Conditions: Infertility
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 373
Healthy volunteers: no

Brief summary:
To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian stimulation.

Detailed description:

Arms:
arm 1: FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days. arm 2: FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.

Interventions: intervention 1: Follitropin delta intervention 2: Follitropin beta
Intervention descriptions: intervention 1: Single daily subcutaneous administration through pre-filled injection pen intervention 2: Single daily subcutaneous injection in the abdomen

Protocol document:
Prot_000.pdf: 
Protocol 
Title of trial: 
A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial 
Assessing the Efficacy and Safety of FE 999049 in Controlled Ovarian 
Stimulation in Japanese Women Undergoing an Assisted Reproductive 
Technology Programme 
NCT number: 
NCT03228680 
Sponsor trial code: 
000273 
Date:  
16 Mar 2018 


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Clinical Trial Protocol
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CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A randomised, controlled, assessor-blind, parallel groups, multicentre trial assessing the 
efficacy and safety of FE 999049 in controlled ovarian stimulation in Japanese women 
undergoing an assisted reproductive technology programme 
Trial Code 000273
IND Number:
103,040
Investigational Medicinal Product:
FE 999049, human recombinant follicle-stimulating 
hormone, solution for subcutaneous injection
Indication:
Controlled ovarian stimulation for the development of 
multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro 
fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle
Phase:
3
Global Sponsor:
Ferring Pharmaceuticals A/S
Global Clinical R&D
Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark
Local Sponsor:
Ferring Pharmaceuticals Co., Ltd.
Toranomon 2-chome Tower, 2-3-17 Toranomon, 
Minato-ku, Tokyo 105-0001, Japan
Version
2.0 (Consolidated protocol; changes introduced with 
amendment #01 implemented)
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, assessor-blind, parallel groups, multicentre trial assessing the efficacy 
and safety of FE 999049 in controlled ovarian stimulation in Japanese women undergoing an 
assisted reproductive technology programme
SIGNATORY INVESTIGATOR
 Department of Obstetrics and Gynaecology
Saitama Medical University, Faculty of Medicine
TRIAL SITES
Approximately 15-20 sites in Japan
PLANNED TRIAL PERIOD
First patient first visit (FPFV):
Estimated Q3 2017
Last patient last visit (LPLV) / end-of-trial: Estimated Q1 2019
Pregnancy follow-up completed: 
Estimated Q4 2019
CLINICAL PHASE
3
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) developed by Ferring 
Pharmaceuticals. FE 999049 is intended for the following indication: “Controlled ovarian 
stimulation for the development of multiple follicles in women undergoing assisted reproductive 
technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle”. Ferring has received Marketing Authorisation approval from the European
Commission for FE 999049 (December 2016). 
FE 999049 is derived from a human cell line (PER.C6®). This is in contrast to other currently-
approved rFSH products for the proposed indication, such as follitropin alfa (GONAL-F, Merck
Serono Co., Ltd.) and follitropin beta (FOLLISTIM, MSD K.K.), which 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 


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CONFIDENTIAL
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.
The clinical translation of the differential glycosylation profile of FE 999049 has been reflected in 
clinical trials. Thus, daily multiple-dose administration of identical IU doses of FE 999049 and a 
CHO-derived rFSH product as determined in the rat in vivo Steelman-Pohley bioassay did not 
provide comparable pharmacokinetics (PK) and pharmacodynamics (PD), with the differential 
glycosylation profile of FE 999049 being considered the most likely cause for this finding. 
Consequently, it was considered that the rat in vivo Steelman Pohley bioassay might not fully 
reflect the potency of FE 999049 in humans, as supported by biotransformation studies in mice and 
rats and that using the protein content (µg) in combination with a consistent drug substance quality 
profile would be more appropriate for expressing doses of FE 999049 than the bioactivity 
(international units (IU)). Therefore, FE 999049 is dosed by mass (µg) rather than in IU.
A phase 1 trial conducted in healthy female Japanese volunteers demonstrated a linear, dose-
response relationship of FE 999049 with respect to exposure. Furthermore, comparisons between 
Japanese and Caucasian women indicated similar PK profile with respect to Cmax, AUC, tmax and t½.
Two randomised, controlled, assessor-blind, parallel groups, multi-centre phase 2 anti-Müllerian 
hormone (AMH)-stratified trials were conducted in IVF/ICSI patients, one in overseas IVF/ICSI 
patients and one in Japanese IVF/ICSI patients with the purpose of determining the dose-response 
relationship of FE 999049 and the number of oocytes retrieved. In both trials, a statistically 
significant dose-response relationship for FE 999049 with respect to the number of oocytes 
retrieved was observed for the overall population and for each AMH randomisation stratum (low 
AMH stratum: 5.0-14.9 pmol/L, high AMH stratum: 15.0-44.9 pmol/L). Furthermore, the observed 
dose-response profile was similar in the overseas trial and in the Japanese trial. 
The development of FE 999049 has prospectively incorporated the use of a biomarker of ovarian 
response to gonadotropins (AMH) to identify patients at higher risk of reduced efficacy or 
increased safety concern, enabling stratification according to the patients’ potential to respond to 
FE 999049. Furthermore, body weight has been shown to influence the exposure to FE 999049. 
Therefore, the posology of FE 999049 is individualised for each patient based on her body weight 
and serum AMH to obtain an ovarian response with favourable safety/efficacy profile. The outcome 
is a fixed-dose regimen supporting individualised ovarian stimulation with safe and efficient use of 
FE 999049 founded on current scientific knowledge and prospectively confirmed data.


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The efficacy and safety of the FE 999049 individualised dosing regimen based on the woman’s 
serum AMH and body weight has been confirmed in a large phase 3 trial, ESTHER-1 (Evidence-
based Stimulation Trial with Human rFSH in Europe and Rest of World), conducted in 11 countries 
overseas including Europe, North America and Latin America. The ESTHER-1 trial was conducted 
in 1,326 IVF/ICSI patients who were randomised 1:1 to controlled ovarian stimulation with one of 
the following treatments: 1) FE 999049 in its individualised dosing regimen with the daily dose 
fixed throughout stimulation, or 2) an approved CHO-derived rFSH product (follitropin alfa, 
GONAL-F) at a standard starting dose of 150 IU/day followed by dose adjustments based on the 
subject’s follicular response during stimulation. FE 999049 in its individualised dosing regimen 
was demonstrated to be non-inferior to follitropin alfa with respect to ongoing pregnancy rate 
(30.7% versus 31.6%) and ongoing implantation rate (35.2% versus 35.8%). For the overall 
population, there was no statistically significant difference between treatment groups in terms of 
number of oocytes retrieved, with an average of 10.0 for FE 999049 and 10.4 for follitropin alfa. 
Nevertheless, the individualised FE 999049 dosing regimen in comparison to follitropin alfa led to 
statistically significantly more oocytes retrieved among patients with AMH <15 pmol/L (population 
at risk of hyporesponse) with an average of 8.0 versus 7.0 and statistically significantly fewer 
oocytes among patients with AMH ≥15 pmol/L (population at risk of hyperresponse) with an 
average of 11.6 versus 13.3. The immediate clinical relevance of this shift in ovarian response with 
FE 999049 therapy was realised as statistically significantly fewer patients with extreme ovarian 
response compared to follitropin alfa, i.e. <4 oocytes among patients with AMH <15 pmol/L (12% 
versus 18%) and ≥15 or ≥20 oocytes among patients with AMH ≥15 pmol/L (28% versus 35%, and 
10% versus 16%). The percentage of patients with an appropriate ovarian response, defined for 
FE 999049 as 8-14 oocytes, was reached by statistically significantly more patients treated with 
FE 999049 compared to follitropin alfa, i.e. 43% versus 38%, despite implementation of dose 
adjustments during stimulation for 37% of the patients in the follitropin alfa group in contrast to the 
fixed-dose individualised dosing regimen for FE 999049. A statistically significantly lower total 
gonadotropin dose in the FE 999049 group compared to the CHO-derived rFSH product group was 
observed with an average of 90 µg and 104 µg, respectively. From a safety perspective, the 
individualised dosing regimen of FE 999049 was associated with a statistically significant reduction 
in the proportion of subjects with early ovarian hyperstimulation syndrome (OHSS) and/or 
preventive interventions for early OHSS in comparison to the standard regimen of CHO-derived 
rFSH product, with an incidence of 4.7% in the FE 999049 group and 6.2% in the follitropin alfa 
group.
In Japan, the only rFSH preparation approved for the pursued indication is follitropin beta 
(FOLLISTIM).
The present trial aims to establish non-inferiority of FE 999049 versus FOLLISTIM with respect to 
number of oocytes retrieved and will document the efficacy and safety of FE 999049 in Japanese 
IVF/ICSI patients.


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OBJECTIVES
Primary Objective

To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to 
number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian 
stimulation
Secondary Objectives

To compare FE 999049 with FOLLISTIM with respect to achieving pregnancy

To compare FE 999049 with FOLLISTIM with respect to ovarian response and endocrine 
profile 

To compare FE 999049 with FOLLISTIM with respect to oocyte fertilisation and number 
and quality of embryos/blastocysts 

To compare FE 999049 with FOLLISTIM with respect to the frequency of OHSS and/or
preventive interventions for early OHSS

To compare FE 999049 with FOLLISTIM with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To compare FE 999049 with FOLLISTIM with respect to gonadotropin use
ENDPOINTS
Primary Endpoint

Number of oocytes retrieved
Important Secondary Endpoint 

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
Secondary Endpoints 

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred)

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
blastocyst transfer cancellation due to excessive ovarian response / OHSS risk 

Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes 
retrieved


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
Proportion of subjects with preventive interventions for early OHSS

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Proportion of subjects with OHSS (early and/or late) and/or preventive interventions for 
early OHSS

Number and size of follicles on stimulation day 6 and end-of-stimulation

Fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on day 
5 after oocyte retrieval

Circulating concentrations of FSH, LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Total gonadotropin dose and number of stimulation days

Frequency and intensity of adverse events 

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Technical malfunctions of the administration pens
Pregnancy Follow-up Information

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer) 
and live birth rate 

Neonatal health at birth and at 4 weeks after birth
Note: Ferring intends to submit the Japanese New Drug Application (J-NDA) following completion 
of the main part of the trial (i.e. up to the clinical pregnancy visit), and to include the pregnancy 
follow-up data available at that time in the J-NDA. The pregnancy follow-up data can be submitted 
after completion.
METHODOLOGY
This will be a randomised, assessor-blind, controlled, parallel groups, multicentre trial assessing the 
efficacy and safety of FE 999049 in its individualised dosing regimen when used in first cycle 
Japanese patients aged 20-40 years undergoing controlled ovarian stimulation for IVF/ICSI 
following a gonadotropin-releasing hormone (GnRH) antagonist protocol. The trial has been 
designed to demonstrate non-inferiority of FE 999049 versus an rFSH product approved in Japan, 


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i.e. FOLLISTIM, with respect to number of oocytes retrieved. 
Subjects will be screened within 60 days prior to start of stimulation for compliance with the 
inclusion and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 
1:1 ratio to controlled ovarian stimulation with FE 999049 or FOLLISTIM. Randomisation will be 
stratified by centre and according to AMH levels at screening (<15 pmol/L and ≥15 pmol/L). 
Subjects randomised to FE 999049 will have their individual FE 999049 dose determined on the 
basis of their AMH level at screening and their body weight at start of stimulation. The daily 
FE 999049 dose will be fixed throughout the stimulation period. For subjects with 
AMH <15 pmol/L, the daily FE 999049 dose is 12 μg, irrespective of body weight. For subjects 
with AMH ≥15 pmol/L the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 
0.10 μg/kg, i.e. dependent on actual AMH and body weight. The minimum allowed daily 
FE 999049 dose is 6 μg and the maximum allowed daily FE 999049 dose is 12 μg. Subjects can be 
treated with FE 999049 for a maximum of 20 days, and coasting is not allowed. For subjects 
randomised to FOLLISTIM, the dosing regimen is within labelling. The starting dose of 
FOLLISTIM is 150 IU and fixed for the first five stimulation days after which it may be adjusted 
by 75 IU based on the individual response. The maximum daily FOLLISTIM dose allowed is 
375 IU. Subjects can be treated with FOLLISTIM for a maximum of 20 days, and coasting is not 
allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When 3 follicles of ≥15 mm are observed, visits must be 
performed daily. To prevent a premature luteinising hormone (LH) surge, a GnRH antagonist will
be initiated on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the 
stimulation period. Triggering of final follicular maturation will be done with 5,000 IU urinary 
human chorionic gonadotropin (hCG) on the day when ≥3 follicles with a diameter ≥17 mm are 
observed. In case of excessive follicular development, defined as ≥25 follicles with a diameter 
≥12 mm, the cycle should be cancelled (note: in case of 25-35 follicles with a diameter ≥12 mm, a 
GnRH agonist may be administered as triggering for final follicular maturation). In case of poor 
follicular development, defined as the investigator judging that ≥3 follicles with a diameter ≥17 mm 
cannot be reached by day 20, the cycle is to be cancelled. 
Oocyte retrieval will take place 36h (± 2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Fertilisation and embryo development will be assessed 
from oocyte retrieval to the day of transfer. One blastocyst of the best quality available will be 
transferred on day 5 after oocyte retrieval while remaining blastocysts may be cryopreserved. For 
subjects who underwent triggering of final follicular maturation with GnRH agonist, no transfer 
will take place and blastocysts may instead be cryopreserved on day 5. All cryopreserved 
blastocysts can be used by the subject after completion of the trial, in accordance with the 
declaration by Japan Society of Obstetrics and Gynaecology (JSOG).
Vaginal progesterone tablets (LUTINUS, Ferring Pharmaceuticals) 100 mg three times daily will be 


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provided for luteal phase support from the day after oocyte retrieval until the day of the clinical 
pregnancy visit. Luteal phase support will only be provided to subjects planned to undergo transfer 
and can be terminated earlier in case of no transfer or a negative βhCG test. A βhCG test is 
performed 13-15 days after transfer followed by a transvaginal ultrasound 5-6 weeks after transfer 
to assess clinical and vital pregnancy. Subjects experiencing a full menstrual bleeding following 
transfer must have the βhCG test performed 7-15 days after transfer. The βhCG test is mandatory 
for all subjects who undergo transfer, irrespective of bleeding.
Blood samples will be collected during the trial for the purpose of evaluating the endocrine profile 
as well as clinical chemistry and haematology parameters. Endocrine parameters are measured at 
screening, stimulation day 1, stimulation day 6 and end-of-stimulation. Clinical chemistry and 
haematology parameters are assessed at screening, end-of-stimulation and end-of-trial. Local 
tolerability of FE 999049 following subcutaneous administration will be assessed by the subjects 
three times daily: immediately, 30 minutes and 24 hours after the injection. The assessment of 
injection site reactions will be made throughout the stimulation period and recorded by the subjects 
in a diary. 
If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule) or cancelled, if appropriate.
Pregnancy Follow-up 
As obligatory follow-up, pregnancy progress and outcome data will be gathered for subjects with a 
vital pregnancy. Data will be collected on ongoing pregnancy (10-11 weeks after transfer) and 
pregnancy outcome as well as neonatal health at birth and at 4 weeks after birth. The pregnancy 
follow-up does not include any interventions but only data collection. The pregnancy follow-up 
data will be based on reports obtained from the subject’s gynaecologist / obstetrician and the 
subject’s Maternal and Child Health Handbook. The data will be retrieved by the trial site, either 
via the subject’s gynaecologist / obstetrician, the subject herself, or other sources, as applicable.
Ferring intends to submit the J-NDA following completion of the main part of the trial (i.e. up to 
the clinical pregnancy visit), and to include the pregnancy follow-up data available at that time in 
the J-NDA. The pregnancy follow-up data can be submitted after completion.
NUMBER OF SUBJECTS
Approximately 328 subjects will be randomised in a 1:1 ratio to FE 999049 and FOLLISTIM.
CRITERIA FOR INCLUSION / EXCLUSION
Women eligible for IVF and/or ICSI treatment, undergoing their first IVF/ICSI cycle and diagnosed 


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with tubal infertility, unexplained infertility, infertility related to endometriosis stage I/II or with 
partners diagnosed with male factor infertility, will be included in this trial. Subjects will be 
20-40 years of age, with a body mass index (BMI) of 17.5-32.0 kg/m2. 
Women with endometriosis stage III/IV, history of recurrent miscarriage or with contraindications 
to controlled ovarian stimulation with gonadotropins will be excluded from participation in this 
trial. 
The complete list of inclusion and exclusion criteria is provided below.
Inclusion Criteria
Informed Consent Documents signed prior to any trial-related procedures.
In good physical and mental health.
Japanese females between the ages of 20 and 40 years. The subjects must be at least 20 
years (including the 20th birthday) when they sign the Informed Consent Documents and no 
more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised American Society for Reproductive Medicine (ASRM)
classification) or with partners diagnosed with male factor infertility, eligible for in vitro 
fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated 
sperm from male partner.
Infertility for at least 1 year before randomisation (not applicable in case of tubal or severe 
male factor infertility).
The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
Hysterosalpingography, hysteroscopy, saline infusion sonography or transvaginal ultrasound 
documenting a uterus consistent with expected normal function (e.g. no evidence of 
clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 
3 cm in diameter, no polyps and no congenital structural abnormalities which are associated 
with a reduced chance of pregnancy) within 1 year prior to screening. This also includes 
women who have been diagnosed with any of the above medical conditions but have had 
them surgically corrected within 1 year prior to screening.
Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or 
enlarged ovaries which would contraindicate the use of gonadotropins) and fallopian tubes 
and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) 
within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to screening).
Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to screening. 
Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
Willing to accept transfer of one blastocyst. 


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Exclusion Criteria
Known endometriosis stage III-IV (defined by the revised ASRM classification).
One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound 
prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomisation is 
allowed).
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. In case the sperm production is 
severely impaired (concentration <1 million/mL), normal karyotype, including no 
Y-chromosome microdeletion, must be documented.
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of 
these events.
Known porphyria.
Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
Known inherited or acquired thrombophilia disease.
Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) which can compromise participation in the trial with the exception of controlled 
thyroid function disease.
Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records). 
Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus 
which would contraindicate the use of gonadotropins.
Any abnormal finding of clinical chemistry, haematology or vital signs at screening, which 
is judged clinically relevant by the investigator. 
Known moderate or severe impairment of renal or hepatic function.
Currently breast-feeding.
Undiagnosed vaginal bleeding.
Known abnormal cervical cytology of clinical significance observed within 3 years prior to 
screening (unless the clinical significance has been resolved).
Findings from the laboratory analyses at screening which preclude gonadotropin 
stimulation.
Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation.
Findings at the gynaecological examination at screening which are associated with a 
reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine 
device.
Pregnancy (must be confirmed by negative urinary pregnancy tests at screening and prior to 
randomisation) or contraindication to pregnancy.
Known current active pelvic inflammatory disease.


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Use of hormonal preparations (except for thyroid medication) or fertility modifiers during 
the last menstrual cycle before randomisation, including dehydroepiandrosterone (DHEA), 
metformin and cycle programming with oral contraceptives, progestogen or estrogen 
preparations.
Known history of chemotherapy (except for gestational conditions) or radiotherapy.
Current or past (1 year prior to randomisation) abuse of alcohol or drugs, and/or current 
(last month) intake of more than 14 units of alcohol per week.
Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
Hypersensitivity to any drug substance or excipients in the medicinal products used in the 
trial.
Hypersensitivity to any drug substance or excipients in a GnRH or any GnRH analogue / 
derivative.
Previous participation in the trial. 
Current participation in another trial, including follow-up period.
Use of any non-registered investigational drugs during the last 3 months prior to screening.
MEDICINAL PRODUCTS
Investigational Medicinal Products (IMPs) 
Name
Drug type
Active ingredient, route of 
administration and 
concentration
Daily dose
FE 999049 
rFSH
FE 999049 (follitropin 
delta) in solution for 
subcutaneous injection; 72 
μg / 2.16 mL
Pre-filled pen
AMH <15 pmol/L: 12 μg. 
AMH ≥15 pmol/L: ranging from 
0.19 to 0.10 μg/kg, i.e. depending 
on actual AMH 
Dose is fixed throughout 
stimulation
Minimum dose is 6 μg/day
Maximum dose is 12 μg/day
FOLLISTIM 
rFSH
Follitropin beta in solution 
for subcutaneous injection; 
900 IU / 1.08 mL 
Cartridge and pen
Starting dose of 150 IU fixed for 
the first five stimulation days, 
followed by potential adjustments 
of 75 IU
Minimum dose is 75 IU/day
Maximum dose is 375 IU/day


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Concomitant Fertility Medication
Name
Drug type
Active ingredient and 
route of administration 
Dose
GANIREST
GnRH 
antagonist
Ganirelix pre-filled 
syringe for subcutaneous 
injection
0.25 mg, daily dose
hCG FUJI
hCG
Choriogonadotropin for 
intramuscular injection
5,000 IU, single dose
LUTINUS
Progesterone
Progesterone tablets for 
vaginal administration
3 x 100 mg daily
Note: In case of triggering of final follicular maturation with a GnRH agonist, a GnRH agonist 
nasal spray such as SUPRECUR (Sanofi / Mochida Pharmaceuticals Co., Ltd) or NASANYL 
(Pfizer) can be used according to local availability and at a dose according to site-specific 
procedures, e.g., a single dose of 300 μg SUPRECUR or 400 μg NASANYL.
STATISTICAL METHODS
Sample Size Calculation 
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing 
controlled ovarian stimulation. The non-inferiority margin for the difference between treatments 
(FE 999049 versus FOLLISTIM) is -3.0 oocytes. The standard deviation for the primary endpoint is 
estimated to 8.1 oocytes based on historical data with FOLLISTIM.
The sample size is determined to obtain 90% power to achieve the primary objective for the per-
protocol (PP) analysis set for a 1:1 randomisation ratio between FE 999049 and FOLLISTIM and a 
one-sided t-test at a 2.5% significance level. Assuming the two treatments to be equally effective 
and a standard deviation of 8.1 oocytes, a sample size of 155 randomised subjects per treatment 
group would give 90% power. The proportion of subjects with major protocol deviations is 
assumed to be at most 5% and hence 328 randomised subjects are needed to provide 155 
subjects/group in the PP analysis set.
Primary Statistical Analysis
The primary endpoint ‘number of oocytes retrieved’ will be analysed using an analysis of variance 
model with treatment and AMH stratum as fixed factors. The 2-sided 95% confidence limits for the 
mean treatment differences (FE 999049 - FOLLISTIM) will be calculated based on the fitted model 
for the full analysis set (FAS). Non-inferiority of FE 999049 compared with FOLLISTIM will be 
established if the 95% confidence interval lies entirely above -3.0 (the non-inferiority margin) for 
the FAS. 


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The hypotheses to be tested is: 
H0: ORFE 999049 - ORFOLLISTIM ≤ -3.0
H1: ORFE 999049 - ORFOLLISTIM > -3.0
where ORFE 999049 and ORFOLLISTIM denote the number of oocytes retrieved with respective 
treatment.


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 18
LIST OF FIGURES...................................................................................................................................... 18
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 19
1
INTRODUCTION ............................................................................................................................. 22
1.1
Background............................................................................................................................. 22
1.2
Scientific Justification for Conducting the Trial..................................................................... 25
1.3
Benefit / Risk Aspects............................................................................................................. 25
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 29
2.1
Objectives ............................................................................................................................... 29
2.2
Endpoints ................................................................................................................................ 29
3
INVESTIGATIONAL PLAN ........................................................................................................... 31
3.1
Overall Trial Design................................................................................................................ 31
3.1.1
Trial Design Diagram................................................................................................. 31
3.1.2
Overall Design and Control Methods ........................................................................ 32
3.1.3
Trial Schedule............................................................................................................ 34
3.2
Planned Number of Trial Sites and Subjects........................................................................... 34
3.3
Interim Analysis...................................................................................................................... 34
3.4
Data Monitoring Committee (DMC) ...................................................................................... 34
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 34
3.5.1
Trial Design ............................................................................................................... 34
3.5.2
Selection of Endpoints ............................................................................................... 35
3.5.3
Blinding...................................................................................................................... 36
3.5.4
Selection of Doses in the Trial................................................................................... 37
3.5.5
Selection of the Trial Population ............................................................................... 38
3.5.6
Follow-up Procedures ................................................................................................ 39
4
SELECTION OF TRIAL POPULATION ...................................................................................... 40
4.1
Trial Population....................................................................................................................... 40
4.1.1
Inclusion Criteria ....................................................................................................... 40
4.1.2
Exclusion Criteria ...................................................................................................... 41
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 42
4.2.1
Recruitment................................................................................................................ 42
4.2.2
Randomisation ........................................................................................................... 42
4.3
Restrictions ............................................................................................................................. 43
4.4
Withdrawal Criteria................................................................................................................. 43
4.5
Subject Replacement............................................................................................................... 43
5
TREATMENTS ................................................................................................................................. 44
5.1
Investigational Medicinal Products (IMPs) ............................................................................ 44
5.1.1
FE 999049 Dosing Regimen...................................................................................... 44
5.1.2
FOLLISTIM Dosing Regimen................................................................................... 46
5.2
Non-investigational Medicinal Products (NIMPs).................................................................. 47
5.3
Characteristics and Source of Supply ..................................................................................... 47


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5.4
Packaging and Labelling......................................................................................................... 48
5.5
Conditions for Storage and Use .............................................................................................. 49
5.6
Blinding / Unblinding ............................................................................................................. 50
5.6.1
Blinding...................................................................................................................... 50
5.6.2
Unblinding of Individual Subject Treatment ............................................................. 51
5.7
Dispensing and Accountability, Return and Destruction........................................................ 52
5.8
Auxiliary Supplies................................................................................................................... 53
6
TRIAL PROCEDURES .................................................................................................................... 54
6.1
Screening................................................................................................................................. 55
6.2
Stimulation.............................................................................................................................. 56
6.2.1
Stimulation Day 1 ...................................................................................................... 56
6.2.2
Stimulation Day 6 ...................................................................................................... 57
6.2.3
Stimulation Days ≥7 to ≤20 ....................................................................................... 58
6.2.4
End-of-Stimulation .................................................................................................... 58
6.3
Oocyte Retrieval ..................................................................................................................... 60
6.4
Oocyte / Embryo / Blastocyst Evaluation............................................................................... 60
6.5
Blastocyst Transfer ................................................................................................................. 62
6.6
βhCG Test............................................................................................................................... 62
6.7
Clinical Pregnancy.................................................................................................................. 63
6.8
End-of-Trial ............................................................................................................................ 63
6.9
Pregnancy Follow-up .............................................................................................................. 64
7
TRIAL ASSESSMENTS ................................................................................................................... 65
7.1
Assessments Related to Primary Endpoint ............................................................................. 65
7.1.1
Number of Oocytes Retrieved.................................................................................... 65
7.2
Assessments Related to Important Secondary Endpoint......................................................... 65
7.2.1
Clinical Pregnancy..................................................................................................... 65
7.3
Assessments Related to Secondary Endpoints........................................................................ 65
7.3.1
βhCG Test.................................................................................................................. 65
7.3.2
Vital Pregnancy.......................................................................................................... 65
7.3.3
Implantation............................................................................................................... 66
7.3.4
Cycle Cancellation due to Poor or Excessive Ovarian Response or Blastocyst 
Transfer Cancellation due to Excessive Ovarian Response / OHSS Risk ................. 66
7.3.5
Ovarian Response ...................................................................................................... 66
7.3.6
Extreme Ovarian Response........................................................................................ 66
7.3.7
Preventive Interventions for Early OHSS.................................................................. 66
7.3.8
Early OHSS (including Moderate/Severe) and/or Preventive Interventions for 
Early OHSS................................................................................................................ 67
7.3.9
Late OHSS (including Moderate/Severe) .................................................................. 67
7.3.10 Number and Size of Follicles during Stimulation...................................................... 67
7.3.11 Fertilisation Rate........................................................................................................ 67
7.3.12 Number and Quality of Embryos on Day 3 ............................................................... 67
7.3.13 Number and Quality of Blastocysts on Day 5............................................................ 68
7.3.14 Circulating Levels of Endocrine Parameters.............................................................. 69
7.3.15 Total Gonadotropin Dose and Number of Stimulation Days..................................... 69
7.3.16 Adverse Events .......................................................................................................... 69
7.3.17 Clinical Chemistry and Haematology Parameters ..................................................... 70


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7.3.18 Injection Site Reactions to IMP ................................................................................. 70
7.3.19 Pen Malfunctions ....................................................................................................... 70
7.4
Other Assessments.................................................................................................................. 71
7.4.1
Demographics ............................................................................................................ 71
7.4.2
Medical History ......................................................................................................... 71
7.4.3
Infertility History ....................................................................................................... 71
7.4.4
Menstrual History ...................................................................................................... 71
7.4.5
Reproductive History................................................................................................. 71
7.4.6
Body Measurements................................................................................................... 71
7.4.7
Physical Examination................................................................................................. 71
7.4.8
Gynaecological Examination..................................................................................... 72
7.4.9
Endocrine Parameters at Screening............................................................................ 72
7.4.10 Vital Signs.................................................................................................................. 72
7.4.11 Ovarian Size and Volume .......................................................................................... 73
7.4.12 Endometrial Status..................................................................................................... 73
7.4.13 Maturity Stage............................................................................................................ 73
7.4.14 Blastocyst Transfer Procedure ................................................................................... 73
7.4.15 Concomitant Medication............................................................................................ 73
7.4.16 Drug Dispensing and Accountability......................................................................... 73
7.4.17 End-of-Trial Form...................................................................................................... 74
7.5
Assessments Related to Pregnancy Follow-up Information ................................................... 74
7.6
Handling of Biological samples.............................................................................................. 74
8
ADVERSE EVENTS ......................................................................................................................... 76
8.1
Adverse Event Definition........................................................................................................ 76
8.2
Collection and Recording of Adverse Events......................................................................... 76
8.2.1
Collection of Adverse Events .................................................................................... 76
8.2.2
Recording of Adverse Events .................................................................................... 77
8.3
Adverse Events of Special Interest ......................................................................................... 80
8.3.1
OHSS ......................................................................................................................... 80
8.3.2
Local Tolerability....................................................................................................... 81
8.3.3
Menstrual Bleeding.................................................................................................... 82
8.3.4
Pregnancy Losses....................................................................................................... 82
8.4
Serious Adverse Events .......................................................................................................... 83
8.4.1
Serious Adverse Event Definition.............................................................................. 83
8.4.2
Collection, Recording and Reporting of Serious Adverse Events in Core Trial........ 84
8.4.3
Collection, Recording and Reporting of Serious Adverse Events in Pregnancy 
Follow-up................................................................................................................... 86
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 87
9
STATISTICAL METHODS ............................................................................................................. 88
9.1
Determination of Sample Size ................................................................................................ 88
9.2
Subject Disposition ................................................................................................................. 88
9.3
Protocol Deviations................................................................................................................. 89
9.4
Analysis Sets........................................................................................................................... 89
9.5
Trial Population....................................................................................................................... 90
9.5.1
General Considerations.............................................................................................. 90


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9.5.2
Trial Population Parameters....................................................................................... 90
9.6
Treatment Compliance............................................................................................................ 91
9.7
Endpoint Assessments............................................................................................................. 92
9.7.1
General Considerations.............................................................................................. 92
9.7.2
Primary Endpoint....................................................................................................... 93
9.7.3
Important Secondary Endpoint .................................................................................. 94
9.7.4
Secondary Endpoints ................................................................................................. 94
9.8
Additional Safety Evaluations .............................................................................................. 100
9.9
Pregnancy Follow-up Information........................................................................................ 101
9.10
Interim Analyses ................................................................................................................... 101
10
DATA HANDLING ......................................................................................................................... 102
10.1
Source Data and Source Documents..................................................................................... 102
10.2
eCRF ..................................................................................................................................... 103
10.3
Data Management ................................................................................................................. 104
10.4
Provision of Additional Information..................................................................................... 104
11
MONITORING PROCEDURES ................................................................................................... 105
11.1
Periodic Monitoring.............................................................................................................. 105
11.2
Audit and Inspection............................................................................................................. 105
11.3
Confidentiality of Subject Data............................................................................................. 106
12
CHANGES IN THE CONDUCT OF THE TRIAL...................................................................... 107
12.1
Protocol Amendments........................................................................................................... 107
12.2
Deviations from the Protocol ................................................................................................ 107
12.3
Premature Trial Termination................................................................................................. 107
13
REPORTING AND PUBLICATION ............................................................................................ 108
13.1
Clinical Trial Report ............................................................................................................. 108
13.2
Confidentiality and Ownership of Trial Data........................................................................ 108
13.3
Publications and Public Disclosure....................................................................................... 108
13.3.1 Publication Policy.................................................................................................... 108
13.3.2 Public Disclosure Policy.......................................................................................... 109
14
ETHICAL AND REGULATORY ASPECTS............................................................................... 110
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ........................ 110
14.2
Regulatory Authority Notification........................................................................................ 110
14.3
End-of-Trial and End-of-Trial Notification .......................................................................... 110
14.4
Ethical Conduct of the Trial.................................................................................................. 110
14.5
Subject Information and Consent.......................................................................................... 111
14.6
Trial Participation Card......................................................................................................... 111
14.7
Compliance Reference Documents....................................................................................... 112
15
LIABILITIES AND INSURANCE ................................................................................................ 113
15.1
ICH-GCP Responsibilities.................................................................................................... 113
15.2
Liabilities and Insurance....................................................................................................... 113
16
ARCHIVING.................................................................................................................................... 114
16.1
Investigator File .................................................................................................................... 114
16.2
Trial Master File.................................................................................................................... 114


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17
REFERENCES................................................................................................................................. 115
APPENDIX 1
Master Informed Consent Documents
APPENDIX 2
Contact List
ATTACHMENT I
Agreement on the Protocol
LIST OF TABLES 
Table 5-1
FE 999049 Dosing Regimen...........................................................................................45
Table 5-2
FOLLISTIM Dosing Regimen........................................................................................46
Table 5-3
Characteristics and Source of Supply of Medicinal Products.........................................48
Table 5-4
Packaging of Medicinal Products ...................................................................................49
Table 5-5
Conditions for Storage of Medicinal Products................................................................50
Table 6-1
Trial Flow Chart – Subject Procedures...........................................................................54
Table 6-2 Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures........................................61
Table 8-1
Classification of Mild, Moderate and Severe OHSS ......................................................80
LIST OF FIGURES
Figure 3-1 Trial Diagram – Trial Period...........................................................................................31
Figure 5-1 FE 999049 Dosing Regimen...........................................................................................44


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
AMH
anti-Müllerian hormone
ANCOVA
analysis of covariance
ART
assisted reproductive technologies
ASRM
American Society for Reproductive Medicine
ATC
Anatomical Therapeutic Chemical classification system
AUC
area under the curve
βhCG
beta unit of human chorionic gonadotropin 
BMI
body mass index
CBC
complete blood count
CHO
Chinese hamster ovary
Cmax
maximum concentration
DHEA
dehydroepiandrosterone
EC
Ethics Committee
eCRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FPFV
first patient first visit
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GCU
growing care unit
GMP
Good Manufacturing Practice
GnRH
gonadotropin-releasing hormone
h
hour(s)
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th revision
ICH
International Conference on Harmonisation
ICMART
International Committee Monitoring Assisted Reproductive Technologies
ICMJE
International Committee of Medical Journal Editors


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ICSI
intracytoplasmic sperm injection
IMP
investigational medicinal product
IND
investigational new drug
IRB
Institutional Review Board
ITT
intention-to-treat
IU
international units
IVF
in vitro fertilisation
J-GCP
Japanese Good Clinical Practice
J-NDA
Japanese New Drug Application 
JSOG
Japan Society of Obstetrics and Gynaecology
L
Litre
LH
luteinising hormone
LLOQ
lower limit of quantification
LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
mL
millilitre
NCU
neonatal care unit
NICU
neonatal intensive care unit
NIMP
non-investigational medicinal product
OHSS
ovarian hyperstimulation syndrome
OR
oocyte retrieval
PER.C6®
name of cell line of human fetal retinal origin
PD
pharmacodynamics
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency
pmol
picomol
PP
per-protocol
PT
preferred term
rFSH
recombinant follicle-stimulating hormone
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction 
t½
elimination/terminal half-life
tmax
time to Cmax
TSH
thyroid-stimulating hormone


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μg
microgram
ULOQ
upper limit of quantification
WHO
World Health Organization
AMH Unit Conversion Factors 
1 pmol/L = 0.140 ng/mL
1 ng/mL = 7.143 pmol/L


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1
INTRODUCTION
1.1
Background
FE 999049 is a human recombinant follicle-stimulating hormone (rFSH) developed by Ferring 
Pharmaceuticals. FE 999049 is intended for the following indication: “Controlled ovarian 
stimulation for the development of multiple follicles in women undergoing assisted reproductive 
technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle”. Ferring has received Marketing Authorisation approval from the European 
Commission for FE 999049 (December 2016).
FE 999049 is expressed from a host cell line of human fetal retinal origin (PER.C6®). The PER.C6®
cell line is well-characterised, and bio-testing of the master cell bank has demonstrated safety and 
consistency. FE 999049 is a glycoprotein which is composed of two non-covalently bound 
polypeptide chains, denoted alfa (α) and beta (β). The α-subunit contains 92 amino acid residues 
with 5 intrachain-disulphide bonds. The β-subunit contains 111 amino acid residues with 
6 intrachain-disulphide bonds. Each subunit is N-glycosylated at two positions, and about 40% of 
the total mass is carbohydrates. 
FE 999049 is derived from a human cell line. This is in contrast to other currently-approved rFSH 
products for the proposed indication, such as follitropin alfa (GONAL-F, Merck Serono Co., Ltd) 
and follitropin beta (FOLLISTIM, MSD K.K.), which 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.
The clinical translation of the differential glycosylation profile of FE 999049 has been reflected in 
clinical trials. Thus, daily multiple-dose administration of identical international unit (IU) doses of 
FE 999049 and a CHO-derived rFSH product as determined in the rat in vivo Steelman-Pohley 
bioassay did not provide comparable pharmacokinetics (PK) and pharmacodynamics (PD), with the 
differential glycosylation profile of FE 999049 being considered the most likely cause for this 
finding. Consequently, it was considered that the rat in vivo Steelman Pohley bioassay might not 
fully reflect the potency of FE 999049 in humans, as supported by biotransformation studies in 
mice and rats and that using the protein content (µg) in combination with a consistent drug 


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substance quality profile would be more appropriate for expressing doses of FE 999049 than the 
bioactivity (IU). Therefore, FE 999049 is dosed by mass (µg) rather than in IU.
A phase 1 trial (CS03) conducted in healthy female Japanese volunteers demonstrated a linear, 
dose-response relationship of FE 999049 with respect to exposure. Furthermore, comparisons 
between Japanese and Caucasian women indicated similar PK profile with respect to Cmax, AUC, 
tmax and t½.1
Two randomised, controlled, assessor-blind, parallel groups, multi-centre phase 2 anti-Müllerian 
hormone (AMH)-stratified trials were conducted in IVF/ICSI patients, one in Europe (000009)2 and 
one in Japan (000124)3, with the purpose of determining the dose-response relationship of 
FE 999049 and the number of oocytes retrieved. In both trials, randomisation was stratified 
according to AMH levels at screening; low AMH (5.0-14.9 pmol/L) or high AMH (15.0-
44.9 pmol/L).a
In the European dose-response phase 2 trial (000009), five doses of FE 999049 ranging from 
5.2 µg/day to 12.1 µg/day were investigated and a reference group of an approved rFSH product 
(GONAL-F, 150 IU/day) was also included. In the Japanese dose-response phase 2 trial (000124), 
three doses of FE 999049 (6 µg/day, 9 µg/day and 12 µg/day) were investigated and a standard 
therapy of the approved rFSH product (FOLLISTIM, 150 IU/day) was also included. At present, 
follitropin beta (FOLLISTIM) is the only medicinal product approved in Japan for controlled 
ovarian stimulation in IVF/ICSI cycles. In the European and the Japanese phase 2 trials, the daily 
dose was fixed throughout the stimulation period. In both trials, a statistically significant dose-
response relationship for FE 999049 with respect to the number of oocytes retrieved was observed 
for the overall population and for each AMH randomisation stratum. Acceptable pregnancy rates 
were achieved with all FE 999049 doses. Furthermore, the observed FE 999049 dose-response 
profile was similar in the European trial and in the Japanese trial. 
The development of FE 999049 has prospectively incorporated the use of a biomarker of ovarian 
response to gonadotropins (AMH) to identify patients at higher risk of reduced efficacy or 
increased safety concern, enabling stratification according to the patients’ potential to respond to 
FE 999049. Furthermore, body weight has been shown to influence the exposure to FE 999049. 
Therefore, the posology of FE 999049 is individualised for each patient based on her body weight 
and serum AMH to obtain an ovarian response with favourable safety/efficacy profile. The outcome 
is a fixed-dose regimen supporting individualised ovarian stimulation with safe and efficient use of 
FE 999049 founded on current scientific knowledge and prospectively confirmed data.
The efficacy and safety of the FE 999049 individualised dosing regimen based on the woman’s 
serum AMH and body weight has been confirmed in a large phase 3 trial, ESTHER-1 (Evidence-
based Stimulation Trial with Human rFSH in Europe and Rest of World)4, conducted in 11 
countries overseas including Europe, North America and Latin America. The ESTHER-1 trial was 
                                                
a
See conversion factor between the AMH units pmol/L and ng/mL on page 21.


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conducted in 1,326 IVF/ICSI patients who were randomised 1:1 to controlled ovarian stimulation 
with one of the following treatments: 1) FE 999049 in its individualised dosing regimen with the 
daily dose fixed throughout simulation, or 2) an approved CHO-derived rFSH product (follitropin 
alfa, GONAL-F) at a standard starting dose of 150 IU/day followed by dose adjustments based on 
the subject’s follicular response during stimulation. FE 999049 in its individualised dosing regimen 
was demonstrated to be non-inferior to follitropin alfa with respect to ongoing pregnancy rate 
(30.7% versus 31.6%) and ongoing implantation rate (35.2% versus 35.8%). For the overall 
population, there was no statistically significant difference between treatment groups in terms of 
number of oocytes retrieved, with an average of 10.0 for FE 999049 and 10.4 for follitropin alfa. 
Nevertheless, the individualised FE 999049 dosing regimen in comparison to follitropin alfa led to 
statistically significantly more oocytes retrieved among patients with AMH <15 pmol/L (population 
at risk of hyporesponse) with an average of 8.0 versus 7.0 and statistically significantly fewer 
oocytes among patients with AMH ≥15 pmol/L (population at risk of hyperresponse) with an 
average of 11.6 versus 13.3. The immediate clinical relevance of this shift in ovarian response with 
FE 999049 therapy was realised as statistically significantly fewer patients with extreme ovarian 
response compared to follitropin alfa, i.e. <4 oocytes among patients with AMH <15 pmol/L (12% 
versus 18%) and ≥15 or ≥20 oocytes among patients with AMH ≥15 pmol/L (28% versus 35%, and 
10% versus 16%). The percentage of patients with an appropriate ovarian response, defined for 
FE 999049 as 8-14 oocytes, was reached by statistically significantly more patients treated with 
FE 999049 compared to follitropin alfa, i.e. 43% versus 38%, despite implementation of dose 
adjustments during stimulation for 37% of the patients in the follitropin alfa group in contrast to the 
fixed-dose individualised dosing regimen for FE 999049. A statistically significantly lower total 
gonadotropin dose in the FE 999049 group compared to the CHO-derived rFSH product group was 
observed with an average of 90 µg and 104 µg, respectively. 
The most serious risk associated with gonadotropin treatment is ovarian hyperstimulation syndrome 
(OHSS). Overall in the phase 3 trials overseas, OHSS and/or preventive interventions of early 
OHSS occurred in 4.4% of the FE 999049 cycles and 6.5% of the follitropin alfa cycles. 
Moderate/severe OHSS and/or preventive interventions for early OHSS were observed at an 
incidence of 3.3% and 5.6% of the treatment cycles with FE 999049 and follitropin alfa, 
respectively. 
Previous studies have reported OHSS rates in Japanese patients between 5% and 28.3%.5,6,7 In the 
FE 999049 phase 2 trial in Japan, the incidence of early moderate/severe OHSS was 19.5% for
subjects in the FOLLISTIM group. Despite the variation in the OHSS incidence reporting, the high 
OHSS incidence in Japanese IVF/ICSI patients illustrates a clear need in Japan for a treatment 
option with a safer OHSS profile. Based on more than 1,300 cycles in the ESTHER-1 phase 3 trial, 
the individualised dosing regimen of FE 999049 was associated with a statistically significant 
reduction in the proportion of subjects with early OHSS and/or preventive interventions for early 
OHSS in comparison to the standard regimen of CHO-derived rFSH product, with an incidence of 
4.7% in the FE 999049 group and 6.2% in the follitropin alfa group. For further information 
regarding FE 999049, please refer to the Investigator’s Brochure.8


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The present trial aims to establish non-inferiority of FE 999049 versus FOLLISTIM with respect to 
number of oocytes retrieved and will document the efficacy and safety of FE 999049 in Japanese 
IVF/ICSI patients.
1.2
Scientific Justification for Conducting the Trial
As part of the global development programme for FE 999049, the purpose of the present trial is to 
establish non-inferiority of FE 999049 versus FOLLISTIM with respect to number of oocytes 
retrieved and to document the efficacy and safety of FE 999049 in Japanese IVF/ICSI patients.
1.3
Benefit / Risk Aspects
Benefits
Patients participating in this trial may benefit by achieving a pregnancy because of the treatment 
cycle and/or by obtaining blastocysts to be cryopreserved for later use in cryopreserved cycles. 
Subjects in this trial will be closely monitored, and they will have either the same or more frequent 
visits to the clinic compared to routine treatment, depending on local practice. In addition, the data 
obtained from the treatment cycle may provide useful information for optimising the ovarian 
response and for clinical planning of subsequent treatment cycles. Finally, Ferring bears the 
expenses for the treatment cycle.
Risks
The risks associated with ART treatment, including the risk of controlled ovarian stimulation and 
clinical and laboratory procedures, are explained to the subjects as part of the counselling prior to 
starting treatment. 
Gonadotropins
In this trial, controlled ovarian stimulation will be performed with one of two rFSH preparations: 
FE 999049 or FOLLISTIM, a widely available recombinant FSH preparation, used according to its 
approved labelling. Both preparations will be administered subcutaneously.
As part of the development programme for FE 999049, a total of 1,927 subjects have to date been 
included in four phase 1 trials, two phase 2 trials (one conducted in EU and one in Japan) and the 
overseas phase 3 programme. 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 overall adverse 
event profile of the individualised FE 999049 dosing regimen appeared to be comparable to that of 
GONAL-F with the exception of fewer OHSS and/or preventive interventions for early OHSS with 
FE 999049. The most frequently reported adverse drug reactions during 1,012 treatment cycles with 


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FE 999049 in the phase 3 programme were headache, pelvic discomfort, OHSS, pelvic pain, adnexa 
uteri pain, nausea and fatigue (all reported as common, i.e. 1% to <10%). Uncommon adverse drug 
reactions reported with FE 999049 were diarrhoea, dizziness, mood swings, constipation, vomiting, 
abdominal discomfort, breast pain, breast tenderness, vaginal haemorrhage and somnolence. 
FE 999049 administered with the injection pen was well-tolerated with a low incidence of local 
injection site reactions. The severity of local injection site reactions was in general mild and 
comparable to that reported for GONAL-F administered with the pre-filled pen.
FOLLISTIM is a commercially available CHO-derived rFSH product with established safety and 
efficacy.7 The most frequent adverse drug reactions in relation to use of FOLLISTIM are as 
follows: OHSS, headache, abdominal pain and injection site pain (all reported between 0.5% to 
≤5%).7 The FOLLISTIM dosing regimen used in this trial is in line with labelling 
recommendations.
In the phase 2 trial in Japan, the adverse drug reactions most commonly reported (≥1%) by subjects 
exposed to FE 999049 were OHSS, ovarian enlargement, high progesterone and ascites. Injection 
site reactions following FE 999049 administration were recorded with very low incidences, with no 
apparent differences across dose levels and similar to that observed with FOLLISTIM.
OHSS
The most serious risk associated with gonadotropin treatment is OHSS. OHSS manifests itself with 
increasing degrees of severity. Moderate/severe OHSS is associated with marked ovarian 
enlargement, fluid accumulation and other complications. The incidence of early OHSS can be 
minimised by withholding gonadotropins, withholding human chorionic gonadotropin (hCG) or 
administering gonadotropin-releasing hormone (GnRH) agonist for triggering of final follicular 
maturation. 
Immunogenicity
Concerning immunogenicity, the risk of treatment-induced anti-drug-antibodies for gonadotropin 
products has previously been reported as very low (estimated to be 0-2%).9,10,11,12,13 In the Japanese 
phase 2 trial (000124), the incidence of treatment-induced anti-FSH antibodies was 0.8% (1/117) in 
subjects treated with FE 999049. The titre was below the limit of quantification, and the anti-FSH 
antibodies were not of neutralising capacity. In the overseas phase 3 trial ESTHER-1, the incidence 
of treatment-induced anti-FSH antibodies was 1.05% (7/665) in the FE 999049 group. None of the 
anti-FSH antibodies were of neutralising capacity. A phase 3 trial overseas (ESTHER-2) was 
designed to evaluate the immunogenicity in patients undergoing up to two repeated treatment 
cycles, and was conducted in women who had failed to achieve an ongoing pregnancy in ESTHER-
1. The trial consisted of two treatment cycles, cycle 2 and cycle 3, where women who failed to 
achieve an ongoing pregnancy in cycle 2 could be offered to start cycle 3. A total of 513 patients 
were included in cycle 2 and 188 patients in cycle 3. After repeated treatment with FE 999049, the 
incidence of anti-FSH antibodies was 0.8% (2/252) in cycle 2 and 1.1% (1/95) in cycle 3, indicating 


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no increase in anti-FSH antibodies during repeated exposure to FE 999049.14 Furthermore, these 
incidences were similar to those observed for the comparator (GONAL-F). All treatment-induced 
anti-FSH antibody samples in cycle 2 and 3 had titres below the limit of quantification. In addition, 
no treatment-induced anti-FSH antibodies in FE 999049 patients were of neutralising capacity (0% 
in all cycles).14
In conclusion, repeated treatment with FE 999049 in patients with pre-existing or treatment-
induced anti-FSH antibodies did not increase the antibody titre, was not associated with decreased 
ovarian response, and did not induce immune-related adverse events. Also, the treatment-induced 
anti-FSH responses were shown to be transient in nature. Thus, no safety or efficacy concern has 
been identified with regards to immunogenicity with FE 999049. 
Procedures and Concomitant Fertility Medications
Subjects will undergo standard ART treatment procedures (e.g. ovarian stimulation monitoring by 
transvaginal ultrasound and blood sampling, oocyte retrieval and transfer) and also receive standard 
concomitant fertility medication as part of this trial. The transvaginal ultrasound examinations may 
be associated with mild discomfort and a very rare risk of infection. The blood sampling might be 
associated with mild discomfort, bruising and a very rare risk of infection. Oocyte retrieval is 
associated with discomfort, and transfer is associated with mild discomfort and very rarely 
infections and mild bleeding. The concomitant fertility medications are generally well-tolerated and 
the most frequent adverse events are similar to those reported for gonadotropins, such as headache, 
injection site reactions, pelvic pain, abdominal pain, abdominal distension and allergic reactions. 
Furthermore, the vaginal progesterone (LUTINUS) has been associated with vulvovaginal disorders 
and uterine spasms (at a frequency of 1-2%).
Pregnancy-related Events
Oocytes will be inseminated using IVF or ICSI and subsequently cultured to day 5 (blastocyst 
stage) after oocyte retrieval. Although the frequency of cancellation of transfer is higher when 
culturing to blastocyst stage compared to culturing only to cleavage stage15, the pregnancy rates per 
started cycle are at least as good with blastocyst transfer as with cleavage embryo transfer15 and 
may even be higher.16 A serious concern associated with ART cycles is the frequency of multiple 
pregnancies / births and the related neonatal health problems. To minimise the risk of multiple 
gestations, single blastocyst transfer is mandatory. The incidence of miscarriage and ectopic 
pregnancy is higher in women undergoing controlled ovarian stimulation than in women conceiving 
spontaneously, though the risk of ectopic pregnancy is mainly higher in patients with a history of 
tubal infertility. Furthermore, the prevalence of congenital malformations after ART may be 
slightly higher than after spontaneous conceptions; this is thought to be due to differences in 
parental characteristics (e.g. maternal age and sperm characteristics) and multiple pregnancies.


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


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to 
number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian 
stimulation
Secondary Objectives

To compare FE 999049 with FOLLISTIM with respect to achieving pregnancy

To compare FE 999049 with FOLLISTIM with respect to ovarian response and endocrine 
profile 

To compare FE 999049 with FOLLISTIM with respect to oocyte fertilisation and number 
and quality of embryos/blastocysts 

To compare FE 999049 with FOLLISTIM with respect to the frequency of OHSS and/or 
preventive interventions for early OHSS

To compare FE 999049 with FOLLISTIM with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To compare FE 999049 with FOLLISTIM with respect to gonadotropin use
2.2
Endpoints
Primary Endpoint

Number of oocytes retrieved
Important Secondary Endpoint

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer) 

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer) 

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred)

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
blastocyst transfer cancellation due to excessive ovarian response / OHSS risk 


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
Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes 
retrieved

Proportion of subjects with preventive interventions for early OHSS

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Proportion of subjects with OHSS (early and/or late) and/or preventive interventions for 
early OHSS

Number and size of follicles on stimulation day 6 and end-of-stimulation

Fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on day 
5 after oocyte retrieval

Circulating concentrations of FSH, LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Total gonadotropin dose and number of stimulation days

Frequency and intensity of adverse events 

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Technical malfunctions of the administration pens
Pregnancy Follow-up Information 

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer) 
and live birth rate 

Neonatal health at birth and at 4 weeks after birth
Note: Ferring intends to submit the Japanese New Drug Application (J-NDA) following completion 
of the main part of the trial (i.e. up to the clinical pregnancy visit), and to include the pregnancy 
follow-up data available at that time in the J-NDA. The pregnancy follow-up data can be submitted 
after completion.


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A diagram illustrating the trial period is shown in Figure 3-1.
Figure 3-1 Trial Diagram – Trial Period
As obligatory follow-up, pregnancy progress and outcome data will be gathered for subjects with a 
vital pregnancy. Data will be collected on ongoing pregnancy (10-11 weeks after transfer) and 
pregnancy outcome as well as neonatal health at birth and at 4 weeks after birth. The pregnancy 
follow-up does not include any interventions but only data collection. The pregnancy follow-up 
data will be based on reports obtained from the subject’s gynaecologist / obstetrician and the 
subject’s Maternal and Child Health Handbook. The data will be retrieved by the trial site, either 
via the subject’s gynaecologist / obstetrician, the subject herself, or other sources, as applicable.
Ferring intends to submit the J-NDA following completion of the main part of the trial (i.e. up to 
the clinical pregnancy visit), and to include the pregnancy follow-up data available at that time in 
the J-NDA. The pregnancy follow-up data can be submitted after completion.


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3.1.2
Overall Design and Control Methods
Trial Design 
This will be a randomised, assessor-blind, controlled, parallel groups, multicentre trial assessing the 
efficacy and safety of FE 999049 in its individualised dosing regimen when used in first cycle 
Japanese patients aged 20-40 years undergoing controlled ovarian stimulation for IVF/ICSI 
following a GnRH antagonist protocol. The trial has been designed to demonstrate non-inferiority 
of FE 999049 versus an rFSH product approved in Japan, i.e. FOLLISTIM, with respect to number 
of oocytes retrieved. 
Subjects will be screened within 60 days prior to start of stimulation for compliance with the 
inclusion and exclusion criteria. On day 2-3 of the menstrual cycle, subjects will be randomised in a 
1:1 ratio to controlled ovarian stimulation with FE 999049 or FOLLISTIM. Randomisation will be 
stratified by centre and according to AMH levels at screening (<15 pmol/L and ≥15 pmol/L). 
Subjects randomised to FE 999049 will have their individual FE 999049 dose determined on the 
basis of their AMH level at screening and their body weight at start of stimulation. The daily 
FE 999049 dose will be fixed throughout the stimulation period. For subjects with 
AMH <15 pmol/L, the daily FE 999049 dose is 12 μg, irrespective of body weight. For subjects 
with AMH ≥15 pmol/L the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 
0.10 μg/kg, i.e. dependent on actual AMH and body weight. The minimum allowed daily 
FE 999049 dose is 6 μg and the maximum allowed daily FE 999049 dose is 12 μg. Subjects can be 
treated with FE 999049 for a maximum of 20 days, and coasting is not allowed. For subjects 
randomised to FOLLISTIM, the dosing regimen is within labelling. The starting dose of 
FOLLISTIM is 150 IU and fixed for the first five stimulation days after which it may be adjusted 
by 75 IU based on the individual response. The maximum daily FOLLISTIM dose allowed is 
375 IU. Subjects can be treated with FOLLISTIM for a maximum of 20 days, and coasting is not 
allowed. 
During stimulation, subjects will be monitored by transvaginal ultrasound on stimulation day 1 and 
6 and hereafter at least every second day. When 3 follicles of ≥15 mm are observed, visits must be 
performed daily. To prevent a premature luteinising hormone (LH) surge, a GnRH antagonist will 
be initiated on stimulation day 6 at a daily dose of 0.25 mg and continued throughout the 
stimulation period. Triggering of final follicular maturation will be done with 5,000 IU urinary hCG 
on the day when ≥3 follicles with a diameter ≥17 mm are observed. In case of excessive follicular 
development, defined as ≥25 follicles with a diameter ≥12 mm, the cycle should be cancelled (note:
in case of 25-35 follicles with a diameter ≥12 mm, a GnRH agonist may be administered as 
triggering for final follicular maturation). In case of poor follicular development, defined as the 
investigator judging that ≥3 follicles with a diameter ≥17 mm cannot be reached by day 20, the 
cycle is to be cancelled.
Oocyte retrieval will take place 36h (± 2h) after triggering of final follicular maturation and the 
oocytes can be inseminated by IVF or ICSI. Fertilisation and embryo development will be assessed 


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from oocyte retrieval to the day of transfer. One blastocyst of the best quality available will be 
transferred on day 5 after oocyte retrieval while remaining blastocysts may be cryopreserved. For 
subjects who underwent triggering of final follicular maturation with GnRH agonist, no transfer 
will take place and blastocysts may instead be cryopreserved on day 5. All cryopreserved 
blastocysts can be used by the subject after completion of the trial, in accordance with the 
declaration by Japan Society of Obstetrics and Gynaecology (JSOG).
Vaginal progesterone tablets (LUTINUS, Ferring Pharmaceuticals) 100 mg three times daily will 
be provided for luteal phase support from the day after oocyte retrieval until the day of the clinical 
pregnancy visit. Luteal phase support will only be provided to subjects planned to undergo transfer 
and can be terminated earlier in case of no transfer or a negative βhCG test. A βhCG test is 
performed 13-15 days after transfer followed by a transvaginal ultrasound 5-6 weeks after transfer 
to assess clinical and vital pregnancy. Subjects experiencing a full menstrual bleeding following 
transfer must have the βhCG test performed 7-15 days after transfer. The βhCG test is mandatory 
for all subjects who undergo transfer, irrespective of bleeding.
Blood samples will be collected during the trial for the purpose of evaluating the endocrine profile 
as well as clinical chemistry and haematology parameters. Endocrine parameters are measured at 
screening, stimulation day 1, stimulation day 6 and end-of-stimulation. Clinical chemistry and 
haematology parameters are assessed at screening, end-of-stimulation and end-of-trial. Local 
tolerability of FE 999049 following subcutaneous administration will be assessed by the subjects 
three times daily: immediately, 30 minutes and 24 hours after the injection. The assessment of 
injection site reactions will be made throughout the stimulation period and recorded by the subjects 
in a diary. 
If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule) or cancelled, if appropriate.
Pregnancy Follow-up 
As obligatory follow-up, pregnancy progress and outcome data will be gathered for subjects with a 
vital pregnancy. Data will be collected on ongoing pregnancy (10-11 weeks after transfer) and 
pregnancy outcome as well as neonatal health at birth and at 4 weeks after birth. The pregnancy 
follow-up does not include any interventions but only data collection. The pregnancy follow-up 
data will be based on reports obtained from the subject’s gynaecologist / obstetrician and the 
subject’s Maternal and Child Health Handbook. The data will be retrieved by the trial site, either 
via the subject’s gynaecologist / obstetrician, the subject herself, or other sources, as applicable.
Ferring intends to submit the J-NDA following completion of the main part of the trial (i.e. up to 
the clinical pregnancy visit), and to include the pregnancy follow-up data available at that time in 


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the J-NDA. The pregnancy follow-up data can be submitted after completion.
3.1.3
Trial Schedule
The estimated timelines for the trial are listed below.
First patient first visit (FPFV):
Estimated Q3 2017
Last patient last visit (LPLV) / end-of-trial:
Estimated Q1 2019
Pregnancy follow-up completed:
Estimated Q4 2019
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise approximately 328 subjects from approximately 15-20 sites in Japan.
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 (DMC)
No Data Monitoring Committee will be established for this trial.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
The primary objective of the trial is to demonstrate non-inferiority of FE 999049 compared with 
FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing 
controlled ovarian stimulation. 
Strict criteria have been incorporated in the design of this comparative efficacy trial to properly 
assess the effect of the interventions on treatment outcome. In general, standardisation of criteria, 
timing of assessments, procedures and interventions have to a great extent been incorporated in the 
design of this trial to minimise variation.17,18,19
This is a randomised controlled trial using an approved gonadotropin preparation as active 
comparator. It is a parallel group design restricted to a single treatment cycle, as this design is 
preferred over a cross-over design in fertility trials. The trial will be open-label but assessor-blind. 
A double-blind design is not considered feasible for the present trial for various practical reasons, 
which are described in detail in section 3.5.3. The assessor-blinding will ensure blinding and 
thereby unbiased evaluation by the investigators, embryologists and central laboratory personnel. 
Similarly, the Ferring clinical trial team will also remain blinded to individual subject treatment 


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allocation during the conduct of the trial. The trial will be a multi-centre trial, this set-up ensures 
that the required number of subjects can be recruited within a reasonable time and also has the 
advantage that it should facilitate subsequent generalisation of the results.
The trial is designed to demonstrate non-inferiority of FE 999049 versus FOLLISTIM with respect 
to number of oocytes retrieved. The non-inferiority margin for the primary endpoint has been set 
at -3.0 oocytes, based on considerations to clinical relevance and overseas regulatory precedence.
The non-inferiority margin for the primary endpoint has been reviewed and agreed at the follow-up 
meeting for the Pharmaceuticals and Medical Devices Agency (PMDA) post-phase 2 trial 
consultation in December 2016.
Subjects will undergo controlled ovarian stimulation with an individualised dosing regimen of 
FE 999049 based on considerations of the subject’s AMH level and body weight, or with a 
labelling recommended dosing regimen of FOLLISTIM, following a GnRH antagonist protocol. 
The selection of doses is described in detail in section 3.5.4. Monitoring of ovarian response by 
transvaginal ultrasound and blood sampling for assessment of several endocrine parameters will be 
performed regularly during stimulation.
Oocytes will be inseminated by either IVF or ICSI reflecting the procedures used in the target 
population for the proposed indication. Embryos will be cultured for 5 days and embryo 
development will be assessed from oocyte retrieval till the day of transfer, allowing evaluation of 
embryo development until blastocyst stage. One blastocyst of the best quality available will be 
transferred on day 5 after oocyte retrieval while remaining blastocysts may be cryopreserved.
Subjects who achieve vital pregnancy will be followed till live birth to collect information on 
pregnancy outcome. In addition, neonatal health data will be gathered at birth and at 4 weeks after 
birth.
3.5.2
Selection of Endpoints
The present trial has been designed as a non-inferiority trial with number of oocytes retrieved as the 
primary endpoint. This parameter provides a direct measure of the main pharmacological action of 
gonadotropin preparations. The number of oocytes retrieved is considered an appropriate marker of 
ovarian response and thereby of the pharmacodynamics of an FSH preparation. The number of 
oocytes retrieved has also been used as the primary endpoint in the Japanese dose-response trial 
(000124). This primary endpoint is in accordance with the PMDA scientific advice (agreed upon 
during consultation post-phase 2 trial). In addition, per PMDA recommendation, clinical pregnancy 
rate is an important secondary endpoint. 
One of the secondary objectives is to compare the clinical benefits of FE 999049 in its dosing 
regimen to those of FOLLISTIM with respect to efficacy and safety. This objective is investigated 
by multiple endpoints to address it from several angles; i.e. the feasibility of pregnancy, proportion 
of subjects with extreme ovarian response, early OHSS (including moderate/severe grade), 


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preventive interventions for early OHSS, cycle cancellations due to poor ovarian response and 
cycle cancellations due to excessive ovarian response.
Additional secondary endpoints include pharmacodynamic parameters, such as ovarian response in 
terms of follicular development, endocrine profile and also oocyte / embryo / blastocyst quality. 
Follicular development and endocrine profile will be evaluated after the initial 5 days as well as at 
the end of stimulation. The endocrine profile consists of FSH, LH, estradiol, progesterone, inhibin 
A and inhibin B. 
Clinical safety endpoints cover adverse events, early and late OHSS, preventive interventions for 
early OHSS, local tolerability, clinical chemistry and haematology parameters. Pre-defined 
injection site reactions, i.e. redness, pain, itching, swelling and bruising, will be assessed by the 
subjects at three occasions (after each injection) spanning from immediately after the subcutaneous 
injection till 24 hours after. Technical malfunction of the pens used for administration of the 
gonadotropin preparations will also be monitored.
As obligatory follow-up, pregnancy progress and outcome data will be gathered for subjects with a
vital pregnancy. Neonatal health data will be gathered to provide additional safety information. The 
follow-up extends till 4 weeks after birth.
3.5.3
Blinding
The FE 999049 and FOLLISTIM administration pens have different appearances. A double-blind 
design would require the patient to come to the clinic every day during the stimulation phase (an 
average of 9 days) to have the gonadotropin administered by a trial medication delegate. During the 
injections as well as the time immediately before and after, the patient would have to be blind-
folded in order to not see the FE 999049 or FOLLISTIM pen. Furthermore, in clinical practice 
patients will perform self-administration of the FSH preparation, therefore a double-blind design 
would not reflect routine practice and it is considered to be unacceptable for the patients and not in 
accordance with medical practice of self-administration. The trial, however, is assessor-blind, 
ensuring unbiased evaluation by the investigators, embryologists and central laboratory personnel.
Only the trial medication delegate personnel (persons responsible for investigational medicinal 
products (IMPs) / non-investigational medicinal products (NIMPs)), the monitors and the 
participating subjects will know the treatment allocation once the subjects are randomised. This 
assessor-blinded design has been reviewed and agreed with PMDA during consultation post-phase 
2 trial.
The present trial is assessor-blind, and all investigators, embryologists and central laboratory 
personnel will be blinded to treatment allocation throughout the trial. The trial medication delegate 
at site, the monitors and the participating subjects will know the treatment allocation once the 
subjects are randomised. The trial medication delegate will be responsible for all trial medication 
related issues, both practically at the clinic and in interactions with the subject. 


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To maintain the assessor-blinding, the trial medication delegate is not allowed to perform any 
assessments in the trial. Information on treatment allocation is only available to the trial medication 
delegate (the person entering data into the electronic case report form (eCRF)). The investigator 
does not have access to these modules in the eCRF. Precaution will be taken to ensure that the 
treatment allocations are not available to the investigators or other assessors throughout the trial. 
Subjects will be clearly instructed not to discuss their treatment allocation with the investigator.
Drug accountability forms and other forms identifying treatment allocation are kept unavailable to
the investigator. The subject will during the informed consent process be informed, both verbally 
and in writing, to not disclose her treatment allocation to the investigator. Trial staff is provided
with training in the importance of maintaining blinding, and trial medication delegates are also 
helped to set up systems at the clinic.
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and responsible medical officer) will be blinded to treatment allocation 
until breaking of the blind. The blind will be broken when the trial database is declared clean and 
locked.
3.5.4
Selection of Doses in the Trial
FE 999049
Modelling and simulation based on the efficacy and safety data obtained in the European phase 2
trial (000009) have been used to identify the overall dosing regimen for FE 999049. The objective 
of the FE 999049 dosing regimen is to obtain an appropriate ovarian response of 8-14 oocytes in 
most subjects, to minimise the proportion of subjects with <4 oocytes due to risk of unavailability 
of blastocysts for transfer, and to minimise the proportion of subjects with 15 oocytes or more as 
well as 20 oocytes or more due to the risk of early moderate/severe OHSS.
AMH and body weight were found to influence the dose-response with regard to obtaining the aim 
of the model of the FE 999049 dosing regimen. The impact of body weight on ovarian response is 
clinically relevant for low dose levels of FE 999049, while the effect is only minor at dose levels of 
12 μg and above. The proposed individualised dosing regimen of FE 999049 is described in detail 
in section 5.1 and is summarised as follows: for subjects with AMH <15 pmol/L the daily 
FE 999049 dose is 12 μg, irrespective of body weight, and for subjects with AMH ≥15 pmol/L the 
daily FE 999049 dose is on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on 
actual AMH and body weight. The safety and efficacy of this dosing regimen has been confirmed 
in a phase 3 trial overseas (ESTHER-1). The phase 2 trial in Japan (000124) showed a similar dose-
response for the Japanese population, which was corroborated by modelling and simulation of the 
efficacy data obtained in the Japanese phase 2 trial. 


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The dosing regimen of FE 999049 in this trial will be the same as the dosing regimen that was 
evaluated in the overseas phase 3 trial. However, a minimum daily dose of 6 µg FE 999049 is 
established to account for the lower body weight in the Japanese population and the maximum 
allowed daily FE 999049 dose is 12 μg. Thus, the daily dose of FE 999049 will be in the span from 
6 µg to 12 µg. This dose range was evaluated in the Japanese phase 2 trial. 
The FE 999049 dosing regimen has been reviewed and agreed at the PMDA post-phase 2 trial
consultation on 27 June 2016. The present trial aims to confirm the efficacy and safety of the 
proposed dosing regimen in the Japanese population.
FOLLISTIM
Subjects randomised to FOLLISTIM will be dosed according to the approved labelling in Japan. 
The starting dose of FOLLISTIM in this trial is 150 IU. The labelling for FOLLISTIM states a 
starting dose of 150-225 IU, but provides no recommendation for when to use 150 IU and when to 
use 225 IU. In the absence of a recommendation from the manufacturer, the lowest effective dose 
has been selected as this would be a reasonable approach in clinical practice, especially as the 
efficacy trial will include patients with no previous controlled ovarian stimulation for IVF/ICSI. 
This approach was also adopted in the phase 3 trial overseas (ESTHER-1). The FOLLISTIM 
starting dose is fixed for the first five stimulation days after which it may be adjusted by 75 IU 
based on the individual response. For FOLLISTIM, the minimum daily dose allowed is 75 IU and 
the maximum daily dose allowed is 375 IU.
Concomitant Fertility Medication 
The doses and overall treatment regimens for the GnRH antagonist (GANIREST), hCG (hCG 
FUJI) and progesterone (LUTINUS) products are in line with the recommendations in the 
respective products’ labelling for the indication of ART and/or standard clinical practice. 
The GnRH agonist (used according to local availability and at a dose according to site-specific 
procedures, e.g., a single dose of 300 μg SUPRECUR or 400 μg NASANYL) is included as an 
option for triggering of final follicular maturation in subjects with 25-35 follicles with a diameter 
≥12 mm, as this approach is associated with a reduced risk of early moderate/severe OHSS despite 
high ovarian response. The use of a GnRH agonist for triggering of final follicular maturation in a 
GnRH antagonist protocol is well-described in the literature and considered an acceptable 
alternative to cycle cancellation.20,21,22,23,24
3.5.5
Selection of the Trial Population
The trial population is representative of patients undergoing IVF/ICSI treatment. The subjects are 
women diagnosed with tubal infertility, unexplained infertility, infertility related to endometriosis 
stage I/II or with partners diagnosed with male factor infertility, eligible for IVF and/or ICSI 


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treatment. Classification of endometriosis is based on the revised American Society for 
Reproductive Medicine (ASRM) classification.25 Women with a history of recurrent miscarriage or 
with contraindications to controlled ovarian stimulation with gonadotropins will be excluded from 
participation in this trial. 
For the purpose of this trial, subjects within the age group 20-40 years are considered suitable as 
increasing female age is associated with lower AMH and consequently fewer oocytes as well as a 
reduction in oocyte/embryo quality.26 In this trial, oocytes will be cultured to blastocyst stage to 
gather as much information as possible on embryo development and single transfer has been 
implemented to facilitate interpretation of the pregnancy data. 
The allowed body mass index (BMI) is within 17.5-32.0 kg/m2 (both inclusive). This broad range in 
BMI will facilitate the subsequent recommendation of doses in underweight, normal weight, 
overweight and obese patients.
The exclusion criteria incorporate the contraindications for the use of gonadotropins and the 
concomitant fertility medication.
Altogether, the population selected for this trial would be expected to be representative for patients 
undergoing controlled ovarian stimulation in IVF/ICSI cycles.
3.5.6
Follow-up Procedures
Pregnancy Follow-up 
As obligatory follow-up, pregnancy progress and outcome data will be gathered for subjects with a 
vital pregnancy. Data will be collected on ongoing pregnancy (10-11 weeks after transfer) and 
pregnancy outcome as well as neonatal health at birth and at 4 weeks after birth. The pregnancy 
follow-up does not include any interventions but only data collection.
Access to Therapy after End-of-Trial
Concerning access to therapy after completion of the trial, FE 999049 is currently under clinical 
development in Japan and cannot be offered to patients after participation in this clinical trial. 
However, FOLLISTIM is approved for controlled ovarian stimulation and is commercially 
available in Japan.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects must meet all of the criteria listed below to be eligible for participation in the trial.
Informed Consent Documents signed prior to any trial-related procedures.
In good physical and mental health.
Japanese females between the ages of 20 and 40 years. The subjects must be at least 
20 years (including the 20th birthday) when they sign the Informed Consent Documents and 
no more than 40 years (up to the day before the 41st birthday) at the time of randomisation.
Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage 
I/II (defined by the revised American Society for Reproductive Medicine (ASRM) 
classification) or with partners diagnosed with male factor infertility, eligible for in vitro 
fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated 
sperm from male partner.
Infertility for at least 1 year before randomisation (not applicable in case of tubal or severe 
male factor infertility).
The trial cycle will be the subject’s first controlled ovarian stimulation cycle for IVF/ICSI.
Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
Hysterosalpingography, hysteroscopy, saline infusion sonography or transvaginal ultrasound 
documenting a uterus consistent with expected normal function (e.g. no evidence of 
clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 
3 cm in diameter, no polyps and no congenital structural abnormalities which are associated 
with a reduced chance of pregnancy) within 1 year prior to screening. This also includes 
women who have been diagnosed with any of the above medical conditions but have had 
them surgically corrected within 1 year prior to screening.
Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or 
enlarged ovaries which would contraindicate the use of gonadotropins) and fallopian tubes 
and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) 
within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results 
obtained within 3 months prior to screening).
Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and 
Human Immunodeficiency Virus (HIV) antibody tests within 1 year prior to screening. 
Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening. 
Willing to accept transfer of one blastocyst.


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4.1.2
Exclusion Criteria
Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.
Known endometriosis stage III-IV (defined by the revised ASRM classification25).
One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound 
prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomisation is 
allowed).
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. In case the sperm production is 
severely impaired (concentration <1 million/mL), normal karyotype, including no 
Y-chromosome microdeletion, must be documented.
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these 
events.
Known porphyria.
Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
Known inherited or acquired thrombophilia disease.
Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) which can compromise participation in the trial with the exception of controlled 
thyroid function disease.
Known presence of anti-FSH antibodies (based on the information available in the subject’s 
medical records). 
Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
Any abnormal finding of clinical chemistry, haematology or vital signs at screening, which 
is judged clinically relevant by the investigator. 
Known moderate or severe impairment of renal or hepatic function.
Currently breast-feeding.
Undiagnosed vaginal bleeding.
Known abnormal cervical cytology of clinical significance observed within 3 years prior to 
screening (unless the clinical significance has been resolved).
Findings from the laboratory analyses at screening which preclude gonadotropin 
stimulation.
Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation.
Findings at the gynaecological examination at screening which are associated with a 
reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine 
device.
Pregnancy (must be confirmed by negative urinary pregnancy tests at screening and prior to 
randomisation) or contraindication to pregnancy.
Known current active pelvic inflammatory disease.


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Use of hormonal preparations (except for thyroid medication) or fertility modifiers during 
the last menstrual cycle before randomisation, including dehydroepiandrosterone (DHEA), 
metformin and cycle programming with oral contraceptives, progestogen or estrogen 
preparations.
Known history of chemotherapy (except for gestational conditions) or radiotherapy.
Current or past (1 year prior to randomisation) abuse of alcohol or drugs, and/or current (last 
month) intake of more than 14 units of alcohol per week.
Current or past (3 months prior to randomisation) smoking habit of more than 10 cigarettes 
per day.
Hypersensitivity to any drug substance or excipients in the medicinal products used in the 
trial.
Hypersensitivity to any drug substance or excipients in a GnRH or any GnRH analogue / 
derivative.
Previous participation in the trial. 
Current participation in another trial, including follow-up period.
Use of any non-registered investigational drugs during the last 3 months prior to screening.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The participating subjects will be recruited among the patients attending the clinics included in the 
trial. Advertisements may be used if approved by the local Institutional Review Board (IRB) / 
Ethics Committees (ECs) and regulatory authorities, as applicable according to local regulations.
A screening number is allocated to each subject who has given written informed consent to 
participate in the trial. A subject must always be assigned to the lowest available screening number 
at each site. A subject screening / enrolment log for all screened subjects must be maintained by the 
investigator.
4.2.2
Randomisation
On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to treatment with 
either FE 999049 or FOLLISTIM, and stimulation will be initiated. Randomisation is performed 
centrally through the eCRF and will be stratified according to AMH levels at screening 
(<15 pmol/L and ≥15 pmol/L) and centre. The randomisation number will be allocated to the 
subject together with the treatment allocation and starting dose. When a subject is randomised to
the trial, she will always be assigned to the lowest available randomisation number. An independent 
statistician at the Ferring Global Biometrics Department will prepare a computer-generated 
randomisation list and randomisation is performed in blocks. Blocks will be maintained within trial 
sites, i.e. the randomisation will be stratified by trial site. The block size will only be revealed when 
the trial database is declared clean and locked. An overview of recruitment will be recorded on a 


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subject identification code list for all randomised subjects kept by the investigator.
4.3
Restrictions
Prohibited Therapy before and during the Trial
The subjects must not have used hormonal preparations (except for thyroid medication) or fertility 
modifiers, including DHEA, metformin and cycle programming with oral contraceptives, 
progestogen or estrogen preparations from the start of the last menstrual cycle before randomisation
until the end of the trial.
It is prohibited to administer other gonadotropins than FE 999049 or FOLLISTIM and concomitant 
fertility medication provided as part of the trial regimen.
Prohibited Therapy after the Trial
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial.
4.4
Withdrawal Criteria
Withdrawal from Trial
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. The investigator also has the right to withdraw subjects. For any 
discontinuation, the investigator will obtain all the required details and document the date of the 
premature termination and the main reason in the eCRF.
Withdrawal of Consent
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analysed. This will be described in the Informed Consent Documents. The subject 
can request destruction of samples which would otherwise have been kept in storage.
4.5
Subject Replacement
A subject can only be assigned one screening number and one randomisation number.
Subjects who discontinue prematurely from the trial after randomisation are not to be replaced, i.e. 
randomisation numbers are uniquely linked to each subject and cannot be re-used.


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5
TREATMENTS
5.1
Investigational Medicinal Products (IMPs)
On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1 ratio to treatment with 
either FE 999049 or FOLLISTIM, and controlled ovarian stimulation will be initiated.
5.1.1
FE 999049 Dosing Regimen
Subjects randomised to FE 999049 will have their individual dose determined on the basis of their 
AMH level at screening and their body weight at randomisation. For subjects with 
AMH <15 pmol/L the daily FE 999049 dose is 12 μg, irrespective of body weight. For subjects 
with AMH ≥15 pmol/L the daily FE 999049 dose is on a continuous scale ranging from 0.19 to 
0.10 μg/kg, i.e. dependent on actual AMH and body weight.
The daily FE 999049 dose will be fixed throughout the stimulation period. The minimum allowed 
daily FE 999049 dose is 6 μg. The maximum allowed daily FE 999049 dose is 12 μg. Dosing will 
continue until the criterion for triggering of final follicular maturation has been met. Subjects can 
be treated with FE 999049 for a maximum of 20 days. Coasting is not allowed.
The continuous part of the FE 999049 dosing regimen is illustrated in Figure 5-1, and the complete 
FE 999049 dosing regimen is tabulated in detail in Table 5-1.
Figure 5-1 FE 999049 Dosing Regimen
0.10
0.12
0.14
0.16
0.18
0.20
15
20
25
30
35
40
45
AMH (pmol/L)
FE 999049 Dose (ug/kg)


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Table 5-1
FE 999049 Dosing Regimen
Treatment 
group
AMH 
concentration 
(pmol/L)
Daily dose fixed 
throughout 
stimulation
Minimum 
daily dose
Maximum 
daily dose
FE 999049
<15
12 μg 
-
12 μg
15-16
0.19 μg/kg 
6 μg
12 μg
17
0.18 μg/kg 
6 μg
12 μg
18
0.17 μg/kg 
6 μg
12 μg
19-20
0.16 μg/kg 
6 μg
12 μg
21-22
0.15 μg/kg 
6 μg
12 μg
23-24
0.14 μg/kg 
6 μg
12 μg
25-27
0.13 μg/kg 
6 μg
12 μg
28-32 
0.12 μg/kg 
6 μg
12 μg
33-39 
0.11 μg/kg 
6 μg
12 μg
≥40 
0.10 μg/kg 
6 μg
12 μg
AMH concentration will be rounded off to integers.
Subjects can be treated for a maximum of 20 days.
.
The FE 999049 preparation is administered as a single daily subcutaneous injection in the 
abdomen. The dose must not be split into two injections. To minimise local injection site reactions, 
it is advisable to change injection site regularly.
The first FE 999049 injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer FE 999049.
Calculation of the FE 999049 Dose and Setting the Dose on the FE 999049 Pre-Filled Pen
The subject’s serum AMH concentration will be available from the blood sample taken at screening 
and analysed by a central laboratory using Elecsys® AMH assay from Roche Diagnostics. The 
AMH concentration will be provided from the central laboratory directly to the eCRF. The 
subject’s body weight will be measured at randomisation using a calibrated scale and performed 
without shoes and overcoat. The body weight result will be entered into the eCRF. The FE 999049 
dosing algorithm has been programmed in the eCRF, which calculates the FE 999049 dose based 
on the subject’s AMH and body weight. 
The FE 999049 pre-filled injection pen is intended for subcutaneous administration of FE 999049. 
It is a non-sterile needle-based disposable device with integrated non-replaceable 3 mL cartridge 
containing the liquid FE 999049 drug product. Each cartridge holds multiple doses, the size of 
which are adjustable by the user. It is possible to set doses from 0.33 µg to 20.0 µg in increments of 


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0.33 µg. The FE 999049 pre-filled injection pen has a dosing scale numbered from 0 to 20 µg. Each 
number is separated by two lines, each line representing 0.33 μg.
The pre-filled injection pen can be set to deliver doses rounded to the nearest 0.33 μg. Rounding off 
of the calculated dose may be needed, as in this example of a subject weighing 75.0 kg with an 
AMH level of 35 pmol/L for whom the calculated dose is 8.25 μg (0.11 μg/kg * 75.0 kg), which 
will then be rounded to 8.33 μg, i.e. 8 μg + 1 line on the pen. The eCRF will provide the calculated 
dose in an output that matches the numbers and lines on the pre-filled injection pen; i.e. any 
rounding off will be done automatically prior to providing the subject’s calculated dose.
The trial medication delegate will be instructed and trained in the correct use of the pre-filled 
injection pen, so that correct instructions can be provided to the subject.
5.1.2
FOLLISTIM Dosing Regimen
For subjects randomised to FOLLISTIM, the dosing regimen is within labelling. The starting dose 
of FOLLISTIM is 150 IU and fixed for the first five stimulation days, after which it may be 
adjusted by 75 IU based on the individual response. The maximum daily FOLLISTIM dose allowed 
is 375 IU. Dosing will continue until the criterion for triggering of final follicular maturation has 
been met. Subjects can be treated with FOLLISTIM for a maximum of 20 days. Coasting is not 
allowed.
The FOLLISTIM dosing regimen is shown in detail in Table 5-2.
Table 5-2
FOLLISTIM Dosing Regimen
Treatment 
group
Starting dose 
stimulation day 
1-5
Daily dose stimulation day 6 
and onwards
Minimum
daily dose
Maximum 
daily dose
FOLLISTIM 
150 IU
Adjustments of 75 IU allowed 
according to the individual 
response. 
75 IU
375 IU
Subjects can be treated for a maximum of 20 days.
The FOLLISTIM preparation is administered as a single daily subcutaneous injection in the 
abdomen. The dose must not be split into two injections. To minimise local injection site reactions, 
it is advisable to change injection site regularly.
The first FOLLISTIM injection will take place at the clinic and will be performed either by the trial 
medication delegate or the subject under supervision by the trial medication delegate. Subsequent 
injections can be done at home or at the clinic. The trial medication delegate will give the subject 
instructions for how to administer FOLLISTIM.


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5.2
Non-investigational Medicinal Products (NIMPs)
The following medicinal products will be used as concomitant fertility therapy in the controlled 
ovarian stimulation cycle: 

GnRH antagonist (GANIREST): 0.25 mg subcutaneous injection once daily starting on 
stimulation day 6 and continued throughout the stimulation period, although for a maximum 
of 15 days. GANIREST and FE 999049 / FOLLISTIM should be administered 
approximately at the same time. However, the preparations should not be mixed and 
different injection sites are to be used.

hCG (hCG FUJI): 5,000 IU as a single intramuscular injection on the day of reaching the 
criterion for triggering of final follicular maturation with hCG. 

Vaginal progesterone (LUTINUS): 100 mg vaginal tablets three times daily, starting on the 
day after oocyte retrieval and continued until the day of the clinical pregnancy visit 
(5-6 weeks after transfer) unless progesterone support is terminated earlier in case of no 
transfer, menses, negative βhCG or pregnancy loss. Thus, the maximum duration of vaginal 
progesterone use within the trial is approximately 6-7 weeks.
All NIMPs are used in line with the recommendations in the respective products’ labelling for the 
indication of ART and/or standard clinical practice supported by literature.
5.3
Characteristics and Source of Supply
All medicinal products are provided by Ferring and will be handled according to the principles of 
Good Manufacturing Practice (GMP). Table 5-3 provides an overview of the presentation and 
manufacturer of each medicinal product.


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Table 5-3
Characteristics and Source of Supply of Medicinal Products
Medicinal Product
Presentation
Manufacturer
FE 999049
(rFSH)
FE 999049 is provided as a pre-
filled injection pen containing 
72 μg/ 2.16 mL FE 999049.
Ferring Pharmaceuticals 
FOLLISTIM
(rFSH)
FOLLISTIM (follitropin beta) is 
provided as a cartridge and an 
administration pen. Each cartridge 
contains a solution for injection 
delivering 900 IU FSH in 1.08 mL.
MSD K.K.
GANIREST
(GnRH antagonist)
GANIREST (ganirelix acetate) is 
provided as a pre-filled syringe. The 
syringe contains a solution for 
injection delivering 0.25 mg of 
ganirelix in 0.5 mL. 
MSD K.K.
hCG FUJI
(hCG)
hCG FUJI is provided as an
ampoule and a diluent. An ampoule
contains 5,000 IU of hCG. 
Fuji Pharma
LUTINUS 
(vaginal progesterone)
LUTINUS is provided as tablets to 
be administered vaginally, each 
containing 100 mg of progesterone. 
Ferring Pharmaceuticals
5.4
Packaging and Labelling
Packaging and labelling of the medicinal products will be done under the responsibility of Ferring 
Pharmaceuticals in accordance with GMP and national regulatory requirements. Details on the 
packaging of each medicinal product are provided in Table 5-4.


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Table 5-4
Packaging of Medicinal Products
Medicinal Product
Packaging
FE 999049
(rFSH)
FE 999049 is provided in boxes containing 1 pre-filled pen. Single use 
disposable needles are packed separately in a commercial box containing 
70 needles labelled with a trial-specific label. Pen and boxes will be 
labelled with trial-specific labels.
FOLLISTIM 
(rFSH)
FOLLISTIM is provided in commercial boxes containing 1 cartridge for 
multiple use. The commercial box of cartridge will be packed in a box 
with a trial-specific label. Pen for administration of FOLLISTIM is 
provided separately in a commercial box containing 1 pen. The 
commercial box of pen will be labelled with a trial-specific label. 
GANIREST 
(GnRH antagonist)
GANIREST is provided in commercial boxes containing 1 prefilled 
syringe. The commercial box will be labelled with a trial-specific label. 
hCG FUJI
(hCG)
hCG FUJI is provided in commercial boxes containing 10 ampoules and 
diluents. The commercial box will be labelled with a trial-specific label. 
LUTINUS
(vaginal progesterone)
LUTINUS is provided in boxes containing 21 vaginal applicators 
(without any printings) and 21 vaginal tablets individually wrapped in a 
sealed foil pouch. The box will be labelled with a trial-specific label. 
FOLLISTIM, GnRH antagonist (GANIREST), hCG (hCG FUJI) and progesterone (LUTINUS) are 
commercially available in Japan and will be purchased centrally. No modification from the usual 
commercial state will be made of FOLLISTIM, GANIREST, hCG FUJI and LUTINUS except for 
trial-specific labelling. A leaflet specific for Japan will be distributed together with each medicinal 
product.
5.5
Conditions for Storage and Use
The investigator will ensure that the medicinal products are stored in appropriate conditions in a 
secure location with controlled access. The storage compartment will be monitored regularly and 
the temperature values will be documented. Deviations in storage temperature must be reported 
without delay and the medicinal products must not be used until further instructions from Ferring 
are received. Conditions for storage of the medicinal products before and after dispensing to the 
subjects are listed in Table 5-5.


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Table 5-5
Conditions for Storage of Medicinal Products
Medicinal Product
Before dispensing to subject
After dispensing to subject
FE 999049
(rFSH)
Store refrigerated at 2-8 ºC. 
Do not freeze. Store in original 
package to protect from light.
Store at 2-30°C for up to 28 days. 
Do not freeze. Store in original 
package to protect from light. 
FOLLISTIM
(rFSH)
Store in refrigerator at 2-8 ºC. 
Do not freeze. Store in original 
package to protect from light.
Store at 2-25 °C. 
Do not freeze. Store in original 
package to protect from light.
GANIREST
(GnRH antagonist)
Store at 1-30 °C. 
Do not freeze. Store in original 
package to protect from light.
Store at 1-30 °C. 
Do not freeze. Store in original 
package to protect from light.
hCG FUJI
(hCG)
Store at 1-15 ºC. 
Do not freeze. Store in original 
package to protect from light.
Generally this medicinal product 
will not be dispensed to subjects, 
but if dispensing to subjects is 
required, the conditions for storage 
are:
Store at 1-15 ºC. 
Do not freeze. Store in original 
package to protect from light.
LUTINUS
(vaginal progesterone)
Store at 1-30 °C. 
Do not freeze. Store in original 
package to protect from light.
Store at 1-30 °C. 
Do not freeze. Store in original 
package to protect from light.
In case of technical malfunction of an administration pen, all relevant details (including time, date, 
a description of the malfunction and whether dosing was affected) of the incidence should be 
reported, the pen should be replaced and the treatment continued.
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for FE 999049, and to the effective versions of the commercial product 
information for FOLLISTIM, GANIREST, hCG FUJI and LUTINUS.
5.6
Blinding / Unblinding
5.6.1
Blinding
The trial is assessor-blind, and all investigators, embryologists and central laboratory personnel will 
be blinded to treatment allocation throughout the trial. The trial medication delegate at site (person 


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responsible for IMP/NIMP), the monitors and the participating subjects will know the treatment 
allocation once the subjects are randomised. Precaution must be taken to ensure that the treatment 
allocations are not available to the investigators or other assessors throughout the trial. Subjects 
must be clearly instructed to only discuss their treatment allocation with the trial medication 
delegate, and to not mention it to the investigator.
The trial medication delegate will dispense the trial medication to the subject (and may also do the 
actual administration at the clinic, if required). The investigator will, based on the follicular 
development, judge if dose adjustments are recommended and state his/her directions on a form 
developed for that purpose, which will be used to inform the trial medication delegate. Depending 
on whether the subject is being treated with FE 999049 or FOLLISTIM, the trial medication 
delegate will provide detailed instructions to the subject in line with the dosing regimen for each 
preparation as outlined in the protocol. In other words, if the investigator recommends a dose 
adjustment, the trial medication delegate will implement a decrease or increase of 75 IU/day as 
applicable if the subject is in the FOLLISTIM group, while no dose adjustments will be 
implemented if the subject is in the FE 999049 group. Requests for cycle cancellation due to 
inappropriate response or other medical reasons are followed, irrespective of treatment group.
The randomisation list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information in the eCRF will not be accessible to assessors or the Ferring clinical trial team or 
laboratory personnel during the trial.
The Ferring clinical trial team (i.e. data manager, statistician, trial manager, medical writer, 
pharmacovigilance manager and sponsor’s responsible medical officer) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when the trial database is declared 
clean and locked.
5.6.2
Unblinding of Individual Subject Treatment
An emergency unblinding procedure will be available for the investigator and designated personnel 
at the sponsor through the eCRF. It is the investigator’s responsibility to decide whether it is 
medically necessary to know the investigational product the subject receives (i.e., unblinding) to 
ensure the subject’s welfare and safety. 
Breaking of the blind for individual subjects in emergency situations could be required in case of 
suspected unexpected serious adverse reactions (SUSARs) or in case of other important adverse 
events when the knowledge of the IMP in question is required for therapeutic decisions for the 
management of the subject. As far as the emergency permits, the need to break the blind will be 
agreed by the investigator and the sponsor. Where the event requires immediate unblinding by the 
investigator, the sponsor must be informed of the unblinding as soon as possible and provided with 
the rationale for unblinding. 


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The investigator who unblinds a treatment will use the eCRF and is required to enter a password 
and must record the reason for unblinding before the treatment code can be broken. The eCRF 
records when, and by whom, the code was broken. The investigator must record the event of 
unblinding in the subject’s medical record, including the reason for unblinding, but not the 
treatment allocation if this can be avoided.
In case of accidental unblinding (e.g. the subject tells the investigator), the same procedure as for 
emergency unblinding must be followed, i.e. the investigator/person who was accidentally 
unblinded will enter a password in the eCRF and must record the reason for unblinding. The eCRF 
records when, and by whom, the code was broken. In addition the event must also be recorded in 
the subject’s medical record. 
If Ferring needs to unblind a treatment, the eCRF will be used for unblinding. It is a requirement 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 operational procedures for unplanned unblinding of trial subjects. It may be necessary to 
unblind an individual subject’s treatment for the purposes of expedited reporting to the authorities 
and/or IRBs/ECs. In that situation, every effort will be made to maintain blinding of sponsor 
personnel involved in data analysis and interpretation. Other personnel may be unblinded for 
SUSARs, including trial site staff as well as staff acting on behalf of Ferring.
Information on whether the blind has been broken for any subjects is available in the 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 Global 
Pharmacovigilance using the contact details below:
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
Tel: 
In case Ferring Global Pharmacovigilance cannot access the eCRF, a backup procedure involving 
the eCRF vendor is in place.
5.7
Dispensing and Accountability, Return and Destruction
All handling of medicinal products will be done by a trial medication delegate at the site. The trial 
medication delegate will maintain subject dispensing logs, detailing the dates, quantities and batch 
numbers of dispensed and returned medicinal products for each subject. The trial medication 
delegate will also manage the overall drug accountability at the site.
The monitor will verify drug accountability of medicinal products throughout the trial and will 
document any discrepancies.


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Concerning destruction, the trial medication delegate at the site must ensure destruction of 
dispensed/used medicinal products in accordance with local legislation after drug accountability 
have been verified by the monitor.
Non-dispensed / unused medicinal products will be returned for destruction as instructed by Ferring
after drug accountability have been verified by the monitor.
5.8
Auxiliary Supplies
Ferring will supply safety containers for the collection of used syringes and needles.


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6
TRIAL PROCEDURES
The flow of the trial procedures for subjects is shown in Table 6-1.
Table 6-1
Trial Flow Chart – Subject Procedures 
Scree-
ning
Stimulation
Oocyte 
re-
trieval
Transfer
Pregnancy monitoring
End
During stimulation
End-of-
stimula-
tion
OR
Transfer /
cryopreser-
vation
βhCG
Clinical
End-of-
trial
Timing
<60 days 
before 
random-
isation
Day 1
Day 6
Day 
≥7 to 
<20 a)
End
36h 
±2h 
after 
trigger-
ing
5 days
after OR
13-15 days 
after transfer
5-6 weeks 
after 
transfer
b)
Written informed consent
X
Inclusion / exclusion criteria
X
 Xc)
Demographics
X
Medical history 
X
Infertility history
X
Menstrual history
X
Reproductive history
X
Body measurements
X
 Xc)
X
Physical examination
X
X
Gynaecological examination
X
X
Urinary pregnancy test
X
 Xc)
Blood collection, clin chem / 
haem
X
X
X
Blood collection, endocrine
 Xe)
    Xd) e)
 Xf)
 Xf)
Ultrasound (ovaries and/or 
uterus)
  Xc)
X
X
X
X
Vital signs
 Xd)
X
Randomisation
X
FE 999049 or FOLLISTIM 
dispensing
  Xg)
  Xg)
Xg)
Local tolerability (diary) 
X
X
X
X
X
Concomitant fertility 
medication dispensing
X
X
X
X
X
X
Oocyte retrieval
X
Transfer / cryopreservation
X
βhCG test 
 Xh)
Drug accountability
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
End-of-trial form
X
a) Visits must be scheduled at least every second day; when 3 follicles of ≥15 mm are observed visits must be scheduled daily.
b) End-of-trial assessments must be performed at the subject’s last scheduled visit. 
c) Performed before randomisation. 
d) Performed before the first FE 999049 or FOLLISTIM dose. 
e) Including AMH analysis
f) Must be drawn at least 8h after the previous administration of FE 999049 or FOLLISTIM and GnRH antagonist, as 
applicable. 
g) If dispensing of FE 999049 or FOLLISTIM in special cases is not possible during stimulation, as an exception all FE 999049
or FOLLISTIM can be dispensed on stimulation day 1. 
h) Subjects experiencing a full menstrual bleeding following transfer must have the βhCG test performed 7-15 days after 
transfer.
AMH: anti-Müllerian hormone; OR: oocyte retrieval.


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If trial procedures and/or assessments are to be performed on Sundays, public holidays or outside 
the opening hours of the clinic, the procedures and/or assessments can be postponed to the 
upcoming weekday (maximum one day after original visit schedule) or cancelled, if appropriate.
6.1
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 60 days prior stimulation day 1 (randomisation). 
The following must take place during the screening period:

Signed and dated written informed consent, obtained prior to any trial-related procedures

Allocation of a screening number

Check of inclusion and exclusion criteria (those which are possible to check at screening)

Demographics (age, ethnicity, race)

Collection of the following data:
–
Medical history
–
Infertility history
–
Menstrual history
–
Reproductive history

Body measurements (body weight, height) [note: these are used for calculation of BMI]

Physical examination

Gynaecological examination

Urinary pregnancy test – must be negative

Blood collection for central laboratory analysis of 
–
Endocrine parameters: AMH, thyroid-stimulating hormone (TSH) and prolactin
[note: the results must be available prior to randomisation]
–
Clinical chemistry and haematology parameters
[note: the results must be available prior to randomisation]

Recording of use of any concomitant medication (within the last 3 months prior to signed 
informed consent for participation in the trial)

Recording of adverse events (from the date of signed informed consent for participation in 
the trial)
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit, scheduled on day 2-3 of the menstrual cycle. 


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6.2
Stimulation 
6.2.1
Stimulation Day 1 
Subjects will attend the stimulation day 1 visit on day 2-3 of the menstrual cycle.
The following must take place prior to randomisation:

Ensure that the subject is still eligible for participation in the trial

Check those inclusion and exclusion criteria that were not possible during screening 

Body measurements (body weight [note: this body weight result is used for dose calculation 
in the FE 999049 group])

Urinary pregnancy test – must be negative

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial 
echogenicity pattern, ovarian volume, number and size of follicles)
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation:

Randomisation, i.e. assignment to the lowest available subject number and thereby 
allocation to either FE 999049 or FOLLISTIM
The following must take place after randomisation but before administration of the first dose of 
FE 999049 or FOLLISTIM:

Vital signs

Blood collection for central laboratory analysis of endocrine parameters
Once the above has been completed, the following must be performed by the trial medication 
delegate. Care must be taken to ensure blinding of the investigator and other assessors.

Dispense FE 999049 or FOLLISTIM according to randomisation and instruct the subject on 
how to administer FE 999049 or FOLLISTIM, including that all subsequent FE 999049 or 
FOLLISTIM administrations are preferably to be done in the evening 

Administer the 1st dose of IMP according to randomisation [administration of IMP takes 
place at the clinic and can be done by either the trial medication delegate or the subject 
under supervision by the trial medication delegate]: 
-
If randomised to FE 999049; daily dose is calculated by the eCRF according to 
AMH level at screening and body weight at randomisation (see Table 5-1 on page 45
for detailed instructions)

If randomised to FOLLISTIM; starting dose for the first 5 days is fixed at 150 IU.

Hand out the diary to the subject. The subject must be instructed to assess and record local 
tolerability immediately, 30 min and 24 hours after each injection of FE 999049 or 
FOLLISTIM throughout the entire stimulation period 


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After the first administration of FE 999049 or FOLLISTIM, the subject must do the following: 

Assessment of local tolerability (recorded in a diary) – the first evaluation of injection site 
reactions is done immediately after the subcutaneous injection of FE 999049 or 
FOLLISTIM, followed by the second evaluation 30 min after injection of FE 999049 or 
FOLLISTIM and the third evaluation 24 hours after injection of FE 999049 or FOLLISTIM
(before the next day’s injection of FE 999049 or FOLLISTIM)
Finally, this must be done before the subject leaves the clinic:

Take precautions in the event that the subject experiences an acute allergic reaction. In the 
first 30 min following the administration of FE 999049 or FOLLISTIM, the trial medication 
delegate (or another qualified trial staff) must observe the subject’s general health with 
emphasis on symptoms of an acute allergic reaction. The trial sites are requested to have 
facilities (i.e. medication, equipment and trained staff) and procedures in place for diagnosis 
and treatment of acute allergic reactions

Recording of use of any concomitant medication

Recording of adverse events
The next visit must be scheduled for stimulation day 6.
6.2.2
Stimulation Day 6
The following must take place at stimulation day 6:

Blood collection for central laboratory analysis of endocrine parameters – the blood sample 
must be drawn at least 8 hours after the latest FE 999049 or FOLLISTIM administration

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial 
echogenicity pattern, number and size of follicles)

Dispensing of FE 999049 or FOLLISTIM
[Note: If dispensing of FE 999049 or FOLLISTIM in special cases is not possible during 
stimulation, as an exception all FE 999049 or FOLLISTIM can be dispensed on stimulation 
day 1]

Dispensing and administration of GnRH antagonist [the first administration of GnRH 
antagonist takes place at the clinic and can be done by either the trial medication delegate or 
the subject under supervision by the trial medication delegate]

Drug accountability of FE 999049 or FOLLISTIM

Collection of diary pages

Recording of use of any concomitant medication

Recording of adverse events


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Finally, this must be done before the subject leaves the clinic:

In the first 30 min following the GnRH antagonist administration, the trial medication 
delegate (or another qualified trial staff) must observe the subject’s general health with 
emphasis on symptoms of an acute allergic reaction 

Instruct the subject to administer the GnRH antagonist at a daily dose of 0.25 mg throughout 
the stimulation period
After the stimulation day 6 visit, the next visits must be scheduled at least every second day 
throughout the remaining stimulation period.
6.2.3
Stimulation Days ≥7 to ≤20
These visits will take place at least every second day throughout the remaining stimulation period. 
When 3 follicles of ≥15 mm are observed, visits must be scheduled daily. The maximum period of 
stimulation is 20 days.
The following must take place at all visits throughout the remainder of the stimulation period with 
exception of the end-of-stimulation visit (section 6.2.4):

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial 
echogenicity pattern, number and size of follicles)

Dispensing of FE 999049 or FOLLISTIM, as applicable
[Note: If dispensing of FE 999049 or FOLLISTIM in special cases is not possible during the 
stimulation period, as an exception all FE 999049 or FOLLISTIM can be dispensed on 
stimulation day 1]

Dispensing of GnRH antagonist, as applicable

Drug accountability of FE 999049 or FOLLISTIM and GnRH antagonist

Collection of diary pages

Recording of use of any concomitant medication

Recording of adverse events
6.2.4
End-of-Stimulation
The end-of-stimulation visit takes place on the day when the subject reaches the criterion for 
triggering of final follicular maturation or any of the cycle cancellation criteria because of poor or 
excessive ovarian response.


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Poor ovarian response
Triggering criterion 
Excessive ovarian response
If it is judged by the 
investigator that ≥3 follicles 
with a diameter ≥17 mm cannot 
be reached by stimulation day 
20, the cycle is to be cancelled.
Criterion for triggering of final 
follicular maturation:
≥3 follicles with a 
diameter ≥17 mm
hCG a) must be administered the
day the triggering criterion is 
met. 
In case of ≥25 follicles 
≥12 mm, the cycle should be 
cancelled.
(note: in case of 25-35 
follicles with a diameter 
≥12 mm, GnRH agonist may 
be administered) b)
a)
hCG FUJI 5,000 IU as a single intramuscular injection will be administered on the day of reaching the criterion for triggering of 
final follicular maturation with hCG. In case it is not possible for the subject to attend a visit at the clinic for the intramuscular 
injection (typically occurring late in the evening), it will be accepted to implement site-specific routines for ensuring 
administration of hCG FUJI 5,000 IU. 
b)
In case of triggering of final follicular maturation with a GnRH agonist, a GnRH agonist nasal spray such as SUPRECUR 
(buserelin acetate, Sanofi / Mochida Pharmaceuticals Co., Ltd) or NASANYL (nafarelin acetate, Pfizer) can be used according 
to local availability and at a dose according to site-specific procedures, e.g. a single dose of 300 μg SUPRECUR or 400 μg 
NASANYL. 
The investigator also has the option of cancelling the cycle for other relevant medical reasons, 
including adverse events and technical malfunctions of the administration pens.
As the injections of gonadotropin (FE 999049 or FOLLISTIM) and GnRH antagonist preferably are 
done in the evening, the last injections of these preparations occur the evening before the criterion 
for triggering of final follicular maturation is met and the triggering drug (hCG or GnRH agonist) is 
administered. 
The following must take place at the end-of-stimulation visit:

Blood collection for central laboratory analysis of:
–
Clinical chemistry and haematology parameters
–
Endocrine parameters – the blood sample must be drawn at least 8 hours after the 
previous administration of FE 999049 or FOLLISTIM and GnRH antagonist, as 
applicable

Transvaginal ultrasound of uterus and ovaries (endometrial thickness, endometrial 
echogenicity pattern, number and size of follicles)

Administration of hCG (or GnRH agonist, if applicable)

Drug accountability of FE 999049 or FOLLISTIM and GnRH antagonist

Collection of diary pages

Recording of use of any concomitant medication

Recording of adverse events


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For subjects who receive a triggering drug, the next visit is the oocyte retrieval visit which must be 
scheduled 36h (±2h) after administration of the triggering drug.
Subjects with cycle cancellation will proceed to end-of-trial assessments.
6.3
Oocyte Retrieval
Oocyte retrieval must take place 36h (± 2h) after administration of the triggering drug. All oocytes 
from follicles with an estimated diameter ≥12 mm should be retrieved. Below are listed the 
procedures related to the subjects attending the oocyte retrieval visit, while procedures related to 
the oocytes are described in section 6.4.
The following must take place at the oocyte retrieval visit:

Oocyte retrieval

Dispensing of progesterone for luteal 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

Collection of diary pages

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with oocytes retrieved following hCG administration, the next visit is the transfer visit 
5 days after oocyte retrieval. For subjects with oocytes retrieved following GnRH agonist 
administration, the oocytes will undergo the procedures described in section 6.4 and blastocysts 
will be cryopreserved as according to local practice and declaration by JSOG.
Subjects with no oocytes retrieved will proceed to end-of-trial assessments.
6.4
Oocyte / Embryo / Blastocyst Evaluation 
The laboratory procedures regarding handling and evaluations of oocytes, embryos and blastocysts 
are described in detail in a trial-specific manual. This section provides an overview of the 
procedures and assessments to be made from oocyte retrieval till transfer at the blastocyst stage. 
The flow of the trial procedures for embryos is shown in Table 6-2. 


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Table 6-2
Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures
Day 0 (OR)
Day 1
Day 3
Day 5
Timing
-2h 
(± 2h)
0h
19h
(± 2h)
68h
(± 2h)
120h
(± 3h)
Oocyte retrieval (OR)
X
Assessment of maturity stage (applicable for oocytes 
undergoing ICSI)
X
Insemination by IVF or ICSI
X
Assessment of oocyte fertilisation
X
Assessment of embryo/blastocyst quality
X
X
Transfer of a single blastocyst a)
X
Cryopreservation of blastocysts
Xb)
a) In the absence of a viable blastocyst, a single morula may be used for transfer. 
b) Cryopreservation may also occur after day 5.
Assisted hatching is prohibited and pre-implantation genetic diagnosis (PGD) / pre-implantation 
genetic screening (PGS) are prohibited.
Day 0 (Oocyte Retrieval)

Oocyte retrieval at 2h (± 2h), i.e. 0-4 hrs, before start of any insemination procedure. 
Oocytes must be cultured individually in separate dishes / droplets

Procedures between oocyte retrieval and insemination:
–
Assessment of maturity stage (applicable for oocytes undergoing ICSI)

Insemination using IVF or ICSI using ejaculated sperm (fresh or frozen) from partner
Day 1 after Oocyte Retrieval

Assessment of fertilisation (number of pronuclei) at 19h (± 2h) post-insemination
Day 3 after Oocyte Retrieval

Assessment of embryo quality at 68h (± 2h) post-insemination
Day 5 after Oocyte Retrieval

Assessment of blastocyst quality at 120h (± 3h) post-insemination

Transfer of a single blastocyst at 120h (± 3h) post-insemination (section 6.5)


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
Cryopreservation at 120h (± 3h) post-insemination, in line with local practice and 
declaration by JSOG [note: cryopreservation may also occur after day 5] 
6.5
Blastocyst Transfer 
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. 
The subject-related procedures are described below.

Transfer of a single blastocyst of the best quality available 
[note: only applicable for subjects who underwent triggering of final follicular maturation 
with hCG. Subjects who were administered GnRH agonist will not undergo transfer in this 
cycle]

Dispensing of progesterone for luteal phase support. Progesterone support should be 
continued until the day of the clinical pregnancy visit, but can be terminated earlier in case 
of menses, a negative βhCG test or pregnancy loss.

Drug accountability of progesterone

Recording of use of any concomitant medication 

Recording of adverse events
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
13-15 days after transfer (section 6.6). Subject with no blastocyst transfer will proceed to end-of-
trial assessments.
6.6
βhCG Test
Subjects who have undergone transfer must attend a visit 13-15 days after transfer, unless the 
subject experiences a full menstrual bleeding following transfer, then the βhCG test must be 
performed 7-15 days after transfer. The βhCG test is mandatory for all subjects who have 
undergone transfer, irrespective of bleeding.
The following must take place:

Blood collection for central laboratory analysis of hCG

Dispensing of progesterone for luteal phase support, if applicable

Drug accountability of progesterone

Recording of use of any concomitant medication 

Recording of adverse events
The blood sample will be analysed for βhCG by a central laboratory and evaluated according to the 
central laboratory’s reference ranges. In case of a doubtful hCG result, the test may be repeated. 


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Subjects with a positive hCG test must attend a clinical pregnancy visit 5-6 weeks after transfer 
(section 6.7). Subjects with a negative hCG test must proceed to the end-of-trial assessments 
(section 6.8).
6.7
Clinical Pregnancy
Subjects with a positive hCG test must attend a visit 5-6 weeks after transfer. 
The following must take place:

Transvaginal ultrasound of uterus to assess any clinical pregnancy

Drug accountability of progesterone, if applicable

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.
6.8
End-of-Trial
Subjects who have a positive βhCG test and continue to the clinical pregnancy visit will have 
end-of-trial assessments done at that visit. Subjects who have a negative βhCG test will proceed 
directly to end-of-trial assessments. Subjects experiencing a full menstrual bleeding following 
transfer can also proceed to the end-of-trial visit and have the βhCG test performed as part of the 
end-of-trial assessments, if this occurs 7-15 days after transfer. 
The following must take place at the end-of-trial visit: 

Body measurements (body weight)

Physical examination

Gynaecological examination

Vital signs 

Blood collection for central laboratory analysis of clinical chemistry and haematology 
parameters

Drug accountability, if applicable

Recording of use of any concomitant medication

Recording of adverse events

Completion of end-of-trial form 


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These assessments serve to document the subject’s physical health at the end of the trial.
6.9
Pregnancy Follow-up 
Pregnancy progress and outcome data will be gathered for subjects with a vital pregnancy. Data 
will be collected on ongoing pregnancy (10-11 weeks after transfer) and pregnancy outcome as well 
as neonatal health at birth and at 4 weeks after birth. The pregnancy follow-up does not include any 
interventions but only data collection. The pregnancy follow-up data will be based on reports 
obtained from the subject’s gynaecologist / obstetrician and the subject’s Maternal and Child 
Health Handbook. The data will be retrieved by the trial site, either via the subject’s gynaecologist / 
obstetrician, the subject herself, or other sources, as applicable. 


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Primary Endpoint
7.1.1
Number of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit.
7.2
Assessments Related to Important Secondary Endpoint
7.2.1
Clinical Pregnancy
The clinical pregnancy rate is considered an important secondary endpoint. A transvaginal 
ultrasound of the uterus will be performed 5-6 weeks after transfer. Clinical pregnancy will be 
defined as at least one gestational sac, either intrauterine or ectopic. The inclusion of ectopic 
pregnancies and the lack of specification of heart beat in the definition of clinical pregnancy is in 
line with the current International Committee Monitoring Assisted Reproductive Technologies 
(ICMART) and World Health Organization (WHO) glossary on ART terminology.b,27
For intrauterine and ectopic pregnancies, the number of gestational sacs with fetal heart beat as well 
as without fetal heart beat will be recorded.
7.3
Assessments Related to Secondary Endpoints
7.3.1
βhCG Test
A blood hCG test must be obtained 13-15 days after transfer, unless the subject experiences a full 
menstrual bleeding following transfer, then the hCG test must be performed 7-15 days after 
transfer. If the test is positive according to the central laboratory’s reference ranges, this confirms a 
positive hCG. The βhCG test is mandatory for all subjects who have undergone transfer, 
irrespective of bleeding.
7.3.2
Vital Pregnancy 
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Vital pregnancy 
will be defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after 
transfer.
                                                
b
ICMART and WHO glossary on ART terminology: Clinical pregnancy – a pregnancy diagnosed by 
ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes 
ectopic pregnancy.


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7.3.3
Implantation 
Implantation is determined based on the transvaginal ultrasound performed at the clinical 
pregnancy visit. Implantation rate will be defined as the number of gestational sacs 5-6 weeks after 
transfer divided by number of blastocysts transferred.
7.3.4
Cycle Cancellation due to Poor or Excessive Ovarian Response or Blastocyst 
Transfer Cancellation due to Excessive Ovarian Response / OHSS Risk
The reason for each cycle cancellation will be recorded. Cycle cancellations related to inappropriate 
ovarian response will include poor and excessive follicular development. Cycle cancellation due to 
poor follicular development is implemented when the investigator judges that ≥3 follicles with a 
diameter ≥17 mm cannot be reached by stimulation day 20. Cycle cancellation due to excessive 
follicular development is implemented when ≥25 follicles with a diameter ≥12 mm are observed (in 
case of 25-35 follicles with a diameter ≥12 mm, GnRH agonist may be administered). The reason 
for each blastocyst transfer cancellation will be recorded. Transfer cancellation due to adverse 
events such as the Medical Dictionary for Regulatory Activities preferred terms (MedDRA PTs)
”ovarian hyperfunction”, “ovarian hyperstimulation syndrome” and “high progesterone” in subjects 
with blastocysts available for transfer will be considered as transfer cancellations due to excessive 
response / OHSS risk.
7.3.5
Ovarian Response
The proportion of subjects with <4 oocytes (low response), 4-7 oocytes (moderate response), 
8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe 
hyperresponse) will be calculated.
7.3.6
Extreme Ovarian Response
The number of oocytes retrieved will be counted at the oocyte retrieval visit. Extreme ovarian 
response will be defined as retrieval of <4, ≥15 or ≥20 oocytes.
7.3.7
Preventive Interventions for Early OHSS
Preventive interventions for early OHSS cover cycle cancellation due to excessive ovarian 
response, triggering of final follicular maturation with GnRH agonist and administration of 
dopamine agonist (the latter is only considered as preventive intervention in subjects with 
≥20 follicles of ≥12 mm).


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7.3.8
Early OHSS (including Moderate/Severe) and/or Preventive Interventions for Early 
OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3.1 for details) 
and all OHSS cases will be graded as mild, moderate or severe. Preventive interventions for early 
OHSS cover cycle cancellation due to excessive ovarian response, triggering of final follicular 
maturation with GnRH agonist and administration of dopamine agonist (the latter is only 
considered as preventive intervention in subjects with ≥20 follicles of ≥12 mm).
7.3.9
Late OHSS (including Moderate/Severe)
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
Classification of grade is according to Golan’s classification system (see section 8.3.1 for details) 
and all OHSS cases will be graded as mild, moderate or severe.
7.3.10
Number and Size of Follicles during Stimulation
Transvaginal ultrasound will be performed at all visits during the stimulation period to count the 
number of follicles and measure the size of the follicles. Data will be recorded separately for the 
right and left ovary.
7.3.11
Fertilisation Rate 
The number of pronuclei will be counted at 19h (±2h) post-insemination and recorded as 0, 1, 2 or 
>2. Fertilised oocytes with 2 pronuclei will be regarded as correctly fertilised.
7.3.12
Number and Quality of Embryos on Day 3
Each embryo will be evaluated 68h (2h) post-insemination. The quality evaluation will consist of 
assessment of cleavage stage and embryo morphology parameters (blastomere uniformity, cell size, 
degree of fragmentation and visual signs of multinucleation). 
Cleavage stage will be defined by the number of blastomeres: 1, 2, 3, 4, 5, 6, 7, 8, …. On day 3, it 
will also be possible to indicate the compaction status instead of number of blastomeres.
Blastomere uniformity will be classified as equally sized blastomeres or unequally sized 
blastomeres (largest blastomere >25% larger in average diameter compared to the smallest 
blastomere). 
Cell size will be classified as stage-specific cell size or not stage-specific cell size. 
Degree of fragmentation will be classified as one of the following: 0%, 1-10%, 11-20%, 21-25%, 
26-30%, 31-50% or >50% fragmentation, or totally fragmented (no blastomeres recognised).


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Visual sign of multinucleation will be evaluated as yes or no.
7.3.13
Number and Quality of Blastocysts on Day 5
Blastocyst Expansion and Hatching Status, Blastocyst Inner Cell Mass Grading and 
Trophectoderm Grading 
The quality evaluation of blastocysts on day 5 after oocyte retrieval will consist of assessment of 
three parameters: blastocyst expansion and hatching status, blastocyst inner cell mass grading and 
trophectoderm grading. The scoring is based on the classification system by Gardner & 
Schoolcraft28 with the addition of D-categories for inner cell mass and trophectoderm.
Blastocyst expansion and hatching status will be assessed as one of the following:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, 
that of the embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early 
embryo, with a thinning zona
5. A hatching blastocyst with the trophectoderm starting to herniate through the 
zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the 
zona
For blastocysts with expansion and hatching status 3-6, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as one of the following:
A. Tightly packed, many cells
B. Loosely grouped, several cells
C. Very few cells
D. Degenerative or no inner cell mass


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Trophectoderm grading will be assessed as one of the following:
A. Many cells forming a cohesive epithelium
B. Few cells forming a loose epithelium
C. Very few, large cells 
D. Degenerative or very large cells
Blastocysts with expansion and hatching status 3-6 will have a score combining the three 
parameters (blastocyst expansion and hatching status, inner cell mass and trophectoderm); e.g. 4AB 
for a blastocyst with blastocyst expansion and hatching status 4, inner cell mass grading A and 
trophectoderm grading B.
7.3.14
Circulating Levels of Endocrine Parameters
During treatment, the following panel of endocrine parameters will be evaluated: FSH, LH, 
estradiol, progesterone, inhibin A and inhibin B. 
Blood samples will be drawn at stimulation day 1c, stimulation day 6 and the end-of-stimulation 
visit. The sample on stimulation day 1 (baseline) will be collected prior to the first dose of 
FE 999049 or FOLLISTIM, and samples drawn at stimulation day 6 and the end-of-stimulation 
visit will be collected at least 8 hours after the previous FE 999049, FOLLISTIM or GnRH 
antagonist administration. The samples will be analysed at a central laboratory. The investigator 
will review and evaluate the laboratory results. The Laboratory Report will be signed and dated by 
the investigator.
7.3.15
Total Gonadotropin Dose and Number of Stimulation Days 
The start and end dates as well as daily dose of IMP will be recorded and used to calculate the total 
FE 999049 or FOLLISTIM dose administered and the number of stimulation days.
7.3.16
Adverse Events 
Adverse events will be recorded from the signed informed consent until the end-of-trial visit. For 
each adverse event the following parameters are recorded by the investigator on the Adverse Event 
Log: description of event, date and time of onset, intensity, causal relation to gonadotropin (i.e. 
FE 999049 / FOLLISTIM), action taken, seriousness of the adverse event, date and time of 
outcome, and outcome. Definitions are provided in section 8.
                                                
c
AMH will also be included in the stimulation day 1 analyses.


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7.3.17 Clinical Chemistry and Haematology Parameters
Blood samples for analysis of circulating levels of clinical chemistry and haematology parameters 
will be drawn on the following occasions: screening, end-of-stimulation and end-of-trial.
All samples will be analysed at a central laboratory for the following clinical chemistry and 
haematology parameters: 
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, white blood cells, red blood cells morphology, 
white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
The investigator will review the laboratory results and evaluate and document whether the 
abnormal results are non-clinically or clinically significant. The results from the screening sample 
will be reviewed prior to randomisation. The Laboratory Report will be signed and dated by the 
investigator.
7.3.18 Injection Site Reactions to IMP
Every day throughout the stimulation period, the subjects will assess the local tolerability of 
subcutaneous injections of FE 999049 or FOLLISTIM 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 diary and the diary data will subsequently be 
transcribed to the eCRF.
7.3.19
Pen Malfunctions
Incidences of technical malfunctions of the administration pens will be recorded.


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7.4
Other Assessments
7.4.1
Demographics
Demographic information will be obtained during the screening period, including date of birth and 
confirmation that the subject is Japanese.
7.4.2
Medical History
Any relevant medical history will be recorded during the screening period. This includes diagnosis / 
symptoms, and whether it is a past or ongoing occurrence.
7.4.3
Infertility History
Information about the reasons 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.
7.4.4
Menstrual History
Information about the menstrual history (average cycle length) will be obtained during the 
screening period.
7.4.5
Reproductive History
Information about the reproductive history will be obtained during the screening period. This will 
include number of clinical pregnancies, number of fetuses and outcome.
7.4.6
Body Measurements
Body weight will be measured at screening, stimulation day 1 and end-of-trial. In addition, height 
will be measured at screening. Body weight will be done without shoes and overcoat and using a 
calibrated scale. The body weight at randomisation will be used for dose calculation in the 
FE 999049 group.
7.4.7
Physical Examination
A complete physical examination will be performed at screening and end-of-trial. Information will 
be recorded for general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth and throat), respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system and skin. 


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At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events.
7.4.8
Gynaecological Examination
A complete gynaecological examination will be performed at screening and end-of-trial. 
Information will be recorded for breasts, external genitalia, vagina, cervix, uterus, ovaries and 
fallopian tubes. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events.
7.4.9
Endocrine Parameters at Screening
At screening, the following panel of endocrine parameters will be evaluated: AMH, TSH and 
prolactin. The AMH level at screening will be used for stratification (<15 pmol/L and ≥15 pmol/L) 
and will furthermore be used for dose determination for subjects randomised to FE 999049.
The sample will be analysed at a central laboratory. The results of the screening panel must be 
available prior to randomisation. The investigator will review and evaluate the laboratory results 
(with the exception of AMH, which will not be made available to the investigator). The Laboratory 
Report will be signed and dated by the investigator.
7.4.10 Vital Signs
Systolic and diastolic blood pressure as well as pulse will be measured at stimulation day 1 and 
end-of-trial. All assessments of vital signs will be done while the subject is in supine position after 
resting for 3 minutes.


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7.4.11 Ovarian Size and Volume
As part of the transvaginal ultrasound performed on stimulation day 1, ovarian size is recorded. The 
size – length, width and depth (recorded in mm) – of each ovary is measured and used for 
subsequent calculation of ovarian volume.
7.4.12
Endometrial Status
Transvaginal ultrasound of the uterus to assess the endometrial status will be conducted at all visits 
during the stimulation period. The endometrial status assessments consist of the following 
parameters: endometrial thickness and echogeneity pattern. 
Endometrial thickness (composed of both layers of the endometrium) will be measured in the 
sagittal view of the uterus from the proximal and distal interfaces between the echogenic 
endometrium and the hypoechoic inner layer of the myometrium. Care should be taken not to 
include the hypoechoic subendometrial halo and to account for the presence of any fluid in the 
uterine cavity (not to be included in the endometrial thickness value). Endometrial thickness will be 
recorded in mm.
Endometrial echogenicity pattern will be recorded as hypoechogenic, isoechogenic, 
hyperechogenic, or not possible to evaluate.
7.4.13 Maturity Stage
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity 
stage will be categorised as germinal vesicle, metaphase I, metaphase II, degenerated or other.
7.4.14 Blastocyst Transfer Procedure
Any difficulty and eventuality during transfer procedure will be noted.
7.4.15 Concomitant Medication
The use of any concomitant medication within the last 3 months prior to informed consent (except 
medication used in previous infertility treatment cycles) and throughout the trial will be recorded. 
Recording of concomitant medication will be performed at all visits. Any changes in concomitant 
medications or treatments must be recorded at each visit.
7.4.16 Drug Dispensing and Accountability
For all medicinal products, dates of administration and dose administered will be recorded. 
Furthermore, time of administration will also be recorded for IMP as well as GnRH antagonist and 


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hCG or GnRH agonist, as applicable. Details on drug dispensing and accountability are provided in 
section 5.7.
7.4.17 End-of-Trial Form
An end-of-trial form must be filled in at the subject’s last visit, irrespective of whether the subject 
completes the trial or not. Completion / discontinuation status will be recorded, as well as date and 
reason for discontinuation in case the subject did not complete the trial.
7.5
Assessments Related to Pregnancy Follow-up Information 
The source data for the pregnancy follow-up data will be reports obtained from the subject’s 
gynaecologist / obstetrician and the subject’s Maternal and Child Health Handbook (or a copy of 
the relevant pages). The data will be retrieved by the trial site, either via the subject’s 
gynaecologist/obstetrician, the subject herself, or other sources, as applicable.
Ongoing Pregnancy Rate and Live Birth Rate
For all subjects with a vital pregnancy, data will be collected on ongoing pregnancy, defined as at 
least one intrauterine viable fetus 10-11 weeks after transfer. Pregnancy losses after vital pregnancy 
will be recorded. Furthermore, information on pregnancy outcome, e.g. live birth, stillbirth, will 
also be collected. These data will be reported separately in a Clinical Trial Report Addendum.
Neonatal Health
Neonatal health data will be collected at birth and at 4 weeks after birth for all children born. At 
birth, the data collected will include date of birth, gender, birth weight and length as well as 
information on minor/major congenital anomalies and admission to neonatal intensive care unit 
(NICU), neonatal care unit (NCU) or growing care unit (GCU). At 4 weeks after birth, the data 
collected will include minor/major congenital anomalies, hospitalisations and any other relevant 
medical conditions. These data will be reported separately in a Clinical Trial Report Addendum.
7.6
Handling of Biological samples
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples in this trial. All biological samples will be 
analysed at central laboratories and will be maintained in storage after the end of the trial. 
Destruction will take place within 2 years after reporting of the trial or when methods/results have 
been adequately validated. An exception is the blood sample for βhCG which is analysed by a 
central laboratory and subsequently destroyed. For all biological samples collected in the trial, it 
applies that analyses beyond those described in the protocol can only be performed after obtaining 


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the required approvals. The processes related to handling biological samples will be described in 
the informed consent documents, and biobank / data protection legislation including local 
legislation will be adhered to.


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


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8.2.2
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.d
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event).
                                                
d
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 with the IMP or the event recurs on rechallenge with 
the IMP.
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the adverse event.
Examples:

Known consequences of the underlying disease or condition 
under investigation.

Adverse events common in the trial population, which are also 
anticipated to occur with some frequency during the course of the 
trial, regardless of IMP exposure.


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Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:

No change (medication schedule maintained or no action taken)

Discontinued

Interrupted

Dose reduced

Dose increased
Other Action Taken
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date and time the subject recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment)

Recovered with sequelae (resulted in persistent or significant disability/incapacity)

Recovering (the event is improving)

Not recovered

Fatal


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8.3
Adverse Events of Special Interest
8.3.1
OHSS
OHSS is an adverse event of special interest during controlled ovarian stimulation. Investigators 
will record OHSS symptoms and will use Golan’s system29 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
Mild OHSS
Grade 1
Abdominal distension and discomfort. 
Grade 2 
Features of grade 1 plus nausea, vomiting, and/or diarrhoea. Ovaries enlarged to 5 to 12 cm.
Moderate OHSS
Grade 3 
Features of mild OHSS plus ultrasonic evidence of ascites. 
Severe OHSS
Grade 4 
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or breathing 
difficulties. 
Grade 5 
All of the above plus change in blood volume, increased blood viscosity due to haemoconcentration, 
coagulation abnormalities, and diminished renal perfusion and function. 
All cases of OHSS must be reported as adverse events. Those that fall under the category serious 
adverse events must be reported as such. Note that the classification ‘mild OHSS’, ‘moderate 
OHSS’ and ‘severe OHSS’ does not refer to the classification of an adverse event’s intensity (also 
rated mild, moderate, or severe).
Subject narratives will be prepared for all OHSS cases.
Concerning timing, early OHSS will be defined as OHSS with onset ≤ 9 days after triggering of 
final follicular maturation and late OHSS will be defined as OHSS with onset > 9 days after 
triggering of final follicular maturation.
OHSS rate will be evaluated in the context of whether triggering of final follicular maturation was 
done with hCG or GnRH agonist and also whether the cycle was cancelled.


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Preventive Interventions of Early OHSS
Preventive interventions of early OHSS include the following: 

Cycle cancellation due to excessive ovarian response

Triggering of final follicular maturation with GnRH agonist 

Administration of dopamine agonist (this is only considered as preventive intervention in 
subjects with ≥20 follicles of ≥12 mm)
Investigations to be Conducted in Subjects where OHSS Symptoms are Observed
The following investigations must be conducted when OHSS symptoms are first observed and 
repeated when there are clinically relevant changes in the OHSS presentation: 

Body weight (for all OHSS)

Blood sample for central lab analysis of the following (for moderate/severe OHSS):

Progesterone and estradiol

CBC (red blood cells, red blood cell morphology, white blood cells, white blood cell 
morphology, haemoglobin, haematocrit, mean corpuscular volume, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets)

CHEM-20 (alanine transaminase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, 
calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, 
glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric 
acid)

Coagulation parameters (prothrombin time, activated partial thrombin time)
Any treatments of OHSS, e.g. intravenous administration of volume expanders, paracentesis, use of 
low-molecular-weight heparin and intravenous administration of albumin, must be recorded as 
concomitant medication.
8.3.2
Local Tolerability
Injection site reactions after administration of IMP (FE 999049/FOLLISTIM) are only to be 
reported as adverse events if they require active management, i.e. discontinuation of FE 999049 or 
FOLLISTIM, additional investigations or treatment of the injection site reaction. Local tolerability 
is a secondary endpoint and will be evaluated in detail based on the subjects’ recordings in the 
diary. 
Local tolerability reactions after administration of concomitant fertility medication are to be 
reported as adverse events if they fulfil the definition of an adverse event.


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8.3.3
Menstrual Bleeding
Menstrual bleeding is only to be reported as an adverse event in case it is excessive, painful, 
delayed or in any other way deviating from the subject’s normal menstruation. Menstrual bleeding 
associated with lack of pregnancy will be reported as part of the efficacy evaluation.
8.3.4
Pregnancy Losses
The following terminology should be used for reporting of pregnancy losses during the trial:
Biochemical pregnancy: 
Positive βhCG test but no gestational sac is observed on later 
transvaginal ultrasound, or menstruation is reported
Spontaneous abortion: 
Positive βhCG test but all intrauterine gestational sacs are 
without fetal heart beat as documented by ultrasound, or there 
are no viable fetuses observed by ultrasound
Vanishing twin:
Spontaneous disappearance of an intrauterine gestational sac 
with or without heart beat in a pregnancy where one viable 
fetus remains as documented by ultrasound
Ectopic pregnancy:
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery
Concerning timing, a pregnancy loss occurring before ongoing pregnancy (i.e. during 1st trimester) 
will be defined as an early pregnancy loss, while a pregnancy loss occurring after ongoing 
pregnancy during the pregnancy follow-up will be defined as a late pregnancy loss.


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


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Serious Adverse Events in Connection with Pregnancy Outcome and Neonatal Health
The following untoward medical occurrences reported as part of the pregnancy outcome and 
neonatal health data collection will be reported as serious adverse events:

Death of mother in connection with pregnancy or labour

Death of neonate

Stillbirth (occurring after gestational age 24 weeks + 0 days and calculated from the day of 
transfer + 19 days)

Neonate admitted to the NICU irrespective of duration, or neonate admitted to NCU or
GCU for at least 2 hours

Congenital anomaly / birth defect

Medically important event
In case of admission to NICU, NCU or GCU, the reason for admission must be reported as a 
serious adverse event, rather than just the act of hospitalisation. 
Congenital anomalies will be coded using both MedDRA and International Statistical Classification 
of Diseases and Related Health Problems, 10th revision (ICD-10) and classified as minor or majore
in accordance with the European Medicines Agency (EMA) guideline.30
8.4.2
Collection, Recording and Reporting of Serious Adverse Events in Core Trial
Reporting by the Investigator
All serious adverse events must be reported immediately to Ferring Pharmacovigilance (i.e., Global 
Pharmacovigilance at Ferring Pharmaceuticals A/S and Ferring Pharmaceuticals Co., Ltd.) as soon 
as it becomes known to the investigator and not later than within 24 hours of their knowledge of 
the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the serious adverse event. The 
process is as follows:

Report to Ferring Global Pharmacovigilance in English language using the serious adverse 
event (SAE) Report Form in the eCRF system (the form must be completed and submitted 
according to the instructions provided on the form).
                                                
e
Major abnormalities: a life threatening structural anomaly or one likely to cause significant impairment of health or 
functional capacity and which needs medical or surgical treatment. 
Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems.


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Back-up Procedure
In case the eCRF cannot be accessed and hence the SAE Report Form cannot be filled in within the 
eCRF system, the English paper SAE Report Form should be sent according to the above timelines 
to Ferring Pharmacovigilance by fax, 
When the eCRF again can be accessed the information from the paper SAE Report Form should be 
entered in the eCRF.
Serious Adverse Event Information
The investigator must capture information for each serious adverse event on the SAE Report Form 
as described below.
A meaningful description of the serious adverse event and a narrative with relevant details 
including the clinical course leading up to an event should be made. The description should be 
written by the investigator and should be similar to the epicrisis generally written at disease 
termination/discharge. Course of event(s) must be stated as accurately and thoroughly as possible. 
The scope of the narrative is to give a full overview of the cause of event(s), making the case 
understandable to people without existing knowledge of the subject and without access to the 
subject’s hospital records. Information relevant for the assessment of the case must be enclosed, 
e.g., medical history, concomitant medications, outcome, copies of source records, results from 
laboratory or other tests, surgery reports, hospital discharge letters, autopsy reports, etc. If 
laboratory results are presented, reference ranges should be included. If the subject was 
hospitalised, dates of hospital admission and discharge should be included. In any case this 
information must be supplied by the investigator upon request from Ferring. On any copies 
provided, details such as subject’s name, address, and hospital identification number should be 
concealed and instead subject number should be provided.
Information to be Entered / Updated in the eCRF
Completion of the Demographics, Adverse Event form, Medical History form and Concomitant 
Medication form are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the eCRF for Ferring 
Global Pharmacovigilance to access the information.
Overdoses and medication errors of IMP with and without clinical consequences will be tracked in 
the eCRF and reviewed by Ferring GPV on an ongoing basis.
Additional information relevant to the serious adverse event such as hospital records, results from 
investigations, e.g. laboratory parameters (that are not already uploaded in the eCRF), invasive 
procedures, scans and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 
Global Pharmacovigilance using the contact details in the section above. In any case this 


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information must be supplied by the investigator upon request from Ferring. On any copies 
provided, such details such as subject’s name, address, and hospital ID number should be concealed 
and instead subject number should be provided.
The investigator will supply Ferring and the ethics committee with any additional requested 
information such as results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.
The expectedness is assessed by Ferring according to the most recent Investigator’s Brochure for 
FE 999049 and the Product Information for FOLLISTIM.
Serious adverse events will be considered reportable regardless of whether or not these medicinal 
products were used in accordance with the provisions in the protocol and Investigator’s Brochure
and labelling.
8.4.3
Collection, Recording and Reporting of Serious Adverse Events in Pregnancy Follow-
up
All serious adverse events reported as part of the pregnancy outcome and neonatal health data 
collection must be reported immediately to Ferring Pharmacovigilance not later than within 
24 hours of their knowledge of the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the serious adverse event. The 
process is as follows:

Report to Ferring Global Pharmacovigilance in English language using the serious adverse 
event (SAE) Report Form in the eCRF system (the form must be completed and submitted 
according to the instructions provided on the form).
Back-up Procedure
In case the eCRF cannot be accessed and hence the SAE Report Form cannot be filled in within the 
eCRF system, the English paper SAE Report Form should be sent according to the above timelines 
to Ferring Pharmacovigilance by fax, 


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8.5
Follow-up of Adverse Events and Serious Adverse Events
Follow-up of Adverse Events with Onset during the Trial
During the trial, i.e. from the time of obtaining informed consent until the end-of-trial visit (for 
each subject individually), the investigator must follow up on each adverse event until it is resolved 
or until the medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. If the event is a chronic condition the investigator and Ferring may agree that 
further follow up is not required.
Adverse events on NIMPs during the trial
In case an adverse event is recognised as an adverse drug reaction caused by a concomitant NIMP,
investigators should report to each Marketing Authorisation Holder. For adverse drug reactions
caused by an NIMP where Ferring is the Marketing Authorisation Holder, the case will have to be 
reported to Ferring.
Collection of Serious Adverse Events with Onset after End-of-Trial
If an investigator becomes aware of a serious adverse event after the end of the trial, and he/she 
assesses the serious adverse event to have a reasonable possible causality to the IMP or an NIMP 
where Ferring is Marketing Authorisation Holder, the case will have to be reported to Ferring, 
regardless how long after the end of the trial this takes place. 


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9
STATISTICAL METHODS
The Ferring Global Biometrics Department will be responsible for the statistical analyses of the 
primary and secondary endpoints. All analyses and further descriptions of the statistical 
methodology for the primary and secondary endpoints will be included in the Statistical Analysis 
Plan (SAP) available before the first patient is randomised.
9.1
Determination of Sample Size
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing 
controlled ovarian stimulation. The non-inferiority margin for the difference between treatments 
(FE 999049 versus FOLLISTIM) is -3.0 oocytes. The standard deviation for the primary endpoint is 
estimated to 8.1 oocytes based on historical data with FOLLISTIM.
The sample size is determined to obtain 90% power to achieve the primary objective for the per-
protocol (PP) analysis set for a 1:1 randomisation ratio between FE 999049 and FOLLISTIM and a 
one-sided t-test at a 2.5% significance level. Assuming the two treatments to be equally effective 
and a standard deviation of 8.1 oocytes, a sample size of 155 randomised subjects per treatment 
group would give 90% power. The proportion of subjects with major protocol deviations is 
assumed to be at most 5% and hence 328 randomised subjects are needed to provide 155 
subjects/group in the PP analysis set.
9.2
Subject Disposition
All screened subjects will be accounted for. 
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening 
failures.
Subject disposition with respect to analysis sets will be tabulated by treatment group overall and by 
AMH stratum (screening AMH: <15 pmol/L, ≥15 pmol/L) for all randomised subjects. This table 
will include the number of completed and discontinued subjects including reason for 
discontinuation. Screening failures and their primary reason for screening failure will also be 
included. Screening failures will not otherwise be accounted for. 
A separate table will summarise the subject disposition with respect to analysis sets by trial site 
overall and by AMH stratum. 
A subject is considered a completer if she attends all scheduled trial visits and undergoes the
end-of-trial assessments. Likewise, a subject is considered a non-completer if she does not attend 
all scheduled trial visits and does not undergo the end-of-trial assessments.


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The number of subjects completed and discontinued (including reason) will be summarised for the 
following trial parts: stimulation, triggering of final follicular maturation, oocyte retrieval, transfer, 
and pregnancy monitoring. This table will be produced for the full analysis set (FAS) overall and 
by AMH stratum.
Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately.
9.3
Protocol Deviations
Major protocol deviations, such as significant non-compliance or other serious unforeseen 
deviations 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. The list of major protocol deviations include, but is not restricted to:

Unblinding of assessor or investigator 

IMP regimen (treatment not in accordance with randomisation or non-compliance with IMP 
for two or more days)

Non-compliance with the triggering criterion
The rating of protocol deviations as ‘minor’ and ‘major’ will be decided by the Ferring clinical 
team on the basis of a blinded review of data before declaration of clean file and lock of database. If 
the blinded review identifies unforeseen deviations deemed to impact the primary endpoint, these 
will also be rated as major deviations. 
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be summarised and listed by subject for the 
intention-to-treat (ITT) analysis set.
9.4
Analysis Sets
Intention-to-Treat (ITT) Analysis Set
The ITT analysis set is defined as all randomised subjects. Subjects will be analysed according to 
planned (randomised) treatment.
The Full Analysis Set (FAS)
The FAS is defined as all randomised and exposed subjects. Subjects will be analysed according to
planned (randomised) treatment.


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Per-Protocol (PP) Analysis Set
The PP analysis set is defined as all randomised and exposed subjects except those excluded as a 
result of major protocol deviations as described in section 9.3. 
Safety Analysis Set
The safety analysis set is defined as all randomised and exposed subjects. Subjects will be analysed 
according to actual treatment received.
9.5
Trial Population
9.5.1
General Considerations
All relevant baseline data will be summarised in tables including both treatment groups and a total 
column. The purpose of these tabulations is to characterise the treatment groups and assess the 
degree of similarity achieved by the randomisation. Baseline data will not be compared using 
statistical tests. Unless otherwise noted, tabulations will be produced overall and by AMH stratum
for both the FAS and the PP analysis set. Continuous variables will be presented with number of 
subjects, mean, standard deviation, median, inter-quartile range, minimum, and maximum. 
Categorical variables will be presented with number and percentage of subjects within each specific 
category. 
Listings will only be produced for the FAS.
9.5.2
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 
tabulated.
Medical History
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarised for each medical item. This summary 
table will only be produced overall (i.e. not by AMH stratum) for the FAS.


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


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9.7
Endpoint Assessments
9.7.1
General Considerations
Primary and Secondary Endpoints
The results of the analyses of the primary endpoint (number of oocytes retrieved) is essential for the 
non-inferiority claim. The analyses of the important secondary endpoint and the other secondary 
endpoints are intended to provide additional characterisation of the safety and efficacy of 
FE 999049. However, non-inferiority does not need to be established for these endpoints.
Analysis and Presentation of Primary and Secondary Endpoints
Summary tables and treatment comparisons for the primary endpoint, the important secondary 
endpoint and the secondary efficacy endpoints will be presented overall and by AMH stratum for 
both the FAS and the PP analysis set. In addition, summary tables per age group will be provided as 
applicable.
All tabulations will present the treatment groups and include a total column. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category. 
All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of ‘equal effect’ against the alternative of 
‘different effect’.
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will 
be listed. Listings will only be produced for the FAS.
Multiplicity 
No adjustment for multiplicity is required for the primary endpoint since there is only one 
hypothesis and one analysis set (FAS). Concerning the secondary endpoints, no formal adjustment 
for multiplicity will be utilised.
Missing Data
For the primary endpoint, number of oocytes retrieved, no missing data are expected. Subjects that 
discontinue stimulation, do not continue from stimulation to triggering of final follicular 
maturation, or do not undergo the oocyte retrieval procedure, will be regarded as having zero 
oocytes retrieved.


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For the secondary endpoints, positive βhCG rate, clinical pregnancy rate, vital pregnancy rate, and 
implantation rate occurrence of missing data is unlikely but may occur in case the assessment was 
not done. For these endpoints, a subject’s response is considered as ‘negative’ unless recorded as 
‘positive’. An exception to this is if a later observation confirms that a previous missing observation 
was in fact positive. If, for example, the βhCG test result is missing but clinical pregnancy is 
recorded as ‘positive’, then the βhCG test result will be imputed as ‘positive’.
9.7.2
Primary Endpoint
The primary endpoint ‘number of oocytes retrieved’ will be analysed using an analysis of variance 
model with treatment and AMH stratum as fixed factors. The 2-sided 95% confidence limits for the 
mean treatment differences (FE 999049 - FOLLISTIM) will be calculated based on the fitted model 
for the FAS. 
The hypotheses to be tested is:
H0: ORFE 999049 - ORFOLLISTIM ≤ -3.0
H1: ORFE 999049 - ORFOLLISTIM > -3.0
where ORFE 999049 and ORFOLLISTIM denote the number of oocytes retrieved with respective 
treatment.
The null hypothesis (H0) will be tested against the alternative (H1) by constructing a two-sided 95% 
confidence interval for the difference in number of oocytes retrieved. The null hypothesis will be 
rejected if the lower-limit of the two-sided 95% confidence interval is greater than the 
non-inferiority limit (-3.0 oocytes) for the FAS. In this case it will be claimed that FE 999049 is 
non-inferior to FOLLISTIM with respect to number of oocytes retrieved in women undergoing 
controlled ovarian stimulation.
Primary Endpoint: Number Oocytes Retrieved – Sensitivity Analysis and Additional Analysis
and Descriptions
The FAS is the primary analysis population for this trial, and the analysis of the PP analysis set is 
only considered supportive for the application in Japan. In the EMA guideline “Points to consider 
on switching between superiority and non-inferiority”31, the FAS and the PP analysis sets are 
considered equally important. FE 999049 is a compound under global development. Therefore, for 
applications in countries applying the EMA guideline, Ferring would intend to demonstrate non-
inferiority for both the FAS and PP analysis sets, and in such a case both would be considered as 
confirmatory analyses.


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The primary analysis will be repeated using the PP analysis set. This sensitivity analysis will 
address the assay sensitivity of the primary analysis by excluding subjects with major protocol 
deviations, e.g. substantial non-compliance with randomised treatment.
To investigate the possibility for different treatment differences in the two AMH strata, an analysis 
of variance model will be fitted where the treatment-by-stratum interaction is included. In addition, 
subgroup analyses will be performed for the two AMH strata separately (using a simpler model 
with only treatment as factor). The trial is not powered to show non-inferiority in the two strata 
separately and these analyses should only be regarded as descriptive. 
Additional descriptions will be made based only on subjects with oocytes retrieved. The purpose of 
this is purely descriptive.
9.7.3
Important Secondary Endpoint
Clinical Pregnancy Rate
Clinical pregnancy is defined as at least one gestational sac 5-6 weeks after transfer. The clinical 
pregnancy rate will be summarised for all subjects, for subjects with at least one oocyte retrieved 
and for subjects with transfer. The difference between FE 999049 and FOLLISTIM in clinical 
pregnancy rate will be estimated by constructing a two-sided 95% confidence interval. The Mantel-
Haenszel method will be used to combine results across AMH strata. In brief, this corresponds to 
deriving a weighted average across AMH strata where the weight depends on the number of 
observations in each treatment group in each AMH stratum.
9.7.4
Secondary Endpoints
Secondary endpoints will be evaluated based on the FAS.
Positive βhCG Rate
Positive βhCG is defined as positive serum βhCG test 13-15 days after transfer. The positive βhCG 
rate will be summarised and analysed in a similar manner as the clinical pregnancy rate.
Vital Pregnancy Rate
Vital pregnancy is defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer. The vital pregnancy rate will be summarised and analysed in a similar manner as the 
clinical pregnancy rate. For subjects with a vital pregnancy, the number of intrauterine gestational 
sacs with fetal heart beat and the number of fetuses with fetal heart beat will be tabulated.


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Implantation Rate
Implantation rate is defined as the number of gestational sacs 5-6 weeks after transfer divided by 
number of blastocysts transferred. The implantation rate will be summarised and analysed in a 
similar manner as the vital pregnancy rate. The transferred blastocysts are the experimental unit.
Cycle Cancellation due to Poor or Excessive Ovarian Response or Blastocyst Transfer 
Cancellation due to Excessive Ovarian Response / OHSS Risk
For this endpoint, treatment groups will be compared using a logistic regression model with 
treatment and AMH stratum as fixed factors. If both factors are significant then the possibility of an 
interaction will be investigated. The difference between treatments will be reported as an odds ratio 
including 95% confidence interval and p-value for test of no treatment difference. If the expected 
number of observations is less than five in any of the cells in the contingency table then Fisher’s 
exact test will be used as alternative.
The analysis will be performed for the composite endpoint and the separate components defined as: 
the proportion of subjects with cycle cancellation due to poor ovarian response, the proportion of 
subjects with cycle cancellation due to excessive ovarian response, the proportion of subjects with 
cycle cancellation due to poor or excessive ovarian response, the proportion of subjects with 
blastocyst transfer cancellation due to excessive ovarian response/ OHSS risk.
Ovarian Response
The number of oocytes retrieved will be tabulated with subjects grouped according to number of 
oocytes retrieved (<4 (low response), 4-7 (moderate response), 8-14 (targeted response), 15-19 
(hyperresponse) and ≥20 (severe hyperresponse)). Subjects with cycle cancellation due to poor 
ovarian response will be included in the <4 oocytes group. Subjects with cycle cancellation due to 
excessive ovarian response will be included in the ≥20 oocytes group. For each definition the 
proportion of subjects will be tabulated. This endpoint will be analysed in a similar manner as the 
proportion of subjects with cycle cancellation.
Extreme Ovarian Response
The analyses of extreme ovarian response will be performed using the following definitions of 
extreme ovarian response: <4 oocytes retrieved, ≥15 oocytes retrieved, ≥20 oocytes retrieved, <4 or 
≥15 oocytes retrieved and <4 or ≥20 oocytes retrieved. Subjects with cycle cancellation due to poor 
ovarian response will be included as <4 oocytes retrieved. Subjects with cycle cancellation due to 
excessive ovarian response will be included as ≥15 and ≥20 oocytes retrieved.
For each definition the proportion of subjects with extreme ovarian response will be tabulated. This 
endpoint will be analysed in a similar manner as the proportion of subjects with cycle cancellation.


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Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions 
for Early OHSS
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe, 
moderate or severe) and grade (1, 2, 3, 4, 5). Early OHSS is defined as OHSS with onset ≤9 days 
after triggering of final follicular maturation. Note this includes OHSS with onset before triggering 
and OHSS with onset during stimulation where triggering is not performed.
This endpoint will be tabulated in a similar manner as the proportion of subjects with cycle 
cancellation. Analyses will be performed for subjects with early OHSS, subjects with early OHSS 
of moderate or severe grade, subjects with preventive interventions for early OHSS, subjects with 
early OHSS and/or preventive interventions for early OHSS, and subjects with early OHSS of 
moderate or severe grade and/or preventive interventions for early OHSS.
The risk of preventive interventions for early OHSS and/or early OHSS is related to the ovarian 
response potential. AMH is a well-established predictor of ovarian response to gonadotropin 
treatment and was confirmed to be the best endocrine marker of ovarian response to FE 999049 
treatment in the phase 2 trial. 
For each endpoint two different logistic regression models will be fitted assuming an increasing risk 
with increasing AMH as follows:
LOGIT(π) = β0 + β1 log(AMH),
where π denotes the risk and the β’s denotes the regression coefficients. 
A comparison of the two treatment regimens with respect to the risk will be performed by adding 
treatment group as factor and the interaction term between treatment group and log(AMH) to the 
model as follows:
LOGIT(π) = β0 + β1 Treatment + β2log(AMH) + β3 Treatment*log(AMH)
The two models will be compared using the likelihood ratio test. Adjusted odds ratio estimates 
(comparing FE 999049 to FOLLISTIM) and associated 95% Wald CI will be provided.
The adequacy of the model fits will be evaluated using the Hosmer-Lemeshow goodness-of-fit test. 
The estimated risks based on the models will be plotted as a function of AMH, i.e. overall and for 
each treatment group.
Late OHSS (Including OHSS of Moderate/Severe Grade) 
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe, 
moderate and severe) and grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days 
after triggering of final follicular maturation.


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This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS. The analysis will be performed for subjects with late OHSS, and subjects with late 
OHSS of moderate or severe grade.
OHSS (Early and/or Late) and/or Preventive Interventions for Early OHSS
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS and/or preventive interventions for early OHSS. Analyses will be performed for 
subjects with early and/or late OHSS, subjects with early and/or late OHSS of moderate or severe 
grade, subjects with early and/or late OHSS and/or preventive interventions for early OHSS, and 
subjects with early and/or late OHSS of moderate or severe grade and/or preventive interventions 
for early OHSS.
Number and Size of Follicles during Stimulation 
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised by treatment on 
the follicle level (number of follicles 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and ≥17 mm) and 
on the subject level (total number of follicles, size of largest follicle, average follicle size, average 
size of three largest follicles, and number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and 
≥17 mm). Continuous data will be compared between treatment groups using van Elteren test 
stratified for AMH and within each AMH stratum using the Wilcoxon’s test. Categorical data will 
be compared between treatment groups using a logistic regression model with treatment and AMH 
stratum as fixed factors and within each AMH stratum the chi-square test.
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei at 19 hours. For subjects with oocytes 
retrieved, the rate of fertilised oocytes to oocytes retrieved (and also the rate of fertilised oocytes to 
metaphase II oocytes for those inseminated using ICSI) will be tabulated. Further, the number of 
fertilised oocytes per subject will be tabulated including both summary statistics and a frequency 
table. Number of fertilised oocytes and fertilisation rate will be compared between treatment groups 
using van Elteren test stratified for AMH and within each AMH stratum using the Wilcoxon’s test. 
Categorical data will be compared between treatment groups using a logistic regression model with 
treatment and AMH stratum as fixed factors and within each AMH stratum the chi-square test.
Number and Quality of Embryos on Day 3 
The number of embryos on day 3 including a breakdown by selected quality parameters will be 
tabulated including both summary statistics and frequency tables. Further, for subjects with oocytes 
retrieved, the rate of embryos to oocytes retrieved will be summarised overall and by selected 
quality parameters. Continuous data will be compared between treatment groups using van Elteren 


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test stratified for AMH and within each AMH stratum using the Wilcoxon’s test. Categorical data 
will be compared between treatment groups using a logistic regression model with treatment and 
AMH stratum as fixed factors and within each AMH stratum the chi-square test.
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. The number of subjects with at least one 
good-quality blastocyst, i.e. of grade 3BB or higher, will be reported. Further, for subjects with 
oocytes retrieved, the rate of blastocysts to oocytes retrieved will be summarised overall and by 
quality score. Continuous data will be compared between treatment groups using van Elteren test 
stratified for AMH and within each AMH stratum using the Wilcoxon’s test. Categorical data will 
be compared between treatment groups using a logistic regression model with treatment and AMH 
stratum as fixed factors and within each AMH stratum the chi-square test.
Circulating Levels of Endocrine Parameters
Blood samples drawn at stimulation days 1 and 6 and end-of-stimulation are analysed for FSH, LH, 
estradiol, progesterone, inhibin A and inhibin B. 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 6 and end-of-stimulation. For each 
parameter the change from baseline will be compared between treatment groups using an analysis 
of covariance model (ANCOVA). In this model change from baseline in ln-transformed 
measurements will be the dependent variable and the linear predictor will include treatment and 
AMH stratum as fixed factors and the baseline measurement (ln-transformed) as covariate. The 
estimated treatment ratio (FE 999049/FOLLISTIM) with 95% confidence interval will be presented 
accompanied by the p-value for test of no treatment difference.
Total Gonadotropin Dose and Number of Stimulation Days
The total gonadotropin dose and the number of stimulation days will be tabulated and compared 
between treatment groups. These endpoints will be compared between treatments using van Elteren 
test stratified for AMH and within each AMH stratum using the Wilcoxon’s test.
Adverse Events
Adverse Events – General 
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 


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Adverse events are grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before start of IMP, or a pre-existing medical condition that worsens in intensity after 
signed informed consent but before start of IMP.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of IMP and 
before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of IMP and before the end-of-trial visit.
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only.
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: all adverse events, severe adverse events, 
adverse reactions, adverse events leading to discontinuation, serious adverse events and deaths. An 
adverse reaction is an adverse event judged by the investigator to be related to IMP with a 
reasonable possibility.
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported.
Summary tables will be produced for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate / severe), adverse reactions by intensity (mild / moderate / severe), 
serious adverse events, adverse events leading to discontinuation, adverse events with an incidence 
of ≥5% in any treatment group, and non-serious adverse events with an incidence of ≥5% in any 
treatment group.
Clinical Chemistry and Haematology Parameters
Safety laboratory variables will be grouped under “Haematology” and “Clinical Chemistry”.
The baseline is based on the blood sample drawn at screening. Treatment-emergent laboratory data 
will be obtained at end-of-stimulation and end-of-trial.
The circulating levels of clinical chemistry and haematology parameters including change from 
baseline will be tabulated for each time-point for each laboratory variable. 


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Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-trial 
values, using a categorisation of low, normal and high values at each visit. Low, normal and high 
will be defined according to the reference ranges provided by the central laboratory.
For each laboratory variable, a summary table will be prepared displaying the proportion of 
subjects who have at least one markedly abnormal value. The table will also include a break-down 
by classification of the baseline value. Markedly abnormal criteria for the safety laboratory 
variables will be specified in the SAP.
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged.
Injection Site Reactions to IMP
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
and number of subjects experiencing those events will be tabulated by time (immediately, 
30 minutes, 24 hours), reaction and intensity (none, mild, moderate and severe).
Pen Malfunction
The frequency of technical malfunctions of the administration pens will be tabulated.
9.8
Additional Safety Evaluations
Vital Signs
Vital signs and their change from stimulation day 1 (baseline) to end-of-trial will be summarised. 
Shift tables will be prepared to compare the baseline values with the end-of-trial values using the 
categorisation of low, normal and high values. Low, normal and high values will be specified in the 
SAP. All vital signs values will be listed per subject. Values outside the reference range will be 
flagged.
Physical Examination
Physical examination at end-of-trial compared to baseline (screening) will be summarised in shift 
tables and all subjects with any abnormal finding will be listed per subject. The list will include 
both baseline and end-of-trial assessment for comparison.


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Gynaecological Examination
Gynaecological examination at end-of-trial compared to baseline (screening) will be summarised in 
shift tables and all subjects with any abnormal finding will be listed by subject. The list will include 
both baseline and end-of-trial assessment for comparison.
9.9
Pregnancy Follow-up Information
For all subjects with a vital pregnancy, data will be collected on ongoing pregnancy. Ongoing 
pregnancy rate will be analysed similar to the pregnancy endpoints. 
Pregnancy losses between clinical and ongoing pregnancy will also be tabulated. Furthermore, 
information on pregnancy outcome, e.g. live birth, stillbirth or late pregnancy loss will be tabulated.
Live birth rate will be summarised overall and by the same subgroups as the pregnancy endpoints.
Neonatal health data will be collected and tabulated at birth and at 4 weeks after birth for all 
children born.
9.10
Interim Analyses 
No interim analysis is planned.


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


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
Results of serum βhCG test and ultrasound at the clinical pregnancy visit 

Pregnancy progress, i.e. ongoing pregnancy information

Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth and 
4 weeks after birth

Injection site reactions after IMP administration – diary 

Adverse events (description as well as start/stop date and time)

Reason for discontinuation

Event of unblinding, including the reason for unblinding
No specific protocol data can be recorded directly in the eCRF without prior written or electronic 
record.
If the trial sites use electronic patient record systems, Ferring will decide if the electronic patient 
records qualify for the trial and document the decision. If the electronic patient records system does 
not qualify for the trial, it may be considered to utilise certified print outs of the data in the 
electronic patients record system for source data as an exception.
The source data for the endocrine parameters, clinical chemistry, haematology parameters and 
βhCG will be available at the central laboratory. Laboratory reports will be available at the sites.
The source data for the pregnancy follow-up data will be reports obtained from the subject’s 
gynaecologist / obstetrician / paediatrician, and the subject’s Maternal and Child Health Handbook 
(or a copy of the relevant pages) and information by the subject herself, or other sources, as 
applicable.
10.2
eCRF
An eCRF system provided by an independent third-party contract research organisation, Target 
Health Inc., will be used for data capture. The system is validated and access at all levels to the 
system is granted / revoked following Ferring and vendor procedures, in accordance with regulatory 
requirements and system requirements. 
Data should be entered into the system within a reasonable time after the subject has attended a 
visit or after the data become available, as applicable.
The investigator will approve / authorise the eCRF entries for each subject, with the exception of 
the treatment allocation module which is un-accessible to the investigator to maintain the assessor-
blinding, with an electronic signature which equals a handwritten signature.


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The eCRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and locked, a final copy of the database will be stored at the Global Biometrics 
Department, Ferring. The investigator will also receive a copy of the trial site’s final and locked 
data (including audit trail, electronic signature and queries) as write-protected pdf-files produced by 
Target Health Inc. The pdf-files will be stored in an electronic format and will be provided to the 
investigator before access to the eCRF is revoked. 
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.
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), Japanese Good 
Clinical Practice (J-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 
randomised at the trial site a monitoring visit will take place shortly afterwards. For this trial, the 
frequency of monitoring visits per site will be determined through a risk-based approach depending 
on recruitment rate, observed data quality and overall site performance. The source data verification 
process and definition of key variables to be monitored will be described in detail in the Monitoring 
Plan for the trial.
For the pregnancy follow-up data, accuracy and verifiability of the eCRF entries compared to the 
reports obtained from the subject’s gynaecologist / obstetrician / paediatrician the subject’s 
Maternal and Child Health Handbook (or a copy of the relevant pages), information by the subject 
herself, or other sources, as applicable, will be ensured.
11.2
Audit and Inspection
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from IRBs/ECs 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 and J-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 
authorised Ferring representatives and representatives from regulatory authorities and IRBs/ECs
may wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the 
screening/randomisation number will appear on these copies.


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The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IRB/EC.
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 
(Global Sponsor), and agreed upon by the investigator and Ferring prior to its implementation.
Amendments may be submitted for consideration to the approving IRBs/ECs and regulatory 
authorities, in accordance with local regulations. Changes to the protocol to eliminate immediate 
hazard(s) to trial subjects may be implemented prior to IRB/EC approval or favourable opinion.
12.2
Deviations from the Protocol
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
monitor, and the implications of the deviation must be reviewed and discussed. Any deviation must 
be documented in the eCRF. A log of protocol deviation reports will be available in the eCRF.
Protocol deviation reports and supporting documentation must be kept in the Investigator’s File and 
in the Trial Master File at the end of the trial.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and IRBs/ECs 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 (Global Sponsor) and submitted for comments and signature to the signatory 
investigator.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial.
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE)
criteria (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 published. Under such conditions the publication will be modified or delayed at the investigator’s 
discretion, to allow sufficient time for Ferring to seek patent protection of the invention.


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13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate 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 local regulatory requirements. A summary of the trial results is made publicly 
available in accordance with applicable regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
IRBs/ECs will review the protocol, any potential protocol amendments and potential 
advertisements used for recruitment. The IRBs/ECs will review the Informed Consent Documents, 
their updates (if any), and any written materials given to the subjects. All IRB/EC approvals 
relevant for the clinic must be available before a subject is exposed to any trial-related procedure, 
including screening tests for eligibility. A list of all IRBs/ECs to which the protocol has been 
submitted and the name of the IRB/EC chairmen will be included in the Clinical Trial Report.
14.2
Regulatory Authority Notification
The sponsor will submit the clinical trial notification to the regulatory authorities in accordance 
with applicable regulatory requirements. Within the following 15 days of evaluation by the 
regulatory authority, no subject can be exposed to any trial-related procedure, including screening 
tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
The end-of-trial is defined as the date of the last visit of the last subject participating in the trial. 
Ferring shall notify the regulatory authorities of declaration of termination of the clinical trial. 
For each clinical site, after confirmation of end of trial activities, the investigator must submit the 
end-of-trial notification to the head of institution. The head of institution must then notify the end-
of-trial to IRBs/ECs and Ferring. A second end-of-trial notification is submitted by the investigator 
after completion of pregnancy follow-up if applicable in accordance with SOPs at each site.
In the case of early termination, Ferring must notify the end of the trial to the national regulatory 
authorities and the head of institutions immediately and at the latest within 15 days after the trial is 
halted, clearly explain the reasons, and describe follow-up measures, if any, taken for safety 
reasons. The head of institutions must notify to IRBs/ECs and investigator immediately.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP, J-GCP and 
applicable regulatory requirements.


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14.5
Subject Information and Consent
The subject information describes both the clinical trial and the pregnancy follow-up data 
collection, and freely written consent to both parts will be obtained.
The investigator will obtain a freely given written consent from each subject and her partner after 
an appropriate explanation of the aims, methods, anticipated benefits, potential hazards, and any 
other aspects of the trial and pregnancy follow-up data collection which are relevant to the decision 
to participate. The subject and her partner must be given ample time to consider participation in the 
trial and acceptance of the pregnancy follow-up data collection before consents to both activities 
are obtained. The Informed Consent Documents (consisting of the Subject Information and the 
Informed Consent Form) must be signed and dated before the subject is exposed to any trial-related 
procedure, including screening tests for eligibility. The following persons must sign and date the 
Informed Consent Documents: the subject, the subject’s partner, the investigator providing the 
explanation, the person providing the supplementary explanation, and the investigator obtaining the 
consent information.
The investigator will explain that the subject and her partner are completely free to refuse to enter 
the trial, refuse to agree to the pregnancy follow-up data collection or to withdraw their consent at 
any time, without any consequences for their further care and without the need to justify their 
decision.
The subject will receive a copy of the Informed Consent Documents.
If new information becomes available that may be relevant to the subject’s and her partner’s 
willingness to continue participation, a new Subject Information and Informed Consent Form will 
be forwarded to the IRBs/ECs (and regulatory authorities, if required). The subject and her partner 
will be informed about this new information and re-consent will be obtained. 
Each subject will be informed that the monitor(s) and quality assurance auditor(s) mandated by 
Ferring, IRB/EC representatives or regulatory authority inspector(s), in accordance with applicable 
regulatory requirements, may review her and her neonate’s source records and data. Data protection 
will be handled in compliance with national / local regulations.
14.6
Trial Participation Card
The subject will be provided with a Trial Participation Card, as a minimum bearing the following 
information:

That she is participating in a clinical trial

That the trial involves controlled ovarian stimulation with recombinant FSH (randomisation 
to an FSH preparation under clinical development in Japan or to an FSH product approved 
in Japan)


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
The name and phone number of the investigator
The subject will be asked to return the Trial Participation Card at the end-of-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
Compliance Reference Documents
The Declaration of Helsinki, the consolidated ICH-GCP, J-GCP and other national laws in Japan 
shall constitute the main reference guidelines for ethical and regulatory conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP
and J-GCP consolidated guideline, and applicable local regulatory requirements. The investigator is 
responsible for adhering to the ICH-GCP and J-GCP responsibilities of investigators, for dispensing 
the IMP in accordance with the protocol or an amendment reviewed by the regulatory authorities, 
and for the secure storage and safe handling of medicinal products 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
Olsson H, Sandström R, Bagger Y. Dose-exposure proportionality of a novel recombinant 
follicle-stimulating hormone (rFSH), FE 999049, derived from a human cell line, with 
comparison between Caucasian and Japanese women after subcutaneous administration. Clin 
Drug Investig 2015; 35: 247–253.
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.
000124 A randomised, controlled, assessor-blind, parallel groups, multicentre trial assessing 
the dose-response relationship of FE 999049 in controlled ovarian stimulation in Japanese 
women undergoing an assisted reproductive technology programme. Ferring Pharmaceuticals 
A/S. Report, September 2016.
Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein BM, Arce J-C; 
ESTHER-1 study group. 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.
Nakamura Y, Yamada H, Yoshida K, Manno T, Ubukata Y, Suzuki M, Yoshimura Y. 
Induction of ovulation with pulsatile subcutaneous administration of human menopausal 
gonadotropin in patients with polycystic ovary syndrome. Horm Res 1990; 33: 43-48.
Fujiwara T. A multi-center, randomized, open-label, parallel group study of a natural 
micronized progesterone vaginal tablet as a luteal support agent in Japanese women 
undergoing assisted reproductive technology. Reprod Med Biol 2015; 14: 185–193.
FOLLISTIM Prescribing Information. February 2013.
FE 999049 Investigator’s Brochure. Japanese version effective at trial start. 
Coelingh Bennink HJT, Fauser BCJM, Out HJ. Recombinant follicle-stimulating hormone 
(FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene 
citrate-resistant, normogonadotrophic, chronic anovulation: a prospective, multicenter, 
assessor-blind, randomized, clinical trial. Fertil Steril 1998; 69: 19-25.
Human FSH Study Group. Clinical assessment of recombinant human follicle-stimulating 
hormone in stimulating ovarian follicular development before in vitro fertilization. Fertil 
Steril 1995; 63: 77-86. 


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Wadhwa M, Thorpe R. Unwanted immunogenicity: implications for follow-on biologicals. 
Drug Information Journal 2007; 41: 1-10.
TNO. Determination of anti-FSH antibodies in patient serum samples using a validated 
bridging enzyme-linked immunosorbent assay (ELISA). FE999902 CS001. January 2009. 
(Report prepared for Ferring Pharmaceuticals)
European Medicines Agency. CHMP Assessment Report for Elonva (corifollitropin alfa). 
EMA/CHMP/802299/2009. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/001106/WC500074789.pdf 
Buur Rasmussen B, Mannaerts M, Klein BM, Helmgaard L, Arce J-C on behalf of the 
ESTHER-1 and ESTHER-2 trial group (Evidence-based Stimulation Trial with Human rFSH 
in Europe and Rest of World). 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): i376.
Blake DA, Proctor M, Johnson NP. The merits of blastocyst versus cleavage stage embryo 
transfer: a Cochrane review. Hum Reprod 2004; 19: 795-807.
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.
Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. 
Hum Reprod 2003; 18: 1000-1004.
Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 2003; 
18: 1005-1009.
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.
Griesinger G, von Otte S, Schroer A, Ludwig AK, Diedrich K, Al-Hasani S, Schultze-
Mosgau A. Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering 
of final oocyte maturation in patients at risk of developing OHSS: a prospective, 
observational proof-of-concept study. Hum Reprod 2007; 22: 1348-1352.
Griesinger G, Kolibianakis EM, Papanikolaou EG, Diedrich K, Van Steirteghem A, Devroey 
P, Ejdrup Bredkjær H, Humaidan P. Triggering of final oocyte maturation with gonadotropin-
releasing hormone agonist or human chorionic gonadotropin. Live birth after frozen-thawed 
embryo replacement cycles. Fertil Steril 2007; 88: 616-621.


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Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of 
gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after 
cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization 
prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled 
study. Fertil Steril 2008; 89: 84-91.
Humaidan P, Papanikolaou EG, Tarlatzis BC. GnRHa to trigger final oocyte maturation: a 
time to reconsider. Hum Reprod 2009; 24: 2389-2394.
Herrero L, Pareja S, Losada C, Cobo AC, Pellicer A, García-Velasco JA. Avoiding the use of 
human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist 
triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome. Fertil 
Steril 2011; 95: 1137-1140.
American Society for Reproductive Medicine. Revised American Society for Reproductive 
Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67: 817-821.
Practice Committee of the Society of Assisted Reproductive Technology and the Practice 
Committee of the American Society for Reproductive Medicine. Guidelines on number of 
embryos transferred. Fertil Steril 2006; 86: S51-S52.
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.
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards 
reproductive certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th 
world congress on in vitro fertilization and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388.
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation 
syndrome: an update review. Obstet Gynecol Survey 1989; 44: 430-440.
European Medicines Agency (EMA). Committee for medicinal products for human use 
(CHMP). Guideline on the exposure to medicinal products during pregnancy: need for post-
authorisation data. EMEA/CHMP/313666/2005.
European Medicines Agency (EMA). Points to consider on switching between superiority and 
non-inferiority. CPMP/EWP/482/99.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan  
 
Title of trial:  
A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial 
Assessing the Efficacy and Safety of FE 999049 in Controlled Ovarian 
Stimulation in Japanese Women Undergoing an Assisted Reproductive 
Technology Programme 
NCT number: 
NCT03228680 
Sponsor trial code: 
000273  
Date:  
22 August 2019  
 
 
 
 
 


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Statistical Analysis Plan
STATISTICAL ANALYSIS PLAN
A randomised, controlled, assessor-blind, parallel groups, multicentre trial assessing the efficacy 
and safety of FE 999049 in controlled ovarian stimulation in Japanese women undergoing an 
assisted reproductive technology programme
Trial Code 000273
Investigational Product:
FE 999049, human recombinant follicle-stimulating hormone, solution 
for subcutaneous injection
Indication:
Controlled ovarian stimulation for the development of multiple follicles 
in women undergoing assisted reproductive technologies (ART) such as 
an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) 
cycle
Phase:
3
Author:
Date of issue:
22 August 2019
Version:
3.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Statistical Analysis Plan
Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1.0
14 July 2017
New version
None
2.0
25 July 2019
Section 1 Introduction
The text "... and is based on the final protocol version. 
1.0 dated 28FEB2017." is replaced by "... is based on 
the final protocol version. 2.0 dated 16 March 2018 and 
the protocol amendment Version 1.0 (dated 13th 
November 2018).".
1.0
2.0
25 July 2019
Section 3.1 General Design Considerations
The following clarification is added:
"The randomisation strata by AMH reflect the FE 
999049 dosing regimen, and therefore each subject’s 
AMH value is rounded off to the nearest integer before 
allocation into one of the two strata, <15 pmol/L or ≥15 
pmol/L. The rounding off rules used for AMH with 
respect to randomisation strata are identical to those 
described in Section 5.1.1 “FE 999049 Dosing 
Regimen” of the protocol. Consequently, the 
randomisation stratum AMH <15 pmol/L corresponds 
to the description of the AMH <15 pmol/L category in 
the FE 999049 dosing regimen, meaning that it 
includes AMH values up to and including 14.49 
pmol/L. The randomisation stratum AMH ≥15 pmol/L 
includes AMH values from 14.50 pmol/L and higher. 
These rounding off rules are implemented in the eCRF 
and used in the automated allocation of subjects into 
either the AMH <15 pmol/L or ≥15 pmol/L strata."
1.0


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2.0
25 July 2019
Section 4 Subject Disposition
The text " ... full analysis set (FAS) overall and by 
AMH stratum. All subjects screened will be accounted 
for." is changed to "... full analysis set (FAS) overall 
and by AMH stratum." as sentence the "All subjects 
screened will be accounted for." is presented earlier in 
the section.
The sentence "The number of subjects screened but not 
randomized/allocated to treatment will be presented 
with the reason(s) for screen failure in a data listing." is 
removed.
1.0
2.0
25 July 2019
Section 5 Protocol Deviations
The text “The rating of protocol deviations as ‘minor’ 
and ‘major’ will be decided by the Ferring clinical team 
on the basis of a blinded …” is changed to “The rating 
of protocol deviations as ‘minor’ and ‘major’ will be 
decided by the medical officer, medical monitor and 
project statistician based on a blinded …”.
1.0
2.0
25 July 2019
Section 7.2 Medical History
The text "All medical history will be coded using 
MedDRA. The version of MedDRA will be 
documented." is changed to "All medical history will 
be coded using MedDRA version 20.0."
1.0
2.0
25 July 2019
Section 8.1.1 Extent of Exposure
Comparison for "The total gonadotropin dose" was 
removed as FE 999049 and FOLLISTIM cannot be 
converted to be presented using a common unit. 
The comparison of duration of stimulation (days) 
between treatments for three age groups (<35, 35-37 
and 38-40 years) has been removed.
1.0
2.0
25 July 2019
Section 9.1 General Considerations
Under “Analysis and Presentation of Primary and 
Secondary Endpoints” 
The text “In addition, summary tables per age group 
(<35, 35-37 and 38-40 years) will be provided.” is 
changed to “In addition, summary tables and treatment 
comparisons for the efficacy endpoints will be 
presented per age group (<35, 35-37 and 38-40 years) 
unless it is specified otherwise.”.
1.0


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Statistical Analysis Plan
2.0
25 July 2019
Section 9.2.2 Sensitivity Analyses and Additional 
Analysis
The text “The distribution of the number of oocytes 
retrieved will be plotted using histograms and the 
percentage …” is changed to “The percentage …”.
1.0
2.0
25 July 2019
Section 9.3 Important Secondary Endpoint
Under "Clinical Pregnancy Rate":
The text "are the treatment specific standards error of 
the observed difference in rates within stratum i," is 
corrected to "is the standards error of the observed 
difference in rates within stratum i,".  
The text "Both analyses will be based on all subjects in 
the FAS."  is changed to "The analyses will be based on 
all subjects as well as all subjects with transfer and they 
are done on the FAS.".
1.0
2.0
25 July 2019
Section 9.4 Secondary Endpoints
Under "Implantation Rate":
The text " This analysis does not adhere to the 
randomisation principle and is less relevant than the 
analysis of clinical pregnancy rate for all subjects.” is 
removed.
Under "Number and Size of Follicles during 
Stimulation":
The text "Categorical data will be compared between 
treatment groups using a logistic regression model with 
treatment and AMH stratum as fixed factors and within 
each AMH stratum the chi-square test." is not 
corresponding to any analysis and therefore it is 
removed.
Under "Fertilisation Rate":
The text "Categorical data will be compared between 
treatment groups using a logistic regression model with 
treatment and AMH stratum as fixed factors and within 
each AMH stratum the chi-square test." is not 
corresponding to any analysis and therefore it is 
removed.
1.0


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Statistical Analysis Plan
The text "Number of fertilised oocytes and fertilisation 
rate will be compared ..." is changed to "Number of 
fertilised oocytes, number of metaphase II oocytes, 
fertilisation rate, the rate of metaphase II oocytes to 
oocytes retrieved, and fertilisation rate relative to 
metaphase II oocytes will be compared ...".
Under “Circulating Levels of Endocrine 
Parameters”:
The text “For each parameter the change from baseline 
will be compared between treatment groups using an 
analysis of covariance model (ANCOVA).” is changed 
to “Each parameter will be compared between 
treatment groups using an analysis of covariance model 
(ANCOVA). No subgroup analysis will be performed 
per age group”.
The text "In this model change from baseline in ln-
transformed measurements will be the dependent 
variable and ..." is changed to "In this model ln-
transformed measurements will be the dependent 
variable and ...". With this change it will be possible to 
obtain adjusted treatment means.
2.0
25 July 2019
Section 10.2 Adverse Events
The text "Adverse events will be coded using 
MedDRA. The version of MedDRA will be 
documented." is changed to "Adverse events will be 
coded using MedDRA version 20.0."
1.0
2.0
25 July 2019
Section 10.2.2 Incidence of Adverse Events
The text "... adverse events with an incidence of ≥5% in 
any treatment group, and non-serious adverse events 
with an incidence of ≥5% in any treatment group." is 
changed to "... adverse events with an incidence of ≥2% 
in any treatment group, and non-serious adverse events 
with an incidence of ≥2% in any treatment group."
1.0
2.0
25 July 2019
Section 10.10 Pregnancy Follow-up Information
This section has been deleted since it is out of the scope 
of this SAP.
1.0
3.0
22 Aug 2019
Section 1.1 Definitions/ Abbreviations
The definition of “Completer” is added to “Table 1.1.1 
Definition of Terms”.
2.0


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Statistical Analysis Plan
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Section 9.3 Important Secondary Endpoint
Under "Clinical Pregnancy Rate":
The text "The analyses will be based on all subjects as 
well as all subjects with transfer." is changed to “The 
analyses will be done based on all subjects, all subjects 
with oocytes retrieved, and all subjects with transfer.”.
2.0
3.0
22 Aug 2019
Section 9.4 Secondary Endpoints
Under “Cycle Cancellation due to Poor or Excessive 
Ovarian Response or Blastocyst Transfer 
Cancellation due to Excessive Ovarian Response / 
OHSS Risk”:
The text “If the expected number of observations is less 
than five in any of the cells in the contingency table 
then Fisher’s exact test will be used as alternative.” is 
changed to “In case of sparse data, treatments will be 
compared using the Cochran-Mantel-Haenszel test 
stratified for AMH stratum. Within AMH stratum the 
comparisons will be based on Fisher’s exact test.”. 
Under “Extreme Ovarian Response”:
The text “In addition, they will be analysed based on all 
subjects with triggering of final follicular maturation.” 
is added.
Under “Number and Quality of Embryos on Day 3”:
The text “Categorical data (subjects with at least one 
good-quality embryos) will be compared between 
treatment groups using a logistic regression model with 
treatment and AMH stratum as fixed factors and within 
each AMH stratum using the chi-square test.” is added.
2.0
3.0
22 Aug 2019
Section 12 Deviations from Protocol Analysis
The text “The description of the analysis set used for 
analyses, summary tables, listings, and figures are 
further clarified in the SAP.” is added  
2.0


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Ferring Pharmaceuticals 
CONFIDENTIAL
Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
Review and Approval of Statistical Analysis Plan
Author (e-signed in REAL):
Director of Biometrics
Ferring Pharmaceuticals Co., Ltd, Japan
Review (Review using PleaseReview or similar system and stored in LSAF):
Vice President, Therapeutic Area, Reproductive Health
Ferring Pharmaceuticals A/S
Medical Director, Therapeutic Area, Reproductive Medicin & Women's Health
Ferring Pharmaceuticals A/S
Pharmacovigilance Physician, Global Pharmacovigilance
Ferring Pharmaceuticals A/S
Senior Director, Medical Writing, Global Development
Ferring Pharmaceuticals A/S
Lead Statistical Programmer, Global Biometrics
Ferring Pharmaceuticals A/S
Approval (e-signed in REAL):
Senior Director, Global Biometrics
Ferring Pharmaceuticals A/S


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Ferring Pharmaceuticals 
CONFIDENTIAL
Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
TABLE OF CONTENTS
1
Introduction........................................................................................................................................ 10
1.1
Definitions/ Abbreviations...................................................................................................... 10
1.1.1
Definition of Terms.................................................................................................... 10
1.1.2
Abbreviations............................................................................................................. 10
2
Trial Objectives and Endpoints........................................................................................................ 12
3
Trial Design ........................................................................................................................................ 13
3.1
General Design Considerations............................................................................................... 13
3.2
Determination of Sample Size ................................................................................................ 14
4
Subject Disposition ............................................................................................................................ 14
5
Protocol Deviations............................................................................................................................ 15
6
Analysis Sets....................................................................................................................................... 15
6.1
Intention-To-Treat Analysis Set.............................................................................................. 15
6.2
Full Analysis Set..................................................................................................................... 15
6.3
Per Protocol Analysis Set........................................................................................................ 16
6.4
Safety Analysis Set ................................................................................................................. 16
7
Trial Population................................................................................................................................. 16
7.1
Demographics and Other Baseline Characteristics................................................................. 16
7.1.1
Demographics ............................................................................................................ 16
7.1.2
Infertility History, Menstrual History and Reproductive History.............................. 16
7.2
Medical History....................................................................................................................... 16
7.3
Prior and Concomitant Medication......................................................................................... 16
7.4
Physical Examination and Gynaecological Examination........................................................ 17
8
Exposure and Treatment Compliance ............................................................................................. 17
8.1.1
Extent of Exposure..................................................................................................... 17
8.1.2
Treatment Compliance............................................................................................... 17
9
Efficacy ............................................................................................................................................... 17
9.1
General Considerations........................................................................................................... 17
9.2
Primary Endpoint.................................................................................................................... 18
9.2.1
Primary Variable Analysis......................................................................................... 18
9.2.2
Sensitivity Analyses and Additional Analysis........................................................... 19
9.3
Important Secondary Endpoint ............................................................................................... 20
9.4
Secondary Endpoints............................................................................................................... 20
10
Safety................................................................................................................................................... 24
10.1
General Considerations........................................................................................................... 24
10.2
Adverse Events ....................................................................................................................... 24
10.2.1 Overview of Treatment-Emergent Adverse Events................................................... 24
10.2.2 Incidence of Adverse Events...................................................................................... 24
10.3
OHSS ...................................................................................................................................... 25
10.4
Injection Site Reactions to IMP .............................................................................................. 26
10.5
Pen Malfunction...................................................................................................................... 26
10.6
Safety Laboratory Variables ................................................................................................... 26
10.6.1 Summary Statistics..................................................................................................... 26


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Statistical Analysis Plan
10.6.2 Laboratory Variable Changes Relative to Normal Range.......................................... 27
10.6.3 Markedly Abnormal Changes.................................................................................... 27
10.6.4 Data Listings.............................................................................................................. 27
10.7
Vital Signs............................................................................................................................... 27
10.7.1 Vital Signs.................................................................................................................. 27
10.8
Physical Examination.............................................................................................................. 27
10.9
Gynaecological Examination.................................................................................................. 27
11
Interim Analyses ................................................................................................................................ 27
12
Deviations from Protocol Analysis ................................................................................................... 27
13
References........................................................................................................................................... 29
14
Tables, Listings and Figures ............................................................................................................. 30
Appendix 1
Markedly Abnormal Laboratory Values and Vital Signs................................................. 31


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Trial Code: 000273
Statistical Analysis Plan
1
Introduction
This document describes the planned statistical analyses for 000273 and is based on the final 
protocol version. 2.0 dated 16 March 2018 and the protocol amendment Version 1.0 (dated 13th
November 2018). No changes are done to the analyses planned in the protocol. Details and context 
of the analyses described in the protocol have been clarified and some additional analyses have 
been included to make the result description more complete.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
ESTHER-1 trial
Phase 3 trial, ESTHER-1 (Evidence based Stimulation Trial with 
Human rFSH in Europe and Rest of World), conducted in 11 countries 
overseas including Europe, North America and Latin America. Ferring 
trial ID 000004.
Randomised
Subject randomised to trial treatment
Screened
Subject who signed informed consent
Completer
A subject is considered a completer if she attends all scheduled trial 
visits and undergoes the end-of-trial assessments. A subject who is not 
a completer will be considered a non-completer subject.
1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
Adverse event
AMH
Anti-Müllerian hormone
ANCOVA
Analysis of covariance
ART
Assisted reproductive technologies
βhCG
Beta unit of human chorionic gonadotropin
CV
Coefficient of variation
eCRF
Electronic case report form
EMA
European Medicines Agency
FAS
Full analysis set
FSH
Follicle-stimulating hormone
GnRH
Gonadotropin-releasing hormone
hCG
Human chorionic gonadotropin
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th revision
ICSI
Intracytoplasmic sperm injection
IMP
Investigational Medicinal Product
ITT
Intention-to-treat


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Statistical Analysis Plan
Abbreviations
Meaning of abbreviations in document
IVF
In vitro fertilisation
LH
Luteinising hormone
LLOQ
Lower limit of quantification
LSAF
Life Science Analytics Framework
MedDRA
Medical Dictionary for Regulatory Activities
OHSS
Ovarian hyperstimulation syndrome
OR
Oocytes retrieved
PMDA
Pharmaceuticals and Medical Devices Agency
PP
Per protocol
PT
Preferred term
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
System organ class
ULN
Upper limit of normal
ULOQ
Upper limit of quantification


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Trial Code: 000273
Statistical Analysis Plan
2
Trial Objectives and Endpoints
Primary Objective

To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to 
number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian 
stimulation
Secondary Objectives

To compare FE 999049 with FOLLISTIM with respect to achieving pregnancy

To compare FE 999049 with FOLLISTIM with respect to ovarian response and endocrine 
profile

To compare FE 999049 with FOLLISTIM with respect to oocyte fertilisation and number 
and quality of embryos/blastocysts

To compare FE 999049 with FOLLISTIM with respect to the frequency of OHSS and/or 
preventive interventions for early OHSS

To compare FE 999049 with FOLLISTIM with respect to safety profile, including adverse 
events, routine safety laboratory parameters and local tolerability

To compare FE 999049 with FOLLISTIM with respect to gonadotropin use
Primary Endpoint

Number of oocytes retrieved
Important Secondary Endpoint

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
Secondary Endpoints

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer)

Implantation rate (number of gestational sacs 5-6 weeks after transfer divided by number of 
blastocysts transferred)

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or 
blastocyst transfer cancellation due to excessive ovarian response / OHSS risk

Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved

Proportion of subjects with extreme ovarian responses, defined as <4, ≥15 or ≥20 oocytes 
retrieved

Proportion of subjects with preventive interventions for early OHSS

Proportion of subjects with early OHSS (including OHSS of moderate/severe grade) and/or 
preventive interventions for early OHSS


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Statistical Analysis Plan

Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)

Proportion of subjects with OHSS (early and/or late) and/or preventive interventions for 
early OHSS

Number and size of follicles on stimulation day 6 and end-of-stimulation

Fertilisation rate as well as number and quality of embryos on day 3 and blastocysts on day 
5 after oocyte retrieval

Circulating concentrations of FSH, LH, estradiol, progesterone, inhibin A and inhibin B on 
stimulation day 6 and end-of-stimulation

Total gonadotropin dose and number of stimulation days

Frequency and intensity of adverse events

Changes in circulating levels of clinical chemistry and haematology parameters and 
proportion of subjects with markedly abnormal changes

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period

Technical malfunctions of the administration pens
Pregnancy Follow-up Information

Ongoing pregnancy rate (at least one intrauterine viable fetus 10-11 weeks after transfer) 
and live birth rate

Neonatal health at birth and at 4 weeks after birth
3
Trial Design
3.1
General Design Considerations
This is a randomised, assessor-blind, controlled, parallel groups, multicentre trial assessing the 
efficacy and safety of FE 999049 in its individualised dosing regimen when used in first cycle 
Japanese patients aged 20-40 years undergoing controlled ovarian stimulation for IVF/ICSI 
following a GnRH antagonist protocol. 
The trial has been designed to demonstrate non-inferiority of FE 999049 versus an rFSH product 
approved in Japan, i.e. FOLLISTIM, with respect to number of oocytes retrieved.
Eligible subjects will be randomised in a 1:1 ratio to controlled ovarian stimulation with FE 999049
or FOLLISTIM. Randomisation will be stratified by centre and according to AMH levels at 
screening (<15 pmol/L and ≥15 pmol/L). The randomisation strata by AMH reflect the FE 999049 
dosing regimen, and therefore each subject’s AMH value is rounded off to the nearest integer 
before allocation into one of the two strata, <15 pmol/L or ≥15 pmol/L. The rounding off rules used 
for AMH with respect to randomisation strata are identical to those described in Section 5.1.1 “FE 
999049 Dosing Regimen” of the protocol. Consequently, the randomisation stratum AMH <15 
pmol/L corresponds to the description of the AMH <15 pmol/L category in the FE 999049 dosing
regimen, meaning that it includes AMH values up to and including 14.49 pmol/L. The 


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Statistical Analysis Plan
randomisation stratum AMH ≥15 pmol/L includes AMH values from 14.50 pmol/L and higher.
These rounding off rules are implemented in the eCRF and used in the automated allocation of 
subjects into either the AMH <15 pmol/L or ≥15 pmol/L strata.
The last scheduled visit in the main part of the trial is the clinical pregnancy visit (end-of-trial). 
Non-pregnant subjects should complete the end-of-trial assessments at time of discontinuation. 
Subjects with a vital pregnancy will be followed for pregnancy outcome as well as neonatal health 
at birth and at 4 weeks after birth.
3.2
Determination of Sample Size
The primary objective of this trial is to demonstrate non-inferiority of FE 999049 compared with 
FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing 
controlled ovarian stimulation. The non-inferiority margin for the difference between treatments 
(FE 999049 versus FOLLISTIM) is -3.0 oocytes. This margin is based on considerations of clinical 
relevance and overseas regulatory precedence, and has been reviewed and agreed at the follow-up 
meeting for the Pharmaceuticals and Medical Devices Agency (PMDA) post-phase 2 trial 
consultation in December 2016. 
The standard deviation for the primary endpoint is estimated to 8.1 oocytes based on historical data 
with FOLLISTIM. The sample size is determined to obtain 90% power to achieve the primary 
objective for the per-protocol (PP) analysis set for a 1:1 randomisation ratio between FE 999049
and FOLLISTIM and a one-sided t-test at a 2.5% significance level. Assuming the two treatments 
to be equally effective and a standard deviation of 8.1 oocytes, a sample size of 155 randomised 
subjects per treatment group would give 90% power. The proportion of subjects with major 
protocol deviations is assumed to be at most 5% and hence 328 randomised subjects are needed to 
provide 155 subjects/group in the PP analysis set.
4
Subject Disposition
All screened subjects will be accounted for.
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening 
failures.
Subject disposition with respect to analysis sets will be tabulated by treatment group overall and by 
AMH stratum (screening AMH: <15 pmol/L, ≥15 pmol/L) for all randomised subjects. This table 
will include the number of completed and discontinued subjects including reason for 
discontinuation. Screening failures and their primary reason for screening failure will also be 
included. Screening failures will not otherwise be accounted for.
A separate table will summarise the subject disposition with respect to analysis sets by trial site 
overall and by AMH stratum.


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Trial Code: 000273
Statistical Analysis Plan
The number of subjects completed and discontinued (including reason) will be summarised for the 
following trial parts: stimulation, triggering of final follicular maturation, oocyte retrieval, transfer, 
and pregnancy monitoring. This table will be produced for the full analysis set (FAS) overall and 
by AMH stratum.
Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately.
5
Protocol Deviations
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. The list of major protocol deviations include, but is not restricted to:

Unblinding of assessor or investigator

IMP regimen (treatment not in accordance with randomisation or non-compliance with IMP 
for two or more days)

Non-compliance with the triggering criterion
The rating of protocol deviations as ‘minor’ and ‘major’ will be decided by the medical officer, 
medical monitor and project statistician based on a blinded review of data before declaration of 
clean file and lock of database. If the blinded review identifies unforeseen deviations deemed to 
impact the primary endpoint, these will also be rated as major deviations.
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be summarised and listed by subject for the 
intention-to-treat (ITT) analysis set.
6
Analysis Sets
6.1
Intention-To-Treat Analysis Set
The ITT analysis set is defined as all randomised subjects. Subjects will be analysed according to 
planned (randomised) treatment.
6.2
Full Analysis Set
The FAS is defined as all randomised and exposed (to IMP) subjects. Subjects will be analysed 
according to planned (randomised) treatment.


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Trial Code: 000273
Statistical Analysis Plan
6.3
Per Protocol Analysis Set
The PP analysis set is defined as all randomised and exposed (to IMP) subjects except those 
excluded as a result of major protocol deviations as described in Section 5.
6.4
Safety Analysis Set 
The safety analysis set is defined as all randomised and exposed (to IMP) subjects. Subjects will be 
analysed according to actual treatment received.
7
Trial Population
All relevant baseline data will be summarised in tables including both treatment groups and a total 
column. The purpose of these tabulations is to characterise the treatment groups and assess the 
degree of similarity achieved by the randomisation. Baseline data will not be compared using 
statistical tests. Unless otherwise noted, tabulations will be produced overall and by AMH stratum 
for both the FAS and the PP analysis set. Continuous variables will be presented with number of 
subjects, mean, standard deviation, median, inter-quartile range, minimum, and maximum. 
Categorical variables will be presented with number and percentage of subjects within each specific 
category.
Listings will be produced for the ITT analysis set.
7.1
Demographics and Other Baseline Characteristics
7.1.1
Demographics
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.
7.1.2
Infertility History, Menstrual History and Reproductive History
Infertility history, menstrual history and reproductive history will be listed by subject and presented 
in summary tables.
7.2
Medical History
All medical history will be coded using MedDRA version 20.0. Medical history will be listed by 
subject and summarised for each medical item. This summary table will only be produced overall 
(i.e. not by AMH stratum) for the FAS.
7.3
Prior and Concomitant Medication
Concomitant medications will be coded using the WHO Drug Reference List. Prior and 
concomitant medication will be summarised by ATC classification 1st level (alphabetically) and 


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Trial Code: 000273
Statistical Analysis Plan
ATC classification 2nd level (in decreasing order of frequency). These medications will be tabulated 
separately for the following parameters:

Prior medication, i.e. medication taken exclusively prior to treatment (i.e. with stop 
date/time before date/time of 1st IMP administration)

Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date/time of 1st IMP administration and not started after the 
end-of-trial visit)
These tables will only be produced overall (i.e. not by AMH stratum) for the FAS.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
Concomitant medications will be listed by subject.
7.4
Physical Examination and Gynaecological Examination
Physical examination and gynaecological examination performed during screening will be 
summarised per category. These tables will only be produced overall (i.e. not by AMH stratum) for 
the FAS.
8
Exposure and Treatment Compliance
8.1.1
Extent of Exposure 
The total gonadotropin dose and the duration of stimulation (days) will be tabulated based on the 
safety analysis set. The duration of stimulation (days) will be compared between treatments on the 
safety analysis set using van Elteren test stratified for AMH and within each AMH stratum using 
the Wilcoxon’s test. Descriptive summaries will be presented overall, and for the two AMH strata.
8.1.2
Treatment Compliance 
Treatment non-compliance will be presented in listings as non-compliance is expected to be 
limited.
9
Efficacy
9.1
General Considerations
Primary and Secondary Endpoints
The results of the analyses of the primary endpoint (number of oocytes retrieved) is essential for the 
non-inferiority claim. The analyses of the important secondary endpoint and the other secondary 
endpoints are intended to provide additional characterisation of the safety and efficacy of 
FE 999049. However, non-inferiority does not need to be established for these endpoints.


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Trial Code: 000273
Statistical Analysis Plan
Analysis and Presentation of Primary and Secondary Endpoints
Summary tables and treatment comparisons for the primary endpoint, the important secondary 
endpoint and the secondary efficacy endpoints will be presented overall and by AMH stratum for 
the FAS. In addition, summary tables and treatment comparisons for the efficacy endpoints will be 
presented per age group (<35, 35-37 and 38-40 years) unless it is specified otherwise.
All tabulations will present the treatment groups and include a total column. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category.
Visual displays will be produced as appropriate. All primary and secondary efficacy endpoints will 
be listed. Listings will only be produced for the FAS.
Multiplicity
No adjustment for multiplicity is required for the primary endpoint since there is only one 
hypothesis and one analysis set (FAS). Concerning the secondary endpoints, no formal adjustment 
for multiplicity will be utilised.
Missing Data
For the primary endpoint, number of oocytes retrieved, no missing data are expected. Subjects that 
discontinue stimulation, do not continue from stimulation to triggering of final follicular 
maturation, or do not undergo the oocyte retrieval procedure, will be regarded as having zero 
oocytes retrieved.
For the secondary endpoints, positive βhCG rate, clinical pregnancy rate, vital pregnancy rate, and 
implantation rate occurrence of missing data is unlikely but may occur in case the assessment was 
not done. For these endpoints, a subject’s response is considered as ‘negative’ unless recorded as 
‘positive’. An exception to this is if a later observation confirms that a previous missing observation 
was in fact positive. If, for example, the βhCG test result is missing but clinical pregnancy is 
recorded as ‘positive’, then the βhCG test result will be imputed as ‘positive’.
9.2
Primary Endpoint
9.2.1
Primary Variable Analysis
The primary endpoint ‘number of oocytes retrieved’ will be analysed using an analysis of variance 
model with treatment and AMH stratum as fixed factors. The 2-sided 95% confidence limits for the 
mean treatment differences (FE 999049 - FOLLISTIM) will be calculated based on the fitted model 
for the FAS. 


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Statistical Analysis Plan
The hypothesis to be tested is:
H0: ORFE 999049 - ORFOLLISTIM ≤ -3.0 against
H1: OR FE 999049 - ORFOLLISTIM > -3.0
where OR FE 999049 and ORFOLLISTIM denote the mean number of oocytes retrieved with respective 
treatment.
The null hypothesis (H0) will be tested against the alternative (H1) by constructing a two-sided 95% 
confidence interval for the difference in mean number of oocytes retrieved. The null hypothesis will 
be rejected if the lower-limit of the two-sided 95% confidence interval is greater than the non-
inferiority limit (-3.0 oocytes) for the FAS. In this case it will be claimed that FE 999049 is non-
inferior to FOLLISTIM with respect to number of oocytes retrieved in women undergoing 
controlled ovarian stimulation.
9.2.2
Sensitivity Analyses and Additional Analysis
The FAS is the primary analysis population for this trial, and the analysis of the PP analysis set is 
only considered supportive for the application in Japan. In the EMA guideline “Points to consider 
on switching between superiority and non-inferiority”1, the FAS and the PP analysis sets are 
considered equally important. FE 999049 is a compound under global development. Therefore, for 
applications in countries applying the EMA guideline, Ferring would intend to demonstrate non-
inferiority for both the FAS and PP analysis sets, and in such a case both would be considered as 
confirmatory analyses.
The primary analysis will therefore be repeated using the PP analysis set. This sensitivity analysis 
will address the assay sensitivity of the primary analysis by excluding subjects with major protocol 
deviations, e.g. substantial non-compliance with randomised treatment.
To investigate the possibility for different treatment differences in the two AMH strata, an analysis 
of variance model will be fitted where the treatment-by-stratum interaction is included. In addition, 
subgroup analyses will be performed for the two AMH strata separately (using a simpler model 
with only treatment as factor). The trial is not powered to show non-inferiority in the two strata 
separately and these analyses should only be regarded as descriptive.
Additional descriptions will be made based only on subjects with oocytes retrieved. The purpose of 
this is purely descriptive.
The percentage of subjects with <4 oocytes, 4-7 oocytes, 8-14 oocytes, 15-19 oocytes, and >20 
oocytes retrieved will be tabulated both for all subjects in the FAS and for the two AMH strata.


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Statistical Analysis Plan
9.3
Important Secondary Endpoint
Clinical Pregnancy Rate
Clinical pregnancy is defined as at least one gestational sac 5-6 weeks after transfer. The clinical 
pregnancy rate will be summarised for all subjects, for subjects with at least one oocyte retrieved 
and for subjects with transfer. The difference between FE 999049 and FOLLISTIM in clinical 
pregnancy rate will be estimated and a two-sided 95% confidence interval will be constructed using
the Mantel-Haenszel method (described below) will to combine results across AMH strata. In brief, 
this corresponds to deriving a weighted average across AMH strata where the weight depends on 
the number of observations in each treatment group in each AMH stratum. 
The two-sided 95% confidence intervals will be constructed based on the asymptotic normal 
distribution as


2
2
2
)
(
96
.1





i
i
i
i
i
i
w
RD
SE
w
w
RD
w
,
where the sums are over the two AMH strata (i.e. i = 1, 2), 
i
FO
i
FE
i
RD
,
,
ˆ
ˆ




are the observed 
difference in rates (FE 999049 – FOLLISTIM) within stratum i,
i
FO
i
FO
i
FO
i
FE
i
FE
i
FE
i
n
n
RD
SE
,
,
,
,
,
,
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
(








is the standards error of the observed difference in 
rates within stratum i, 
i
FO
i
FE
i
FO
i
FE
i
n
n
n
n
w
,
,
,
,


is the weight assigned to stratum i,
i
FO
i
FE
,
,
ˆ
,
ˆ


are the observed rates for each treatment group and stratum and 
i
FO
i
FE
n
n
,
, ,
, are the 
number of observations in each treatment group and stratum.
To align with the reporting of the ESTHER-1 trial, the above analysis will be repeated using age-
group instead of AMH strata as stratification factor. The analyses will be done based on all 
subjects, all subjects with oocytes retrieved, and all subjects with transfer.
9.4
Secondary Endpoints 
Secondary efficacy endpoints will be evaluated based on the FAS only.
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 


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Ferring Pharmaceuticals 
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Statistical Analysis Plan
corresponding to the statistical test of the hypothesis of ‘equal effect’ against the alternative of 
‘different effect’.
Positive βhCG Rate
Positive βhCG is defined as positive serum βhCG test 13-15 days after transfer. The positive βhCG 
rate will be summarised and analysed in a similar manner as the clinical pregnancy rate.
Vital Pregnancy Rate
Vital pregnancy is defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer. The vital pregnancy rate will be summarised and analysed in a similar manner as the 
clinical pregnancy rate. For subjects with a vital pregnancy, the number of intrauterine gestational 
sacs with fetal heart beat and the number of fetuses with fetal heart beat will be tabulated.
Implantation Rate
Implantation rate is defined as the number of gestational sacs 5-6 weeks after transfer divided by 
number of blastocysts transferred. The implantation rate will be summarised and analysed in a 
similar manner as the vital pregnancy rate. The transferred blastocysts are the experimental unit.
Note that since single blastocyst transfer is mandatory in this trial, these descriptions and analyses 
are likely to be identical to a description and analysis of the clinical pregnancy rate in the subgroup 
of subjects that had a blastocyst transfer.
Cycle Cancellation due to Poor or Excessive Ovarian Response or Blastocyst Transfer
Cancellation due to Excessive Ovarian Response / OHSS Risk
For this endpoint, treatment groups will be compared using a logistic regression model with
treatment and AMH stratum as fixed factors. The difference between treatments will be reported as 
an odds ratio including 95% confidence interval and p-value for test of no treatment difference. In 
case of sparse data, treatments will be compared using the Cochran-Mantel-Haenszel test stratified 
for AMH stratum. Within AMH stratum the comparisons will be based on Fisher’s exact test.
If both the factors treatment and AMH stratum are significant in the logistic regression analysis the 
possibility of a treatment-by-AMH interaction will be investigated.
The analysis will be performed for the composite endpoint (all cancellations of either the cycle due 
to poor or excessive response, or of the transfer due to excessive ovarian response/OHSS risk) and 
each of the separate components defined as: the proportion of subjects with cycle cancellation due 
to poor ovarian response, the proportion of subjects with cycle cancellation due to excessive 
ovarian response, the proportion of subjects with cycle cancellation due to poor or excessive 
ovarian response, the proportion of subjects with blastocyst transfer cancellation due to excessive 
ovarian response/OHSS risk, and the combination of cycle cancellations due to excessive response 
and transfer cancellation due to excessive ovarian response/OHSS risk.


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Trial Code: 000273
Statistical Analysis Plan
Ovarian Response
The number of oocytes retrieved will be tabulated with subjects grouped according to number of
oocytes retrieved (<4 (low response), 4-7 (moderate response), 8-14 (targeted response), 15-19
(hyperresponse) and ≥20 (severe hyperresponse)). Subjects with cycle cancellation due to poor
ovarian response will be included in the <4 oocytes group. Subjects with cycle cancellation due to
excessive ovarian response will here be included in the ≥20 oocytes group. For each definition the
proportion of subjects will be tabulated. These endpoints will be analysed in a similar manner as the
proportion of subjects with cycle cancellation.
Extreme Ovarian Response
The analyses of extreme ovarian response will be performed using the following definitions of
extreme ovarian response: <4 oocytes retrieved, ≥15 oocytes retrieved, ≥20 oocytes retrieved, <4 or
≥15 oocytes retrieved and <4 or ≥20 oocytes retrieved. Subjects with cycle cancellation due to poor
ovarian response will be included as <4 oocytes retrieved. Subjects with cycle cancellation due to
excessive ovarian response will be included as ≥15 and ≥20 oocytes retrieved.
For each definition the proportion of subjects with extreme ovarian response will be tabulated. 
These endpoints will be analysed in a similar manner as the proportion of subjects with cycle 
cancellation. In addition, they will be analysed based on all subjects with triggering of final 
follicular maturation.
Number and Size of Follicles during Stimulation
The follicle cohort on stimulation day 6 and end-of-stimulation will be summarised by treatment on
the follicle level (number of follicles 8-9 mm, 10-11 mm, 12-14 mm, 15-16 mm and ≥17 mm) and
on the subject level (total number of follicles, size of largest follicle, average follicle size, average
size of three largest follicles, and number of follicles ≥8 mm, ≥10 mm, ≥12 mm, ≥15 mm and ≥17 
mm). Continuous data will be compared between treatment groups using van Elteren test stratified 
for AMH and within each AMH stratum using the Wilcoxon’s test. 
Fertilisation Rate
An oocyte is defined as fertilised if it is scored as 2 pronuclei at 19 hours. For subjects with oocytes
retrieved, the rate of fertilised oocytes to oocytes retrieved (and also the rate of fertilised oocytes to
metaphase II oocytes for those inseminated using ICSI) will be tabulated. Further, the number of
fertilised oocytes per subject will be tabulated including both summary statistics and a frequency
table. Number of fertilised oocytes, number of metaphase II oocytes, fertilisation rate, the rate of 
metaphase II oocytes to oocytes retrieved, and fertilisation rate relative to metaphase II oocytes will 
be compared between treatment groups using van Elteren test stratified for AMH and within each 
AMH stratum using the Wilcoxon’s test. Note that the analysis of fertilisation rates excludes
subjects without oocytes retrieved and do therefore not adhere to the randomisation principle.


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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
Number and Quality of Embryos on Day 3
The number of embryos on day 3 including a breakdown by selected quality parameters will be
tabulated including both summary statistics and frequency tables. Further, for subjects with oocytes
retrieved, the rate of embryos to oocytes retrieved will be summarised overall and by selected
quality parameters. Numbers and rates will be compared between treatment groups using van 
Elteren test stratified for AMH and within each AMH stratum using the Wilcoxon’s test. 
Categorical data (subjects with at least one good-quality embryos) will be compared between 
treatment groups using a logistic regression model with treatment and AMH stratum as fixed 
factors and within each AMH stratum using the chi-square test.
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. The number of subjects with at least one
good-quality blastocyst, i.e. of grade 3BB or higher, will be reported. Further, for subjects with
oocytes retrieved, the rate of blastocysts to oocytes retrieved will be summarised overall and by
quality score. Numbers and rates will be compared between treatment groups using van Elteren test
stratified for AMH and within each AMH stratum using the Wilcoxon’s test. Categorical data 
(subjects with at least one good-quality blastocyst) will be compared between treatment groups 
using a logistic regression model with treatment and AMH stratum as fixed factors and within each 
AMH stratum using the chi-square test.
Circulating Levels of Endocrine Parameters
Blood samples drawn at stimulation days 1 and 6 and end-of-stimulation are analysed for FSH, LH,
estradiol, progesterone, inhibin A and inhibin B. 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. For LH, progesterone and LH surge (both LH and progesterone) a summary 
table will be prepared displaying the proportion of subjects who have at least one markedly 
abnormal value. The table will also be produced based on data from day 6 only and for end-of-
stimulation only. The markedly abnormal criteria is specified in Appendix 1.
Each endocrine parameter and the change from baseline for post-baseline measurements will be
tabulated for stimulation day 1 (baseline), stimulation day 6 and end-of-stimulation. Each parameter 
will be compared between treatment groups using an analysis of covariance model (ANCOVA). No 
subgroup analysis will be performed per age group. In this model ln-transformed measurements 
will be the dependent variable and the linear predictor will include treatment and AMH stratum as 
fixed factors and the baseline measurement (ln-transformed) as covariate. The estimated treatment 
ratio (FE 999049/FOLLISTIM) with 95% confidence interval will be presented accompanied by the 
p-value for test of no treatment difference.


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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis set.
10.2
Adverse Events
Adverse events will be coded using MedDRA version 20.0.
Adverse events are grouped according to start of IMP as follows:

Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent
and before start of IMP, or a pre-existing medical condition that worsens in intensity after
signed informed consent but before start of IMP.

Treatment-emergent adverse event, i.e. any adverse event occurring after start of IMP and
before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical
condition that worsens in intensity after start of IMP and before the end-of-trial visit.
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment
adverse events will be presented in a listing only.
10.2.1
Overview of Treatment-Emergent Adverse Events
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: all adverse events, severe adverse events, 
adverse drug reactions, adverse events leading to discontinuation, serious adverse events and 
deaths. An adverse reaction is an adverse event judged by the investigator to be related to IMP with 
a reasonable possibility.
10.2.2
Incidence of Adverse Events
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported.
Summary tables will be produced for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate / severe), adverse reactions by intensity (mild / moderate / severe), 
serious adverse events, adverse events leading to discontinuation, adverse events with an incidence 
of ≥2% in any treatment group, and non-serious adverse events with an incidence of ≥2% in any 
treatment group.


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Trial Code: 000273
Statistical Analysis Plan
10.3
OHSS
Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions 
for Early OHSS
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe, 
moderate or severe) and grade (1, 2, 3, 4, 5). Early OHSS is defined as OHSS with onset ≤9 days 
after triggering of final follicular maturation. Note this includes OHSS with onset before triggering 
and OHSS with onset during stimulation where triggering is not performed.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
cycle cancellation, i.e. using a logistic regression model with treatment and AMH stratum as fixed
factors. Analyses will be performed for subjects with early OHSS, subjects with early OHSS of 
moderate or severe grade, subjects with preventive interventions for early OHSS, subjects with 
early OHSS and/or preventive interventions for early OHSS, and subjects with early OHSS of 
moderate or severe grade and/or preventive interventions for early OHSS. The difference between 
treatments will be reported as an odds ratio including a 95% confidence interval and a p-value for 
the test of no difference between treatments.
The risk of preventive interventions for early OHSS and/or early OHSS is related to the ovarian 
response potential. AMH is a well-established predictor of ovarian response to gonadotropin 
treatment and was confirmed to be the best endocrine marker of ovarian response to FE 999049
treatment in the phase 2 trial. Since FE 999049 is dosed based on AMH it is likely that the 
relationship between AMH and the risk of experiencing preventive interventions for early OHSS 
and/or early OHSS differs between FE 999049 and FOLLISTIM. To further explore this for each of 
the endpoints above, two different logistic regression models will be fitted assuming an increasing 
risk with increasing AMH with two nested models as follows:
Model 1: LOGIT(π) = β0 + β1∙ln(AMH),
where π denotes the risk and the β’s denotes the regression coefficients.
Model 2: LOGIT(π) = β0 + β1∙ln(AMH) + β2,i + β3,i ∙ln(AMH), where i=1, 2 indicates the two 
treatments. This is model 1 with addition of treatment and treatment-by-ln(AMH) interaction terms.
The two models will be compared using the likelihood ratio test. Adjusted odds ratio estimates 
(comparing FE 999049 to FOLLISTIM) and associated 95% Wald CI will be provided. A 
statistically significant improvement with model 2 compared to model 1 should be interpreted as a 
treatment difference in that the relationship between AMH and the risk of experiencing preventive 
interventions for early OHSS and/or early OHSS.
The estimated risks based on the models will be plotted as a function of AMH, i.e. overall and for 
each treatment group. The plots will include observed incidences for AMH-based subgroups of 


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Trial Code: 000273
Statistical Analysis Plan
subjects. The adequacy of the model fits will be evaluated using the Hosmer-Lemeshow goodness-
of-fit test and by examining how well the model fit describes the data in the plot.
It can be noted that the likelihood ratio test using two nested models above corresponds to a test of 
the contrast β2,1 = β2,2 = β3,1 = β3,2 = 0 in model 2 above.
Late OHSS (Including OHSS of Moderate/Severe Grade)
OHSS will for each treatment group be tabulated by classification (mild, moderate, severe, 
moderate and severe) and grade (1, 2, 3, 4, 5). Late OHSS is defined as OHSS with onset >9 days 
after triggering of final follicular maturation.
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS. The analysis will be performed for subjects with late OHSS, and subjects with late 
OHSS of moderate or severe grade.
OHSS (Early and/or Late) and/or Preventive Interventions for Early OHSS
This endpoint will be tabulated and analysed in a similar manner as the proportion of subjects with 
early OHSS and/or preventive interventions for early OHSS. Analyses will be performed for 
subjects with early and/or late OHSS, subjects with early and/or late OHSS of moderate or severe 
grade, subjects with early and/or late OHSS and/or preventive interventions for early OHSS, and 
subjects with early and/or late OHSS of moderate or severe grade and/or preventive interventions 
for early OHSS.
10.4
Injection Site Reactions to IMP
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
and number of subjects experiencing those events will be tabulated by time (immediately, 30 
minutes, 24 hours), reaction and intensity (none, mild, moderate and severe).
10.5
Pen Malfunction
The frequency of technical malfunctions of the administration pens will be tabulated.
10.6
Safety Laboratory Variables
Safety laboratory variables will be grouped under “Haematology” and “Clinical Chemistry”.
The baseline is based on the blood sample drawn at screening. Treatment-emergent laboratory data 
will be obtained at end-of-stimulation and end-of-trial.
10.6.1
Summary Statistics
The circulating levels of clinical chemistry and haematology parameters including change from 
baseline will be tabulated for each time-point for each laboratory variable.


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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
10.6.2
Laboratory Variable Changes Relative to Normal Range
Shift tables will be prepared to compare baseline values to the end-of-stimulation and end-of-trial 
values, using a categorisation of low, normal and high values at each visit. Low, normal and high 
will be defined according to the reference ranges provided by the central laboratory.
10.6.3
Markedly Abnormal Changes
For each laboratory variable, a summary table will be prepared displaying the proportion of 
subjects who have at least one markedly abnormal value. The table will also include a break-down 
by classification of the baseline value. Markedly abnormal criteria for the safety laboratory 
variables is specified in Appendix 1.
10.6.4
Data Listings
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged.
10.7
Vital Signs
10.7.1
Vital Signs
Vital signs and their change from stimulation day 1 (baseline) to end-of-trial will be summarised. 
Shift tables will be prepared to compare the baseline values with the end-of-trial values using the 
categorisation of low, normal and high values. Low, normal and high values will are specified in
Appendix 1. All vital signs values will be listed per subject. Values outside the reference range will
be flagged.
10.8
Physical Examination
Physical examination at end-of-trial compared to baseline (screening) will be summarised in shift 
tables and all subjects with any abnormal finding will be listed per subject. The list will include 
both baseline and end-of-trial assessment for comparison.
10.9
Gynaecological Examination
Gynaecological examination at end-of-trial compared to baseline (screening) will be summarised in 
shift tables and all subjects with any abnormal finding will be listed by subject. The list will include 
both baseline and end-of-trial assessment for comparison.
11
Interim Analyses
No interim analysis is planned.
12
Deviations from Protocol Analysis
There are no deviations from the analyses planned in the protocol. Details and context of the 
analyses described in the protocol have been clarified in this SAP and some additional analyses 


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Ferring Pharmaceuticals 
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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
have been included to make the result description more complete. The description of the analysis 
set used for analyses, summary tables, listings, and figures are further clarified in the SAP.


Date: 22 Aug 2019
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Ferring Pharmaceuticals 
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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
13
References
European Medicines Agency (EMA). Points to consider on switching between superiority 
and non-inferiority. CPMP/EWP/482/99.


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Ferring Pharmaceuticals 
CONFIDENTIAL
Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
14
Tables, Listings and Figures
The tables, figures and listings (TLF) shells will be presented in a separate document.


Date: 22 Aug 2019
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Ferring Pharmaceuticals 
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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
Appendix 1 Markedly Abnormal Laboratory Values and Vital Signs
Table 1:
Markedly Abnormal Criteria for Haematology
Markedly abnormal criteria
Variable
Units
Low
High
Haemoglobin
g/L
115
Not applicable
Haematocrit
Ratio
0.37
0.56
Total WBC
109/L
2.8
16.0
Eosinophils
%
Not applicable
10
Neutrophils
%
15
90
Lymphocytes
%
10
80
Monocytes
%
Not applicable
20
Basophils
%
Not applicable
5
Bands
%
Not applicable
20
Platelets
109/L
75
700
Total RBC
1012/L
3.5
Not applicable
RBC: Red blood cells, WBC: White blood cells


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Trial Code: 000273
Statistical Analysis Plan
Table 2:
Markedly Abnormal Criteria for Clinical Chemistry (including Coagulation)
Markedly abnormal criteria
Variable
Units
Low
High
Albumin
g/L
< 20
Not applicable
ALT 
IU/L
Not applicable
> 3xULN
Alkaline 
phosphatase
IU/L
Not applicable
> 3xULN 
AST 
IU/L
Not applicable
> 3xULN
Bicarbonate
mmol/L
< 15.1
> 34.9
Bilirubin direct
umol/L
Not applicable  
> 2xULN
Bilirubin total
umol/L
Not applicable
> 2xULN
Blood urea 
nitrogen
mmol/L
Not applicable
> 12.5
Calcium
mmol/L
< 1.75
> 2.74
Chloride
mmol/L
Not applicable
Not applicable 
Cholesterol (30-
40Y) 
mmol/L
Not applicable
> 10.34
Creatinine
umol/L
Not applicable
> 3xULN
GGT
IU/L
Not applicable
> 3xULN
Glucose
mmol/L
< 2.5
> 16.7
LDH
IU/L
Not applicable
> 3xULN
Phosphate
mmol/L
< 0.6
Not applicable
Potassium
mmol/L
< 3.0
> 5.8
Sodium
mmol/L
< 125
> 155
Total protein
g/L
< 20
> 90
Uric acid
umol/L
Not applicable
> 595
MCV: Mean corpuscular volume, MCH: Mean corpuscular haemoglobin, MCHC: Mean corpuscular 
haemoglobin concentration, ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, GGT: 
Gamma Glutamyl Transferase, LDH: Lactate Dehydrogenase.
Table 3:
Markedly Abnormal Criteria for Endocrine Parameters
Variable
Units
Markedly abnormal criteria (High)
LH
IU/L
> 10
Progesterone
nmol/L
> 3.18
LH surge
Not applicable
LH > 10 IU/L and Progesterone > 3.18 nmol/L on the same day
LH: Luteinizing Hormone


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Ferring Pharmaceuticals 
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Follitropin Delta, FE 999049
Trial Code: 000273
Statistical Analysis Plan
Table 4:
Reference Ranges and Markedly Abnormal Criteria for Vital Signs
Variable
Reference range
Markedly abnormal criteria
Low
High
Low
High
Systolic blood 
pressure (mmHg)
<90
>140
< 80 and 
decrease of 20 from 
baseline
> 155 and 
increase of 20 from 
baseline 
Diastolic blood 
pressure (mmHg)
<60
>90
< 50 and 
decrease of 15 from 
baseline
> 100 and 
increase of 15 from 
baseline
Pulse rate (bmp)
<50
>100
< 45 and 
decrease of 15 from 
baseline
> 130 and 
increase of 15 from 
baseline