hatching status 4, inner cell mass grading A and 
trophectoderm grading B.
Compaction Assessment in Morulas 
Embryos that have not reached the blastocyst stage on day 5, but are morulas, will also be 
evaluated. Morulas will be categorised as one of the following three options: 

Compacted: Complete compaction. Tightly compacted cells. Individual cell membranes are 
no longer visible.

Compacting: Early stage. Cells can be distinguished.

Abnormal compaction: Regional or partial compaction, or few cells (<8) in compaction.
7.2.9
Circulating Levels of Endocrine Parameters
During treatment, the following panel of endocrine parameters will be evaluated: FSH, LH, 
estradiol, progesterone and inhibin B. 
Blood samples will be drawn at stimulation day 1c, stimulation day 6, end-of-stimulation and at the 
oocyte retrieval visit. The sample on stimulation day 1 (baseline) will be collected prior to the first 
dose of FE 999049, and samples drawn at stimulation day 6 and the end-of-stimulation visit will be 
                                                
c
AMH will also be included in the stimulation day 1 analyses.


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collected at least 8 hours after the previous administration of FE 999049 and GnRH agonist or
GnRH antagonist, as applicable. The sample drawn at the oocyte retrieval visit should preferably be 
collected before the oocyte retrieval procedure. 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.
7.2.10
Total Gonadotropin Dose and Number of Stimulation Days
The start and end dates as well as daily dose of FE 999049 will be recorded and used to calculate 
the total FE 999049 dose administered and the number of stimulation days.
7.2.11
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.
7.2.12
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 blastocysts transferred.
7.2.13
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,24 For intrauterine and ectopic pregnancies, the number of gestational sacs with fetal 
heart beat as well as without fetal heart beat will be recorded.
7.2.14
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.
                                                
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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7.2.15
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.
7.2.16
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 
10-11 weeks after transfer divided by number of blastocysts transferred.
7.2.17
Early OHSS (including Moderate/Severe)
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation. 
Classification of grade is according to a classification system based on Golan’s classification 
system (see section 8.3.1 for details) and all OHSS cases will be graded as mild, moderate or 
severe.
7.2.18
Late OHSS (including Moderate/Severe)
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
Classification of grade is according to a classification system based on Golan’s classification 
system (see section 8.3.1 for details) and all OHSS cases will be graded as mild, moderate or 
severe.
7.2.19
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.
7.2.20
Pen Malfunction
Incidences of technical malfunctions of the pre-filled injection pen will be recorded.


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7.3
Other Assessments
7.3.1
Demographics
Demographic information will be obtained during the screening period, including the following: 
date of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White). In countries where it is not allowed to collect ‘date of birth’ according to national 
regulations, ‘age’ will be collected at the screening and randomisation visits.
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 calculated at randomisation. 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.
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 Measurements
Body measurements will be made at screening and stimulation day 1. Body weight will be 
measured without shoes and overcoat and using a calibrated scale. The body weight at stimulation 
day 1 will be used for dose calculation in the FE 999049 group. Height will only be measured at 


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screening and will be used to calculate BMI.
7.3.8
Physical Examination
A complete physical examination will be performed at screening. 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.
7.3.9
Gynaecological Examination
A complete gynaecological examination will be performed at screening. 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 on the Medical History Log.
7.3.10
Endocrine Parameters at Screening
At screening, the following panel of endocrine parameters will be evaluated: AMH, FSH, prolactin 
and TSH. 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. The Laboratory Report will be signed and dated by the 
investigator.
7.3.11
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.
7.3.12
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 


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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.
7.3.13
Blastocyst Transfer Procedure
Any difficulty or eventuality during the transfer procedure will be noted.
7.3.14
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.
7.3.15
Drug Dispensing and Accountability
For IMP, GnRH antagonist and hCG, dates and time of administration will be recorded. 
Furthermore, the dose of IMP administered will be recorded. For GnRH agonist and progesterone, 
only date of first and last administration will be recorded. For each day between first and last GnRH 
agonist administration and between first and last progesterone administration, information about 
whether the drug was administered will be recorded. If progesterone is continued after the positive 
βhCG test is obtained, information about progesterone administration hereafter will not be recorded 
in the trial specific diary but will be entered on the concomitant medication form in the e-CRF.
Details on drug dispensing and accountability are provided in section 5.6.1.
7.3.16
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.


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7.4
Assessments related to Post-trial Information
7.4.1
Pregnancy Follow-up
For subjects with an ongoing pregnancy in the fresh cycle, 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, type of delivery, fetal presentation and apgar score as well 
as information on minor/major congenital anomalies and admission to neonatal intensive care unit
(NICU)/pediatric intensive care unit (PICU) or neonatal care unit (NCU)/pediatric care unit (PCU). 
At 4 weeks after birth, the data collected will include minor/major congenital anomalies, 
hospitalisations and any other relevant medical conditions. These follow-up data can be obtained 
from the subject, unless medical judgement is required, and 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 destroyed after the end of the trial. 
Exceptions are the blood samples for estradiol, if applicable, and βhCG which are analysed by a 
local laboratory at the trial clinic / hospital and subsequently destroyed. AMH back-up samples will 
be stored for up to 4 years after submission of the clinical trial report and may be used for 
additional AMH measurement with any AMH assay or for recalibration against a new reference 
standard. 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.


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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.
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


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
Date and time of onset 

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.e
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.
                                                
e
Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
worsens in intensity after IMP administration, this must be recorded as two separate events. The initial adverse 
event should be recorded with outcome “not 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 (the event is improving)

Not recovered

Fatal
8.3
Adverse Events of Special Interest
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 using a classification system based on Golan’s system25 as shown in 
Table 8-1 to grade (1, 2, 3, 4 or 5) each OHSS case.


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Table 8-1
Classification of Mild, Moderate and Severe OHSS
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) Haemoconcentration is defined as haematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalaemia (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 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.


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Investigations in case of OHSS
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

Blood sample for central laboratory analysis of the following (for moderate/severe OHSS):

Progesterone and estradiol

Complete Blood Count: 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: albumin, alanine transaminase, 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
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


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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.
8.4
Events Requiring Special Handling
8.4.1
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.
8.4.2
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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8.5
Serious Adverse Events
8.5.1
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. 


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Elective Termination
In connection with elective termination due to a congenital anomaly, the congenital anomaly of the 
fetus should be reported as a serious adverse event.
The congenital anomaly leading to elective termination will be coded using both MedDRA and 
ICD-10 and classified as minor or major.f
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 / infant

Stillbirthg

Neonate admitted to NICU/PICU regardless of duration or NCU/PCU for at least 2 hours

Congenital anomaly / birth defecth

Medically important event
In case of admission to NICU/PICU or NCU/PCU, the reason for admission must be reported as a 
serious adverse event, rather than just the act of hospitalisation. 
Congenital anomalies will be coded using both MedDRA and ICD-10 and classified as minor or 
majori in accordance with the EMA guideline.1
                                                
f Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems. 
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. 
g Stillbirth: gestational age ≥24 weeks + 0 days. Gestational age is calculated from the day of transfer + 19 days.
h Congenital anomaly / birth defect in any off spring of the subject conceived during treatment with the IMP.
i 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.


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8.5.2
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 Report Form 
with the fullest possible details within 3 calendar days of his/her knowledge of the serious adverse 
event.
Serious Adverse Event Report Form
The Serious Adverse Event 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 Serious Adverse Event Report Form cannot be filled in within the e-CRF
system, a paper Serious Adverse Event Report Form should be used and sent to Ferring Global 
Pharmacovigilance using the contact details below. As soon as the e-CRF is accessible again, the 
serious adverse event must be entered and notified to Ferring Global Pharmacovigilance.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: 
Fax: 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log 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.
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 Independent Ethics Committee (IEC) with any 
additional requested information such as results of post-mortem examinations and hospital records.


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Overdose and medication errors of IMP with and without clinical consequences will be tracked in 
the e-CRF and reviewed by Ferring Global Pharmacovigilance on an ongoing basis.
Ferring will report serious adverse events according to local regulations.
8.6
Follow-up of Adverse Events and Serious Adverse Events 
8.6.1
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 Global Pharmacovigilance. Follow-up should continue until the outcome of 
recovered, recovered with sequelae or fatal, has been reached. If the event is a chronic condition,
the investigator and Ferring may agree that further follow-up is not required.
8.6.2
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, the case will 
have to be reported to Ferring Global Pharmacovigilance, regardless how long after the end of the 
trial this takes place.
8.6.3
Follow-up of Serious Adverse Events with Onset during 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 the serious adverse event has 
resolved. If the serious adverse event 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.
8.6.4
Adverse Events on Non-investigational Medicinal Products 
During the trial, any case of adverse event that is recognised as an adverse drug reaction caused by 
a concomitant NIMP where Ferring is the Marketing Authorisation Holder (i.e. GONAPEPTYL 
and LUTINUS), must be reported to Ferring Global Pharmacovigilance. 
If an investigator becomes aware of an adverse event with onset after the end of the trial, and he/she 
assesses the adverse event to have a reasonable possible causality to a concomitant NIMP where 
Ferring is the Marketing Authorisation Holder (i.e. GONAPEPTYL and LUTINUS), the case will 


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have to be reported to Ferring Global Pharmacovigilance.
8.6.5
Pregnancy during Down-regulation
If spontaneous pregnancy occurs during the down-regulation period it should be reported to Ferring 
Global Pharmacovigilance. An electronic pregnancy form should be filled out and sent to Ferring 
Global Pharmacovigilance using the contact information mentioned in section 8.5.2.


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9
STATISTICAL METHODS
The Global Biometrics department of Ferring Pharmaceuticals will be responsible for the statistical 
analyses. All analyses will be detailed in a separate Statistical Analysis Plan.
9.1
Determination of Sample Size
The purpose of this trial is to gain clinical experience with the use of FE 999049 when applied in a 
long GnRH agonist protocol. The trial is descriptive and does not include any hypothesis testing. 
The sample size is based on achieving a reasonable precision in the estimate of the difference in 
mean number of oocytes retrieved between treatment with FE 999049 in a long GnRH agonist 
protocol versus treatment with FE999049 in a GnRH antagonist protocol.
In the ESTHER-1 trial, the standard deviation for the number of oocytes retrieved was 5.8 in the 
FE 999049 treatment group. Due to a potentially higher number of oocytes retrieved in the long 
agonist protocol, the standard deviation in this trial may be slightly higher. Assuming a standard 
deviation of 7.0, a sample size of 400 subjects (200 subjects per group) will give a 95% CI that 
ranges from -1.4 to +1.4 of the observed mean difference, i.e. the interval from the observed mean 
difference 1.4 to the observed mean difference +1.4 will with 95% probability include the true 
mean difference. This is regarded to be reasonably precise for describing the comparability of 
individualised FE 999049 dosing using the two protocols.
9.2
Subject Disposition
All subjects screened and randomised will be accounted for. All post-randomisation 
discontinuations will be summarised by time of, and reason for, discontinuation. Discontinuations 
will be classified as occurring before or after start of FE 999049 treatment. The number of subjects 
screened and not randomised will be presented.
9.3
Protocol Deviations
Important protocol deviations will be summarised and listed by subject. The impact of important 
protocol deviations on the trial results may be addressed in additional sensitivity analyses. 
9.4
Analysis Sets
9.4.1
Full Analysis Set 
The FAS will consist of all subjects that were randomised, regardless of whether they started 
FE 999049 treatment or not. However, subjects that discontinued before starting FE 999049 
treatment due to the COVID-19 pandemic (e.g. due to operational and/or societal issues) will be 
excluded from the FAS. Subjects will be analysed according to the protocol to which they were 
randomised.


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9.4.2
Safety Analysis Set
The safety analysis set will consist of all subjects that were randomised in the trial and were 
exposed to FE 999049. Subjects will be analysed according to the protocol they were actually 
treated with.
9.5
Trial Population
9.5.1
Demographics and other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics (body measurements, 
infertility history, menstrual history, reproductive history, smoking and alcohol habits, physical 
examination, and gynaecological examination) will be presented for the FAS. In addition, a 
summary of demographic characteristics will be presented by trial site.
9.5.2
Medical History and Concomitant Medication 
Medical history and concomitant medication will be presented for the FAS. Medical history 
recorded at the screening visit will be coded using MedDRA and summarised. The version of 
MedDRA will be documented. 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 only be produced overall (i.e. not by 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
Endpoint Assessments
9.6.1
General Considerations
The primary objective of the trial is to evaluate the effect of individualised FE 999049 treatment on 
ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocol. The primary 
endpoint is the number of oocytes retrieved. 


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The estimand of interest is the difference between FE 999049 treatment in the long GnRH agonist 
protocol versus treatment with FE 999049 in the GnRH antagonist protocol for all randomised 
subjects, assuming that all subjects start treatment with FE 999049. In the statistical analyses, 
subjects that discontinue after randomisation but before start of FE 999049 treatment (except for 
subjects that never started treatment due to the COVID-19 pandemic) will have their endpoint data 
imputed from subjects who started FE 999049 treatment in the same protocol, using a multiple 
imputation method. No imputation will be done for subjects who discontinue the trial after starting 
FE 999049 treatment. For these subjects, the actual data will be used and not be regarded as 
missing. Therefore, the number of oocytes retrieved will be regarded as zero and pregnancy 
outcomes will be regarded as negative.
The trial is descriptive and no formal hypothesis will be tested. The statistical analyses aims at
estimating any potential differences between FE 999049 treatment when applied in the two 
different GnRH protocols. The results will generally be described as an estimated mean treatment 
difference or treatment ratio and an associated 95% CI.
Since the trial is descriptive without any hypothesis testing, no corrections for multiplicity will be 
applied.
All analyses and descriptions for ovarian response endpoints and other pharmacodynamics 
endpoints will be based on the FAS. Analyses and descriptions for pregnancy endpoints will be 
based on the FAS but excluding subjects that had transfer cancellation due to the COVID-19 
pandemic. Additional descriptions will be made based on the FAS. Analyses and descriptions of 
safety endpoints and exposure will be based on the safety analysis set.
9.6.2
Primary Endpoint
The primary endpoint will be analysed using a negative binomial regression model with protocol
(long GnRH agonist protocol or GnRH antagonist protocol), age stratum (<35, 35-37, or 
38-40 years), and AMH at screening (<15 pmol/L or or ≥15 pmol/L) as factors. A logarithmic link 
function will be used for the mean in the model. From this model, the mean difference between the 
two protocols in number of oocytes retrieved will be estimated, and a 95% CI for the estimate will 
be calculated using the delta method. The analyses will be done using the multiple imputation 
method described below. 
Age stratum is included as factor in the model since randomisation is stratified by age. AMH at 
screening is additionally included as a factor since AMH is known to influence the number of 
oocytes retrieved. Although randomisation is stratified by centre, centre and the interaction between 
centre and age stratum are not included in the model as all centres may not randomise subjects from 
all age strata, and therefore the inclusion of the interaction in the model is likely to give empty cells 
in the analysis. The potential influence of centre differences on the results will instead be 
investigated in a sensitivity analysis.


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For subjects in the FAS who discontinue the trial after randomisation but before start of FE 999049 
treatment, the number of oocytes retrieved will be imputed from subjects who started FE 999049 
treatment in the same protocol, using the following multiple imputation method:

First, a negative binomial regression model with age stratum and AMH at screening as 
factors will be fitted to data from subjects who started FE 999049 treatment for each 
protocol separately. 

In the second step, 1000 complete datasets will be constructed. For the construction of each 
complete dataset, a set of parameter values will be sampled from a normal distribution with 
characteristics determined by the estimated parameters and covariance matrix for the two 
models in the first step. Missing individual subject data will then be imputed from a 
negative binomial distribution with the sampled parameters. 

In the third step, each complete dataset will be analysed using the negative binomial 
regression model described in the first paragraph of this section. 

In the final step, the estimated mean differences and the standard deviations from the 1000 
analyses will be combined using Rubin’s formula:
Where mi and SDi are the estimated mean differences and standard deviations for the 
differences for the 1000 copies of the dataset (derived using the delta method), and mMI and
SDMI are the pooled estimates.

The mean difference in number of oocytes retrieved between the long GnRH agonist 
protocol and the GnRH antagonist protocol will be estimated as mMI, and the 95% CI for the 
estimate will be calculated as mMI ± 1.96*SDMI.
The assumption underlying the above imputation procedure is that all randomised subjects could 
have started FE 999049 treatment, and that their outcome would not have differed in any systematic 
way from the subjects that started FE 999049 treatment.
For subjects who discontinue the trial after start of FE 999049 treatment but before oocyte retrieval 
the number of oocytes retrieved will be regarded as zero.
Sensitivity Analyses and Additional Descriptions for the Primary Endpoint
The potential influence of centre differences on the results for the primary endpoint will be 
investigated by repeating the analyses of the 1000 complete datasets generated above, with the 
addition of centre and the interaction between centre and age strata as factors in the model. 
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Additional analyses will be made for two subgroups based on AMH at screening (<15 pmol/L or 
≥15 pmol/L) and for the three age strata (<35, 35-37, or 38-40 years). These analyses will be based 
on the 1000 complete datasets used for the primary analyses and will use the same analysis model,
except that age stratum will not be included as factor in the age strata analyses and AMH will not 
be included in the AMH subgroup analyses. The results of the subgroup analyses will be illustrated 
in forest plots.
9.6.3
Secondary Endpoints
Proportion of Subjects with Cycle Cancellation due to Poor Ovarian Response or Excessive 
Ovarian Response
The proportion of subjects with cycle cancellation due to poor ovarian response or excessive 
ovarian response will be described. Additional descriptions will be made for the two subgroups 
based on AMH at screening (<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, 
or 38-40 years).
Proportion of Subjects with Blastocyst Transfer Cancellation after Oocyte Retrieval due to 
(Risk of) OHSS
The proportion of subjects with blastocyst transfer cancellation after oocyte retrieval due to (risk of) 
OHSS will be described. Additional descriptions will be made for the two subgroups based on 
AMH at screening (<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, or 
38-40 years).
Number and Size of Follicles on Stimulation Day 6 and End-of-stimulation
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised by protocol 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). 
Proportion of Subjects with <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
The distribution of the number of oocytes retrieved will be described for the two protocols using 
histograms. The percentage of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved will be 
described. Additional descriptions will be made for the two subgroups based on AMH at screening 
(<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, or 38-40 years).


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Number of Metaphase II Oocytes
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The total 
number of metaphase II oocytes will be compared between the long GnRH agonist protocol and the 
GnRH antagonist protocol using the same analysis method as for the primary endpoint.
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei on day 1 after oocyte retrieval. The 
total number of fertilised oocytes will be compared between the long GnRH agonist protocol and 
the GnRH antagonist protocol using the same analysis method as for the primary endpoint. The 
proportion of fertilised oocytes will be described.
Number and Quality of Embryos on Day 3 after Oocyte Retrieval
The number and the quality of embryos on day 3 will be described.
Number and Quality of Blastocysts on Day 5 after Oocyte Retrieval
The number and the quality of blastocysts on day 5 will be described.
The total number of good-quality blastocysts (grade 3BB or higher) will be compared between the 
long GnRH agonist protocol and the GnRH antagonist protocol using the same analysis method as 
for the primary endpoint.
Circulating Concentrations of FSH, LH, Estradiol, Progesterone and Inhibin B on 
Stimulation Day 6, End-of-stimulation and at Oocyte Retrieval
For each parameter, the concentrations on stimulation day 6, end-of-stimulation, and at oocyte 
retrieval will be described and compared for the long GnRH agonist protocol versus the GnRH 
antagonist protocol using analysis of variance models with age stratum and AMH at screening as 
factors. Multiplicative models will be used, i.e. the concentrations will be log-transformed before 
analysis. The results of the analyses will be back-transformed and presented as estimated geometric 
means for each parameter, and the mean ratios for long GnRH agonist protocol versus GnRH 
antagonist protocol with 95% CIs. Values below the lower limit of quantification (LLOQ) will be 
estimated with LLOQ/2.
Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose and the number of stimulation days will be described for each of the 
two protocols and for subgroups based on age strata and AMH at screening.


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Pregnancy Rates
The percentage of subjects with positive βhCG, clinical pregnancy, vital pregnancy, and ongoing 
pregnancy will be described for each of the two protocols and for subgroups based on age strata and 
AMH. Pregnancy rates will be compared between the long GnRH agonist protocol and the GnRH 
antagonist protocol using a logistic regression model with protocol (long GnRH agonist or GnRH 
antagonist), age stratum (<35, 35-37, or 38-40 years), and AMH at screening (<15 pmol/L or 
≥15 pmol/L) as factors. The results of this analysis (in terms of odds for pregnancy) will be 
converted into proportions, differences in proportions, and 95% CIs for differences in proportions 
using the delta method.
To account for subjects withdrawing from the trial before starting FE 999049 treatment, the 
multiple imputation method applied for the primary endpoint will be used, using a logistic 
regression model instead of a negative binomial regression model. Pregnancy data for subjects with 
pregnancies occurring before start of FE 999049 treatment will not be included in the analysis. 
These subjects are withdrawn and their data will be imputed.
Missing pregnancy assessments will be assumed to indicate a negative test. If, however, a 
subsequent test is positive, a previous missing assessment will be considered as positive (if e.g. the 
clinical pregnancy assessment is missing but the ongoing pregnancy assessment is positive, the 
missing clinical pregnancy assessment will be regarded as positive).
Implantation Rates
The implantation rate will be calculated as the number of gestational sacs 5-6 weeks after transfer 
divided by the number of blastocysts transferred. 
Ongoing implantation rate will be calculated as the number of intrauterine viable fetuses 
10-11 weeks after transfer divided by the number of blastocysts transferred. 
The implantation rate and the ongoing implantation rate will be described for each of the two 
protocols and for subgroups based on age strata and AMH at screening.
Proportion of Subjects with Early OHSS (including OHSS of Moderate/Severe grade)
Incidence of early OHSS will be tabulated by classification (mild, moderate, severe, moderate or 
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 this includes OHSS with onset before triggering and OHSS with 
onset during stimulation where triggering is not performed.


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Proportion of Subjects with Late OHSS (including OHSS of Moderate/Severe grade) 
Incidence of late OHSS will be tabulated by classification (mild, moderate, severe, moderate and 
severe) and grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days after triggering 
of final follicular maturation.
Adverse Events
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events will be grouped according to start of FE 999049 as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before start of FE 999049 treatment, or a pre-existing medical condition that worsens in 
intensity after signed informed consent but before start of FE 999049 treatment.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of FE 999049
treatment 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 FE 999049 treatment and before the 
end-of-trial visit.
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only. Treatment-emergent adverse events will be 
summarised overall and tabulated by System Organ Class (SOC) and PT in decreasing order of 
frequency. The total number of subjects reporting an adverse event, the percentage of subjects with 
an adverse event, and the number of events reported will be presented.
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.
Technical Malfunctions of the Pre-filled Injection Pen
The frequency of technical malfunctions of the administration pen will be tabulated.
Post-trial Information
Live birth rate and neonatal health, including minor / major congenital anomalies, at birth and at
4 weeks after birth will be described. These data will be reported separately. 


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9.7
Interim Analyses
No interim analysis is planned.


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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 or age at screening and randomisation, as 
applicable) 

Confirmation of participation in trial (trial ID, subject ID)

Informed consent(s) (date and time of obtaining written informed consent(s))

Eligibility for participation in the trial (documenting all inclusion / exclusion criteria, and 
successful pituitary down-regulation, if applicable)

Continuous eligibility for participation in the trial (documenting that none of the withdrawal 
criteria are met)

Relevant medical history, infertility history, menstrual history and reproductive history

Body weight measurements

Visit dates

Dates and time of IMP, GnRH antagonist and hCG administration 

Daily dose of IMP administered

Dates of first day and last day of GnRH agonist and progesterone administration


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
Dates and daily doses of concomitant medication 

Date of oocyte retrieval and number of oocytes retrieved

Date of transfer and number and quality of blastocysts transferred

Results of βhCG test and ultrasound at clinical and ongoing pregnancy visits

Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth and 
4 weeks after birth 

Adverse events (description as well as start/stop date and time)

OHSS symptoms, preventive intervention (i.e. cycle cancellation), investigations and 
treatments

Reason for discontinuation / withdrawal
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record.
If the trial sites use electronic patient record systems, the sponsor will decide if the electronic 
patient records qualify for the trial and document the decision. If the electronic patient records 
system does not qualify for the trial, it may be considered to utilise certified printouts of the data in 
the electronic patient records system for source data as an exception.
The source data for the endocrine 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 (CRO)
will be used for data capture. The system is validated and access at all levels to the system is 
granted / revoked following Ferring and vendor procedures, in accordance with regulatory 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 an electronic 
signature which is equivalent to a handwritten signature. 
The e-CRF system and the database will be hosted at the independent third-party CRO. After the 
trial database is declared clean and released to the statistician, 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 the 
independent third-party CRO. 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.


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Entry 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.
10.3
Use of Patient Reported Outcome 
All medication will be dispensed at the trial site and the subject will enter dates and time of IMP, 
GnRH antagonist and hCG administration, dose of IMP administered, and date of first and last 
GnRH agonist and progesterone administration in a trial specific diary. For each day between first 
and last GnRH agonist administration and between first and last progesterone administration, 
information about whether the drug was administered will also be entered in the trial specific diary. 
This will later be entered into the e-CRF by delegated and trained trial staff (for GnRH agonist and 
progesterone administration between first day and last day of administration, summary information 
will be entered into the e-CRF). If progesterone is continued after the positive βhCG test is 
obtained, information about progesterone administration hereafter will not be recorded in the trial 
specific diary but will be entered on the concomitant medication form in the e-CRF. In case the 
subject has taken an incorrect IMP dose, this will be captured in the e-CRF as a medication error.
10.4
Health Economics
Not applicable.
10.5
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
Department of Ferring Pharmaceuticals A/S. 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.
The data management plan will include information about the intended use of computerized 
systems, a description of the security measures employed to protect the data, and a description of 
the electronic data flow.
10.6
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 of 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 
thereafter. For this trial, the frequency of monitoring visits per site will be determined through a 
risk-based approach depending on recruitment rate, observed data quality, and overall site 
performance. The source data verification process and definition of key variables to be monitored 
will be described in detail in the Monitoring Plan for the trial.
For the pregnancy follow-up data, accuracy and verifiability of the e-CRF entries compared to the 
reports obtained from the subject’s gynaecologist / obstetrician / paediatrician or information by the 
subject herself, or other sources, as applicable, will be ensured.
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 IECs 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 Helsinki26 and all other relevant regulations.
The subjects must be informed by the investigator and in the Informed Consent Form that 
authorised Ferring representatives and representatives from regulatory authorities and IECs 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 IEC.


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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 Forms, 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 IEC(s) 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 IEC(s) 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. 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 IEC(s) 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 International Committee of Medical Journal Editors (ICMJE)
criteria.27 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 CRO 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 comments prior to 
submission. Comments will be given within four 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.
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 


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the responsibility of Ferring to register the trial in an appropriate public 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). The trial will also be made publicly available at the EU 
Clinical Trials Register at www.clinicaltrialsregister.eu. 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
Independent Ethics Committee 
An IEC will review the protocol and any amendments and advertisements used for recruitment. The 
IEC will review the Subject Information Sheet and the Informed Consent Form, their updates (if 
any), and any written materials given to the subjects. A list of all IECs to which the protocol has 
been submitted and the name of the committee chairmen will be included in the Clinical Trial 
Report.
14.2
Regulatory Authorities Authorisation / Approval / Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available 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 the trial is defined as the date of LPLV. 
The primary completion date is when the last subject undergoes oocyte retrieval. 
The sponsor shall make an end-of-trial declaration to the regulatory authorities and the concerned 
ethics committees in the participating countries, when the last data in the post-trial follow-up period 
has been collected in all Member States / third countries concerned (global end-of-trial).
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 explain the reasons, and describe follow-up measures, if any, taken for 
safety reasons. 
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 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 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 Form.
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 regarding Data Collection on the Neonate – Child-custody Holders
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 Form 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 Form.


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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.
Informed Consent regarding Participation in the Trial – Partner
For countries where a separate information and informed consent form is required in order to 
collect data on the partner and use the partner’s sperm for IVF or ICSI, the investigator will obtain 
a freely given written consent from the partner. The partner must be given ample time before the 
consent is obtained. The Informed Consent Form must be signed and dated by the partner and the 
investigator who has provided information to the partner. Written consent by the partner 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 partner is completely free to refuse to consent to this data 
collection or to withdraw consent at any time without the need to justify the decision.
The partner will receive a copy of the Informed Consent Form.
The partner 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, will review the partner’s source records and data. Data protection will be 
handled in compliance with national / local regulations.
14.6
Subject Participation Card
The subject will be provided with a Subject Participation Card bearing the following information:

That she is participating in a clinical trial (incl. trial code)

That the trial involves controlled ovarian stimulation with recombinant FSH 

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 keep the Subject Participation Card in her possession at all times 
during the trial and to return it at the last trial visit, if applicable.
Additionally, each subject’s primary care physician will be notified of her participation in the trial 
by the investigator, if the subject agrees and if applicable.


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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 

Type of delivery (vaginal / vacuum extraction / forceps / caesarean section)

Fetal presentation (head / breech / transverse / other – please specify)

Gender

Birth weight 

Birth length

Apgar score after 1, 5 and 10 minutes

Admission to NICU/PICU regardless of duration 

Admission to NCU/PCU for at least 2 hours

Any medically important event requiring treatment

Congenital anomaly 

Neonatal death
4 weeks after delivery: 
Relevant important conditions since birth:

Admission to NICU/PICU regardless of duration 

Admission to NCU/PCU for at least 2 hours 

Any medically important event requiring treatment

Any congenital anomaly discovered since birth

Neonatal death
14.8
Compliance Reference Documents
The Declaration of Helsinki, the consolidated ICH-GCP, the EU Clinical Trials Directive 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 are 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 Forms 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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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
Nyboe Andersen A, Nelson SM, Fauser BCJM, Garcia-Velasco JA, Klein BM, Arce J-C on 
behalf of the ESTHER-1 study group. Individualized versus conventional ovarian 
stimulation for in vitro fertilization: a multicentre, randomized, controlled, assessor-blinded, 
phase 3 noninferiority trial. Fertil Steril 2017; 107: 387-396.
4
REKOVELLE Summary of Product Characteristics. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003994/WC500220235.pdf
5
European Orgalutran Study Group, Borm G, Mannaerts B. Treatment with the 
gonadotrophin releasing hormone antagonist ganirelix in women undergoing ovarian 
stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: 
results of a controlled, randomized, multicenter trial. Hum Reprod 2000; 15: 1490-1498.
6
Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonist 
for assisted conception: a Cochrane Review. RBMOnline 2007; 14: 640-649. 
7
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.
8
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.
9
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.
10
Wadhwa M, Thorpe R. Unwanted immunogenicity: implications for follow-on biologicals. 
Drug Information Journal 2007; 41: 1-10.
11
Buur Rasmussen B, Mannaerts B, Klein BM, Helmgaard L, Arce J-C on behalf of the 
ESTHER-1 and ESTHER-2 trial group. Low immunogenicity potential of follitropin delta, a 
recombinant FSH preparation produced from a human cell line: Results from phase 3 trials 
(ESTHER-1 and ESTHER-2). Poster presented at the 32nd Annual Meeting of ESHRE; 
2016 Jul 3-6; Helsinki, Finland.
12
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Assessment Report for Elonva (corifollitropin alfa). EMA/CHMP/802299/2009. 


Date: 09 Dec 2020
E-Study Protocol-22707; Ver. 3.0
Supersedes: 2.0
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Solution for Injection
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Ferring Pharmaceuticals
CONFIDENTIAL
13
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.
14
Blake DA, Proctor M, Johnson NP. The merits of blastocyst versus cleavage stage embryo 
transfer: a Cochrane review. Hum Reprod 2004; 19: 795-807.
15
Papanikolaou EG, Kolibianakis EM, Tournaye H, Venetis CA, Fatemi H, Tarlatzis B, 
Devroey P. Live birth rates after transfer of equal number of blastocysts or cleavage-stage 
embryos in IVF. A systematic review and meta-analysis. Hum Reprod 2008; 23: 91-99.
16
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.
17
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.
18
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.
19
Rehman KS, Bukulmez O, Langley M, Carr BR, Nackley AC, Doody KM, Doody KJ. Late 
stages of embryo progression are a much better predictor of clinical pregnancy than early 
cleavage in intracytoplasmic sperm injection and in vitro fertilization cycles with blastocyst-
stage transfer. Fertil Steril 2007; 87: 1041-1052.
20
Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. 
Gonadotrophin-releasing hormone antagonists for assisted reproductive technology 
(Review). Cochrane Database Syst Rev 2016; 4: CD001750.
21
European Society of Human Reproduction and Embryology (ESHRE). ART fact sheet. 
https://www.eshre.eu/Guidelines/ART-fact-sheet_vFebr18_VG.pdf
Accessed on 29th May 2018.
22
American Society for Reproductive Medicine. Revised American Society for Reproductive 
Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67: 817-821.
23
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards 
reproductive certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th
world congress on in vitro fertilization and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388.
24
Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, 
Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The international glossary on 
infertility and fertility care. Hum Reprod 2017; 32: 1786-1801. 
25
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.


Date: 09 Dec 2020
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Solution for Injection
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26
World Medical Association Declaration of Helsinki. Ethical Principles for Medical
Research Involving Human Subjects. 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013.
27
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. Downloaded from www.ICMJE.org
on May 14th 2018.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Cover page for Statistical Analysis Plan 
 
 
Sponsor name 
Ferring Pharmaceuticals A/S 
NCT Number: 
NCT03809429 
Sponsor trial ID: 
000304 
Official title of trial: 
A randomised, controlled, open label, parallel group, 
multicentre trial comparing the efficacy and safety of 
individualised FE 999049 (follitropin delta) dosing, using 
a long GnRH agonist protocol and a GnRH antagonist 
protocol in women undergoing controlled ovarian 
stimulation 
Document Date:  
26 Jan 2022 
 
 
 
 
 


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Follitropin Delta, FE 999049
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
A randomised, controlled, open label, parallel group, multicentre trial comparing the efficacy 
and safety of individualised FE 999049 (follitropin delta) dosing, using a long GnRH agonist 
protocol and a GnRH antagonist protocol in women undergoing controlled ovarian 
stimulation
Trial 000304
Investigational 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:
3b
  Author:
     
  Date of issue:
     January 26, 2022
  Version:
     1.0
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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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1.0
See title page
First version
None


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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Review and Approval of Statistical Analysis Plan
Author (e-signed in REAL):  
             
Global Biometrics
Ferring Pharmaceuticals A/S
Reviewers (Review using PleaseReview and stored in LSAF):
                     
Global Biometrics
Ferring Pharmaceuticals A/S
Global Pharmacovigilance
Ferring Pharmaceuticals A/S
Medical Writing
Ferring Pharmaceuticals A/S
R&D, Therapeutic Area, Reproductive Health
Ferring Pharmaceuticals A/S
Global Biometrics
Ferring Pharmaceuticals A/S
Approval by (e-signed in REAL):
Global Biometrics
Ferring Pharmaceuticals A/S


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
1
List of abbreviations............................................................................................................................ 5
2
Introduction.......................................................................................................................................... 6
3
Trial Objectives and Endpoints.......................................................................................................... 6
3.1
Objectives ................................................................................................................................. 6
3.2
Endpoints .................................................................................................................................. 6
3.3
Post-trial Information................................................................................................................ 7
4
Trial design........................................................................................................................................... 8
4.1
Design Considerations .............................................................................................................. 9
4.2
Determination of Sample Size ................................................................................................ 10
5
Subject Disposition ............................................................................................................................ 11
6
Protocol Deviations............................................................................................................................ 11
7
Analysis sets........................................................................................................................................ 11
7.1
Full Analysis Set..................................................................................................................... 11
7.2
Safety Analysis Set ................................................................................................................. 11
8
Trial population ................................................................................................................................. 11
8.1
Demographics and Other Baseline Characteristics................................................................. 11
8.2
Medical History and Concomitant Medication....................................................................... 11
9
Treatment Compliance...................................................................................................................... 12
10
Efficacy ............................................................................................................................................... 13
10.1
General Considerations........................................................................................................... 13
10.2
Primary Endpoint.................................................................................................................... 13
10.3
Secondary Efficacy Endpoints................................................................................................ 15
11
Safety................................................................................................................................................... 18
11.1
OHSS ...................................................................................................................................... 18
11.2
Adverse Events ....................................................................................................................... 19
11.3
Technical Malfunctions of the Pre-filled Injection Pen .......................................................... 19
12
Post-trial Information........................................................................................................................ 19
13
Interim analyses................................................................................................................................. 20
14
Changes to the analyses described in the protocol.......................................................................... 20


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1
List of abbreviations
AMH
anti-Müllerian hormone
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ART
assisted reproductive technologies
ATC
Anatomical Therapeutic Chemical classification system
βhCG
beta unit of human chorionic gonadotropin
FAS
full analysis set
FSH
follicle-stimulating hormone
GnRH
gonadotropin-releasing hormone
hCG
human chorionic gonadotropin
ICSI
intracytoplasmic sperm injection
IMP
investigational medicinal product
IU
international units
LH
luteinising hormone
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
OHSS
ovarian hyperstimulation syndrome
SAE
serious adverse event
SAP 
statistical analysis plan
SOC
system organ class


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2
Introduction
This document describes the planned statistical analyses for Trial FE 999049 000304 and is based 
on the final protocol version 3.0 dated 09DEC2020. This document do not introduce any changes to 
the statistical analyses described in the protocol. Some details of the analyses are clarified and some 
additional analyses are introduced. 
The scope of the Statistical Analysis Plan (SAP) is the statistical analysis of data. It does not cover 
dataset content/structure or content and format of tables, listings, and figures. The latter is described 
with a similar level of detail as in the protocol. 
3
Trial Objectives and Endpoints
3.1
Objectives
Primary Objective

To evaluate the effect of individualised FE 999049 treatment on ovarian response in a 
long GnRH agonist protocol versus a GnRH antagonist protocol 
Secondary Objectives

To evaluate the effect of individualised FE 999049 treatment on other pharmacodynamic 
parameters in a long GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the effect of individualised FE 999049 treatment on pregnancy rates in a 
long GnRH agonist protocol versus a GnRH antagonist protocol

To evaluate the safety of individualised FE 999049 treatment in a long GnRH agonist 
protocol versus a GnRH antagonist protocol
3.2
Endpoints
Primary Endpoint

Number of oocytes retrieved 
Secondary Endpoints

Proportion of subjects with cycle cancellation due to poor ovarian response or excessive 
ovarian response 

Proportion of subjects with blastocyst transfer cancellation after oocyte retrieval due to 
(risk of) OHSS

Number and size of follicles on stimulation day 6 and end-of-stimulation

Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Number of metaphase II oocytes (only applicable for subjects where all oocytes are 
inseminated using ICSI) fertilisation rate as well as number and quality of embryos on
day 3 and blastocysts on day 5 after oocyte retrieval


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
Circulating concentrations of FSH, luteinising hormone (LH), estradiol, progesterone 
and inhibin B on stimulation day 6, end-of-stimulation and at oocyte retrieval

Total gonadotropin dose and number of stimulation days

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by 
number of blastocysts transferred)

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) 

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer)

Ongoing implantation rate (number of intrauterine viable fetuses 10-11 weeks after 
transfer divided by number of blastocysts transferred)

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) 

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Frequency and intensity of adverse events 

Technical malfunctions of the pre-filled injection pen
3.3
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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4
Trial design
This is a randomised, controlled, open label, parallel group, multicentre trial comparing the efficacy 
and safety of individualised FE 999049 dosing in first cycle patients aged 18-40 years undergoing 
controlled ovarian stimulation for IVF/ICSI following either a long GnRH agonist protocol or a 
GnRH antagonist protocol. The trial has been designed to describe potential differences in the mean 
number of oocytes retrieved with adequate precision. 
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. Randomisation may take place as soon as all eligibility criteria are met. 
Subjects will be randomised in a 1:1 ratio to controlled ovarian stimulation with FE 999049 in a 
long GnRH agonist protocol or to controlled ovarian stimulation with FE 999049 in a GnRH 
antagonist protocol. Randomisation will be stratified by centre and according to age (<35, 35-37 
and 38-40 years). The subject will be informed of treatment allocation and when to start treatment 
by the delegated trial staff.
Subjects randomised to treatment with FE 999049 in the long GnRH agonist protocol will start 
down-regulation with GnRH agonist (triptorelin acetate, GONAPEPTYL) 0.1 mg/day 
subcutaneously in the mid-luteal phase (i.e. cycle day 21-24) of their menstrual cycle. Ovarian 
stimulation with FE 999049 will start after 14 days (±1 day) if the subject has experienced 
withdrawal bleeding and down-regulation criteria are fulfilled. If down-regulation is confirmed and 
ovarian stimulation is initiated, treatment with GnRH agonist is continued throughout the 
stimulation period. If the subject has not experienced withdrawal bleeding after 14 days (±1 day), a 
urinary pregnancy test is to be performed. If the subject is not pregnant and down-regulation is not 
confirmed, treatment with GnRH agonist will be continued and stimulation will be postponed until 
down-regulation is confirmed. Subsequent visit(s) for confirmation of down-regulation will be 
scheduled according to local practice. If down-regulation is not achieved after 28 days, treatment 
with GnRH agonist will be stopped and the subject will be withdrawn from the trial. 
Subjects randomised to treatment with FE 999049 in the GnRH antagonist protocol will start 
stimulation with FE 999049 on day 2 or 3 of their menstrual cycle. To prevent a premature LH 
surge, a GnRH antagonist (cetrorelix acetate, CETROTIDE) 0.25 mg/day subcutaneously will be 
initiated on stimulation day 6 and continued throughout the stimulation period. 
Subjects will have their individual FE 999049 dose determined on the basis of their AMH level at 
screening and their body weight on stimulation day 1. The daily FE 999049 dose will be fixed 
throughout the stimulation period. For subjects with AMH <15 pmol/L the daily FE 999049 dose is 
12 μg, irrespective of body weight. For subjects with 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. AMH will be measured by Elecsys® AMH Plus Immunoassay (Roche Diagnostics). The 
maximum allowed daily FE 999049 dose is 12 µg. Subjects can be treated with FE 999049 for a 
maximum of 20 days, and coasting is not allowed. 


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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. 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, a single dose of 
hCG (OVITRELLE) 250 µg will be administered. If there are ≥25 follicles with a diameter 
≥12 mm, the cycle will 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.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF and/or ICSI. Fertilisation and embryo development will be 
assessed from oocyte retrieval to the day of transfer. For all subjects blastocyst transfer is 
performed on day 5 after oocyte retrieval. Subjects <38 years at randomisation will have single 
blastocyst transfer. Subjects ≥38 years at randomisation will have single blastocyst transfer if they 
have a good-quality blastocyst available, i.e. a blastocyst of grade 3BB or higher; otherwise they 
may have double blastocyst transfer. Remaining blastocysts may be cryopreserved and used by the 
subject after completion of the trial, in accordance with local guidelines and/or regulations. All 
procedures and assessments related to cryopreserved cycles will take place outside this protocol and 
will not be paid for by Ferring.
Vaginal progesterone tablets (LUTINUS) 100 mg three times daily will be provided for luteal phase 
support from the day after oocyte retrieval and until the serum βhCG test. Luteal phase support may 
be continued after a positive βhCG is obtained if this is local practice. A serum βhCG test is 
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 assessed at screening, stimulation day 1, stimulation day 6, end-of-stimulation and at oocyte 
retrieval. 
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 minor/major congenital anomalies, at birth and at 
4 weeks after birth. These data will be reported separately.
4.1
Design Considerations
The trial will be open label as a double–blind design is not feasible due to the required GnRH 
agonist treatment prior to start of stimulation in a long GnRH agonist protocol. In contrast, in a 
GnRH antagonist protocol, the GnRH antagonist is only started during the mid-follicular phase of 


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the stimulation period. Prior to start of stimulation in a long GnRH agonist protocol, down-
regulation needs to be confirmed based on ultrasound findings, thus neither patients nor the 
assessors in this trial can be blinded. The lack of blinding may result in different withdrawal 
patterns for the two protocols. To minimise this, only subjects without strong preference for one of 
the protocols will be included. No measures are taken to prevent investigators, delegated trial staff 
or subjects from knowing the treatment allocation. 
Subjects with an AMH level >35 pmol/L at screening will be excluded from the trial as these 
subjects are likely to have polycystic ovaries and may have an increased risk of OHSS. 
The primary endpoint of this trial will allow the comparison of distribution of the number of 
oocytes retrieved following each GnRH analogue protocol, and more specifically in subjects with 
low AMH (<15 pmol/L) and high AMH (≥15 pmol/L). Based on current knowledge about the 
difference in ovarian response following treatment with CHO-derived rFSH in either protocol an 
overall treatment difference of at least 1 oocyte is to be anticipated, the difference being smaller in 
subjects with low AMH than in subjects with high AMH. This treatment difference, especially in 
subjects with high AMH, will indicate whether the FE 999049 dosing algorithm remains safe and 
effective when applied in a GnRH agonist protocol. 
4.2
Determination of Sample Size
The purpose of this trial is to gain clinical experience with the use of FE 999049 when applied in a 
long GnRH agonist protocol. The trial is descriptive and does not include any hypothesis testing. 
The sample size is based on achieving a reasonable precision in the estimate of the difference in 
mean number of oocytes retrieved between treatment with FE 999049 in a long GnRH agonist 
protocol versus treatment with FE999049 in a GnRH antagonist protocol.
In the ESTHER-1 trial, the standard deviation for the number of oocytes retrieved was 5.8 in the 
FE 999049 treatment group. Due to a potentially higher number of oocytes retrieved in the long 
agonist protocol, the standard deviation in this trial may be slightly higher. Assuming a standard 
deviation of 7.0, a sample size of 400 subjects (200 subjects per group) will give a 95% CI that 
ranges from -1.4 to +1.4 of the observed mean difference, i.e. the interval from the observed mean 
difference -1.4 to the observed mean difference +1.4 will with 95% probability include the true 
mean difference. This is regarded to be reasonably precise for describing the comparability of 
individualised FE 999049 dosing using the two protocols.


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5
Subject Disposition
All subjects screened and randomised will be accounted for. All post-randomisation 
discontinuations will be summarised by time of, and reason for, discontinuation. Discontinuations 
will be classified as occurring before or after start of FE 999049 treatment. The number of subjects 
screened and not randomised will be presented.
6
Protocol Deviations
Important protocol deviations will be summarised and listed by subject. The impact of important 
protocol deviations on the trial results may be addressed in additional sensitivity analyses. 
7
Analysis sets
7.1
Full Analysis Set
The FAS will consist of all subjects that were randomised, regardless of whether they started 
FE 999049 treatment or not. However, subjects that discontinued before starting FE 999049 
treatment due to the COVID-19 pandemic (e.g. due to operational and/or societal issues) will be 
excluded from the FAS. In the analyses of efficacy endpoints subjects will be analysed according to 
the protocol to which they were randomised.
7.2
Safety Analysis Set 
The safety analysis set will consist of all subjects that were randomised in the trial and were 
exposed to FE 999049. In all presentation of safety data subjects will be presented according to the 
protocol they were actually treated with.
8
Trial population
8.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics (body measurements, 
infertility history, menstrual history, reproductive history, smoking and alcohol habits, physical 
examination, and gynaecological examination) will be presented for the FAS. In addition, a 
summary of demographic characteristics will be presented by trial site.
8.2
Medical History and Concomitant Medication 
Medical history and concomitant medication will be presented for the FAS. Medical history 
recorded at the screening visit will be coded using MedDRA and summarised. The version of 
MedDRA will be documented. 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)  


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
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)
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.
9
Treatment Compliance
Number of days with GnRH agonist and GnRH antagonist treatment will be summarised.
Compliance with progesterone treatment for luteal phase support will be summarised (number of 
days with treatment, completed according to instruction, number of tablets missed, and prematurely 
stopped due to menstrual bleeding).


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10
Efficacy
10.1
General Considerations
The primary objective of the trial is to evaluate the effect of individualised FE 999049 treatment on 
ovarian response in a long GnRH agonist protocol versus a GnRH antagonist protocol. The primary 
endpoint is the number of oocytes retrieved. 
The estimand of interest is the difference between FE 999049 treatment in the long GnRH agonist 
protocol versus treatment with FE 999049 in the GnRH antagonist protocol for all randomised 
subjects, assuming that all subjects start treatment with FE 999049. In the statistical analyses, 
subjects that discontinue after randomisation but before start of FE 999049 treatment (except for 
subjects that never started treatment due to the COVID-19 pandemic, which are not included in any 
analysis) will have their endpoint data imputed from subjects who started FE 999049 treatment in 
the same protocol, using a multiple imputation method. No imputation will be done for subjects 
who discontinue the trial after starting FE 999049 treatment. For these subjects, the actual data will 
be used and not be regarded as missing. Therefore, the number of oocytes retrieved will be regarded 
as zero and pregnancy outcomes will be regarded as negative.
The trial is descriptive and no formal hypothesis will be tested. The statistical analyses aims at 
estimating any potential differences between FE 999049 treatment when applied in the two 
different GnRH protocols. The results will generally be described as an estimated mean treatment 
difference or treatment ratio and an associated 95% confidence interval.
Since the trial is descriptive without any hypothesis testing, no corrections for multiplicity will be 
applied.
Analyses and descriptions for ovarian response endpoints and other pharmacodynamics endpoints 
will be based on the FAS. Analyses and descriptions for pregnancy endpoints will be based on the 
FAS but excluding subjects that had transfer cancellation due to the COVID-19 pandemic. 
Additional descriptions for pregnancy endpoints will be made based on the FAS (i.e. including also 
the subjects with transfer cancellation due to the COVID-19 pandemic). Analyses and descriptions 
of safety endpoints and exposure will be based on the safety analysis set.
Subjects in the FAS that did not start treatment with FE 999049 will not have any data after 
exposure to FE 999049. For these subjects, post-randomisation data will only be imputed for the 
purpose of statistical analysis, using multiple imputation techniques. In tables, figures and listings 
all post-randomisation data from these subjects will be missing. Therefore tables, figures and 
listings will be based on subjects in the FAS starting treatment with FE 999049, i.e. randomised and 
exposed subjects (i.e. same as the safety analysis set).
10.2
Primary Endpoint
The primary endpoint, number of oocytes retrieved, will be analysed using a negative binomial 
regression model with treatment (long GnRH agonist protocol or GnRH antagonist protocol), age 


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stratum (<35, 35-37, or 38-40 years), and AMH at screening (<15 pmol/L or ≥15 pmol/L) as 
factors. A logarithmic link function will be used for the mean in the model. From this model, the 
mean difference between the two protocols in number of oocytes retrieved will be estimated, and a 
95% CI for the estimate will be calculated using the delta method. The analyses will be done using 
the multiple imputation method described below. 
Age stratum is included as factor in the model since randomisation is stratified by age. AMH at 
screening is additionally included as a factor since AMH is known to influence the number of 
oocytes retrieved. Although randomisation is stratified by centre, centre and the interaction between 
centre and age stratum are not included in the model as all centres may not randomise subjects from 
all age strata, and therefore the inclusion of the interaction in the model is likely to give empty cells 
in the analysis. The potential influence of centre differences on the results will instead be 
investigated in a sensitivity analysis.
For subjects in the FAS who discontinue the trial after randomisation but before start of FE 999049 
treatment, the number of oocytes retrieved will be imputed from subjects who started FE 999049 
treatment in the same protocol, using the following multiple imputation method: 

First, a negative binomial regression model with age stratum and AMH at screening as factors 
will be fitted to data from subjects who started FE 999049 treatment for each protocol 
separately. 

In the second step, 1000 complete datasets will be constructed. For the construction of each 
complete dataset, a set of parameter values will be sampled from a normal distribution with 
characteristics determined by the estimated parameters and covariance matrix for the two 
models in the first step. Missing individual subject data will then be imputed from a negative 
binomial distribution with the sampled parameters. 

In the third step, each complete dataset will be analysed using the negative binomial regression 
model described in the first paragraph of this section. 

In the final step, the estimated mean differences and the standard deviations from the 1000 
analyses will be combined using Rubin’s formula:
Where mi and SDi are the estimated mean differences and standard deviations for the differences 
for the 1000 copies of the dataset (derived using the delta method), and mMI and SDMI are the 
pooled estimates.

The mean difference in number of oocytes retrieved between the long GnRH agonist protocol 
and the GnRH antagonist protocol will be estimated as mMI, and the 95% CI for the estimate 
will be calculated as mMI ± 1.96*SDMI.
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Date: January 26, 2022
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Follitropin Delta, FE 999049
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
The assumption underlying the above imputation procedure is that all randomised subjects could 
have started FE 999049 treatment, and that their outcome would not have differed in any systematic 
way from the subjects that started FE 999049 treatment.
For subjects who discontinue the trial after start of FE 999049 treatment but before oocyte retrieval 
the number of oocytes retrieved will be regarded as zero.
Supplementary analyses and descriptions for the Primary Endpoint
The primary analysis will be repeated based on subjects in FAS that started treatment with 
FE 999049, i.e. without using multiple imputations (this is the same as the safety analysis set).
The potential influence of centre differences on the results for the primary endpoint will be 
investigated by repeating the analyses of the 1000 complete datasets generated above, with the 
addition of centre and the interaction between centre and age strata as factors in the model. 
Additional analyses will be made for two subgroups based on AMH at screening (<15 pmol/L or 
≥15 pmol/L) and for the three age strata (<35, 35-37, or 38-40 years). These analyses will be based 
on the 1000 complete datasets used for the primary analyses and will use the same analysis model, 
except that age stratum will not be included as factor in the age strata analyses and AMH will not 
be included in the AMH subgroup analyses. The results of the subgroup analyses will be illustrated 
in a forest plot.
The distribution of number of oocytes retrieved will be described using the empirical distribution 
and approximated using kernel estimates.
10.3
Secondary Efficacy Endpoints
Proportion of Subjects with Cycle Cancellation due to Poor Ovarian Response or Excessive 
Ovarian Response
The proportion of subjects with cycle cancellation due to poor ovarian response or excessive 
ovarian response will be described. Additional descriptions will be made for the two subgroups 
based on AMH at screening (<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, 
or 38-40 years).
Proportion of Subjects with Blastocyst Transfer Cancellation after Oocyte Retrieval due to 
(Risk of) OHSS
The proportion of subjects with transfer cancellation after oocyte retrieval due to (risk of) OHSS 
will be described. Additional descriptions will be made for the two subgroups based on AMH at 
screening (<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, or 38-40 years).


Date: January 26, 2022
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Follitropin Delta, FE 999049
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Number and Size of Follicles on Stimulation Day 6 and End-of-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). 
The mean number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and ≥17 mm at end-of-
stimulation will (in separate analyses) be compared between the long GnRH agonist protocol and 
the GnRH antagonist protocol using the same negative binomial regression model as used for the 
primary endpoint. The analysis will only include subjects in the FAS that started treatment with FE 
999049, i.e. multiple imputations will not be used (this is the same as using the safety analysis set).
Proportion of Subjects with <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
The percentage of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved will be described in 
histograms. Additional descriptions will be made for the two subgroups based on AMH at 
screening (<15 pmol/L or ≥15 pmol/L) and for the three age strata (<35, 35-37, or 38-40 years).
Number of Metaphase II Oocytes
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The total 
number of metaphase II oocytes will be compared between the long GnRH agonist protocol and the 
GnRH antagonist protocol using the same analysis method as for the primary endpoint. This 
analysis will be based on subjects that had all their oocytes inseminated using ICSI. No imputation 
will be done for subjects having their oocytes inseminated by IVF, or a combination of IVF and 
ICSI, and consequently no imputation will be done for subjects not starting treatment with FE 
999049. Therefore, multiple imputations will not be used and the analysis will be based on subjects 
in FAS that had all their oocytes inseminated using ICSI (this is the same as subjects in the safety 
analysis set that had all their oocytes inseminated using ICSI).
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei on day 1 after oocyte retrieval. The 
total number of fertilised oocytes will be compared between the long GnRH agonist protocol and 
the GnRH antagonist protocol using the same analysis method as for the primary endpoint. The 
proportion of oocytes becoming fertilised will be summarised by treatment.
Number and Quality of Embryos on Day 3 after Oocyte Retrieval
The number and the quality of embryos on day 3 will be described. The number of embryos and the 
number of good-quality embryos will be compared between the long GnRH agonist protocol and 
the GnRH antagonist protocol using the same analysis method as for the primary endpoint. A good-
quality embryo is defined as an embryo with ≥6 blastomeres and  ≤25% fragmentation, or with 
embryo stage classified as compacting/compacted. 


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Follitropin Delta, FE 999049
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Number and Quality of Blastocysts on Day 5 after Oocyte Retrieval
The number and the quality of blastocysts on day 5 will be described, as well as the quality and 
number of blastocysts transferred.
The number of blastocysts and the number of good-quality blastocysts (grade 3BB or higher) will 
be compared between treatments using the same analysis method as for the primary endpoint.
Circulating Concentrations of FSH, LH, Estradiol, Progesterone and Inhibin B on 
Stimulation Day 6, End-of-stimulation and at Oocyte Retrieval
For each parameter, the concentrations on stimulation day 6, end-of-stimulation, and at oocyte 
retrieval will be described and compared for the long GnRH agonist protocol versus the GnRH 
antagonist protocol using analysis of variance models with treatment, age stratum, and AMH at 
screening (<15 pmol/L or ≥15 pmol/L) as factors. Multiplicative models will be used, i.e. the 
concentrations will be log-transformed before analysis. The results of the analyses will be back-
transformed and presented as estimated geometric means for each parameter, and the mean ratios 
for long GnRH agonist protocol versus GnRH antagonist protocol with 95% confidence intervals. 
The analyses will be based on subjects in the FAS starting treatment with FE 999049, i.e. multiple 
imputations will not be used (this is the same as using the safety analysis set). Values below the 
lower limit of quantification (LLOQ) will be estimated with LLOQ/2.
Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose and the number of stimulation days will be described for each of the 
two protocols and for subgroups based on age strata and AMH at screening.
Number of stimulation days, total dose, and the average daily dose will be compared between long 
GnRH agonist protocol and the GnRH antagonist protocol using an analysis of variance model with 
treatment, age stratum, and AMH at screening (<15 pmol/L or ≥15 pmol/L) as factors. This analysis 
will be based on subjects in the FAS that started treatment with FE 999049, i.e. multiple 
imputations will not be used (this is the same as using the safety analysis set).
Pregnancy Rates
The percentage of subjects with positive βhCG, clinical pregnancy, vital pregnancy, and ongoing 
pregnancy will be described for each of the two protocols and for subgroups based on age strata and 
AMH. Pregnancy rates will be compared between the long GnRH agonist protocol and the GnRH 
antagonist protocol using a logistic regression model with treatment (long GnRH agonist or GnRH 
antagonist), age stratum (<35, 35-37, or 38-40 years), and AMH at screening (<15 pmol/L or 
≥15 pmol/L) as factors. The results of this analysis (in terms of odds for pregnancy) will be 
converted into proportions, differences in proportions, and 95% CIs for differences in proportions 
using the delta method.


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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
To account for subjects withdrawing from the trial before starting FE 999049 treatment, the 
multiple imputation method applied for the primary endpoint will be used, using a logistic 
regression model instead of a negative binomial regression model. Pregnancy data for subjects with 
pregnancies occurring before start of FE 999049 treatment will not be included in the analysis. 
These subjects are withdrawn and their data will be imputed.
Missing pregnancy assessments will be assumed to indicate a negative test. If, however, a 
subsequent test is positive, a previous missing assessment will be considered as positive (if e.g. the 
clinical pregnancy assessment is missing but the ongoing pregnancy assessment is positive, the 
missing clinical pregnancy assessment will be regarded as positive).
The main analyses of pregnancy rates will be based on subjects in the FAS, but excluding subjects 
that had transfer cancellation due to the COVID-19 pandemic. Additional analyses will be made for 
the FAS, and also for subjects in the FAS that started treatment with FE 999049, i.e. without using 
multiple imputations (i.e. the safety analysis set).
Implantation Rates
The implantation rate will be calculated as the number of gestational sacs 5-6 weeks after transfer 
divided by the number of blastocysts transferred. 
Ongoing implantation rate will be calculated as the number of intrauterine viable fetuses 
10-11 weeks after transfer divided by the number of blastocysts transferred. 
The implantation rate and the ongoing implantation rate will be described for each of the two 
protocols and for subgroups based on age strata and AMH at screening.
11
Safety
11.1
OHSS
Proportion of Subjects with Early OHSS (including OHSS of Moderate/Severe grade) 
Incidence of early OHSS will be tabulated by classification (mild, moderate, severe, moderate or 
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 this includes OHSS with onset before triggering and OHSS with 
onset during stimulation where triggering is not performed.
Proportion of Subjects with Late OHSS (including OHSS of Moderate/Severe grade) 
Incidence of late OHSS will be tabulated by classification (mild, moderate, severe, moderate and 
severe) and grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days after triggering 
of final follicular maturation.


Date: January 26, 2022
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Follitropin Delta, FE 999049
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Proportion of Subjects with Any OHSS (including OHSS of Moderate/Severe grade) Incidence 
of any OHSS will be tabulated by classification (mild, moderate, severe, moderate and severe) and 
grade (1, 2, 3, 4, 5). 
11.2
Adverse Events
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events will be grouped according to start of FE 999049 as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent and 
before start of FE 999049 treatment, or a pre-existing medical condition that worsens in 
intensity after signed informed consent but before start of FE 999049 treatment.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of FE 999049 
treatment 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 FE 999049 treatment and before the 
end-of-trial visit.
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only. Treatment-emergent adverse events will be 
summarised overall and tabulated by System Organ Class (SOC) and PT in decreasing order of 
frequency. The total number of subjects reporting an adverse event, the percentage of subjects with 
an adverse event, and the number of events reported will be presented.
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 reactionsI 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.
11.3
Technical Malfunctions of the Pre-filled Injection Pen
The frequency of technical malfunctions of the administration pen will be tabulated and all 
technical malfunctions will be listed.
12
Post-trial Information
Live birth rate and neonatal health, including minor / major congenital anomalies, at birth and at 
4 weeks after birth will be described. These data will be reported separately. Live birth and live at 4 
weeks status will be analysed using the same method as for pregnancy endpoints.
                                                
I An adverse reaction is defined as an adverse event with reasonable possible causal relationship to IMP


Date: January 26, 2022
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Statistical Analysis Plan
Ferring Pharmaceuticals
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13
Interim analyses
No interim analysis is planned.
14
Changes to the analyses described in the protocol
This SAP does not introduce any changes to the analyses already described in the trial protocol. A 
few additional details and clarifications have been added, and a few additional analyses have been 
added. These include the following: 

Addition of supplementary analyses based on subjects in the FAS starting treatment with 
FE 999049, i.e. analyses without the use of multiple imputations (this is the same as 
using the safety analysis set).

Clarification that the analysis of number of MII oocytes will be based on subjects that 
had all their oocytes inseminated using ICSI, and subsequently multiple imputations will 
not be used.

Addition of analyses for number of follicles, embryos, number of good-quality embryos, 
and number of blastocysts.

Addition of analyses for number of stimulation days, total dose, and the average daily 
dose of FE 999049 treatment.