A Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Trial Investigating the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Women Aged 18-34 Years Undergoing Assisted Reproductive Technology
Phase: PHASE3
Conditions: Infertility
Sponsor: Ferring Pharmaceuticals

 
 
 
 
 
 
 
 
Protocol 
 
Title of trial:  
A randomized, double-blind, placebo-controlled, parallel groups, multicenter 
trial investigating the efficacy and safety of FE 999049 in controlled ovarian 
stimulation in women aged 18-34 years undergoing assisted reproductive 
technology  
NCT number: 
NCT03740737 
Sponsor trial code: 
000001 
Date:  
Date of the original protocol: 25 April 2018 
Date of the protocol amendment (1 amendment only): 19 March 2020  
 
 
 
 
 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
 
A randomized, double-blind, placebo-controlled, parallel groups, multicenter trial investigating 
the efficacy and safety of FE 999049 in controlled ovarian stimulation in women aged 18-34 years 
undergoing assisted reproductive technology 
 
 
Trial 000001 
 
Recombinant FSH Investigation in the Treatment of Infertility with ART 
(RITA-1) 
 
 
 
 
IND Number: 
103040 
Investigational Medicinal Product: 
FE 999049, human recombinant follicle-stimulating 
hormone (rFSH), solution for subcutaneous injection 
Indication: 
Development of multiple follicles and pregnancy after 
fresh and/or cryopreserved embryo transfer in ovulatory 
women undergoing assisted reproductive technology 
(ART) 
Phase: 
3 
Name and Address of Sponsor: 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. 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 authorized officer of Ferring Pharmaceuticals Inc. or another company within the 
Ferring Group. 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A randomized, double-blind, placebo-controlled, parallel groups, multicenter trial investigating the 
efficacy and safety of FE 999049 in controlled ovarian stimulation in women aged 18-34 years 
undergoing assisted reproductive technology 
 
Short title: Recombinant FSH Investigation in the Treatment of Infertility with ART (RITA-1) 
 
SIGNATORY INVESTIGATOR 
 M.D., M.P.H. 
 
 
TRIAL SITES 
Approximately 25 sites in the U.S. 
 
PLANNED TRIAL PERIOD 
First patient first visit: 
 
 Q3 2018 
Last ongoing pregnancy after fresh and cryopreserved cycles:  
 
 Q2 2020 
Last live birth after fresh and cryopreserved cycles:  
 
 Q4 2020 
Last 1-year neonatal health follow-up after fresh and cryopreserved cycles: Q4 2021 
 
CLINICAL 
PHASE 
3 
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL 
The present trial is a randomized, placebo-controlled, phase 3 trial designed to demonstrate the 
efficacy and safety of the human-derived recombinant follicle-stimulating hormone (rFSH) 
preparation FE 999049 in women aged 18-34 years undergoing controlled ovarian stimulation for the 
development of multiple follicles for assisted reproductive technologies (ART). FE 999049 is 
expressed from a host cell line of human fetal retinal origin (PER.C6®), and is thereby the first rFSH 
from a human cell line. Ferring received marketing authorization approval for FE 999049 for the 
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” from the European Commission in 2016. As of early 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
2018, FE 999049 is approved in 37 countries also including countries outside the European Union 
such as Australia, Switzerland, and Canada. 
The primary endpoint is the cumulative ongoing pregnancy rate after the fresh cycle and 
cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. The 
trial will be conducted in the U.S., and it is the first U.S. clinical registration trial with a cumulative 
endpoint covering outcomes from both the fresh and subsequent cryopreserved cycles and thus 
capturing the clinical efficacy of a single controlled ovarian stimulation cycle in a more complete 
manner. 
 
OBJECTIVES 
Primary Objective 
• To demonstrate the efficacy and safety of FE 999049 in controlled ovarian stimulation 
 
Secondary Objectives 
• To establish the efficacy of FE 999049 in controlled ovarian stimulation with respect to 
pregnancy rates based on the fresh cycle and/or cryopreserved cycles 
• To characterize the ovarian response, including follicular development, oocytes retrieved and 
endocrine profile, as well as the embryo development associated with controlled ovarian 
stimulation with FE 999049 
• To characterize the safety profile of FE 999049 treatment, including adverse events, routine 
safety laboratory parameters, local tolerability and immunogenicity 
 
ENDPOINTS 
Primary Endpoint 
• Cumulative ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after 
transfer) after the fresh cycle and cryopreserved cycles initiated within 12 months from the 
start of controlled ovarian stimulation 
 
Secondary Endpoints 
• Ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after transfer) in the 
fresh cycle and in the cryopreserved cycles 

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Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
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CONFIDENTIAL 
• Time from start of controlled ovarian stimulation to ongoing pregnancy across the fresh and 
cryopreserved cycles, including duration and number of cycles before achieving ongoing 
pregnancy 
• Ongoing implantation rate (number of intrauterine viable fetuses 8-9 weeks after transfer 
divided by number of blastocysts transferred) in the fresh cycle, the cryopreserved cycles and 
cumulatively 
• Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) in the fresh 
cycle, the cryopreserved cycles and cumulatively 
• Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) in the fresh cycle, the cryopreserved cycles and cumulatively 
• Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred) in the fresh cycle, the cryopreserved cycles and cumulatively 
• Positive βhCG rate (positive serum βhCG test 10-14 days after transfer) in the fresh cycle, 
the cryopreserved cycles and cumulatively 
• Proportion of subjects in the fresh cycle with triggering of final follicular maturation (with 
hCG, with GnRH agonist, and in total), cycle cancellation and transfer cancellation 
• Number and size of follicles on stimulation day 5 and end-of-stimulation 
• Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and 
≥20 oocytes retrieved 
• Number and percentage of metaphase II oocytes (only applicable for those inseminated using 
ICSI), number of fertilized oocytes, fertilization rate as well as number and quality of 
blastocysts on day 5 after oocyte retrieval 
• Endometrial thickness and echogenicity pattern on stimulation day 5 and end-of-stimulation 
• Oocyte utilization rate (number of blastocysts transferred or cryopreserved divided by the 
number of oocytes retrieved) and oocyte efficiency index (cumulative number of ongoing 
pregnancies per oocyte retrieved) 
• Number and percentage of blastocysts surviving cryopreservation and number and 
percentage of blastocysts with re-expansion after cryopreservation 
• Number of cryopreserved cycles initiated within 12 months from the start of controlled 
ovarian stimulation, and number and percentage of cryopreserved cycles with blastocyst 
transfer 
• Circulating concentrations of AMH, FSH, LH, estradiol, progesterone, inhibin A and 
inhibin B on stimulation day 5, end-of-stimulation and oocyte retrieval, and FSH population 
pharmacokinetic parameters 
• Total gonadotropin dose, number of stimulation days and number of dose adjustments 

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Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Frequency and intensity of adverse events 
• Changes in circulating levels of clinical chemistry and hematology parameters and proportion 
of subjects with markedly abnormal changes 
• Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period 
• Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralizing capacity 
• Frequency and intensity of immune-related adverse events 
• Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen 
• Proportion of subjects with OHSS, overall and by grade, and proportion of subjects with 
moderate/severe OHSS 
• Proportion of subjects hospitalized due to OHSS and proportion of subjects undergoing 
paracentesis due to OHSS 
• Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical intervention) and vanishing twins in the fresh 
cycle and in the cryopreserved cycles 
• Technical malfunctions of the administration pen 
 
POST-TRIAL INFORMATION 
Post-trial Objectives 
• To establish the efficacy of controlled ovarian stimulation with FE 999049 with respect to 
live birth rates based on the fresh cycle and/or cryopreserved cycles  
• To characterize the neonatal health associated with controlled ovarian stimulation with 
FE 999049, including minor/major congenital anomalies at birth, 4 weeks and 1 year after 
birth in the fresh cycle and cryopreserved cycles  
 
Post-trial Endpoints 
• Cumulative live birth rate after the fresh cycle and cryopreserved cycles initiated within 
12 months from the start of controlled ovarian stimulation 
• Live birth rate in the fresh cycle and in the cryopreserved cycles  
• Live birth rate of singletons born at term (≥37 weeks of gestation) in the fresh cycle, the 
cryopreserved cycles and cumulatively 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Time from start of controlled ovarian stimulation to live birth of a singleton born at term 
across the fresh and cryopreserved cycles, including duration and number of cycles before 
achieving a live birth of a singleton born at term 
• Rate of minor/major congenital anomalies at birth, 4 weeks and 1 year after birth in the fresh 
cycle and cryopreserved cycles 
 
METHODOLOGY 
This will be a randomized, double-blind, placebo-controlled, parallel groups, multicenter trial 
assessing the efficacy and safety of the rFSH preparation FE 999049 in subjects aged 18-34 years 
undergoing controlled ovarian stimulation for IVF / ICSI following a gonadotropin-releasing 
hormone (GnRH) antagonist protocol. The primary endpoint is the cumulative ongoing pregnancy 
rate after the fresh cycle and cryopreserved cycles initiated within 12 months from the start of 
controlled ovarian stimulation. Thereby, the trial is designed to capture the clinical efficacy of a 
single controlled ovarian stimulation cycle in a more complete manner by following outcomes from 
both the fresh and subsequent cryopreserved cycles. Secondary endpoints include pharmacodynamic 
parameters of FSH action as well as efficacy and safety parameters related to controlled ovarian 
stimulation from the fresh cycle and subsequent cryopreserved cycles. 
 
Controlled Ovarian Stimulation and Fresh Cycle 
Subjects will be screened within 90 days prior to randomization for compliance with the inclusion 
and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomized in a 10:1 ratio 
to FE 999049 or placebo, and controlled ovarian stimulation will be initiated. FE 999049 and 
placebo will be self-administered subcutaneously using a pre-filled injection pen. 
Subjects assigned to treatment with FE 999049 will receive a starting dose of 12 µg daily that is 
fixed for the first four stimulation days. Based on ovarian response, the dose may be adjusted by 
3 µg, with dose increases implemented not more frequently than once every 2 days and dose 
decreases implemented per investigator’s judgement. The minimum daily dose is 6 µg, and the 
maximum daily dose is 24 µg. Subjects assigned to placebo will have the injection pen dialed to the 
same value (dose) as if administered FE 999049. Subjects can be treated with FE 999049 or placebo 
for a maximum of 20 days. Coasting, use of dopamine agonist or any other drug to prevent early 
ovarian hyperstimulation syndrome (OHSS) with the exception of GnRH agonist for triggering of 
final follicular maturation, are not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation days 1 and 
5 and thereafter at least every second day. When the leading follicle reaches a diameter of ≥14 mm, 
transvaginal ultrasound will be performed daily. To prevent a premature luteinizing hormone (LH) 
surge, 250 µg GnRH antagonist (ganirelix acetate, GANIRELIX, Merck Sharp & Dohme) will be 

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Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
initiated on stimulation day 5 for subjects with ≥3 follicles with a diameter of ≥10 mm. Subjects who 
fail to satisfy this GnRH antagonist criterion on stimulation day 5 will continue to be monitored at 
least every second day, and GnRH antagonist will be initiated when/if the criterion is met. The 
GnRH antagonist will be continued throughout the stimulation period. Triggering of final follicular 
maturation will be done as soon as ≥2 follicles with a diameter of ≥17 mm are observed. If there are 
<20 follicles with a diameter of ≥12 mm, 10,000 IU human chorionic gonadotropin (hCG; 
NOVAREL, Ferring Pharmaceuticals) will be administered. If there are ≥20 follicles with a diameter 
of ≥12 mm or the serum estradiol concentration is ≥3,000 pg/mL (local laboratory), 4.0 mg GnRH 
agonist (leuprolide acetate, LEUPROLIDE ACETATE, Sandoz) will be administered, and the fresh 
blastocyst transfer will be canceled. If after 8 days of stimulation, the investigator judges that the 
triggering criterion is not likely to be reached by day 20, the cycle will be canceled. If the triggering 
criterion is not met after 20 days of stimulation, the cycle will be canceled.  
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation, and oocytes 
will be inseminated by IVF or ICSI 4h (±1h) after retrieval. Rescue ICSI is not allowed. Fertilization 
and embryo development will be assessed. For subjects who undergo triggering of final follicular 
maturation with hCG and have <20 oocytes retrieved, transfer will be performed on day 5 (blastocyst 
stage) after oocyte retrieval. All subjects will have transfer of one blastocyst of the highest quality 
available and remaining blastocysts will be cryopreserved by vitrification. For subjects with 
≥20 oocytes retrieved following hCG administration and for subjects who undergo triggering of final 
follicular maturation with GnRH agonist, no transfer will take place in the fresh cycle and 
blastocysts will instead be cryopreserved.  
A subject who fails to reach the triggering criterion due to poor ovarian response or who has 
≤3 oocytes retrieved will be offered medication and financial support for an ART cycle with an 
approved gonadotropin preparation outside of the trial. 
Vaginal progesterone inserts (progesterone, ENDOMETRIN, Ferring Pharmaceuticals) 100 mg three 
times daily (TID) will be provided for luteal phase support from the day after oocyte retrieval and 
continuing until menses, negative β human chorionic gonadotropin (βhCG test), pregnancy loss or 
until ongoing pregnancy has been documented. 
A serum βhCG test will be performed 10-14 days after transfer, clinical and vital pregnancy will be 
confirmed by transvaginal ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be 
confirmed by transvaginal or abdominal ultrasound 8-9 weeks after transfer. 
Blood samples will be collected for the purpose of evaluating the endocrine profile, clinical 
chemistry and hematology parameters as well as anti-FSH antibodies. Endocrine parameters will be 
assessed at screening, stimulation day 1, stimulation day 5, end-of-stimulation and oocyte retrieval. 
Clinical chemistry and hematology will be assessed at screening, end-of-stimulation, and end-of-
cycle. Anti-FSH antibodies will be assessed on four occasions. The first sample will be taken at the 
screening visit and will be used exclusively to re-establish the anti-drug antibody analytical assays. 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
The subsequent three samples will be used for analysis of anti-FSH antibodies in individual subjects 
in the trial, and taken prior to dosing on stimulation day 1 and on two occasions post-dosing: 
7-10 days after the last FE 999049 or placebo dose (this may coincide with the transfer visit) and 
21-28 days after the last FE 999049 or placebo dose (this may coincide with the βhCG test visit). 
Subjects with a treatment-induced anti-FSH antibody response will be followed until the response 
has become negative, returned to the pre-dosing level, or for a maximum of 1 year after the second 
post-dose sampling. These subjects will be called in for assessments 2 months after the last post-
dosing anti-FSH antibody sampling. If required, further assessments will be made at 3, 4, 6, 9 and 
12 months after the last post-dosing anti-FSH antibody sampling. The follow-up will also be 
terminated if the subject commences a new treatment cycle with any gonadotropin preparation. 
Local tolerability of FE 999049 and placebo following subcutaneous administration will be assessed 
by the subject three times daily: immediately, 30 minutes and 24 hours after each injection. The 
presence and intensity of injection site reactions will be rated as none, mild, moderate or severe. The 
assessments will be made throughout the stimulation period and recorded by the subject in a diary. 
 
Cryopreserved Cycles 
The trial covers cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation. Either a programmed or natural cycle can be selected for any cryopreserved cycle.  
Any programmed cryopreserved cycle will be initiated within 3 days of start of menses with 
administration of estradiol (ESTRADIOL Tablets USP, Teva Pharmaceuticals USA, Inc.) 2 mg TID 
or 3 mg two times daily (BID) (or 3 mg TID at the investigator’s discretion, if a daily dose of 6 mg 
has been shown to be insufficient in a previous cycle). If after 10-12 days of estradiol treatment the 
endometrial thickness is ≥8 mm, the subject will initiate daily intramuscular (IM) injections of 
50 mg progesterone (PROGESTERONE Injection USP, West-ward Pharmaceutical Corp or Watson 
Pharma, Inc.) within the next 5 days in conjunction with the estradiol treatment. The ultrasound 
evaluation can be repeated within 7 days if the endometrial thickness criterion is not met. In 
programmed cryopreserved cycles, transfer of one blastocyst of the highest quality available will 
occur on the 6th day from start of progesterone after warming and assessment of blastocyst survival 
and re-expansion. Luteal phase support (estradiol and IM progesterone) will continue to be 
administered until menses, negative βhCG test, pregnancy loss or until ongoing pregnancy has been 
documented. 
Any natural cryopreserved cycle will be initiated 7 days after start of menses with monitoring of 
urinary LH on a daily basis by the subject. The day after confirmation of LH surge by serum LH 
(local laboratory) and endometrial thickness of ≥8 mm, the subject will start luteal phase support 
with vaginal progesterone inserts (progesterone, ENDOMETRIN, Ferring Pharmaceuticals) 100 mg 
TID. In a natural cryopreserved cycle, transfer of one blastocyst of the highest quality available will 
occur on day LH surge +7 after warming and assessment of blastocyst survival and re-expansion. 

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Trial Code:  000001 
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CONFIDENTIAL 
Luteal phase support (vaginal progesterone) will continue to be administered until menses, negative 
βhCG test, pregnancy loss or until ongoing pregnancy has been documented. 
Failure to achieve endometrial thickness ≥8 mm in the first cryopreserved cycle will result in cycle 
cancellation, and in the programmed cycles, administration of 100 mg IM progesterone 
(PROGESTERONE Injection USP, West-ward Pharmaceutical Corp or Watson Pharma, Inc.) to 
induce withdrawal bleeding. In subsequent cryopreserved cycles, blastocyst transfer can take place 
regardless of endometrial thickness at the investigator’s discretion.  
In both programmed and natural cryopreserved cycles, a serum βhCG test is performed 10-14 days 
after transfer, clinical and vital pregnancy will be confirmed by transvaginal ultrasound 5-6 weeks 
after transfer, and ongoing pregnancy will be confirmed by transvaginal or abdominal ultrasound 
8-9 weeks after transfer. 
After completion of the trial, the subject is allowed to use cryopreserved blastocysts in accordance 
with local guidelines and/or regulations. 
 
Post-trial Activities 
Post-trial activities cover pregnancy and neonatal health follow-up after the fresh cycle and 
cryopreserved cycles. 
All subjects with an ongoing pregnancy obtained in the fresh cycle or in cryopreserved cycles 
initiated within 12 months from the start of controlled ovarian stimulation will be followed until 
delivery to collect information on live birth rate. Furthermore, data will be collected on neonatal 
health, including minor/major congenital anomalies, at birth, 4 weeks and 1 year after birth. 
 
Optional Exploratory Analyses 
For subjects who have provided a separate informed consent, a blood sample and a saliva sample for 
potential future genome sequencing will be collected on stimulation day 1, and a tongue coat sample 
for potential future microbial profiling will be collected on stimulation day 1 and at the transfer 
visit(s) in the fresh and cryopreserved cycles, as applicable.  
 
NUMBER OF SUBJECTS 
It is planned to randomize 550 subjects in a 10:1 ratio to FE 999049 and placebo, i.e. 500 subjects 
assigned to FE 999049 and 50 subjects assigned to placebo. Blocked randomization will be utilized 
to distribute the placebo subjects randomly over the trial enrollment period. It is estimated that 
approximately 625 subjects should be screened to achieve 550 subjects eligible for the trial. 
 

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CONFIDENTIAL 
CRITERIA FOR INCLUSION / EXCLUSION 
This trial will include women aged 18-34 years who are eligible for IVF or ICSI and who have 
undergone no more than one previous controlled ovarian stimulation cycle. They should have been 
diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have partners 
diagnosed with male factor infertility. The allowed body mass index (BMI) is 17.5-38.0 kg/m2. The 
exclusion criteria incorporate the contraindications for the use of gonadotropins and other 
concomitant fertility medications used in the trial. The complete list of inclusion and exclusion 
criteria is provided below. 
 
Inclusion Criteria 
1. Informed Consent Documents signed prior to any trial-related procedure. 
2. In good physical and mental health in the judgement of the investigator. 
3. Pre-menopausal females between the ages of 18 and 34 years. The subjects must be at least 
18 years (including the 18th birthday) when they sign the informed consent and no more than 
34 years (up to the day before the 35th birthday) at the time of randomization. 
4. Body mass index (BMI) between 17.5 and 38.0 kg/m2 (both inclusive) at screening. 
5. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization 
(IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm 
from male partner or sperm donor. 
6. Documented history of infertility for at least 12 months before randomization (not applicable 
in case of tubal or severe male factor infertility, or when the use of donor sperm is 
indicated). 
7. Regular menstrual cycles of 24-35 days (both inclusive). 
8. Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus 
consistent with expected normal function (e.g. no evidence of clinically interfering uterine 
fibroids defined as submucous fibroids of any size or intramural fibroids larger than 3 cm in 
diameter, no polyps and no congenital structural abnormalities which are associated with a 
reduced chance of pregnancy) at screening or within 1 year prior to screening.  
9. Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would 
contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) at 
screening. Both ovaries must be accessible for oocyte retrieval. 
10. Early follicular phase (cycle day 2-4) serum levels of follicle-stimulating hormone (FSH) 
between 1 and 15 IU/L (results obtained within 3 months prior to randomization). 

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11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human 
Immunodeficiency Virus (HIV) antibody tests at screening or within 6 months prior to 
screening.  
12. Willing to accept single blastocyst transfer in the fresh cycle and in the cryopreserved cycles 
initiated within 12 months from the start of controlled ovarian stimulation using blastocysts 
obtained in this trial. 
13. Willing and able to comply with trial procedures, including filling in the diary and attending 
scheduled visits as well as providing the neonatal health data up to 1 year after birth. 
 
Exclusion Criteria 
1. More than one previous controlled ovarian stimulation cycle for IVF/ICSI. 
2. Known endometriosis stage III-IV (defined by the revised American Society for 
Reproductive Medicine (ASRM) classification, 2012). 
3. Known history of anovulation. 
4. One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound 
prior to randomization on stimulation day 1. 
5. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy [excl. ectopic pregnancy] and before week 24 of pregnancy).  
6. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial. In case partner sperm will 
be used and the sperm production is severely impaired (concentration <1 million/mL), 
normal karyotype, including no Y-chromosome microdeletion, must be documented. 
7. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes). 
8. Known inherited or acquired thrombophilia. 
9. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events. 
10. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of pharmacologically controlled sub-clinical hypothyroidism. 
11. Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins. 
12. Known moderate or severe impairment of renal or hepatic function. 
13. Any abnormal finding of clinical chemistry, hematology, thyroid-stimulating hormone 
(TSH) or prolactin, or vital signs at screening, which is judged clinically significant by the 
investigator.  
14. Currently breast-feeding. 
15. Undiagnosed vaginal bleeding. 
16. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomization (unless the clinical significance has been resolved). 

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17. Findings at the gynecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine 
abnormalities or retained intrauterine device. 
18. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomization) or contraindication to pregnancy. 
19. Known current active pelvic inflammatory disease. 
20. Use of fertility modifiers during the last menstrual cycle before randomization, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral 
contraceptives, progestogen or estrogen preparations. 
21. Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle 
before randomization. 
22. Known history of chemotherapy (except for gestational conditions) or radiotherapy.  
23. Current or past (1 year prior to randomization) abuse of alcohol or drugs. 
24. Current (last month) intake of more than 14 units of alcohol per week (one unit is equivalent 
to 12 fluid ounces of regular beer (5% alcohol), 5 fluid ounces of wine (12% alcohol), or 
1.5 fluid ounces of 80 proof distilled spirits (40% alcohol). 
25. Current or past (3 months prior to randomization) smoking habit of more than 10 cigarettes 
per day. 
26. Known hypersensitivity to any active ingredient or excipients in the medicinal products used 
in this trial. 
27. Any known clinical condition that would prevent the use of estrogen or progestin 
compounds.  
28. Previous participation in this trial.  
29. Use of any non-registered investigational drugs during the last 3 months prior to 
randomization. 
 
 
 
 
 
 
 
 
 
 

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MEDICINAL PRODUCTS 
Investigational Medicinal Products (IMPs) 
IMP name 
Drug type 
Active ingredient; route of 
administration; concentration 
Daily administration 
FE 999049 
 
rFSH 
FE 999049 in solution for 
subcutaneous injection in pre-
filled injection pen; 
72 μg/2.16 mL 
Starting dose of 12 µg daily fixed for the 
first four stimulation days. Based on ovarian 
response, the dose may be adjusted by 3 µg, 
with dose increases implemented not more 
frequently than once every 2 days and dose 
decreases implemented per investigator’s 
judgement. The minimum daily dose is 6 µg, 
and the maximum daily dose is 24 µg 
Placebo to 
FE 999049 
Placebo 
Solution for subcutaneous 
injection in pre-filled injection 
pen 
Pen will be dialed to the same value (dose) 
as if administered FE 999049 
 
 
Concomitant Fertility Medication / Non-investigational Medicinal Products (NIMPs) 
Controlled Ovarian Stimulation and Fresh Cycle 
NIMP name 
Drug type 
Active ingredient and route of administration  
Dose 
GANIRELIX 
GnRH antagonist 
Ganirelix acetate in solution for subcutaneous 
injection 
250 µg, daily 
injection 
NOVAREL 
hCG 
Chorionic gonadotropin in solution for 
intramuscular injection 
10,000 IU, single 
injection 
LEUPROLIDE 
ACETATE 
GnRH agonist 
Leuprolide acetate in solution for 
subcutaneous injection 
4.0 mg, single 
injection 
ENDOMETRIN 
Progesterone 
Progesterone vaginal inserts for vaginal 
administration 
100 mg, TID  
 
 
 
 
 
 
 

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Clinical Trial Protocol 
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CONFIDENTIAL 
Programmed Cryopreserved Cycles 
NIMP name 
Drug type 
Active ingredient and route of administration  
Dose 
ESTRADIOL 
Estradiol 
Estradiol oral tablet 
2 mg TID or 3 mg 
BID 
(or 3 mg TID at the 
investigator’s 
discretion, if a daily 
dose of 6 mg has been 
shown insufficient in 
a previous cycle) 
PROGESTERONE 
 
Progesterone 
Progesterone injection USP in sesame oil for 
intramuscular (IM) injection 
50 mg, daily injection 
(100 mg, single 
injection for induction 
of withdrawal 
bleeding, as 
applicable) 
 
Natural Cryopreserved Cycles 
NIMP name 
Drug type 
Active ingredient and route of administration  
Dose 
ENDOMETRIN 
Progesterone 
Progesterone vaginal inserts for vaginal 
administration 
100 mg, TID  
 
 
DURATION OF TREATMENT 
The maximum period of exposure to FE 999049 or placebo is 20 days. 
 
STATISTICAL METHODS 
The primary objective of this trial is to demonstrate the efficacy and safety of FE 999049 in 
controlled ovarian stimulation. 
 
Sample Size 
The proposed sample size of 550 subjects (FE 999049:placebo = 500:50) can adequately address 
both the efficacy and safety objectives of the trial: 
• The cumulative ongoing pregnancy rate in the FE 999049-treated subjects aged 18-34 years 
after single blastocyst transfer in fresh and cryopreserved cycles is estimated to be 
approximately 45%. By comparison, the pregnancy rate in the placebo arm is expected not to 

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Follitropin Delta, FE 999049 
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Solution for Injection  
Clinical Trial Protocol 
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CONFIDENTIAL 
exceed 3%, the monthly spontaneous pregnancy rate in infertile women. Therefore, the 
proposed sample size of 550 (FE 999049:placebo = 500:50), will provide at least 99% power 
for the primary efficacy comparison. Based on the estimated cumulative ongoing pregnancy 
rate, the cumulative live birth rate from the fresh and/or cryopreserved cycles is estimated to 
be approximately 40%, resulting in a power for the comparison of the cumulative live birth 
rate to be at least 99%. 
• The safety and tolerability of daily rFSH preparations as part of an ART treatment cycle have 
been well documented for the population studied in previous clinical trials. OHSS was 
reported to occur in 3.6% to 6.3% of the subjects, with moderate/severe OHSS occurring in 
2.0% to 4.5% of the subjects and OHSS resulting in hospitalization in approximately 0.7% to 
1.3% of the subjects. Other adverse events were pelvic pain, pelvic discomfort and headache, 
reported in 4% to 20% of the subjects in each treatment group. 
 
Table 1 shows that the planned sample size of 500 subjects exposed to FE 999049 provides a 
high probability to detect a rare adverse event or safety signal occurring in 0.5% or more 
subjects: 
Table 1: Probabilities to Detect at Least One Rare Event 
Incidence rate of rare event Chance of detecting at least 1 event 
0.5% 
91.8% 
0.6% 
95.1% 
1% 
99.3% 
 
Table 2 presents the margin width estimates of the 95% confidence intervals for a range of 
adverse event rates with the planned sample size. 
Table 2: Estimated Margin Widths of 95% Confidence Intervals 
Adverse event rate 
Margin of error width estimate 
5% 
1.9% 
10% 
2.6% 
15% 
3.1% 
20% 
3.5% 
 
 
 
 

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Follitropin Delta, FE 999049 
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Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
Primary Endpoint 
The hypothesis to be tested for the primary endpoint, cumulative ongoing pregnancy rate, is: 
H0: πFE 999049 – πPlacebo ≤ 0 against the alternative HA: πFE 999049 – πPlacebo > 0, 
where πFE 999049 and πPlacebo denote the cumulative ongoing pregnancy rate after the fresh cycle and 
cryopreserved cycles in subjects aged 18-34 years treated with FE 999049 or placebo, respectively. 
H0 will be tested against the alternative HA by constructing a two-sided 95% confidence interval for 
the difference in the cumulative ongoing pregnancy rates between the two treatment groups using the 
traditional Wald interval. If the lower limit of the two-sided 95% confidence interval is greater than 
0, the null hypothesis H0 will be rejected. In the case that the number of pregnancies observed in the 
placebo group is small (<5), then the one-sided Fisher’s exact test will be used. 
The primary endpoint will be determined as soon as the subject has achieved an ongoing pregnancy, 
or when all cryopreserved blastocysts have been exhausted, or after assessment of ongoing 
pregnancy status in cryopreserved cycles initiated within 12 months from the start of controlled 
ovarian stimulation.  
The efficacy analysis will be based on the modified intention-to-treat (mITT) analysis set, defined as 
all subjects who were randomized and received at least one dose of IMP (FE 999049 or placebo). 
 

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Follitropin Delta, FE 999049 
Trial Code:  000001 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................................................... 2 
LIST OF TABLES ........................................................................................................................................ 24 
LIST OF FIGURES ...................................................................................................................................... 24 
LIST OF ABBREVIATIONS ...................................................................................................................... 25 
1 
INTRODUCTION ............................................................................................................................. 27 
1.1 
Background ............................................................................................................................. 27 
1.2 
Scientific Justification for Conducting the Trial ..................................................................... 29 
1.3 
Benefit / Risk Aspects ............................................................................................................. 30 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 33 
2.1 
Objectives ............................................................................................................................... 33 
2.2 
Endpoints ................................................................................................................................ 33 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 36 
3.1 
Overall Trial Design................................................................................................................ 36 
 
Trial Design Diagram................................................................................................. 36 
 
Overall Design and Control Methods ........................................................................ 39 
 
Trial Schedule ............................................................................................................ 43 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 43 
3.3 
Interim Analysis ...................................................................................................................... 43 
3.4 
Data Monitoring Committee ................................................................................................... 43 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 43 
 
Trial Design ............................................................................................................... 43 
 
Selection of Endpoints ............................................................................................... 45 
 
Blinding...................................................................................................................... 46 
 
Selection of Doses in the Trial ................................................................................... 47 
3.5.4.1 FE 999049 .................................................................................................... 47 
3.5.4.2 Concomitant Fertility Medication ................................................................ 54 
 
Selection of the Trial Population ............................................................................... 55 
 
Follow-up Procedures ................................................................................................ 55 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 57 
4.1 
Trial Population....................................................................................................................... 57 
 
Inclusion Criteria ....................................................................................................... 57 
 
Exclusion Criteria ...................................................................................................... 58 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 59 
 
Recruitment ................................................................................................................ 59 
 
Randomization ........................................................................................................... 59 
4.3 
Restrictions ............................................................................................................................. 60 
 
Prior and Concomitant Therapies .............................................................................. 60 
 
Prohibited Therapy ..................................................................................................... 60 
4.4 
Withdrawal Criteria................................................................................................................. 60 

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CONFIDENTIAL 
4.5 
Trial Stopping Criteria ............................................................................................................ 61 
5 
TREATMENTS ................................................................................................................................. 62 
5.1 
Treatments Administered ........................................................................................................ 62 
 
Investigational Medicinal Products ............................................................................ 62 
 
Non-investigational Medicinal Products .................................................................... 62 
5.2 
Characteristics and Source of Supply ..................................................................................... 65 
5.3 
Packaging and Labelling ......................................................................................................... 65 
5.4 
Conditions for Storage and Use .............................................................................................. 66 
5.5 
Blinding / Unblinding ............................................................................................................. 67 
 
Blinding...................................................................................................................... 67 
 
Unblinding of Individual Subject Treatment ............................................................. 67 
5.6 
Treatment Compliance, Dispensing and Accountability......................................................... 68 
5.7 
Return and Destruction of Medicinal Products and Auxiliary Supplies ................................. 69 
6 
TRIAL PROCEDURES .................................................................................................................... 70 
6.1 
Controlled Ovarian Stimulation and Fresh Cycle ................................................................... 70 
 
Screening.................................................................................................................... 72 
 
Stimulation Day 1 ...................................................................................................... 73 
 
Stimulation Day 5 ...................................................................................................... 74 
 
Stimulation Days ≥6 to <20 ....................................................................................... 75 
 
End-of-stimulation ..................................................................................................... 76 
 
Oocyte Retrieval ........................................................................................................ 78 
 
Oocyte / Blastocyst Evaluation .................................................................................. 78 
 
Transfer ...................................................................................................................... 80 
6.1.8.1 Blastocyst Transfer ....................................................................................... 80 
6.1.8.2 First Post-dosing Anti-FSH Antibody Assessment (7-10 Days after Last 
IMP Dose) .................................................................................................... 80 
 
βhCG Test .................................................................................................................. 81 
6.1.9.1 βhCG Test .................................................................................................... 81 
6.1.9.2 Second Post-dosing Anti-FSH Antibody Assessment (21-28 Days after 
Last IMP Dose) ............................................................................................ 81 
 Clinical Pregnancy ..................................................................................................... 82 
 Ongoing Pregnancy .................................................................................................... 82 
 End-of-cycle ............................................................................................................... 83 
6.2 
Cryopreserved Cycles ............................................................................................................. 84 
 
Programmed Cryopreserved Cycles ........................................................................... 84 
6.2.1.1 Cycle Initiation / Preparation of the Endometrium ...................................... 85 
6.2.1.2 Blastocyst Evaluation ................................................................................... 86 
6.2.1.3 Transfer ........................................................................................................ 86 
6.2.1.4 βhCG Test .................................................................................................... 87 
6.2.1.5 Clinical Pregnancy ....................................................................................... 87 
6.2.1.6 Ongoing Pregnancy ...................................................................................... 88 
6.2.1.7 End-of-cycle ................................................................................................. 88 
 
Natural Cryopreserved Cycles ................................................................................... 89 

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Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6.2.2.1 Cycle Initiation ............................................................................................. 90 
6.2.2.2 Confirmation of LH Surge ........................................................................... 90 
6.2.2.3 Blastocyst Evaluation ................................................................................... 90 
6.2.2.4 Transfer ........................................................................................................ 91 
6.2.2.5 βhCG Test .................................................................................................... 91 
6.2.2.6 Clinical Pregnancy ....................................................................................... 92 
6.2.2.7 Ongoing Pregnancy ...................................................................................... 92 
6.2.2.8 End-of-cycle ................................................................................................. 93 
6.3 
Post-trial Activities ................................................................................................................. 93 
7 
TRIAL ASSESSMENTS ................................................................................................................... 94 
7.1 
Assessments Related to Efficacy Endpoints ........................................................................... 94 
 
Ongoing Pregnancy .................................................................................................... 94 
 
Time to Ongoing Pregnancy ...................................................................................... 94 
 
Ongoing Implantation ................................................................................................ 94 
 
Clinical Pregnancy ..................................................................................................... 94 
 
Vital Pregnancy .......................................................................................................... 95 
 
Implantation ............................................................................................................... 95 
 
Positive βhCG ............................................................................................................ 95 
 
Triggering of Final Follicular Maturation, Cycle Cancellation and Transfer 
Cancellation ............................................................................................................... 95 
 
Number and Size of Follicles during Stimulation ...................................................... 95 
 Number and Distribution of Oocytes Retrieved......................................................... 96 
 Number of Metaphase II Oocytes .............................................................................. 96 
 Number of Fertilized Oocytes and Fertilization Rate ................................................ 96 
 Number and Quality of Blastocysts on Day 5 ............................................................ 96 
 Endometrial Thickness and Echogenicity Pattern ...................................................... 97 
 Oocyte Utilization Rate and Oocyte Efficiency Index ............................................... 98 
 Blastocyst Survival and Re-expansion after Cryopreservation .................................. 98 
 Number of Cryopreserved Cycles .............................................................................. 98 
 Circulating Levels of Endocrine Parameters .............................................................. 98 
 Total Gonadotropin Dose, Number of Stimulation Days and Number of Dose 
Adjustments ............................................................................................................... 99 
7.2 
Assessments Related to Safety Endpoints............................................................................... 99 
 
Adverse Events .......................................................................................................... 99 
 
Clinical Chemistry and Hematology Parameters ..................................................... 100 
 
Injection Site Reactions ........................................................................................... 100 
 
Anti-FSH Antibodies ............................................................................................... 100 
 
Immune-related Adverse Events .............................................................................. 102 
 
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen ..................... 103 
 
Ovarian Hyperstimulation Syndrome ...................................................................... 103 
 
Hospitalizations and Paracentesis due to Ovarian Hyperstimulation Syndrome ..... 103 

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Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins .............................................................................. 103 
 Technical Malfunctions of the Administration Pen ................................................. 103 
7.3 
Other Assessments ................................................................................................................ 104 
 
Demographics .......................................................................................................... 104 
 
Medical History ....................................................................................................... 104 
 
Infertility History ..................................................................................................... 104 
 
Menstrual History .................................................................................................... 104 
 
Reproductive History ............................................................................................... 104 
 
Body Measurements ................................................................................................. 104 
 
Physical Examination ............................................................................................... 104 
 
Gynecological Examination ..................................................................................... 105 
 
Endocrine Parameters at Screening .......................................................................... 106 
 Vital Signs ................................................................................................................ 106 
 Ovarian Volume ....................................................................................................... 106 
 Endometrial Evaluation in Cryopreserved Cycles ................................................... 106 
 Concomitant Medication .......................................................................................... 106 
 Drug Dispensing and Accountability ....................................................................... 107 
 End-of-cycle Form ................................................................................................... 107 
7.4 
Assessments Related to Post-trial Endpoints ........................................................................ 107 
 
Live Birth ................................................................................................................. 107 
 
Live Birth of Singletons Born at Term .................................................................... 107 
 
Time to Live Birth of a Singleton Born at Term ...................................................... 107 
 
Minor/Major Congenital Anomalies ........................................................................ 107 
7.5 
Other Post-trial Assessments ................................................................................................ 108 
7.6 
Optional Exploratory Analyses ............................................................................................. 108 
 
Genome Sequencing ................................................................................................ 108 
 
Microbial Profiling ................................................................................................... 108 
7.7 
Handling of Biological Samples ........................................................................................... 109 
8 
ADVERSE EVENTS ....................................................................................................................... 110 
8.1 
Adverse Event Definition ...................................................................................................... 110 
8.2 
Collection and Recording of Adverse Events ....................................................................... 110 
 
Collection of Adverse Events .................................................................................. 110 
 
Recording of Adverse Events .................................................................................. 111 
8.3 
Adverse Events of Special Interest ....................................................................................... 114 
 
Ovarian Hyperstimulation Syndrome ...................................................................... 114 
 
Pregnancy Losses ..................................................................................................... 116 
8.4 
Events Requiring Special Handling ...................................................................................... 116 
 
Injection Site Reactions ........................................................................................... 116 
 
Treatment-induced Anti-FSH Antibodies ................................................................ 117 
 
Menstrual Bleeding .................................................................................................. 117 
 
Multiple Pregnancies ............................................................................................... 117 
8.5 
Serious Adverse Events ........................................................................................................ 118 

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Follitropin Delta, FE 999049 
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Clinical Trial Protocol 
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CONFIDENTIAL 
 
Serious Adverse Event Definition ............................................................................ 118 
 
Collection, Recording and Reporting of Serious Adverse Events ........................... 120 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .................................................. 121 
 
Follow-up of Adverse Events with Onset during the Trial ...................................... 121 
 
Follow-up of Serious Adverse Events with Onset during the Post-Trial Period ..... 121 
 
Collection of Serious Adverse Events with Onset after End-of-trial ....................... 121 
9 
STATISTICAL METHODS ........................................................................................................... 122 
9.1 
Determination of Sample Size .............................................................................................. 122 
9.2 
Subject Disposition ............................................................................................................... 123 
9.3 
Protocol Deviations ............................................................................................................... 123 
9.4 
Analysis Sets ......................................................................................................................... 124 
9.5 
Trial Population..................................................................................................................... 124 
 
General Considerations ............................................................................................ 124 
 
Trial Population Parameters ..................................................................................... 125 
9.6 
Exposure and Treatment Compliance ................................................................................... 126 
 
General Considerations ............................................................................................ 126 
 
Controlled Ovarian Stimulation (Fresh Cycle) ........................................................ 126 
 
Cryopreserved Cycles .............................................................................................. 127 
 
Treatment Compliance ............................................................................................. 127 
9.7 
Efficacy Endpoints Assessments .......................................................................................... 127 
 
General Considerations ............................................................................................ 127 
 
Primary Endpoint ..................................................................................................... 129 
 
Secondary Efficacy Endpoints ................................................................................. 130 
9.7.3.1 Ongoing Pregnancy Rate ............................................................................ 130 
9.7.3.2 Time to Ongoing Pregnancy ...................................................................... 130 
9.7.3.3 Ongoing Implantation Rate ........................................................................ 131 
9.7.3.4 Clinical Pregnancy Rate ............................................................................. 131 
9.7.3.5 Vital Pregnancy Rate .................................................................................. 131 
9.7.3.6 Implantation Rate ....................................................................................... 131 
9.7.3.7 Positive βhCG Rate .................................................................................... 131 
9.7.3.8 Triggering of Final Follicular Maturation, Cycle Cancellation and 
Transfer Cancellation ................................................................................. 132 
9.7.3.9 Number and Size of Follicles during Stimulation ...................................... 132 
9.7.3.10 Number and Distribution of Oocytes Retrieved ......................................... 132 
9.7.3.11 Number of Metaphase II Oocytes .............................................................. 132 
9.7.3.12 Number of Fertilized Oocytes and Fertilization Rate ................................ 133 
9.7.3.13 Number and Quality of Blastocysts on Day 5 ............................................ 133 
9.7.3.14 Endometrial Thickness and Echogenicity Pattern ...................................... 133 
9.7.3.15 Oocyte Utilization Rate and Oocyte Efficiency Index ............................... 133 
9.7.3.16 Blastocyst Survival and Re-expansion after Cryopreservation .................. 134 
9.7.3.17 Number of Cryopreserved Cycles .............................................................. 134 
9.7.3.18 Circulating Levels of Endocrine Parameters .............................................. 134 

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Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9.7.3.19 Total Gonadotropin Dose, Number of Stimulation Days, and Number of 
Dose Adjustments ...................................................................................... 135 
9.8 
Safety Endpoints Assessments .............................................................................................. 135 
 
General Considerations ............................................................................................ 135 
 
Secondary Safety Endpoints .................................................................................... 136 
9.8.2.1 Adverse Events ........................................................................................... 136 
9.8.2.2 Clinical Chemistry and Hematology Parameters ....................................... 137 
9.8.2.3 Injection Site Reactions .............................................................................. 137 
9.8.2.4 Treatment-induced Anti-FSH Antibodies .................................................. 137 
9.8.2.5 Immune-related Adverse Events ................................................................ 137 
9.8.2.6 Cycle Cancellations due to an Adverse Event, including Immune-related 
Adverse Events, or due to Technical Malfunctions of the Administration 
Pen…… ...................................................................................................... 138 
9.8.2.7 Ovarian Hyperstimulation Syndrome ......................................................... 138 
9.8.2.8 Hospitalization and Paracentesis due to Ovarian Hyperstimulation 
Syndrome ................................................................................................... 138 
9.8.2.9 Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, 
Ectopic Pregnancy and Vanishing Twins ................................................... 138 
9.8.2.10 Technical Malfunctions of the Administration Pen ................................... 138 
9.9 
Additional Safety Evaluations .............................................................................................. 138 
9.10 
Post-trial Activities ............................................................................................................... 139 
 Post-trial Endpoints .................................................................................................. 139 
9.10.1.1 Cumulative Live Birth Rate ....................................................................... 139 
9.10.1.2 Live Birth Rate ........................................................................................... 139 
9.10.1.3 Live Birth Rate of Singletons Born at Term .............................................. 139 
9.10.1.4 Time to Live Birth of a Singleton Born at Term ........................................ 140 
9.10.1.5 Minor/Major Congenital Anomalies .......................................................... 140 
 Other Post-trial Evaluations ..................................................................................... 140 
9.11 
Optional Exploratory Analyses ............................................................................................. 140 
9.12 
Interim Analysis .................................................................................................................... 140 
10 
DATA HANDLING ......................................................................................................................... 141 
10.1 
Source Data and Source Documents ..................................................................................... 141 
10.2 
eCRF ..................................................................................................................................... 143 
10.3 
Data Management ................................................................................................................. 143 
10.4 
Provision of Additional Information ..................................................................................... 143 
11 
MONITORING PROCEDURES ................................................................................................... 144 
11.1 
Periodic Monitoring .............................................................................................................. 144 
11.2 
Audit and Inspection ............................................................................................................. 144 
11.3 
Confidentiality of Subject Data ............................................................................................. 145 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ...................................................................... 146 
12.1 
Protocol Amendments ........................................................................................................... 146 
12.2 
Deviations from the Protocol ................................................................................................ 146 
12.3 
Premature Trial Termination ................................................................................................. 146 

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Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
13 
REPORTING AND PUBLICATION ............................................................................................ 147 
13.1 
Clinical Trial Report ............................................................................................................. 147 
13.2 
Confidentiality and Ownership of Trial Data ........................................................................ 147 
13.3 
Publications and Public Disclosure ....................................................................................... 147 
 Publication Policy .................................................................................................... 147 
 Public Disclosure Policy .......................................................................................... 148 
14 
ETHICAL AND REGULATORY ASPECTS ............................................................................... 149 
14.1 
Institutional Review Board (IRB) ......................................................................................... 149 
14.2 
Regulatory Authority Notification ........................................................................................ 149 
14.3 
End-of-Trial and End-of-Trial Notification .......................................................................... 149 
14.4 
Ethical Conduct of the Trial .................................................................................................. 149 
14.5 
Subject Information and Consent .......................................................................................... 149 
14.6 
Subject Participation Card .................................................................................................... 152 
14.7 
Checklist for Pregnancy Follow-up ...................................................................................... 152 
14.8 
Compliance Reference Documents ....................................................................................... 153 
15 
LIABILITIES AND INSURANCE ................................................................................................ 154 
15.1 
ICH-GCP Responsibilities .................................................................................................... 154 
15.2 
Liabilities and Insurance ....................................................................................................... 154 
16 
ARCHIVING .................................................................................................................................... 155 
16.1 
Investigator File .................................................................................................................... 155 
16.2 
Trial Master File.................................................................................................................... 155 
17 
REFERENCES ................................................................................................................................. 156 
 

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Solution for Injection  
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CONFIDENTIAL 
LIST OF TABLES  
 
 
 
 
 
Table 5-1 FE 999049 and Placebo Dosing Regimen............................................................................ 62 
Table 5-2 NIMP Dosing Regimen – Controlled Ovarian Stimulation and Fresh Cycle ...................... 63 
Table 5-3 NIMP Dosing Regimen – Programmed Cryopreserved Cycles ........................................... 64 
Table 5-4 NIMP Dosing Regimen – Natural Cryopreserved Cycles ................................................... 64 
Table 5-5 Characteristics of Medicinal Products ................................................................................. 65 
Table 5-6 Packaging of Medicinal Products ........................................................................................ 66 
Table 6-1 Trial Flow Chart – Subject Procedures – Controlled Ovarian Stimulation and Fresh 
Cycle .................................................................................................................................... 71 
Table 6-2 Trial Flow Chart – Oocyte / Blastocyst Procedures ............................................................. 79 
Table 6-3 Trial Flow Chart – Subject and Blastocyst Procedures – Programmed Cryopreserved 
Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation ...... 84 
Table 6-4 Trial Flow Chart – Subject and Blastocyst Procedures – Natural Cryopreserved 
Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation ...... 89 
Table 8-1 Classification of Mild, Moderate and Severe OHSS (Based on Golan’s Classification 
System)............................................................................................................................... 114 
Table 9-1 Probabilities to Detect at Least One Rare Event ................................................................ 122 
Table 9-2 Estimated Margin Widths of 95% Confidence Intervals ................................................... 123 
 
LIST OF FIGURES 
Figure 3-1 Trial Diagram – Controlled Ovarian Stimulation and Fresh Cycle ..................................... 36 
Figure 3-2 Trial Diagram – Programmed Cryopreserved Cycles Initiated Within 12 Months 
From the Start of Controlled Ovarian Stimulation............................................................... 37 
Figure 3-3 Trial Diagram – Natural Cryopreserved Cycles Initiated Within 12 Months From the 
Start of Controlled Ovarian Stimulation .............................................................................. 38 
Figure 3-4 Trial Diagram – Post-trial Activities .................................................................................... 39 
 
 
 
 
 
 
 
 
 

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Solution for Injection  
Clinical Trial Protocol 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS 
βhCG 
β unit of human chorionic gonadotropin 
ASRM 
American Society for Reproductive Medicine 
AMH 
anti-Müllerian hormone 
ART 
assisted reproductive technology 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
area under the time-concentration curve 
BID 
“bis in die”, two times daily 
BMI 
body mass index 
CHO 
Chinese hamster ovary 
CRO 
contract research organization 
DHEA 
dehydroepiandrosterone 
eCRF 
electronic case report form 
ESTHER 
Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World 
EU 
European Union 
FDA 
Food and Drug Administration, USA 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
GMP 
Good Manufacturing Practice 
Cmax 
maximum concentration observed 
hCG 
human chorionic gonadotropin 
HLT 
high level term 
ICH 
International Conference on Harmonisation 
ICSI 
intracytoplasmic sperm injection 
ID 
identifier 
Ig 
immunoglobulin 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug (application) 

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CONFIDENTIAL 
IRB 
institutional review board 
ITT 
intention-to-treat 
IU 
international unit 
IVF 
in vitro fertilization 
LH 
luteinizing hormone 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 
NCU 
neonatal care unit 
NICU 
neonatal intensive care unit 
NIMP 
non-investigational medicinal product 
NME 
new molecular entity 
OHSS 
ovarian hyperstimulation syndrome 
PCU 
pediatric care unit 
PGD 
preimplantation genetic diagnosis 
PGS 
preimplantation genetic screening 
PP 
per-protocol 
PT 
preferred term 
rFSH 
recombinant follicle-stimulating hormone 
RITA 
Recombinant FSH Investigation in the Treatment of Infertility with ART 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SMQ 
Standardised MedDRA Queries 
SUSAR 
suspected unexpected serious adverse reaction  
TID 
“ter in die”, three times daily 
TSH  
thyroid-stimulating hormone  
U.S. 
United States 
WHO 
World Health Organization 

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1 
INTRODUCTION 
1.1 
Background 
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) belonging to the 
pharmaceutical class of gonadotropins. The current trial is intended to support the following indication 
being pursued for FE 999049 in the United States (U.S.): “Development of multiple follicles and 
pregnancy after fresh and/or cryopreserved embryo transfer in ovulatory women undergoing assisted 
reproductive technology (ART)”.  
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6® 
cell line is well-characterized, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound polypeptide 
chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues with 5 intrachain-
disulphide bonds. The β-subunit contains 111 amino acid residues with 6 intrachain-disulphide bonds. 
Each subunit is N-glycosylated at two positions, and about 40% of the total mass is carbohydrates. 
Ferring received marketing authorization approval for FE 999049 for the 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” from the European Commission in 2016. As of early 2018, FE 999049 is 
approved in 37 countries also including countries outside the European Union (EU) such as Australia, 
Switzerland, and Canada. 
There are no commercially available rFSH products derived from human cell lines in the U.S. The 
rFSH products currently approved in the U.S. for controlled ovarian stimulation in ovulatory women 
undergoing ART, e.g. follitropin alfa (GONAL-F, EMD Serono) and follitropin beta (FOLLISTIM, 
Merck), are derived from a Chinese hamster ovary (CHO) cell line. The amino acid sequence of 
FE 999049 is identical to the endogenous human FSH sequence and to that in existing CHO-derived 
rFSH products. Manufacturing from different cell systems leads to glycosylation heterogeneity 
between rFSH preparations. The glycosylation profile of recombinant proteins is dependent on the 
expressing cell line and the cell culture conditions. Differences in glycosylation profile, sialic acid 
pattern and isoform profile have been documented between FE 999049 and existing rFSH products 
from a CHO cell line. Comparison between the FE 999049 and the GONAL-F and FOLLISTIM 
profiles indicate differences in acidity and carbohydrate side chains. As CHO cells lack enzymatic 
functions to construct more complex carbohydrate structures found in humans, the glycosylation 
profile of FE 999049 is more complex. In addition, FE 999049 contains both α2,3 and α2,6 sialylation 
patterns, while CHO-derived rFSH products exclusively carry 2,3 linked sialic acid; this difference 
further contributes to the observed differences in glycosylation profiles between FE 999049 and CHO-
derived rFSH products. For the purpose of clinical trials, FE 999049 is being treated as a new 
molecular entity (NME) by the Food and Drug Administration (FDA). 

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In total, eight previous clinical trials have been completed as part of the development program for 
FE 999049, covering four phase 1 trials, two phase 2 trials (one conducted in EU and one in Japan) and 
two phase 3 trials. A total of 1,927 subjects were included in these trials, of whom 1,112 subjects were 
exposed to FE 999049, in a range from a single dose up to exposure in three consecutive stimulation 
cycles. During the phase 3 trials, 665 IVF/ICSI patients were treated with FE 999049 in 1,012 
treatment cycles. In addition, two phase 3 trials are currently ongoing; one in Japan and one in Pan-
Asia.  
The two completed phase 3 trials support the efficacy and safety of FE 999049 (ESTHER-1 / 
ESTHER-2: Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World). 
ESTHER-1 (Trial 000004)1 was a randomized, controlled, assessor-blind trial conducted in 11 
countries in women 18-40 years undergoing IVF/ICSI followed predominantly by single blastocyst 
transfer. The trial was designed to demonstrate non-inferiority of FE 999049 versus an approved 
recombinant FSH preparation (GONAL-F) with ongoing pregnancy rate and ongoing implantation rate 
as co-primary endpoints and also to prospectively evaluate the outcome of an individualized 
FE 999049 dosing regimen based on the serum anti-Müllerian hormone (AMH) concentration 
(measured by Elecsys® AMH Immunoassay, Roche Diagnostics) and body weight. The ESTHER-1 
trial demonstrated non-inferiority of FE 999049 to GONAL-F for ongoing pregnancy rate and ongoing 
implantation rate for both the per-protocol (PP) and modified intention-to-treat (mITT; randomized and 
exposed) populations. For the overall trial population randomized and exposed to FE 999049, the 
ongoing pregnancy rate was 30.7% and the ongoing implantation rate was 35.2%. Among the women 
aged <35 years single blastocyst transfer was mandatory, and the ongoing pregnancy rate with 
FE 999049 was 33.2% and the ongoing implantation rate was 38.3%. ESTHER-2 (Trial 000071)2 was 
a safety immunogenicity trial covering up to two repeated treatment cycles in subjects who did not 
achieve an ongoing pregnancy in ESTHER-1. The trial confirmed the low immunogenicity potential 
with incidences of anti-FSH antibodies after exposure to FE 999049 of 0.8% in cycle 2 and 1.1% in 
cycle 3, which was not higher than the incidence of 1.1% in cycle 1 (ESTHER-1) or the incidence of 
pre-existing anti-FSH antibodies before exposure to FE 999049, which was 1.4%.2 ESTHER-2 
furthermore documented the efficacy of FE 999049 in repeated cycles with similar ongoing pregnancy 
rates between FE 999049 and GONAL-F as well as documented the safety of FE 999049 in an 
extended dose range up to 24 µg daily. Cryopreserved cycles using blastocysts derived from the 
controlled ovarian stimulation cycle in ESTHER-1 or ESTHER-2 and initiated within 1 year after start 
of stimulation in the subject’s last stimulation cycle were followed and showed good efficacy of 
FE 999049 in cryopreserved cycles with an ongoing pregnancy rate of 32.3% per initiated cycle. 
For further information regarding FE 999049, please refer to the current edition of the Investigator’s 
Brochure.3 
 

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1.2 
Scientific Justification for Conducting the Trial 
A clinical development program for FE 999049 has been conducted outside the U.S. applying an 
individualized dosing regimen based on the patient’s serum AMH concentration and body weight, and 
with a fixed dose throughout stimulation. As per FDA recommendations, the FE 999049 dosing 
regimen in phase 3 in the U.S. will not be based on AMH and body weight. Consequently, a phase 3 
program is required for the U.S. to document the efficacy and safety of FE 999049 in the dosing 
regimen applied in the present trial (see section 3.5.4). The present phase 3 trial will be conducted in 
the U.S. and will meet the FDA requirements of exposure in the intended target population in the U.S. 
The trial is designed to demonstrate the efficacy and safety of FE 999049 in women aged 18-34 years 
undergoing controlled ovarian stimulation for the development of multiple follicles and pregnancy 
after fresh and/or cryopreserved cycles.  
Cryopreservation of surplus embryos for potential use after the fresh cycle is standard practice in ART 
treatment, and serves to improve chances of pregnancy from a single stimulation cycle. The 
development of the vitrification method for freezing of embryos has resulted in significant 
improvement in post-thaw embryo survival4,5 with resulting ongoing pregnancy rates at least as good 
as those from fresh embryo transfer.6,7 As a consequence, the percentage of transfer cycles involving 
cryopreserved embryos has steadily increased in the U.S. over the last years, with a doubling from 
26.6% in 2011 to 52.4% in 2015.8,9 The higher frequency of cryopreserved cycles also reflects an 
increase of “cryo-all” cycles (ovarian stimulation cycles with cryopreservation of all embryos), which 
when coupled to a gonadotropin-releasing hormone (GnRH) agonist trigger improves patient safety, by 
reducing the risk of early severe ovarian hyperstimulation syndrome (OHSS).10 With the observed 
higher proportion of cryopreserved cycles, it becomes increasingly relevant to include these cycles in 
the assessment of pregnancy outcome following controlled ovarian stimulation. The present trial is the 
first U.S. clinical registration trial with a cumulative endpoint covering outcomes from both the fresh 
and subsequent cryopreserved cycles and thus capturing the clinical efficacy of a single controlled 
ovarian stimulation cycle in a more complete manner. 
The primary endpoint of cumulative ongoing pregnancy rate will be based on the fresh cycle and 
cryopreserved cycles initiated within 12 months of the start of controlled ovarian stimulation. The 
cumulative nature of the primary endpoint selected for this trial reflects the evolution in clinical 
management of infertility. Contemporary approaches have also been applied to improve the safety of 
infertility treatment, with implementation of GnRH agonist triggering in patients with excessive 
response to reduce the risk of OHSS as well as implementation of mandatory single blastocyst transfer 
to maximize the incidence of singletons and reduce the risk of multiple gestation, thereby addressing 
the most common safety concerns.  
 

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1.3 
Benefit / Risk Aspects 
Benefits 
Subjects who participate in this trial will undergo fertility screening procedures useful for their future 
clinical management. They will also be closely monitored and may benefit by achieving pregnancy. If 
subjects exhibit poor response to therapy (pre-established protocol criteria), they will be offered 
medication and financial support for an ART cycle with an approved gonadotropin preparation outside 
of the trial. 
 
Risks 
The risks associated with ART treatment, including the risks associated with controlled ovarian 
stimulation and clinical and laboratory procedures, are explained to the subjects as part of the 
counselling prior to starting treatment. 
FE 999049 
In the completed clinical trials of the development program for FE 999049, covering four phase 1 
trials, two phase 2 trials and two phase 3 trials, a total of 1,927 subjects were included. Of these, 
1,112 subjects were exposed to FE 999049 in a range from a single dose up to exposure in three 
consecutive stimulation cycles. During the phase 3 trials, 665 IVF/ICSI subjects were treated with 
FE 999049 in 1,012 treatment cycles. The most frequently reported adverse drug reactions during 
1,012 treatment cycles with FE 999049 in the phase 3 program were headache, pelvic discomfort, 
OHSS, pelvic pain, adnexa uteri pain, nausea and fatigue (all reported as common, i.e. 1% to <10%). 
Uncommon adverse drug reactions reported with FE 999049 were diarrhea, dizziness, mood swings, 
constipation, vomiting, abdominal discomfort, breast pain, breast tenderness, vaginal hemorrhage and 
somnolence. The incidence of injection site reactions was low after administration of FE 999049, and 
the severity of the injection site reactions was in general mild and comparable to that observed for 
GONAL-F. 
Concerning well-known risks associated with the use of gonadotropin products for controlled ovarian 
stimulation, subjects are closely monitored throughout the trial. The most serious risk associated with 
gonadotropin treatment is OHSS. OHSS manifests itself with increasing degrees of severity. 
Moderate/severe OHSS is associated with marked ovarian enlargement, fluid accumulation and other 
complications. The incidence of early OHSS can be minimized by withholding gonadotropins, 
withholding human chorionic gonadotropin (hCG) or administering GnRH agonist for triggering of 
final follicular maturation. In the current trial, a GnRH agonist will be administered for triggering of 
final follicular maturation in subjects who might be at risk of OHSS (as per defined criteria), and 
transfer in the fresh cycle will be cancelled. In addition, subjects with excessive ovarian response after 
triggering with hCG (as per defined criteria) will also have transfer in the fresh cycle cancelled to 

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reduce the risk of late OHSS which would be amplified by pregnancy. In both instances, blastocysts 
will be cryopreserved. Very rare cases of serious allergic reactions have been reported after injection of 
gonadotropins. Concerning immunogenicity, the risk of treatment-induced anti-drug-antibodies 
following FE 999049 treatment is very low. In the ESTHER-1 and ESTHER-2 trials, the observed 
incidence of anti-FSH antibodies after treatment with FE 999049 was 1.1% in cycle 1, 0.8% in cycle 2 
and 1.1% in cycle 3, which was not higher than the incidence of pre-existing anti-FSH antibodies of 
1.4% before exposure of FE 999049.2 In all instances, titers were undetectable or very low and without 
neutralizing capacity. No safety or efficacy concern has been identified with regard to immunogenicity 
with FE 999049.  
Concomitant Fertility Medications 
Subjects will receive concomitant fertility medication as part of the fresh cycle and the cryopreserved 
cycles in this trial. The most frequently reported adverse events with GnRH antagonist and hCG 
products are similar to those reported for FSH preparations and include headache, injection site 
reactions, pelvic pain, abdominal pain, abdominal distension and allergic reactions. Further, similar 
adverse events are expected after a single injection of GnRH agonist. Use of progesterone can cause 
skin reactions, fluid retention, somnolence, and arterial and venous thromboembolic events, including 
retinal thrombosis. Furthermore, the vaginal progesterone has been associated with vulvovaginal 
disorders and uterine spasms (at a frequency of 1-2%). Intramuscular progesterone can cause injection 
site reactions and sterile abscesses. Estrogen can cause breast tenderness, nausea, vomiting, skin 
reactions, headache, anaphylactic reactions, increase in blood pressure, and arterial and venous 
thromboembolic events, including retinal thrombosis. For detailed information on adverse events, 
please refer to the respective products Prescribing Information. 
Procedures 
Subjects will undergo standard ART treatment procedures (e.g. transvaginal ultrasound, blood 
sampling, oocyte retrieval and transfer). 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. 
Pregnancy-related Events 
Oocytes will be inseminated using IVF or ICSI and subsequently cultured to blastocyst stage (day 5 or 
later depending on embryo development). Although the frequency of cancellation of transfer is higher 
when culturing to blastocyst stage compared to culturing only to cleavage stage, the pregnancy rates 
per started cycle are at least as good with blastocyst transfer as with cleavage embryo transfer11 and 
may even be higher.12 A serious concern associated with ART cycles is the frequency of multiple 

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pregnancies / births and the related neonatal health problems. To minimize the risk of multiple 
gestations, single blastocyst transfer is mandatory in this trial for both the fresh and the cryopreserved 
cycles. 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 women 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, maternal and paternal genetic 
background, and sperm characteristics) and multiple pregnancies.  
 
Benefits / Risks 
Participation in this trial does not create extra risks for the subjects compared to routine controlled 
ovarian stimulation. The majority of subjects will receive active treatment, with an expected likelihood 
of conceiving similar to that in standard clinical practice. Subjects who exhibit poor response to 
therapy as per pre-established protocol criteria will be offered medication and financial support for an 
ART cycle with an approved gonadotropin preparation outside of the trial. In conclusion, the 
evaluation of benefits and risks indicate that participation in this trial is associated with a favorable 
benefit-risk ratio. 
 

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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• To demonstrate the efficacy and safety of FE 999049 in controlled ovarian stimulation 
 
Secondary Objectives 
• To establish the efficacy of FE 999049 in controlled ovarian stimulation with respect to 
pregnancy rates based on the fresh cycle and/or cryopreserved cycles 
• To characterize the ovarian response, including follicular development, oocytes retrieved and 
endocrine profile, as well as the embryo development associated with controlled ovarian 
stimulation with FE 999049 
• To characterize the safety profile of FE 999049 treatment, including adverse events, routine 
safety laboratory parameters, local tolerability and immunogenicity 
 
Post-trial Objectives 
• To establish the efficacy of controlled ovarian stimulation with FE 999049 with respect to live 
birth rates based on the fresh cycle and/or cryopreserved cycles 
• To characterize the neonatal health associated with controlled ovarian stimulation with 
FE 999049, including minor/major congenital anomalies at birth, 4 weeks and 1 year after birth 
in the fresh cycle and cryopreserved cycles 
 
2.2 
Endpoints 
Primary Endpoint 
• Cumulative ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after 
transfer) after the fresh cycle and cryopreserved cycles initiated within 12 months from the start 
of controlled ovarian stimulation 
 

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Secondary Endpoints 
• Ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after transfer) in the 
fresh cycle and in the cryopreserved cycles 
• Time from start of controlled ovarian stimulation to ongoing pregnancy across the fresh and 
cryopreserved cycles, including duration and number of cycles before achieving ongoing 
pregnancy 
• Ongoing implantation rate (number of intrauterine viable fetuses 8-9 weeks after transfer 
divided by number of blastocysts transferred) in the fresh cycle, the cryopreserved cycles and 
cumulatively 
• Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer) in the fresh cycle, 
the cryopreserved cycles and cumulatively 
• Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) in the fresh cycle, the cryopreserved cycles and cumulatively 
• Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred) in the fresh cycle, the cryopreserved cycles and cumulatively 
• Positive βhCG rate (positive serum βhCG test 10-14 days after transfer) in the fresh cycle, the 
cryopreserved cycles and cumulatively 
• Proportion of subjects in the fresh cycle with triggering of final follicular maturation (with 
hCG, with GnRH agonist, and in total), cycle cancellation and transfer cancellation 
• Number and size of follicles on stimulation day 5 and end-of-stimulation 
• Number of oocytes retrieved and proportion of subjects with <4, 4-7, 8-14, 15-19 and 
≥20 oocytes retrieved 
• Number and percentage of metaphase II oocytes (only applicable for those inseminated using 
ICSI), number of fertilized oocytes, fertilization rate as well as number and quality of 
blastocysts on day 5 after oocyte retrieval 
• Endometrial thickness and echogenicity pattern on stimulation day 5 and end-of-stimulation 
• Oocyte utilization rate (number of blastocysts transferred or cryopreserved divided by the 
number of oocytes retrieved) and oocyte efficiency index (cumulative number of ongoing 
pregnancies per oocyte retrieved) 
• Number and percentage of blastocysts surviving cryopreservation and number and percentage 
of blastocysts with re-expansion after cryopreservation 
• Number of cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation, and number and percentage of cryopreserved cycles with blastocyst transfer 

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• Circulating concentrations of AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B 
on stimulation day 5, end-of-stimulation and oocyte retrieval, and FSH population 
pharmacokinetic parameters 
• Total gonadotropin dose, number of stimulation days and number of dose adjustments 
• Frequency and intensity of adverse events 
• Changes in circulating levels of clinical chemistry and hematology parameters and proportion 
of subjects with markedly abnormal changes 
• Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period 
• Proportion of subjects with treatment-induced anti-FSH antibodies, overall as well as with 
neutralizing capacity 
• Frequency and intensity of immune-related adverse events 
• Proportion of subjects with cycle cancellations due to an adverse event, including immune-
related adverse events, or due to technical malfunctions of the administration pen 
• Proportion of subjects with OHSS, overall and by grade, and proportion of subjects with 
moderate/severe OHSS 
• Proportion of subjects hospitalized due to OHSS and proportion of subjects undergoing 
paracentesis due to OHSS 
• Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic pregnancy 
(with and without medical/surgical intervention) and vanishing twins in the fresh cycle and in 
the cryopreserved cycles 
• Technical malfunctions of the administration pen 
 
Post-trial Endpoints 
• Cumulative live birth rate after the fresh cycle and cryopreserved cycles initiated within 
12 months from the start of controlled ovarian stimulation 
• Live birth rate in the fresh cycle and in the cryopreserved cycles 
• Live birth rate of singletons born at term (≥37 weeks of gestation) in the fresh cycle, the 
cryopreserved cycles and cumulatively 
• Time from start of controlled ovarian stimulation to live birth of a singleton born at term across 
the fresh and cryopreserved cycles, including duration and number of cycles before achieving a 
live birth of a singleton born at term 
• Rate of minor/major congenital anomalies at birth, 4 weeks and 1 year after birth in the fresh 
cycle and cryopreserved cycles 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
 
Trial Design Diagram 
A diagram illustrating the controlled ovarian stimulation and fresh cycle is presented in Figure 3-1. 
 
 
Figure 3-1 Trial Diagram – Controlled Ovarian Stimulation and Fresh Cycle 
 
Diagrams illustrating the cryopreserved cycles initiated within 12 months from the start of controlled 
ovarian stimulation are presented in Figure 3-2 for programmed cryopreserved cycles and in Figure 3-3 
for natural cryopreserved cycles. 

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Figure 3-2 Trial Diagram – Programmed Cryopreserved Cycles Initiated Within 12 Months 
From the Start of Controlled Ovarian Stimulation 
 
 

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Figure 3-3 Trial Diagram – Natural Cryopreserved Cycles Initiated Within 12 Months From 
the Start of Controlled Ovarian Stimulation 
 

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A diagram illustrating the post-trial activities for the fresh and cryopreserved cycles is shown in 
Figure 3-4. 
 
 
Figure 3-4 Trial Diagram – Post-trial Activities 
 
 
Overall Design and Control Methods 
This will be a randomized, double-blind, placebo-controlled, parallel groups, multicenter trial assessing 
the efficacy and safety of the rFSH preparation FE 999049 in subjects aged 18-34 years undergoing 
controlled ovarian stimulation for IVF / ICSI following a GnRH antagonist protocol. The primary 
endpoint is the cumulative ongoing pregnancy rate after the fresh cycle and cryopreserved cycles 
initiated within 12 months from the start of controlled ovarian stimulation. Thereby, the trial is 
designed to capture the clinical efficacy of a single controlled ovarian stimulation cycle in a more 
complete manner by following outcomes from both the fresh and subsequent cryopreserved cycles. 
Secondary endpoints include pharmacodynamic parameters of FSH action as well as efficacy and 
safety parameters related to controlled ovarian stimulation from the fresh cycle and subsequent 
cryopreserved cycles. 
 
Controlled Ovarian Stimulation and Fresh Cycle 
Subjects will be screened within 90 days prior to randomization for compliance with the inclusion and 
exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomized in a 10:1 ratio to 
FE 999049 or placebo, and controlled ovarian stimulation will be initiated. FE 999049 and placebo will 
be self-administered subcutaneously using a pre-filled injection pen. 
Subjects assigned to treatment with FE 999049 will receive a starting dose of 12 µg daily that is fixed 
for the first four stimulation days. Based on ovarian response, the dose may be adjusted by 3 µg, with 

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dose increases implemented not more frequently than once every 2 days and dose decreases 
implemented per investigator’s judgement. The minimum daily dose is 6 µg, and the maximum daily 
dose is 24 µg. Subjects assigned to placebo will have the injection pen dialed to the same value (dose) 
as if administered FE 999049. Subjects can be treated with FE 999049 or placebo for a maximum of 
20 days. Coasting, use of dopamine agonist or any other drug to prevent early OHSS with the 
exception of GnRH agonist for triggering of final follicular maturation, are not allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation days 1 and 5 
and thereafter at least every second day. When the leading follicle reaches a diameter of ≥14 mm, 
transvaginal ultrasound will be performed daily. To prevent a premature luteinizing hormone (LH) 
surge, 250 µg GnRH antagonist (ganirelix acetate, GANIRELIX, Merck Sharp & Dohme) will be 
initiated on stimulation day 5 for subjects with ≥3 follicles with a diameter of ≥10 mm. Subjects who 
fail to satisfy this GnRH antagonist criterion on stimulation day 5 will continue to be monitored at least 
every second day, and GnRH antagonist will be initiated when/if the criterion is met. The GnRH 
antagonist will be continued throughout the stimulation period. Triggering of final follicular maturation 
will be done as soon as ≥2 follicles with a diameter of ≥17 mm are observed. If there are <20 follicles 
with a diameter of ≥12 mm, 10,000 IU hCG (NOVAREL, Ferring Pharmaceuticals) will be 
administered. If there are ≥20 follicles with a diameter of ≥12 mm or the serum estradiol concentration 
is ≥3,000 pg/mL (local laboratory), 4.0 mg GnRH agonist (leuprolide acetate, LEUPROLIDE 
ACETATE, Sandoz) will be administered, and the fresh blastocyst transfer will be canceled. If after 
8 days of stimulation, the investigator judges that the triggering criterion is not likely to be reached by 
day 20, the cycle will be canceled. If the triggering criterion is not met after 20 days of stimulation, the 
cycle will be canceled.  
Oocyte retrieval will take place 36h (±2h) after triggering of final follicular maturation, and oocytes 
will be inseminated by IVF or ICSI 4h (±1h) after retrieval. Rescue ICSI is not allowed. Fertilization 
and embryo development will be assessed. For subjects who undergo triggering of final follicular 
maturation with hCG and have <20 oocytes retrieved, transfer will be performed on day 5 (blastocyst 
stage) after oocyte retrieval. All subjects will have transfer of one blastocyst of the highest quality 
available and remaining blastocysts will be cryopreserved by vitrification. For subjects with 
≥20 oocytes retrieved following hCG administration and for subjects who undergo triggering of final 
follicular maturation with GnRH agonist, no transfer will take place in the fresh cycle and blastocysts 
will instead be cryopreserved.  
A subject who fails to reach the triggering criterion due to poor ovarian response or who has 
≤3 oocytes retrieved will be offered medication and financial support for an ART cycle with an 
approved gonadotropin preparation outside of the trial. 
Vaginal progesterone inserts (progesterone, ENDOMETRIN, Ferring Pharmaceuticals) 100 mg three 
times daily (TID) will be provided for luteal phase support from the day after oocyte retrieval and 

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continuing until menses, negative β human chorionic gonadotropin (βhCG test), pregnancy loss or until 
ongoing pregnancy has been documented. 
A serum βhCG test will be performed 10-14 days after transfer, clinical and vital pregnancy will be 
confirmed by transvaginal ultrasound 5-6 weeks after transfer, and ongoing pregnancy will be 
confirmed by transvaginal or abdominal ultrasound 8-9 weeks after transfer. 
Blood samples will be collected for the purpose of evaluating the endocrine profile, clinical chemistry 
and hematology parameters as well as anti-FSH antibodies. Endocrine parameters will be assessed at 
screening, stimulation day 1, stimulation day 5, end-of-stimulation and oocyte retrieval. Clinical 
chemistry and hematology will be assessed at screening, end-of-stimulation, and end-of-cycle. Anti-
FSH antibodies will be assessed on four occasions. The first sample will be taken at the screening visit 
and will be used exclusively to re-establish the anti-drug antibody analytical assays. The subsequent 
three samples will be used for analysis of anti-FSH antibodies in individual subjects in the trial, and 
taken prior to dosing on stimulation day 1 and on two occasions post-dosing: 7-10 days after the last 
FE 999049 or placebo dose (this may coincide with the transfer visit) and 21-28 days after the last 
FE 999049 or placebo dose (this may coincide with the βhCG test visit). Subjects with a treatment-
induced anti-FSH antibody response will be followed until the response has become negative, returned 
to the pre-dosing level, or for a maximum of 1 year after the second post-dose sampling. These 
subjects will be called in for assessments 2 months after the last post-dosing anti-FSH antibody 
sampling. If required, further assessments will be made at 3, 4, 6, 9 and 12 months after the last post-
dosing anti-FSH antibody sampling. The follow-up will also be terminated if the subject commences a 
new treatment cycle with any gonadotropin preparation. 
Local tolerability of FE 999049 and placebo following subcutaneous administration will be assessed by 
the subject three times daily: immediately, 30 minutes and 24 hours after each injection. The presence 
and intensity of injection site reactions will be rated as none, mild, moderate or severe. The 
assessments will be made throughout the stimulation period and recorded by the subject in a diary. 
 
Cryopreserved Cycles 
The trial covers cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation. Either a programmed or natural cycle can be selected for any cryopreserved cycle.  
Any programmed cryopreserved cycle will be initiated within 3 days of start of menses with 
administration of estradiol (ESTRADIOL Tablets USP, Teva Pharmaceuticals USA, Inc.) 2 mg TID or 
3 mg two times daily (BID) (or 3 mg TID at the investigator’s discretion, if a daily dose of 6 mg has 
been shown to be insufficient in a previous cycle). If after 10-12 days of estradiol treatment the 
endometrial thickness is ≥8 mm, the subject will initiate daily intramuscular (IM) injections of 50 mg 

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progesterone (PROGESTERONE Injection USP, West-ward Pharmaceutical Corp or Watson Pharma, 
Inc.) within the next 5 days in conjunction with the estradiol treatment. The ultrasound evaluation can 
be repeated within 7 days if the endometrial thickness criterion is not met. In programmed 
cryopreserved cycles, transfer of one blastocyst of the highest quality available will occur on the 6th 
day from start of progesterone after warming and assessment of blastocyst survival and re-expansion. 
Luteal phase support (estradiol and IM progesterone) will continue to be administered until menses, 
negative βhCG test, pregnancy loss or until ongoing pregnancy has been documented. 
Any natural cryopreserved cycle will be initiated 7 days after start of menses with monitoring of 
urinary LH on a daily basis by the subject. The day after confirmation of LH surge by serum LH (local 
laboratory) and endometrial thickness of ≥8 mm, the subject will start luteal phase support with vaginal 
progesterone inserts (progesterone, ENDOMETRIN, Ferring Pharmaceuticals) 100 mg TID. In a 
natural cryopreserved cycle, transfer of one blastocyst of the highest quality available will occur on day 
LH surge +7 after warming and assessment of blastocyst survival and re-expansion. Luteal phase 
support (vaginal progesterone) will continue to be administered until menses, negative βhCG test, 
pregnancy loss or until ongoing pregnancy has been documented. 
Failure to achieve endometrial thickness ≥8 mm in the first cryopreserved cycle will result in cycle 
cancellation, and in the programmed cycles, administration of 100 mg IM progesterone 
(PROGESTERONE Injection USP, West-ward Pharmaceutical Corp or Watson Pharma, Inc.) to 
induce withdrawal bleeding. In subsequent cryopreserved cycles, blastocyst transfer can take place 
regardless of endometrial thickness at the investigator’s discretion. 
In both programmed and natural cryopreserved cycles, a serum βhCG test is performed 10-14 days 
after transfer, clinical and vital pregnancy will be confirmed by transvaginal ultrasound 5-6 weeks after 
transfer, and ongoing pregnancy will be confirmed by transvaginal or abdominal ultrasound 8-9 weeks 
after transfer. 
After completion of the trial, the subject is allowed to use cryopreserved blastocysts in accordance with 
local guidelines and/or regulations. 
 
Post-trial Activities 
Post-trial activities cover pregnancy and neonatal health follow-up after the fresh cycle and 
cryopreserved cycles. 
All subjects with an ongoing pregnancy obtained in the fresh cycle or in cryopreserved cycles initiated 
within 12 months from the start of controlled ovarian stimulation will be followed until delivery to 
collect information on live birth rate. Furthermore, data will be collected on neonatal health, including 

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minor/major congenital anomalies, at birth, 4 weeks and 1 year after birth. 
 
Optional Exploratory Analyses 
For subjects who have provided a separate informed consent, a blood sample and a saliva sample for 
potential future genome sequencing will be collected on stimulation day 1, and a tongue coat sample 
for potential future microbial profiling will be collected on stimulation day 1 and at the transfer visit(s) 
in the fresh and cryopreserved cycles, as applicable. 
 
 
Trial Schedule 
First patient first visit: 
 
 
 
 
 
 
 Q3 2018 
Last ongoing pregnancy after fresh and cryopreserved cycles:  
 
 Q2 2020 
Last live birth after fresh and cryopreserved cycles:   
 
 
 Q4 2020 
Last 1-year neonatal health follow-up after fresh and cryopreserved cycles: Q4 2021 
 
3.2 
Planned Number of Trial Sites and Subjects 
It is planned to randomize 550 subjects from approximately 25 sites in the U.S. It is estimated that 
approximately 625 subjects should be screened to achieve 550 subjects eligible for the trial. 
 
3.3 
Interim Analysis 
No interim analysis intended to compare treatment groups with respect to efficacy or safety is planned. 
 
3.4 
Data Monitoring Committee 
No Data Monitoring Committee will be established for this trial. During the trial, the internal 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 
 
Trial Design 
The trial is designed to demonstrate the efficacy and safety of FE 999049 in controlled ovarian 
stimulation, taking into account the clinical outcome of the blastocysts transferred in the fresh cycle 
and subsequent cryopreserved cycles initiated within 12 months from start of controlled ovarian 
stimulation. It is the first U.S. clinical registration trial with a cumulative endpoint covering outcomes 
from both the fresh and subsequent cryopreserved cycles and thus capturing the clinical efficacy of a 

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single controlled ovarian stimulation cycle in a more complete manner. Contemporary approaches have 
also been applied to improve the safety of infertility treatment, with implementation of GnRH agonist 
triggering in patients with excessive response to reduce the risk of OHSS as well as implementation of 
mandatory single blastocyst transfer to maximize the incidence of singletons and reduce the risk of 
multiple gestation, thereby addressing the most common safety concerns. 
The trial is a randomized, double-blind, placebo-controlled trial. The double-blind, placebo-controlled 
clinical trial has a long history as the standard for investigations of new drugs in the U.S., including 
those for the treatment of infertility (ClinicalTrials.gov NCT01976728). Moreover, the placebo 
response has not been rigorously characterized in the indicated trial population undergoing ART. A 
placebo solution has been manufactured for the purpose of this trial; it is indistinguishable from the 
active FE 999049 solution and is provided in identical pre-filled injection pens. Only placebo to 
FE 999049 is used in the trial and NIMPs will be supplied to subjects both in the placebo and 
FE 999049 treatment groups as per protocol description, facilitating a focused comparison of 
FE 999049 versus placebo to FE 999049. Clinical considerations have been made to maximize the 
probability for pregnancy in the placebo group, including that the criterion for starting the GnRH 
antagonist is based on follicular development and not fixed to a specific stimulation day. It will not be 
possible to distinguish between poor responders to FE 999049 and women in the placebo group, which 
supports the double-blinded design.  
The double-blind design will ensure that the subjects, the investigator and other trial staff such as trial 
nurses, ultrasound technicians, local laboratory technicians and embryologists, as well as central 
laboratory personnel are blinded to individual treatment allocation throughout the trial, including the 
post-trial activities. Sponsor staff will also remain blinded to individual subject treatment allocation 
during the conduct of the trial. 
The trial will be a multi-center trial. This set-up ensures that the required number of subjects can be 
recruited within a reasonable time and also has the advantage that it should facilitate subsequent 
generalization of the results. 
The trial covers a fresh cycle and cryopreserved cycles initiated within 12 months from the start of 
controlled ovarian stimulation. Subjects will undergo controlled ovarian stimulation in a GnRH 
antagonist protocol with either FE 999049 or placebo. Subjects randomized to FE 999049 will receive 
a starting dose of 12 µg daily that is fixed for the first four stimulation days. Based on ovarian 
response, the dose may be adjusted by 3 µg, with dose increases implemented not more frequently than 
once every 2 days and dose decreases implemented per investigator’s judgement. The minimum daily 
dose is 6 µg, and the maximum daily dose is 24 µg. For subjects randomized to placebo the injection 
pen will be dialed to the same value (dose) as if administered FE 999049. The selection of FE 999049 
starting dose and dose adjustments is described in detail in section 3.5.4.  

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Oocytes will be inseminated by either IVF or ICSI reflecting the procedures used in the target 
population for the proposed indication, and embryo development parameters will be assessed. 
Blastocyst biopsy, assisted hatching, and preimplantation genetic diagnosis (PGD) / preimplantation 
genetic screening (PGS) are not allowed. 
The present protocol requires transfer of a single blastocyst in both the fresh cycle and cryopreserved 
cycles. These criteria are stricter than the current American Society for Reproductive Medicine 
(ASRM) guidelines for embryo transfer but is justifiable to reduce the risk of multiple gestations.13 
There is increasing evidence suggesting that late stages of embryo progression are better predictors of 
clinical pregnancy than early embryo development parameters.14 In good-prognosis patients, the 
transfer of blastocysts yields a higher live birth rate than that achieved with transfer of the same 
number of cleavage-stage embryos. 
Concerning cryopreserved cycles, both the option of programmed cycles and natural cycles is being 
provided. The methodology has been standardized within each approach.  
Subjects who achieve an ongoing pregnancy in the fresh cycle or in cryopreserved cycles initiated 
within 12 months from the start of controlled ovarian stimulation will be followed until live birth to 
collect information on pregnancy outcome. In addition, neonatal health data will be collected at birth, 
4 weeks and 1 year after birth. 
 
 
Selection of Endpoints 
The primary endpoint of cumulative ongoing pregnancy rate covers outcome from both the initial 
stimulated fresh cycle and the subsequent cryopreserved cycles and thereby captures the clinical 
efficacy of a single controlled ovarian stimulation cycle in a more complete manner. 
It has been observed in previous clinical trials that most women who return to use their cryopreserved 
blastocysts undergo 2-3 cryopreserved cycles, and in this context 6 months would be a sufficient 
follow-up period if exclusively natural cycles were applied. In the present trial, the extent of 
cryopreserved cycles is 12 months due to the option of the programmed cycle approach; this expansion 
to 12 months allows the trial to capture the greatest potential of the blastocysts derived from a single 
controlled ovarian stimulation cycle. 
Positive βhCG, clinical pregnancy and vital pregnancy are included as secondary endpoints in the trial. 
Additional secondary endpoints include total dose of gonadotropins and pharmacodynamic parameters 
of FSH, such as ovarian response in terms of follicular development, endocrine profile and oocytes 
retrieved, and also oocyte / blastocyst quality, including blastocyst survival and re-expansion in the 
cryopreserved cycles. Follicular development and endocrine profile will be evaluated after the initial 
4 days of ovarian stimulation (i.e. before any potential IMP dose adjustments and before start of the 

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GnRH antagonist) as well as at the end of stimulation. The endocrine profile consists of AMH, FSH, 
LH, estradiol, progesterone, inhibin A and inhibin B.  
Clinical safety endpoints cover adverse events, clinical chemistry and hematology parameters, local 
tolerability, immunogenicity, OHSS and pregnancy-related events (i.e. multi-fetal gestations, 
biochemical pregnancies, spontaneous abortions, ectopic pregnancies and vanishing twins). Pre-
defined local tolerability reactions, i.e. redness, pain, itching, swelling and bruising, will be assessed by 
the subjects on three occasions after each subcutaneous IMP injection spanning from immediately to 
24 hours after. Presence of anti-FSH antibodies will be evaluated 7-10 and 21-28 days after the last 
administration of FE 999049 for assessment of a potential immunoglobulin M (IgM) response and a 
fully mounted immunoglobulin G (IgG) immune response, respectively.15 Technical malfunction of the 
pens used for administration of FE 999049 and placebo will also be monitored. 
Live birth is the ultimate objective for couples starting infertility treatment. Nevertheless, it can be 
justified to use ongoing pregnancy rate as an endpoint indicative of the final treatment outcome as few 
pregnancy losses occur after confirmation of ongoing pregnancy.16 In the ESTHER-1 trial, the absolute 
difference between live birth rate and ongoing pregnancy rate was -1.0% among the women younger 
than 35 years. Similarly, the late pregnancy loss was -0.8% in another large controlled trial conducted 
by Ferring in IVF/ICSI patients aged below 35 years undergoing controlled ovarian stimulation with 
currently available gonadotropins and compulsory single blastocyst transfer.17 In the present trial, 
ongoing pregnancies in the fresh and cryopreserved cycles will be followed until live birth, allowing 
for evaluation of cumulative live birth rate. Neonatal health data at birth, 4 weeks and 1 year after birth 
will be collected for infants born after the fresh cycle and cryopreserved cycles to provide additional 
safety information. 
In conclusion, the primary and secondary endpoints are appropriate for a phase 3 trial designed to 
document the efficacy and safety of a gonadotropin intended for controlled ovarian stimulation. 
 
 
Blinding 
The randomized, placebo-controlled, double-blind trial design will ensure random allocation of eligible 
subjects to the FE 999049 and placebo treatment groups. It will also allow for the unbiased evaluation 
by the subject, the investigator and other site staff such as trial nurses, ultrasound technicians, local 
laboratory technicians and embryologists, as well as central laboratory personnel.  
Sponsor staff (e.g., field monitor, data manager, statistician, clinical trial manager, medical writer, 
pharmacovigilance physician, pharmacovigilance manager, medical monitor and medical officer) will 
also be blinded to treatment allocation until breaking of the blind.  

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The pre-filled injection pens and solutions of FE 999049 and placebo will be identical in appearance to 
maintain the blinding. Central laboratory analysis results of endocrine parameters, including serum 
FSH, from blood samples drawn after stimulation day 1 will not be available to site or sponsor staff 
until after unblinding of the trial, and local laboratory analysis of serum FSH is prohibited.  
The blind will be broken when the trial database is declared clean and released to the statistician. 
 
 
Selection of Doses in the Trial 
3.5.4.1 
FE 999049 
The dosing regimen for FE 999049 in women aged <35 years is a starting dose of 12 µg daily for the 
first four stimulation days, after which dose adjustments of 3 µg based on the individual subject’s 
ovarian response can be implemented, with the minimum daily dose being 6 µg and the maximum 
daily dose being 24 µg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.5.4.2 
Concomitant Fertility Medication 
Controlled Ovarian Stimulation and Fresh Cycle 
The doses and overall treatment regimens for the GnRH antagonist (GANIRELIX), hCG (NOVAREL) 
and progesterone (ENDOMETRIN) products are in line with the recommendations in the respective 
products’ Prescribing Information and/or standard clinical practice within ART. The GnRH agonist 
(LEUPROLIDE ACETATE) is included as an option for triggering of final follicular maturation in 
subjects with ≥20 follicles with a diameter of ≥12 mm or serum estradiol concentration ≥3,000 pg/mL 
as this approach is associated with a decreased risk of early severe OHSS despite high ovarian 
response.20,21,22,23,24 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.25,26,27 Although subjects with GnRH agonist triggering do not undergo blastocyst transfer 
in the fresh cycle, the trial design with cryopreserved cycles and a cumulative ongoing pregnancy 

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endpoint means that the efficacy evaluation is not compromised. 
 
Cryopreserved Cycles 
For the programmed cryopreserved cycles, the doses and treatment regimens for estradiol 
(ESTRADIOL Tablets USP) and progesterone (PROGESTERONE Injection USP) are in line with 
standard clinical practice within ART.  
For the natural cryopreserved cycles, the dose of progesterone (ENDOMETRIN) is in line with the 
Prescribing Information. 
 
 
Selection of the Trial Population 
This trial will include women aged 18-34 years who are eligible for IVF or ICSI and who have 
undergone no more than one previous controlled ovarian stimulation cycle. The subjects have been 
diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or have partners 
diagnosed with male factor infertility. The allowed body mass index (BMI) is 17.5-38.0 kg/m2, thus 
including underweight, normal weight, overweight and obese subjects. 
The exclusion criteria incorporate the contraindications for the use of gonadotropins and other 
concomitant fertility medications used in the trial. 
 
 
Follow-up Procedures 
Post-trial Activities 
Post-trial activities cover pregnancy and neonatal health follow-up at birth, 4 weeks and 1 year after 
birth, after the fresh cycle and all cryopreserved cycles initiated within 12 months from the start of 
controlled ovarian stimulation. 
It is foreseen that the long extent of follow-up will pose challenges. While the ongoing pregnancy visit 
will take place at the trial sites, later pregnancy monitoring and delivery does not occur at the trial site 
but at the subject’s general practitioner, OB/GYN specialist, hospital etc. Likewise, neonatal health 
follow-up is not performed at the trial sites. Efforts will be made to capture the follow-up information 
described in the protocol by use of contact logs and other measures, but instances of missing data 
especially as the follow-up period advances cannot be ruled out. 
 

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Immunogenicity Follow-up 
As a safety precaution, subjects with treatment-induced anti-FSH antibody response will be followed 
until the response has become negative or returned to the pre-dosing level, or for a maximum of 1 year 
after the second post-dose sampling. The follow-up procedure involves frequent visits/samples in the 
beginning after detecting a positive signal, followed by longer intervals later in the follow-up period. 
The follow-up will be terminated if the subject commences a new treatment cycle with any 
gonadotropin preparation. 
 
Access to Therapy after End-of-trial 
Concerning access to therapy after completion of the trial, FE 999049 is currently under clinical 
development in the U.S. and cannot be offered to subjects after participation in this clinical trial. 
However, several gonadotropin preparations are commercially available. 
 

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4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
 
Inclusion Criteria 
Subjects must meet all of the criteria listed below to be eligible for participation in this trial. 
 Informed Consent Documents signed prior to any trial-related procedure. 
 In good physical and mental health in the judgement of the investigator. 
 Pre-menopausal females between the ages of 18 and 34 years. The subjects must be at least 
18 years (including the 18th birthday) when they sign the informed consent and no more than 
34 years (up to the day before the 35th birthday) at the time of randomization. 
 Body mass index (BMI) between 17.5 and 38.0 kg/m2 (both inclusive) at screening. 
 Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization 
(IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm 
from male partner or sperm donor. 
 Documented history of infertility for at least 12 months before randomization (not applicable 
in case of tubal or severe male factor infertility, or when the use of donor sperm is indicated). 
 Regular menstrual cycles of 24-35 days (both inclusive). 
 Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus 
consistent with expected normal function (e.g. no evidence of clinically interfering uterine 
fibroids defined as submucous fibroids of any size or intramural fibroids larger than 3 cm in 
diameter, no polyps and no congenital structural abnormalities which are associated with a 
reduced chance of pregnancy) at screening or within 1 year prior to screening.  
 Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, 
without evidence of significant abnormality (e.g. enlarged ovaries which would contraindicate 
the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) at screening. Both ovaries 
must be accessible for oocyte retrieval. 
 Early follicular phase (cycle day 2-4) serum levels of follicle-stimulating hormone (FSH) 
between 1 and 15 IU/L (results obtained within 3 months prior to randomization). 
 Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human 
Immunodeficiency Virus (HIV) antibody tests at screening or within 6 months prior to 
screening.  
 Willing to accept single blastocyst transfer in the fresh cycle and in the cryopreserved cycles 
initiated within 12 months from the start of controlled ovarian stimulation using blastocysts 
obtained in this trial. 
 Willing and able to comply with trial procedures, including filling in the diary and attending 
scheduled visits as well as providing the neonatal health data up to 1 year after birth. 
 

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Exclusion Criteria 
Subjects meeting any of the criteria listed below will not be eligible for participation in this trial. 
 More than one previous controlled ovarian stimulation cycle for IVF/ICSI. 
 Known endometriosis stage III-IV (defined by the revised ASRM classification, 201228). 
 Known history of anovulation. 
 One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound prior 
to randomization on stimulation day 1. 
 Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy [excl. ectopic pregnancy] and before week 24 of pregnancy).  
 Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial. In case partner sperm will be 
used and the sperm production is severely impaired (concentration <1 million/mL), normal 
karyotype, including no Y-chromosome microdeletion, must be documented. 
 Any known clinically significant systemic disease (e.g. insulin-dependent diabetes). 
 Known inherited or acquired thrombophilia. 
 Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events. 
 Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) 
with the exception of pharmacologically controlled sub-clinical hypothyroidism. 
 Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins. 
 Known moderate or severe impairment of renal or hepatic function. 
 Any abnormal finding of clinical chemistry, hematology, thyroid-stimulating hormone (TSH) 
or prolactin, or vital signs at screening, which is judged clinically significant by the 
investigator.  
 Currently breast-feeding. 
 Undiagnosed vaginal bleeding. 
 Known abnormal cervical cytology of clinical significance observed within three years prior to 
randomization (unless the clinical significance has been resolved). 
 Findings at the gynecological 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. 
 Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to 
randomization) or contraindication to pregnancy. 
 Known current active pelvic inflammatory disease. 

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 Use of fertility modifiers during the last menstrual cycle before randomization, including 
dehydroepiandrosterone (DHEA), metformin or cycle programming with oral contraceptives, 
progestogen or estrogen preparations. 
 Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle 
before randomization. 
 Known history of chemotherapy (except for gestational conditions) or radiotherapy.  
 Current or past (1 year prior to randomization) abuse of alcohol or drugs. 
 Current (last month) intake of more than 14 units of alcohol per week (one unit is equivalent to 
12 fluid ounces of regular beer (5% alcohol), 5 fluid ounces of wine (12% alcohol), or 1.5 fluid 
ounces of 80 proof distilled spirits (40% alcohol). 
 Current or past (3 months prior to randomization) smoking habit of more than 10 cigarettes per 
day. 
 Known hypersensitivity to any active ingredient or excipients in the medicinal products used in 
this trial. 
 Any known clinical condition that would prevent the use of estrogen or progestin compounds.  
 Previous participation in this trial.  
 Use of any non-registered investigational drugs during the last 3 months prior to 
randomization. 
 
4.2 
Method of Assigning Subjects to Treatment Groups 
 
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 Institutional Review Boards (IRBs). 
A screening number is allocated to each subject who has given written informed consent to participate 
in the trial. A subject must always be assigned to the lowest available screening number at each site. A 
subject screening / enrolment log for all screened subjects must be maintained by the investigator. 
 
 
Randomization 
On day 2-3 of the menstrual cycle, subjects will be randomized in a 10:1 ratio to FE 999049 or 
placebo, and ovarian stimulation will be initiated. 
Randomization is performed centrally through the electronic case report form (eCRF). When a subject 
is randomized to the trial, she will always be assigned to the lowest available randomization number. 
An independent statistician will prepare a computer-generated randomization list and randomization is 
performed in blocks to distribute placebo subjects randomly over the trial enrollment period. The block 
size will only be revealed when the trial database is declared clean and released to the statistician. 

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Details of subject enrolment will be recorded on a subject identification code list for all randomized 
subjects kept by the investigator. 
 
4.3 
Restrictions 
 
Prior and Concomitant Therapies 
The subjects must not have used fertility modifiers, including DHEA, metformin or cycle 
programming with oral contraceptives, progestogen or estrogen preparations, or hormonal preparations 
(except for thyroid medication) during the last menstrual cycle before randomization.  
Any concomitant therapies used during the trial or within 3 months prior to screening will be recorded 
in the source documents and eCRF, along with the main reason for their prescription/use. 
 
 
Prohibited Therapy 
Use of any medications other than the trial medication provided for this trial should be avoided from 
the screening period until completion of the trial. Occasional use of over the counter medications or 
prescription drugs may be allowed at the discretion of the investigator. 
During the trial it is prohibited to administer any other fertility medication than the ones provided as 
part of the trial regimen. Metformin use as an ongoing treatment during the trial is not permitted, nor is 
the use of dopamine agonist as an intervention to prevent OHSS. 
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial. 
 
4.4 
Withdrawal Criteria 
Withdrawal from Trial 
Every subject has the right to withdraw from the trial at any time for any reason, without the need to 
justify her decision. A subject's participation is to terminate immediately upon her request. However, 
the investigator should record the reason for the subject’s withdrawal, if possible. 
Randomized subjects will be asked to attend an end-of-cycle visit, which will include all procedures 
outlined in section 6.1.12 for the fresh cycle, in section 6.2.1.7 for programmed cryopreserved cycles, 
and in section 6.2.2.8 for natural cryopreserved cycles. 

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The subject can also be withdrawn from the trial at any time at the discretion of the investigator. 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 eCRF. 
A subject that withdraws from the trial will not be replaced. 
 
Withdrawal of Consent 
If the subject withdraws her consent, data collected up to withdrawal will remain in the database, but 
no further data will be collected. Samples and recordings obtained before withdrawal may be analyzed. 
This will be described in the Informed Consent Documents. The subject can request destruction of 
samples which would otherwise have been kept in storage. 
 
4.5 
Trial Stopping Criteria 
Occurrence of the following adverse events or abnormal laboratory values may warrant consideration 
of trial termination: 
• Life-threatening serious adverse events (SAEs) with suspected causality to the IMP, including 
but not limited to OHSS (section 8.3.1) 
• Formation of treatment-induced neutralizing antibodies to FSH 
 
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 the 
first subject’s first visit. 
 

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5 
TREATMENTS 
5.1 
Treatments Administered 
 
Investigational Medicinal Products 
Subjects will be randomized in a 10:1 ratio to FE 999049:placebo. The dosing regimen for FE 999049 
and placebo is described in Table 5-1. 
 
Table 5-1 
FE 999049 and Placebo Dosing Regimen  
IMP 
Dosing regimen 
FE 999049 
Starting dose of 12 µg daily fixed for the first four stimulation days. Based on the 
ovarian response, the dose may be adjusted by 3 µg, with dose increases implemented 
not more frequently than once every 2 days and dose decreases implemented per 
investigator’s judgement. The minimum daily dose is 6 µg, and the maximum daily 
dose is 24 µg. 
Subcutaneous injection in the lower part of the abdomen. 
Placebo to 
FE 999049 
Pen will be dialed to the same value (dose) as if administered FE 999049. 
Subcutaneous injection in the lower part of the abdomen. 
 
The investigational medicinal products (IMPs) will be self-administered by the subject as a daily 
subcutaneous injection in the lower part of the abdomen using a pre-filled injection pen. The start and 
end dates as well as daily dose of IMP will be recorded by the subject in a diary. To minimize local 
injection site reactions, it is advisable to change the injection site regularly, i.e. between the right and 
left lower part of the abdomen. 
Administration of IMP after reaching the triggering criterion is not allowed. 
For information on warnings and precautions, please refer to the Investigator’s Brochure for 
FE 999049.3 
 
 
Non-investigational Medicinal Products 
The non-investigational medicinal products (NIMPs) are listed in Table 5-2 for the controlled ovarian 
stimulation and fresh cycle, in Table 5-3 for the programmed cryopreserved cycles, and in Table 5-4 
for the natural cryopreserved cycles. 
 

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Table 5-2 
NIMP Dosing Regimen – Controlled Ovarian Stimulation and Fresh Cycle 
NIMP 
Trade name  
(active ingredient) 
Dosing regimen 
GnRH 
antagonist  
GANIRELIX  
(ganirelix acetate) 
250 µg, daily injection  
Will be initiated on stimulation day 5 for subjects 
with ≥3 follicles with a diameter of ≥10 mm (subjects 
who fail to satisfy this GnRH antagonist criterion on 
stimulation day 5 will continue to be monitored at 
least every second day, and GnRH antagonist will be 
initiated when/if the criterion is met); will be 
continued throughout the stimulation period.  
The timing of the GnRH antagonist injections should 
be aligned with the IMP injections. 
Subcutaneous injection in the upper thigh (to 
distinguish from IMP injection site) 
hCG  
NOVAREL 
(chorionic gonadotropin) 
10,000 IU, single injection 
Will be administered for triggering of final follicular 
maturation if there are <20 follicles with a diameter 
of ≥12 mm. 
2 x 5,000 IU reconstituted in one vial with diluent. 
Intramuscular injection 
GnRH agonist  LEUPROLIDE ACETATE 
(leuprolide acetate) 
4.0 mg, single injection 
Will be administered for triggering of final follicular 
maturation if there are ≥20 follicles with a diameter 
of ≥12 mm or the serum estradiol concentration is 
≥3,000 pg/mL (local laboratory). 
Subcutaneous injection 
Progesterone 
ENDOMETRIN 
(progesterone) 
 
100 mg, TID  
Will be initiated the day after oocyte retrieval; will be 
continued until menses, negative βhCG, pregnancy 
loss or until ongoing pregnancy has been 
documented.  
Vaginal administration 
 
 

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Table 5-3 
NIMP Dosing Regimen – Programmed Cryopreserved Cycles  
NIMP 
Trade name  
(active ingredient) 
Dosing regimen 
Estradiol 
ESTRADIOL  
Tablets USP 
(estradiol) 
2 mg TID or 3 mg BID  
(or 3 mg TID at the investigator’s discretion, if a 
daily dose of 6 mg has been shown insufficient in a 
previous cycle). 
Will be initiated within 3 days of start of menses; 
will be continued until menses, negative βhCG, 
pregnancy loss or until ongoing pregnancy has been 
documented. 
Oral administration 
Progesterone 
PROGESTERONE 
Injection USP 
(progesterone) 
50 mg, daily injection 
Will be initiated within 5 days of confirmed 
endometrial thickness ≥8 mm; will be continued until 
menses, negative βhCG, pregnancy loss or until 
ongoing pregnancy has been documented. 
Intramuscular injection 
100 mg, single injection can be administered for 
induction of withdrawal bleeding, as applicable. 
 
Table 5-4 
NIMP Dosing Regimen – Natural Cryopreserved Cycles 
NIMP 
Trade name  
(active ingredient) 
Dosing regimen 
Progesterone 
ENDOMETRIN 
(progesterone) 
 
100 mg, TID  
Will be initiated the day after confirmed LH surge 
(local laboratory); will be continued until menses, 
negative βhCG, pregnancy loss or until ongoing 
pregnancy has been documented.  
Vaginal administration 
 
The doses and treatment regimens of the NIMPs are in line with the recommendations in the respective 
products’ Prescribing Information and/or standard clinical practice within ART. For information on 
warnings and precautions, please refer to the Prescribing Information for the NIMPs. 
 

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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 5-5 provides an overview of the presentation of each medicinal 
product. 
 
Table 5-5 
Characteristics of Medicinal Products 
IMP / NIMP 
Presentation 
Manufacturer or 
Distributor 
FE 999049 
Pre-filled injection pen for multiple use 
containing 72 µg of FSH in 2.16 mL. 
Ferring Pharmaceuticals 
Placebo 
Pre-filled injection pen for multiple use 
containing 2.16 mL of placebo.  
Ferring Pharmaceuticals 
GANIRELIX 
Pre-filled syringe for single use delivering 
250 µg of ganirelix acetate in 0.5 mL. 
Merck Sharp & Dohme 
NOVAREL 
Vials with lyophilized powder and vials 
with diluent. After reconstitution, each vial 
delivers 5,000 IU chorionic gonadotropin. 
Ferring Pharmaceuticals 
LEUPROLIDE ACETATE 
 
Vial containing 14 mg of leuprolide 
acetate in 2.8 mL. 
Sandoz Inc. 
ENDOMETRIN 
Vaginal inserts of 100 mg of progesterone. Ferring Pharmaceuticals 
ESTRADIOL  
Tablets USP 
Oral tablets of 1 mg estradiol. 
Teva Pharmaceuticals 
USA, Inc. 
PROGESTERONE 
Injection USP  
Vial containing 500 mg of progesterone in 
10 mL sesame oil solution. 
West-ward 
Pharmaceutical Corp or 
Watson Pharma, Inc. 
 
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 U.S. regulatory requirements. 
Details on the packaging of each medicinal product is provided in Table 5-6. 
 

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Table 5-6 
Packaging of Medicinal Products 
IMP / NIMP 
Packaging 
FE 999049 
FE 999049 is provided in boxes containing 1 pre-filled injection pen 
for multiple use and single-use disposable needles.  
Placebo 
Placebo is provided in boxes containing 1 pre-filled injection pen for 
multiple use and single-use disposable needles. 
GANIRELIX 
GANIRELIX is provided in boxes containing 1 pre-filled syringe. 
NOVAREL 
NOVAREL is provided in boxes containing one vial with powder and 
one vial with diluent. 
LEUPROLIDE ACETATE LEUPROLIDE ACETATE is provided in boxes containing 1 vial and 
disposable syringes. 
ENDOMETRIN 
ENDOMETRIN is provided in boxes containing 21 vaginal inserts and 
21 disposable vaginal applicators. 
ESTRADIOL  
Tablets USP 
ESTRADIOL Tablets USP is provided in bottles containing 
100 tablets. 
PROGESTERONE 
Injection USP  
PROGESTERONE Injection USP is provided in boxes containing 
1 vial.  
 
All NIMPs are commercially available and will be purchased centrally. No modification from the usual 
commercial state of the NIMPs will be made, except for trial-specific labelling. 
All products (IMPs and NIMPs) will be labelled with trial-specific labels, which contain a self-
adhesive tear-off portion to be affixed to the subject dispensing log, maintained at the trial site. 
 
5.4 
Conditions for Storage and Use 
The investigator will ensure that the medicinal products will be stored in appropriate conditions in a 
secure location with controlled access. The storage compartment shall be monitored regularly and the 
temperature shall be documented. Deviations in storage temperature must be reported to Ferring as 
instructed in the IMP/NIMP handling guideline. 
The storage conditions for the IMPs and NIMPs will be as described in the trial-specific or commercial 
box labelling. 
Information on how to administer the medicinal products will be provided in Instructions for Use 
prepared for the IMPs and in the Package Inserts for the NIMPs.  

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In case of technical malfunction of an administration pen, all relevant details (including time, date, a 
description of the malfunction and whether dosing was affected) of the incidence should be reported, 
the pen should be replaced and the treatment continued. 
 
5.5 
Blinding / Unblinding 
 
Blinding 
The pre-filled injection pens with FE 999049 and placebo will be identical in appearance. Likewise, 
the FE 999049 and placebo solutions will be identical in appearance. 
The IMP will be packaged according to a computer-generated randomization list. The randomization 
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 eCRF will 
not be accessible to investigators, other trial staff at site, central laboratory personnel, or sponsor staff 
during the trial. 
 
 
Unblinding of Individual Subject Treatment  
An emergency decoding possibility will be available to the investigator and designated persons at 
Ferring. 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 
Ferring. Where the event requires immediate unblinding by the investigator, Ferring must be informed 
of the unblinding as soon as possible and provided with the rationale for unblinding. The 
investigator/person who unblinds a treatment will use the eCRF in which he/she is required to enter a 
password and record the reason for unblinding before the treatment code can be broken. The eCRF 
automatically records when and by whom the code is 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. 
In case of accidental unblinding, the same procedure as for emergency unblinding must be followed, 
i.e. the person who is accidentally unblinded will enter a password in the eCRF and must record the 
reason for unblinding, while the eCRF records when and by whom the code is broken. In addition the 
event must also be recorded in the subject’s medical record. 

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If Ferring needs to unblind a subject’s treatment, the eCRF will be used for unblinding. It is required to 
enter a password and the reason for unblinding before the treatment code can be broken. The eCRF 
records when and by whom the code was broken. The code break will occur according to corporate 
standard operating 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 relevant health 
authorities and/or IRBs. In that situation, every effort will be made to maintain blinding of Ferring 
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 eCRF and must 
be collected before the database is declared clean and is released to the trial statistician. 
In case the eCRF cannot be accessed by the investigator, and hence the emergency unblinding cannot 
be performed within the eCRF system, the investigator should contact Ferring Pharmacovigilance 
using the contact details given below. 
Ferring Pharmacovigilance 
US Toll-free number: 
 
If Ferring Pharmacovigilance cannot access the eCRF, a back-up procedure involving the eCRF vendor 
is in place. 
 
5.6 
Treatment Compliance, Dispensing and Accountability 
The IMP will only be dispensed to subjects who meet the eligibility criteria and are randomized to a 
treatment group in the trial. The investigator (or his/her designated staff, e.g. trial nurse) will maintain 
a drug-dispensing log detailing the dates and quantities of IMPs/NIMPs dispensed to, and used by, 
each subject, as well as the batch numbers, IMP/NIMP numbers or other identifier used in the trial.  
The monitor will verify the drug accountability during the trial and if applicable document any 
discrepancies. 
In order to monitor compliance, the subjects are to return empty, partially used, and unused vials, pens, 
syringes, tablets or inserts to the investigator at each visit. The investigator (or his/her designated staff, 
e.g. trial nurse) will reconcile and document the return on the drug accountability log. Any 
discrepancies should be discussed with the subject at the time of the return. 
 

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5.7 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
All dispensed IMP and NIMP is to be destroyed at the trial site in accordance with local legislation 
after the drug accountability has been finalized.  
Used syringes and needles should be destroyed immediately after usage according to normal 
procedures at each trial site.  
Any non-dispensed IMP/NIMP must be returned for destruction, as instructed by the Ferring Clinical 
Trial Supply Department, after the drug accountability has been finalized. 
 

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6 
TRIAL PROCEDURES 
6.1 
Controlled Ovarian Stimulation and Fresh Cycle 
The flow of the trial procedures for subjects in the controlled ovarian stimulation and fresh cycle is 
shown in Table 6-1. 

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Table 6-1 
Trial Flow Chart – Subject Procedures – Controlled Ovarian Stimulation and Fresh 
Cycle 
 
Screening 
Stimulation 
OR  
Transfer 
Pregnancy monitoring 
End 
 
During stimulation 
End-of-
stimula
-tion 
Oocyte 
retrieval 
Transfer 
βhCG 
Clinical 
Ongoing End-of-
cycle 
Timing 
<90 days 
before ran-
domization 
Day 1 
Day 5  
Day ≥6 
to <20 a)  
End 
36h ±2h 
after 
triggering 
Day 5 
after OR 
10-14 days 
after 
transfer 
5-6 weeks 
after 
transfer 
8-9 weeks 
after 
transfer 
b) 
Written informed consent(s) 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
   X c) 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Infertility history 
X 
 
 
 
 
 
 
 
 
 
 
Menstrual history 
X 
 
 
 
 
 
 
 
 
 
 
Reproductive history 
X 
 
 
 
 
 
 
 
 
 
 
Body measurements 
X 
   X c,d) 
 
 
 
 
 
 
 
 
   X d) 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Gynecological examination 
X 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
X 
   X c) 
 
 
 
 
 
 
 
 
 
Ultrasound sonographye) 
 
   X c) 
X 
X 
X 
 
 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
   X f) 
 
 
 
 
 
 
 
 
X 
Blood collection, clin chem / hem 
X 
 
 
 
X 
 
 
 
 
 
X 
Blood collection, endocrine 
X 
   X f) 
   X g) 
 
   X g) 
X 
 
 
 
 
 
Blood collection, antibodies h) 
   X i) 
   X f) 
 
   
 
 
   X j) 
    X k) 
 
 
   X k) 
Blood collection, estradiol 
 
 
X 
X 
X 
 
 
 
 
 
 
Blood collection, genome l) 
 
X 
 
 
 
 
 
 
 
 
 
Saliva collection, genome l) 
 
X 
 
 
 
 
 
 
 
 
 
Tongue coat collection, microbiome l) 
 
X 
 
 
 
 
X 
 
 
 
 
IMP dispensing 
 
X 
   X m) 
   X m) 
 
 
 
 
 
 
 
NIMP dispensing 
 
 
   X n) 
X 
X 
X 
X 
X 
X 
 
 
Local tolerability (diary)  
 
X 
X 
X 
X 
 
 
 
 
 
 
Oocyte retrieval 
 
 
 
 
 
X 
 
 
 
 
 
Blastocyst transfer / cryo 
 
 
 
 
 
 
X 
 
 
 
 
βhCG test (local lab) 
 
 
 
 
 
 
 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End-of-cycle form 
 
 
 
 
 
 
 
 
 
 
X 
a) Visits must be scheduled at least every second day; when the leading follicle reaches ≥14 mm visits must be performed daily.  
b) End-of-cycle assessments must be performed at the subject’s last scheduled visit: at the earliest 21-28 days after the last IMP dose.  
c) Performed before randomization. 
d) Only body weight. 
e)  Transvaginal ultrasound with exception of the ongoing pregnancy visit, where it can be either transvaginal or abdominal ultrasound. 
f)  Performed before the first IMP dose.  
g) Performed at least 8 h after IMP administration (and NIMP administration at end-of-stimulation visit). 
h) All subjects with a treatment-induced antibody response must be followed until the response is negative or has returned to pre-dosing level.  
i) Sample exclusively used to re-establish the anti-drug antibody analytical assays. 
j) Blood sampling for antibody assessment must be done 7-10 days after the last IMP dose (this may coincide with the transfer visit; alternatively, 
a separate visit must be scheduled). 
k) Blood sampling for antibody assessment must be done 21-28 days after the last IMP dose (this may coincide with the βhCG test visit; alternatively, 
a separate visit must be scheduled). 
l) Optional sampling for future potential exploratory analyses for subjects who have provided separate written informed consent.  
m) The starting dose of 12 µg FE 999049 is fixed for the first 4 stimulation days. Based on the ovarian response, the daily dose may be adjusted by 3 µg, 
with dose increases implemented not more frequently than once every 2 days and dose decreases implemented per investigator’s judgement. The 
minimum dose is 6 µg, and the maximum dose is 24 µg. 
n) GnRH antagonist will be initiated on stimulation day 5 for subjects with ≥3 follicles with a diameter of ≥10 mm. Subjects who fail to satisfy this 
GnRH antagonist criterion on stimulation day 5 will continue to be monitored at least every second day, and GnRH antagonist will be initiated 
when/if the criterion is met. 
βhCG: β human chorionic gonadotropin; IMP: investigational medicinal product; NIMP: non-investigational medicinal product; OR: oocyte retrieval 
 

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Screening 
Potential subjects will be scheduled to come to the site for the screening assessments. Screening must 
be initiated within 90 days before stimulation day 1 (randomization).  
The following must take place during the screening period: 
• Signed and dated written informed consent for participation in the trial, obtained prior to any 
trial-related procedures 
• Signed and dated written informed consent for parental consent to data collection on the 
neonate, obtained prior to randomization 
• Signed and dated written informed consent for exploratory analyses covering potential future 
genome sequencing and microbial profiling (optional), obtained prior to sampling 
• Allocation of a screening number 
• Check of inclusion and exclusion criteria (those which are possible to check at screening) 
• Demographics (age, ethnicity, race) 
• Collection of the following data: 
− 
Medical history 
− 
Infertility history 
− 
Menstrual history 
− 
Reproductive history 
• Body measurements (body weight, height) [note: these are used for calculation of BMI] 
• Physical examination 
• Gynecological examination 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Urine pregnancy test – must be negative 
• Blood collection for central laboratory analysis of:  
− 
clinical chemistry and hematology parameters [note: the results must be available prior to 
randomization] 
− 
endocrine parameters (screening panel: AMH, TSH and prolactin) [note: the results for TSH 
and prolactin must be available prior to randomization] 
− 
anti-FSH antibodies [exclusively used to re-establish the anti-drug antibody analytical 
assays] 

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• Recording of use of any concomitant medication (within the last 3 months prior to signed 
informed consent for participation in the trial) 
• Recording of adverse events (from the date of signed informed consent for participation in the 
trial) 
 
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at this 
time point may proceed to the next visit, scheduled on day 2-3 of the subject’s menstrual cycle. 
In case of positive findings of HBsAg, HCV or HIV antibody tests obtained at screening, it is the 
investigator’s responsibility to ensure that standard reporting and referral procedures at the sites are 
followed in line with local regulations. 
 
 
Stimulation Day 1 
Subjects will attend the stimulation day 1 visit on day 2-3 of their menstrual cycle. 
The following must take place prior to randomization: 
• Ensure that the subject is still eligible for participation in the trial 
• Check those inclusion and exclusion criteria that were not possible during screening  
• Body weight 
• Urine pregnancy test – must be negative 
• Transvaginal ultrasound of uterus (endometrial thickness, echogenicity pattern) and ovaries 
(number and size of follicles, ovarian volume) 
 
If the subject fulfills all inclusion and exclusion criteria, she will proceed to randomization: 
• Randomization, i.e. assignment to the lowest available subject number and thereby allocation to 
either FE 999049 or placebo 
 
The following must take place after randomization but before administration of the first dose of IMP 
(FE 999049 or placebo): 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Blood collection for central laboratory analysis of: 
− 
endocrine parameters (AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B) 
− 
anti-FSH antibodies 

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• Blood collection for future potential genome sequencing (applicable for subjects who have 
provided a separate informed consent) 
• Saliva collection for future potential genome sequencing (applicable for subjects who have 
provided a separate informed consent) 
• Tongue coat collection for future potential microbial profiling (applicable for subjects who 
have provided a separate informed consent)  
 
Once the above has been completed, the following must be performed: 
• Hand out the diary for recording of local tolerability to the subject.  
The subject must be instructed to assess and record local tolerability after each IMP 
administration throughout the entire stimulation period. The first evaluation of local tolerability 
reactions at the injection site is done immediately after the injection of IMP, followed by a 
second evaluation 30 minutes after injection of IMP and a third evaluation 24 hours after 
injection of IMP (before the next day’s injection of IMP). In case the subject has any concern 
related to an injection site reaction, the investigator should be contacted for possible further 
assessment, prior to the next IMP injection. 
• Dispense IMP according to randomization and instruct the subject on how to administer the 
IMP. The subject will self-administer the IMP (at the trial site or at home) as a subcutaneous 
injection in the lower part of the abdomen. The starting dose for the first 4 days is fixed at 
12 µg. 
 
Finally, the following must be done before the subject leaves the site: 
• 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). 
 
 
Stimulation Day 5 
The following must take place on stimulation day 5: 
• Transvaginal ultrasound of uterus (endometrial thickness, echogenicity pattern) and ovaries 
(number and size of follicles) 
• Blood collection for central laboratory analysis of: 

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− 
endocrine parameters (AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B) – 
the blood sample must be drawn at least 8 hours after the latest IMP administration 
• Blood collection for local laboratory analysis of estradiol (optional; can be used for assessing 
potential IMP dose adjustment) 
• Dispensing of IMP 
• Implementation of potential dose adjustments 
From stimulation day 5 and onwards, the daily dose may be adjusted by 3 µg, with dose 
increases implemented not more frequently than once every 2 days and dose decreases 
implemented per investigator’s judgement. The minimum daily dose is 6 µg, and the maximum 
daily dose is 24 µg. In case of dose adjustments, the reason will be collected. 
• Dispensing of GnRH antagonist, as applicable 
Daily administration of 250 µg GnRH antagonist will be initiated on stimulation day 5 for 
subjects with ≥3 follicles with a diameter of ≥10 mm. Subjects who fail to satisfy this GnRH 
antagonist criterion on stimulation day 5 will continue to be monitored at least every second 
day, and GnRH antagonist will be initiated when/if the criterion is met. 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.  
• Collection of local tolerability data (diary pages) 
• Drug accountability of IMP 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
Finally, this must be done before the subject leaves the site: 
• Remind the subject to assess and record local tolerability immediately, 30 minutes and 24 hours 
after each IMP administration 
 
After the stimulation day 5 visit, visits must be scheduled at least every second day throughout the 
remaining stimulation period. 
 
 
Stimulation Days ≥6 to <20 
Visits will take place at least every second day throughout the remaining stimulation period. When the 
leading follicle reaches ≥14 mm, visits must be performed daily. Coasting or use of dopamine agonist 
as preventive intervention of OHSS are not allowed. The maximum period of stimulation is 20 days.  

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The following must take place at the visits throughout the remainder of the stimulation period (with the 
exception of the end-of-stimulation visit, which is described in section 6.1.5):  
• Transvaginal ultrasound of uterus (endometrial thickness, echogenicity pattern) and ovaries 
(number and size of follicles, ovarian volume) 
• Blood collection for local laboratory analysis of estradiol (optional; can be used for assessing 
potential IMP dose adjustment) 
• Dispensing of IMP 
• Implementation of potential dose adjustments 
From stimulation day 5 and onwards, the daily dose may be adjusted by 3 µg, with dose 
increases implemented not more frequently than once every 2 days and dose decreases 
implemented per investigator’s judgement. The minimum daily dose is 6 µg, and the maximum 
daily dose is 24 µg. In case of dose adjustments, the reason will be collected. 
• Dispensing of GnRH antagonist, as applicable 
For subjects who did not initiate GnRH antagonist on stimulation day 5, initiation should be 
performed when the criterion of ≥3 follicles with a diameter of ≥10 mm is met. A daily dose of 
250 µg should be continued throughout the stimulation period. 
• Collection of local tolerability data (diary pages) 
• Drug accountability of IMP and GnRH antagonist 
• Recording of use of any concomitant medication 
• Recording of adverse events 
• Remind the subject to assess and record local tolerability immediately, 30 minutes and 24 hours 
after each IMP administration 
 
 
End-of-stimulation 
The end-of-stimulation visit will take place when the subject reaches the criterion for triggering of final 
follicular maturation or if the cycle is canceled. Administration of hCG or GnRH agonist must take 
place the same day as the criterion for triggering of final follicular maturation, i.e. ≥2 follicles with a 
diameter of ≥17 mm, is met. Administration of FE 999049 or placebo after reaching the triggering 
criterion is not allowed. 
Criterion for triggering of final follicular maturation with 10,000 IU hCG: 
• <20 follicles with a diameter of ≥12 mm 
 

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Criterion for triggering of final follicular maturation with 4 mg GnRH agonist: 
• ≥20 follicles with a diameter of ≥12 mm or serum estradiol concentration ≥3,000 pg/mL (local 
laboratory) 
 
If after 8 days of stimulation, the investigator judges that the triggering criterion, i.e. ≥2 follicles with a 
diameter of ≥17 mm, is not likely to be reached by day 20, the cycle will be canceled. If the triggering 
criterion is not met after 20 days of stimulation, the cycle will be canceled. 
The investigator also has the option of canceling the cycle for other relevant medical reasons, including 
adverse events and technical malfunctions of the administration pen. In the latter event, the option of 
replacing the administration pen and continuing treatment should be considered.  
The following must take place at end-of-stimulation visit: 
• Transvaginal ultrasound of uterus (endometrial thickness, echogenicity pattern) and ovaries 
(number and size of follicles, ovarian volume) 
• Blood collection for central laboratory analysis of: 
− 
clinical chemistry and hematology parameters 
− 
endocrine parameters (AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B) – 
the blood sample must be drawn at least 8 hours after the latest administration of IMP and 
GnRH antagonist 
• Blood collection for local laboratory analysis of estradiol (used to determine the triggering 
drug) 
• Dispensing of hCG or GnRH agonist, as applicable 
• Collection of local tolerability data (diary pages) 
• Drug accountability of IMP and GnRH antagonist 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
For subjects who receive a triggering drug, the next visit is the oocyte retrieval visit which must be 
scheduled 36h (±2h) after the administration of hCG or GnRH agonist.  
For subjects with cycle cancellation, the next visit is the first post-dosing anti-FSH antibody blood 
sampling visit 7-10 days after the last FE 999049 or placebo dose (section 6.1.8.2). 
 

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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 should 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 6.1.7. 
The following must take place at the oocyte retrieval visit: 
• Blood collection for central laboratory analysis of: 
− 
endocrine parameters (AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B) 
• Oocyte retrieval 
• Dispensing of progesterone vaginal inserts for luteal phase support – must be started on the day 
after oocyte retrieval [note: only applicable for subjects who underwent triggering of final 
follicular maturation with hCG and who had oocytes retrieved] 
• Drug accountability of hCG or GnRH agonist, as applicable 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
For subjects with <20 oocytes retrieved following hCG administration, the next visit is the transfer visit 
5 days after oocyte retrieval (section 6.1.8.1). 
For subjects with ≥20 oocytes retrieved following hCG administration and for subjects with oocytes 
retrieved following GnRH agonist administration the fresh blastocyst transfer will be canceled. The 
oocytes will undergo the procedures described in section 6.1.7 and blastocysts will be cryopreserved by 
vitrification. The next visit for these subjects is the first post-dosing anti-FSH antibody assessment visit 
which must be scheduled 7-10 days after the last FE 999049 or placebo dose (section 6.1.8.2). 
For subjects with no oocytes retrieved, the next visit is the first post-dosing anti-FSH antibody 
assessment visit which must be scheduled 7-10 days after the last FE 999049 or placebo dose 
(section 6.1.8.2). 
 
 
Oocyte / Blastocyst Evaluation 
The laboratory procedures regarding handling and evaluations of oocytes and blastocysts are described 
in a trial-specific manual. This section provides an overview of the procedures and assessments to be 
made from oocyte retrieval until transfer at the blastocyst stage. The flow of the trial procedures for 

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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 
Timing 
-4h  
(±1h) 
0h 
19h 
(±2h) 
Day 5 
Oocyte retrieval (OR) 
X 
 
 
 
Assessment of maturity stage (applicable for oocytes 
undergoing ICSI) 
X 
 
 
 
Insemination by IVF and/or ICSI 
 
X 
 
 
Assessment of oocyte fertilization 
 
 
X 
 
Assessment of blastocyst quality 
 
 
 
X 
Transfer of a single blastocyst of the highest quality available 
 
 
 
X 
Cryopreservation of blastocysts by vitrification, as applicable  
 
 
 
Xa 
a In case the embryologist judges that a blastocyst/morula is still developing, continued culturing and cryopreservation on day 6 is allowed. 
ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; OR: oocyte retrieval 
 
Blastocyst biopsy, assisted hatching and PGD/PGS are prohibited. 
 
Day 0 (Oocyte Retrieval) 
• Oocyte retrieval at 4h (±1h) before start of the insemination procedure 
• Assessment of maturity stage (applicable for oocytes undergoing ICSI) 
• Insemination at 0h using IVF or ICSI using ejaculated sperm (fresh or frozen) from partner or 
donor 
 
Day 1 after Oocyte Retrieval 
• Assessment of fertilization (number of pronuclei) at 19h (±2h) post-insemination 
 
Day 5 after Oocyte Retrieval 
• Assessment of blastocyst quality 
• Transfer of blastocyst (section 6.1.8.1) 

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• Cryopreservation of blastocysts by vitrification, as applicable. In case the embryologist judges 
that a blastocyst/morula is still developing, continued culturing and cryopreservation on day 6 
is allowed 
 
 
Transfer 
6.1.8.1 
Blastocyst Transfer 
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 subject-related procedures are described below. 
• Blood collection for central laboratory analysis of anti-FSH antibodies (first post-dosing 
assessment) 
• Tongue coat collection for future potential microbial profiling (applicable for subjects who 
have provided a separate informed consent) 
• Transfer of a single blastocyst of the highest quality available (per judgement of the site 
embryologist) 
• Dispensing of progesterone vaginal inserts for luteal phase support, if applicable  
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
10-14 days after transfer (section 6.1.9.1). 
 
6.1.8.2 
First Post-dosing Anti-FSH Antibody Assessment (7-10 Days after Last IMP Dose) 
Subjects who have been exposed to FE 999049 or placebo must have the first post-dosing anti-FSH 
antibody assessment performed 7-10 days after the last FE 999049 or placebo dose. This may coincide 
with the transfer visit (section 6.1.8.1). 

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For subjects who do not attend the transfer visit, a separate visit must be scheduled, at which the 
following must take place: 
• Blood collection for central laboratory analysis of anti-FSH antibodies 
• Drug accountability of progesterone vaginal inserts, if applicable 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
 
βhCG Test 
6.1.9.1 
βhCG Test 
Subjects who have undergone transfer must attend a visit 10-14 days after transfer.  
The following must take place: 
• Blood collection for local laboratory analysis of βhCG 
• Blood collection for central laboratory analysis of anti-FSH antibodies (second post-dosing 
assessment) 
• Dispensing of progesterone vaginal inserts, if applicable  
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
The blood sample for βhCG will be analyzed by the local laboratory and evaluated according to the 
local reference ranges. In case of a doubtful / inconclusive βhCG result, the test may be repeated, 
preferably within 2 days, and the conclusive result recorded. Subjects with a positive βhCG test must 
attend a clinical pregnancy visit 5-6 weeks after transfer (section 6.1.10). Subjects with a negative 
βhCG test must proceed to the end-of-cycle assessments (section 6.1.12). 
 
6.1.9.2 
Second Post-dosing Anti-FSH Antibody Assessment (21-28 Days after Last IMP 
Dose) 
Subjects who have been exposed to FE 999049 or placebo must have the second post-dosing anti-FSH 
antibody assessment performed 21-28 days after the last FE 999049 or placebo dose. This may 
coincide with the βhCG test visit (section 6.1.9.1).  

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For subjects who do not attend the βhCG test visit, this second post-dosing anti-FSH antibody 
assessment may be done in connection with the end-of-cycle assessments (section 6.1.12) if applicable 
or a separate visit must be scheduled, at which the following must take place: 
• Blood collection for central laboratory analysis of anti-FSH antibodies 
• Drug accountability of progesterone vaginal inserts, if applicable 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
 
Clinical Pregnancy 
Subjects with a positive βhCG test must attend a visit 5-6 weeks (35-48 days) after transfer.  
The following must take place: 
• Transvaginal ultrasound of uterus to assess any clinical pregnancy  
• Dispensing of progesterone vaginal inserts for luteal phase support, if applicable 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms a 
vital pregnancy. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit 
(section 6.1.11). Subjects with no vital pregnancy must undergo end-of-cycle assessments 
(section 6.1.12). 
 
 
Ongoing Pregnancy 
If a vital pregnancy has been documented, the subject must attend a visit 8-9 weeks (56-69 days) after 
transfer.  
The following must take place: 
• Ultrasound (transvaginal or abdominal) of uterus to assess any ongoing pregnancy 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication 

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• Recording of adverse events 
 
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy. 
 
 
End-of-cycle 
If a subject attends the scheduled trial visits, the end-of-cycle assessments should take place at the last 
scheduled cycle visit, i.e. for subjects with a confirmed vital pregnancy, the ongoing pregnancy visit 
will be the last scheduled cycle visit and thus the visit where the end-of-cycle assessments should be 
done. 
Due to the timing of the mandatory anti-FSH antibody assessments, the end-of-cycle assessments can 
at the earliest be performed 21-28 days after the last FE 999049 or placebo dose. This may coincide 
with the βhCG visit for subjects with a negative βhCG test. 
The following must take place at the end-of-cycle visit, irrespective of whether the subject discontinues 
the trial prematurely or completes it:  
• Body weight 
• Physical examination 
• Gynecological examination 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Blood collection for central laboratory analysis of:  
− 
clinical chemistry and hematology parameters 
− 
anti-FSH antibodies (second post-dosing assessment) [note: only applicable for subjects 
who have not already had a blood sample taken for the second post-dosing anti-FSH 
antibodies assessment as described in section 6.1.9.2] 
• Drug accountability, if applicable 
• Recording of use of any concomitant medication  
• Recording of adverse events 
• Complete end-of-cycle form 
 
These assessments serve to document the subject’s physical health at the end of the cycle. 
 

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6.2 
Cryopreserved Cycles 
The trial covers cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation. Either a programmed cycle (section 6.2.1) or a natural cycle (section 6.2.2) can be selected 
for any cryopreserved cycle. 
 
 
Programmed Cryopreserved Cycles 
The flow of the trial procedures in the programmed cryopreserved cycles initiated within 12 months 
from the start of controlled ovarian stimulation is shown in Table 6-3. 
 
Table 6-3 
Trial Flow Chart – Subject and Blastocyst Procedures – Programmed 
Cryopreserved Cycles Initiated Within 12 Months From the Start of Controlled 
Ovarian Stimulation 
 
Preparation of the endometrium  
Transfer 
Pregnancy monitoring 
End 
Start 
estradiola) 
Evaluate 
endometriumb) 
Re-evaluate 
endometriumc) 
 
Transfer 
βhCG 
Clinical 
Ongoing End-of-cycle 
Timing 
Within 3 days 
of start of 
menses  
10-12 days after 
start of estradiol  
Within 7 days 
of first 
evaluation 
6th day from 
start of 
progesterone 
10-14 days 
after  
transfer 
5-6 weeks 
after 
transfer 
8-9 weeks 
after 
transfer 
d) 
Physical examination 
X 
 
 
 
 
 
 
X 
Gynecological examination 
X 
 
 
 
 
 
 
X 
Urine pregnancy test 
  Xe) 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
X 
Ultrasound sonographyf) 
 
X 
X 
 
 
X 
X 
 
NIMP dispensing 
X 
X 
X 
X 
X 
X 
 
 
Assessment of blastocyst 
survival and re-expansion 
 
 
 
X 
 
 
 
 
Blastocyst transfer 
 
 
 
X 
 
 
 
 
Tongue coat collection, 
microbiome g) 
 
 
 
X 
 
 
 
 
βhCG test (local lab) 
 
 
 
 
X 
 
 
 
Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
End-of-cycle form 
 
 
 
 
 
 
 
X 
a) Estradiol (ESTRADIOL Tablets USP) 2 mg TID or 3 mg BID (or 3 mg TID, if a daily dose of 6 mg has been shown to be insufficient in a previous 
cycle). 
b) If endometrial thickness is ≥8 mm, IM progesterone will be initiated within 5 days. 
c)  Only for subjects with endometrial thickness <8 mm at the first evaluation. If endometrial thickness is ≥ 8 mm, IM progesterone will be initiated 
within 5 days. Subjects who fail to achieve adequate endometrial thickness will discontinue estradiol and be administered 100 mg IM progesterone 
to induce withdrawal bleeding.  
d)  End-of-cycle assessments must be performed at the subject’s last scheduled visit in each cryopreserved cycle. 
e)  Performed before start of estradiol treatment. 
f)  Transvaginal ultrasound with exception of the ongoing pregnancy visit, where it can be either transvaginal or abdominal ultrasound. 
g)  Optional sampling for future potential exploratory analyses for subjects who have provided separate written informed consent. 
 
βhCG: β human chorionic gonadotropin; NIMP: non-investigational medicinal product 
 
 

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6.2.1.1 
Cycle Initiation / Preparation of the Endometrium 
Start of Estradiol 
Any programmed cryopreserved cycle is to be initiated within 3 days of start of menses when subjects 
starts preparation of the endometrium with estradiol. 
At that time, the following must be performed: 
• Physical examination 
• Gynecological examination 
• Urine pregnancy test – must be negative  
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Dispensing of estradiol 
The subject will start endometrial preparation with estradiol 2 mg TID or 3 mg BID (or 3 mg 
TID, if a daily dose of 6 mg has been shown to be insufficient in a previous cycle) 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
Evaluation of Endometrium 
After 10-12 days of estradiol treatment the following must be performed: 
• Transvaginal ultrasound of uterus to measure endometrial thickness 
Based on the results of the endometrial evaluation one of the following will take place: 
− 
If endometrial thickness is ≥8 mm, the estradiol dose will be continued and daily 
intramuscular (IM) injections of 50 mg progesterone will be initiated within 5 days 
− 
If endometrial thickness is <8 mm, the estradiol dose will be continued and endometrial 
thickness measurement repeated within 7 days  
• Dispensing of IM progesterone, if applicable 
• Dispensing of estradiol 
• Drug accountability of estradiol 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 

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For subjects with an endometrial thickness ≥8 mm, the next visit is the transfer visit on the 6th day from 
start of progesterone treatment (section 6.2.1.3). 
For subjects with endometrial thickness <8 mm, the endometrial thickness measurement will be 
repeated within 7 days. If the criterion of endometrial thickness ≥8 mm is reached at the repeated 
measurement, daily IM injections of 50 mg progesterone will be initiated within 5 days. 
Subjects who fail to achieve adequate endometrial thickness will discontinue estradiol and will be 
administered 100 mg IM progesterone to induce withdrawal bleeding. In subsequent cryopreserved 
cycles, blastocyst transfer can take place regardless of endometrial thickness at the investigator’s 
discretion. 
 
6.2.1.2 
Blastocyst Evaluation 
The laboratory procedures regarding handling and evaluations of warmed blastocysts are described in a 
trial-specific manual. This section provides an overview of the procedures and assessments to be made 
from warming until transfer. 
Cryopreserved blastocysts must be warmed in order of quality, using the best quality blastocysts first. 
On the day of warming, the following must take place:  
• Assessment of blastocyst survival 0h (+0.5h) after thawing 
− 
In case of survival, the blastocyst proceeds to the re-expansion assessment 
• Assessment of blastocyst re-expansion 2.5h (±0.5h) after thawing 
 
6.2.1.3 
Transfer 
On the 6th day from start of progesterone, one cryopreserved blastocyst will be transferred after 
warming and assessment of blastocyst survival and re-expansion. 
The subject-related procedures are described below: 
• Tongue coat collection for future potential microbial profiling (applicable for subjects who 
have provided a separate informed consent) 
• Transfer of a single blastocyst of the highest quality available (per judgement of the site 
embryologist) 
• Dispensing of estradiol 
• Dispensing of IM progesterone 

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• Drug accountability of estradiol and IM progesterone 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
10-14 days after transfer (section 6.2.1.4). 
 
6.2.1.4 
βhCG Test 
Subjects who have undergone transfer must attend a visit 10-14 days after transfer. 
The following must take place: 
• Blood collection for local laboratory analysis of βhCG 
• Dispensing of estradiol, if applicable 
• Dispensing of IM progesterone, if applicable 
• Drug accountability of estradiol and IM progesterone 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
The blood sample for βhCG will be analyzed by the local laboratory and evaluated according to the 
local reference ranges. In case of a doubtful / inconclusive βhCG result, the test may be repeated, 
preferably within 2 days, and the conclusive result recorded. Subjects with a positive βhCG test must 
attend a clinical pregnancy visit 5-6 weeks after transfer (section 6.2.1.5). Subjects with a negative 
βhCG test must proceed to the end of-cycle assessments (section 6.2.1.7). 
 
6.2.1.5 
Clinical Pregnancy 
Subjects with a positive βhCG test must attend a visit 5-6 weeks (35-48 days) after transfer. 
The following must take place: 
• Transvaginal ultrasound of uterus to assess any clinical pregnancy  
• Dispensing of estradiol, if applicable 
• Dispensing of IM progesterone, if applicable 
• Drug accountability of estradiol and IM progesterone 

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• Recording of use of any concomitant medication 
• Recording of adverse events 
 
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms a 
vital pregnancy. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit 
(section 6.2.1.6). Subjects with no vital pregnancy must undergo end-of-cycle assessments 
(section 6.2.1.7). 
 
6.2.1.6 
Ongoing Pregnancy 
If a vital pregnancy has been documented, the subject must attend a visit 8-9 weeks (56-69 days) after 
transfer.  
The following must take place: 
• Ultrasound (transvaginal or abdominal) of uterus to assess any ongoing pregnancy 
• Drug accountability of estradiol and IM progesterone 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy. 
 
6.2.1.7 
End-of-cycle 
If a subject attends the scheduled trial visits, the end-of-cycle assessments should take place at the last 
scheduled cycle visit, i.e. for subjects with a confirmed vital pregnancy, the ongoing pregnancy visit 
will be the last scheduled cycle visit and thus the visit where the end-of-cycle assessments should be 
performed. 
The following must take place at the end-of-cycle visit, irrespective of whether the subject discontinues 
the cycle prematurely or completes it: 
• Physical examination 
• Gynecological examination 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Drug accountability, if applicable 

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• Recording of use of any concomitant medication  
• Recording of adverse events 
• Complete end-of-cycle form 
 
These assessments serve to document the subject’s physical health at the end of the cycle. 
 
 
Natural Cryopreserved Cycles 
The flow of the trial procedures in the natural cryopreserved cycles initiated within 12 months from the 
start of controlled ovarian stimulation is shown in Table 6-4. 
 
Table 6-4 
Trial Flow Chart – Subject and Blastocyst Procedures – Natural Cryopreserved 
Cycles Initiated Within 12 Months From the Start of Controlled Ovarian 
Stimulation 
 
Start of cryopreserved cycle / 
monitoring of LH surgea) 
Transfer 
Pregnancy monitoring 
End 
Transfer b) 
βhCG 
Clinical 
Ongoing 
End-of-cycle 
Timing 
7 days after start 
of menses c) 
LH surge 
LH surge  
+ 7 days 
10-14 days 
after transfer 
5-6 weeks 
after 
transfer 
8-9 weeks 
after 
transfer 
d) 
Physical examination 
X 
 
 
 
 
 
X 
Gynecological examination 
X 
 
 
 
 
 
X 
Urine pregnancy test 
X 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
X 
Urinary LH assessment 
X 
 
 
 
 
 
 
Serum LH (local lab) 
 
X 
 
 
 
 
 
Ultrasound sonographye) 
 
  Xf) 
 
 
X 
X 
 
NIMP dispensing  
 
  Xg) 
X 
X 
X 
 
 
Assessment of blastocyst survival 
and re-expansion 
 
 
X 
 
 
 
 
Blastocyst transfer 
 
 
X 
 
 
 
 
Tongue coat collection, 
microbiome h) 
 
 
X 
 
 
 
 
βhCG test (local lab) 
 
 
 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
End-of-cycle form 
 
 
 
 
 
 
X 
a) Monitoring of urinary LH will be done on a daily basis by the subject until confirmed LH surge. 
b) One cryopreserved blastocyst will be transferred 7 days after confirmed LH surge (day LH surge + 7).  
c)  Natural cryopreserved cycles will be initiated on day 7 after start of menses in a subsequent menstrual cycle. 
d)  End-of-cycle assessments must be performed at the subject’s last scheduled visit in each cryopreserved cycle. 
e)  Transvaginal ultrasound with exception of the ongoing pregnancy visit, where it can be either transvaginal or abdominal ultrasound. 
f)  To confirm endometrial thickness ≥8 mm. If the endometrial thickness is <8 mm, the cycle will be canceled. 
g)  Progesterone will be initiated on day LH surge + 1. 
h)  Optional sampling for future potential exploratory analyses for subjects who have provided separate written informed consent. 
βhCG: β human chorionic gonadotropin; LH: luteinizing hormone; NIMP: non-investigational medicinal product 
 

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6.2.2.1 
Cycle Initiation 
Any natural cryopreserved cycle is to be initiated 7 days after start of menses in a subsequent 
menstrual cycle. 
The following must take place at cycle initiation: 
• Physical examination 
• Gynecological examination 
• Urine pregnancy test – must be negative 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Urinary LH assessment 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
6.2.2.2 
Confirmation of LH Surge 
The following must take place on the day of confirmation of LH surge: 
• Confirmation of LH surge by: 
− 
blood collection for local laboratory analysis of serum LH, and 
− 
transvaginal ultrasound to confirm endometrial thickness ≥8 mm.  
If the endometrial thickness is <8 mm in the first cryopreserved cycle, the cycle will be 
canceled. In subsequent cryopreserved cycles, blastocyst transfer can take place regardless 
of endometrial thickness at the investigator’s discretion. 
• Dispensing of progesterone vaginal inserts for luteal phase support – must be started on the day 
after confirmed LH surge (day LH surge + 1). 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
6.2.2.3 
Blastocyst Evaluation 
The laboratory procedures regarding handling and evaluations of warmed blastocysts are described in a 
trial-specific manual. This section provides an overview of the procedures and assessments to be made 
from warming until transfer. 
Cryopreserved blastocysts must be warmed in order of quality, using the best quality blastocysts first. 

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On the day of warming, the following must take place:  
• Assessment of blastocyst survival 0h (+ 0.5h) after thawing 
- 
In case of survival, the blastocyst proceeds to the re-expansion assessment. 
• Assessment of blastocyst re-expansion 2.5h (± 0.5h) after thawing 
 
6.2.2.4 
Transfer 
Seven days after confirmed LH surge (day LH surge + 7), one cryopreserved blastocyst will be 
transferred after warming and assessment of blastocyst survival and re-expansion. 
The subject-related procedures are described below: 
• Tongue coat collection for future potential microbial profiling (applicable for subjects who 
have provided a separate informed consent) 
• Transfer of a single blastocyst of the highest quality available (per judgement of the site 
embryologist) 
• Dispensing of progesterone vaginal inserts, if applicable 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
10-14 days after transfer (section 6.2.2.5). 
 
6.2.2.5 
βhCG Test 
Subjects who have undergone transfer must attend a visit 10-14 days after transfer. 
The following must take place: 
• Blood collection for local laboratory analysis of βhCG 
• Dispensing of progesterone vaginal inserts, if applicable 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication 

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• Recording of adverse events 
 
The blood sample for βhCG will be analyzed by the local laboratory and evaluated according to the 
local reference ranges. In case of a doubtful / inconclusive βhCG result, the test may be repeated, 
preferably within 2 days, and the conclusive result recorded. Subjects with a positive βhCG test must 
attend a clinical pregnancy visit 5-6 weeks after transfer (section 6.2.2.6). Subjects with a negative 
βhCG test must proceed to the end of-cycle assessments (section 6.2.2.8). 
 
6.2.2.6 
Clinical Pregnancy 
Subjects with a positive βhCG test must attend a visit 5-6 weeks (35-48 days) after transfer. 
The following must take place: 
• Transvaginal ultrasound of uterus to assess any clinical pregnancy  
• Dispensing of progesterone vaginal inserts, if applicable 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms a 
vital pregnancy. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit 
(section 6.2.2.7). Subjects with no vital pregnancy must undergo end-of-cycle assessments 
(section 6.2.2.8). 
 
6.2.2.7 
Ongoing Pregnancy 
If a vital pregnancy has been documented, the subject must attend a visit 8-9 weeks (56-69 days) after 
transfer.  
The following must take place: 
• Ultrasound (transvaginal or abdominal) of uterus to assess any ongoing pregnancy 
• Drug accountability of progesterone vaginal inserts 
• Recording of use of any concomitant medication 

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• Recording of adverse events 
 
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy. 
 
6.2.2.8 
End-of-cycle 
If a subject attends the scheduled trial visits, the end-of-cycle assessments should take place at the last 
scheduled cycle visit, i.e. for subjects with a confirmed vital pregnancy, the ongoing pregnancy visit 
will be the last scheduled cycle visit and thus the visit where the end-of-cycle assessments should be 
performed. 
The following must take place at the end-of-cycle visit, irrespective of whether the subject discontinues 
the cycle prematurely or completes it: 
• Physical examination 
• Gynecological examination 
• Vital signs (systolic blood pressure, diastolic blood pressure, pulse) 
• Drug accountability, if applicable 
• Recording of use of any concomitant medication  
• Recording of adverse events 
• Complete end-of-cycle form 
 
These assessments serve to document the subject’s physical health at the end of the cycle. 
 
6.3 
Post-trial Activities 
All subjects with an ongoing pregnancy obtained in the fresh cycle, or in cryopreserved cycles initiated 
within 12 months from the start of controlled ovarian stimulation, will be followed until delivery to 
collect information on live birth rate. Furthermore, data will be collected on neonatal health, including 
minor/major congenital anomalies, at birth, 4 weeks and 1 year after birth. These follow-up data can be 
obtained from the subject, unless medical judgement is required. The subject will be contacted by 
telephone and a contact log will be maintained at the trial site. These data will be reported separately. 
 

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7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Efficacy Endpoints 
 
Ongoing Pregnancy 
A transvaginal or abdominal ultrasound of the uterus will be performed 8-9 weeks after transfer in the 
fresh cycle and in the cryopreserved cycles. Ongoing pregnancy will be defined as at least one 
intrauterine viable fetus. For ongoing pregnancies, the number of intrauterine viable fetuses will be 
recorded. 
 
 
Time to Ongoing Pregnancy 
Based on the recordings of start of controlled ovarian stimulation (date) and confirmation of ongoing 
pregnancy (date), the time to ongoing pregnancy will be calculated. Furthermore, based on the 
recording of which cycle the ongoing pregnancy occurred in, the number of cycles before achieving an 
ongoing pregnancy will be determined. 
 
 
Ongoing Implantation 
Ongoing implantation is determined based on the ultrasound performed at the ongoing pregnancy visit 
in the fresh cycle and in the cryopreserved cycles. Ongoing implantation rate will be defined as the 
number of intrauterine viable fetuses 8-9 weeks after blastocyst transfer divided by number of 
blastocysts transferred. 
 
 
Clinical Pregnancy 
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer in the fresh cycle 
and in the cryopreserved cycles. Clinical pregnancy will be defined as at least one gestational sac, 
either intrauterine or ectopic. The inclusion of ectopic pregnancies and the lack of specification of heart 
beat in the definition of clinical pregnancy is in line with the current International Committee 
Monitoring Assisted Reproductive Technologies (ICMART) and World Health Organization (WHO) 
glossary on ART terminology.29,a For intrauterine and ectopic pregnancies, the number of gestational 
sacs with fetal heart beat as well as without fetal heart beat will be recorded. 
 
 
a  ICMART and WHO glossary on ART terminology: Clinical pregnancy – a pregnancy diagnosed by ultrasonographic 
visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. 
 

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Vital Pregnancy 
Vital pregnancy is determined based on the transvaginal ultrasound performed at the clinical pregnancy 
visit in the fresh cycle and in the cryopreserved cycles. Vital pregnancy will be defined as at least one 
intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer. 
 
 
Implantation 
Implantation is determined based on the transvaginal ultrasound performed at the clinical pregnancy 
visit in the fresh cycle and in the cryopreserved cycles. Implantation rate will be defined as the number 
of gestational sacs 5-6 weeks after blastocyst transfer divided by number of blastocysts transferred. 
 
 
Positive βhCG 
A blood serum βhCG test must be obtained 10-14 days after blastocyst transfer in the fresh cycle and in 
the cryopreserved cycles. If the test is positive according to the local laboratory’s reference ranges, this 
confirms a positive βhCG. In case of a doubtful / inconclusive βhCG result, a second test will be 
performed, preferably within 2 days, and the conclusive result recorded. 
 
 
Triggering of Final Follicular Maturation, Cycle Cancellation and Transfer 
Cancellation  
The drug used for triggering of final follicular maturation, i.e. hCG or GnRH agonist, will be recorded. 
The reason for each cycle cancellation will be recorded.  
The reason for each transfer cancellation will be recorded. Transfer cancellation due to adverse events 
such as the Medical Dictionary for Regulatory Activities preferred terms (MedDRA PTs) ‘ovarian 
hyperfunction’ and ‘ovarian hyperstimulation syndrome’ in subjects with blastocysts available for 
transfer will be considered as transfer cancellations due to risk of OHSS. Similarly, transfer 
cancellations in subjects with ≥20 oocytes retrieved will be considered as transfer cancellations due to 
risk of OHSS. 
 
 
Number and Size of Follicles during Stimulation 
Transvaginal ultrasound will be performed at all visits during the controlled ovarian stimulation period 
to count the number of follicles and measure the size of the follicles. Each follicle will be measured in 

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2 dimensions, and its diameter will be calculated as the mean of the largest diameter and its 
perpendicular value. 
The total number of follicles and number of follicles with a diameter of 8-9 mm, 10-11 mm, 
12-14 mm, 15-16 mm, and ≥17 mm on stimulation day 5 and at end-of-stimulation will be recorded. 
Data will be recorded separately for the right and left ovary. 
 
 
Number and Distribution of Oocytes Retrieved 
The number of oocytes retrieved will be recorded at the oocyte retrieval visit. The proportion of 
subjects with <4 oocytes, 4-7 oocytes, 8-14 oocytes, 15-19 oocytes and ≥20 oocytes will be calculated.  
 
 
Number of Metaphase II Oocytes 
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity stage 
will be categorized as germinal vesicle, metaphase I, metaphase II, degenerated or other. 
 
 
Number of Fertilized Oocytes and Fertilization Rate 
The number of pronuclei will be counted at 19h (±2h) after insemination and recorded as 0, 1, 2 or >2. 
Fertilized oocytes with 2 pronuclei (2PN) will be regarded as correctly fertilized. Fertilization rate is 
the number of 2PN oocytes divided by the number of oocytes retrieved. 
 
 
Number and Quality of Blastocysts on Day 5 
The quality evaluation of blastocysts on day 5 after oocyte retrieval will consist of assessment of three 
parameters: blastocyst expansion and hatching status, blastocyst inner cell mass grading, and 
trophectoderm grading. The scoring is based on the classification system by Gardner & Schoolcraft,30 
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. 
 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. 

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 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. 
In the event of continued culture, blastocyst grading will be recorded after day 5. 
In the fresh cycle, the number of transferred and cryopreserved blastocysts will be recorded. In each 
cryopreserved cycle, the number of transferred blastocysts will be recorded. 
 
 
Endometrial Thickness and Echogenicity Pattern 
Transvaginal ultrasound of the uterus to assess the endometrial thickness and endometrial echogenicity 
pattern will be conducted on stimulation day 1, stimulation day 5, stimulation days 6 to 20, and at end-
of-stimulation. 
Endometrial thickness (composed of both layers of the endometrium) will be measured in the sagittal 
view of the uterus from the proximal and distal interfaces between the echogenic endometrium and the 

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hypoechoic inner layer of the myometrium. Care should be taken not to include the hypoechoic 
subendometrial halo and to account for the presence of any fluid in the uterine cavity (not to be 
included in the endometrial thickness value). 
Endometrial echogenicity pattern will be recorded as hypoechogenic, isoechogenic, hyperechogenic, or 
not possible to evaluate. 
 
 
Oocyte Utilization Rate and Oocyte Efficiency Index 
Based on the recordings of the number of oocytes retrieved and the number of blastocysts transferred 
or cryopreserved, the oocyte utilization rate will be calculated. 
Based on the recordings of the number of oocytes retrieved and the cumulative number of ongoing 
pregnancies, the oocyte efficiency index rate will be calculated. 
 
 
Blastocyst Survival and Re-expansion after Cryopreservation 
Blastocyst survival after cryopreservation will be assessed for all thawed blastocysts at 0h (+0.5h) after 
thawing. Furthermore, re-expansion will be assessed for all surviving blastocysts at 2.5h (±0.5h) after 
thawing. 
 
 
Number of Cryopreserved Cycles 
A programmed cryopreserved cycle is considered as initiated if the subject has started estradiol 
treatment. 
A natural cryopreserved cycle is considered as initiated if the subject has started LH surge monitoring. 
The number of cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation, and the number of cryopreserved cycles with blastocyst transfer will be recorded. 
 
 
Circulating Levels of Endocrine Parameters 
The following endocrine parameters will be evaluated during controlled ovarian stimulation: AMH, 
FSH, LH, estradiol, progesterone, inhibin A and inhibin B. 
Blood samples will be drawn on stimulation day 1, stimulation day 5, end-of-stimulation and oocyte 
retrieval. The sample on stimulation day 1 (baseline) will be collected prior to the first dose of IMP, 
samples drawn on stimulation day 5 will be collected at least 8 hours after the previous IMP 
administration, and samples drawn at end-of-stimulation will be collected at least 8 hours after the 

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previous IMP and GnRH antagonist administration. The samples will be analyzed at a central 
laboratory.  
The endocrine parameters include pharmacokinetic and pharmacodynamic markers of FSH therapy, 
and therefore to maintain blinding of treatment allocation the laboratory results from samples drawn 
after stimulation day 1 will not be made available to the investigator, other trial staff at site, or sponsor 
staff. 
 
 
Total Gonadotropin Dose, Number of Stimulation Days and Number of Dose 
Adjustments 
The administration dates as well as daily dose of IMP will be recorded by the subject in a diary. These 
data will be used to calculate the total dose of FE 999049 or placebo (actual and intended dose) 
administered, the number of stimulation days, and the number of dose adjustments. 
In addition, the reason for dose adjustment will be recorded by the investigator, using the following 
categories: a) inadequate follicular development, b) inadequate serum estradiol level, c) inadequate 
follicular development and inadequate serum estradiol level, d) excessive follicular development, 
e) excessive serum estradiol level, f) excessive follicular development and excessive serum estradiol 
level.  
 
7.2 
Assessments Related to Safety Endpoints 
 
Adverse Events 
Adverse events will be recorded from the time of signed informed consent for participation in the trial 
until the end-of-cycle visit in the fresh cycle. In any cryopreserved cycle, adverse events will be 
recorded from cycle initiation until the end-of-cycle visit. For each adverse event the following 
parameters will be recorded by the investigator on the Adverse Event Log: description of event, date 
and time of onset, intensity, causal relation to IMP, action taken to IMP, other actions taken, 
seriousness of the adverse event, date and time of outcome, and outcome. Definitions of adverse events 
are provided in section 8. 
 

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Clinical Chemistry and Hematology Parameters 
The following clinical chemistry and hematology parameters will be analyzed at a central laboratory:  
CHEM-20: alanine transaminase, albumin, alkaline phosphatase, aspartate aminotransferase, 
bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, 
creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, 
sodium, total protein, uric acid. 
Complete Blood Count (CBC): red blood cells, red blood cell morphology, white blood cells, white 
blood cell morphology, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelets. 
Blood samples will be drawn at screening, end-of-stimulation and end-of-cycle in the fresh cycle. The 
sample at the screening visit will be used for eligibility evaluation of the subject before randomization. 
The investigator will review the laboratory results from all visits and evaluate and document whether 
the abnormal results are non-clinically or clinically significant. The laboratory report will be signed 
and dated by the investigator. 
 
 
Injection Site Reactions 
Every day throughout the stimulation period, the subjects will assess the local tolerability of 
subcutaneous injections of FE 999049 and placebo at three time points relative to the daily 
administration: immediately after the injection, 30 minutes after the injection and 24 hours after the 
injection. The following injection site reactions will be assessed: redness, pain, itching, swelling and 
bruising. The presence and intensity of each injection site reaction will be rated as one of the 
following: none, mild, moderate or severe. 
The subject will record the assessments in a paper diary and the diary data will subsequently be 
transcribed to the eCRF.  
In case a subject has any concern related to an injection site reaction, the investigator should be 
contacted for possible further assessment, prior to the next IMP injection. 
 
 
Anti-FSH Antibodies 
Blood samples for assessment of anti-FSH antibodies in the individual subjects in the trial will be 
drawn pre-dosing and post-dosing: 
• Screening [note; this sample is exclusively used to re-establish anti-drug antibody analytical 
assays]  

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• Stimulation day 1, prior to dosing (baseline; pre-dosing sample) 
• 7-10 days after the last FE 999049 or placebo dose 
This may coincide with the transfer visit. Subjects not reaching transfer must be called in for 
this extra visit. 
• 21-28 days after the last FE 999049 or placebo dose 
This may coincide with the βhCG visit. In case of discontinuation before the βhCG visit, this 
assessment should be done at the end-of-cycle visit scheduled 21-28 days after the last 
FE 999049 or placebo dose. 
 
Ferring has developed the following assays for evaluating the immunogenicity of FE 999049: 
Assay 1 A screening immunoassay, assessing the presence of anti-FSH antibodies in serum, 
using a cut-point approach with a 5% false positive rate.  
Assay 2 A confirmatory immunoassay, confirming or disconfirming the specificity of any 
positive results in assay 1, using a cut-point approach with a 1% false positive rate. 
Assay 3 A titer immunoassay determining the antibody response titer of any anti-FSH antibodies 
confirmed in assay 2. 
Assay 4 A cell-based assay qualitatively assessing the neutralizing capacity of any anti-FSH 
antibodies confirmed in assay 2, using a cut-point approach with a 1% false positive 
rate. 
Assay 5 A cell-based assay determining the neutralizing antibody response titer of any positive 
result in assay 4. 
Assay 6 A confirmatory assay based on native FSH, in order to assess cross-reactivity with 
native FSH of any anti-FSH antibodies confirmed to be specific towards exogenous FSH 
in assay 2, using a cut-point approach with a 1% false positive rate. 
 
In subjects with a negative pre-dosing sample, a treatment-induced anti-FSH antibody response will be 
defined as any post-dosing sample being positive in the confirmatory assay (assay 2).  

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In subjects with a positive pre-dosing sample, a treatment-induced anti-FSH antibody response will be 
defined as a statistically determined fold increase in titers from the pre-dosing assessment to a post-
dosing assessment.b 
All positive samples in the confirmatory assay (assay 2) will be further characterized for titer, 
neutralizing capacity (qualitatively and titer, if applicable) and cross-reactivity. A subject is defined to 
have treatment-induced anti-FSH antibodies with neutralizing capacity if she has a positive outcome of 
assay 4 after IMP administration and if she was negative for anti-FSH antibodies with neutralizing 
capacity at pre-dosing. Ferring will report treatment-induced neutralizing antibodies to the FDA. 
The proportion of subjects with treatment-induced anti-FSH antibodies and the proportion of subjects 
with treatment-induced anti-FSH antibodies with neutralizing capacity are secondary endpoints.  
Subjects with a treatment-induced anti-FSH antibody response (both with and without neutralizing 
capacity) will be followed until the response is negative or has returned to pre-dosing level or after a 
maximum of 1 year. These subjects will be called in for assessments 2 months after the last post-dosing 
anti-FSH antibody sampling. If required, further assessments will be made at 3, 4, 6, 9 and 12 months 
after the last post-dosing anti-FSH antibody sampling. The assessments will be terminated when two 
consecutive assessments are negative or indicate that the pre-dosing level has been reached, or after a 
maximum of 1 year. The assessments will also be terminated if the subject commences a new treatment 
cycle with any gonadotropin preparation. 
 
 
Immune-related Adverse Events 
All treatment-emergent adverse events will be analyzed to identify those that potentially are immune-
related. To identify all possible cases, a broad-scope search on Standardized MedDRA Queries 
(SMQs), including ‘Hypersensitivity’, ‘Anaphylactic reactions’, ‘Angioedema’ and ‘Severe cutaneous 
adverse reactions’ will be considered. Moreover, to identify the potential cases manifested by non-
specific symptoms and not covered by these SMQs, other MedDRA PTs like ‘Musculoskeletal pain’, 
‘Asthenia’, ‘Pyrexia’, ‘Chills’, ‘Body temperature increased’, ‘Influenza like illness’, ‘Injection related 
reaction’, ‘Presyncope’ and ‘Syncope’ will also be taken into account. Hypersensitivity reactions 
manifested by local symptoms will be identified using the MedDRA high level term (HLT) ‘injection 
site reactions’. The SMQs may include very specific as well as less specific terms; hence a narrow-
scope search on these SMQs will be carried out to identify those cases that are highly likely to 
represent an immune-related etiology. 
 
 
b  The fold increase in titers is determined by minimum significant ratio (MSR) experiments during assay validation and 
will be stated in the validation report and the clinical trial report. 

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Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen 
The reason for each cycle cancellation will be recorded, allowing subsequent tabulation of cycle 
cancellations due to adverse events, including immune-related adverse events (see section 7.2.5), and 
technical malfunctions of the administration pen. 
 
 
Ovarian Hyperstimulation Syndrome 
All cases of OHSS will be reported as adverse events with further details on signs and symptoms 
recorded on a specific OHSS form. Golan’s classification system31 (see section 8.3.1 for details) will 
be used for grading of each OHSS case as mild, moderate or severe. In the fresh cycle, early OHSS is 
defined as OHSS with onset ≤9 days after triggering of final follicular maturation, and late OHSS is 
defined as OHSS with onset >9 days after triggering of final follicular maturation. 
 
 
Hospitalizations and Paracentesis due to Ovarian Hyperstimulation Syndrome 
Based on the recordings in the OHSS form, the cases of hospitalization due to OHSS and paracentesis 
due to OHSS will be identified. Associated parameters to be recorded include dates of admission and 
discharge from the hospital, and volume of fluid, respectively. 
 
 
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins 
Data related to multi-fetal gestation defined as a pregnancy with more than one fetus will be recorded. 
Furthermore, data related to the occurrence of biochemical pregnancy, spontaneous abortion, ectopic 
pregnancy (with and without medical/surgical interventions) and vanishing twins will also be recorded 
(section 8.3.2). 
 
 
Technical Malfunctions of the Administration Pen 
In case of technical malfunction of an administration pen that results in a replacement of the pen, all 
relevant details (including time, date, a description of the malfunction and whether dosing was 
affected) of the incidence should be reported in the eCRF, the pen should be replaced and the treatment 
continued. Human errors such as misunderstanding of instructions or incorrect handling of the device 
should not be regarded as technical malfunctions. 
In case of adverse events caused by malfunction of the administration pen, these will be identified and 
described. 
 

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7.3 
Other Assessments 
 
Demographics 
Demographic information will be obtained during the screening period, including the following: date 
of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or Alaska 
Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White). 
 
 
Medical History 
Any relevant medical history will be recorded during the screening period. This includes diagnosis / 
symptoms, and start and end dates (or marked ongoing in case it has not been resolved). 
 
 
Infertility History 
Information about the causes of infertility and duration of infertility will be obtained during the 
screening period. This will also cover information about any previous treatment for infertility, 
including type of treatment and gonadotropin preparations used. 
 
 
Menstrual History 
Information about the menstrual history (average cycle length and onset of last menstrual cycle prior to 
the screening visit) will be obtained during the screening period. 
 
 
Reproductive History 
Information about the reproductive history will be obtained during the screening period. This will 
include number of clinical pregnancies, number of fetuses and outcome. Information on primary versus 
secondary infertility will be derived. 
 
 
Body Measurements 
Body weight will be measured at screening, stimulation day 1, and at end-of-cycle in the fresh cycle. 
Body weight will be measured without shoes and coat, using a calibrated scale. 
Height will only be measured at screening and will be used to calculate BMI. 
 
 
Physical Examination 
A complete physical examination will be performed at screening and end-of-cycle in the fresh cycle. In 
any cryopreserved cycle, a complete physical examination will be performed at cycle initiation and at 

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end-of-cycle. 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. 
Each category will be evaluated as normal, abnormal not clinically significant or abnormal clinically 
significant. Abnormal clinically significant findings at screening must be reported on the Medical 
History Log. 
At each end-of-cycle visit, potential changes from screening to end-of-cycle in the fresh cycle or from 
cycle initiation to end-of-cycle in any cryopreserved cycle 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-cycle in the fresh cycle 
and from cycle initiation to end-of-cycle in any cryopreserved cycle must be recorded as adverse 
events. 
 
 
Gynecological Examination 
A complete gynecological examination will be performed at screening and end-of-cycle in the fresh 
cycle. In any cryopreserved cycle, a complete gynecological examination will be performed at cycle 
initiation and at end-of-cycle. Information will be recorded for 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. Abnormal clinically significant findings at screening must be reported on the Medical 
History Log. 
At each end-of-cycle visit, potential changes from screening to end-of-cycle in the fresh cycle or from 
cycle initiation to end-of-cycle in any cryopreserved cycle 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-cycle in the fresh cycle 
and from cycle initiation to end-of-cycle in any cryopreserved cycle must be recorded as adverse 
events. 
 

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Endocrine Parameters at Screening 
At screening, the following panel of endocrine parameters will be evaluated: AMH, TSH and prolactin.  
The sample will be analyzed at a central laboratory.  
The results for TSH and prolactin must be available prior to randomization. The investigator will 
review and evaluate the laboratory results. The laboratory report will be signed and dated by the 
investigator. 
 
 
Vital Signs 
Systolic and diastolic blood pressure and pulse will be measured at screening, on stimulation day 1, 
and at end-of-cycle in the fresh cycle. In any cryopreserved cycle, vital signs will be measured at cycle 
initiation and at end-of-cycle. Assessments of blood pressure and heart rate are to be measured while 
the subject is in supine position after resting for 3 minutes. 
 
 
Ovarian Volume 
As part of the transvaginal ultrasounds performed on stimulation day 1, stimulation days 6 to 20, and 
end-of-stimulation, the size – length, width and depth (recorded in mm) – of each ovary is measured 
and used for subsequent calculation of ovarian volume. 
 
 
Endometrial Evaluation in Cryopreserved Cycles 
Transvaginal ultrasound of the uterus to measure the endometrial thickness prior to transfer will be 
conducted in the cryopreserved cycles. In programmed cryopreserved cycles, the transvaginal 
ultrasound will be performed after 10-12 days of estradiol treatment (a second assessment may be 
performed within 7 additional days, if applicable). In natural cryopreserved cycles, the transvaginal 
ultrasound will be performed on the day of confirmation of LH surge. 
 
 
Concomitant Medication 
The use of any concomitant medication within the last 3 months prior to informed consent for 
participation in the trial (except medication used in previous infertility treatment cycles which will be 
recorded as part of the infertility history) and throughout the trial will be recorded. Recording of 
concomitant medication will be performed at all visits. Any changes in concomitant medications or 
treatments must be recorded at each visit.  
 

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Drug Dispensing and Accountability 
For all medicinal products used in the fresh cycle and the cryopreserved cycles, dates of administration 
and dose administered will be recorded. Furthermore, time of administration will also be recorded for 
IMP, GnRH antagonist, hCG and GnRH agonist in the fresh cycle. Details on drug dispensing and 
accountability are provided in section 5.6. 
 
 
End-of-cycle Form 
An end-of-cycle form must be filled in at the subject’s last visit in each cycle, irrespective of whether 
the subject completes the cycle or not. Completion / discontinuation status will be recorded, as well as 
date and reason for discontinuation in case the subject did not complete the cycle. 
 
7.4 
Assessments Related to Post-trial Endpoints 
 
Live Birth 
Each cycle with an ongoing pregnancy will be followed until delivery. The outcome of each delivery, 
i.e. live birth or stillbirth, will be recorded. 
 
 
Live Birth of Singletons Born at Term 
Based on recordings of timing of blastocyst transfer as well as timing and outcome of delivery, the live 
birth rate of singletons born at term (≥37 weeks of gestation) will be calculated. 
 
 
Time to Live Birth of a Singleton Born at Term 
Based on the recordings of start of controlled ovarian stimulation (date) as well as timing (date) and 
outcome of delivery, the time to live birth of a singleton born at term will be calculated. Furthermore, 
based on the recording of which cycle the live birth of a singleton at term occurred in, the number of 
cycles before achieving this will be determined. 
 
 
Minor/Major Congenital Anomalies 
All neonates will be followed as part of the post-trial follow-up. Congenital anomalies detected at 
birth, 4 weeks and 1 year after birth for all infants born after the fresh cycle and after the cryopreserved 
cycles will be reported and classified as minor or major as described in section 8.5.1.  
 

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7.5 
Other Post-trial Assessments 
Gender, birth weight and length, and Apgar score after 1 and 5 minutes will be recorded. 
Furthermore, admission to neonatal intensive care unit (NICU), neonatal care unit (NCU) or pediatric 
care unit (PCU) will be recorded as described in section 8.5.1. At 4 weeks and 1 year after birth, the 
information collected will include minor/major congenital anomalies, admission to NICU, NCU or 
PCU and any other relevant medical conditions. 
 
7.6 
Optional Exploratory Analyses 
 
Genome Sequencing 
For subjects who have provided a separate informed consent, a blood sample and a saliva sample for 
potential future genome sequencing will be collected on stimulation day 1. The informed consent for 
these optional exploratory analyses signed by the subject must be obtained prior to the sampling. 
Resultant sequence data may be used in exploratory pharmacogenomic analyses aimed at identifying 
novel relationships between ovarian response/associated outcomes and subjects’ genomic variants. 
Results of these potential future exploratory analyses will not be provided to the sites. 
 
 
Microbial Profiling 
For subjects who have provided a separate informed consent, a tongue coat sample for potential future 
microbial profiling will be collected on stimulation day 1 and at the transfer visit(s) in the fresh and 
cryopreserved cycles, as applicable. The informed consent for these optional exploratory analyses 
signed by the subject must be obtained prior to the sampling. 
Subjects will be asked to rinse and gargle twice with sterile water prior to using a tongue scraper to 
collect the tongue coat from the posterior middle area to the anterior middle area. 
Analyses may be performed to identify relationships between ovarian response/associated outcomes 
and subjects’ microbiome. 
Results of these potential future exploratory analyses will not be provided to the sites. 
 

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7.7 
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. Biological samples will be 
analyzed at central laboratories and will be maintained in storage and destruction will take place within 
2 years after reporting of the trial. Exceptions are the blood, saliva and tongue coat samples collected 
for potential future genome sequencing and microbial profiling, 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. Blood samples analyzed by 
a local laboratory, e.g. in connection with eligibility criteria, estradiol for monitoring of ovarian 
response, and the βhCG tests, will be destroyed after analysis. For all biological samples collected in 
the trial, it applies that analyses beyond those described in the protocol can only be performed after 
obtaining the required approvals. The processes related to handling of biological samples will be 
described in the informed consent documents, and biobank / data protection legislation will be adhered 
to. 
 

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8 
ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes: 
• Any unfavorable 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 gynecological examination 
assessed as clinically significant by the investigator [note: pre-existing conditions diagnosed 
through assessments and examinations at the screening visit or during the screening period are 
not adverse events, but are recorded as medical history]. 
• Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for any 
medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical 
procedures. 
 
All adverse events will be coded by Ferring Global Pharmacovigilance using MedDRA (the version 
effective at trial start). 
 
8.2 
Collection and Recording of Adverse Events 
 
Collection of Adverse Events 
The investigator must monitor the condition of the subject throughout the trial from the time of signed 
informed consent for participation in the trial until the end-of-cycle visit in the fresh cycle. In any 
cryopreserved cycle, adverse events will be recorded from cycle initiation until the end-of-cycle visit. 
The sources of adverse events cover: 
• The subject’s response to questions about her health (a standard non-leading question such as 
“How have you been feeling since your last visit?” is asked at each visit). 
• Symptoms spontaneously reported by the subject. 
• Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
• Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization). 
 

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Recording of Adverse Events 
The investigator must record all adverse events in the Adverse Event Log provided in each subject’s 
eCRF with information about: 
• Adverse event 
• Date and time of onset 
• Intensity 
• Causal relationship to IMP 
• Action taken to IMP 
• Other action taken 
• Date and time of outcome 
• Outcome 
• Seriousness 
 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
 
Adverse Event 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record. 
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in intensity, a 
worst-case approach should be used when recording the event, i.e. the highest intensity and the longest 
duration of the event.c 
Note: a procedure is not an adverse event; the reason for conducting the procedure is. Hospitalization is 
not an adverse event; the reason for hospitalization 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). 
 
 
c  Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
worsens in intensity, this must be recorded as two separate events. The initial adverse event should be recorded with 
outcome “not recovered” and the date and time of outcome is when the intensity changed. The second adverse event 
should be recorded with date and time of onset when the intensity changed.  
 

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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 activity. 
Moderate: 
Event sufficient to affect usual activity (disturbing). 
Severe: 
Inability to work or perform usual activities (unacceptable). 
 
Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event must be classified as one of the following: 
Reasonable possibility:  
There is evidence or argument to suggest a causal relationship between the IMP and the adverse event. 
The adverse event may occur as part of the pharmacological action of the IMP or may be unpredictable 
in its occurrence. 
Examples:  
• Adverse events that are uncommon but are known to be strongly associated with IMP exposure. 
• Adverse events that are not commonly associated with IMP exposure, but the event occurs in 
association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge with the IMP. 
 
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and the 
adverse event. 
Examples: 
• Known consequences of the underlying disease or condition under investigation. 

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• Adverse events common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure. 
 
Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the following: 
• No change (medication schedule maintained or no action taken) 
• Discontinued 
• Interrupted 
• Dose reduced 
• Dose increased 
 
Other Action Taken 
Adverse events requiring therapy must be treated with recognized 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 
 
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 system31 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 diarrhea. 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 
hemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d) Hospitalization due to OHSS symptoms.e) 
a)  For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded.  
b)  For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc.) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis.  
c)  In case of paracentesis, the volume of fluid drained should be measured. 
d)  Hemoconcentration is defined as hematocrit >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. 
e)    Hospitalization is defined as admission exceeding 24 hours. 
 

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All cases of OHSS must be reported as adverse events and followed until the adverse event has an 
outcome of recovered. Any case of OHSS that requires hospitalization (admission exceeding 24 hours) 
or surgical/medical intervention (e.g. paracentesis) should be considered severe. All cases of severe 
OHSS should be reported as an SAE.  
Please note, that the classification of ‘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), but to 
the grades in Golan’s Classification System described above.  
Subject narratives will be prepared for all OHSS cases.  
Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of final 
follicular maturation and late OHSS will be defined as OHSS with onset >9 days after triggering of 
final follicular maturation. 
 
Investigations in Case of OHSS 
The investigator should report signs, symptoms and laboratory assessments used to diagnose and 
classify all cases of OHSS in the eCRF. The following investigations must be conducted when OHSS 
symptoms are first observed and repeated when there are clinically relevant changes in the OHSS 
presentation suggestive of a worsening, i.e. higher grading:  
• Body weight  
• Ultrasound of ovarian size and if applicable, measurement of pelvic/abdominal/thoracic fluid  
• Vital signs 
• Blood sample for central laboratory analysis of the following: 
- 
Progesterone and estradiol 
- 
CBC (red blood cells, red blood cell morphology, white blood cells, white blood cell 
morphology, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelets) 
- 
CHEM-20 (alanine transaminase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, 
chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid) 
- 
Coagulation parameters (prothrombin time, activated partial thrombin time) 
 
Any treatments of OHSS, e.g. intravenous administration of volume expanders, paracentesis, use of 
low-molecular-weight heparin and intravenous administration of albumin, must be recorded as 

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concomitant medication. 
 
 
Pregnancy Losses 
The following terminology should be used for reporting of pregnancy losses as adverse events: 
Biochemical pregnancy:  
Positive βhCG test but no gestational sac is observed on later 
transvaginal ultrasound, or menstruation is reported 
 
Spontaneous abortion:  
Positive βhCG test but all intrauterine gestational sacs are without 
fetal heart beat as documented by ultrasound, or there are no 
viable fetuses observed by ultrasound 
 
Vanishing twin: 
Spontaneous disappearance of at least one intrauterine gestational 
sac with or without heart beat in a pregnancy where one viable 
fetus remains as documented by ultrasound 
 
Ectopic pregnancy: 
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery 
 
Concerning timing, a pregnancy loss occurring before ongoing pregnancy (i.e. a positive βhCG test but 
no ongoing pregnancy at 8-9 weeks after transfer) will be defined as an early pregnancy loss, while a 
pregnancy loss occurring after ongoing pregnancy (i.e. at least one intrauterine viable fetus at 
8-9 weeks after transfer but no live birth) during the post-trial follow-up will be defined as a late 
pregnancy loss. 
 
8.4 
Events Requiring Special Handling 
 
Injection Site Reactions 
Injection site reactions after administration of IMP (FE 999049 or placebo) are only to be reported as 
adverse events if they require active management, i.e. discontinuation of IMP, additional investigations 
or treatment of the injection site reaction. Local tolerability of IMP constitutes a secondary endpoint 
and will be evaluated in detail based on the subjects’ recordings in the diary.  
Local tolerability reactions after administration of NIMP are to be reported as adverse events if they 
fulfil the definition of an adverse event. 
 

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Treatment-induced Anti-FSH Antibodies 
Presence of treatment-induced anti-FSH antibodies is not to be reported as an adverse event. These 
data will be described as part of the secondary endpoints. 
 
 
Menstrual Bleeding 
Menstrual bleeding is only to be reported as an adverse event in case it is excessive, painful, delayed or 
in any other way deviating from the subject’s normal menstruation. Menstrual bleeding associated with 
lack of pregnancy will be reported as part of the efficacy evaluation. 
 
 
Multiple Pregnancies 
Multi-fetal gestations are not to be reported as adverse events. 
 

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8.5 
Serious Adverse Events 
 
Serious Adverse Event Definition 
Serious Adverse Events during the Trial 
An event is defined a serious 
adverse event (SAE) 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 
hospitalization or prolongation 
of existing hospitalization 
The term hospitalization means that the subject was admitted to hospital or that 
existing hospitalization was extended as a result of an event. Hospitalization 
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 
hospitalization. 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). Hospitalizations for administrative 
or social purposes do not constitute an SAE. Hospital admissions and/or 
surgical operations planned before trial inclusion are not considered adverse 
events, if the illness or disease existed before the subject was enrolled in the 
trial, provided that the condition did not deteriorate during the trial. 
results in persistent or 
significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgement by the investigator. 
is an important medical event 
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization 
but might jeopardize the patient or might require intervention to prevent one of 
the other outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
 

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Elective Termination 
In connection with elective termination due to a congenital anomaly, the congenital anomaly of the 
fetus should be reported as an SAE. 
The congenital anomaly leading to elective termination will be coded using both MedDRA and ICD-10 
and classified as minor or major.d 
 
Serious Adverse Events during Post-trial Activities 
Pregnancy outcome will be gathered for all subjects with an ongoing pregnancy in the fresh or any 
cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation. 
Furthermore, data will be collected on neonatal health, including minor/major congenital anomalies, at 
birth, 4 weeks and 1 year after birth. These data will be reported separately. 
The following untoward medical occurrences reported as part of this post-trial follow-up information 
will be recorded as SAEs: 
• Death of mother in connection with pregnancy or labor 
• Death of neonate / infant 
• Stillbirthe 
• Neonate admitted to the neonatal intensive care unit (NICU) regardless of duration, or neonate / 
infant admitted to the neonatal care unit (NCU) / pediatric care unit (PCU) for more than 
2 hours 
• Congenital anomaly / birth defect 
• Medically important event 
 
In case of admission to NICU or NCU / PCU, the reason for admission must be reported as an SAE, 
rather than just the act of hospitalization. 
Congenital anomalies will be coded by Ferring using both MedDRA and ICD-10 and classified as 
minor or major.32 
 
 
d  Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems.  
Major abnormalities: a life threatening structural anomaly or one likely to cause significant impairment of health or 
functional capacity and which needs medical or surgical treatment.  
e  Stillbirth: gestational age ≥24 weeks + 0 days, calculated from the day of day 5 blastocyst transfer + 19 days 

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Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported 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 submitting the completed SAE Report Form with the fullest possible 
details within 3 calendar days of his/her knowledge of the SAE. 
SAE Report Form 
The SAE Report Form is included in the eCRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the eCRF cannot be accessed and hence the 
SAE Report Form cannot be filled in within the eCRF system, a paper SAE Report Form should be 
used and sent to Ferring Pharmacovigilance using the contact details below. 
Ferring Pharmacovigilance  
E-mail: 
 
US Fax: 
 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes have 
been made since the initial report. Data entries must have been made in the eCRF 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 eCRF), 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, such details such as subject’s name, 
address, and hospital ID number should be concealed and instead subject number should be provided. 
The investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records. 
Overdose and medication errors of IMP with and without clinical consequences will be tracked in the 
eCRF and reviewed by Ferring Pharmacovigilance on an ongoing basis. 
Ferring will report SAEs according to local regulations. 
 

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8.6 
Follow-up of Adverse Events and Serious Adverse Events  
 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the investigator must follow-up on each adverse event until it is resolved or until the 
medical condition of the subject is stable. 
After the subject’s last visit, the investigator must follow-up on any adverse event classified as serious 
or considered to have a reasonable possible causality to the IMP until it is resolved or until the medical 
condition of the subject is stable. All such relevant follow-up information must be reported to Ferring. 
Follow-up should continue until the outcome of recovered, recovered with sequelae or fatal, has been 
reached. Further, if the event is a chronic condition, the investigator and Ferring may agree that further 
follow-up is not required. 
 
 
Follow-up of Serious Adverse Events with Onset during the Post-Trial Period 
For post-trial SAEs in neonates, where the neonate has not recovered at the 1-year follow-up 
assessment, the investigator must follow up until the SAE has resolved. If the SAE is a chronic 
condition or the medical condition of the neonate is stable, the investigator and Ferring may agree that 
further follow-up is not required. 
 
 
Collection of Serious Adverse Events with Onset after End-of-trial 
If an investigator becomes aware of an SAE after the subject’s last visit in the trial, and he/she assesses 
the SAE to have a reasonable possible causality to the IMP or to the NIMP where Ferring is the NDA 
holder (i.e., ENDOMETRIN and NOVAREL), the case will have to be reported to Ferring 
Pharmacovigilance, regardless how long after the end of the trial this takes place. 

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9 
STATISTICAL METHODS 
This section details the planned statistical analyses for the primary endpoint and outlines the analysis 
plan for the secondary endpoints. All analyses and further descriptions of the statistical methodology 
for the primary and secondary endpoints will be included in the statistical analysis plan (SAP). The 
SAP will be available before the first subject is randomized in the trial. A separate SAP will be 
prepared to cover the post-trial information. 
 
9.1 
Determination of Sample Size 
The proposed sample size of 550 (FE 999049:placebo = 500:50) can adequately address both the 
efficacy and safety objectives of the trial: 
• The cumulative ongoing pregnancy rate in the FE 999049-treated subjects aged 18-34 years 
after single blastocyst transfer in fresh and cryopreserved cycles is estimated to be 
approximately 45%.33 By comparison, the pregnancy rate in the placebo arm is expected not to 
exceed 3%, the monthly spontaneous pregnancy rate in infertile women.34 Therefore, the 
proposed sample size of 550 (FE 999049:placebo=500:50), will provide at least 99% power for 
the primary efficacy comparison. Based on the estimated cumulative ongoing pregnancy rate, 
the cumulative live birth rate from the fresh and/or cryopreserved cycles is estimated to be 
approximately 40%, resulting in a power for the comparison of the cumulative live birth rate to 
be at least 99%. 
• The safety and tolerability of daily rFSH preparations as part of an ART treatment cycle have 
been well documented for the population studied in previous clinical trials.1,35,36 OHSS was 
reported to occur in 3.6% to 6.3% of the subjects, with moderate/severe OHSS occurring in 
2.0% to 4.5% of the subjects and OHSS resulting in hospitalization occurring in approximately 
0.7% to 1.3% of the subjects. Other adverse events were pelvic pain, pelvic discomfort and 
headache, reported in 4% to 20% of the subjects in each treatment group. 
Table 9-1 shows that the planned sample size of 500 subjects exposed to FE 999049 provides a 
high probability to detect a rare adverse event or safety signal occurring in 0.5% or more 
subjects. 
Table 9-1 
Probabilities to Detect at Least One Rare Event 
Incidence rate of rare event Chance of detecting at least 1 event 
0.5% 
91.8% 
0.6% 
95.1% 
1% 
99.3% 
 

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Table 9-2 presents the margin width estimates of the 95% confidence intervals for a range of 
adverse event rates with the planned sample size. 
Table 9-2 
Estimated Margin Widths of 95% Confidence Intervals 
Adverse event rate 
Margin of error width estimate 
5% 
1.9% 
10% 
2.6% 
15% 
3.1% 
20% 
3.5% 
 
 
9.2 
Subject Disposition 
All screened subjects will be accounted for. Screened subjects who discontinue from the trial prior to 
randomization are regarded as screening failures. Screening failures and their primary reason for 
screening failure will be tabulated. Screening failures will not otherwise be accounted for. 
Subject disposition with respect to analysis sets will be tabulated. A separate table will summarize the 
subject disposition with respect to analysis sets by trial site. Subject attendance at selected trial visits 
and adherence to selected trial procedures will be tabulated. The number of completed and 
discontinued subjects including reason for discontinuation will also be tabulated.  
Subject disposition with respect to analysis sets will be listed for all randomized subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately. 
 
9.3 
Protocol Deviations 
The rating of protocol deviations as ‘minor’ and ‘major’, as well as the criteria for major protocol 
deviations with the implication of exclusions from the per-protocol (PP) analysis set will be decided by 
the medical officer, medical monitor and statistician on the basis of a blinded review of data before 
declaration of clean file and lock of database.  
The list of major protocol deviations will be detailed and documented in the clean file document prior 
to database release. Major protocol deviations will be summarized and listed by subject. 

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Major protocol deviations, such as significant non-compliance or other serious unforeseen deviations 
that may affect the conclusions of the trial, will lead to exclusion of data from the PP analysis set. Data 
will not be excluded from the PP analysis set in case of minor protocol deviations. 
 
9.4 
Analysis Sets 
Intention-to-Treat Analysis Set 
The intention-to-treat (ITT) analysis set comprises all randomized subjects. Subjects will be analyzed 
according to planned treatment. 
 
Modified Intention-to-Treat Analysis Set 
The modified intention-to-treat (mITT) analysis set comprises all randomized and exposed subjects. 
Subjects will be analyzed according to planned treatment. 
 
Per-Protocol Analysis Set 
The PP analysis set comprises all mITT subjects except those excluded as a result of major protocol 
deviations as described in section 9.3. 
 
Safety Analysis Set 
The safety analysis set comprises all randomized and exposed treated subjects. Subjects will be 
analyzed according to actual treatment received. 
 
9.5 
Trial Population 
 
General Considerations 
All relevant baseline data will be summarized in tables including both treatment groups and a total 
column. The purpose of these tabulations is to characterize the treatment groups and assess the degree 
of similarity achieved by the randomization. Baseline data will not be compared using statistical tests. 
Unless otherwise noted, tabulations will be produced overall for the mITT analysis set, as well as in the 
ITT analysis set if the ITT analysis set differs from the mITT analysis set. Continuous variables will be 
presented with number of subjects, mean, standard deviation, median, inter-quartile range, minimum, 
and maximum. Categorical variables will be presented with number and percentage of subjects within 
each specific category. 

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Listings will only be produced for the mITT. 
Unless otherwise noted, missing data will not be imputed. 
 
 
Trial Population Parameters 
Demographics and other Baseline Characteristics 
Demographics and other baseline characteristics (body measurements, ultrasound parameters, vital 
signs, and endocrine parameters) obtained before first exposure to IMP will be listed by subject and 
presented in summary tables.  
 
Medical History 
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarized for each medical item.  
 
Infertility History, Menstrual History and Reproductive History 
Infertility history, menstrual history and reproductive history will be listed by subject and presented in 
summary tables.  
 
Physical Examination and Gynecological Examination 
Physical examination and gynecological examination performed during screening will be summarized 
per category.  
 
Concomitant Medication 
Concomitant medications will be coded using the WHO Drug Reference List. Prior and concomitant 
medication will be summarized by anatomical therapeutic chemical (ATC) classification 1st level 
(alphabetically) and ATC classification 2nd level (in decreasing order of frequency). These medications 
will be tabulated separately for: 
• Prior medication, i.e. medication taken exclusively prior to treatment (i.e. with stop date/time 
before date/time of 1st IMP administration) 

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• Concomitant medication, i.e. medication taken during the treatment period (i.e. medication that 
was not stopped before date/time of 1st IMP administration and not started after the end-of-
cycle visit) 
 
Concomitant medication will be presented separately for the fresh cycle and the cryopreserved cycles. 
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication. 
Concomitant medications will be listed by subject. 
 
9.6 
Exposure and Treatment Compliance 
 
General Considerations 
Duration of treatment (days) is defined as the number of days from first exposure to the day of last 
exposure (both inclusive). Tabulations will be produced for the mITT analysis set. 
 
 
Controlled Ovarian Stimulation (Fresh Cycle) 
IMP 
Exposure to gonadotropins, including total dose, duration of stimulation and number of dose 
adjustments is covered by a secondary endpoint (section 9.7.3.19).  
 
NIMPs 
Exposure to GnRH antagonist will be summarized as the total dose administered (µg) and duration of 
treatment (days).  
Exposure to drug used for triggering of final follicular maturation, i.e. hCG or GnRH agonist, is 
covered by a secondary endpoint (section 9.7.3.8).  
Exposure to progesterone will be summarized as the total dose administered (mg) and duration of 
treatment (days). 
 

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Cryopreserved Cycles 
In the programmed cryopreserved cycles, exposure to estradiol will be summarized by cycle as the 
total dose administered (mg) and duration of treatment (days), and exposure to IM progesterone will be 
summarized by cycle as the total dose administered (mg) and duration of treatment (days). 
In the natural cryopreserved cycles, exposure to vaginal progesterone will be summarized by cycle as 
the total dose administered (mg) and duration of treatment (days). 
 
 
Treatment Compliance  
Non-compliance to IMP is expected to be limited and will be presented in listings. Similarly, listings 
will be prepared for subjects with deviations in the NIMP schedules for the fresh and cryopreserved 
cycles. 
 
9.7 
Efficacy Endpoints Assessments 
 
General Considerations 
Primary Endpoint and Secondary Efficacy Endpoints 
Upon achieving statistical significance about the primary endpoint at the 0.05 alpha level, the 
cumulative live birth rate will be formally tested at the 0.05 alpha level for inferential conclusions. 
The secondary endpoints related to pregnancy and implantation parameters are considered supportive 
of the primary endpoint (cumulative ongoing pregnancy rate). The secondary efficacy endpoints related 
to ovarian response and embryo development parameters are intended to provide additional 
characterization of FE 999049.  
 
Analysis and Presentation of Primary and Secondary Efficacy Endpoints 
Summary tables and treatment comparisons for the primary endpoint will be presented for both the 
mITT and PP analysis sets. In case that the mITT and ITT analysis sets are not identical (i.e. at least 
one subject is randomized but not exposed) the summary tables and treatment comparisons will also be 
presented for the ITT analysis set. As applicable for the secondary endpoints, summary tables and 
treatment comparisons may be presented for the mITT and PP analysis sets.  
All tabulations will be presented 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.  

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All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of ‘equal effect’ against the alternative of 
‘different effect’. 
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will be 
listed. Listings will only be produced for the mITT. 
 
Multiplicity 
In order to handle the formal testing procedures for the primary endpoint of cumulative ongoing 
pregnancy rate and the key post-trial endpoint of cumulative live birth rate, the overall type-I error will 
be controlled by the use of a hierarchical inferential approach. Statistical significance of the primary 
endpoint at the 0.05 alpha level is required before drawing inferential conclusions about the key post-
trial endpoint of the cumulative live birth rate. This fixed hierarchical approach will ensure a strong 
control of the overall type-I error rate at the 0.05 level. 
All additional analyses of the primary endpoint and secondary efficacy endpoints are considered as 
supportive. Adjustments for multiplicity will therefore not be applied.  
 
Missing Data 
Missing observations for the primary endpoint of cumulative ongoing pregnancy rate will be imputed 
as ‘negative’ irrespective of the reason why data are not recorded. Similarly, for other pregnancy 
endpoints (βhCG, clinical pregnancy and vital pregnancy) missing data will be imputed as ‘negative’ 
with the exception of a later observation in that cycle confirming that an earlier missing observation 
was in fact ’positive’, e.g. in case of a missing βhCG test result and a confirmed clinical pregnancy in 
the same cycle then the βhCG test result will be imputed as ‘positive’.  
For subjects with transfer but missing observations on the number of viable fetuses 8-9 weeks after 
transfer the number of viable fetuses will be imputed as zero irrespective of why data is not recorded. 
For subjects with transfer but missing information on the number of gestational sacs 5-6 weeks after 
transfer, the number of gestational sacs will be imputed as the number of viable fetuses 8-9 weeks after 
transfer.  
For subjects with cycle cancellation, the numbers of oocytes retrieved, metaphase II oocytes, fertilized 
oocytes, and blastocysts on day 5 will be imputed as zero.  

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Missing values will not be imputed for any of the other secondary endpoints, unless otherwise noted. 
 
 
Primary Endpoint 
The hypothesis to be tested for the primary endpoint, cumulative ongoing pregnancy rate, is: 
H0: πFE 999049 – πPlacebo ≤ 0 against the alternative HA: πFE 999049 – πPlacebo > 0, 
where πFE 999049 and πPlacebo denote the cumulative ongoing pregnancy rate after the fresh cycle and 
cryopreserved cycles in subjects aged 18-34 years treated with FE 999049 or placebo, respectively. 
H0 will be tested against the alternative HA by constructing a two-sided 95% confidence interval for the 
difference in the cumulative ongoing pregnancy rates between the two treatment groups using the 
traditional Wald interval. If the lower limit of the two-sided 95% confidence interval is greater than 0, 
the null hypothesis H0 will be rejected. In the case that the number of pregnancies observed in the 
placebo group is small (<5), then the one-sided Fisher’s exact test will be used. 
The primary endpoint will be determined as soon as the subject has achieved an ongoing pregnancy, or 
when all cryopreserved blastocysts have been exhausted, or after assessment of ongoing pregnancy 
status in cryopreserved cycles initiated within 12 months from the start of controlled ovarian 
stimulation. 
The efficacy analysis will be based on the mITT analysis set, defined as all subjects who were 
randomized and received at least one dose of IMP (FE 999049 or placebo). 
 
Sensitivity Analyses 
The primary analysis will be repeated for the subjects in the PP analysis set as sensitivity analysis, as 
well as in the ITT analysis set if the ITT analysis set differs from the mITT analysis set. The outcomes 
of these analyses are considered supportive. 
The primary analyses described above will be repeated restricted to subjects with oocytes retrieved and 
to subjects undergoing blastocyst transfer. 
Missing data for the primary endpoint is expected to be limited due to the trial design, but may occur if 
the subject is lost to follow-up before ongoing pregnancy is assessed. If one or more such subjects have 
a positive pregnancy test result (βhCG test, clinical pregnancy or vital pregnancy) prior to lost to 
follow-up, the impact of imputing the ongoing pregnancy will be investigated in a sensitivity analysis. 
 

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Subgroup Displays 
The primary endpoint will also be displayed by the following subgroups: 
• Primary reason for infertility (unexplained infertility, tubal infertility, male factor, 
endometriosis stage I/II, other) 
• Method of insemination (IVF, ICSI, IVF/ICSI) 
• Age (18-24, 25-29, 30-34 years)  
• Body weight (≤75, >75 kg) 
• AMH on stimulation day 1 (<7.5, 7.5-<15, 15-<25, ≥25 pmol/L) 
• Center 
 
For each subgroup factor, descriptive statistics for the cumulative ongoing pregnancy rate will be 
presented by subgroup level and treatment group. These subgroup displays will be prepared for the 
mITT and PP analysis sets. 
 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed based on the mITT analysis set. As specified below, for 
selected endpoints, analyses will be repeated on the PP analysis set. 
 
9.7.3.1 
Ongoing Pregnancy Rate 
The ongoing pregnancy rate will be calculated for the fresh cycle, for each cryopreserved cycle, and for 
cryopreserved cycles cumulatively based on both the total number of subjects in the treatment group 
and the total number of subjects who started the respective cycle. For subjects with an ongoing 
pregnancy, the number of intrauterine viable fetuses will be tabulated. Analyses similar to that used for 
the primary endpoint will be applied as applicable and will be applied to both the mITT and PP 
analysis sets. 
 
9.7.3.2 
Time to Ongoing Pregnancy  
For subjects who achieve ongoing pregnancy following a fresh or cryopreserved transfer, time to 
ongoing pregnancy across the fresh and cryopreserved cycles will be calculated as the number of days 
from the start of controlled ovarian stimulation to the visit confirming ongoing pregnancy, as well as 
the number of cycles until ongoing pregnancy is achieved. Descriptive statistics will be presented by 
treatment group, and will be applied to both the mITT and PP analysis sets. 
 

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9.7.3.3 
Ongoing Implantation Rate 
The ongoing implantation rate will be calculated for the fresh cycle, for each cryopreserved cycle, 
cumulatively for the cryopreserved cycles, and cumulatively across the fresh and cryopreserved cycles 
for subjects with at least one transferred blastocyst in the applicable cycles. For subjects where the 
number of viable fetuses 8-9 weeks after transfer is greater than the number of blastocysts transferred, 
the number of viable fetuses will be set to the number of blastocyst transferred in the analysis. 
Descriptive statistics will be presented by treatment group and the two treatment groups will be 
compared using the nonparametric Wilcoxon rank-sum test as applicable. The analyses will be applied 
to both the mITT and PP analysis sets. 
 
9.7.3.4 
Clinical Pregnancy Rate 
The clinical pregnancy rate will be calculated for the fresh cycle, for each cryopreserved cycle, 
cumulatively for the cryopreserved cycles, and cumulatively across the fresh and cryopreserved cycles 
based on both the total number of subjects in the treatment group and the total number of subjects who 
started the respective cycle. The analyses will be conducted in a similar manner as ongoing pregnancy 
rate and will be applied to both the mITT and PP analysis sets. For subjects with clinical pregnancy, 
the type of clinical pregnancy (intrauterine or ectopic) will be tabulated. 
 
9.7.3.5 
Vital Pregnancy Rate  
The vital pregnancy rate will be calculated and analyzed in a similar manner as ongoing pregnancy rate 
and will be applied to both the mITT and PP analysis sets. 
 
9.7.3.6 
Implantation Rate 
The implantation rate will be calculated and analyzed in a similar manner as ongoing implantation rate 
and will be applied to both the mITT and PP analysis sets. 
 
9.7.3.7 
Positive βhCG Rate 
The positive βhCG rate will be calculated and analyzed in a similar manner as ongoing pregnancy rate 
and will be applied to both the mITT and PP analysis sets. 
 

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9.7.3.8 
Triggering of Final Follicular Maturation, Cycle Cancellation and Transfer 
Cancellation 
The proportion of subjects with triggering of final follicular maturation will be tabulated by triggering 
drug (hCG, GnRH agonist) and in total. The proportion of subjects with cycle cancellation or transfer 
cancellation in the cycle will also be tabulated, including the reasons. 
 
9.7.3.9 
Number and Size of Follicles during Stimulation 
The follicle cohort on stimulation day 5 and end-of-stimulation will be summarized by treatment on the 
follicle level (number of follicles 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and ≥17 mm) and on the 
subject level (total number of follicles, size of largest follicle, average follicle size, average size of 
three largest follicles, and number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and ≥17 mm). 
Continuous data will be compared between treatment groups using Wilcoxon’s test. Categorical data 
will be compared between treatment groups using the chi-square test or Fisher’s exact test in case of 
sparse data. The analyses will be applied to both the mITT and PP analysis sets. 
 
9.7.3.10 
Number and Distribution of Oocytes Retrieved 
The number of oocytes retrieved will be tabulated including summary statistics. Furthermore, a 
frequency table with subjects grouped according to number of oocytes retrieved will be prepared using 
these categories: <4, 4-7, 8-14, 15-19 and ≥20 oocytes. Subjects with cycle cancellation due to poor 
ovarian response will be included in the <4 oocytes group. Continuous data will be compared between 
treatment groups using Wilcoxon’s test. Categorical data will be compared between treatment groups 
using the chi-square test or Fisher’s exact test in case of sparse data. The analyses will be applied to 
both the mITT and PP analysis sets. 
 
9.7.3.11 
Number of Metaphase II Oocytes 
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The number of 
metaphase II (MII) oocytes per subject will be tabulated including both summary statistics and a 
frequency table. Furthermore, the percentage of MII oocytes to oocytes retrieved for subjects where all 
oocytes are inseminated using ICSI will be tabulated. Continuous data will be compared between 
treatment groups using Wilcoxon’s test. Categorical data will be compared between treatment groups 
using the chi-square test or Fisher’s exact test in case of sparse data. The analyses will be applied to 
both the mITT and PP analysis sets. 
 

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9.7.3.12 
Number of Fertilized Oocytes and Fertilization Rate 
An oocyte is defined as fertilized if it is scored as 2PN at 19h (±2h). The number of fertilized oocytes 
per subject will be tabulated including both summary statistics and a frequency table. Furthermore, for 
subjects with oocytes retrieved, the rate of fertilized oocytes to oocytes retrieved (and also the rate of 
fertilized oocytes to metaphase II oocytes for those inseminated using ICSI) will be tabulated overall 
and by method of insemination. Continuous data will be compared between treatment groups using 
Wilcoxon’s test as applicable. Categorical data will be compared between treatment groups using the 
chi-square test or Fisher’s exact test in case of sparse data. The analyses will be applied to both the 
mITT and PP analysis sets. 
 
9.7.3.13 
Number and Quality of Blastocysts on Day 5 
The number of blastocysts on day 5 including a breakdown in quality scores will be tabulated including 
both summary statistics and frequency tables. Tables will be produced overall and by method of 
insemination. The percentage of subjects with at least one good-quality blastocyst, i.e. of grade 3BB or 
abovef, will be reported. Further, for subjects with oocytes retrieved, the rate of blastocysts to oocytes 
retrieved will be summarized overall and by quality score. Continuous data will be compared between 
treatment groups using Wilcoxon’s test. Categorical data will be compared between treatment groups 
using the chi-square test or Fisher’s exact test in case of sparse data. The analyses will be applied to 
both the mITT and PP analysis sets. 
 
9.7.3.14 
Endometrial Thickness and Echogenicity Pattern 
Endometrial thickness on stimulation day 5 and at end-of-stimulation will be tabulated including 
summary statistics. Endometrial echogenicity pattern on stimulation day 5 and at end-of-stimulation 
will be tabulated. Continuous data will be compared between treatment groups using Wilcoxon’s test. 
Categorical data will be compared between treatment groups using the chi-square test or Fisher’s exact 
test in case of sparse data. The analyses will be applied to both the mITT and PP analysis sets. 
 
9.7.3.15 
Oocyte Utilization Rate and Oocyte Efficiency Index 
The oocyte utilization rate (number of blastocysts transferred or cryopreserved divided by the number 
of oocytes retrieved) will be analyzed in a similar manner as ongoing implantation rate and will be 
applied to both the mITT and PP analysis sets.  
 
f  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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The oocyte efficiency index (cumulative number of ongoing pregnancies per oocyte retrieved) will be 
analyzed in a similar manner as ongoing implantation rate and will be applied to both the mITT and PP 
analysis sets. 
 
9.7.3.16 
Blastocyst Survival and Re-expansion after Cryopreservation 
The number and percentage of blastocysts surviving cryopreservation will be tabulated. Further, among 
the blastocysts that survived cryopreservation, the number and percentage of blastocysts with re-
expansion will be tabulated.  
 
9.7.3.17 
Number of Cryopreserved Cycles 
The number of cryopreserved cycles initiated (i.e. cycles with subjects starting estradiol treatment), as 
well as the number and percentage of cryopreserved cycles with blastocyst transfer will be tabulated. 
Further, the total number of blastocysts transferred in fresh and cryopreserved cycles will be tabulated.  
 
9.7.3.18 
Circulating Levels of Endocrine Parameters 
Blood samples drawn on stimulation day 1, stimulation day 5, end-of-stimulation, and oocyte retrieval 
will be analyzed for AMH, FSH, LH, estradiol, progesterone, inhibin A and inhibin B. Values below 
the lower limit of quantification (LLOQ) will be included as LLOQ/2. Values above the upper limit of 
quantification (ULOQ) will be included as ULOQ.  
Each endocrine parameter and the change from baseline for post-baseline measurements will be 
tabulated for stimulation day 1 (baseline), stimulation day 5, end-of-stimulation and oocyte retrieval. 
For each parameter the change from baseline will be compared between treatment groups using a log-
normal model. In this model change from baseline in log-transformed measurements will be the 
dependent variable and the linear predictor will include treatment as factor and baseline measurement 
(log-transformed) as covariate. The estimated treatment difference with 95% confidence interval will 
be presented on the original scale of measurement (i.e. exp-transformation applied to the log-
transformed measurement) and accompanied by the p-value for test of no treatment difference. 
Further, a population pharmacokinetic model will be used for evaluating the effects of subject 
characteristics on FSH concentrations and for assessing the variability in exposure. The modelling 
analysis will be described in a modelling analysis plan and the results reported separately from the 
clinical trial report. 
 

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9.7.3.19 
Total Gonadotropin Dose, Number of Stimulation Days, and Number of Dose 
Adjustments 
The total gonadotropin dose will be tabulated by treatment group. For the placebo group, both the 
actual total dose administered and the intended total dose (i.e. the sum of the dialed doses recorded by 
the subject) will be presented. In addition, the average daily dose, i.e. the total dose divided by the 
number of stimulation days, will be tabulated by treatment group. 
The number of stimulation days will be tabulated by treatment group. 
Investigator-requested decreases and increases of the gonadotropin dose will be captured during the 
stimulation period. The requested dose change (decrease / increase / no change) on stimulation day 5 
will be tabulated. Furthermore, the total number of dose increase requests and dose decrease requests 
per subject will be tabulated. 
These tables will be produced for all subjects who started stimulation, and for subjects who underwent 
triggering of final follicular maturation as well as separately according to whether triggering was done 
with hCG or GnRH agonist. 
 
9.8 
Safety Endpoints Assessments 
 
General Considerations 
Analyses for the safety analysis set will be conducted according to the actual treatment received. 
Data will be presented by summary tables and listings. Categorical data will be summarized by 
treatment using the number and percentage of subjects in each category. For calculation of percentages, 
the denominator will be the total number of subjects in the respective treatment group in the safety 
analysis set. Continuous data will be summarized by treatment using number, mean, standard 
deviation, median, minimum, and maximum. 
All individual subject data will be listed per subject and treatment as observed including any derived 
values. 
 
Missing Data 
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome of 
adverse events. A worst-case approach will be used: if causality is missing, the adverse event will be 
regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse event will be 
regarded as severe; if seriousness is missing, the adverse event will be regarded as serious; if outcome 

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is missing, and no date of outcome is present, the outcome is regarded as ‘ongoing’. 
 
 
Secondary Safety Endpoints 
9.8.2.1 
Adverse Events 
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. Adverse 
events will be grouped according to start of IMP as follows: 
• Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent and 
before start of IMP, or a pre-existing medical condition that worsens in intensity after signed 
informed consent but before start of IMP. 
• Treatment-emergent adverse event in the fresh cycle, i.e. any adverse event occurring after start 
of IMP and before the end-of-cycle visit, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after start of IMP and before the end-of-cycle visit. 
• Adverse events in cryopreserved cycles, i.e. any adverse event occurring after initiation of a 
cryopreserved cycle and before the end-of-cycle visit, or a pre-existing medical condition that 
worsens in intensity after initiation of a cryopreserved cycle and before the end-of-cycle visit. 
 
Treatment-emergent adverse events and adverse events in cryopreserved cycles will be presented in 
summary tables and listings. Pre-treatment adverse events will be presented in a listing only. 
A treatment-emergent adverse event overview table will be prepared including the number of subjects 
reporting an adverse event, the percentage of subjects with an adverse event, and the number of events 
reported, for the following categories: all adverse events, severe adverse events, adverse reactions, 
adverse events leading to discontinuation, SAEs and deaths. An adverse reaction is an adverse event 
judged by the investigator to be related to IMP with a reasonable possibility. 
Treatment-emergent adverse events will be tabulated by system organ class alphabetically and PT in 
decreasing order of frequency. The following will be presented: number of subjects reporting an 
adverse event, the percentage of subjects with an adverse event, and the number of events reported. 
Summary tables will be produced for the following: all treatment-emergent adverse events, treatment-
emergent adverse events by causality (reasonable possibility / no reasonable possibility), treatment-
emergent adverse events leading to death, adverse events by intensity (mild / moderate / severe), 
treatment-emergent adverse reactions by intensity (mild / moderate / severe), serious treatment-
emergent adverse events, treatment-emergent adverse events leading to discontinuation, treatment-
emergent adverse events with an incidence of ≥5% in any treatment group, and non-serious treatment-
emergent adverse events with an incidence of ≥5% in any treatment group.  

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Similar displays will be prepared for the adverse events in cryopreserved cycles. 
 
9.8.2.2 
Clinical Chemistry and Hematology Parameters 
The circulating levels of clinical chemistry and hematology parameters including change from baseline 
will be tabulated for each time-point for each laboratory variable.  
Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-cycle 
values, using a categorization of low, normal and high values at each visit. Low, normal and high will 
be defined according to the reference ranges provided by the central laboratory. 
A summary table will be prepared displaying the proportion of subjects who have at least one markedly 
abnormal value. The table will also include a break-down by classification of the baseline value. 
Markedly abnormal criteria for the safety laboratory variables will be specified in the SAP.  
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged. 
 
9.8.2.3 
Injection Site Reactions  
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
and number of subjects experiencing those events will be tabulated by time (immediately, 30 minutes, 
24 hours), reaction type and intensity (none, mild, moderate and severe). 
 
9.8.2.4 
Treatment-induced Anti-FSH Antibodies 
The proportion of subjects with treatment-induced anti-FSH antibodies as well as the proportion of 
subjects with treatment-induced anti-FSH antibodies with neutralizing capacity will be tabulated. 
Furthermore, all assessments of anti-FSH antibodies will be listed for subjects with a positive result in 
assay 2.  
 
9.8.2.5 
Immune-related Adverse Events 
Potential immune-related adverse events will be tabulated using the SMQs, PTs and HLTs mentioned 
in section 7.2.5. 
 

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9.8.2.6 
Cycle Cancellations due to an Adverse Event, including Immune-related Adverse 
Events, or due to Technical Malfunctions of the Administration Pen
 
A summary table will be prepared showing the proportion of subjects with cycle cancellations in the 
fresh cycle including reason for cancellation. 
 
9.8.2.7 
Ovarian Hyperstimulation Syndrome 
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe) and grade 
(1, 2, 3, 4, 5). The tabulation will also include the total incidence of OHSS and the incidence of 
moderate/severe OHSS. OHSS will be presented overall and by timing (early, late, and early and late 
combined). Separate tabulations will be made for the fresh and the cryopreserved cycles. 
 
9.8.2.8 
Hospitalization and Paracentesis due to Ovarian Hyperstimulation Syndrome 
The number and percentage of subjects hospitalized due to OHSS as well as the number and 
percentage of subjects who underwent paracentesis due to OHSS will be tabulated. Separate 
tabulations will be made for the fresh and the cryopreserved cycles. 
 
9.8.2.9 
Multi-fetal Gestation, Biochemical Pregnancy, Spontaneous Abortion, Ectopic 
Pregnancy and Vanishing Twins 
Summary tables will be prepared for these endpoints. Separate tabulations will be made for the fresh 
and the cryopreserved cycles. 
 
9.8.2.10 
Technical Malfunctions of the Administration Pen 
The frequency of technical malfunctions of the administration pen will be presented in a summary 
table. 
 
9.9 
Additional Safety Evaluations 
Vital Signs 
Vital signs and their change from stimulation day 1 (baseline) to end-of-cycle will be summarized. 
Shift tables will be prepared to compare the baseline values with the end-of-cycle values using the 
categorization of low, normal and high values. Low, normal and high values will be specified in the 
SAP. All vital signs values will be listed per subject. Values outside the reference range will be 
flagged. 
 

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Physical Examination 
Physical examination at end-of-cycle in the fresh cycle compared to screening will be summarized in 
shift tables and all subjects with any abnormal finding will be listed per subject. For each 
cryopreserved cycle, physical examination at end-of-cycle in the cryopreserved cycle compared to 
cycle initiation in the respective cycle will be summarized in shift tables and all subjects with any 
abnormal finding will be listed per subject.  
 
Gynecological Examination 
Gynecological examination at end-of-cycle in the fresh cycle compared to screening will be 
summarized in shift tables and all subjects with any abnormal finding will be listed per subject. For 
each cryopreserved cycle, gynecological examination at end-of-cycle in the cryopreserved cycle 
compared to cycle initiation in the respective cycle will be summarized in shift tables and all subjects 
with any abnormal finding will be listed per subject. 
 
9.10 
Post-trial Activities 
 
Post-trial Endpoints  
9.10.1.1 
Cumulative Live Birth Rate 
The live birth rate will be calculated cumulatively across the fresh and cryopreserved cycles. Subjects 
with no information on live birth will be defaulted to a negative response. Descriptive statistics will be 
presented by treatment group. 
 
9.10.1.2 
Live Birth Rate 
The live birth rate will be calculated for the fresh cycle, for each cryopreserved cycle, and cumulatively 
for the cryopreserved cycles. Subjects with no information on live birth will be defaulted to a negative 
response. Descriptive statistics will be presented by treatment group. 
 
9.10.1.3 
Live Birth Rate of Singletons Born at Term 
The live birth rate of singletons born at term will be calculated for the fresh cycle, for each 
cryopreserved cycle, cumulatively for the cryopreserved cycles, and cumulatively across the fresh and 
cryopreserved cycles. Subjects with no information on live birth will be defaulted to a negative 
response. Descriptive statistics will be presented by treatment group. 
 

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9.10.1.4 
Time to Live Birth of a Singleton Born at Term 
For subjects who achieve live birth of a singleton born at term, time to live birth of a singleton born at 
term across the fresh and cryopreserved cycles will be calculated as the number of days from the start 
of controlled ovarian stimulation to delivery, as well as the number of cycles until delivery. Descriptive 
statistics will be presented by treatment group. 
 
9.10.1.5 
Minor/Major Congenital Anomalies  
The rate of minor/major congenital anomalies at birth, 4 weeks and 1 year after birth in the fresh cycle 
and cryopreserved cycles will be calculated. Descriptive statistics will be presented by treatment group. 
 
 
Other Post-trial Evaluations 
Gender, birth weight and length, and Apgar score will be tabulated. Descriptive statistics will be 
presented by treatment group. 
 
9.11 
Optional Exploratory Analyses  
Results on the potential future genome sequencing and microbial profiling will be reported separately 
from the clinical trial report. 
 
9.12 
Interim Analysis 
No interim analysis intended to compare treatment groups with respect to efficacy or safety is planned. 

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

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• Date of oocyte retrieval and number of oocytes retrieved 
• Date of transfer and number and quality of blastocysts transferred (fresh cycle + cryopreserved 
cycles)  
• Number and quality of blastocysts cryopreserved 
• Number of blastocysts thawed, number of surviving blastocysts, quality of surviving 
blastocysts (cryopreserved cycles) 
• Confirmation of LH surge (natural cryopreserved cycles) 
• Results of βhCG test and ultrasound at clinical and ongoing pregnancy visits (fresh cycle + 
cryopreserved cycles) 
• Pregnancy outcome, i.e. live birth or pregnancy loss (fresh cycle + cryopreserved cycles), and 
neonatal health at birth, 4 weeks and 1 year after birth (fresh cycle + cryopreserved cycles) 
• Injection site reactions after IMP administration – diary  
• Adverse events (description as well as start/stop date and time) (fresh cycle + cryopreserved 
cycles) 
• OHSS symptoms, investigations and treatments 
• Reason for discontinuation (fresh cycle + cryopreserved cycles) 
• Event of unblinding, including the reason for unblinding 
• Follow-up on treatment-induced anti-FSH antibody response 
 
No specific protocol data can be recorded directly in the eCRF without prior written or electronic 
record. 
If the trial sites use electronic medical record systems, the sponsor will decide if the electronic medical 
records qualify for the trial and document the decision. If the electronic medical records system does 
not qualify for the trial, it may be considered to utilize paper data sheets for source data as an 
exception. 
The source data for the endocrine parameters, clinical chemistry and hematology parameters as well as 
anti-FSH antibodies will be available at the central laboratory. Laboratory reports will be available at 
the sites for clinical chemistry and hematology parameters. 
 

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10.2 
eCRF 
An eCRF system provided by an independent third-party contract research organization (CRO) will be 
used for data capture. The system is validated and access at all levels to the system is granted/revoked 
following Ferring and vendor procedures, in accordance with regulatory and system requirements. 
Trial data should be entered into the eCRF in a timely manner. The time-frame will be specified in the 
investigator agreement. 
The investigator will approve/authorize the eCRF entries for each subject, with an electronic signature 
which is equivalent to a handwritten signature.  
The eCRF system and the database will be hosted at the independent third party CRO. After the trial 
database is declared clean and released to the statistician, a final copy of the database will be stored at 
Ferring. The investigator will also receive a copy of the trial site’s final and locked data (including 
audit trail, electronic signature and queries) as write-protected PDF-files produced by the independent 
third party CRO. The PDF-files will be stored in an electronic format and will be provided to the 
investigator before access to the eCRF is revoked. 
Entry errors occurring in the eCRF 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, cleaning and validation. 
The data management plan will also include information about the intended use of computerized 
systems, a description of the security measures employed to protect the data, and a description of the 
electronic data flow. 
 
10.4 
Provision of Additional Information 
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements. 

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11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of eCRF entries compared to source data, verification of drug 
accountability and compliance to safety reporting instructions.  
The investigator will permit the monitor direct access to all source data, including electronic medical 
records, and/or documents in order to facilitate data verification. The investigator will co-operate with 
the monitor to ensure that any discrepancies that may be identified are resolved. The investigator is 
expected to be able to meet the monitor during these visits. 
When the first subject is randomized at the trial site, a monitoring visit will take place shortly 
afterwards. For this trial, the frequency of the monitoring visits per site will be determined by the 
enrolment rate, observed data quality, overall site performance and will be detailed in the Monitoring 
Plan. 
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 IRBs who may audit/inspect the trial. 
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki and all other relevant regulations. 
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorized Ferring representatives and representatives from regulatory authorities and 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/randomization number 
will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by a regulatory authority or 
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 eCRF 
or any other documents submitted to Ferring, the subjects will not be identified by their names, but by 
an identification system, which consists of an assigned number in the trial. Documents that are not for 
submission to Ferring, e.g. the confidential subject identification code and the signed Informed 
Consent Documents, will be maintained by the investigator in strict confidence. 

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12 
CHANGES IN THE CONDUCT OF THE TRIAL 
12.1 
Protocol Amendments 
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and, if 
applicable, agreed upon by the investigator and Ferring prior to its implementation. Amendments may 
be submitted for consideration to the approving IRBs and FDA, in accordance with U.S. regulations. 
Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be implemented prior to 
IRBs approval/favorable 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 eCRF, 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 the Trial Master File. 
 
12.3 
Premature Trial Termination 
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate the 
trial at any time. Should this become necessary, the procedures will be agreed upon after consultation 
between the two parties. In terminating the trial, Ferring and the investigator will ensure that adequate 
consideration is given to the protection of the best interests of the subjects. The appropriate authorities 
and 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. Furthermore, the data 
and information collected during the post-trial follow-up activities will be reported in clinical trial 
report addendums, including live birth, neonatal health at birth, 4 weeks and 1 year after birth in the 
fresh cycle and the cryopreserved cycles, respectively. 
 
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 
 
Publication Policy 
At the end of the trial, one or more manuscripts for joint publication may be prepared in collaboration 
between the investigator(s) offered authorship and Ferring. In a multi-site trial based on the 
collaboration of many sites, any publication of results must acknowledge all sites. Results from multi-
site trials must be reported in entirety in a responsible and coherent manner and results from subsets 
should not be published in advance or without clear reference to the primary publication of the entire 
trial. 
Authorship is granted based on the 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 external CRO or laboratory involved in the conduct of this trial has no publication rights regarding 
this trial. 
If the investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to Ferring for comments prior to submission. 
Comments will be given within four weeks from receipt of the draft manuscript. This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application is 

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published. Under such conditions the publication will be modified or delayed at the investigator’s 
discretion, to allow sufficient time for Ferring to seek patent protection of the invention. 
 
 
Public Disclosure Policy  
ICMJE member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials will be registered in a public, clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate public registry, i.e. 
www.ClinicalTrials.gov; a website maintained by the National Library of Medicine (NLM) at the U.S. 
National Institutes of Health (NIH). Trial registration may occur in other registries in accordance with 
U.S. regulatory requirements. A summary of the trial results is made publicly available in accordance 
with U.S. regulatory requirements. 

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14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Institutional Review Board (IRB) 
An IRB will review the protocol and any amendments and advertisements used for recruitment. The 
IRB will review the Subject Information Sheet and the Informed Consent Form, their updates (if any), 
and any written materials given to the subjects. A list of all 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 Authority Notification 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical approvals must be obtained 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 last patient last visit (LPLV), i.e. when the last subject 
completes the last end-of-cycle visit in a cryopreserved cycle. This date is also the primary completion 
date. 
Post-trial follow-up will cover the period from LPLV to the end of the 1-year follow-up of the 
neonates. 
The IRBs will be notified about the completion of the clinical trial and the post-trial follow-up 
according to local legislation.  
In the case of early termination for safety reasons, Ferring will notify the relevant authorities and IRBs 
about the end of the trial as soon as possible, clearly explain the reasons, and describe follow-up 
measures, if any. 
 
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 Helsinki37, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
 
14.5 
Subject Information and Consent 
This trial will use three sets of Informed Consent Documents (consisting of Subject Information and 
Informed Consent Form): one covering trial participation, one covering potential future genome 

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sequencing and microbial profiling, and one covering data collection on the neonate. The latter two 
documents will only describe the aspects relevant to the exploratory analyses or to the neonate and 
should be read in conjunction with the Informed Consent Document for the general trial. Participation 
in the investigation of exploratory analyses is optional.  
 
Informed Consent Documents regarding Participation in the Trial – Subject 
The investigator (or the person delegated by the investigator) will obtain a freely given written consent 
from each subject after an appropriate explanation of the aims, methods, sources of funding, any 
possible conflicts of interest, anticipated benefits, potential risks of the trial and the discomfort it may 
entail, post-trial provisions and any other aspects of the trial which are relevant to the subject’s 
decision to participate. The trial subject must be given ample time to consider participation in the trial, 
before the consent is obtained. The Informed Consent Documents 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. Subjects must be given the option of being informed about the general 
outcome and the results of the trial. 
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 Subject Information and her signed Informed Consent Form. 
If new important information becomes available that may be relevant to the trial subject’s willingness 
to continue participation in the trial, a new Subject Information and Informed Consent Form will be 
forwarded to the IRBs (and FDA, 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, 
IRB representatives or FDA inspector(s), in accordance with applicable regulatory requirements, may 
review her source records and data. Data protection will be handled in compliance with U.S. and EU 
regulations. 
 
Informed Consent Documents regarding Exploratory Analyses – Subject (Optional) 
The investigator (or the person delegated by the investigator) will obtain a freely given written consent 
from the subject after an appropriate explanation of the potential future genome sequencing and 
microbial profiling and after information that participation in these exploratory analyses is optional. 

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The trial subject must be given ample time to consider participation in these exploratory analyses, 
before the consent is obtained. The Informed Consent Documents 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 exploratory analyses, before any associated samples are collected.  
The investigator (or the person delegated by the investigator) will explain that the subject is completely 
free to refuse to consent to these exploratory analyses or to withdraw consent 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 Subject Information and her signed Informed Consent Form. 
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by Ferring, 
IRB representatives or FDA inspector(s), in accordance with applicable regulatory requirements, may 
review her source records and data. Data protection will be handled in compliance with U.S. and EU 
regulations. 
 
Informed Consent Documents regarding Data Collection on the Neonate – Parental Consent 
A separate Subject Information and Informed Consent Form is required to collect pregnancy outcome 
data on the neonate and the investigator (or the person delegated by the investigator) will obtain a 
freely given written consent from the child-custody holders, i.e. the subject and the subject’s partner in 
case of joint custody. The child-custody holders must be given ample time before the consent is 
obtained. The Informed Consent Documents must be signed and dated by the child-custody holders 
and the investigator, or the person delegated by the investigator, who has provided information to the 
child-custody holders. Written consent by the child-custody holders regarding collection of pregnancy 
outcome data on the neonate must be obtained before the subject is randomized and preferably at the 
time of obtaining written consent by the subject regarding participation in the trial. 
The investigator (or the person delegated by the investigator) will explain that the child-custody 
holders are completely free to refuse to consent to this data collection or to withdraw consent at any 
time, without any consequences and without the need to justify their decision.  
The child-custody holders will receive a copy of the Subject Information and their signed Informed 
Consent Form. 
The child-custody holders will be informed that the monitor(s), quality assurance auditor(s) mandated 
by Ferring, ethics committee representatives or FDA inspector(s), in accordance with applicable 
regulatory requirements, may review the neonate’s source records and data. Data protection will be 
handled in compliance with U.S. and EU regulations. 
 

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14.6 
Subject Participation Card 
The subject will be provided with a Subject Participation Card bearing the following information: 
• That she is participating in a clinical trial. 
• That the trial involves controlled ovarian stimulation, and the subject receives/has received 
either a recombinant FSH under clinical development in the U.S., or placebo. 
• The name and phone number of the investigator. 
• The name, address and phone number of Ferring contact (as required by local regulations). 
 
The subjects will be asked to keep the Subject Participation Card in their possession at all times during 
the trial and to return it at the last trial visit. 
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 
Checklist for Pregnancy Follow-up 
In addition to the trial participation card, the subject will be provided with a checklist for pregnancy 
follow-up, where the subject will be reminded to report the following information to the investigator: 
At delivery: 
• Date of delivery  
• Way of delivery (vaginal / vacuum extraction / forceps / caesarean section) 
• Position of neonate (head / breech / transverse / other – please specify) 
• Gender 
• Birth weight 
• Birth length 
• Apgar score after 1 and 5 minutes 
• Admission to NICU regardless of duration  
• Admission to NCU for more than 2 hours 
• Any medically important event  
• Congenital anomaly  
• Neonatal death 
 

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4 weeks after delivery:  
Relevant important conditions since birth: 
• Admission to NICU regardless of duration  
• Admission to NCU for more than 2 hours  
• Any medically important event  
• Any congenital anomaly discovered since birth 
• Neonatal death 
 
1 year after delivery: 
Relevant important conditions since the 4-weeks follow-up: 
• Admission to NICU regardless of duration  
• Admission to NCU/PCU for more than 2 hours 
• Any medically important event  
• Any congenital anomaly discovered since the 4-weeks follow-up 
• Death of infant 
 
14.8 
Compliance Reference Documents 
The Helsinki Declaration, the consolidated ICH-GCP and other national law(s) in the U.S. 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 U.S. The investigator is 
responsible for adhering to the ICH-GCP responsibilities of investigators, for dispensing the IMP in 
accordance with the approved protocol or an approved amendment, and for its secure storage and safe 
handling throughout the trial. 
 
15.2 
Liabilities and Insurance 
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, as 
required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial. 

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

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17 
REFERENCES 
 
1 
Nyboe Andersen A, Nelson SM, Fauser BCJM, Garcia-Velasco JA, Klein BM, Arce J-C. 
Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, 
randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril 2017; 107: 
387-396. 
2 
Buur Rasmussen B, Mannaerts B, Klein BM, Helmgaard L, Arce J-C on behalf of the 
ESTHER-1 and ESTHER-2 trial group. Low immunogenicity potential of follitropin delta, a 
recombinant FSH preparation produced from a human cell line: Results from phase 3 trials 
(ESTHER-1 and ESTHER-2). Hum Reprod 2016; 31 (Suppl.1). 
3  
FE 999049 Investigator’s Brochure, Ferring Pharmaceuticals, current edition. 
4 
Loutradi KE, Kolibianakis EM, Venetis CA, Papanikolaou EG, Pados G, Bontis I, Tarlatzis BZ. 
Cryopreservation of human embryos by vitrification or slow freezing: a systematic review and 
meta-analysis. Fertil Steril 2008; 90: 186-193. 
5 
Kolibianakis EM, Venetis CA, Tarlatzis BC. Cryopreservation of human embryos by 
vitrification or slow freezing: which one is better? Curr Opin Obstet Gynecol 2009; 21: 270-
274.  
6 
Zhu D, Zhang J, Cao S, Heng BC, Huang M, Ling X, Duan T, Tong GQ. Vitrified-warmed 
blastocyst transfer cycles yield higher pregnancy and implantation rates compared with fresh 
blastocyst transfer cycles - time for a new embryo transfer strategy? Fertil Steril 2011; 95:1691-
1695. 
7 
Feng G, Zhang B, Zhou H, Shu J, Gan X, Wu F, Deng X. Comparable clinical outcomes and 
live births after single vitrified-warmed and fresh blastocyst transfer. Reprod Biomed Online 
2012; 25: 466-473. 
8 
2011 CDC ART National Summary Report 
https://www.cdc.gov/art/ART2011/PDFs/ART_2011_National_Summary_Report.pdf. 
Accessed on 19 April 2018. 
9 
2015 CDC ART National Summary Report 
https://www.cdc.gov/art/pdf/2015-report/ART-2015-National-Summary-Report.pdf. Accessed 
on 19 April 2018. 
10 
Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian 
hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering 
of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in 
combination with a "freeze-all" strategy: a prospective multicentric study. Fertil Steril 2011; 95: 
2029-2033. 
11 
Glujovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo 
transfer in assisted reproductive technology. Cochrane Database Syst Rev 2012; 11. 

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12 
Papanikolaou EG, Kolibianakis EM, Tournaye H, Venetis CA, Fatemi H, Tarlatzis B, Devroey 
P. Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in 
IVF. A systematic review and meta-analysis. Hum Reprod 2008; 23: 91-99. 
13 
Practice Committee of the Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Guidance on the limits to the 
number of embryos to transfer: a committee opinion. Fertil Steril 2017; 107: 901-903. 
14 
Rehman KS, Bukulmez O, Langley M, Carr BR, Nackley AC, Doody KM, Doody KJ. Late 
stages of embryo progression are a much better predictor of clinical pregnancy than early 
cleavage in intracytoplasmic sperm injection and in vitro fertilization cycles with blastocyst-
stage transfer. Fertil Steril 2007; 87: 1041-1052. 
15 
Food and Drug Administration (FDA). Guidance for Industry: Assay development and 
validation for immunogenicity testing of therapeutic protein products. Draft, 2016. 
16  
Arce J-C, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the 
design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod 
2005; 20: 1757-1771. 
17  
Devroey P, Pellicer A, Nyboe Andersen A, Arce J-C on behalf of the Menopur in GnRH 
Antagonist Cycles with Single Embryo Transfer (MEGASET) Trial Group. A randomized 
assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH 
antagonist cycle with compulsory single-blastocyst transfer. Fertil Steril 2012; 97: 561-571. 
18  
Arce J-C, Nyboe Andersen A, Fernández-Sánchez M, Visnova H, Bosch E, García-Velasco JA, 
Barri P, de Sutter P, Klein BM, Fauser BC. Ovarian response to recombinant human follicle-
stimulating hormone: a randomized, anti-Müllerian hormone-stratified, dose-response trial in 
women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2014; 
102: 1633-1640. 
19  
Understanding the SART Clinic Report 
http://www.sart.org/patients/fyi-videos/understanding-the-sart-clinic-report/. Accessed on 
19 April 2018 
20 
Practice Committee of the American Society for Reproductive Medicine. Prevention and 
treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril 
2016; 106: 1634-1647. 
21 
Sousa M, Cunha M, Teixeira da Silva J, Oliveira C, Silva J, Viana P, Barros A. Ovarian 
hyperstimulation syndrome: a clinical report on 4894 consecutive ART treatment cycles. 
Reprod Biol Endocrinol 2015; 13: 66. 
22 
Johnson MD, Williams SL, Seager CK, Liu JH, Barker NM, Hurd WW. Relationship between 
human chorionic gonadotropin serum levels and the risk of ovarian hyperstimulation syndrome. 
Gynecol Endocrinol 2014; 30: 294–297. 

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23 
Danninger B, Brunner M, Obruca A, Feichtinger W. Prediction of ovarian hyperstimulation 
syndrome by ultrasound volumetric assessment [corrected] of baseline ovarian volume prior to 
stimulation. Hum Reprod 1996; 11: 1597–1599. 
24 
Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, Yang YS, Lee MS. Serum anti-
Müllerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in 
assisted reproduction technology cycles. Hum Reprod 2008; 23: 160–167. 
25 
Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, van Hooren HG. 
Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after 
cotreatment with GnRH antagonist Ganirelix during ovarian hyperstimulation for in vitro 
fertilization. J Clin Endocrinol Metab 2002; 87: 709-715. 
26 
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. 
27 
Engmann L, Siano L, Schmidt D, Nulsen J, Maier D, Benediva C. GnRH agonist to induce 
oocyte maturation during IVF in patients at high risk of OHSS. Reprod Biomed Online 2006; 
13: 639-644. 
28  
Practice Committee of the Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: 
a committee opinion. Fertil Steril. 2012; 98: 591-598. 
29 
Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan 
E, van der Poel S on behalf of ICMART and WHO. The International Committee for 
Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization 
(WHO) Revised glossary on ART terminology, 2009. Hum Reprod 2009; 24: 2683-2687. 
30 
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. 
31  
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. 
32  
Food and Drug Administration (FDA). Center for Drug Evaluation and Research (CDER) and 
Center for Biologics Evaluation and Research (CBER). Reviewer Guidance: Evaluating the risk 
of drug exposure in human pregnancies. April 2005. 
 

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33  
Boostanfar R, Mannaerts B, Pang S, Fernandez M, Witjes H and Devroey P on behalf of the 
Engage investigators. A comparison of live birth rates and cumulative ongoing pregnancy rates 
between Europe and North America after ovarian stimulation with corifollitropin alfa or 
recombinant follicle-stimulating hormone. Fertil Steril 2012; 97: 1351-1358. 
34  
Jones HW, Toner JP. The infertile couple. N Eng J Med 1993; 329: 1710–1715. 
35 
Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC; 
ENGAGE Investigators. A double-blind, non-inferiority RCT comparing corifollitropin alfa 
and recombinant FSH during the first seven days of ovarian stimulation using a GnRH 
antagonist protocol. Hum Reprod 2009; 24: 3063-3072. 
36  
Rettenbacher M, Andersen AN, Garcia-Velasco JA, Sator M, Barri P, Lindenberg S, van der 
Ven K, Khalaf Y, Bentin-Ley U, Obruca A, Tews G, Schenk M, Strowitzki T, Narvekar N, 
Sator K, Imthurn B. A multi-centre phase 3 study comparing efficacy and safety of Bemfola® 
versus Gonal-f® in women undergoing ovarian stimulation for IVF. Reprod Biomed Online 
2015; 30: 504-513. 
37 
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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CLINICAL TRIAL PROTOCOL 
SUMMARY OF CHANGES #01 
 
 
 
A randomized, double-blind, placebo-controlled, parallel groups, multicenter trial 
investigating the efficacy and safety of FE 999049 in controlled ovarian stimulation in women 
aged 18-34 years undergoing assisted reproductive technology 
 
Trial 000001 
 
Recombinant FSH Investigation in the Treatment of Infertility with ART 
(RITA-1) 
 
IND Number: 
103040 
Investigational Medicinal Product: 
FE 999049, human recombinant follicle-stimulating 
hormone (rFSH), solution for subcutaneous injection 
Indication: 
Development of multiple follicles and pregnancy after 
fresh and/or cryopreserved embryo transfer in ovulatory 
women undergoing assisted reproductive technology 
(ART) 
Phase: 
3 
Name and Address of Sponsor: 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
Amendment Number: 
01 
Sites where Effective: 
All trial sites 
Date of Original Protocol: 
25 Apr 2018 
 
________________________________________________________________________________ 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. 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 authorized officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group.  

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This Protocol Amendment  
- implications for continued trial conduct -  
is issued as urgent safety measures due to COVID-19 required to protect subjects against 
immediate hazard to their health and safety and is implemented immediately  
 
 
DOCUMENT INFORMATION: 
Protocol change intended to eliminate an apparent immediate hazard to subjects. 
 
REASON FOR CHANGE TO THE CLINICAL TRIAL PROTOCOL: 
• The COVID-19 pandemic has caused extensive restrictions on the movement of local 
populations in countries worldwide and recommendations to focus health care resources on 
essential activities only. Subsequently, clinical trial participants are experiencing increased 
difficulty in attending scheduled visits and trial sites are operating at reduced capacity. 
 
• On 17 March 2020, the American Society for Reproductive Medicine (ASRM) issued a 
guidance on patient management and clinical recommendations, including: “Suspend 
initiation of new treatment cycles…. Strongly consider cancellation of all embryo transfers 
whether fresh or frozen… Continue to care for patients who are currently “in-cycle””.  
 
• On 18 March 2020, the Food and Drug Administration (FDA) issued a guidance on conduct 
of clinical trials of medicinal products during the COVID-19 pandemic, including general 
considerations for how to ensure the safety of trial participants, maintain compliance with 
GCP and minimize risks to trial integrity. 
Ferring has conducted a risk assessment, which led to this change to the clinical trial protocol. This 
document outlines the deliberations and decisions. 
 

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SUMMARY OF MAIN CHANGES TO CLINICAL TRIAL PROTOCOL: 
Recruitment to the trial has been completed and all fresh cycles have been completed up to the 
ongoing pregnancy visit. The current activities are cryopreserved cycles initiated within 12 months 
from the start of controlled ovarian stimulation as well as pregnancy follow-up to birth, 4 weeks 
and 1 year after birth in the fresh and cryopreserved cycles. 
Ferring is issuing guidance for continued trial conduct and management of subjects included in the 
trial. The table below provides guidance for how to manage the subjects according to stage in the 
trial.  
Continued trial conduct for management of subjects included in the trial  
• Cryopreserved cycles:  
o Cycles not yet initiated:  
do not initiate until this COVID-19 related temporary deferral of cryopreserved cycles 
has been lifted 
o Cycles already initiated and where transfer has not occurred: 
continue per protocol and document any deviations 
o Cycles where transfer has occurred:  
continue per protocol and document any deviations 
o Note: timelines for cryopreserved cycles will be extended by the approximate duration 
of the temporary deferral of cryopreserved cycles required by this change to the 
protocol 
• Pregnancy follow-up:  
continue per protocol and document any deviations  
 
In case subjects are prevented from attending scheduled visits, 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.  
 

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IMPLICATIONS OF CHANGE: 
The implications of these changes to the protocol are summarized below. The actions are 
considered urgent safety measures due to COVID-19 required to protect subjects against immediate 
hazard to their health and safety and are therefore implemented immediately.  
 
• Trial sites, regulatory authorities and independent research boards will be informed.  
• Subjects will be verbally informed by the investigator of potential changes to the course of 
action, as applicable for the individual subject. This will be documented in the subject’s 
medical records. 
• Protocol deviations (including deviations to the aspects described in this ‘change to 
protocol’) should be avoided whenever possible except where 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 
situation.  
• Ferring will continuously monitor the situation and will resume the trial activities as per 
protocol when it is judged that the situation allows for this. Ferring will notify sites, 
regulatory authorities and independent research boards accordingly.