Conditions: Infertility
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 302
Healthy volunteers: no

Brief summary:
Hormone preparations like REKOVELLE and GONAL-F are used to make the body produce multiple egg sacs, allowing more eggs to be collected from women undergoing infertility treatment.

The main purpose of this trial is to see how many eggs are produced with a starting dose of 15 µg REKOVELLE compared to a starting dose of 225 IU GONAL-F. This research is intended to provide more knowledge about REKOVELLE, including the doses given in the trial.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: REKOVELLE (Follitropin Delta) intervention 2: GONAL-F (Follitropin Alfa)
Intervention descriptions: intervention 1: REKOVELLE administered as single daily subcutaneous injections in the abdomen. The starting dose of REKOVELLE was 15 μg fixed for the first four stimulation days. Dose adjustments could be implemented on the day of starting the gonadotropin-releasing hormone (GnRH) antagonist (stimulation day 5 or day 6) or later, could occur no more frequently than every second day. At each dose adjustment, the daily REKOVELLE dose could be increased or decreased by 5 μg based on the participant's response. The minimum REKOVELLE dose was 5 μg and the maximum REKOVELLE was 20 μg. Participants could be treated for a maximum of 20 days. intervention 2: GONAL-F administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F was 225 IU fixed for the first four stimulation days. Dose adjustments could be implemented on the day of starting the GnRH antagonist (stimulation day 5 or day 6) or later, could occur no more frequently than every second day. At each dose adjustment, the daily GONAL-F dose could be adjusted by 75 IU based on the participant's response. The minimum GONAL-F dose was 75 IU and the maximum GONAL-F dose was 300 IU. Participants could be treated for a maximum of 20 days.

Protocol document:
Prot_SAP_000.pdf: 
For Internal Use - Internal
Cover page for protocol
Sponsor Name
Ferring Pharmaceuticals A/S
NCT Number
NCT05263388
Sponsor Trial ID:
000401
OƯicial Title of Study
A randomised, controlled, assessor-
blind, parallel groups, multicentre,
multinational trial comparing 
the
ovarian response of a starting dose of
15 µg follitropin delta (REKOVELLE) to
a starting dose of 225 IU follitropin alfa
(GONAL-F) in conventional regimens
in controlled ovarian stimulation in
women 
undergoing 
an 
assisted
reproductive technology programme
Document Date
26 April 2024


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CONFIDENTIAL
Follitropin Delta, FE 999049
Trial Code:  000401
Solution for Injection
Clinical Trial Protocol
CLINICAL TRIAL PROTOCOL
A randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial 
comparing the ovarian response of a starting dose of 15 µg follitropin delta (REKOVELLE) 
to a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional regimens in controlled 
ovarian stimulation in women undergoing an assisted reproductive technology programme
Trial 000401 
ADAPT-1
(Assessment of Conventional Dosing in Women undergoing ART 
with Follitropin Delta Treatment)
EudraCT Number:
2021-001785-38
UTN Number:
U1111-1267-1119
Investigational Medicinal Product:
Follitropin delta (REKOVELLE)
(Ferring compound ID: FE 999049)
human recombinant follicle-stimulating hormone (rFSH)
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
Superseded Version
1.0
Name and Address of Sponsor:
Ferring Pharmaceuticals A/S
Kay Fiskers Plads 11,
2300 Copenhagen S, Denmark
Tel: (+45) 88 33 88 34
From 01 Feb 2022: Amager Strandvej 405, 
2770 Kastrup, Denmark
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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Clinical Trial Protocol
SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial 
comparing the ovarian response of a starting dose of 15 µg follitropin delta (REKOVELLE) to a 
starting dose of 225 IU follitropin alfa (GONAL-F) in conventional regimens in controlled 
ovarian stimulation in women undergoing an assisted reproductive technology programme
SIGNATORY INVESTIGATOR(S)
TBD
TRIAL SITES
Approximately 15-20 sites in 3-6 European countries 
PLANNED TRIAL PERIOD
First patient first visit (FPFV):
Q2 2022
Last patient last visit (LPLV) / end-of-trial:
Q3 2023
Follow-up period (first transfer cycle) completed: Q1 2024
CLINICAL PHASE
3b
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE 
TRIAL
Follitropin delta (REKOVELLE) is a novel recombinant human follicle-stimulating hormone 
(rFSH) derived from a human cell line (PER.C6®). It is intended for the development of multiple 
follicles during controlled ovarian stimulation (COS) in women undergoing assisted reproductive 
technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle. The first Marketing Authorisation approval was obtained by the European 
Commission in December 2016, and as of 01 May 2021 REKOVELLE is approved in 
69 countries and regions worldwide. 
The currently approved REKOVELLE dosing regimen is based on each woman’s serum anti-
Müllerian hormone (AMH) concentration and her body weight, and is a fixed-dose regimen with 
the daily dose maintained throughout the stimulation period. The approved maximum daily dose 
of REKOVELLE is 12 µg for the first treatment cycle and 24 µg in subsequent treatment cycles. 
Other approved rFSH preparations, such as follitropin alfa (GONAL-F) and follitropin beta 
(PUREGON/FOLLISTIM), apply a conventional dosing approach with a starting dose of 
150-225 IU, fixed for the initial days of stimulation, followed by the possibility for subsequent 
dose adjustments, with a maximum daily dose of 450 IU. 


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Clinical Trial Protocol
The present trial will explore the use of REKOVELLE in a conventional dosing approach; i.e. a 
standard starting dose fixed for the initial days of stimulation, followed by the possibility for 
subsequent dose adjustments. Based on clinical trial data from more than 1,500 patients, it has 
been possible to establish the daily REKOVELLE dose that provides a comparable ovarian 
response (i.e. number of oocytes retrieved and number of follicles ≥12 mm and serum estradiol at 
end of stimulation) as 150 IU/day GONAL-F. These clinical trial data suggest that a daily dose of 
10.0 [95% CI 9.2; 10.8] µg REKOVELLE provides an ovarian response equal to that obtained 
with 150 IU GONAL-F. Applying this dose equivalence factor, it is extrapolated that 15 µg/day 
REKOVELLE will provide an ovarian response comparable to that obtained with 225 IU/day 
GONAL-F.
OBJECTIVES
Primary Objective

To compare a starting dose of 15 µg REKOVELLE to a starting dose of 225 IU 
GONAL-F in conventional regimens with respect to ovarian response in women 
undergoing controlled ovarian stimulation
Secondary Objectives

To compare the follicular development, endocrine profile and embryo development 
associated with conventional dosing of REKOVELLE and GONAL-F

To compare the treatment efficiency associated with conventional dosing of 
REKOVELLE and GONAL-F

To compare the safety profile associated with conventional dosing of REKOVELLE and 
GONAL-F
ENDPOINTS
Primary Endpoint

Number of oocytes retrieved 
Secondary Endpoints

Number of follicles (total and by size category) at end-of-stimulation

Serum concentrations of estradiol and progesterone at end-of-stimulation

Number of fertilised oocytes and fertilisation rate

Number of blastocysts (total and by quality) 

Total gonadotropin dose and number of stimulation days


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Clinical Trial Protocol

Early OHSS (overall and by grade) and/or preventive interventions for early OHSS
Exploratory Assessment

Blood sample on stimulation day 1 for potential future analysis of possible biomarkers 
associated with ovarian response (requires additional, optional consent)
Follow-up Assessments

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) in the first 
transfer cycle 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number 
of blastocysts transferred) in the first transfer cycle
Note: the first transfer cycle covers cycles with transfer occurring within 3 months after start of 
stimulation
METHODOLOGY
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, multinational 
trial comparing the ovarian response associated with a starting dose of 15 µg follitropin delta 
(REKOVELLE) and a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional 
regimens. The primary endpoint is the number of oocytes retrieved, and secondary endpoints 
include pharmacodynamic parameters of FSH action as well as efficacy and safety parameters 
related to controlled ovarian stimulation. Treatment efficiency in terms of gonadotropin use and 
duration of stimulation will also be evaluated. The assessor-blind design ensures that the 
investigators and other assessors such as embryologists are blinded to individual treatment 
allocation. A trial medication delegate will be responsible for all trial medication related issues, 
both practically at the clinic and in interactions with the subject.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 2:1 
ratio to treatment with either REKOVELLE or GONAL-F, and stimulation will be initiated. 
Subjects randomised to REKOVELLE will receive a daily starting dose of 15 µg which will be 
fixed for at least the first four stimulation days. Dose adjustments may be implemented on the 
day of starting the gonadotropin-releasing hormone (GnRH) antagonist (stimulation day 5 or 
day 6) or later, and can occur no more frequently than once every second day. At each dose 
adjustment, the daily REKOVELLE dose can be increased or decreased by 5 µg based on the 
subject’s response. The minimum REKOVELLE dose is 5 µg and the maximum REKOVELLE 
dose is 20 µg. Subjects randomised to GONAL-F will receive a daily starting dose of 225 IU 
which will be fixed for at least the first four stimulation days. Dose adjustments may be 
implemented on the day of starting the GnRH antagonist (stimulation day 5 or day 6) or later, and 


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Clinical Trial Protocol
can occur no more frequently than once every second day. At each dose adjustment, the daily 
GONAL-F dose may be adjusted by 75 IU based on the subject’s response. The minimum 
GONAL-F dose is 75 IU and the maximum GONAL-F dose is 300 IU. Subjects can be treated 
with rFSH for a maximum of 20 days, and coasting is not allowed. 
To prevent a premature luteinising hormone (LH) surge, a GnRH antagonist (ganirelix acetate, 
FYREMADEL, SUN Pharma) will be initiated on stimulation day 5 or day 6 at a daily dose of 
0.25 mg and continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥3 follicles with a diameter ≥17 mm are observed (i.e. on the 
day or the day after). Triggering can also be done in case 1 or 2 follicles with a diameter ≥17 mm 
are observed and the investigator judges that ≥3 follicles with a diameter ≥17 mm cannot be 
reached, and that triggering is preferred instead of cycle cancellation. The triggering drug will be 
either human chorionic gonadotropin (hCG) or GnRH agonist, depending on the extent of ovarian 
response and whether transfer in the fresh cycle or in a subsequent frozen cycle (including a 
freeze-all approach) is intended. If transfer in the fresh cycle is intended, 250 µg hCG
(choriogonadotropin alfa, OVITRELLE, Merck) will be administered. If there are ≥25 follicles 
with a diameter ≥12 mm or the serum estradiol is ≥5,000 pg/mL (18,355 pmol/L) (local 
laboratory) or a freeze-all approach is intended, 0.2 mg GnRH agonist (triptorelin acetate, 
GONAPEPTYL, Ferring) will be administered. Moreover, if these criteria for triggering with 
GnRH agonist are not met, but the investigator judges that the subject is at risk of developing 
early ovarian hyperstimulation syndrome (OHSS) and that triggering with hCG is not advisable, 
the subject can undergo triggering with GnRH agonist. In case of poor ovarian response, defined 
as the investigator judging that the triggering criterion cannot be reached by day 20, the cycle is 
to be cancelled. In case of excessive ovarian response, defined as the investigator judging that 
triggering of final follicular maturation is not advisable due to safety concerns, the cycle is to be 
cancelled. The number and size of follicles at the end-of-stimulation will be recorded.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation. All 
oocytes from follicles with an estimated diameter ≥12 mm must be retrieved. The oocytes can be 
inseminated by IVF and/or ICSI. Fertilisation will be assessed on day 1 after oocyte retrieval. The 
number and quality of blastocysts will be assessed at the last day of culture, i.e. day 5 or day 6 (as 
applicable) after oocyte retrieval. The day 5 / day 6 blastocyst quality assessment will be based 
on the Gardner & Schoolcraft blastocyst scoring system. Blastocysts that are not transferred in 
the fresh cycle will be cryopreserved in accordance with local guidelines and/or regulations. 
Blood samples will be collected at stimulation day 1 for measurement of AMH, estradiol and 
progesterone as well as at end-of-stimulation for measurement of estradiol and progesterone. For 
subjects who provide additional, optional consent, blood samples will be collected at stimulation 
day 1 for potential future analysis of possible biomarkers associated with ovarian response.
For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take 
place 9-14 days after triggering to cover the assessment of early OHSS (onset ≤9 days after 


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Clinical Trial Protocol
triggering). For subjects who do not undergo triggering of final follicular maturation, the end-of-
trial assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a 
separate end-of-trial visit within 7 days of the last scheduled trial visit).
If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule).
Follow-up Period
Follow-up information will be collected from the subject’s first transfer cycle, irrespective of 
whether the first transfer takes place in a fresh or frozen cycle. This follow-up covers cycles with 
the transfer procedure occurring within 3 months after start of stimulation. 
Depending on blastocyst availability, it is expected that subjects who underwent triggering of 
final follicular maturation with hCG will undergo transfer on day 5 after oocyte retrieval and that 
subjects who underwent triggering of final follicular maturation with GnRH agonist will undergo 
transfer in a frozen cycle using blastocysts cryopreserved on day 5 or day 6 after oocyte retrieval. 
The number of transferred blastocyst(s) in the first fresh or frozen cycle will be based on the 
subject’s wishes and the investigator’s recommendation and in accordance with local guidelines 
and/or regulations. The number and quality of transferred blastocyst(s) will be recorded. Luteal 
phase support in fresh and frozen cycles as well as potential other medicinal products for 
programming of frozen cycles will be in accordance with the site’s clinical practice.
Clinical pregnancy in the first transfer cycle will be assessed by transvaginal ultrasound 
5-6 weeks (35-48 days) after transfer, and the number of gestational sacs will be recorded. For 
subjects who undergo transfer in the fresh cycle, assessment of late OHSS (onset >9 days after 
triggering) will take place during the follow-up period.
NUMBER OF SUBJECTS
The total number of subjects to be randomised is approximately 300, i.e. 200 randomised to 
treatment with REKOVELLE and 100 randomised to treatment with GONAL-F. 
CRITERIA FOR INCLUSION / EXCLUSION
Inclusion Criteria
1. Informed Consent Form signed prior to screening evaluations.
2. In good physical and mental health.
3. Pre-menopausal females between the ages of 18 and 40 years. The subjects must be at 
least 18 years (including the 18th birthday) when they sign the informed consent and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.


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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 ≤37 years or for at least 
6 months for subjects ≥38 years (not applicable in case of tubal or severe male factor 
infertility).
6. Regular menstrual cycles of 21-35 days (both inclusive), presumed to be ovulatory.
7. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm, and 
no enlarged ovaries or ovarian cyst not due to polycystic ovarian syndrome, 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.
8. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
Exclusion Criteria
1. Primary ovarian failure.
2. Known endometriosis stage III-IV.
3. Considered unsuitable for controlled ovarian stimulation with a dosing regimen 
corresponding to approximately 225 IU/day gonadotropin, as judged by the investigator.
4. History of previous episode of OHSS or exuberant ovarian response to gonadotropins, and 
polycystic ovarian syndrome.
5. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
6. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) which can compromise participation in the trial with the exception of controlled 
thyroid function disease.
7. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus 
which would contraindicate the use of gonadotropins.
8. Fibroid tumours of the uterus incompatible with pregnancy.
9. Currently breast-feeding.
10. Undiagnosed vaginal bleeding.
11. 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.


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12. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior 
to randomisation) or contraindication to pregnancy.
13. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA) or cycle programming with oral contraceptives, 
progestogen or estrogen preparations.
14. Hypersensitivity to any active ingredient or excipients in the medicinal products used in 
the trial.
15. Previous participation in the trial.
16. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
MEDICINAL PRODUCTS
Investigational Medicinal Product
Name
Active ingredient,
pharmaceutical dosage 
form and concentration
Daily dose
REKOVELLE
Follitropin delta, solution 
for subcutaneous 
injection, 72 µg FSH in 
2.16 mL.
Daily starting dose of 15 µg fixed for at least the first 
four stimulation days. Dose adjustments may be 
implemented on the day of starting the GnRH 
antagonist (stimulation day 5 or day 6) or later, and can 
occur no more frequently than once every second day. 
At each dose adjustment, the daily REKOVELLE dose 
can be increased or decreased by 5 µg based on the 
subject’s response. The minimum REKOVELLE dose 
is 5 µg and the maximum REKOVELLE dose is 20 µg.
GONAL-F
Follitropin alfa, solution 
for subcutaneous 
injection, 900 IU FSH in 
1.5 mL.
Daily starting dose of 225 IU fixed for at least the first 
four stimulation days. Dose adjustments may be 
implemented on the day of starting the GnRH 
antagonist (stimulation day 5 or day 6) or later, and can 
occur no more frequently than once every second day. 
At each dose adjustment, the daily GONAL-F dose 
may be adjusted by 75 IU based on the subject’s
response. The minimum GONAL-F dose is 75 IU and 
the maximum GONAL-F dose is 300 IU.


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Concomitant Fertility Medication
The non-investigational medicinal products mentioned below are used as concomitant fertility 
medication during the trial and will be provided by Ferring. 
Name
Drug type
Active ingredient and route 
of administration 
Dose
FYREMADEL 
GnRH antagonist
Ganirelix acetate, 
subcutaneous injection
0.25 mg, daily dose
OVITRELLE 
hCG
Choriogonadotropin alfa, 
subcutaneous injection
250 µg, single dose
GONAPEPTYL
GnRH agonist
Triptorelin acetate, 
subcutaneous injection
2 x 0.1 mg, single dose
DURATION OF TREATMENT
Subjects can be treated with REKOVELLE or GONAL-F for a maximum of 20 days.
STATISTICAL METHODS
Sample Size Justification
In a previous trial (MERIT), 347 subjects aged 22-37 years were treated with a starting dose of 
225 IU GONAL-F. In these subjects the mean number of oocytes retrieved was 11.8 and the 
standard deviation was 5.7. Assuming that the standard deviation for number of oocytes retrieved 
in this trial will be 6.0, a total sample size of 300 with a 2:1 randomisation will give a 2-sided 
95% confidence interval ranging from -1.44 to +1.44 oocytes from the observed difference. This 
level of precision is considered as sufficient and is also more precise than the equivalence limits 
of ±3 oocytes that has been applied in previous trials comparing biosimilar FSH compounds.
Primary Analysis
All efficacy analyses will be based on the full analysis set (FAS), including all randomised and 
exposed subjects. The primary endpoint, number of oocytes retrieved, will be compared between 
REKOVELLE and GONAL-F using a negative binomial model with treatment and AMH level at 
stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as factors. The absolute 
treatment difference in number of oocytes retrieved and the associated 2-sided 95% confidence 
interval will be derived from the model estimates using the delta method.
The treatment difference will also be investigated for the two sub-groups AMH <15 pmol/L and 
AMH ≥15 pmol/L using the same methods as above.


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TABLE OF CONTENTS
SYNOPSIS .......................................................................................................................................................2
LIST OF TABLES ........................................................................................................................................14
LIST OF FIGURES ......................................................................................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................15
1
INTRODUCTION..............................................................................................................................17
1.1
Background .............................................................................................................................17
1.2
Scientific Justification for Conducting the Trial .....................................................................17
1.3
Benefit / Risk Aspects .............................................................................................................17
2
TRIAL OBJECTIVES AND ENDPOINTS.....................................................................................20
2.1
Objectives................................................................................................................................20
2.2
Endpoints.................................................................................................................................20
3
INVESTIGATIONAL PLAN............................................................................................................22
3.1
Overall Trial Design................................................................................................................22
3.1.1
Trial Design Diagrams ...............................................................................................22
3.1.2
Overall Design and Control Methods.........................................................................23
3.1.3
Trial Schedule.............................................................................................................25
3.2
Planned Number of Trial Sites and Subjects...........................................................................25
3.3
Interim Analysis ......................................................................................................................25
3.4
Data Monitoring Committee....................................................................................................26
3.5
Discussion of Overall Trial Design and Choice of Control Groups........................................26
3.5.1
Trial Design................................................................................................................26
3.5.2
Selection of Endpoints................................................................................................26
3.5.3
Blinding......................................................................................................................27
3.5.4
Selection of Doses in the Trial ...................................................................................28
3.5.5
Selection of the Trial Population................................................................................28
3.5.6
Follow-up Procedures.................................................................................................28
4
SELECTION OF TRIAL POPULATION.......................................................................................30
4.1
Trial Population.......................................................................................................................30
4.1.1
Inclusion Criteria........................................................................................................30
4.1.2
Exclusion Criteria.......................................................................................................30
4.2
Method of Assigning Subjects to Treatment Groups ..............................................................31
4.2.1
Recruitment ................................................................................................................31
4.2.2
Randomisation............................................................................................................32
4.3
Restrictions..............................................................................................................................32
4.3.1
Prior and Concomitant Therapies...............................................................................32
4.3.2
Prohibited Therapy.....................................................................................................32
4.3.3
Withdrawal Criteria....................................................................................................32
4.4
Subject Replacement ...............................................................................................................33
4.5
Trial Stopping Criteria.............................................................................................................33
5
TREATMENTS..................................................................................................................................34
5.1
Treatments Administered ........................................................................................................34
5.1.1
Investigational Medicinal Products............................................................................34


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5.1.2
Non-investigational Medicinal Products....................................................................35
5.2
Characteristics and Source of Supply......................................................................................36
5.3
Packaging and Labelling .........................................................................................................37
5.4
Conditions for Storage and Use...............................................................................................37
5.5
Blinding / Unblinding..............................................................................................................38
5.5.1
Blinding......................................................................................................................38
5.5.2
Unblinding of Individual Subject Treatment..............................................................38
5.6
Treatment Compliance, Dispensing and Accountability.........................................................39
5.7
Auxiliary Supplies...................................................................................................................39
5.8
Return and Destruction of Medicinal Products .......................................................................39
6
TRIAL PROCEDURES.....................................................................................................................40
6.1
Screening.................................................................................................................................40
6.2
Stimulation ..............................................................................................................................41
6.2.1
Start of Stimulation – Day 1.......................................................................................41
6.2.2
Start of GnRH Antagonist – Day 5 or Day 6..............................................................42
6.2.3
End-of-stimulation......................................................................................................43
6.3
Oocyte Retrieval......................................................................................................................44
6.4
Oocyte / Blastocyst Evaluation ...............................................................................................45
6.5
End-of-trial..............................................................................................................................46
6.6
Follow-up Assessments...........................................................................................................46
6.6.1
Transfer ......................................................................................................................47
6.6.2
Clinical Pregnancy .....................................................................................................47
6.6.3
Late OHSS..................................................................................................................48
7
TRIAL ASSESSMENTS....................................................................................................................49
7.1
Assessments Related to Primary Endpoint..............................................................................49
7.1.1
Number of Oocytes Retrieved....................................................................................49
7.2
Assessments Related to Secondary Endpoints ........................................................................49
7.2.1
Number of Follicles (Total and by Size Category) at End-of-stimulation .................49
7.2.2
Serum Concentrations of Estradiol and Progesterone at End-of-stimulation.............49
7.2.3
Number of Fertilised Oocytes and Fertilisation Rate.................................................49
7.2.4
Number of Blastocysts (Total and by Quality)...........................................................49
7.2.5
Total Gonadotropin Dose and Number of Stimulation Days .....................................50
7.2.6
Early OHSS (Overall and by Grade) and/or Preventive Interventions for Early 
OHSS..........................................................................................................................51
7.3
Exploratory Assessment..........................................................................................................51
7.3.1
Blood Collection for Potential Biomarkers................................................................51
7.4
Other Assessments ..................................................................................................................51
7.4.1
Demographics.............................................................................................................51
7.4.2
Medical History..........................................................................................................51
7.4.3
Infertility History........................................................................................................51
7.4.4
Body Measurements...................................................................................................52
7.4.5
Physical Examination.................................................................................................52
7.4.6
Gynaecological Examination .....................................................................................52
7.4.7
Concomitant Medication............................................................................................52
7.4.8
Drug Dispensing and Accountability .........................................................................53
7.5
Assessments Related to Follow-up Information......................................................................53


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7.6
Handling of Biological Samples..............................................................................................53
7.7
Implications of COVID-19 Pandemic.....................................................................................54
8
ADVERSE EVENTS..........................................................................................................................55
8.1
Adverse Event Definition........................................................................................................55
8.2
Collection and Recording of Adverse Events..........................................................................55
8.2.1
Collection of Adverse Events.....................................................................................55
8.2.2
Recording of Adverse Events.....................................................................................56
8.3
Adverse Events of Special Interest..........................................................................................59
8.4
Ovarian Hyperstimulation Syndrome......................................................................................59
8.5
Serious Adverse Events...........................................................................................................61
8.5.1
Serious Adverse Event Definition..............................................................................61
8.5.2
Collection, Recording and Reporting of Serious Adverse Events in Core Trial........62
8.6
Follow-up of Adverse Events and Serious Adverse Events....................................................63
8.6.1
Follow-up of Adverse Events with Onset during the Trial ........................................63
8.6.2
Collection of Serious Adverse Events with Onset after Last Visit in the Trial..........63
8.7
Technical Complaints..............................................................................................................63
9
STATISTICAL METHODS..............................................................................................................64
9.1
Justification of Sample Size ....................................................................................................64
9.2
Subject Disposition..................................................................................................................64
9.3
Protocol Deviations.................................................................................................................64
9.4
Analysis Sets ...........................................................................................................................64
9.4.1
Full Analysis Set ........................................................................................................64
9.4.2
Safety Analysis Set.....................................................................................................64
9.5
Trial Population.......................................................................................................................65
9.6
Treatment Compliance ............................................................................................................66
9.7
Endpoint Assessments.............................................................................................................66
9.7.1
General Considerations ..............................................................................................66
9.7.2
Primary Endpoint .......................................................................................................66
9.7.3
Secondary Endpoints..................................................................................................67
9.8
Exploratory Assessment..........................................................................................................68
9.9
Adverse Events........................................................................................................................68
9.10
Additional Safety Evaluations.................................................................................................69
9.11
Follow-up Assessments...........................................................................................................69
9.12
Interim Analyses......................................................................................................................70
10
DATA HANDLING............................................................................................................................71
10.1
Source Data and Source Documents .......................................................................................71
10.2
EDC.........................................................................................................................................72
10.3
Data Management....................................................................................................................73
10.4
Provision of Additional Information .......................................................................................73
11
MONITORING PROCEDURES......................................................................................................74
11.1
Monitoring...............................................................................................................................74
11.2
Audit and Inspection ...............................................................................................................74
11.3
Confidentiality of Subject Data...............................................................................................75
12
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................76


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12.1
Protocol Amendments .............................................................................................................76
12.2
Deviations from the Protocol...................................................................................................76
12.3
Premature Trial Termination...................................................................................................76
13
REPORTING AND PUBLICATION...............................................................................................77
13.1
Clinical Trial Report................................................................................................................77
13.2
Confidentiality and Ownership of Trial Data..........................................................................77
13.3
Publications and Public Disclosure .........................................................................................77
13.3.1 Publication Policy.......................................................................................................77
13.3.2 Public Disclosure Policy ............................................................................................78
14
ETHICAL AND REGULATORY ASPECTS .................................................................................79
14.1
Independent Ethics Committee / Institutional Review Board .................................................79
14.2
Regulatory Authorities Authorisation / Approval / Notification.............................................79
14.3
End-of-trial and End-of-trial Notification ...............................................................................79
14.4
Ethical Conduct of the Trial ....................................................................................................79
14.5
Subject Information and Consent............................................................................................80
14.6
Trial Participation Card...........................................................................................................81
14.7
Compliance Reference Documents .........................................................................................81
15
LIABILITIES AND INSURANCE...................................................................................................82
15.1
ICH-GCP Responsibilities.......................................................................................................82
15.2
Liabilities and Insurance..........................................................................................................82
16
ARCHIVING......................................................................................................................................83
16.1
Investigator File.......................................................................................................................83
16.2
Trial Master File......................................................................................................................83
17
REFERENCES...................................................................................................................................84


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Follitropin Delta, FE 999049
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LIST OF TABLES 
Table 5-1
Investigational Medicinal Products.................................................................................35
Table 5-2
Non-Investigational Medicinal Products.........................................................................36
Table 5-3
Characteristics of Medicinal Products.............................................................................37
Table 6-1
Trial Flow Chart Subject Procedures ...........................................................................40
Table 6-2
Trial Flow Chart – Oocyte / Blastocyst Procedures........................................................45
Table 6-3
Follow-up Trial Flow Chart – First Transfer Cycle ........................................................47
Table 8-1
Classification of Mild, Moderate, and Severe OHSS (Based on Golan’s 
Classification System).....................................................................................................59
LIST OF FIGURES
Figure 3-1 Trial Diagram Trial Period...........................................................................................22
Figure 3-2 Trial Diagram – Follow-up Period (First Transfer Cycle) ..............................................23


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
AMH
anti-Müllerian hormone
ANCOVA
analysis of covariance 
ART
assisted reproductive technologies
ATC
Anatomical Therapeutic Chemical Classification System
COS
controlled ovarian stimulation 
CRO
contract research organisation
COVID-19
coronavirus disease 2019
DHEA
dehydroepiandrosterone
EDC
electronic data capture system
EU
European Union
EudraCT
European Union Clinical Trial Database
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
ICH
International Council for Harmonisation
ICMART
International Committee Monitoring Assisted Reproductive Technologies
ICMJE
International Committee of Medical Journal Editors
ICSI
intracytoplasmic sperm injection
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology system
IVF
in vitro fertilisation
LH
luteinising hormone
LLOQ
lower limit of quantification
LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
NIH
National Institutes of Health


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NIMP
non-investigational medicinal product
NLM
National Library of Medicine
OHSS
ovarian hyperstimulation syndrome
rFSH
recombinant follicle-stimulating hormone
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction 
ULOQ
upper limit of quantification
U.S.
United States
UTN
Universal Trial Number
WHO
World Health Organisation
Company Names
Ferring will be used as abbreviation for Ferring Pharmaceuticals.


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Follitropin Delta, FE 999049
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1
INTRODUCTION
1.1
Background
Follitropin delta (REKOVELLE) is a novel human recombinant follicle-stimulating hormone 
(rFSH) derived from a human cell line (PER.C6®). It is intended for the development of multiple 
follicles during controlled ovarian stimulation (COS) in women undergoing assisted reproductive 
technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) 
cycle. The first Marketing Authorisation approval was obtained by the European Commission in 
December 2016, and as of 01 May 2021 REKOVELLE is approved in 69 countries and regions 
worldwide. 
The currently approved REKOVELLE dosing regimen is based on each woman’s serum anti-
Müllerian hormone (AMH) concentration and her body weight, and is a fixed-dose regimen with 
the daily dose maintained throughout the stimulation period. The approved maximum daily dose of 
REKOVELLE is 12 µg for the first treatment cycle and 24 µg in subsequent treatment cycles. Other 
approved rFSH preparations, such as follitropin alfa (GONAL-F) and follitropin beta (PUREGON / 
FOLLISTIM), apply a conventional dosing approach with a starting dose of 150-225 IU, fixed for 
the initial days of stimulation, followed by the possibility for subsequent dose adjustments, with a 
maximum daily dose of 450 IU.
1.2
Scientific Justification for Conducting the Trial
The present trial will explore the use of REKOVELLE in a conventional dosing approach; i.e. a 
standard starting dose fixed for the initial days of stimulation, followed by the possibility for 
subsequent dose adjustments. Based on clinical trial data from more than 1,500 patients, it has been 
possible to establish the daily REKOVELLE dose that provides a comparable ovarian response 
(i.e. number of oocytes retrieved and number of follicles ≥12 mm and serum estradiol at end of 
stimulation) as 150 IU/day GONAL-F.1 These clinical trial data suggest that a daily dose of 
10.0 [95% CI 9.2; 10.8] µg REKOVELLE provides an ovarian response equal to that obtained with 
150 IU GONAL-F. Applying this dose equivalence factor, it is extrapolated that 15 µg/day 
REKOVELLE will provide an ovarian response comparable to that obtained with 225 IU/day 
GONAL-F.
1.3
Benefit / Risk Aspects
Benefits
The fertility medication used for controlled ovarian stimulation, prevention of premature luteinising 
hormone (LH) surge, and triggering of final follicular maturation will be 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. 


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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
In this trial, controlled ovarian stimulation will be performed with one of two rFSH preparations: 
REKOVELLE or GONAL-F. Both preparations will be administered subcutaneously. 
REKOVELLE and GONAL-F are commercially available rFSH preparations with established 
safety and efficacy.2,3 The most frequent adverse events in relation to use of REKOVELLE are as 
follows: headache, pelvic discomfort, ovarian hyperstimulation syndrome (OHSS), pelvic pain, 
nausea, adnexa uteri pain, and fatigue (all reported as common, i.e. 1% to <10%).2 The most 
frequent adverse events in relation to use of GONAL-F are as follows: headache, ovarian cysts and 
injection site reactions (all reported as very common, i.e. ≥10%) and abdominal pain, abdominal 
distension, abdominal discomfort, nausea, vomiting, diarrhoea, and mild or moderate OHSS 
including associated symptomatology (all reported as common, i.e. 1% to <10%).3
The most serious risk associated with gonadotropin treatment is OHSS. OHSS manifests itself with 
increasing degrees of severity. Moderate / severe OHSS is associated with marked ovarian 
enlargement, fluid accumulation and other complications. Early OHSS can be prevented by 
withholding gonadotropins, withholding human chorionic gonadotropin (hCG) or administering 
gonadotropin-releasing hormone (GnRH) agonist for triggering of final follicular maturation. Very 
rare cases of serious allergic reactions have been reported after injection of gonadotropins.
Trial Procedures and Concomitant Fertility Medications
Subjects will undergo standard ART treatment procedures (e.g. ovarian stimulation monitoring by
transvaginal ultrasound and blood sampling, oocyte retrieval and transfer) and also receive standard
concomitant fertility medication as part of 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 generally well-tolerated. The most frequent adverse events are 
similar to those reported for gonadotropins, such as headache, injection site reactions, pelvic pain, 
abdominal pain, abdominal distension and allergic reactions. 


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Pregnancy-related Events
The trial includes a follow-up period with collection of data from the subject’s first transfer cycle, if 
the transfer procedure occurs within 3 months after start of stimulation. In this regard, a serious 
concern associated with ART cycles is the frequency of multiple pregnancies / births and the related 
neonatal health problems. The number of blastocysts transferred will, for each subject, depend on 
the local regulations and clinical practice. Participation in this trial does not imply transfer of more 
blastocysts than what is judged appropriate by the subject, the investigator and local guidelines 
and/or regulations. 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 
achieving an adequate ovarian response compared to normal clinical practice. Furthermore, 
participation does not imply extra risks for the subjects in comparison to routine controlled ovarian 
stimulation. In conclusion, the evaluation of benefits and risks indicate that participation is this trial 
is associated with a favourable benefit-risk ratio.


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Follitropin Delta, FE 999049
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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To compare a starting dose of 15 µg REKOVELLE to a starting dose of 225 IU GONAL-F 
in conventional regimens with respect to ovarian response in women undergoing controlled 
ovarian stimulation
Secondary Objectives

To compare the follicular development, endocrine profile and embryo development 
associated with conventional dosing of REKOVELLE and GONAL-F

To compare the treatment efficiency associated with conventional dosing of REKOVELLE 
and GONAL-F

To compare the safety profile associated with conventional dosing of REKOVELLE and 
GONAL-F
2.2
Endpoints
Primary Endpoint

Number of oocytes retrieved
Secondary Endpoints

Number of follicles (total and by size category) at end-of-stimulation

Serum concentrations of estradiol and progesterone at end-of-stimulation

Number of fertilised oocytes and fertilisation rate

Number of blastocysts (total and by quality) 

Total gonadotropin dose and number of stimulation days

Early OHSS (overall and by grade) and/or preventive interventions for early OHSS
Exploratory Assessment

Blood sample on stimulation day 1 for potential future analysis of possible biomarkers 
associated with ovarian response (requires additional, optional consent)


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Follow-up Assessments

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) in the first 
transfer cycle 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred) in the first transfer cycle
Note: the first transfer cycle covers cycles with transfer occurring within 3 months after start of 
stimulation


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Clinical Trial Protocol
3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagrams
A diagram illustrating the trial period is shown in Figure 3-1.
Figure 3-1 Trial Diagram – Trial Period
A diagram illustrating the follow-up period in the first transfer cycle is shown in Figure 3-2.
Randomisation
day 2-3 of
menstrual cycle
Screening
Triggering + 
36±2 h
Oocyte retrieval
Transfer 
(if fresh cycle)
9-14 days after 
triggering
End-of-trial
OR +
5 days
Triggering 
of final follicular 
maturation
Endocrine
Stimulation 
day 1
TVU
Triggering 
drug
End of stimulation
Controlled ovarian stimulation  
REKOVELLE
GONAL-F
GnRH antagonist
FYREMADEL 0.25 mg
Endocrine
TVU
Bio-
markers
Start of GnRH 
antagonist
Stimulation 
day 5 or 6
OR: Oocyte retrieval; TVU: Transvaginal ultrasound


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Figure 3-2 Trial Diagram – Follow-up Period (First Transfer Cycle)
3.1.2
Overall Design and Control Methods
Trial Period
This will be a randomised, controlled, assessor-blind, parallel groups, multicentre, multinational 
trial comparing the ovarian response associated with a starting dose of 15 µg follitropin delta 
(REKOVELLE) and a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional 
regimens. The primary endpoint is the number of oocytes retrieved, and secondary endpoints 
include pharmacodynamic parameters of FSH action as well as efficacy and safety parameters 
related to controlled ovarian stimulation. Treatment efficiency in terms of gonadotropin use and 
duration of stimulation will also be evaluated. The assessor-blind design ensures that the 
investigators and other assessors such as embryologists are blinded to individual treatment 
allocation. A trial medication delegate will be responsible for all trial medication related issues, 
both practically at the clinic and in interactions with the subject.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 2:1 ratio 
to treatment with either REKOVELLE or GONAL-F, and stimulation will be initiated. Subjects 
randomised to REKOVELLE will receive a daily starting dose of 15 µg which will be fixed for at 
least the first four stimulation days. Dose adjustments may be implemented on the day of starting 
the GnRH antagonist (stimulation day 5 or day 6) or later, and can occur no more frequently than 
once every second day. At each dose adjustment, the daily REKOVELLE dose can be increased or 
decreased by 5 µg based on the subject’s response. The minimum REKOVELLE dose is 5 µg and 
the maximum REKOVELLE dose is 20 µg. Subjects randomised to GONAL-F will receive a daily 
starting dose of 225 IU which will be fixed for at least the first four stimulation days. Dose 
adjustments may be implemented on the day of starting the GnRH antagonist (stimulation day 5 or 
day 6) or later, and can occur no more frequently than once every second day. At each dose 
adjustment, the daily GONAL-F dose may be adjusted by 75 IU based on the subject’s response. 
Transfer
5-6 weeks after 
transfer
TVU
TVU: Transvaginal ultrasound
Number and 
quality of 
transferred 
blastocyst(s)
Clinical pregnancy


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The minimum GONAL-F dose is 75 IU and the maximum GONAL-F dose is 300 IU. Subjects can 
be treated with rFSH for a maximum of 20 days, and coasting is not allowed. 
To prevent a premature LH surge, a GnRH antagonist (ganirelix acetate, FYREMADEL, 
SUN Pharma) will be initiated on stimulation day 5 or day 6 at a daily dose of 0.25 mg and 
continued throughout the stimulation period. Triggering of final follicular maturation will be done 
as soon as ≥3 follicles with a diameter ≥17 mm are observed (i.e. on the day or the day after). 
Triggering can also be done in case 1 or 2 follicles with a diameter ≥17 mm are observed and the 
investigator judges that ≥3 follicles with a diameter ≥17 mm cannot be reached, and that triggering 
is preferred instead of cycle cancellation. The triggering drug will be either human chorionic 
gonadotropin (hCG) or GnRH agonist, depending on the extent of ovarian response and whether 
transfer in the fresh cycle or in a subsequent frozen cycle (including a freeze-all approach) is 
intended. If transfer in the fresh cycle is intended, 250 µg hCG (choriogonadotropin alfa, 
OVITRELLE, Merck) will be administered. If there are ≥25 follicles with a diameter ≥12 mm or the 
serum estradiol is ≥5,000 pg/mL (18,355 pmol/L) (local laboratory) or a freeze-all approach is 
intended, 0.2 mg GnRH agonist (triptorelin acetate, GONAPEPTYL, Ferring) will be administered. 
Moreover, if these criteria for triggering with GnRH agonist are not met, but the investigator judges 
that the subject is at risk of developing OHSS and that triggering with hCG is not advisable, the 
subject can undergo triggering with GnRH agonist. In case of poor ovarian response, defined as the 
investigator judging that the triggering criterion cannot be reached by day 20, the cycle is to be 
cancelled. In case of excessive ovarian response, defined as the investigator judging that triggering 
of final follicular maturation is not advisable due to safety concerns, the cycle is to be cancelled.
The number and size of follicles at the end-of-stimulation will be recorded.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation. All oocytes 
from follicles with an estimated diameter ≥12 mm must be retrieved. The oocytes can be 
inseminated by IVF and/or ICSI. Fertilisation will be assessed on day 1 after oocyte retrieval. The 
number and quality of blastocysts will be assessed at the last day of culture, i.e. day 5 or day 6 (as 
applicable) after oocyte retrieval. The day 5 / day 6 blastocyst quality assessment will be based on 
the Gardner & Schoolcraft blastocyst scoring system.15 Blastocysts that are not transferred in the 
fresh cycle will be cryopreserved in accordance with local guidelines and/or regulations. 
Blood samples will be collected at stimulation day 1 for measurement of AMH, estradiol and 
progesterone as well as at end-of-stimulation for measurement of estradiol and progesterone. For 
subjects who provide additional, optional consent, blood samples will be collected at stimulation 
day 1 for potential future analysis of possible biomarkers associated with ovarian response.
For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take 
place 9-14 days after triggering to cover the assessment of early OHSS (onset ≤9 days after 
triggering). For subjects who do not undergo triggering of final follicular maturation, the end-of-
trial assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a 
separate end-of-trial visit within 7 days of the last scheduled trial visit).


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Clinical Trial Protocol
If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule).
Follow-up Period – First Transfer Cycle
Follow-up information will be collected from the subject’s first transfer cycle, irrespective of 
whether the first transfer takes place in a fresh or frozen cycle. This follow-up covers cycles with 
the transfer procedure occurring within 3 months after start of stimulation. 
Depending on blastocyst availability, it is expected that subjects who underwent triggering of final 
follicular maturation with hCG will undergo transfer on day 5 after oocyte retrieval and that 
subjects who underwent triggering of final follicular maturation with GnRH agonist will undergo 
transfer in a frozen cycle using blastocysts cryopreserved on day 5 or day 6 after oocyte retrieval. 
The number of transferred blastocyst(s) in the first fresh or frozen cycle will be based on the 
subject’s wishes and the investigator’s recommendation and in accordance with local guidelines 
and/or regulations. The number and quality of transferred blastocyst(s) will be recorded. Luteal 
phase support in fresh and frozen cycles as well as potential other medicinal products for 
programming of frozen cycles will be in accordance with the site’s clinical practice.
Clinical pregnancy in the first transfer cycle will be assessed by transvaginal ultrasound 5-6 weeks 
(35-48 days) after transfer, and the number of gestational sacs will be recorded. For subjects who 
undergo transfer in the fresh cycle, assessment of late OHSS (onset >9 days after triggering) will 
take place during the follow-up period.
3.1.3
Trial Schedule
First patient first visit (FPFV):
Q2 2022
Last patient last visit (LPLV) / end-of-trial:
Q3 2023
Follow-up period (first transfer cycle) completed: Q1 2024
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise approximately 300 subjects from 15-20 sites in 3-6 European countries.
3.3
Interim Analysis
No interim analysis is planned.


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3.4
Data Monitoring Committee 
No Data Monitoring Committee will be established for this trial. During the trial, the Safety 
Management Team at the sponsor will evaluate blinded safety data on a regular basis.
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 compare a starting dose of 15 µg REKOVELLE to a starting 
dose of 225 IU GONAL F in conventional regimens with respect to ovarian response in women 
undergoing controlled ovarian stimulation
This is a randomised controlled trial using an approved gonadotropin preparation as active 
comparator. It is a parallel group design restricted to a single treatment cycle, as this design is 
preferred over a cross-over design in fertility trials.4,5 The trial will be open-label but assessor-blind. 
A double-blind design is not considered feasible for the present trial for various practical reasons, 
which are described in detail in section 3.5.3. The assessor-blinding will ensure blinding and 
thereby unbiased evaluation by the investigators and other assessors such as embryologists. 
Similarly, Ferring staff will also remain blinded to individual subject treatment allocation during the 
conduct of the trial (see section 3.5.3). The trial will be a multi-centre, multinational trial. This 
set-up ensures that the required number of subjects can be recruited within a reasonable time and 
also has the advantage of facilitating subsequent generalisation of the results.
Subjects will be randomised in 2:1 ratio to controlled ovarian stimulation with REKOVELLE or 
GONAL-F following a GnRH antagonist protocol. 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 selected endocrine parameters will be performed at start and end-of-stimulation.
Follow-up information will be collected from the subject’s first transfer cycle, irrespective of 
whether the first transfer takes place in a fresh or frozen cycle. This follow-up covers cycles with 
the transfer procedure occurring within 3 months after start of stimulation. 
3.5.2
Selection of Endpoints
The primary endpoint of this trial, number of oocytes retrieved, is an objective parameter. The 
number of oocytes retrieved provides a direct measure of the main pharmacological action of
gonadotropin preparations. The number of oocytes retrieved is considered an appropriate marker of
ovarian response and thereby of the pharmacodynamics of an FSH preparation.
Secondary endpoints include pharmacodynamic parameters of FSH, such as ovarian response in 
terms of follicular development, endocrine profile, and also oocyte / blastocyst quality. Follicular 
development and endocrine profile, represented by estradiol and progesterone, will be evaluated at 
the end-of-stimulation. In addition, treatment efficiency in terms of gonadotropin use and duration 


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of stimulation, and a specific relevant clinical safety endpoint covering early OHSS and preventive 
interventions for early OHSS will also be evaluated.
As obligatory follow-up, pregnancy data at 5-6 weeks (35-48 days) after transfer will be gathered 
for subjects in the first transfer cycle.
3.5.3
Blinding
The two investigational medicinal products (IMPs), i.e. REKOVELLE and GONAL-F, have 
different appearances. Blinding would therefore require a double-blind, double-dummy design
which is not easily feasible, and furthermore, would add an extra burden on the subjects. The trial, 
however, is assessor-blind, ensuring unbiased evaluation by the investigators and other assessors 
such as embryologists. Only the trial medication delegate personnel (persons responsible for IMPs / 
non-investigational medicinal products [NIMPs]), the monitors, and the participating subjects will 
know the treatment allocation once the subject is randomised.
The trial medication delegate will be responsible for all trial medication related issues, both 
practically at the clinic and in interactions with the subject. To maintain the assessor-blinding, the 
trial medication delegate is not allowed to perform any efficacy or safety assessments in the trial. 
Information on treatment allocation is only available to the trial medication delegate (the person 
entering data into the electronic data capture system [EDC] and with access to the interactive 
response technology system [IRT]). The investigator does not have access to these modules in the 
EDC and IRT. Precaution will be taken to ensure that the treatment allocations are not available to 
the investigators or other assessors throughout the trial. Subjects will be clearly instructed not to 
discuss their treatment allocation with the investigator.
Drug accountability forms and other forms identifying treatment allocation are kept unavailable to
the blinded trial staff, including the investigator. The subject will during the informed consent 
process be informed, both verbally and in writing, to not disclose her treatment allocation to the 
investigator. Trial staff will be provided with training in the importance of maintaining blinding.
The Ferring clinical trial teama will be blinded to treatment allocation until breaking of the blind. 
The blind will be broken when the trial database is declared clean and locked. This will occur after 
LPLV (last patient’s end-of-trial visit), i.e. before completion of the follow-up period (first transfer 
cycle).
                                                
a
This excludes the representatives from Clinical Trial Supply. Furthermore, it may be necessary for representatives 
from Pharmacovigilance to unblind an individual subject’s treatment during the trial for the purpose of expedited 
reporting.


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3.5.4
Selection of Doses in the Trial
Based on clinical trial data from more than 1,500 patients, it has been possible to establish that a 
daily dose of 10.0 µg REKOVELLE provides an ovarian response equal to that obtained with 
150 IU GONAL-F. The present trial investigates the extrapolation that conventional dosing 
regimens with a daily starting dose of 15 µg REKOVELLE or 225 IU GONAL-F will result in a 
similar number of oocytes retrieved. The possible dose adjustments are 5 µg REKOVELLE and 
75 IU GONAL-F, and therefore considered to be of similar magnitude. The highest REKOVELLE 
dose possible to administer as a single injection with the REKOVELLE pre-filled pen is 20 µg, and 
for patient convenience reasons 20 µg has therefore been set as the maximum daily dose in this 
trial. Correspondingly, the maximum daily GONAL-F dose has been set at 300 IU.
The doses and overall treatment regimens for the GnRH antagonist (FYREMADEL) and hCG 
(OVITRELLE) are in line with the recommendations in the respective products’ labelling for the 
indication of ART and/or standard clinical practice. The GnRH agonist (GONAPEPTYL) is 
included as an option for triggering of final follicular maturation in subjects with ≥25 follicles with 
a diameter ≥12 mm or serum estradiol concentration ≥5,000 pg/mL (18,355 pmol/L) (local 
laboratory) or a freeze-all approach is intended, as this approach is associated with almost an 
elimination of the risk of early moderate / severe OHSS despite high ovarian response. The use of a 
GnRH agonist for triggering of final follicular maturation in a GnRH antagonist protocol is well
described in the literature and considered an acceptable alternative to cycle cancellation. 6,7,8,9,10 The 
use of 0.2 mg GONAPEPTYL is also in line with literature.6,7,10,11
3.5.5
Selection of the Trial Population
This trial will include women who have been diagnosed with tubal infertility, unexplained 
infertility, endometriosis stage I/II, or have partners diagnosed with male factor infertility, and who 
are considered eligible for IVF or ICSI. 
The exclusion criteria incorporate the contraindications for the use of gonadotropins.
Altogether, the population selected for this trial would be expected to be representative for patients 
undergoing controlled ovarian stimulation in IVF/ICSI cycles.
3.5.6
Follow-up Procedures
Follow-up Activities
Follow-up information will be collected from the subject’s first transfer cycle, irrespective of 
whether the first transfer takes place in a fresh or frozen cycle. This follow-up covers cycles with 
the transfer procedure occurring within 3 months after start of stimulation.


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Access to Therapy after End-of-trial
Concerning access to therapy after completion of the trial, both REKOVELLE and GONAL-F are 
approved for controlled ovarian stimulation and are commercially available.


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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 Form signed prior to screening evaluations.
2.
In good physical and mental health.
3.
Pre-menopausal females between the ages of 18 and 40 years. The subjects must be at least 
18 years (including the 18th birthday) when they sign the informed consent and no more than 
40 years (up to the day before the 41st birthday) at the time of randomisation.
4.
Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II 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 ≤37 years or for at least 
6 months for subjects ≥38 years (not applicable in case of tubal or severe male factor 
infertility).
6.
Regular menstrual cycles of 21-35 days (both inclusive), presumed to be ovulatory.
7.
Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm, and 
no enlarged ovaries or ovarian cyst not due to polycystic ovarian syndrome, 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.
8.
Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to randomisation).
4.1.2
Exclusion Criteria
Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.
1.
Primary ovarian failure.
2.
Known endometriosis stage III-IV.
3.
Considered unsuitable for controlled ovarian stimulation with a dosing regimen 
corresponding to approximately 225 IU/day gonadotropin, as judged by the investigator.
4. History of previous episode of OHSS or exuberant ovarian response to gonadotropins, and 
polycystic ovarian syndrome.


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5.
One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to 
randomisation).
6.
Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) which can compromise participation in the trial with the exception of controlled 
thyroid function disease.
7.
Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
8.
Fibroid tumours of the uterus incompatible with pregnancy.
9.
Currently breast-feeding.
10. Undiagnosed vaginal bleeding.
11. 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.
12. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomisation) or contraindication to pregnancy.
13. Use of fertility modifiers during the last menstrual cycle before randomisation, including 
dehydroepiandrosterone (DHEA) or cycle programming with oral contraceptives, 
progestogen or estrogen preparations.
14. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
15. Previous participation in the trial.
16. 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 sites included in the 
trial. Advertisements may be used if approved by the local Independent Ethics Committee (IECs) / 
Institutional Review Board (IRB)b and regulatory authorities, as applicable according to local 
regulations.
                                                
b
The term IEC/IRB will be used throughout this document to cover all committees as per local regulations.


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4.2.2
Randomisation
On day 2-3 of the menstrual cycle, subjects will be randomised in a 2:1 ratio to treatment with 
either REKOVELLE or GONAL-F, and stimulation will be initiated. Randomisation is performed 
centrally through the IRT. 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 trial sites, i.e. randomisation will be 
stratified by trial site. The block size will only be revealed when the trial database is declared clean 
and locked. An overview of recruitment will be recorded on a subject identification code list for all 
randomised subjects kept by the investigator.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
The subjects must not have used fertility modifiers, including DHEA or cycle programming with 
oral contraceptives, progestogen, or estrogen preparations during the last menstrual cycle before 
randomisation.
It is prohibited to administer other gonadotropins than REKOVELLE or GONAL-F, or other
concomitant fertility medication not provided as part of the trial regimen. This restriction does not 
include the follow-up period (first transfer cycle), e.g. luteal phase support as well as potential other 
medicinal products for programming of frozen cycles.
4.3.2
Prohibited Therapy
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial.
4.3.3
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 also has the right to discontinue subjects. For any discontinuation, the investigator 
will obtain all the required details and document the date of the premature termination and the main 
reason in the EDC.


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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. The subject can 
request destruction of samples which would otherwise have been kept in storage.
4.4
Subject Replacement
A subject can only be assigned one screening number and one randomisation number, i.e. a subject 
cannot be re-screened.
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.
4.5
Trial Stopping Criteria
Occurrence of the following may warrant consideration of trial termination:

Life-threatening serious adverse events (SAEs) with suspected causality to the IMP
The internal Safety Management Team at the sponsor will review each occurrence and provide a 
recommendation as to whether to terminate the trial. The responsibilities and composition of the 
internal Safety Management Team are provided in a separate charter document, available before 
FPFV.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Products
On day 2-3 of the menstrual cycle, subjects will be randomised in a 2:1 ratio to either 
REKOVELLE or GONAL-F, and controlled ovarian stimulation will be initiated.
Subjects randomised to REKOVELLE will receive a daily starting dose of 15 µg, which will be 
fixed for at least the first four stimulation days. Dose adjustments may be implemented on the day 
of starting the GnRH antagonist (stimulation day 5 or day 6) or later, and can occur no more 
frequently than once every second day. At each dose adjustment, the daily REKOVELLE dose can 
be increased or decreased by 5 µg based on the subject’s response. The minimum REKOVELLE 
dose is 5 µg and the maximum REKOVELLE dose is 20 µg. Subjects can be treated with 
REKOVELLE for a maximum of 20 days, and coasting is not allowed.
Subjects randomised to GONAL-F will receive a daily starting dose of 225 IU which will be fixed 
for at least the first four stimulation days. Dose adjustments may be implemented on the day of 
starting the GnRH antagonist (stimulation day 5 or day 6) or later, and can occur no more 
frequently than once every second day. At each dose adjustment, the daily GONAL-F dose may be 
adjusted by 75 IU based on the subject’s response. The minimum GONAL-F dose is 75 IU and the 
maximum GONAL-F dose is 300 IU. Subjects can be treated with GONAL-F for a maximum of 
20 days, and coasting is not allowed. 
The IMP is administered as a daily subcutaneous injection in the abdomen. The first IMP injection 
will take place at the clinic and will be performed either by the trial medication delegate or the 
subject under supervision by the trial medication delegate. Subsequent injections can be done at 
home or at the clinic. The trial medication delegate will give the subject instructions on how to 
administer the IMP.
The REKOVELLE and GONAL-F dosing regimen is tabulated in Table 5-1.


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Table 5-1
Investigational Medicinal Products
IMP
Active ingredient, 
pharmaceutical dosage 
form and concentration
Daily dose a)
REKOVELLE
Follitropin delta, solution 
for subcutaneous 
injection, 72 µg FSH in 
2.16 mL.
Daily starting dose of 15 µg fixed for at least the 
first four stimulation days. Dose adjustments may 
be implemented on the day of starting the GnRH 
antagonist (stimulation day 5 or day 6) or later, and 
can occur no more frequently than once every 
second day. At each dose adjustment, the daily 
REKOVELLE dose can be increased or decreased 
by 5 µg based on the subject’s response. The 
minimum REKOVELLE dose is 5 µg and the 
maximum REKOVELLE dose is 20 µg. 
GONAL-F
Follitropin alfa, solution 
for subcutaneous 
injection, 900 IU FSH in 
1.5 mL.
Daily starting dose of 225 IU fixed for at least the 
first four stimulation days. Dose adjustments may 
be implemented on the day of starting the GnRH 
antagonist (stimulation day 5 or day 6) or later, and 
can occur no more frequently than once every 
second day. At each dose adjustment, the daily 
GONAL-F dose may be adjusted by 75 IU based on 
the subject’s response. The minimum GONAL-F 
dose is 75 IU and the maximum GONAL-F dose is 
300 IU. 
a)
Subjects can be treated for a maximum of 20 days.
5.1.2
Non-investigational Medicinal Products
As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the following 
NIMPs as illustrated in Table 5-2.


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Table 5-2
Non-Investigational Medicinal Products
NIMP
Trade name
Dose
GnRH antagonist
FYREMADELa)
0.25 mg subcutaneous injection once daily starting 
on stimulation day 5 or day 6 and continued 
throughout the stimulation period. FYREMADEL 
and REKOVELLE / GONAL-F should be 
administered approximately at the same time. 
However, the preparations should not be mixed and 
different injection sites are to be used.
hCG
OVITRELLE
A single 250 μg subcutaneous injection as soon as 
reaching the criterion for triggering of final follicular 
maturation with hCG (≥3 follicles with a diameter of 
≥17 mm and intended transfer in the fresh cycle. 
Note: triggering can also be done in case 1 or 
2 follicles with a diameter ≥17 mm are observed and 
the investigator judges that ≥3 follicles with a 
diameter ≥17 mm cannot be reached, and that 
triggering is preferred instead of cycle cancellation).
GnRH agonist
GONAPEPTYLb)
Two consecutive subcutaneous injections of 0.1 mg, 
i.e. a total of 0.2 mg, as soon as reaching the 
additional criteria for triggering of final follicular 
maturation with GnRH agonist (≥25 follicles with a 
diameter of ≥12 mm or serum estradiol concentration 
≥5,000 pg/mL (18,355 pmol/L) (local laboratory) or 
intended freeze-all approach). Note: the subject can 
undergo triggering with GnRH agonist if the 
investigator judges that the subject is at risk of 
developing early OHSS.
a)
Other tradenames in Europe include FYREMADEL GÉ.
b)
Other tradenames in Europe include FERTIPEPTIL and DECAPEPTYL.
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). Table 5-3 provide an overview of the presentation of each 
medicinal product.


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Table 5-3
Characteristics of Medicinal Products
IMP / NIMP
Presentation
Manufacturer 
REKOVELLE 
(rFSH)
Pre-filled pen for multiple use containing 
72 µg follitropin delta in 2.16 mL.
Ferring Pharmaceuticals
GONAL-F 
(rFSH)
Pre-filled pen containing 900 IU 
follitropin alfa in 1.5 mL.
Merck
FYREMADEL 
(GnRH antagonist)
Pre-filled syringe for single use delivering 
0.25 mg of ganirelix acetate in 0.5 mL.
SUN Pharma
OVITRELLE
(hCG)
Pre-filled syringe or pre-filled pen for 
single use delivering 250 µg 
choriogonadotropin alfa in 0.5 mL.
Merck
GONAPEPTYL
(GnRH agonist)
Pre-filled syringe for single use delivering 
0.1 mg triptorelin acetate in 1 mL.
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.
Details on the packaging and labelling of each medicinal product are provided in the Trial Supply 
Manual.
5.4
Conditions for Storage and Use
The investigator will ensure that the medicinal products will be stored under appropriate conditions 
in a secure location with controlled access. The storage conditions shall be monitored regularly and 
the temperature shall be documented as instructed in the Trial Supply Manual.
The storage conditions for the medicinal products will be as described on the trial-specific or 
commercial box labels. Deviations in temperature must be reported to Ferring as instructed in the 
Trial Supply Manual.
For information on warnings, precautions, and treatment of overdose, please refer to the Summary 
of Product Characteristics for REKOVELLE2, GONAL-F3, FYREMADEL12, OVITRELLE13, and 
GONAPEPTYL14.


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5.5
Blinding / Unblinding
5.5.1
Blinding
The trial is assessor-blind, and all investigators, embryologists, other assessors (e.g. trial nurses, 
depending on delegation of authority) and central laboratory personnel will be blinded to treatment 
allocation throughout the trial. The trial medication delegate at site (person responsible for the 
medicinal products), the monitors, and the participating subjects will know the treatment allocation 
once the subjects are randomised. Precaution must be taken to ensure that the treatment allocations 
are not available to the investigators or other assessors throughout the trial. Subjects must be clearly 
instructed to only discuss their treatment allocation with the trial medication delegate, and to not 
mention it to the investigator.
The randomisation list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information in the EDC or IRT will not be accessible to assessors or the Ferring clinical trial team 
or laboratory personnel during the trial.
The Ferring clinical trial teamc will be blinded to treatment allocation until breaking of the blind. 
The blind will be broken when the trial database is declared clean and locked.
5.5.2
Unblinding of Individual Subject Treatment
An emergency unblinding procedure will be available for the investigator and designated personnel 
at the sponsor through the IRT. It is the investigator’s responsibility to decide whether it is 
medically necessary to know the investigational product the subject receives (i.e. unblinding) to 
ensure the subject’s welfare and safety. 
Breaking of the blind for individual subjects in emergency situations could be required in case of 
suspected unexpected serious adverse reactions (SUSARs) or in case of other important adverse 
events when the knowledge of the IMP in question is required for therapeutic decisions for the 
management of the subject. As far as the emergency permits, the need to break the blind will be 
agreed by the investigator and the sponsor. Where the event requires immediate unblinding by the 
investigator, the sponsor must be informed of the unblinding as soon as possible and provided with 
the rationale for unblinding. 
The investigator who unblinds a treatment will use the IRT and is required to enter a password 
before the treatment code can be broken. The IRT records when, and by whom, the code was 
broken. The investigator must record the event of unblinding in the subject’s medical record, 
including the reason for unblinding, but not the treatment allocation if this can be avoided.
                                                
c
This excludes the representatives from Clinical Trial Supply. Furthermore, it may be necessary for representatives 
from Pharmacovigilance to unblind an individual subject’s treatment during the trial for the purpose of expedited 
reporting.


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In case of accidental unblinding (e.g. the subject tells the investigator), the same procedure as for 
emergency unblinding must be followed, i.e. the investigator / person who was accidentally 
unblinded will enter a password in the IRT for unblinding. The IRT records when, and by whom, 
the code was broken. In addition, the event and reason for unblinding must also be recorded in the 
subject’s medical record. 
If Ferring needs to unblind a treatment, the IRT will be used for unblinding. It is a requirement to 
enter a password before the treatment code can be broken. The IRT records when, and by whom, 
the code was broken. The code break will occur according to corporate operational procedures for 
unplanned unblinding of trial subjects. It may be necessary to unblind an individual subject’s 
treatment for the purposes of expedited reporting to the authorities and/or IECs/IRBs. In that 
situation, every effort will be made to maintain blinding of sponsor personnel involved in data 
analysis and interpretation. Other personnel may be unblinded for SUSARs, including trial site staff 
as well as staff acting on behalf of Ferring.
Information on whether the blind has been broken for any subjects is available in the IRT and must 
be collected before the database is declared clean and locked.
In case the IRT cannot be accessed by the investigator, and hence the emergency unblinding cannot 
be performed within the IRT, a backup procedure is in place.
5.6
Treatment Compliance, Dispensing and Accountability
All handling of medicinal products will be done by a trial medication delegate at the site and an IRT 
will be used to assign the medicinal products to the subject.
The trial medication delegate will maintain subject dispensing logs, detailing the dates, quantities 
and batch numbers of dispensed and returned medicinal products for each subject in the IRT. The 
trial medication delegate will also manage the overall drug accountability at the site.
The monitor will verify the drug accountability during the trial.
IMP medication errors with and without clinical consequences will be tracked in the EDC and 
reviewed on an ongoing basis by Ferring Global Pharmacovigilance.
5.7
Auxiliary Supplies
Ferring will supply safety containers for the collection of used needles, etc.
5.8
Return and Destruction of Medicinal Products 
All used and unused (non-dispensed / non-allocated) trial medication will be disposed as instructed 
in the Trial Supply Manual, after drug accountability has been finalised and verified by the monitor, 
and all issues solved.


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6
TRIAL PROCEDURES
The flow of the trial procedures for subjects is shown in Table 6-1.
Table 6-1
Trial Flow Chart – Subject Procedures
Screening
Stimulation
Oocyte retrieval
End
Start of stimulation
Start of GnRH 
antagonist
End-of-stimulation
End-of-trial a)
<90 days 
before 
randomisation
Day 1
Day 5 or day 6 b)
End
36h ± 2h after 
triggering
Written informed consent
X
Inclusion/exclusion criteria
X
  X c)
Demographics
X
Medical history 
X
Infertility history
X
Body weight, height
X
Physical examination
X
X
Gynaecological examination
X
X
Urinary pregnancy test
X
  X c)
Transvaginal ultrasound
  X c)
X
Blood collection, endocrine d)
  X c)
X
Blood collection, potential 
biomarkers e)
  X c)
Randomisation
X
IMP dispensing
X
X
NIMP dispensing
X
X
Oocyte retrieval
X
Drug accountability
X
X
X
Concomitant medication
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
a) For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take place 9-14 days after triggering to cover 
the assessment of early OHSS (onset ≤9 days after triggering). For subjects who do not undergo triggering of final follicular maturation, the 
end-of-trial assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a separate end-of-trial visit within 
7 days of the last scheduled trial visit).
b) GnRH antagonist will be initiated on stimulation day 5 or day 6. 
c) Performed before the first IMP dose.
d) Stimulation day 1: AMH, estradiol and progesterone; end-of-stimulation: estradiol and progesterone. 
e) Additional, optional, consent required. 
GnRH: gonadotropin-releasing hormone, IMP: investigational medicinal product, NIMP: non-investigational medicinal product, OHSS: ovarian 
hyperstimulation syndrome
If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule).
6.1
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before stimulation day 1 (randomisation).


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The following must take place during the screening period:

Signed and dated written informed consent, obtained prior to any trial-related procedures

Allocation of a screening number

Check of inclusion and exclusion criteria (those which are possible to check at screening)

Demographics (date of birthd, ethnicity, race)

Medical history

Infertility history

Body weight, height

Physical examination

Gynaecological examination

Urinary pregnancy test must be negative

Recording of use of any concomitant medication (within the last month prior to signed 
informed consent)

Recording of adverse events (from the date of signed informed consent)
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit, scheduled on day 2-3 of the menstrual cycle.
6.2
Stimulation
6.2.1
Start of Stimulation – Day 1
Subjects 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 IMP dose:

Ensure that the subject is still eligible for participation in the trial

Check those inclusion and exclusion criteria that were not possible during screening 

Urinary pregnancy test must be negative 

Transvaginal ultrasound of ovaries (number and size of follicles)

Blood collection for central laboratory analysis of endocrine parameters (AMH, estradiol, 
and progesterone) 
                                                
d
Alternatively, age may be recorded in case country-specific restrictions do not permit recording the full date of birth.


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
Blood collection for potential future biomarkers (applicable for subjects who have provided 
additional, optional consent) 
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation:

Randomisation, i.e. assignment to the lowest available subject number and thereby 
allocation to either REKOVELLE or GONAL-F
Once the above has been completed, the following must be performed by the trial medication 
delegate. Care must be taken to ensure blinding of the investigator and other assessors.

Dispensing of IMP according to randomisation and instruct the subject on how to administer 
the IMP. The subject will self-administer the IMP (at the trial site) as a subcutaneous 
injection in the lower part of the abdomen. The IMP starting dose of 15 μg/day with 
REKOVELLE or 225 IU/day with GONAL-F must be maintained for at least 4 days.
Finally, this must be done before the subject leaves the clinic:

Recording of use of any concomitant medication

Recording of adverse events
The IMP should preferably be administered at the same time each day during the stimulation period 
(with the possible exception of stimulation day 1). 
6.2.2
Start of GnRH Antagonist – Day 5 or Day 6
The following must take place on stimulation day 5 or day 6:

Dispensing of IMP

Evaluation of potential dose adjustments based on the subject’s response

Implementation of dose adjustments, if applicable
The daily REKOVELLE dose can be increased or decreased by 5 µg based on the subject’s 
response. The minimum REKOVELLE dose is 5 µg and the maximum REKOVELLE dose 
is 20 µg. The daily GONAL-F dose may be adjusted by 75 IU based on the subject’s 
response. The minimum GONAL-F dose is 75 IU and the maximum GONAL-F dose is 
300 IU. 

Dispensing of GnRH antagonist
Daily administration of 0.25 mg GnRH antagonist will be initiated on stimulation day 5 or 
day 6. The subject will self-administer the GnRH antagonist as a subcutaneous injection in 
the upper thigh throughout the stimulation period. The timing of the GnRH antagonist 
injections should be aligned with the IMP injections. 


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
Drug accountability of IMP

Recording of use of any concomitant medication

Recording of adverse events
6.2.3
End-of-stimulation
The end-of-stimulation visit will take place when the subject reaches the criterion for triggering of 
final follicular maturation. Triggering of final follicular maturation will be done either with hCG or 
GnRH agonist, depending on the extent of ovarian response and whether transfer in the fresh cycle 
or in a subsequent frozen cycle (including a freeze-all approach) is intended. Administration of 
REKOVELLE or GONAL-F after reaching the triggering criterion is not allowed.
Criterion for triggering of final follicular maturation with 250 µg hCG:

≥3 follicles with a diameter of ≥17 mm and intended transfer in the fresh cycle
[note: triggering can also be done in case 1 or 2 follicles with a diameter ≥17 mm are 
observed and the investigator judges that ≥3 follicles with a diameter ≥17 mm cannot be 
reached, and that triggering is preferred instead of cycle cancellation]
Additional criteria for triggering of final follicular maturation with 0.2 mg GnRH agonist:

≥25 follicles with a diameter of ≥12 mm 
or

serum estradiol concentration ≥5,000 pg/mL (18,355 pmol/L) (local laboratory)
or

intended freeze-all approach
Moreover, if these criteria for triggering with GnRH agonist are not met, but the investigator judges 
that the subject is at risk of developing early OHSS and that triggering with hCG is not advisable, 
the subject can undergo triggering with GnRH agonist.
In case of poor ovarian response, defined as the investigator judging that the triggering criterion
cannot be reached by day 20, the cycle is to be cancelled. In case of excessive ovarian response, 
defined as the investigator judging that triggering of final follicular maturation is not advisable due 
to safety concerns, the cycle is to be cancelled.
The investigator also has the option of cancelling the cycle for other relevant medical reasons, 
including adverse events.


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The following must take place at the end-of-stimulation visit:

Transvaginal ultrasound of ovaries (number and size of follicles)

Blood collection for central laboratory analysis of endocrine parameters (estradiol, and 
progesterone)

Dispensing of hCG or GnRH agonist, as applicable

Drug accountability of IMP and GnRH antagonist

Recording of use of any concomitant medication

Recording of adverse events
For subjects who receive a triggering drug, the next visit is the oocyte retrieval visit which must be 
scheduled 36h (±2h) after the administration of hCG or GnRH agonist. 
Subjects with cycle cancellation will proceed to end-of-trial assessments.
6.3
Oocyte Retrieval
Oocyte retrieval must take place 36h (±2h) after hCG or GnRH agonist administration. All oocytes 
from follicles with an estimated diameter of ≥12 mm must be retrieved. The procedures related to 
subjects attending the oocyte retrieval visit are listed below, while procedures related to the oocytes 
are described in section 6.4.
The following must take place at the oocyte retrieval visit:

Oocyte retrieval

Drug accountability of hCG or GnRH agonist, as applicable

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with oocytes retrieved following hCG administration, the next visit is the transfer visit
which takes place on day 5 after oocyte retrieval.
For subjects with oocytes retrieved following GnRH agonist no transfer will take place in the fresh 
cycle. The oocytes will undergo the procedures described in section 6.4 and the blastocysts 
available on day 5 / day 6 will be cryopreserved in accordance with local guidelines and/or 
regulations.
Subjects with no oocytes retrieved will proceed to end-of-trial assessments.


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6.4
Oocyte / Blastocyst Evaluation
The laboratory procedures regarding handling and evaluation of oocytes and blastocysts are 
described in a trial-specific manual. This section provides an overview of the oocyte and blastocyst 
evaluation. The assessment of blastocyst quality is to be performed on the last day of culture. The 
flow of the trial procedures for oocytes is shown in Table 6-2.
Table 6-2
Trial Flow Chart – Oocyte / Blastocyst Procedures
Day 0 (OR)
Day 1 
after OR
Day 5 after 
OR
Day 6 after 
OR
Oocyte retrieval (OR)
X
Insemination by IVF and/or ICSI
X
Assessment of oocyte fertilisation
X
Assessment of blastocyst quality a)
X
X
Transfer in fresh cycle, if applicable
X
Cryopreservation
X
X
a)
Assessment to be performed on last day of culture only.
ICSI: intracytoplasmic sperm injection, IVF: in vitro fertilisation, OR: oocyte retrieval
Assisted hatching is prohibited. 
Day 0 (Oocyte Retrieval)

Oocyte retrieval before start of the insemination procedure

Insemination using IVF or ICSI using ejaculated sperm (fresh or frozen) from partner or 
donor
Day 1 after Oocyte Retrieval

Assessment of fertilisation 
Day 5 after Oocyte Retrieval

Assessment of number and quality of blastocysts based on the Gardner & Schoolcraft 
blastocyst scoring system15 [note: this assessment is to be performed on last day of culture
only]

Transfer of blastocyst in fresh cycle, if applicable (section 6.6.1)

Cryopreservation in accordance with local guidelines and/or regulations


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Day 6 after Oocyte Retrieval

Assessment of number and quality of blastocysts based on the Gardner & Schoolcraft 
blastocyst scoring system15 [note: this assessment is to be performed on last day of culture 
only]

Cryopreservation in accordance with local guidelines and/or regulations
6.5
End-of-trial
For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take 
place 9-14 days after triggering to cover the assessments of early OHSS (onset ≤9 days after 
triggering). 
For subjects who do not undergo triggering of final follicular maturation, the end-of-trial 
assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a 
separate end-of-trial visit within 7 days of the last scheduled trial visit).
The following end-of-trial procedures / assessments must take place, irrespective of whether the 
subject discontinues the trial prematurely or completes it:

Physical examination

Gynaecological examination

Recording of use of any concomitant medication

Recording of adverse events
The assessments serve to document the subject’s health at the end of the trial.
6.6
Follow-up Assessments
Follow-up assessments are to be performed in the first transfer cycle, irrespective of whether the 
first transfer takes place in a fresh or frozen cycle. The first transfer cycle covers cycles with 
transfer occurring within 3 months after start of stimulation. The flow of the follow-up trial 
procedures is shown in Table 6-3.


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Table 6-3
Follow-up Trial Flow Chart – First Transfer Cycle
Transfer
Clinical pregnancy
Fresh cycle
Frozen cycle
Day 5 after oocyte 
retrieval
Within 3 months 
after start of 
stimulation
5-6 weeks (35-48 days)
after transfer
Transfer 
X
Number and quality of blastocyst(s) 
transferred
X
Transvaginal ultrasound
X
Late OHSS a)
X
a)
For subjects who undergo transfer in the fresh cycle, assessment of late OHSS (onset >9 days after triggering) will take place during the 
follow-up period.
OHSS: ovarian hyperstimulation syndrome
6.6.1
Transfer
The first transfer cycle can take place either in a fresh cycle or in a frozen cycle, as applicable, with 
the transfer occurring within 3 months after start of stimulation.
Blastocyst Transfer in a Fresh Cycle
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. Transfer of day 6 (or later) 
blastocysts is not allowed in the fresh cycle. 
The following must take place:

Transfer of blastocyst(s) [note: the number of transferred blastocyst(s) will be based on the 
subject’s wishes and the investigator’s recommendation and in accordance with local 
guidelines and/or regulations]
Blastocyst Transfer in a Frozen Cycle
Transfer of cryopreserved blastocyst(s) is performed within 3 months after start of stimulation. 
The following must take place:

Transfer of blastocyst(s) [note: the number of transferred blastocyst(s) will be based on the 
subject’s wishes and the investigator’s recommendation and in accordance with local 
guidelines and/or regulations]
6.6.2
Clinical Pregnancy
The subject must attend a visit 5-6 weeks (35-48 days) after the transfer.


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The following must take place: 

Transvaginal ultrasound of uterus to assess clinical pregnancy
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. 
6.6.3
Late OHSS
For subjects who undergo transfer in the fresh cycle, the following will take place during the 
follow-up period:

Assessment of late OHSS (>9 days after triggering)


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7
TRIAL ASSESSMENTS
7.1
Assessments 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
Assessments Related to Secondary Endpoints
7.2.1
Number of Follicles (Total and by Size Category) at End-of-stimulation
Transvaginal ultrasound will be performed at the end-of-stimulation visit to count the number of 
follicles and measure the size of the follicles. Data will be recorded combined for the right and left 
ovary.
7.2.2
Serum Concentrations of Estradiol and Progesterone at End-of-stimulation
Blood samples will be drawn at stimulation day 1 and at end-of-stimulation for measurement of 
estradiol and progesterone. The sample on stimulation day 1 (baseline) will be collected prior to the 
first dose of REKOVELLE or GONAL-F.
The samples will be analysed at a central laboratory. 
7.2.3
Number of Fertilised Oocytes and Fertilisation Rate
The number of pronuclei will be counted after insemination and recorded as 0, 1, 2 or >2. Fertilised 
oocytes with 2 pronuclei (2PN) will be regarded as correctly fertilised. Fertilisation rate is the 
number of 2PN oocytes divided by the number of oocytes retrieved.
7.2.4
Number of Blastocysts (Total and by Quality)
The number and quality of blastocysts will be assessed on day 5 or day 6 after oocyte retrieval. The 
quality evaluation of blastocysts on day 5 or day 6 (as applicable) 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 & Schoolcraft,15 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:
An early blastocyst, blastocoel being less than half volume of that of the embryo.
A blastocyst with a blastocoel whose volume is half of, or greater than half of, that of the 
embryo.
A blastocyst with a blastocoel completely filling the embryo.


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An expanded blastocyst with a blastocoel volume larger than that of the early embryo, with 
a thinning zona.
A hatching blastocyst with the trophectoderm starting to herniate through the zona.
A hatched blastocyst, in which the blastocyst has completely escaped from the zona.
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:
Tightly packed, many cells.
Loosely grouped, several cells.
Very few cells.
Degenerative or no inner cell mass.
Trophectoderm grading will be assessed as one of the following:
Many cells forming a cohesive epithelium.
Few cells forming a loose epithelium.
Very few large cells.
Degenerative or very large cells.
Blastocysts with expansion and hatching status 3-6 will have a score combining the 3 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.
A good-quality blastocyst is defined as a blastocyst of grade 3BB or above.e
7.2.5
Total Gonadotropin Dose and Number of Stimulation Days
The administration dates as well as daily dose of IMP will be recorded by the trial medication 
delegate and used to calculate the total REKOVELLE or GONAL-F dose administered and the 
number of stimulation days.
                                                
e
3BB and above defined as: 6AA, 6AB, 6AC, 6BA, 6BB, 6BC, 6CA, 6CB, 6CC, 5AA, 5AB, 5AC, 5BA, 5BB, 5BC,
5CA, 5CB, 5CC, 4AA, 4AB, 4AC, 4BA, 4BB, 4BC, 4CA, 4CB, 4CC, 3AA, 3AB, 3AC, 3BA, or 3BB.


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7.2.6
Early OHSS (Overall and by Grade) and/or Preventive Interventions for Early 
OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation.f
Classification of grade is according to Golan’s classification system (see section 8.4 for details) and 
all OHSS cases will be graded as mild, moderate or severe. Preventive interventions for early OHSS 
cover cycle cancellation due to excessive ovarian response, triggering of final follicular maturation 
with GnRH agonist (based on the follicular development and/or serum estradiol criteria) and 
administration of dopamine agonist (the latter is only considered as preventive intervention in 
subjects with ≥20 follicles of ≥12 mm).
7.3
Exploratory Assessment
7.3.1
Blood Collection for Potential Biomarkers
For subjects who provide additional, optional consent, blood samples will be collected at 
stimulation day 1 for potential future analysis of possible biomarkers associated with ovarian 
response.
Results of these potential future exploratory analyses will not be provided to the sites.
7.4
Other Assessments
7.4.1
Demographics
Demographic information will be obtained at screening, including the following: date of birthg,
ethnicity, race.
7.4.2
Medical History
Any relevant medical history will be recorded at screening. This includes diagnoses / symptoms and 
whether it is a past or ongoing occurrence.
7.4.3
Infertility History
Information about the reasons for infertility, duration of infertility, primary infertility and number of 
previous controlled ovarian stimulation cycles will be obtained at screening. 
                                                
f
Note this includes OHSS with onset during stimulation or before triggering.
g
Alternatively, age may be recorded in case country-specific restrictions do not permit recording the full date of birth.


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7.4.4
Body Measurements
Body height and weight will be measured at screening. Body weight will be done without shoes and 
overcoat and using a calibrated scale. 
7.4.5
Physical Examination
A complete physical examination will be performed at screening and end-of-trial. Information will 
be recorded for general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth, and throat), respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system, and skin. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported in the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events.
7.4.6
Gynaecological Examination
A complete gynaecological examination will be performed at screening and end-of-trial. 
Information will be recorded for breast, external genitalia, vagina, cervix, uterus, ovaries and 
fallopian tubes. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported in the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to 
end-of-trial must be recorded as adverse events.
7.4.7
Concomitant Medication
The use of any concomitant medication within the last month 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 medication or treatment must be recorded at each visit. 


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7.4.8
Drug Dispensing and Accountability
The following information will be recorded by the trial medication delegate: 1) dates of 
administration and daily doses of IMP, 2) time of first IMP administration, 3) dates of 
administration and daily doses of GnRH antagonist, 4) date and time of administration as well as 
dose of hCG or GnRH agonist. Details on drug dispensing and accountability are provided in 
section 5.6.
7.5
Assessments Related to Follow-up Information
If a subject achieves a clinical pregnancy after the first transfer cycle, irrespective of whether the 
first transfer takes place in a fresh or frozen cycle, it will be recorded. Clinical pregnancy will be 
defined as at least one gestational sac, either intrauterine or ectopic, 5-6 weeks (35-48 days) after 
transfer. 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.h,16 For intrauterine and ectopic pregnancies, the number of gestational sacs
with fetal heart beat as well as without fetal heart beat will be recorded. Vital pregnancy will be 
defined as at least one intrauterine sac with fetal heart beat 5-6 weeks (35-48 days) after transfer.
The number of blastocysts transferred in the first transfer cycle will also be recorded, allowing for 
calculation of implantation rate (number of gestational sacs 5-6 weeks (35-48 days) after transfer 
divided by number of blastocysts transferred). 
7.6
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. The biological 
samples analysed at central laboratories will be maintained in storage after the end of the trial. 
Destruction will take place within 2 years after reporting of the trial. Exceptions are the blood 
samples collected for potential future analysis of possible biomarkers associated with ovarian 
response, as well as blood samples for which methods / results have not been adequately validated; 
these will be stored for a maximum of 10 years after reporting of the trial, prior to destruction in 
line with local regulations. Potential additional blood samples analysed at local laboratories as part 
of screening assessments or monitoring of the subject during the trial (e.g. criterion for triggering of 
final follicular maturation and evaluation of OHSS), will be destroyed after analysis. The processes 
related to handling of biological samples will be described in the Informed Consent Form, and 
biobank / data protection legislation including local legislation will be adhered to.
                                                
h
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. In addition 
to intrauterine pregnancy, it includes ectopic pregnancy.


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7.7
Implications of COVID-19 Pandemic
The following considerations must be taken into account due to the current coronavirus disease 
2019 (COVID-19) pandemic:

Vaccination against COVID-19
Vaccination against COVID-19 will be recorded at screening as part of the subject’s medical 
history and/or throughout the trial as concomitant medication, and should be reported using 
the term “COVID-19 immunisation”. Based on the currently available information and the 
ESHRE position on COVID-19 vaccination and assisted reproduction17, Ferring’s risk 
assessment is that there will be no protocol-specific requirements on COVID-19 
vaccination.

Medical history related to COVID-19
Past or ongoing occurrence of COVID-19 will be recorded at screening as part of the 
subject’s medical history, and should be reported using the term “COVID-19”.

Adverse events related to COVID-19
In case of confirmed COVID-19 by a SARS-CoV-2 positive test, the term “COVID-19” 
should be used to report the adverse event irrespective of the type of test. In case of 
suspected COVID-19 infection, the term “Suspected COVID-19” should be used to report
the adverse event. In case of recording concomitant medication against COVID-19, the 
indication should be “COVID-19” irrespective of the treatment.

Missing visits / missing data
In case subjects are prevented from attending scheduled visits due to the COVID-19 
pandemic, the investigator (or designee) will attempt to contact the subject by phone or 
other ways to inquire about potential adverse events and changes to concomitant medication.
In case not attending scheduled visits due to the COVID-19 pandemic may have any 
implications in the drug accountability of IMP or NIMP, it should be documented by the 
trial medication delegate.

Protocol deviations due to COVID-19 illness and/or COVID-19 control measures
Protocol deviations should be avoided whenever possible except when necessary to 
eliminate an immediate hazard to the subject. If deviations occur they will be documented as 
per standard practice, with additional specification whether they were related to the 
COVID-19 pandemic.


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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 using MedDRA (the MedDRA version will be documented).
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 last visit (end-of-trial visit). In addition, for subjects who 
undergo transfer in the fresh cycle, assessment of late OHSS (onset >9 days after triggering) will 
take place during the follow-up period.
The sources of adverse events cover:

The subject’s response to questions about his/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).


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8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the Adverse Event Log provided for each subject 
in the EDC with information about:

Adverse event description

Date and time of onset (time can be omitted, if applicable) [note: if date of onset of an event 
is the same as the date of informed consent or date of IMP administration, time is important 
and should not be omitted]

Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

End date and time (time can be omitted, if applicable)

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.i If a subject suffers from a pre-existing medical condition that 
worsens in intensity after signed informed consent, it should be recorded as an adverse event.
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).
                                                
i
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”, without recording end date and time. The second adverse event 
should be recorded with date and time of onset when the intensity changed. 


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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.
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 activities.
Moderate:
Disruption of usual activities (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 or the event recurs on rechallenge.
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.


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An adverse drug reaction is defined as an adverse event assessed to be related to the administration 
of IMP with a reasonable possibility. 
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

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


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8.3
Adverse Events of Special Interest
8.4
Ovarian Hyperstimulation Syndrome
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 classification system18
as shown in Table 8-1 to grade (1, 2, 3. 4 or 5) each OHSS case.
Table 8-1
Classification of Mild, Moderate, and Severe OHSS (Based on Golan’s 
Classification System)
Mild OHSS
Grade 1
Abdominal distension and discomfort 
Grade 2 
Features of grade 1 plus nausea/vomiting and/or diarrhoea. Ovaries enlarged to 
5-12 cm.a)
Moderate OHSS
Grade 3 
Features of mild OHSS plus ultrasonic evidence of ascites.b)
Severe OHSS
Grade 4 
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax (or 
breathing difficulties). Paracentesis due to OHSS symptoms. c)
Grade 5 
All of the above plus change in blood volume, increased blood viscosity due to 
haemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d) Hospitalisation due to OHSS symptoms.
a) For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded. 
b) For subjects with transvaginal evidence of ascitis, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis. 
c) In case of paracentesis, the volume of fluid drained should be measured.
d) Heaemoconcentration is defined as haematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded.
All cases of OHSS must be reported as adverse events. Those that fall under the category SAEs
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). 


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Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of 
final follicular maturationj and late OHSS will be defined as OHSS with onset >9days after 
triggering of final follicular maturation.
Subject narratives will be prepared for all moderate and severe OHSS cases. 
Preventive Interventions of Early OHSS
Preventive interventions of early OHSS include the following: 

Cycle cancellation due to excessive ovarian response

Triggering of final follicular maturation with GnRH agonist 

Administration of dopamine agonist (this is only considered as preventive intervention in 
subjects with ≥20 follicles of ≥12 mm)
Investigations in case of OHSS
The following investigations are recommended for moderate / severe OHSS: 

Blood sample for local laboratory analysis of the following:
-
Progesterone and estradiol
-
CBC
-
CHEM-20 
-
Coagulation parameters (prothrombin time, activated partial thrombin time)
Any preventions of OHSS, e.g. administration of dopamine agonists or other drugs must be 
recorded as concomitant medication. 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.
                                                
j
Note this includes OHSS with onset during stimulation or before triggering.


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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 a congenital anomaly / birth defect
Congenital anomaly / birth defect observed in any offspring of the subject conceived 
during treatment with the IMP.
is an important medical event
Important medical events are events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include adverse events that suggest a 
significant hazard, contraindication or precaution, occurrence of malignancy or 
development of drug dependency or drug abuse. Medical and scientific judgement 
should be exercised in deciding whether events qualify as medically important.
Important medical events include any suspected transmission of an infectious agent 
via a medicinal product. Any organism virus or infectious particle (e.g. prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a subject exposed to a medicinal product.


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8.5.2
Collection, Recording and Reporting of Serious Adverse Events in Core Trial
Serious Adverse Event Reporting by the Investigator
All SAEs must be communicated immediately to Ferring Pharmacovigilance as soon as it becomes 
known to the investigator and not later than within 24 hours of their knowledge of the occurrence of 
an SAE.
The investigator is responsible for providing the completed and signed SAE Report Form with the 
fullest possible details within 3 calendar days of his/her knowledge of the SAE.
The same timelines and requirements apply for both the SAE Report Form and any follow-up with 
additional information regarding the SAE, i.e. 24 hours within obtaining knowledge of the 
follow-up information and 3 calendar days for providing the fullest possible details.
Serious Adverse Event Report Form
The SAE Report Form is included in the EDC, and must be completed and submitted according to 
the instructions provided on the form. In case the EDC cannot be accessed and hence the SAE 
Report Form cannot be filled in within the EDC, a paper SAE Report Form should be used and sent 
to Ferring Pharmacovigilance using the contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: Safety.Mailbox@ferring.com
Fax: (+45) 88 38 01 47
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 EDC for Ferring 
Pharmacovigilance to access the information.
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the EDC), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 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, personal details such as subject’s 
name, address, and hospital name should be concealed and instead subject number should be 
provided.
The investigator will supply Ferring and the IEC/IRB 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 EDC and reviewed by Ferring Pharmacovigilance on an ongoing basis.
Expedited Reporting by Ferring
Ferring will report all 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 the subject’s last visit. 
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 as specified in section 8.5.2. Follow-up must 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 Last Visit in the Trial
If an investigator becomes aware of a SAE after the subject’s last visit, diagnosed either to the 
subject herself or to the fetus / neonate, and the investigator assesses the SAE to have a reasonable 
possible causality to the IMP / NIMP where Ferring is the Marketing Authorisation Holder, the case 
will have to be reported to Ferring, regardless how long after the end of the trial this takes place. 
Follow-up must 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.
8.7
Technical Complaints
If a technical complaint is identified, the investigator must assess whether it may be associated with 
an adverse event and/or an IMP medication error. Technical complaints are reported in accordance 
with the Trial Supply Manual.


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9
STATISTICAL METHODS
9.1
Justification of Sample Size
In a previous trial (MERIT)19, 347 subjects aged 22-37 years were treated with a starting dose of 
225 IU GONAL-F. In these subjects the mean number of oocytes retrieved was 11.8 and the 
standard deviation was 5.7. Assuming that the standard deviation for number of oocytes retrieved in 
this trial will be 6.0, a total sample size of 300 with a 2:1 randomisation will give a 2-sided 95% 
confidence interval ranging from -1.44 to +1.44 oocytes from the observed difference. This level of 
precision is considered as sufficient and is also more precise than the equivalence limits of 
±3 oocytes that has been applied in previous trials comparing biosimilar FSH compounds.
9.2
Subject Disposition
The subject disposition will include all screened subjects and describe the number of randomised, 
treated, completed and discontinued subjects, including reason for discontinuation. For screening 
failures, the primary reason for screening failure will be described. 
9.3
Protocol Deviations
Important protocol deviations are a subset of protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the trial data or that might significantly affect a 
subject’s rights, safety, or well-being. Important protocol deviations will be summarised by 
category and treatment group to reflect general protocol adherence. No protocol deviations will lead 
to exclusion of data from the efficacy analyses. Protocol deviations related to the COVID-19 
pandemic will be identified. 
9.4
Analysis Sets
9.4.1
Full Analysis Set 
The full analysis set (FAS) will consist of all randomised subjects exposed to IMP. Subjects will be 
analysed according to the planned (randomised) treatment.
9.4.2
Safety Analysis Set
The safety analysis set will consist of all randomised subjects exposed to IMP. Subjects will be 
analysed according to the actual treatment received.


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9.5
Trial Population
Demographics and other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics (body measurements, 
ultrasound parameters, endocrine parameters) will be presented for the FAS. A summary of 
demographic characteristics will be presented by trial site.
Medical History
Medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be summarised for the FAS.
Infertility History
Infertility history will be summarised for the FAS.
Physical Examination and Gynaecological Examination
Physical examination and gynaecological examination performed during screening will be 
summarised for the FAS.
Concomitant Medication
Concomitant medications will be coded using the WHO Drug Reference List. Prior and 
concomitant medication will be summarised by Anatomical Therapeutic Chemical Classification 
System (ATC) classification first level (alphabetically) and ATC classification second level for the 
FAS. The following definitions will be used:

Prior medication: medication taken exclusively prior to treatment (i.e. with stop date / time 
before date / time of first IMP administration)

Concomitant medication: medication taken during the treatment period (i.e. medication that 
was not stopped before date / time of first 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.


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9.6
Treatment Compliance
Use of IMP and NIMP will be described for the FAS.
9.7
Endpoint Assessments
9.7.1
General Considerations
Analyses of efficacy endpoints will be based on the FAS. Description of safety data will be based 
on the safety analysis set. Results of statistical analyses will include the estimated treatment 
difference (or ratio), a 95% confidence interval for the difference (or ratio), and the p-value for the 
test of no treatment difference. All analyses are of descriptive nature and no adjustments for 
multiple tests will be applied.
Missing data will in general not be imputed. For subjects without oocyte retrieval, the number of 
oocytes, fertilised oocytes, and blastocysts will be regarded as zero. For pregnancy data, lack of 
data will be interpreted as a negative pregnancy. 
9.7.2
Primary Endpoint
The primary endpoint, number of oocytes retrieved, will be compared between REKOVELLE and 
GONAL-F using a negative binomial model with treatment and AMH level at stimulation day 1 
(AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as factors. The absolute treatment difference in 
number of oocytes retrieved, the associated 95% confidence interval, and the p-value for no 
treatment difference will be derived from the model estimates using the delta method.
The distribution of the number of oocytes retrieved will be described using kernel estimates. 
Furthermore, the ovarian response will be grouped according to the following classification:

<4 oocytes or cycle cancellation due to poor ovarian response

4-7 oocytes

8-14 oocytes

15-19 oocytes

≥20 oocytes or cycle cancellation due to excessive ovarian response

Cycle cancellation due to another reason than poor or excessive ovarian response
The treatment difference will also be investigated for the two sub-groups AMH <15 pmol/L and 
AMH ≥15 pmol/L using the same methods as above.


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9.7.3
Secondary Endpoints
Number of Follicles (Total and by Size Category) at End-of-stimulation
The follicle cohort at end-of-stimulation will be summarised by treatment on the subject level (total 
number of follicles, and number of follicles ≥10 mm, ≥12 mm, ≥15 mm and ≥17 mm). 
The mean number of follicles ≥10 mm, ≥12 mm, ≥15 mm and ≥17 mm at end of stimulation will (in 
separate analyses) be compared between treatments using the same negative binomial regression 
model as used for the primary endpoint. 
Serum Concentrations of Estradiol and Progesterone at End-of-stimulation
Serum concentrations of estradiol and progesterone at the end-of-stimulation visit will be compared 
between treatments using analysis of covariance (ANCOVA) models with treatment and AMH 
level at stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as factors and with the 
serum concentration at stimulation day 1 as a covariate. Multiplicative models will be used, i.e. the 
serum concentrations will be log-transformed before analysis. The results of the analyses will be 
back-transformed and presented as estimated geometric means and mean treatment ratios with 95% 
confidence intervals and p-values. Values below the lower limit of quantification (LLOQ) will be 
estimated with LLOQ/2. Potential values above the upper limit of quantification (ULOQ) will be 
included as ULOQ.
Number of Fertilised Oocytes and Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei on day 1 after oocyte retrieval. The 
mean number of fertilised oocytes will be compared between treatments using the same analysis 
method as for the primary endpoint.  
The proportion of oocytes becoming fertilised will be estimated and compared between treatments 
using a mixed effect binomial model with treatment and AMH level at stimulation day 1 
(AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as fixed factors, and subject as random factor, 
assuming normally distributed log-odds. The treatment difference in fertilisation probability and the 
associated 95% confidence interval will be derived using the delta method. This analysis is based 
on subjects with >0 oocytes retrieved only and is therefore not randomisation based. The 
fertilisation ratio is expected to be equal for the two treatments. If this is not the case, the reason for 
differences will be further explored by including e.g. number of oocytes retrieved as a covariate in 
the analysis model.
Number of Blastocysts (Total and by Quality)
The number and quality of blastocysts on day 5 or day 6 will be described. 


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Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose, the average daily dose, and the number of stimulation days will be 
described for each treatment and also for the subgroups of subjects with AMH <15 pmol/L and 
AMH ≥15 pmol/L. Occurrence of dose adjustments during stimulation will be described.
The number of stimulation days will be compared between treatments using an analysis of variance 
model with treatment and AMH level at stimulation at day 1 (AMH <15 pmol/L,
AMH ≥15 pmol/L, or missing) as factors. 
Early OHSS (Overall and by Grade) and/or Preventive Interventions for Early OHSS
Incidence of early OHSS will be summarised 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.k
Preventive interventions for early OHSS, as well as early OHSS and/or preventive interventions for 
OHSS will be summarised.
Data will be described for each treatment and also for the subgroups of subjects with AMH 
<15 pmol/L and AMH ≥15 pmol/L.
9.8
Exploratory Assessment
Blood Collection for Potential Biomarkers
Potential future analysis of possible biomarkers associated with ovarian response will be reported 
separately from the clinical trial report.
9.9
Adverse Events
Adverse events will be grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before the first dose of IMP, or a pre-existing medical condition that worsens in 
intensity after signed informed consent but before the first dose of IMP.

Treatment-emergent adverse event, i.e. any adverse event occurring after the first dose of 
IMP and before the end-of-trial visit, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after the first dose of IMP and before the end-of-
trial visit.
                                                
k
Note this includes OHSS with onset during stimulation or before triggering.


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Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only. Treatment-emergent adverse events will be 
summarised overall and tabulated by System Organ Class (SOC) and Preferred Term (PT). 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 described.
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.
For adverse events, a worst-case approach will be used for causality, intensity, seriousness, and 
outcome, in case these would be missing. If the timing of the onset of an adverse event cannot be 
established in relation to IMP, it will be considered as a treatment-emergent adverse event.
9.10
Additional Safety Evaluations
Physical Examination
Physical examination at screening and end-of-trial will be summarised in shift tables.
Gynaecological Examination
Gynaecological examination at screening and end-of-trial will be summarised in shift tables.
9.11
Follow-up Assessments
For subjects with a clinical pregnancy, the type of clinical pregnancy (intrauterine or ectopic) will 
be described. For subjects with a vital pregnancy, the number of intrauterine gestational sacs with 
fetal heart beat and the number of fetal heart beats will also be described.
Pregnancy rates in the first transfer cycle will be compared between treatments using logistic 
regression models with treatment and age group (<35, 35-37, or 38-40 years) as factors. The results 
of these analyses (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. In these analyses 
subjects with no transfer or missing data on pregnancy will be regarded as non-pregnant. 
The implantation rate in the first transfer cycle will be estimated and compared between treatments 
using a mixed effect logistic regression model with treatment, age group (<35, 35-37, or 38-40 
years), and number of blastocysts transferred (single or multiple) as fixed factors, and subject as 
random factor, assuming normally distributed log-odds. The estimated treatment difference in 


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probability of implantation and the associated 95% confidence interval will be calculated from the 
model estimates using the delta method. This analysis is based on subjects with transfer only and is 
therefore not randomisation based. The treatment difference for implantation rate is expected to be 
consistent with the treatment difference for pregnancy rates. If this is not the case, the reason for 
differences will be further explored by including e.g. day of transfer as a factor in the analysis 
model.
For subjects who undergo transfer in the fresh cycle, incidence of late OHSS will be summarised by 
classification (mild, moderate, severe, moderate or severe) and grade (1, 2, 3, 4, 5). Late OHSS is 
defined as OHSS with onset >9 days after triggering of final follicular maturation. Data will be 
described for each treatment and also for the subgroups of subjects with AMH <15 pmol/L and 
AMH ≥15 pmol/L.
9.12
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 screened, the investigator will indicate as a minimum in the source 
documents, that the informed consent is obtained, that the subject participates in this trial, and 
whether the subject is a screening failure and the reason for screening failure, if applicable. In 
addition, for each subject randomised the investigator will indicate in the source documents at least 
the following information, if applicable: 

Existence of subject (initials, date of birth) 

Confirmation of participation in trial (trial ID, subject ID)

Informed consent (date and time of obtaining written informed consent)

Eligibility for participation in the trial (documenting all inclusion / exclusion criteria)

Relevant medical history and infertility history

Body weight and height

Visit dates

Dates and daily doses of IMP 

Dates and daily doses of NIMP

Dates and dosage regimen of concomitant medication 

Follicular development


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
Date of oocyte retrieval and number of oocytes retrieved

Number and quality of blastocysts 

Adverse events (description as well as start / stop date and time)

OHSS symptoms, preventive interventions, investigations and treatments

Reason for discontinuation, if applicable

Event of unblinding, including the reason for unblinding

Date of transfer and number of blastocysts transferred (first transfer cycle )

Ultrasound results at clinical pregnancy visit (first transfer cycle)
No specific protocol data can be recorded directly in the EDC 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 paper data sheets for source data 
as an exception.
The source data for the endocrine parameters will be available at the central laboratory.
10.2
EDC
An EDC provided by an independent third-party contract research organisation (CRO) will be used 
for data capture. The EDC is validated and access at all levels is granted / revoked following 
sponsor and vendor procedures, in accordance with regulatory requirements and EDC requirements.
Data should be entered into the EDC within a reasonable time after the subject has attended a visit 
or after the data become available, as applicable.
The investigator will, in a timely manner, approve / authorise the EDC entries for each subject, with 
the exception of the treatment allocation module which is un-accessible to the investigator to 
maintain the assessor-blinding, with an electronic signature which is equivalent to a handwritten 
signature.
The EDC and the database will be hosted at the independent third-party CRO. After the trial 
database is declared clean and locked, a final copy of the database will be stored at Ferring. The 
investigator will also receive a copy of the trial site’s final and locked data (including subject 
treatment allocation, 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 EDC is revoked. 


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Errors occurring in the EDC entries 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
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
department, Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection and validation.
The data management plan will also include information about the intended use of computerised 
systems, a description of the security measures employed to protect the data, and a description of 
the electronic data flow.
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Council for Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of EDC 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. Clinical trial site 
monitoring may also be conducted remotely. In addition to on-site monitoring visits, remote 
monitoring is also an option. Remote monitoring is conducted off-site and may include video 
conference, telephone contact, and remote review of trial systems.
When the first subject is randomised at the trial site, a monitoring visit will take place shortly 
afterwards. 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.
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/IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to evaluate trial conduct and compliance with the 
trial protocol, ICH-GCP, including the Declaration of Helsinki20 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/IRBs 
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/IRB.


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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 
EDC 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 Form, 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, if applicable, prior to its implementation. Amendments 
may be submitted for consideration to the approving IECs/IRBs 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/IRB 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, either as answer to a query in the EDC, in a protocol deviation report or a 
combination of both. A log of protocol deviation reports will be maintained by Ferring. Protocol 
deviation reports and supporting documentation must be kept in the Investigator’s File and in the 
Trial Master File.
12.3
Premature Trial Termination
At any time, the investigator has the right to terminate his/her participation in the trial, and Ferring 
has the right to terminate the trial at any time. Should termination 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 IECs/IRBs 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. The signatory 
investigator will be one of the principal investigators participating in the trial who will be assigned 
by Ferring prior to initiation of this trial. The choice of the signatory investigator among the 
participating investigators will be based on several criteria, such as previous participation in GCP 
trials, national recognition as a fertility expert, and willingness to support this trial including signing
the clinical trial report.
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, any 
publication must acknowledge all sites, and the results must be reported in a responsible and 
coherent manner. Ferring requires that the results from multi-site trials are published only in their 
entirely, and not as individual site data.
In addition, the following requirements must be adhered to:
(i) a presentation or publication of the results must not take place until eighteen (18) months after 
locking of the trial database, unless a) the results of the trial have already been published by 
Ferring, or b) specific written permission for publication is obtained in advance from Ferring; 
(ii) at least sixty (60) days in advance of any publication or presentation (or submission hereof) 
related to the trial, a copy of the relevant publication or presentation must be furnished to Ferring 
for review and redaction of confidential information. At Ferring’s request, investigator(s) must 
delay the publication or presentation for up to an additional ninety (90) days to enable Ferring to 
file patent applications or other intellectual property protection;
(iii) Ferring must be identified as the sponsor of the trial in any publication and presentation 
(including professional meetings and symposia).


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Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE)
criteria (see current official version: http://www.ICMJE.org). 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 CRO or external laboratory involved in the conduct of this trial has no publication rights 
regarding this trial.
13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate public registry, e.g.
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 / Institutional Review Board 
An IEC/IRB will review the protocol, any potential protocol amendments and potential 
advertisements used for recruitment. The IEC/IRB will review the Informed Consent Form, its
updates (if any), and any written materials given to the subjects. A list of all IECs/IRBs 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 (last patient’s end-of-trial visit). 
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 
IEC/IRBs in the participating countries, when the last data in the post-trial follow-up period has 
been collected in all participating countries.
In the case of early termination, Ferring must notify the end of the trial to the national regulatory 
authorities and the concerned IECs/IRBs 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. 
Within one year of the end of the trial, Ferring shall send a summary of the final Clinical Trial 
Report to the national regulatory authorities and the concerned IECs/IRBs.
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 Form 
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 (or the person delegated 
by 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 (or the person delegated by 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 signed 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 Informed Consent Form will be forwarded to the 
IECs/IRBs (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, 
IECs/IRBs 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.
Optional Consent for Potential Future Analysis of Possible Biomarkers
The investigator (or the person delegated by the investigator) will obtain, within the same Informed 
Consent Form, additional, optional consent from the subject after an appropriate explanation of the 
potential future analysis of possible biomarkers associated with ovarian response, and information 
that participation is optional.
The investigator (or the person delegated by the investigator) will explain that the subject is 
completely free to refuse to consent to this optional extra blood sample, without any consequences 
for her further care and without the need to justify her decision.
Partner Privacy Notice
The privacy notice explains the possibility that the partner’s personal information (such as name, 
infertility diagnosis, etc.) may be included in the subject’s medical records. 


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The partner will be informed that the monitor(s), quality assurance auditor(s) mandated by Ferring,
IEC/IRB representatives or regulatory authority inspector(s), in accordance with applicable
regulatory requirements, may have access to the partner’s personal information (such as name, 
infertility diagnosis, etc.). Protection of personal data will be handled in accordance with national / 
local regulations. Ferring will not collect, use or store any of the partner’s personal data. The 
partner privacy notice must be given to the partner before the subject is randomised.
14.6
Trial Participation Card
The subject will be provided with a Trial Participation Card bearing the following information:

That she is participating in a clinical trial

That the trial involves controlled ovarian stimulation with recombinant FSH

The name and phone number of the investigator

The name, address, and phone number of Ferring contact (as required by local regulations).
Additionally, each subject’s primary care physician will be notified of their participation in the trial 
by the investigator, if the subject agrees and if applicable.
14.7
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP and other national law(s) in the countries 
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator 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, 
including being responsible for all trial-related medical decisions, for dispensing the IMP in 
accordance with the approved protocol or an approved amendment, and for its secure storage and 
safe handling throughout the trial.
15.2
Liabilities and Insurance
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records that enable the conduct of the trial at 
the site to be fully understood, and for maintaining a record of the location of their essential 
documents including source documents, in accordance 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 EDC data for Ferring. The investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Form 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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17
REFERENCES
1
Arce J-C, Larsson P, García-Velasco JA. Establishing the follitropin delta dose that provides 
a comparable ovarian response to 150 IU/day follitropin alfa. Reprod Biomed Online 2020; 
41: 616-622.
2
REKOVELLE Summary of Product Characteristics.
https://www.ema.europa.eu/en/documents/product-information/rekovelle-epar-product-
information_en.pdf
3
GONAL-F Summary of Product Characteristics.
https://www.ema.europa.eu/en/documents/product-information/gonal-f-epar-product-
information_en.pdf
4
Daya, S. Issues in assessing therapeutic equivalence. Evidence-based Obstetrics and 
Gynecology 2001; 3: 167-168.
5
Daya, S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 
2003; 18: 1005-1009.
6
Griesinger G, von Otte S, Schroer A, Ludwig AK, Diedrich K, Al-Hasani S, Schultze-
Mosgau A. Elective cryopreservation of all pronuclear oocytes after GnRH agonist 
triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, 
observational proof-of-concept study. Hum Reprod 2007; 22: 1348-1352.
7
Griesinger G, Kolibianakis EM, Papanikolaou EG, Diedrich K, Van Steirteghem A, 
Devroey P, Ejdrup Bredkjær H, Humaidan P. Triggering of final oocyte maturation with 
gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Live birth after 
frozen-thawed embryo replacement cycles. Fertil Steril 2007; 88: 616-621.
8
Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of 
gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after 
cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization 
prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized 
controlled study. Fertil Steril 2008; 89: 84-91.
9
Humaidan P, Papanikolaou EG, Tarlatzis BC. GnRHa to trigger final oocyte maturation: a 
time to reconsider. Hum Reprod 2009; 24: 2389-2394.
10
Herrero L, Pareja S, Losada C, Cobo AC, Pellicer A, García-Velasco JA. Avoiding the use 
of human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist 
triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome. 
Fertil Steril 2011; 95: 1137-1140.


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11
Bodri D, Guillén JJ, Trullenque M, Schwenn K, Esteve C, Coll O. Early ovarian 
hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone 
agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up 
study. Fertil Steril 2010; 93: 2418-2420.
12
FYREMADEL Summary of Product Characteristics.
13
OVITRELLE Summary of Product Characteristics.
https://www.ema.europa.eu/en/documents/product-information/ovitrelle-epar-product-
information_en.pdf
14
GONAPEPTYL Summary of Product Characteristics. 
15
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 fertilisation and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388.
16
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, 2017, 2017. Fertil Steril 2017; 1083: 393-406.
17
European Society of Human Reproduction and Embryology (ESHRE) statement on 
COVID-19 vaccination and medically assisted reproduction. 
https://www.eshre.eu/Europe/Position-statements/COVID19/vaccination (Accessed on 
23 April 2021)
18
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation 
syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430-440.
19
Nyboe Andersen A, Devroey P, Arce J-C. Clinical outcome following stimulation with HP-
hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind 
controlled trial. Hum Reprod 2006; 21: 3217-3227.
20
World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly, Fortaleza, Brazil, October 2013.


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STATISTICAL ANALYSIS PLAN
A randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial 
comparing the ovarian response of a starting dose of 15 µg follitropin delta (REKOVELLE) 
to a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional regimens in controlled 
ovarian stimulation in women undergoing an assisted reproductive technology programme
Trial 000401 
ADAPT-1
(Assessment of Conventional Dosing in Women undergoing ART 
with Follitropin Delta Treatment)
Investigational Medicinal Product:
Follitropin delta (REKOVELLE)
(Ferring compound ID: FE 999049) 
human recombinant follicle-stimulating hormone (rFSH)
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
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
2.0
08OCT2024
First version
Technical update of header to include REAL ID. 
No change in content.
None
1.0


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TABLE OF CONTENTS
1
INTRODUCTION..................................................................................................................................5
1.1
Abbreviations..................................................................................................................................5
2
TRIAL OBJECTIVES AND ENDPOINTS.........................................................................................6
2.1
Objectives .......................................................................................................................................6
2.2
Endpoints........................................................................................................................................6
3
TRIAL DESIGN.....................................................................................................................................7
3.1
Overall Design and Control Methods .............................................................................................7
3.1.1
Trial Design Diagrams...........................................................................................................9
3.1.2
Trial Flow Chart – Subject Procedures................................................................................10
3.1.3
Trial Flow Chart - Oocyte / Blastocyst Procedures.............................................................11
3.2
Determination of Sample Size ......................................................................................................11
4
SUBJECT DISPOSITION...................................................................................................................11
5
PROTOCOL DEVIATIONS...............................................................................................................12
6
ANALYSIS SETS.................................................................................................................................12
6.1
Intention-To-Treat Analysis Set ...................................................................................................12
6.2
Full Analysis Set...........................................................................................................................12
6.3
Per-Protocol Analysis Set.............................................................................................................12
6.4
Safety Analysis Set.......................................................................................................................12
7
TRIAL POPULATION .......................................................................................................................12
7.1
Demographics and other Baseline Characteristics........................................................................12
7.1.1
Demographics......................................................................................................................13
7.1.2
Body Measurements ............................................................................................................13
7.1.3
Endocrine Parameters..........................................................................................................13
7.1.4
Transvaginal ultrasound ......................................................................................................13
7.1.5
Medical History...................................................................................................................13
7.1.6
Infertility History and Previous Fertility Treatment............................................................13
7.1.7
Gynaecological Examination...............................................................................................13
7.1.8
Physical Examination..........................................................................................................13
8
PRIOR AND CONCOMITANT MEDICATION.............................................................................14
9
EXPOSURE AND TREATMENT COMPLIANCE.........................................................................14
9.1
Extent of Exposure........................................................................................................................14
9.1.1
IMP (Gonadotropins)...........................................................................................................14
9.1.2
GnRH Antagonist................................................................................................................14
9.1.3
Triggering of Final Follicular Maturation ...........................................................................14
9.1.4
Treatment Compliance ........................................................................................................15
10
EFFICACY...........................................................................................................................................15
10.1
Primary Efficacy Endpoint ...........................................................................................................15
10.2
Secondary Efficacy Analyses .......................................................................................................16
10.3
Exploratory Assessment ...............................................................................................................18
10.4
Follow-up Assessments ................................................................................................................18
11
SAFETY................................................................................................................................................19
11.1
General Considerations.................................................................................................................19


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11.2
Adverse Events .............................................................................................................................19
11.3
Additional Safety Evaluations ......................................................................................................20
12
INTERIM ANALYSES .......................................................................................................................20
13
DEVIATIONS FROM THE PROTOCOL........................................................................................20
14
REFERENCES.....................................................................................................................................22
List of Tables
Table 3-1
Trial Flow Chart – Subject Procedures...................................................................................10
Table 3-2
Trial Flow Chart – Oocyte / Blastocyst Procedures ...............................................................11
Table 10-1 
Overview of analysis methods for secondary endpoints.........................................................16
Table 10-2 
Overview of analysis methods for follow-up assessments .....................................................18
List of Figures
Figure 3-1
Trial Diagram – Trial Period ....................................................................................................9
Figure 3-2
Trial Diagram – Follow-up Period (First Transfer Cycle)......................................................10


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1
INTRODUCTION
This document describes the planned statistical analyses for the trial 000401 and is based on the 
final Clinical Trial Protocol version 2.0 dated 21st of January 2022. If there are any differences 
between the statistical analysis plan (SAP) and the protocol, the SAP will reflect the updated statistical 
analyses. Main changes to the statistical analyses compared to the protocol, and the reasons for these, 
are described in Section 13.
1.1
Abbreviations
AE
adverse event
AMH
anti-müllerian hormone
ART
assisted reproductive technologies
ATC 
anatomic therapeutic chemical 
BMI
body mass index
EOS
end-of-stimulation
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
IVF
in vitro fertilisation
LH
luteinising hormone
LLOQ
lower limit of quantification
MedDRA
medical dictionary for regulatory activities
NIMP
non-investigational medicinal product
OHSS
ovarian hyperstimulation syndrome
OR
oocyte retrieval
PD
protocol deviation
PN
pronuclei
PP
per-protocol
PT
preferred term
rFSH
recombinant follicle-stimulating hormone
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
ULOQ
upper limit of quantification


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To compare a starting dose of 15 µg REKOVELLE to a starting dose of 225 IU GONAL-F 
in conventional regimens with respect to ovarian response in women undergoing controlled 
ovarian stimulation
Secondary Objectives

To compare the follicular development, endocrine profile and embryo development 
associated with conventional dosing of REKOVELLE and GONAL-F

To compare the treatment efficiency associated with conventional dosing of REKOVELLE 
and GONAL-F

To compare the safety profile associated with conventional dosing of REKOVELLE and 
GONAL-F
2.2
Endpoints
Primary Endpoint

Number of oocytes retrieved
Secondary Endpoints

Number of follicles (total and by size category) at end-of-stimulation

Serum concentrations of estradiol and progesterone at end-of-stimulation

Number of fertilised oocytes and fertilisation rate

Number of blastocysts (total and by quality) 

Total gonadotropin dose and number of stimulation days

Early OHSS (overall and by grade) and/or preventive interventions for early OHSS
Exploratory Assessment

Blood sample on stimulation day 1 for potential future analysis of possible biomarkers 
associated with ovarian response (requires additional, optional consent)
Follow-up Assessments

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) in the first 
transfer cycle 


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
Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred) in the first transfer cycle
Note: the first transfer cycle covers cycles with transfer occurring within 3 months after start of 
stimulation
3
TRIAL DESIGN
3.1
Overall Design and Control Methods
Trial period
This is a randomised, controlled, assessor-blind, parallel groups, multicentre, multinational trial 
comparing the ovarian response associated with a starting dose of 15 µg follitropin delta 
(REKOVELLE) and a starting dose of 225 IU follitropin alfa (GONAL-F) in conventional 
regimens. The primary endpoint is the number of oocytes retrieved, and secondary endpoints 
include pharmacodynamic parameters of FSH action as well as efficacy and safety parameters 
related to controlled ovarian stimulation. Treatment efficiency in terms of gonadotropin use and 
duration of stimulation will also be evaluated. The assessor-blind design ensures that the 
investigators and other assessors such as embryologists are blinded to individual treatment 
allocation. A trial medication delegate will be responsible for all trial medication related issues, 
both practically at the clinic and in interactions with the subject.
Subjects will be screened within 90 days prior to randomisation for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 2:1 ratio 
to treatment with either REKOVELLE or GONAL-F, and stimulation will be initiated. Subjects 
randomised to REKOVELLE will receive a daily starting dose of 15 µg which will be fixed for at 
least the first four stimulation days. Dose adjustments may be implemented on the day of starting 
the GnRH antagonist (stimulation day 5 or day 6) or later, and can occur no more frequently than 
once every second day. At each dose adjustment, the daily REKOVELLE dose can be increased or 
decreased by 5 µg based on the subject’s response. The minimum REKOVELLE dose is 5 µg and 
the maximum REKOVELLE dose is 20 µg. Subjects randomised to GONAL-F will receive a daily 
starting dose of 225 IU which will be fixed for at least the first four stimulation days. Dose 
adjustments may be implemented on the day of starting the GnRH antagonist (stimulation day 5 or 
day 6) or later, and can occur no more frequently than once every second day. At each dose 
adjustment, the daily GONAL-F dose may be adjusted by 75 IU based on the subject’s response. 
The minimum GONAL-F dose is 75 IU and the maximum GONAL-F dose is 300 IU. Subjects can 
be treated with rFSH for a maximum of 20 days, and coasting is not allowed. 
To prevent a premature LH surge, a GnRH antagonist (ganirelix acetate, FYREMADEL, 
SUN Pharma) will be initiated on stimulation day 5 or day 6 at a daily dose of 0.25 mg and 
continued throughout the stimulation period. Triggering of final follicular maturation will be done 
as soon as ≥3 follicles with a diameter ≥17 mm are observed (i.e. on the day or the day after). 
Triggering can also be done in case 1 or 2 follicles with a diameter ≥17 mm are observed and the 
investigator judges that ≥3 follicles with a diameter ≥17 mm cannot be reached, and that triggering 


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is preferred instead of cycle cancellation. The triggering drug will be either human chorionic 
gonadotropin (hCG) or GnRH agonist, depending on the extent of ovarian response and whether 
transfer in the fresh cycle or in a subsequent frozen cycle (including a freeze-all approach) is 
intended. If transfer in the fresh cycle is intended, 250 µg hCG (choriogonadotropin alfa, 
OVITRELLE, Merck) will be administered. If there are ≥25 follicles with a diameter ≥12 mm or the 
serum estradiol is ≥5,000 pg/mL (18,355 pmol/L) (local laboratory) or a freeze-all approach is 
intended, 0.2 mg GnRH agonist (triptorelin acetate, GONAPEPTYL, Ferring) will be administered. 
Moreover, if these criteria for triggering with GnRH agonist are not met, but the investigator judges 
that the subject is at risk of developing OHSS and that triggering with hCG is not advisable, the 
subject can undergo triggering with GnRH agonist. In case of poor ovarian response, defined as the 
investigator judging that the triggering criterion cannot be reached by day 20, the cycle is to be 
cancelled. In case of excessive ovarian response, defined as the investigator judging that triggering 
of final follicular maturation is not advisable due to safety concerns, the cycle is to be cancelled. 
The number and size of follicles at the end-of-stimulation will be recorded.
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation. All oocytes 
from follicles with an estimated diameter ≥12 mm must be retrieved. The oocytes can be 
inseminated by IVF and/or ICSI. Fertilisation will be assessed on day 1 after oocyte retrieval. The 
number and quality of blastocysts will be assessed at the last day of culture, i.e. day 5 or day 6 (as 
applicable) after oocyte retrieval. The day 5 / day 6 blastocyst quality assessment will be based on 
the Gardner & Schoolcraft blastocyst scoring system.1 Blastocysts that are not transferred in the 
fresh cycle will be cryopreserved in accordance with local guidelines and/or regulations. 
Blood samples will be collected at stimulation day 1 for measurement of AMH, estradiol and 
progesterone as well as at end-of-stimulation for measurement of estradiol and progesterone. For 
subjects who provide additional, optional consent, blood samples will be collected at stimulation 
day 1 for potential future analysis of possible biomarkers associated with ovarian response.
For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take 
place 9-14 days after triggering to cover the assessment of early OHSS (onset ≤9 days after 
triggering). For subjects who do not undergo triggering of final follicular maturation, the end-of-
trial assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a 
separate end-of-trial visit within 7 days of the last scheduled trial visit). If trial procedures and/or 
assessments are to be performed on Sundays, public holidays or outside the opening hours of the 
clinic, the procedures and/or assessments can be postponed to the upcoming weekday (maximum 
one day after original visit schedule). 
Follow-up Period – First Transfer Cycle
Follow-up information will be collected from the subject’s first transfer cycle, irrespective of 
whether the first transfer takes place in a fresh or frozen cycle. This follow-up covers cycles with 
the transfer procedure occurring within 3 months after start of stimulation. 
Depending on blastocyst availability, it is expected that subjects who underwent triggering of final 
follicular maturation with hCG will undergo transfer on day 5 after oocyte retrieval and that 


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subjects who underwent triggering of final follicular maturation with GnRH agonist will undergo 
transfer in a frozen cycle using blastocysts cryopreserved on day 5 or day 6 after oocyte retrieval. 
The number of transferred blastocyst(s) in the first fresh or frozen cycle will be based on the 
subject’s wishes and the investigator’s recommendation and in accordance with local guidelines 
and/or regulations. The number and quality of transferred blastocyst(s) will be recorded. Luteal 
phase support in fresh and frozen cycles as well as potential other medicinal products for 
programming of frozen cycles will be in accordance with the site’s clinical practice.
Clinical pregnancy in the first transfer cycle will be assessed by transvaginal ultrasound 5-6 weeks 
(35-48 days) after transfer, and the number of gestational sacs will be recorded. For subjects who 
undergo transfer in the fresh cycle, assessment of late OHSS (onset >9 days after triggering) will 
take place during the follow-up period.
3.1.1
Trial Design Diagrams
A diagram illustrating the trial period is shown in Figure 3-1.
Figure 3-1
Trial Diagram – Trial Period
Randomisation
day 2-3 of
menstrual cycle
Screening
Triggering + 
36±2 h
Oocyte retrieval
Transfer 
(if fresh cycle)
9-14 days after 
triggering
End-of-trial
OR +
5 days
Triggering 
of final follicular 
maturation
Endocrine
Stimulation 
day 1
TVU
Triggering 
drug
End of stimulation
Controlled ovarian stimulation  
REKOVELLE
GONAL-F
GnRH antagonist
FYREMADEL 0.25 mg
Endocrine
TVU
Bio-
markers
Start of GnRH 
antagonist
Stimulation 
day 5 or 6
OR: Oocyte retrieval; TVU: Transvaginal ultrasound


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A diagram illustrating the follow-up period in the first transfer cycle is shown in Figure 3-2.
Figure 3-2
Trial Diagram – Follow-up Period (First Transfer Cycle)
3.1.2
Trial Flow Chart – Subject Procedures
The flow of the trial procedures for subjects is shown in Table 3-1.
Table 3-1
Trial Flow Chart – Subject Procedures
Screening
Stimulation
Oocyte retrieval
End
Start of stimulation
Start of GnRH 
antagonist
End-of-stimulation
End-of-trial a)
<90 days 
before 
randomisation
Day 1
Day 5 or day 6 b)
End
36h ± 2h after 
triggering
Written informed consent
X
Inclusion/exclusion criteria
X
  X c)
Demographics
X
Medical history 
X
Infertility history
X
Body weight, height
X
Physical examination
X
X
Gynaecological examination
X
X
Urinary pregnancy test
X
  X c)
Transvaginal ultrasound
  X c)
X
Blood collection, endocrine d)
  X c)
X
Blood collection, potential 
biomarkers e)
  X c)
Randomisation
X
IMP dispensing
X
X
NIMP dispensing
X
X
Oocyte retrieval
X
Drug accountability
X
X
X
Concomitant medication
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
a) For subjects who undergo triggering of final follicular maturation, the end-of-trial visit must take place 9-14 days after triggering to cover 
the assessment of early OHSS (onset ≤9 days after triggering). For subjects who do not undergo triggering of final follicular maturation, the 
end-of-trial assessments must be performed at the subject’s last scheduled trial visit (or alternatively at a separate end-of-trial visit within 
7 days of the last scheduled trial visit).
b) GnRH antagonist will be initiated on stimulation day 5 or day 6. 
c) Performed before the first IMP dose.
d) Stimulation day 1: AMH, estradiol and progesterone; end-of-stimulation: estradiol and progesterone. 
e) Additional, optional, consent required. 
GnRH: gonadotropin-releasing hormone, IMP: investigational medicinal product, NIMP: non-investigational medicinal product, OHSS: ovarian 
hyperstimulation syndrome
Transfer
5-6 weeks after 
transfer
TVU
TVU: Transvaginal ultrasound
Number and 
quality of 
transferred 
blastocyst(s)
Clinical pregnancy


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3.1.3
Trial Flow Chart - Oocyte / Blastocyst Procedures
The flow of the trial procedures for oocytes and blastocysts is shown in Table 3-2.
Table 3-2
Trial Flow Chart – Oocyte / Blastocyst Procedures
Day 0 (OR)
Day 1 
after OR
Day 5 after 
OR
Day 6 after 
OR
Oocyte retrieval (OR)
X
Insemination by IVF and/or ICSI
X
Assessment of oocyte fertilisation
X
Assessment of blastocyst quality a)
X
X
Transfer in fresh cycle, if applicable
X
Cryopreservation
X
X
a)
Assessment to be performed on last day of culture only.
ICSI: intracytoplasmic sperm injection, IVF: in vitro fertilisation, OR: oocyte retrieval
3.2
Determination of Sample Size
In a previous trial (MERIT)2, 347 subjects aged 22-37 years were treated with a starting dose of 
225 IU GONAL-F. In these subjects the mean number of oocytes retrieved was 11.8 and the 
standard deviation was 5.7. Assuming that the standard deviation for number of oocytes retrieved in 
this trial will be 6.0, a total sample size of 300 with a 2:1 randomisation will give a 2-sided 95% 
confidence interval ranging from -1.44 to +1.44 oocytes from the observed difference. This level of 
precision is considered as sufficient and is also more precise than the equivalence limits of 
±3 oocytes that has been applied in previous trials comparing biosimilar FSH compounds.
4
SUBJECT DISPOSITION
The subject disposition will include all screened subjects and describe the number of randomised, 
treated, completed and discontinued subjects, including reason for discontinuation. Screened 
subjects who discontinue from the trial prior to randomisation are classified as screening failures. 
Screening failures and the primary reason for screening failure will be described. Subject 
disposition with respect to analysis sets will also be tabulated and will include the number of 
subjects in the Intention-To-Treat (ITT) Analysis Set, the Full Analysis Set (FAS), the Per-Protocol 
(PP) Analysis Set and the Safety Analysis Set. Subject disposition tables will be produced overall 
and by AMH level at stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) and will 
include the two treatment groups (i.e. REKOVELLE and GONAL-F) and a total column.  


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5
PROTOCOL DEVIATIONS
Important protocol deviations (PDs) will be rated as either minor or major. Protocol deviations 
substantially impacting the primary endpoint and thereby affecting the conclusions of the trial will 
be rated as major. Major protocol deviations will lead to exclusion of data from the PP analysis set. 
Data will not be excluded from the data analysis in case of minor protocol deviations.
The rating of the important PDs as ‘minor’ and ‘major’ will be decided by the Statistician and Medical 
responsible based on a blinded review of data before declaration of clean file and lock of database. 
Major protocol deviations will be summarised by category and treatment group to reflect general 
protocol adherence.
Major protocol deviations will be tabulated and listed by subject for the FAS. The list will be sorted 
by country, centre and subject number.
6
ANALYSIS SETS
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set comprises all randomised subjects. Subjects will be 
analysed according to the planned (randomised) treatment.
6.2
Full Analysis Set 
The full analysis set (FAS) will consist of all randomised subjects exposed to IMP. Subjects will be 
analysed according to the planned (randomised) treatment.
6.3
Per-Protocol Analysis Set
The Per-Protocol (PP) analysis set is defined as all randomised and exposed subjects except those 
with major protocol deviations as described in Section 5.
6.4
Safety Analysis Set 
The safety analysis set will consist of all randomised subjects exposed to IMP. Subjects will be 
analysed according to the actual treatment received.
7
TRIAL POPULATION
7.1
Demographics and other Baseline Characteristics
All relevant baseline data obtained before first exposure to IMP will be based on the FAS and 
tabulations will be produced overall and by AMH level at stimulation day 1 (AMH<15 pmol/L, 
AMH ≥15 pmol/L, or missing) and will include both treatment groups and a total column. Baseline 
data will not be compared using statistical tests. Continuous variables will be presented with 
number of subjects, mean, standard deviation, median, inter-quartile range, minimum and 
maximum. Categorical variables will be presented with number and percentage of subjects within 
each specific category. Missing data will not be imputed.


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7.1.1
Demographics
The following demographic information will be tabulated: Age at randomisation (years), age 
category at randomisation (<35, 35-37, 38-40), ethnicity, race and country.
7.1.2
Body Measurements
The following body measurements at screening will be summarised: Body weight (kg), body weight 
category (<45, 45-<55, 55-<65, 65-<75, 75-<85, 85-<95, ≥95), height (m), BMI (kg/m2), BMI 
category (<18.5, 18.5-<25.0, 25.0-<30.0, ≥30.0).
7.1.3
Endocrine Parameters
The following endocrine parameters measured at stimulation day 1 will be tabulated: AMH 
(pmol/L), AHM category (<15 pmol/L, ≥15 pmol/L, missing), progesterone (nmol/L) and estradiol 
(pmol/L).  
7.1.4
Transvaginal ultrasound
The number of antral follicles on stimulation day 1 will be summarised and tabulated using 
categories (0-4, 5-9 and ≥10 antral follicles).
7.1.5
Medical History
Medical history recorded at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarised. The version of MedDRA will be documented. 
7.1.6
Infertility History and Previous Fertility Treatment
The following data on infertility history will be tabulated: Number of subjects with primary 
infertility, duration of infertility (months) and primary reason for infertility.
The following data on previous fertility treatment cycles will be tabulated: Number of subjects with 
at least one previous fertility treatment cycle and number of previous fertility treatment cycles per 
subject.
7.1.7
Gynaecological Examination
Gynaecological examination performed at screening covers the categories breast, external genitalia, 
vagina, cervix, uterus, ovaries and fallopian tubes. Each category will be evaluated as normal, 
abnormal not clinically significant or abnormal clinically significant. Gynaecological examination 
at screening will be summarised by category. 
7.1.8
Physical Examination 
Physical examination performed at screening covers the categories general appearance, central and 
peripheral nervous system, head and neck, respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system and skin. Each 
category will be evaluated as normal, abnormal not clinically significant, abnormal clinically 
significant or not done. Physical examination at screening will be summarised by category. 


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8
PRIOR AND CONCOMITANT MEDICATION
Medications will be coded using the World Health Organization Drug Reference List and 
categorised as either

Prior medication: medication taken exclusively prior to treatment (i.e. with stop date/time 
before date/time of first IMP administration)

Concomitant medication: medication taken during the treatment period (i.e. medication that 
was not stopped before date/time of first 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.
Prior and concomitant medication will be summarised by Anatomical Therapeutic Chemical 
Classification System (ATC) classification first level (alphabetically) and ATC classification 
second level for the FAS and produced by treatment group and in total. 
9
EXPOSURE AND TREATMENT COMPLIANCE
9.1
Extent of Exposure 
Duration of treatment (days) is defined as the number of days from first exposure to the day of last 
exposure (both inclusive). If a subject misses an intermediate dose she will still be considered as 
being under treatment. Tabulations will be produced for the Safety Analysis Set and the FAS (in 
case they differ) and will include both treatment groups and a total column. 
9.1.1
IMP (Gonadotropins)
Exposure to gonadotropins will be summarised as the total dose administered, the average daily 
dose and duration of treatment (days). The total dose will be reported in µg for REKOVELLE and 
both in IU and µg for GONAL-F (using the conversion factor of 150 IU=11 µg). This table will be 
produced overall and for subjects that completed stimulation, i.e. subjects that had hCG or GnRH 
agonist administered for triggering of final follicular maturation. 
9.1.2
GnRH Antagonist
Exposure to GnRH antagonist will be summarised as the total dose administered (mg) and duration 
of treatment (days). This table will be produced overall and for subjects that completed stimulation, 
i.e. subjects that had hCG or GnRH agonist administered for triggering of final follicular 
maturation.
9.1.3
Triggering of Final Follicular Maturation
Triggering of final follicular maturation will be done by either an injection of hCG or GnRH 
agonist. The drug used for triggering (hCG or GnRH agonist) will be tabulated for subjects 
undergoing triggering.


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9.1.4
Treatment Compliance 
Subjects not receiving the scheduled dose will be listed by centre and subject number. 
10
EFFICACY
Unless otherwise specified, analyses of efficacy endpoints will be based on the FAS and summary 
tables for the primary and secondary efficacy endpoints will be presented in total and by treatment 
group. Continuous variables will be presented with number of subjects, mean, standard deviation, 
median, inter-quartile range, minimum, and maximum. Categorical variables will be presented with 
number and percentage of subjects within each specific category.
Results of statistical analyses will be based on least-squares means using the observed margins and 
include the estimated treatment difference (or ratio), a 95% confidence interval for the difference 
(or ratio), and the p-value for the test of no treatment difference. All analyses are of descriptive 
nature and no adjustments for multiple tests will be applied.
Missing observations for the endpoints number of oocytes retrieved, number of fertilised oocytes, 
and number of blastocysts will be replaced with zero (i.e. worst-case imputation technique) 
irrespective of the reason why data is not recorded. For pregnancy data, lack of data will be 
interpreted as a negative pregnancy.
10.1
Primary Efficacy Endpoint
The primary endpoint, number of oocytes retrieved, will be compared between REKOVELLE and 
GONAL-F using a negative binomial regression model with treatment and AMH level at 
stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as factors. The absolute 
treatment difference in number of oocytes retrieved, the associated 95% confidence interval, and the 
p-value for no treatment difference will be derived from the model estimates using the delta 
method.
The distribution of the number of oocytes retrieved will be visualised in histograms. Furthermore, 
the number of oocytes will be grouped and presented in tables and figures using the following 
classification:

<4 oocytes or cycle cancellation due to poor ovarian response

4-7 oocytes

8-14 oocytes

15-19 oocytes

≥20 oocytes or cycle cancellation due to excessive ovarian response

Cycle cancellation due to another reason than poor or excessive ovarian response


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The treatment difference will also be investigated for sub-groups defined by AMH level at 
stimulation day 1 (i.e. <15 pmol/L, AMH ≥15 pmol/L or missing) using the same methods as above 
for each sub-group separately.
No formal hypothesis testing will be conducted using these methods. 
As a supplementary analysis, the analysis of the primary endpoint will be repeated using the PP analysis 
set and corresponding summary tables will be presented.
10.2
Secondary Efficacy Analyses
In addition to summary tables, some secondary endpoints will be compared between REKOVELLE 
and GONAL-F using statistical models. An overview is shown in Table 10-1 and further details on 
the statistical models are provided below.
Table 10-1
Overview of analysis methods for secondary endpoints
Secondary Endpoints
Analysis method
Summary 
tables
Negative 
binomial 
regression
ANCOVA
ANOVA
Number of follicles in total and by size category at EOS
X
X
Serum concentration of estradiol at EOS
X
X
Serum concentration of progesterone at EOS
X
X
Number of fertilised oocytes (2PN)
X
X
Fertilisation rate
X
X
Number of blastocysts in total and by quality
X
X
Gonadotropin dose in total and average daily dose
X
Number of dose adjustments
X
Number of stimulation days
X
X
Incidence of early OHSS overall and by grade
X
Preventive interventions for early OHSS
X
Number of Follicles at End-of-stimulation
The follicle cohort at end-of-stimulation (EOS) will be summarised by treatment on the subject 
level (i.e. total number of follicles, and number of follicles ≥10 mm, ≥12 mm, ≥15 mm and 
≥17 mm). Additionally, the mean number of follicles ≥10 mm, ≥12 mm, ≥15 mm and ≥17 mm at 
EOS will (in separate analyses) be compared between treatments using the same negative binomial 
regression model as used for the primary endpoint.


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Serum Concentrations of Estradiol and Progesterone at End-of-stimulation
Serum concentrations of estradiol and progesterone at EOS will be compared between treatments 
using analysis of covariance (ANCOVA) models with treatment and AMH level at stimulation day 
1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) as factors and with the serum concentration 
(log-transformed) at stimulation day 1 as a covariate. Multiplicative models will be used, i.e. the 
serum concentrations will be log-transformed before analysis. The results of the analyses will be 
back-transformed and presented as estimated geometric means and mean treatment ratios with 95% 
confidence intervals and p-values. Values below the lower limit of quantification (LLOQ) will be 
estimated with LLOQ/2. Potential values above the upper limit of quantification (ULOQ) will be 
included as ULOQ.
Number of Fertilised Oocytes and Fertilisation Rate
An oocyte is defined as correctly fertilised if it is scored as 2 pronuclei (PN) on day 1 after oocyte 
retrieval. The mean number of correctly fertilised oocytes will be compared between treatments 
using the same analysis method as for the primary endpoint.  
For subjects with >0 oocytes retrieved, the rate of correctly fertilised oocytes to oocytes retrieved 
will be estimated and compared between treatments using a negative binomial regression model 
with treatment and AMH level at stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or 
missing) as factors and the number of retrieved oocytes (log-transformed) as an offset. The 
treatment difference in fertilisation rate and the associated 95% confidence interval will be derived 
using the delta method. 
Number of Blastocysts (Total and by Quality)
The total number and quality of blastocysts on day 5 or day 6 will be compared between treatments 
using the same negative binomial regression model as used for the primary endpoint.
Total Gonadotropin Dose and Number of Stimulation Days
Tables will be produced overall and by AMH level at stimulation day 1 (AMH <15 pmol/L, AMH 
≥15 pmol/L, or missing) for the total gonadotropin dose, the average daily dose, the number of 
stimulation days and the occurrence of dose adjustments during stimulation (i.e. number of dose 
increases and decreases).
The number of stimulation days will be compared between treatments using an analysis of variance 
model with treatment and AMH level at stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, 
or missing) as factors. 
Early OHSS (Overall and by Grade) and/or Preventive Interventions for Early OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation 
(including OHSS with onset during stimulation or before triggering). Incidence of early OHSS will 
be summarised by classification (mild, moderate, severe) and grade (1, 2, 3, 4, 5). 


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Preventive interventions for early OHSS (i.e. cycle cancellation due to excessive ovarian response, 
triggering of final follicular maturation with GnRH agonist based on follicular development and/or 
serum estradiol criteria, and/or administration of dopamine agonist if  ≥20 follicles of  ≥12 mm is 
observed) will be summarised.
The tabulations will be produced overall and by AMH level at stimulation day 1 
(AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) and will include both treatment groups and a 
total column.
10.3
Exploratory Assessment
Blood Collection for Potential Biomarkers
Potential future analysis of possible biomarkers associated with ovarian response will be reported 
separately from the clinical trial report.
10.4
Follow-up Assessments
Follow-up assessments will be based on the FAS. Unless otherwise specified, summary tables will 
include both treatment groups and a total column. An overview of the methods used for follow-up 
assessments is provided in Table 10-2 and described in detail below.
Table 10-2
Overview of analysis methods for follow-up assessments
Follow-up Assessments
Analysis method
Summary tables
Logistic regression
Negative binomial 
regression
Clinical pregnancy by type
X
Vital pregnancy
X
Pregnancy rate
X
X
Implantation rate
X
X
Incidence of late OHSS
X
Pregnancy
For subjects with a clinical pregnancy (at least one gestational sac 5-6 weeks after transfer), the type 
of clinical pregnancy (intrauterine or ectopic) will be described. For subjects with a vital pregnancy 
(at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer), the number 
of intrauterine gestational sacs with fetal heart beat will also be described. 
Pregnancy rates in the first transfer cycle will be compared between treatments using a logistic 
regression model with treatment and age group (<35, 35-37, or 38-40 years) as factors. The 
estimated probabilities, difference in probabilities and 95% CIs for the estimated difference in 
probabilities will be presented based on the delta method. In these analyses subjects with no transfer 
or missing data on pregnancy will be regarded as non-pregnant. 


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Implantation rate
The implantation rate (i.e. number of gestational sacs 5-6 weeks after transfer relative to number of 
blastocysts transferred) in the first transfer cycle will be estimated and compared between 
treatments using a negative binomial regression model with treatment and age group (<35, 35-37, or 
38-40 years) as factors and the number of transferred blastocysts (log-transformed) as an offset. The 
treatment difference in implantation rate and the associated 95% confidence interval will be derived 
using the delta method. This analysis is based on subjects with transfer only and is therefore not 
randomisation based. The treatment difference for implantation rates is expected to be consistent 
with the treatment difference for pregnancy rates. If this is not the case, the reason for differences 
will be further explored by including e.g. day of transfer as a factor in the analysis model.
Late OHSS
For subjects who undergo transfer in the fresh cycle, incidence of late OHSS will be summarised by 
classification (mild, moderate, severe) and grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with 
onset >9 days after triggering of final follicular maturation. The tabulations will be produced overall 
and by AMH level at stimulation day 1 (AMH <15 pmol/L, AMH ≥15 pmol/L, or missing) and will 
include both treatment groups and a total column.
OHSS (Early and/or Late)
OHSS for each treatment group will be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). The following endpoints are defined:

Subjects with early and/or late OHSS

Subjects with early and/or late OHSS of moderate or severe grade
For each endpoint the proportion of subjects will be tabulated by treatment.
11
SAFETY
11.1
General Considerations
Safety parameters will be evaluated for the safety analysis set, i.e. data will be reported according to 
actual treatment received. Tabulations will be prepared overall, i.e. not by AMH level at stimulation 
day 1.
11.2
Adverse Events
Adverse events will be grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before the first dose of IMP, or a pre-existing medical condition that worsens in 
intensity after signed informed consent but before the first dose of IMP.


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
Treatment-emergent adverse event, i.e. any adverse event occurring after the first dose of 
IMP and before the end-of-trial visit, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after the first dose of IMP 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 Preferred Term (PT). 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 described.
Summary tables will be produced for the following treatment-emergent adverse events: 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.
For adverse events, a worst-case approach will be used for causality, intensity, seriousness, and 
outcome, in case these would be missing. If the timing of the onset of an adverse event cannot be 
established in relation to IMP, it will be considered as a treatment-emergent adverse event.
11.3
Additional Safety Evaluations
Physical Examination
Physical examination at screening and end-of-trial will be listed for subjects with abnormal 
findings.
Gynaecological Examination
Gynaecological examination at screening and end-of-trial will be listed for subjects with abnormal 
findings.
12
INTERIM ANALYSES
No interim analysis is planned.
13
DEVIATIONS FROM THE PROTOCOL
This SAP introduces the following changes to the analyses described in the trial protocol:

A supplementary analysis of the primary efficacy endpoint using the PP analysis set 
(Section 10.1).

Fertilisation rates (Section 10.2) and implantation rates (Section 10.4) will be estimated 
using negative binomial models with an offset to account for the differences in retrieved 


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oocytes and transferred blastocysts, respectively. This method was considered more 
appropriate than the mixed effects models described in the protocol as the proportion of 
subjects with a single observation is expected to be substantial. 

Exposure and treatment compliance (Section 9) will be tabulated for the Safety Analysis Set 
instead of the Full Analysis Set 


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14
REFERENCES
1
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 fertilisation and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388.
2
Nyboe Andersen A, Devroey P, Arce J-C. Clinical outcome following stimulation with HP-
hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled 
trial. Hum Reprod 2006; 21: 3217-3227.