Clinical trial NCT04163458
Conditions: Infertility
Keywords: Controlled Ovarian Stimulation Assisted Reproductive Technology
Sponsor: Ferring Pharmaceuticals
Start date: 2019-10-25; Completion date: 2021-07-16
Enrollment: 405 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Development of multiple follicles and pregnancy in ovulatory women undergoing controlled ovarian stimulation as part of an assisted reproductive technology (ART) cycle.

Detailed description:

Arms: arm 1: MENOPUR liquid (including placebo to MENOPUR powder) initiated at a fixed dose of 225 international units (IU) for first five stimulation days. From stimulation Day 6, dosing could be adjusted as needed every second day by 75 IU per adjustment based on the participant's follicular response. The maximum dose was 450 IU/day and the minimum dose was 75 IU/day. The dosing could continue for a maximum of 20 days. arm 2: MENOPUR powder (including placebo to MENOPUR liquid) initiated at a fixed dose of 225 IU for first five stimulation days. From stimulation Day 6, dosing could be adjusted as needed every second day by 75 IU per adjustment based on the participant's follicular response. The maximum dose was 450 IU/day and the minimum dose was 75 IU/day. The dosing could continue for a maximum of 20 days.
Interventions: intervention 1: MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL intervention 2: MENOPUR powder and solvent for solution for injection, 75 IU intervention 3: Placebo (for MENOPUR solution for injection in pre-filled pen) intervention 4: Placebo (for MENOPUR powder and solvent for solution for injection)
Intervention descriptions: intervention 1: Solution for injection in pre-filled pen, subcutaneous administration intervention 2: Solution for injection in vials (powder and diluent), subcutaneous administration intervention 3: Solution for injection in pre-filled pen, subcutaneous administration intervention 4: Solution for injection in vials (powder and diluent); subcutaneous administration

Protocol documents:
Prot_002.pdf: 
 
 
 
Cover page for Protocol 
 
Sponsor name 
Ferring Pharmaceuticals A/S 
NCT Number 
NCT04163458 
Sponsor trial ID:  
000303 
Official title of study 
A Randomized, Double-blind Double-dummy Trial 
Comparing MENOPUR Solution for Injection in a 
Pre-filled Pen and MENOPUR Powder and Solvent 
for Solution for Injection (Menotropins for 
Injection) in a GnRH Agonist Cycle in Women 
Aged 18-42 Years Undergoing an Assisted 
Reproductive Technology Program   
Document Date 
19 Mar 2020 
 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 1 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program 
Trial 000303 
CLARA 
(Comparison of MENOPUR Liquid and Powder in Women Undergoing ART) 
IND Number: 
Investigational 
Medicinal Product: 
Indication: 
Phase: 
Name and Address of 
Sponsor: 
GCP Statement: 
053954 
MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL 
MENOPUR powder and solvent for solution for injection, 75 IU 
Development of multiple follicles and pregnancy in ovulatory women 
undergoing controlled ovarian stimulation as part of an assisted 
reproductive technology (ART) cycle 
3 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
This trial will be performed in compliance with GCP. 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals, Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals, Inc. or another company 
within the Ferring Group. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 2 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for injection in 
a pre-filled pen and MENOPUR powder and solvent for solution for injection (menotropins for 
injection) in a GnRH agonist cycle in women aged 18-42 years undergoing an assisted 
reproductive technology program 
Short title: CLARA (Comparison of MENOPUR Liquid and Powder in Women Undergoing 
ART) 
SIGNATORY INVESTIGATOR 
 MD. 
 
TRIAL SITES 
Up to 25 infertility centers in the United States (US). 
PLANNED TRIAL PERIOD 
First subject first visit (FSFV): 
Q4 2019 
Last subject last visit (LSLV): 
Q4 2020 
Last 4-weeks neonatal health follow-up:  
Q1 2021 
Last 6-months neonatal health follow-up: 
Q3 2021 
CLINICAL PHASE 
3 
BACKGROUND / RATIONALE 
MENOPUR is a highly purified human menotropin, delivering follicle-stimulating hormone 
(FSH) activity and luteinizing hormone (LH) activity in a 1:1 ratio. 
MENOPUR powder and solvent for solution for injection has been approved in the US since 
2004, for the development of multiple follicles and pregnancy in ovulatory women undergoing 
controlled ovarian stimulation as part of an assisted reproductive technology (ART) cycle. 
The currently available MENOPUR powder and solvent for solution for injection consists of a 
vial with powder containing 75 IU FSH activity and 75 IU LH activity and a vial with diluent. 
As part of the global clinical development program for MENOPUR, Ferring has developed a new 
multi-dose liquid formulation of MENOPUR in a pre-filled pen, containing 625 IU/mL FSH 
activity and 625 IU/mL LH activity. This is intended to offer infertility patients a more 
convenient administration of MENOPUR. The drug substance (highly purified menotropin) in 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 3 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
the MENOPUR multi-dose liquid formulation is the same as in the currently approved 
MENOPUR. 
The trial is designed to compare the pharmacodynamics of MENOPUR solution for injection in 
pre-filled pen, 1200 IU/1.92 mL to the currently approved MENOPUR powder and solvent for 
solution for injection, 75 IU. 
Note: MENOPUR solution for injection in pre-filled pen 1200 IU/1.92 mL will in this document 
hereafter be referred to as MENOPUR liquid, and MENOPUR powder and solvent for solution 
for injection, 75 IU will hereafter be referred to as MENOPUR powder. 
OBJECTIVES 
Primary Objective 
•
To demonstrate non-inferiority of MENOPUR liquid versus MENOPUR powder with
respect to the number of fertilized oocytes in women undergoing controlled ovarian
stimulation.
Secondary Objectives 
•
To evaluate the pregnancy rates after stimulation with MENOPUR liquid and MENOPUR
powder.
•
To evaluate the follicular development during stimulation with MENOPUR liquid and
MENOPUR powder.
•
To evaluate the serum endocrine profile during stimulation with MENOPUR liquid and
MENOPUR powder.
•
To evaluate the number of oocytes retrieved, the number and quality of embryos, and the
number and quality of blastocysts, associated with MENOPUR liquid and MENOPUR
powder.
•
To evaluate treatment efficiency of MENOPUR liquid and MENOPUR powder.
•
To evaluate the safety profile of MENOPUR liquid and MENOPUR powder, including
adverse events, routine safety laboratory parameters, local tolerability and
immunogenicity.
ENDPOINTS 
Primary Endpoint 
•
Number of fertilized (2 pronuclei [2PN]) oocytes at 19±2 hours after insemination.
Secondary Endpoints 
•
Positive βhCG rate (positive βhCG test 10-14 days after blastocyst transfer).


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 4 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
•
Clinical pregnancy rate (transvaginal ultrasound showing at least 1 intrauterine
gestational sac with fetal heart beat at 5-6 weeks after blastocyst transfer).
•
Ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after blastocyst
transfer).
•
Early pregnancy loss (defined as a positive βhCG test but no ongoing pregnancy at
8-9 weeks after blastocyst transfer).
•
Follicular development as assessed by transvaginal ultrasound on stimulation day 6 and
last day of stimulation.
•
Endocrine profile:
•
Serum follicle-stimulating hormone (FSH) on day 6, last day of stimulation and at
oocyte retrieval, and corresponding population pharmacokinetics (PK) analysis.
•
Serum Anti-Müllerian hormone (AMH) on last day of stimulation and at end-of-trial.
•
Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) on day 6 and
last day of stimulation.
•
Estradiol (E2) and progesterone (P4) on day 6 and last day of stimulation.
•
Number of oocytes retrieved, number of metaphase II oocytes, fertilization rate, and
number and quality of blastocysts 5 days after oocyte retrieval.
•
Frequency of ovarian hyperstimulation syndrome (OHSS) (early OHSS if the onset is
≤9 days after triggering of final follicular maturation and late OHSS if the onset is
>9 days after triggering of final follicular maturation).
•
Total gonadotropin dose and number of stimulation days.
•
Frequency and intensity of adverse events.
•
Changes in circulating levels of clinical chemistry and hematology parameters and
proportion of subjects with markedly abnormal changes.
•
Frequency and intensity of injection site reactions (redness, pain, itching, swelling and
bruising) assessed by the subject during the stimulation period.
•
Frequency of treatment-induced anti-MENOPUR antibodies, overall as well as with
neutralizing capacity.
•
Technical malfunctions of the pen.
Post-trial Endpoints 
•
Live birth rate.
•
Late pregnancy loss rate (defined as an ongoing pregnancy but no live birth).
•
Neonatal health including serious adverse events (SAEs) at birth, and SAEs at 4 weeks
and minimum 6 months after birth.


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 5 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
METHODOLOGY 
This is a phase 3, randomized, double-blind double-dummy, parallel-group, multicenter non-
inferiority trial. Approximately 400 females undergoing controlled ovarian stimulation as a part 
of a GnRH agonist protocol at infertility centers in the US will be randomized 1:1 to receive 
either MENOPUR liquid (including Placebo to MENOPUR powder) or MENOPUR powder 
(including Placebo to MENOPUR liquid). Randomization will be stratified by trial site and age 
group (<35 years and ≥35 years). The primary endpoint is the number of fertilized oocytes. 
Pituitary downregulation will be done following a protocol using combined oral contraceptives 
(NORTREL; daily for at least 14 days but no more than 21 days) and a GnRH agonist 
(LEUPROLIDE ACETATE) which will be initiated at a dose of 0.1 mL (500 µg)/day starting 
4 days before the last day on oral contraceptives. Downregulation will be assessed starting on or 
after day 10 of LEUPROLIDE ACETATE administration, but no later than day 20. In the event 
of spontaneous menses, subject should be instructed to continue LEUPROLIDE ACETATE and 
be seen at the center within 3 days to assess downregulation. If downregulation is confirmed 
(serum E2 ≤20 pg/mL (central laboratory) and transvaginal ultrasound showing no ovarian cysts), 
the subject is to be randomized and gonadotropins initiated within 3 days. If an ovarian cyst is 
detected and the E2 level is >20 pg/mL, the subject can undergo outpatient aspiration of the 
ovarian cyst at the discretion of her physician with assessment of estradiol >1 day later. Subjects 
can be reassessed to confirm downregulation a maximum of 3 times. The GnRH agonist dose 
will be reduced to 0.05 mL (250 µg)/day on stimulation day 1 and administration continued until 
end of gonadotropin administration.  
Within 3 days of downregulation confirmation, subjects will be randomized to receive either 
MENOPUR liquid (including Placebo to MENOPUR powder) or MENOPUR powder (including 
Placebo to MENOPUR liquid) initiated at 225 IU for 5 days. From stimulation day 6 onward, 
based on follicular response assessed by transvaginal ultrasound, dosing can be adjusted every 
second day as needed by 75 IU per adjustment. However, the maximum gonadotropin dose will 
be 450 IU/day and the minimum dose will be 75 IU/day; gonadotropin dosing can continue for a 
maximum of 20 days, and coasting is not allowed. Subjects will self-inject the GnRH agonist and 
gonadotropins (including placebo) at home after receiving instruction by a member of the clinical 
trial staff (e.g. a trial nurse).  
Injection of 2 x 5,000 IU hCG (NOVAREL) will be administered for the triggering of final 
follicular maturation as soon as 3 follicles of ≥17 mm are observed on transvaginal ultrasound. In 
the case of excessive ovarian response (>30 follicles of ≥12 mm each and/or E2 levels 
≥5000 pg/mL (local laboratory)), the cycle will be cancelled. Oocyte retrieval will take place 
36±2 hours after triggering of final follicular maturation, and oocytes will be inseminated by 
ICSI 4±2 hours after retrieval; oocyte maturity will be recorded. Fertilization (number of 
pronuclei) will be assessed 19±2 hours following ICSI. Blastocyst quality will be assessed on day 
5 following oocyte retrieval. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 6 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
All subjects will have single blastocyst transfer if they have at least one good-quality (i.e. grade 
3BB or above) blastocyst available on day 5 following oocyte retrieval. If no good-quality 
blastocyst is available, they may have double blastocyst transfer, if at least two blastocysts are 
available. Transfer of day 6 (or later) blastocyst(s) is not allowed. Remaining blastocysts may be 
cryopreserved by vitrification. All cryopreserved blastocysts can be used by the subject after 
completion of the trial in accordance with local guidelines and/or regulations. 
Vaginal progesterone inserts (ENDOMETRIN), 100 mg three times daily will be administered 
for luteal phase support starting the day after oocyte retrieval and continuing up to menses, 
negative βhCG, pregnancy loss or for a maximum of 10 weeks total if pregnancy is confirmed. 
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and hematology parameters as well as anti-MENOPUR antibodies. 
Endocrine parameters (FSH, LH, hCG, E2 and P4) are assessed at baseline (E2 at confirmation of 
downregulation and FSH, LH, hCG and P4 on stimulation day 1), day 6, and at end-of-
stimulation (day of trigger), and furthermore, FSH is also assessed at oocyte retrieval. In 
addition, AMH is assessed on stimulation day 1, on the last day of stimulation, and at end-of-
trial. Clinical chemistry and hematology are assessed at screening, last day of stimulation, and 
end-of-trial. Anti-MENOPUR antibodies are assessed at four occasions. The first sample is taken 
at the screening visit and is exclusively used to re-establish the anti-drug antibody analytical 
assays. The subsequent three samples are used for analysis of anti-MENOPUR antibodies in the 
individual subjects in the trial, and are taken prior to dosing on stimulation day 1 and at two 
occasions post-dosing: 7-10 days after the last MENOPUR liquid or MENOPUR powder dose 
(this may coincide with the transfer visit) and 21-28 days after the last MENOPUR liquid or 
MENOPUR powder dose (this may coincide with the βhCG test visit). Subjects with a treatment-
induced anti-MENOPUR antibody response will be followed until the response has become 
negative or returned to the pre-dosing level. These subjects will be called in for assessments at 2 
months after the last post-dosing anti-MENOPUR antibody sampling. If required, further 
assessments will be made at 3, 4, 6, 9 and 12 months after the last post-dosing anti-MENOPUR 
antibody sampling. The assessments will be terminated when two consecutive assessments are 
negative or indicate that the pre-dosing level has been reached, with a maximum follow-up 
period of one year. The assessments will also be terminated if the subject commences a new 
treatment cycle with any gonadotropin preparation. 
Local tolerability of MENOPUR liquid or MENOPUR powder following subcutaneous 
administration will be assessed by the subject three times daily: immediately, 30 minutes and 
24 hours after each injection. The assessment of injection site reactions will be made throughout 
the stimulation period and recorded by the subject in a diary. 
Concerning post-trial follow-up, all subjects with an ongoing pregnancy will be followed. Data 
will be gathered on delivery information (live birth and neonatal health). In addition, data on 
neonatal SAEs will be collected at 4 weeks and minimum 6 months after birth. 


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Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 10 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
•
Placebo to MENOPUR liquid (solution for injection in pre-filled pen; Ferring
Pharmaceuticals), will be provided as a pre-filled injection pen (with integrated non-
replaceable 3 mL cartridge).
•
MENOPUR powder (MENOPUR powder and solvent for solution for injection, 75 IU;
Ferring Pharmaceuticals), will be provided as vials with powder (75 IU FSH activity and
75 IU LH activity) and vials with diluent. After reconstitution, each vial delivers 75 IU of
FSH activity and 75 IU of LH activity. The starting dose of 225 IU will be fixed for the
first five stimulation days, followed by potential adjustments of 75 IU to a maximum dose
of 450 IU or a minimum dose of 75 IU/day.
•
Placebo to MENOPUR powder (powder and solvent for solution for injection; Ferring
Pharmaceuticals), will be provided as vials with powder and vials with diluent.
Concomitant Therapy (Non-investigational Medicinal Products [NIMPs]) 
•
NORTREL 1/35 (norethindrone [1 mg] and ethinyl estradiol [0.035 mg]; Teva
Pharmaceuticals USA, Inc.), will be provided as oral tablets to be administered at a dose
of 1 mg/0.035 mg (1 tablet) daily for at least 14 days but no more than 21 days during the
downregulation period.
•
LEUPROLIDE ACETATE (leuprolide acetate; Sandoz), will be provided as a vial with
sterile solution (14 mg/2.8 mL), to be administered at a dose of 0.1 mL (500 µg)/day
during the downregulation period, followed by a dose of 0.05 mL (250 µg)/day from
stimulation day 1 throughout the gonadotropin treatment period.
•
NOVAREL (chorionic gonadotropin; Ferring Pharmaceuticals), will be provided as vials
containing 5,000 IU chorionic gonadotropin per vial, 2 x 5,000 IU is to be administered
by intramuscular injection according to label as soon as 3 follicles of ≥17 mm are
observed on transvaginal ultrasound.
•
ENDOMETRIN (progesterone; Ferring Pharmaceuticals), will be provided as inserts to
be administered vaginally. Starting the day after oocyte retrieval, 100 mg three times
daily will be administered for luteal phase support continuing up to menses, negative
βhCG, pregnancy loss, or for a maximum of 10 weeks total if pregnancy is confirmed.
DURATION OF TREATMENT 
The maximum period of exposure to MENOPUR liquid or MENOPUR powder is 20 days. 
STATISTICAL METHODS 
Sample size 
The present trial is a pharmacodynamic comparison of a marketed product to a new formulation 
of the same. With 188 subjects per treatment group, the study has at least 85% power to 
demonstrate the non-inferiority of MENOPUR liquid to MENOPUR powder in the number of 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 11 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
fertilized oocytes at the 1-sided significance level of 0.025. This is based on the results for 
MENOPUR powder from the COMBINE trial conducted in a similar setting (GnRH agonist 
protocol, MENOPUR starting dose of 225 IU for the first five days, insemination by ICSI etc.) 
and in a similar population (infertile women between 18 and 42 years). The mean (SD) of the 
number of fertilized oocytes were 7.88 (5.15) with similar results in the two age groups (7.92 in 
the <35 years age group vs. 7.80 in the ≥35 years age group). The non-inferiority margin of -1.60 
will retain 80% of the expected comparator effect. 
After adjusting for 5% missing data, approximately 400 subjects will be randomized (1:1) into 
this trial, stratified by trial site and age (<35 years and ≥35 years). 
Sample Size Monitoring 
A blinded sample size reassessment will be done when data on the primary endpoint are available 
for 70% of the planned subjects or when 300 subjects are randomized, whichever comes first. 
The sample size reassessment will be done without breaking the blind and without inflating the 
type I error of the trial, in line with current regulatory guidelines. The expected maximum 
number of subjects to be randomized is 500 (250 subjects per treatment group), corresponding to 
a blinded one-sample (both groups pooled) standard deviation estimate of 5.8 and 85% power. 
Primary endpoint 
The primary objective of the trial is to demonstrate the non-inferiority of MENOPUR liquid 
versus MENOPUR powder with respect to the number of fertilized oocytes in women undergoing 
controlled ovarian stimulation. The non-inferiority limit for the difference between treatments 
(MENOPUR liquid minus MENOPUR powder) is set as -1.60. The non-inferiority hypothesis to 
be tested for the primary endpoint will be: 
H0: µMENOPUR liquid - µMENOPUR powder ≤ -1.60 
against the alternative 
H1: µMENOPUR liquid - µMENOPUR powder > -1.60 
where µMENOPUR liquid and µMENOPUR powder denote the mean numbers of fertilized oocytes in 
subjects treated with MENOPUR liquid and MENOPUR powder, respectively. 
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in the least squares mean number of fertilized oocytes 
between the two treatment groups. If the lower-limit of the 95% confidence interval is greater 
than the non-inferiority limit (-1.60), the null hypothesis will be rejected, and it will be claimed 
that MENOPUR liquid is non-inferior to MENOPUR powder with respect to the number of 
fertilized oocytes.  


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0
Supersedes: 5.0 
Page 12 of 103 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Due to the expected large sample size, the primary endpoint will be analyzed using a mixed 
effects two-way analysis of variance (ANOVA) model including the treatment group and the age 
group as fixed factors, as well as the trial site as a random effect. The least squares mean estimate 
of the treatment difference in the number of fertilized oocytes and the associated 95% confidence 
interval will be derived through an LSMEANS statement in the SAS PROC GLM procedure. For 
subjects who do not have any oocytes retrieved, or do not have fertilization assessment due to 
early withdrawal, or any other reason, the number of fertilized oocytes will be considered as zero. 
The primary efficacy analysis will be conducted for the modified intent-to-treat population, 
defined as all randomized (as planned) subjects who received at least 1 dose of IMP. If the lower 
bound of the confidence interval is above 0, superiority will be declared.  


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 13 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................................................... 2 
LIST OF TABLES ........................................................................................................................................ 18 
LIST OF FIGURES ...................................................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................................. 19 
1 
INTRODUCTION ............................................................................................................................. 21 
1.1 
Background ............................................................................................................................. 21 
1.2 
Scientific Justification for Conducting the Trial ..................................................................... 21 
1.3 
Benefit / Risk Aspects ............................................................................................................. 21 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 24 
2.1 
Objectives ............................................................................................................................... 24 
2.2 
Endpoints ................................................................................................................................ 24 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 26 
3.1 
Overall Trial Design................................................................................................................ 26 
3.1.1 
Trial Design Diagram................................................................................................. 26 
3.1.2 
Overall Design and Control Methods ........................................................................ 26 
3.1.3 
Trial Schedule ............................................................................................................ 29 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 29 
3.3 
Interim Analysis and Administrative Review ......................................................................... 29 
3.4 
Data Monitoring Committee ................................................................................................... 29 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 29 
3.5.1 
Trial Design ............................................................................................................... 29 
3.5.2 
Selection of Endpoints ............................................................................................... 31 
3.5.3 
Blinding...................................................................................................................... 31 
3.5.4 
Selection of Doses in the Trial ................................................................................... 31 
3.5.5 
Selection of the Trial Population ............................................................................... 32 
3.5.6 
Follow-up Procedures ................................................................................................ 32 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 34 
4.1 
Trial Population....................................................................................................................... 34 
4.1.1 
Inclusion Criteria ....................................................................................................... 34 
4.1.2 
Exclusion Criteria ...................................................................................................... 35 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 36 
4.2.1 
Recruitment ................................................................................................................ 36 
4.2.2 
Randomization ........................................................................................................... 36 
4.3 
Restrictions ............................................................................................................................. 37 
4.3.1 
Prior and Concomitant Therapies .............................................................................. 37 
4.3.2 
Prohibited Therapy ..................................................................................................... 37 
4.4 
Withdrawal Criteria................................................................................................................. 37 
5 
TREATMENTS ................................................................................................................................. 39 
5.1 
Treatments Administered ........................................................................................................ 39 
5.1.1 
Investigational Medicinal Products ............................................................................ 39 
5.1.2 
Non-Investigational Medicinal Products ................................................................... 40 
5.2 
Characteristics and Source of Supply ..................................................................................... 40 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 14 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5.3 
Packaging and Labelling ......................................................................................................... 41 
5.4 
Conditions for Storage and Use .............................................................................................. 42 
5.5 
Blinding / Unblinding ............................................................................................................. 43 
5.5.1 
Blinding...................................................................................................................... 43 
5.5.2 
Unblinding of Individual Subject Treatment ............................................................. 43 
5.6 
Treatment Compliance, Dispensing and Accountability......................................................... 44 
5.7 
Auxiliary Supplies................................................................................................................... 45 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies ................................. 45 
6 
TRIAL PROCEDURES .................................................................................................................... 46 
6.1 
Screening and Downregulation ............................................................................................... 47 
6.1.1 
Screening.................................................................................................................... 47 
6.1.2 
Downregulation .......................................................................................................... 48 
6.2 
Stimulation .............................................................................................................................. 48 
6.2.1 
Stimulation Day 1 ...................................................................................................... 48 
6.2.2 
Stimulation Day 6 ...................................................................................................... 50 
6.2.3 
Stimulation Day >6 to ≤20 ......................................................................................... 50 
6.2.4 
End-of-stimulation Visit ............................................................................................ 51 
6.3 
Oocyte Retrieval ..................................................................................................................... 52 
6.3.1 
Oocyte / Embryo / Blastocyst Evaluation .................................................................. 52 
6.4 
Transfer ................................................................................................................................... 53 
6.4.1 
Blastocyst Transfer .................................................................................................... 53 
6.4.2 
First Post-dosing Anti-MENOPUR Antibody Assessment (7-10 Days after Last 
IMP Dose) .................................................................................................................. 54 
6.5 
βhCG Test ............................................................................................................................... 55 
6.5.1 
βhCG Test .................................................................................................................. 55 
6.5.2 
Second Post-dosing Anti-MENOPUR Antibody Assessment (21-28 Days after 
Last IMP Dose) .......................................................................................................... 55 
6.6 
Clinical Pregnancy .................................................................................................................. 55 
6.7 
Ongoing Pregnancy ................................................................................................................. 56 
6.8 
End-of-trial .............................................................................................................................. 56 
6.9 
Post-trial Activities ................................................................................................................. 57 
6.9.1 
Pregnancy Outcome and Neonatal Health Follow-up ................................................ 57 
7 
TRIAL ASSESSMENTS ................................................................................................................... 58 
7.1 
Assessments Related to Primary Endpoint ............................................................................. 58 
7.1.1 
Number of Fertilized Oocytes .................................................................................... 58 
7.2 
Assessments Related to Secondary Endpoints ........................................................................ 58 
7.2.1 
βhCG Test .................................................................................................................. 58 
7.2.2 
Clinical Pregnancy ..................................................................................................... 58 
7.2.3 
Ongoing Pregnancy .................................................................................................... 58 
7.2.4 
Early Pregnancy Loss................................................................................................. 58 
7.2.5 
Number and Size of Follicles during Stimulation ...................................................... 58 
7.2.6 
Oocytes Retrieved ...................................................................................................... 59 
7.2.7 
Metaphase II Oocytes................................................................................................. 59 
7.2.8 
Fertilization Rate ........................................................................................................ 59 
7.2.9 
Number and Quality of Blastocysts on Day 5 ............................................................ 59 
7.2.10 Endocrine Parameters during Treatment .................................................................... 60 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 15 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.2.11 Serum FSH Concentrations ........................................................................................ 60 
7.2.12 Ovarian Hyperstimulation Syndrome ........................................................................ 60 
7.2.13 Adverse Events .......................................................................................................... 61 
7.2.14 Injection Site Reactions ............................................................................................. 61 
7.2.15 Anti-MENOPUR Antibodies ..................................................................................... 61 
7.3 
Other Assessments .................................................................................................................. 63 
7.3.1 
Demographics ............................................................................................................ 63 
7.3.2 
Medical History ......................................................................................................... 63 
7.3.3 
Menstrual History ...................................................................................................... 63 
7.3.4 
Reproductive History ................................................................................................. 63 
7.3.5 
Infertility History ....................................................................................................... 63 
7.3.6 
Confirmation of Downregulation ............................................................................... 64 
7.3.7 
Vital Signs .................................................................................................................. 64 
7.3.8 
Physical Examinations ............................................................................................... 64 
7.3.9 
Gynecological Examinations ..................................................................................... 64 
7.3.10 Clinical Laboratory Variables .................................................................................... 65 
7.3.11 Blastocyst Transfer Procedure ................................................................................... 66 
7.3.12 Malfunction of Pen .................................................................................................... 66 
7.3.13 Concomitant Medication ............................................................................................ 66 
7.3.14 Ultrasound for Image Acquisition of the Uterus ........................................................ 66 
7.4 
Assessments Related to Post-trial Information ....................................................................... 67 
7.4.1 
Pregnancy Outcome and Neonatal Health Follow-up ................................................ 67 
7.4.2 
Late Pregnancy Loss .................................................................................................. 67 
7.5 
Handling of Biological Samples and Other Material .............................................................. 67 
8 
ADVERSE EVENTS ......................................................................................................................... 68 
8.1 
Adverse Event Definition ........................................................................................................ 68 
8.2 
Collection and Recording of Adverse Events ......................................................................... 68 
8.2.1 
Collection of Adverse Events .................................................................................... 68 
8.2.2 
Recording of Adverse Events .................................................................................... 68 
8.3 
Adverse Events of Special Interest ......................................................................................... 72 
8.3.1 
Ovarian Hyperstimulation Syndrome ........................................................................ 72 
8.4 
Other Events of Special Interest .............................................................................................. 74 
8.4.1 
Injection Site Reactions ............................................................................................. 74 
8.4.2 
Treatment-induced Anti-MENOPUR Antibodies ...................................................... 74 
8.4.3 
Menstrual Bleeding .................................................................................................... 74 
8.4.4 
Pregnancy Losses ....................................................................................................... 74 
8.4.5 
Multiple Pregnancies ................................................................................................. 75 
8.5 
Serious Adverse Events .......................................................................................................... 76 
8.5.1 
Serious Adverse Event Definition .............................................................................. 76 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ............................. 78 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .................................................... 79 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ........................................ 79 
8.6.2 
Follow-up of Serious Adverse Events with Onset during the Post-Trial ................... 79 
8.6.3 
Collection of Serious Adverse Events with Onset after End-of-trial ......................... 79 
9 
STATISTICAL METHODS ............................................................................................................. 80 
9.1 
Determination of Sample Size ................................................................................................ 80 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 16 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9.2 
Subject Disposition ................................................................................................................. 80 
9.3 
Protocol Deviations ................................................................................................................. 80 
9.4 
Analysis Sets ........................................................................................................................... 81 
9.4.1 
Intention-to-Treat Analysis Set .................................................................................. 81 
9.4.2 
Modified Intention-to-Treat Analysis Set .................................................................. 81 
9.4.3 
Per Protocol Analysis Set ........................................................................................... 81 
9.4.4 
Safety Analysis Set .................................................................................................... 81 
9.5 
Trial Population....................................................................................................................... 81 
9.5.1 
Demographics and other Baseline Characteristics ..................................................... 81 
9.5.2 
Medical History, Concomitant Medication and Other Population Characteristics .... 81 
9.6 
Efficacy Endpoint Assessments .............................................................................................. 82 
9.6.1 
General Considerations .............................................................................................. 82 
9.6.2 
Primary Endpoint ....................................................................................................... 82 
9.6.3 
Secondary Endpoints ................................................................................................. 83 
9.7 
Extent of Exposure and Treatment Compliance ..................................................................... 84 
9.8 
Safety ...................................................................................................................................... 84 
9.8.1 
General Considerations .............................................................................................. 84 
9.8.2 
Adverse Events .......................................................................................................... 84 
9.8.3 
OHSS ......................................................................................................................... 86 
9.8.4 
Injection Site Reactions ............................................................................................. 86 
9.8.5 
Anti-MENOPUR Antibodies ..................................................................................... 87 
9.8.6 
Technical Malfunctions of the Pen ............................................................................ 87 
9.8.7 
Vital Signs .................................................................................................................. 87 
9.8.8 
Physical Examination ................................................................................................. 87 
9.8.9 
Gynecological Examination ....................................................................................... 87 
9.8.10 Safety Laboratory Variables ...................................................................................... 87 
9.8.11 Additional Endpoints ................................................................................................. 87 
9.9 
Interim Analyses and Administrative Review ........................................................................ 88 
10 
DATA HANDLING ........................................................................................................................... 89 
10.1 
Source Data and Source Documents ....................................................................................... 89 
10.2 
e-CRF/Electronic Case Report Form ...................................................................................... 90 
10.3 
Data Management ................................................................................................................... 91 
10.4 
Provision of Additional Information ....................................................................................... 91 
11 
MONITORING PROCEDURES ..................................................................................................... 92 
11.1 
Periodic Monitoring ................................................................................................................ 92 
11.2 
Audit and Inspection ............................................................................................................... 92 
11.3 
Confidentiality of Subject Data ............................................................................................... 92 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................ 94 
12.1 
Protocol Amendments ............................................................................................................. 94 
12.2 
Deviations from the Protocol .................................................................................................. 94 
12.3 
Premature Trial Termination ................................................................................................... 94 
13 
REPORTING AND PUBLICATION .............................................................................................. 95 
13.1 
Clinical Trial Report ............................................................................................................... 95 
13.2 
Confidentiality and Ownership of Trial Data .......................................................................... 95 
13.3 
Publications and Public Disclosure ......................................................................................... 95 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 17 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
13.3.1 Publication Policy ...................................................................................................... 95 
13.3.2 Public Disclosure Policy ............................................................................................ 96 
14 
ETHICAL AND REGULATORY ASPECTS ................................................................................. 97 
14.1 
Institutional Review Board ..................................................................................................... 97 
14.2 
Regulatory Authority Approval .............................................................................................. 97 
14.3 
End-of-Trial and End-of-Trial Notification ............................................................................ 97 
14.4 
Ethical Conduct of the Trial .................................................................................................... 97 
14.5 
Subject Information and Consent ............................................................................................ 97 
14.6 
Subject Participation Card ...................................................................................................... 99 
14.7 
Compliance Reference Documents ......................................................................................... 99 
15 
LIABILITIES AND INSURANCE ................................................................................................ 100 
15.1 
ICH-GCP Responsibilities .................................................................................................... 100 
15.2 
Liabilities and Insurance ....................................................................................................... 100 
16 
ARCHIVING .................................................................................................................................... 101 
16.1 
Investigator File .................................................................................................................... 101 
16.2 
Trial Master File.................................................................................................................... 101 
17 
REFERENCES ................................................................................................................................. 102 
 


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LIST OF TABLES 
Table 5-1 Double-dummy Treatment Overview ............................................................................. 39 
Table 5-2 Non-investigational Medicinal Products ......................................................................... 40 
Table 5-3 Characteristics of Medicinal Products ............................................................................ 41 
Table 5-4 Packaging of Medicinal Products ................................................................................... 42 
Table 6-1 Trial Flow Chart .............................................................................................................. 46 
Table 6-2 Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures ........................................ 53 
Table 8-1 Classification of Mild, Moderate and Severe OHSS (Golan’s Classification 
System)............................................................................................................................ 72 
 
 
LIST OF FIGURES 
Figure 3-1 Trial Flow Diagram ......................................................................................................... 26 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
AMH 
anti-Müllerian hormone 
ART 
assisted reproductive technology 
BMI 
body mass index 
CRO 
contract research organization 
DHEA 
dehydroepiandrosterone 
E2 
estradiol 
e-CRF 
electronic case report form 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
gonadotropin-releasing hormone 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
ICD-10 
International Statistical Classification of Diseases and Related Health Problems, 10th 
revision 
ICH 
International Council for Harmonisation 
ICSI 
intracytoplasmic sperm injection 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IU 
international units 
IVF 
in vitro fertilization 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention-to-treat 
NAb 
neutralizing antibody 
NCU 
neonatal care unit 
NICU 
neonatal intensive care unit 
NIMP 
Non-Investigational Medicinal Product 
OHSS 
ovarian hyperstimulation syndrome 
P4 
progesterone 


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PCU 
pediatric care unit 
PP 
per protocol 
SAE 
serious adverse event 
SOC 
system organ class 
TSH 
thyroid-stimulating hormone 
US 
United States 
 
 
Definition of Terms 
MENOPUR liquid 
 
MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL 
MENOPUR powder  
MENOPUR powder and solvent for solution for injection, 75 IU 
 
Throughout this document, all trade names are written in capitals to comply with Ferring standard 
operating procedures. 


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1 
INTRODUCTION 
1.1 
Background 
MENOPUR is a highly purified human menotropin, delivering follicle-stimulating hormone (FSH) 
activity and luteinizing hormone (LH) activity in a 1:1 ratio. 
MENOPUR powder and solvent for solution for injection has been approved in the United States 
(US) since 2004, for the development of multiple follicles and pregnancy in ovulatory women 
undergoing controlled ovarian stimulation as part of an assisted reproductive technology (ART) 
cycle. 
The currently available MENOPUR powder and solvent for solution for injection consists of a vial 
with powder containing 75 IU FSH activity and 75 IU LH activity and a vial with diluent.1 
As part of the global clinical development program for MENOPUR, Ferring has developed a new 
multi-dose liquid formulation of MENOPUR in a pre-filled pen, containing 625 IU/mL FSH 
activity and 625 IU/mL LH activity. This is intended to offer infertility patients a more convenient 
administration of MENOPUR. The drug substance (highly purified menotropin) in the MENOPUR 
multi-dose liquid formulation is the same as in the currently approved MENOPUR. 
The trial is designed to compare the pharmacodynamics of MENOPUR solution for injection in 
pre-filled pen, 1200 IU/1.92 mL to the currently approved MENOPUR powder and solvent for 
solution for injection, 75 IU. 
Notes: MENOPUR solution for injection in pre-filled pen 1200 IU/1.92 mL will in this document 
hereafter be referred to as MENOPUR liquid, and MENOPUR powder and solvent for solution for 
injection, 75 IU will hereafter be referred to as MENOPUR powder. 
 
1.2 
Scientific Justification for Conducting the Trial 
The present trial is a phase 3 trial designed to demonstrate the non-inferiority of MENOPUR liquid 
versus MENOPUR powder with respect to number of fertilized oocytes in women undergoing 
controlled ovarian stimulation. 
MENOPUR liquid is a new multi-dose liquid formulation of MENOPUR in a pre-filled pen 
developed to offer patients a more convenient administration than the current reconstitution, needle 
and syringe method. 
 
1.3 
Benefit / Risk Aspects 
Benefits 
The treatment cycle is provided to the participating subjects free of charge, as Ferring compensates 
the investigational sites for their expenses. Subjects participating in this trial may benefit by 


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achieving a pregnancy. 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 
optimizing the ovarian response and for clinical planning of subsequent treatment cycles. 
 
Risks 
Participation in this clinical trial does not create additional risks for the subjects beyond those 
associated with ART treatment. The risks associated with ART treatment, including controlled 
ovarian stimulation and intracytoplasmic sperm injection (ICSI), are explained to the subjects as 
part of the counselling prior to starting fertility treatment. 
Gonadotropins 
In this trial, controlled ovarian stimulation will be performed with one of two formulations of 
highly purified menotropin for injection: MENOPUR liquid (new formulation) or MENOPUR 
powder1 (approved formulation), and the treatment regimen applied in this trial is in line with the 
standard posology. MENOPUR powder is a commercially available preparation with established 
safety and efficacy.1 The most common adverse reactions (≥2%) with MENOPUR in ART include: 
abdominal cramps; enlarged abdomen; abdominal pain; headache; injection site pain and reaction; 
injection site inflammation; and ovarian hyperstimulation syndrome (OHSS). 
Subjects are closely monitored throughout the trial and the risks associated with the use of 
gonadotropin products for ovarian stimulation are well known. 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 risk of early OHSS can be minimized by withholding gonadotropins, 
withholding human chorionic gonadotropin (hCG) or administering gonadotropin-releasing 
hormone (GnRH) agonist for triggering of final follicular maturation. Very rare cases of serious 
allergic reactions have been reported after injection of gonadotropins. The risk of treatment-induced 
anti-drug-antibodies for gonadotropin products is very low and no safety or efficacy concern has 
been identified with regards to immunogenicity with MENOPUR. 
Concomitant Fertility Medications and Trial Procedures 
The concomitant fertility medication used in the trial (i.e. the oral contraceptives and GnRH agonist 
for downregulation and prevention of premature LH surge, the hCG for triggering of final follicular 
maturation and the vaginal progesterone for luteal phase support), are approved products 
considered generally well tolerated and are used in accordance with labelling. 
Concerning the trial procedures, the double-blind double-dummy design requires that subjects have 
two investigational medicinal product (IMP) injections daily during the stimulation period, one 
with the active compound and one with placebo, instead of one as in standard clinical practice. This 


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may therefore cause more injection site reactions than normally observed for standard clinical 
practice. The blood sampling might be associated with mild discomfort, bruising and a very rare 
risk of infection. The transvaginal ultrasound examinations may be associated with mild discomfort 
and a very rare risk of infection. The oocyte retrieval procedure is associated with discomfort and 
very rarely infections and bleeding. The transfer procedure is associated with mild discomfort and 
very rarely infections and spotting / mild bleeding. Additional, but less serious, complications 
during controlled ovarian stimulation are mild to moderate ovarian enlargement, local reactions, 
discomfort and pain at the site of injection of gonadotropins and concomitant fertility medication, 
as well as abdominal pain. 
Pregnancy-related Events 
The frequency of multiple pregnancies / births and their associated neonatal health complications, is 
another serious concern associated with ART cycles. To minimize this risk in the present trial, 
single blastocyst transfer is expected to be performed in the majority of patients. Double blastocyst 
transfer will only be allowed in cases where there are no good-quality blastocysts available. The 
incidence of miscarriage is higher in women undergoing controlled ovarian stimulation than in 
women conceiving spontaneously. The risk of ectopic pregnancy is also higher, but mainly in 
patients with a history of tubal obstruction. 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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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• To demonstrate non-inferiority of MENOPUR liquid versus MENOPUR powder with 
respect to the number of fertilized oocytes in women undergoing controlled ovarian 
stimulation. 
 
Secondary Objectives 
• To evaluate the pregnancy rates after stimulation with MENOPUR liquid and MENOPUR 
powder. 
• To evaluate the follicular development during stimulation with MENOPUR liquid and 
MENOPUR powder. 
• To evaluate the serum endocrine profile during stimulation with MENOPUR liquid and 
MENOPUR powder. 
• To evaluate the number of oocytes retrieved, the number and quality of embryos, and the 
number and quality of blastocysts, associated with MENOPUR liquid and MENOPUR 
powder. 
• To evaluate treatment efficiency of MENOPUR liquid and MENOPUR powder. 
• To evaluate the safety profile of MENOPUR liquid and MENOPUR powder, including 
adverse events, routine safety laboratory parameters, local tolerability and immunogenicity. 
 
2.2 
Endpoints 
Primary Endpoint 
• Number of fertilized (2 pronuclei [2PN]) oocytes at 19±2 hours after insemination. 
 
Secondary Endpoints 
• Positive βhCG rate (positive βhCG test 10-14 days after blastocyst transfer). 
• Clinical pregnancy rate (transvaginal ultrasound showing at least 1 intrauterine gestational 
sac with fetal heart beat 5-6 weeks after blastocyst transfer). 
• Ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after blastocyst 
transfer). 
• Early pregnancy loss (defined as a positive βhCG test but no ongoing pregnancy at 
8-9 weeks after blastocyst transfer). 
• Follicular development as assessed by transvaginal ultrasound on stimulation day 6 and last 
day of stimulation. 


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• Endocrine profile: 
• Serum follicle-stimulating hormone (FSH) on day 6, last day of stimulation and at 
oocyte retrieval, and corresponding population pharmacokinetics (PK) analysis. 
• Serum Anti-Müllerian hormone (AMH) on last day of stimulation and at end-of-trial. 
• Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) on day 6 and last 
day of stimulation. 
• Estradiol (E2) and progesterone (P4) on day 6 and last day of stimulation. 
• Number of oocytes retrieved, number of metaphase II oocytes, fertilization rate, and number 
and quality of blastocysts 5 days after oocyte retrieval. 
• Total gonadotropin dose and number of stimulation days. 
• Frequency of OHSS (early OHSS if the onset is ≤9 days after triggering of final follicular 
maturation and late OHSS if the onset is >9 days after triggering of final follicular 
maturation). 
• Frequency and intensity of adverse events. 
• Changes in circulating levels of clinical chemistry and hematology parameters and 
proportion of subjects with markedly abnormal changes. 
• Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period. 
• Frequency of treatment-induced anti-MENOPUR antibodies, overall as well as with 
neutralizing capacity. 
• Technical malfunctions of the pen. 
 
Post-trial Endpoints 
• Live birth rate. 
• Late pregnancy loss rate (defined as an ongoing pregnancy but no live birth). 
• Neonatal health including SAEs at birth, and SAEs at 4 weeks and minimum 6 months after 
birth. 
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
A trial flow diagram is presented in Figure 3-1. 
 
 
Figure 3-1 Trial Flow Diagram 
 
3.1.2 
Overall Design and Control Methods 
This is a phase 3, randomized, double-blind double-dummy, parallel-group, multicenter non-
inferiority trial. Approximately 400 females undergoing controlled ovarian stimulation as a part of a 
GnRH agonist protocol at infertility centers in the US will be randomized 1:1 to receive either 
MENOPUR liquid (including Placebo to MENOPUR powder) or MENOPUR powder (including 
Placebo to MENOPUR liquid). Randomization will be stratified by trial site and age group 
(<35 years and ≥35 years). The primary endpoint is the number of fertilized oocytes. 
a
225 IU MENOPUR liquid or 225 IU MENOPUR powder for the first 5 stimulation days, followed by potential adjustments of 75 IU
b
Combined oral contraceptives (CYCLAFEM) 1 tablet/day for at least 14 days but no more than 21 days
c
GnRH agonist (LEUPROLIDE ACETATE) 0 1 mL (500 µg)/day with reduction of dose to 0 05 mL (250 µg)/day from stimulation day 1 until end of stimulation 
d
hCG (NOVAREL 2x5,000 IU)
e
Progesterone (ENDOMETRIN) 3x100 mg/day 
f
7-10 days after the last MENOPUR liquid or MENOPUR powder dose (may coincide with the transfer visit)
g
21-28 days after the last MENOPUR liquid or MENOPUR powder dose (may coincide with the βhCG visit)
h
Stimulation day 1, 6 and thereafter at least every second day
AMH  anti-Müllerian hormone, COCs  combined oral contraceptives, FSH  follicle-stimulating hormone, GnRH  gonadotropin-releasing hormone,  hCG  human chorionic gonadotropin, OR  oocyte retrieval, US  ultrasound
Screening and 
Downregulation
Oocyte retrieval
Triggering 
of final follicular 
maturation
End of stimulation
Randomization 
day 2-3 of
menstrual cycle
Triggering + 
36 2 h
Transfer
Transfer +
10-14 days
βhCG test
Local tolerability (diary assessments)
OR +
5 days
Clin chem 
/ hem
Endocrine
Stimulation 
day 1
US
Stimulation 
day 6
h
Antibody
Antibody f
Antibody g
Clin chem 
/ hem
Clin chem 
/ hem
End-of-trial
assessments
hCG d
Controlled ovarian stimulation a
MENOPUR liquid (+ Placebo to MENOPUR powder)
MENOPUR powder (+ Placebo to MENOPUR liquid)
Transfer +
4-5 weeks
Clinical pregnancy 
Ongoing pregnancy 
Transfer +
8-9 weeks
Endocrine
Endocrine
US
US
US
GnRH agonist c
Progesterone e
FSH
US
Clin chem 
/ hem
US
Antibody
COCs b
AMH
FSH / AMH


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Pituitary downregulation will be done following a protocol using combined oral contraceptives 
(NORTREL; daily for at least 14 days but no more than 21 days) and a GnRH agonist 
(LEUPROLIDE ACETATE) which will be initiated at a dose of 0.1 mL (500 µg)/day starting 
4 days before the last day on oral contraceptives. Downregulation will be assessed starting on or 
after day 10 of LEUPROLIDE ACETATE administration, but no later than day 20. In the event of 
spontaneous menses, subject should be instructed to continue LEUPROLIDE ACETATE and be 
seen at the center within 3 days to assess downregulation. If downregulation is confirmed (serum 
E2 ≤20 pg/mL (central laboratory) and transvaginal ultrasound showing no ovarian cysts), the 
subject is to be randomized and gonadotropins initiated within 3 days. If an ovarian cyst is detected 
and the E2 level is >20 pg/mL, the subject can undergo outpatient aspiration of the ovarian cyst at 
the discretion of her physician with assessment of estradiol >1 day later. Subjects can be reassessed 
to confirm downregulation a maximum of 3 times. The GnRH agonist dose will be reduced to 
0.05 mL (250 µg)/day on stimulation day 1 and administration continued until end of gonadotropin 
administration.  
Within 3 days of downregulation confirmation, subjects will be randomized to receive either 
MENOPUR liquid (including Placebo to MENOPUR powder) or MENOPUR powder (including 
Placebo to MENOPUR liquid) initiated at 225 IU for 5 days. From stimulation day 6 onward, based 
on follicular response assessed by transvaginal ultrasound, dosing can be adjusted every second day 
as needed by 75 IU per adjustment. However, the maximum gonadotropin dose will be 450 IU/day 
and the minimum dose will be 75 IU/day; gonadotropin dosing can continue for a maximum of 
20 days, and coasting is not allowed. Subjects will self-inject the GnRH agonist and gonadotropins 
(including placebo) at home after receiving instruction by a member of the clinical trial staff (e.g. a 
trial nurse).  
Injection of 2 x 5,000 IU hCG (NOVAREL) will be administered for the triggering of final 
follicular maturation as soon as 3 follicles of ≥17 mm are observed on transvaginal ultrasound. In 
the case of excessive ovarian response (>30 follicles of ≥12 mm each and/or E2 levels 
≥5000 pg/mL (local laboratory)), the cycle will be cancelled. Oocyte retrieval will take place 
36±2 hours after triggering of final follicular maturation, and oocytes will be inseminated by ICSI 
4±2 hours after retrieval; oocyte maturity will be recorded. Fertilization (number of pronuclei) will 
be assessed 19±2 hours following ICSI. Blastocyst quality will be assessed on day 5 following 
oocyte retrieval. 
All subjects will have single blastocyst transfer if they have at least one good-quality (i.e. grade 
3BB or above) blastocyst available on day 5 following oocyte retrieval. If no good-quality 
blastocyst is available, they may have double blastocyst transfer, if at least two blastocysts are 
available. Transfer of day 6 (or later) blastocyst(s) is not allowed. Remaining blastocysts may be 
cryopreserved by vitrification. All cryopreserved blastocysts can be used by the subject after 
completion of the trial in accordance with local guidelines and/or regulations. 


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Vaginal progesterone inserts (ENDOMETRIN), 100 mg three times daily will be administered for 
luteal phase support starting the day after oocyte retrieval and continuing up to menses, negative 
βhCG, pregnancy loss or for a maximum of 10 weeks total if pregnancy is confirmed. 
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and hematology parameters as well as anti-MENOPUR antibodies. 
Endocrine parameters (FSH, LH, hCG, E2 and P4) are assessed at baseline (E2 at confirmation of 
downregulation and FSH, LH, hCG and P4 on stimulation day 1), day 6, and at end-of-stimulation 
(day of trigger), and furthermore, FSH is also assessed at oocyte retrieval. In addition, AMH is 
assessed on stimulation day 1, on the last day of stimulation, and at end-of-trial. Clinical chemistry 
and hematology are assessed at screening, last day of stimulation, and end-of-trial. 
Anti-MENOPUR antibodies are assessed at four occasions. The first sample is taken at the 
screening visit and is exclusively used to re-establish the anti-drug antibody analytical assays. The 
subsequent three samples are used for analysis of anti-MENOPUR antibodies in the individual 
subjects in the trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-
dosing: 7-10 days after the last MENOPUR liquid or MENOPUR powder dose (this may coincide 
with the transfer visit) and 21-28 days after the last MENOPUR liquid or MENOPUR powder dose 
(this may coincide with the βhCG test visit). Subjects with a treatment-induced anti-MENOPUR 
antibody response will be followed until the response has become negative or returned to the pre-
dosing level. These subjects will be called in for assessments at 2 months after the last post-dosing 
anti-MENOPUR antibody sampling. If required, further assessments will be made at 3, 4, 6, 9 and 
12 months after the last post-dosing anti-MENOPUR antibody sampling. The assessments will be 
terminated when two consecutive assessments are negative or indicate that the pre-dosing level has 
been reached, with a maximum follow-up period of one year. The assessments will also be 
terminated if the subject commences a new treatment cycle with any gonadotropin preparation. 
Local tolerability of MENOPUR liquid or MENOPUR powder following subcutaneous 
administration will be assessed by the subject three times daily: immediately, 30 minutes and 
24 hours after each injection. The assessment of injection site reactions will be made throughout the 
stimulation period and recorded by the subject in a diary. 
Concerning post-trial follow-up, all subjects with an ongoing pregnancy will be followed. Data will 
be gathered on delivery information (live birth and neonatal health). In addition, data on neonatal 
SAEs will be collected at 4 weeks and minimum 6 months after birth. 
 


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3.1.3 
Trial Schedule 
The estimated trial schedule is as follows:  
 
First subject first visit (FSFV):  
 
Q4 2019 
 
Last subject last visit (LSLV):  
 
Q4 2020 
 
Last 4-weeks neonatal health follow-up:  
Q1 2021 
 
Last 6-months neonatal health follow-up:  
Q3 2021 
 
3.2 
Planned Number of Trial Sites and Subjects 
The trial is planned to be conducted at up to 25 infertility centers in the US. It is planned to 
randomize 400 subjects of whom 200 subjects will be randomized to MENOPUR liquid and 
200 subjects will be randomized to MENOPUR powder. It is estimated that approximately 
800 subjects should be screened to achieve 400 subjects eligible for randomization. 
A blinded sample size reassessment will be done when data on the primary endpoint are available 
for 70% of the planned subjects or when 300 subjects are randomized, whichever comes first. The 
number of randomized subjects may be adjusted up to a maximum of 500 subjects, corresponding 
to a blinded one-sample standard deviation estimate of 5.8 and 85% power. 
 
3.3 
Interim Analysis and Administrative Review 
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned. 
The assumptions underlying the sample size calculations, such as the variability of the primary 
efficacy endpoint will be monitored in a blinded manner. This monitoring will be performed by the 
project statistician who will evaluate the blinded one-sample standard deviation in relation to the 
assumptions underlying the sample size (see sections 9.1 and 9.9). 
 
3.4 
Data Monitoring Committee 
No Data Monitoring Committee will be established for this trial. During the trial, the internal Safety 
Management Team at the sponsor will evaluate blinded safety data on a regular basis. 
 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
The primary objective of the trial is to demonstrate non-inferiority of MENOPUR liquid compared 
with MENOPUR powder with respect to number of fertilized oocytes in women undergoing an 
ART program. 


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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, to minimize variation, 
standardization of criteria, timing of assessments, procedures and interventions have to a great 
extent been incorporated in the design of this trial.2,3,4  
This is a randomized controlled double-blind double-dummy trial using an approved gonadotropin 
preparation as an active comparator. It is a parallel group design restricted to a single treatment 
cycle. The double-blind double-dummy design ensures that the subjects, investigators and other 
assessors such as embryologists and central laboratory personnel are blinded to individual treatment 
allocation throughout the trial, including the post-trial activities. Similarly, Ferring staff will also 
remain blinded to individual subject treatment allocation during the conduct of the trial. The trial 
will be a multi-center trial. This set-up ensures that the required number of subjects can be recruited 
within a reasonable time and also has the advantage that it should facilitate subsequent 
generalization of the results. 
The trial is designed to demonstrate non-inferiority of MENOPUR liquid versus MENOPUR 
powder with respect to number of fertilized oocytes. The non-inferiority margin has been set at 1.60 
which is considered suitable considering the clinical implications of this margin. A detailed 
justification is provided in section 9.1. 
Subjects will undergo controlled ovarian stimulation with a daily starting dose of 225 IU 
MENOPUR liquid, or 225 IU MENOPUR powder, following a GnRH agonist protocol. The daily 
gonadotropin dose is fixed for the first five stimulation days after which it may be adjusted by 
75 IU based on the individual response. The selection of doses is described in detail in 
section 3.5.4. Monitoring of ovarian response by transvaginal ultrasound and blood sampling for 
assessment of several endocrine parameters will be performed regularly during stimulation. 
In this trial, oocytes will be inseminated using ICSI in order to have a standardized fertilization 
method for all participating subjects. Furthermore, it will facilitate the interpretation of the 
subsequent embryo quality findings, as the timing of these assessments relative to the time of 
insemination can be accurately determined. In clinical practice, the choice of ICSI has previously 
mainly been determined by the presence of male factor infertility or fertilization failure in previous 
in vitro fertilization (IVF) cycles, but in recent years the use of ICSI has increased steadily. ICSI is 
now frequently used in routine management of infertile couples, expanding beyond those with male 
factor infertility. 
The present protocol requires single blastocyst transfer on day 5 for all women with at least one 
good-quality blastocyst available. Women with no good-quality blastocyst may have double 
blastocyst transfer (if two blastocysts are available). The scientific justification for incorporating 
these features is that it will ensure that the data obtained in this trial are in line with the current 
clinical directions taken for maintaining efficacy (i.e. ongoing pregnancy rates) and minimizing 
risks (i.e. multiple pregnancies).5,6,7,8 Further, there is increasing evidence suggesting that late 
stages of embryo progression are better predictors of clinical pregnancy than early embryo 


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development parameters.9 In subjects with good prognosis, the transfer of blastocysts yields a 
higher live birth rate than that achieved with transfer of the same number of cleavage stage 
embryos. 
 
3.5.2 
Selection of Endpoints 
For the present trial, the number of fertilized oocytes at 19±2 hours after insemination has been set 
as the primary endpoint as per agreement with FDA. 
Positive βhCG, clinical pregnancy and ongoing pregnancy are included as secondary endpoints in 
the trial. The secondary endpoints also cover commonly investigated pharmacodynamic parameters 
such as endocrine profile and ovarian response as well as standard evaluations of safety profile. 
Furthermore, oocyte and embryo quality will be assessed and a detailed evaluation of blastocyst 
quality is also included in the trial. 
 
3.5.3 
Blinding 
The two investigational medicinal products (IMPs) differ in presentation as MENOPUR liquid is 
provided in a pre-filled injection pen, while MENOPUR powder is provided as a vial with powder 
and a vial with diluent. The trial design is therefore double-blind, double-dummy, ensuring 
unbiased evaluation by the subject, the investigator and other trial personnel such as personnel 
performing the ultrasound monitoring, embryologists, and central laboratory personnel. 
Similarly, the Ferring clinical trial team (i.e. data manager, statistician, clinical trial manager, 
clinical project leader, field monitor, medical writer, pharmacovigilance physician, 
pharmacovigilance manager, medical monitor and 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 released to the statistician. A more detailed description of the blinding is provided in 
section 5.5.1. 
 
3.5.4 
Selection of Doses in the Trial 
The starting dose of 225 IU for this trial is in accordance with the labelling recommendations for 
MENOPUR powder in the US for women who have received a GnRH agonist for pituitary 
suppression. 
The dose of the IMPs will be initiated at 225 IU for the first 5 days. From stimulation day 6 
onward, based on the subject’s follicular response assessed by transvaginal ultrasound, dosing can 
be adjusted every second day, as needed, by 75 IU per adjustment. However, the maximum 
gonadotropin dose will be 450 IU/day and the minimum dose will be 75 IU/day; gonadotropin 
dosing can continue for a maximum of 20 days and coasting is not allowed. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 32 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
The doses and overall treatment regimens for the combined oral contraceptives (NORTREL), 
GnRH agonist (LEUPROLIDE ACETATE), hCG (NOVAREL) and progesterone 
(ENDOMETRIN) products are in line with the recommendations in the respective products’ 
labelling for the indication of ART and/or standard clinical practice. 
 
3.5.5 
Selection of the Trial Population 
This trial will include women undergoing ICSI who are aged 18-42 years and who may have had up 
to two previous controlled ovarian stimulation cycles. The subjects have been diagnosed with 
unexplained infertility, tubal infertility, endometriosis stage I-II or have partners diagnosed with 
male factor infertility, and are considered eligible for ICSI. Women with a history of recurrent 
miscarriages will not be included in the trial. The allowed BMI is 17.5-38.0 kg/m2, thus including 
underweight, normal weight, overweight and obese subjects. 
The exclusion criteria are aligned with the contraindications for the use of gonadotropins in the 
labelling for these preparations. 
Altogether, the population selected for this trial would be expected to be representative of patients 
undergoing controlled ovarian stimulation in ICSI cycles. 
 
3.5.6 
Follow-up Procedures 
Treatment Monitoring 
Subjects will return to the trial site for regular scheduled clinic visits as required per protocol for 
measurement of hormone levels, transvaginal ultrasound, pregnancy testing, and other safety 
assessments. Unscheduled visits are allowed, per investigator discretion and standard of care. 
Approximately 10-14 days after blastocyst transfer, all subjects will have a serum pregnancy test. 
Clinical pregnancy will be confirmed by transvaginal ultrasound, indicating at least 1 intrauterine 
gestational sac with fetal heart beat at 5-6 weeks after blastocyst transfer. Ongoing pregnancy will 
be confirmed by at least 1 intrauterine viable fetus at 8-9 weeks after blastocyst transfer. 
 
Post-trial Activities 
Post-trial follow-up extends to collection of delivery information (live birth and neonatal health), 
which will be collected for all subjects with an ongoing pregnancy. In addition, data on neonatal 
SAEs will be collected at 4 weeks and minimum 6 months after birth. 
 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 33 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Immunogenicity Follow-up 
Subjects with a treatment-induced anti-MENOPUR antibody response will be followed until the 
response has become negative or returned to the pre-dosing level, or for a maximum of 1 year. 
 
Access to Therapy after End-of-Trial 
Concerning access to therapy after completion of the trial, MENOPUR powder is approved for 
controlled ovarian stimulation and is commercially available in the US, while MENOPUR liquid is 
currently under clinical development and cannot be offered to subjects after participation in this 
clinical trial. 
 


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Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 37 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
code list for all randomized subjects kept by the investigator. 
 
4.3 
Restrictions 
4.3.1 
Prior and Concomitant Therapies 
The subjects must not have used fertility modifiers, including dehydroepiandrosterone (DHEA) and 
metformin, or hormonal preparations (except for thyroid medication) during the last menstrual 
cycle before randomization. 
Use of any medications other than the trial medication provided for this trial should be avoided 
from the screening period until completion of the trial. Occasional use of over the counter 
medications or prescription drugs may be allowed at the discretion of the investigator. 
Any concomitant therapies used during the trial or within 3 months prior to screening will be 
recorded in the source documents and e-CRF, along with the main reason for their prescription/use. 
 
4.3.2 
Prohibited Therapy 
It is prohibited to continue therapy outside the scope of this trial with medicinal products provided 
specifically for this trial. 
 
4.4 
Withdrawal Criteria 
Withdrawal from Trial 
Every subject has the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. A subject's participation is to terminate immediately upon her request. 
However, the investigator should record the reason for the subject’s withdrawal, if possible. 
If, at the time of discontinuation, a dose of the IMP has already been administered, the subject must 
be advised to agree to follow-up safety investigations, which will include all procedures outlined 
for the end-of-trial visit (section 6.8). 
The subject can also be withdrawn from the trial at any time at the discretion of the investigator. 
For any discontinuation, the investigator will obtain all the required details and document the date 
of the premature termination and the main reason in the e-CRF. 
A subject that withdraws from the trial will not be replaced. 
 
Withdrawal of Consent 
If the subject withdraws her consent, data collected up to withdrawal will remain in the database, 
but no further data will be collected. Samples and recordings obtained before withdrawal may be 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 38 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
analyzed. This will be described in the Informed Consent Documents. The subject can request 
destruction of samples which would otherwise have been kept in storage. 
 
Trial Stopping Criteria 
Occurrence of the following adverse events or abnormal laboratory values may warrant 
consideration of trial termination: 
• Life-threatening SAEs with suspected causality to the IMP, including but not limited to 
OHSS (section 8.3.1). 
• Formation of treatment-induced neutralizing antibodies to gonadotropins. 
 
The internal Safety Management Team at the sponsor will review each occurrence and provide a 
recommendation as to whether to discontinue the trial. The responsibilities and composition of the 
internal Safety Management Team are provided in a separate charter document, available before the 
first subject’s first visit. 
 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 39 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5 
TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Investigational Medicinal Products 
Subjects will be randomized to the following IMPs in a 1:1 ratio in the trial: 
• MENOPUR liquid (MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL) 
including Placebo to MENOPUR powder (powder and solvent for solution for injection) 
• MENOPUR powder (MENOPUR powder and solvent for solution for injection, 75 IU) 
including Placebo to MENOPUR liquid (solution for injection in pre-filled pen) 
 
Treatment will be provided to the subjects as double-dummy treatment with the combination of a 
pre-filled injection pen with MENOPUR liquid and vials (powder and diluent) with Placebo to 
MENOPUR powder, or a pre-filled injection pen with Placebo to MENOPUR liquid and vials 
(powder and diluent) with MENOPUR powder. Table 5-1 provides an overview of the 
double-dummy treatment components 
 
Table 5-1 
Double-dummy Treatment Overview 
Randomized to  
Pre-filled injection pen with 
Vials (powder and diluent) with 
MENOPUR liquid 
MENOPUR liquid 
Placebo to MENOPUR powder 
MENOPUR powder 
Placebo to MENOPUR liquid 
MENOPUR powder 
 
In order to maintain the blinding of the trial, the pre-filled injection pens with MENOPUR liquid 
and Placebo to MENOPUR liquid will be identical in appearance. Likewise, the vials (powder and 
diluent) with MENOPUR powder and Placebo to MENOPUR powder will be identical in 
appearance. 
MENOPUR liquid and MENOPUR powder will be initiated at dose of 225 IU for the first 5 days. 
From stimulation day 6 onward, dosing can be adjusted as needed every second day by 75 IU per 
adjustment based on the subject’s follicular response. The maximum dose will be 450 IU/day and 
the minimum dose will be 75 IU/day; dosing can continue for a maximum of 20 days. Coasting is 
not allowed. 
The IMPs are administered as a daily subcutaneous injection in the lower part of the abdomen. 
Subjects will self-inject the IMP at home after being instructed by trial staff at the site (e.g. a trial 
nurse) on how to administer the IMP. To minimize local injection site reactions, it is advisable to 
change the injection site regularly, but it should always be on the same side of the navel in order to 
be able to distinguish between injection site reactions related to MENOPUR liquid or Placebo to 
MENOPUR liquid and those related to MENOPUR powder or Placebo to MENOPUR powder. 


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The timing of the gonadotropin injections should be aligned with the GnRH agonist injections (see 
below).  
For information on warnings and precautions, please refer to the Investigator’s Brochure for 
MENOPUR liquid11 and Prescribing Information for MENOPUR powder.1  
 
5.1.2 
Non-Investigational Medicinal Products 
The non-investigational medicinal products (NIMPs) to be used are listed in Table 5-2. 
 
Table 5-2 
Non-investigational Medicinal Products 
NIMP 
Trade name 
Dose 
Combined oral 
contraceptives 
NORTREL 1/35  
(norethindrone [1 mg] and 
ethinyl estradiol [0.035 mg]) 
1 mg/0.035 mg (1 tablet) daily for at least 14 days 
but no more than 21 days during the downregulation 
period. 
GnRH agonist 
LEUPROLIDE ACETATE 
(leuprolide acetate) 
0.1 mL (500 µg)/day administered as subcutaneous 
injections in the upper thigh during the 
downregulation period, followed by a dose of 
0.05 mL (250 µg)/day from stimulation day 1 
throughout the gonadotropin treatment period.  
hCG 
NOVAREL 
(chorionic gonadotropin) 
1 mL (2 x 5,000 IU) administered by intramuscular 
injection according to label as soon as 3 follicles of 
≥17 mm are observed on transvaginal ultrasound. 
Progesterone 
ENDOMETRIN 
(progesterone) 
100 mg vaginal inserts three times daily, for luteal 
phase support continuing up to menses, negative 
βhCG test, pregnancy loss, or for a maximum of 
10 weeks total if pregnancy is confirmed. 
 
 
All NIMPs are to be used in line with the recommendations in the respective products’ labelling for 
the indication ART and/or standard clinical practice supported by literature. 
For information on warnings and precautions, please refer to the Prescribing Information for 
NORTREL, LEUPROLIDE ACETATE, NOVAREL, and ENDOMETRIN. 
 
5.2 
Characteristics and Source of Supply 
All medicinal products are provided by Ferring and will be handled according to the principles of 
Good Manufacturing Practice (GMP). Table 5-3 provides an overview of the presentation of each 
medicinal product. 
 


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Table 5-3 
Characteristics of Medicinal Products 
IMP / NIMP 
Presentation 
MENOPUR liquid (menotrophin HP), 
Ferring Pharmaceuticals 
MENOPUR liquid is provided as a pre-filled injection pen 
for multiple use (with integrated non-replaceable 3 mL 
cartridge). Each pen delivers 625 IU/mL of FSH activity 
and 625 IU/mL of LH activity 
Placebo to MENOPUR liquid, 
Ferring Pharmaceuticals  
Placebo to MENOPUR liquid is provided as a pre-filled 
injection pen for multiple use containing solution for 
injection. 
MENOPUR powder (menotrophin HP), 
Ferring Pharmaceuticals 
MENOPUR powder is provided as vials with lyophilized 
powder and vials with diluent. After reconstitution, each 
vial delivers 75 IU of FSH activity and 75 IU of LH 
activity. 
Placebo to MENOPUR powder, 
Ferring Pharmaceuticals 
Placebo to MENOPUR powder is provided as a vial with 
lyophilized powder and a vial with diluent. 
NORTREL 1/35 
Teva Pharmaceuticals USA, Inc. 
NORTREL (norethindrone [1 mg] and ethinyl estradiol 
[0.035 mg]) is provided as oral tablets. 
LEUPROLIDE ACETATE (GnRH agonist),  
Sandoz 
LEUPROLIDE ACETATE (leuprolide acetate) is provided 
as a vial with sterile solution (14 mg/2.8 mL). 
NOVAREL (hCG), 
Ferring Pharmaceuticals  
NOVAREL (chorionic gonadotropin) is provided as vials 
with lyophilized powder and vials with diluent. After 
reconstitution, each vial delivers 5,000 IU chorionic 
gonadotropin. 
ENDOMETRIN (progesterone), 
Ferring Pharmaceuticals 
ENDOMETRIN (progesterone) is provided as vaginal 
inserts of 100 mg of progesterone. 
 
 
5.3 
Packaging and Labelling 
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
Clinical Trial Supply department at Ferring in accordance with GMP and U.S. regulatory 
requirements. Details on the packaging of each medicinal product is provided in Table 5-4. 
 


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CONFIDENTIAL 
Table 5-4 
Packaging of Medicinal Products 
IMP / NIMP 
Presentation 
MENOPUR liquid 
(menotrophin HP) 
MENOPUR liquid is provided in boxes containing a pre-filled 
injection pen. 
Placebo to MENOPUR liquid  
 
Placebo to MENOPUR liquid is provided in boxes containing a pre-
filled injection pen. 
MENOPUR powder 
(menotrophin HP) 
MENOPUR powder is provided in boxes containing five vials with 
powder and five vials with diluent. 
Placebo to MENOPUR powder 
 
Placebo to MENOPUR powder is provided in boxes containing five 
vials with powder and five vials with diluent. 
NORTREL1/35 
(combined oral contraceptive) 
NORTRELis provided in boxes containing 3 blister packs each with 
28 tablets. 
LEUPROLIDE ACETATE  
(GnRH agonist) 
LEUPROLIDE ACETATE is provided in boxes containing a vial. 
NOVAREL 
(hCG) 
NOVAREL is provided in boxes containing one vial with powder and 
one vial with diluent. 
ENDOMETRIN  
(progesterone) 
ENDOMETRIN is provided in boxes containing 21vaginal inserts 
and 21 disposable vaginal applicators. 
 
 
All NIMPs are commercially available and will be purchased centrally. No modification from the 
usual commercial state of the NIMPs will be made, except for trial-specific labelling. 
All products (IMPs and NIMPs) will be labelled with trial-specific labels, which contain a self-
adhesive tear-off portion to be affixed to the subject dispensing log, or similar, maintained at the 
trial site. 
 
5.4 
Conditions for Storage and Use 
The investigator will ensure that the medicinal products will be stored in appropriate conditions in a 
secure location with controlled access. The storage compartment shall be monitored regularly and 
the temperature shall be documented. Deviations in storage temperature must be reported to Ferring 
as instructed in the IMP/NIMP handling guideline. 
Specific storage and use instructions for all IMPs and NIMPs are described in the package inserts 
and/or trial specific/commercial box labelling.  
The IMPs will only be dispensed to subjects who meet the eligibility criteria and are randomized to 
a treatment group in the trial. 
 


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5.5 
Blinding / Unblinding 
5.5.1 
Blinding 
The IMP will be packaged according to a computer-generated randomization list prepared for all 
trial sites.  
The packaged IMP kits containing the active and placebo formulation of each presentation will be 
indistinguishable with identical appearance, and will be labelled with random identification 
numbers which are linked to the treatment allocation. Once the subject is assigned a unique 
randomization number in the e-CRF system, the subject’s treatment allocation will be transferred 
automatically to the Interactive Response Technology (IRT) system. Site staff will access the IRT 
system to obtain an identification number for the IMP kits to dispense to the subject, with both the 
site staff and the subject blinded to the treatment allocation. Subjects will receive two different 
treatment kits, one box containing a pre-filled injection pen and one box containing five vials each 
of powder and diluent. 
The Ferring clinical trial team (i.e. data manager, statistician, clinical trial manager, clinical project 
leader, field monitor, medical writer, pharmacovigilance physician, pharmacovigilance manager, 
medical monitor and 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 released to the 
statistician. 
The randomization list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information in the e-CRF will not be accessible to investigators, trial staff at site or laboratory 
personnel during the trial. 
 
5.5.2 
Unblinding of Individual Subject Treatment 
An emergency decoding possibility will be available to the investigator and designated persons at 
Ferring. It is the investigator’s responsibility to decide whether it is medically necessary to know 
the investigational product the subject receives (i.e. unblinding) to ensure the subject’s welfare and 
safety. Breaking of the blind for individual subjects in emergency situations could be required in 
case of suspected, unexpected serious adverse reactions (SUSARs) or in case of other important 
adverse events when the knowledge of the IMP in question is required for therapeutic decisions for 
the management of the subject.  
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
Ferring. Where the event requires immediate unblinding by the investigator, Ferring must be 
informed of the unblinding as soon as possible and provided with the rationale for unblinding. The 
investigator/person who unblinds a treatment will use the e-CRF in which he/she is required to 
enter a password and record the reason for unblinding before the treatment code can be broken. The 
e-CRF automatically records when and by whom the code is broken. The investigator must record 


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the event of unblinding in the subject’s medical record, including the reason for unblinding, but not 
the treatment allocation if this can be avoided. 
In case of accidental unblinding, the same procedure as for emergency unblinding must be 
followed, i.e. the person who is accidentally unblinded will enter a password in the e-CRF and must 
record the reason for unblinding, while the e-CRF records when and by whom the code is broken. 
If Ferring needs to unblind a subject’s treatment, the e-CRF will be used for unblinding. It is 
required to enter a password and the reason for unblinding before the treatment code can be broken. 
The e-CRF records when and by whom the code was broken. The code break will occur according 
to corporate standard operating procedures for unplanned unblinding of trial subjects. It may be 
necessary to unblind an individual subject’s treatment for the purposes of expedited reporting to the 
relevant health authorities and/or IRBs. In that situation, every effort will be made to maintain 
blinding of Ferring personnel involved in data analysis and interpretation. Other personnel may be 
unblinded for SUSARs, including trial site staff as well as staff acting on behalf of Ferring. 
Information on whether the blind has been broken for any subjects is available in the e-CRF and 
must be collected before the database is declared clean and is released to the trial statistician. 
In case the e-CRF cannot be accessed by the investigator, and hence the emergency unblinding 
cannot be performed within the e-CRF system, the investigator should contact Ferring 
Pharmacovigilance using the contact details given below. 
Pharmacovigilance, Ferring Pharmaceuticals 
US Toll-free number: 
 
If Ferring Pharmacovigilance cannot access the e-CRF, a back-up procedure involving the e-CRF 
vendor is in place. 
5.6 
Treatment Compliance, Dispensing and Accountability 
The IMP will only be dispensed to subjects who meet the eligibility criteria and are randomized to a 
treatment group in the trial. The investigator (or his/her designated staff, e.g. trial nurse) will 
maintain a drug-dispensing log detailing the dates and quantities of IMPs dispensed to, and used by, 
each subject, as well as the batch numbers, kit numbers [or other identifier used in the trial]. The 
monitor will verify the drug accountability during the trial. 
In order to monitor compliance, the subjects are to return empty, partially used, and unused vials or 
pens to the investigator at each visit. The investigator (or his/her designated staff, e.g. trial nurse) 
will reconcile and document the return on the drug accountability log. Any discrepancies should be 
discussed with the subject at the time of the return. 


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5.7 
Auxiliary Supplies 
Ferring will provide the sites with sterile pen needles for the MENOPUR liquid pre-filled injection 
pens, and syringes and needles for administration of MENOPUR powder, LEUPROLIDE 
ACETATE, and NOVAREL. 
 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
The monitor will check the supplies, the drug accountability, and inventory records. Following this 
check, the investigator will sign off the records.  
All dispensed IMP and NIMP can be destroyed at the trial site after the drug accountability has 
been finalized, verified by the monitor, and signed off by the investigator. This includes residual 
liquid in a vial, pre-filled syringe or injection pen. Used syringes and needles should be destroyed 
immediately after usage according to normal procedures at each trial site. Any non-dispensed 
IMP/NIMP will be returned for destruction, as instructed by the Ferring Clinical Trial Supply 
Department, and in accordance with local requirements, after the drug accountability has been 
finalized, verified by the monitor, signed off by the investigator, and approved by Ferring. 
 


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6 
TRIAL PROCEDURES 
The flow of trial procedures for subjects is shown in Table 6-1. 
Table 6-1 
Trial Flow Chart 
 
Screening 
and Down-
regulation 
Stimulation 
Oocyte 
retrieval 
Transfer 
Pregnancy monitoring 
End 
Pre-
stimulation 
period 
During stimulation 
End of 
stimula
-tion 
OR 
Transfer 
βhCG Clinical Ongoing End-of-
trial 
Timing <90 days 
before 
stimulation 
Day 1 
Day 1 
≤3 days 
after conf. 
downreg. 
Day 
6 
Day 
>6 to 
<20 
End 
36±2 h 
after 
hCG 
5 days 
after OR 
10-14 
days 
after 
transfer 
5-6 
weeks 
after 
transfer 
8-9 
weeks 
after 
transfer 
a 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xb 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Menstrual history 
X 
 
 
 
 
 
 
 
 
 
 
Reproductive history 
X 
 
 
 
 
 
 
 
 
 
 
Infertility history 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Gynecological examination 
X 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
Blood collection, clin chem/hem. 
X 
 
 
 
X 
 
 
 
 
 
X 
Blood collection, antibodiesc 
 Xd 
 Xe 
 
  
 
 
 Xf 
 Xg 
 
 
 Xg 
Blood collection, endocrine (central)h 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
Blood collection, endocrine (local)i 
 
 
X 
X 
X 
 
 
 
 
 
 
Confirmation of downregulationj 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
IMP dispensing and administration 
 
 Xk 
X 
X 
 
 
 
 
 
 
 
Injection site reactions (diary) 
 
X 
X 
X 
X 
 
 
 
 
 
 
NIMP dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ultrasound sonographyl 
 
Xb 
X 
X 
X 
 
X 
 
X 
X 
 
Oocyte retrieval 
 
 
 
 
 
X 
 
 
 
 
 
Blastocyst transfer/freezing 
 
 
 
 
 
 
X 
 
 
 
 
βhCG test  
 
 
 
 
 
 
 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
 
 
 
 
 
X 
Concomitant medication 
 Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End-of-trial form 
 
 
 
 
 
 
 
 
 
 
X 
a) End-of-trial assessments will be performed at the subject’s last scheduled visit or the following day or within 2 weeks after the last scheduled 
visit in the case of premature discontinuation from the trial. 
b) Performed before randomization. 
c) All subjects with a treatment-induced antibody response must be followed until the response is negative or has returned to pre-dosing level. 
d) Sample exclusively used to re-establish the anti-drug antibody analytical assays. 
e) Performed before the first IMP dose. 
f) Blood sampling for antibody assessment must be done 7-10 days after the last IMP dose (this may coincide with the transfer visit; alternatively, 
a separate visit must be scheduled). 
g) Blood sampling for antibody assessment must be done 21-28 days after the last IMP dose (this may coincide with the βhCG visit; alternatively, a 
separate visit must be scheduled). 
h) Endocrine parameters for analysis by central laboratory: AMH, FSH, hCG, LH, E2 and P4. Special considerations for certain visits are as 
follows: Screening – AMH only, day 1 – no E2, day 6 – no AMH, oocyte retrieval – FSH only, end-of- trial – AMH only.  
i) Endocrine parameters for analysis by local laboratory: E2 and P4, optional assessment; performed as per the site’s standard practice. 
j) Serum E2 ≤20 pg/mL (central laboratory) and transvaginal ultrasound showing no ovarian cysts. 
k) The gonadotropin starting dose is 225 IU for the first 5 days, followed by individual adjustments according to the subject’s follicular response. 
Dose adjustment should be 75 IU per adjustment. Gonadotropin is to be initiated within 3 days of confirmed downregulation. 
l) Transvaginal ultrasound with exception of the transfer and ongoing pregnancy visits, where it can be either transvaginal or abdominal 
examination. 
m) Recording of any concomitant medication within the last 3 months prior to informed consent. 


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6.1 
Screening and Downregulation 
6.1.1 
Screening 
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before stimulation day 1. 
The following procedures / assessments must take place during the screening period: 
• Signed and dated written informed consent must be obtained, and a copy provided to the 
subject, before any trial-related examinations 
• Allocate a screening number 
• Check the inclusion and exclusion criteria (those which are possible to check at screening) 
• Demographics 
• Medical history 
• Menstrual history 
• Reproductive history 
• Infertility history 
• Vital signs 
• Complete physical examination (including height, weight, and BMI calculation) 
• Gynecological examination 
• Urine pregnancy test – must be negative 
• Blood collection for central laboratory analysis of:  
- 
Clinical chemistry and hematology parameters 
- 
AMH [note: the results must be available prior to start of downregulation due to 
inclusion criterion 7] 
- 
Anti-MENOPUR antibodies [exclusively used to re-establish the anti-drug antibody 
analytical assays] 
• Recording of use of any concomitant medication within the last 3 months prior to signed 
informed consent (except medication used in previous infertility treatment cycles which will 
be recorded as part of the infertility history) 
• Recording of adverse events (from time of signed informed consent) 
 
Subjects considered eligible for the trial, based on the inclusion and exclusion criteria assessed at 
this time point, may proceed with downregulation.  
In case of positive findings of HBsAg, HCV or HIV antibody tests obtained at screening, it is the 
investigator’s responsibility to ensure that standard reporting and referral procedures at the sites are 


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followed in line with local regulations. 
 
6.1.2 
Downregulation 
The following procedures / assessments must be performed: 
• Urine pregnancy test – must be negative 
• Prepare and dispense combined oral contraceptives (NORTREL) and GnRH agonist 
(LEUPROLIDE ACETATE) and instruct the subject on how to administer the GnRH 
agonist, the subject will self-inject the GnRH agonist at home 
• Start pituitary downregulation with combined oral contraceptives daily, and 4 days before 
the last day on oral contraceptives start GnRH agonist (LEUPROLIDE ACETATE) 0.1 mL 
(500 µg)/day [self-injection at home] 
 
Combined oral contraceptives should be taken daily for at least 14 days but no more than 21 days, 
at the investigators judgement. 
A minimum of 10 days but no more than 20 days with GnRH agonist administration should be 
ensured prior to confirmation of downregulation. At that time, the following assessments must be 
performed: 
• Transvaginal ultrasound 
• Blood collection for central laboratory analysis of endocrine parameters (E2 only)  
 
Downregulation is confirmed by a serum E2 level ≤20 pg/mL and transvaginal ultrasound showing 
no ovarian cysts. 
If an ovarian cyst is detected and the E2 level is >20 pg/mL, the subject can undergo outpatient 
aspiration of the ovarian cyst at the discretion of her physician with assessment of estradiol >1 day 
later. Subjects can be reassessed to confirm downregulation a maximum of 3 times. 
Once downregulation is confirmed, the subject must proceed to the next scheduled visit within 
3 days (stimulation day 1). 
If downregulation is not obtained within 4 weeks of treatment with GnRH agonist, the subject is 
considered a screening failure and is excluded from the trial.  
 
6.2 
Stimulation 
6.2.1 
Stimulation Day 1 
Subjects will attend the stimulation day 1 visit within 3 days of confirmed downregulation. 


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The following must take place prior to randomization: 
• Ensure that the subject is still eligible for participation in the trial 
• Check those inclusion and exclusion criteria that were not possible during screening 
• Urine pregnancy test – must be negative 
• Transvaginal ultrasound of uterus and ovaries (number and size of follicles) 
 
If the subject fulfills all inclusion and no exclusion criteria, she will proceed to randomization: 
• Randomization, i.e. assignment to the lowest available subject number and thereby 
allocation to either MENOPUR liquid (including Placebo to MENOPUR powder) or 
MENOPUR powder (including Placebo to MENOPUR liquid). 
 
The following must take place after randomization but before administration of the first dose of 
IMP (MENOPUR liquid and Placebo to MENOPUR powder or MENOPUR powder and Placebo to 
MENOPUR liquid): 
• Vital signs 
• Blood collection for central laboratory analysis of: 
- 
Endocrine parameters (AMH, FSH, hCG, LH and P4) 
- 
Anti-MENOPUR antibodies 
Once the above assessments have been completed, the following must be performed: 
• Preparation and dispensing of IMP according to randomization and instruct the subject on 
how to administer the IMP, the subject will self-inject the IMP at home. The IMP should be 
injected in the lower part of the abdomen. 
• Administration of IMP (MENOPUR liquid and Placebo to MENOPUR powder or 
MENOPUR powder and Placebo to MENOPUR liquid depending on randomization) 
[self-injection at home]. The starting dose of 225 IU must be maintained for 5 days.  
• Hand out the diary to the subject. The subject must be instructed to assess and record 
injection site reactions immediately, 30 min and 24 hours after each IMP administration 
throughout the entire stimulation period. 
• Dispensing and administration of GnRH agonist (LEUPROLIDE ACETATE) at a reduced 
dose of 0.05 mL (250 µg)/day [self-injection at home] 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 


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6.2.2 
Stimulation Day 6 
The following must take place at stimulation day 6: 
• Transvaginal ultrasound of uterus and ovaries (number and size of follicles) 
• Blood collection for central laboratory analysis of: 
- 
Endocrine parameters (FSH, hCG, LH, E2 and P4) 
• Blood collection for local laboratory analysis of [note: optional assessment; performed as 
per the site’s standard practice]: 
- 
Endocrine parameters (E2 and P4) 
• Preparation and dispensing of IMP (MENOPUR liquid and Placebo to MENOPUR powder 
or MENOPUR powder and Placebo to MENOPUR liquid) with potential dose adjustments: 
from stimulation day 6 and onwards, the daily dose may be increased by 75 IU every second 
day to a maximum dose of 450 IU, or decreased by 75 IU daily to a minimum dose of 
75 IU, based on the individual response. 
• Dispensing of GnRH agonist (LEUPROLIDE ACETATE) 
• Administration of IMP and GnRH agonist [self-injection at home] 
• Collection of injection site reaction data (diary pages)  
• Drug accountability of IMP and GnRH agonist 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
6.2.3 
Stimulation Day >6 to ≤20 
Visits will take place at least every second day throughout the remaining stimulation period. The 
maximum period of stimulation is 20 days. Coasting is not allowed. 
The following must take place at all subsequent visits during the stimulation period (with the 
exception of the end-of-stimulation visit which is described below): 
• Transvaginal ultrasound of uterus and ovaries (number and size of follicles) 
• Blood collection for local laboratory analysis of [note: optional assessment; performed as 
per the site’s standard practice]: 
- 
Endocrine parameters (E2 and P4) 
• Dispensing of IMP (MENOPUR liquid and Placebo to MENOPUR powder or MENOPUR 
powder and Placebo to MENOPUR liquid) and GnRH agonist (LEUPROLIDE ACETATE) 
• Administration of IMP and GnRH agonist [self-injection at home] 
• Collection of injection site reaction data (diary pages) 


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• Drug accountability of IMP and GnRH agonist 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
6.2.4 
End-of-stimulation Visit 
The end-of-stimulation visit takes place when the subject reaches the criterion for triggering of final 
follicular maturation or if the cycle is cancelled. Administration of hCG (NOVAREL) must take 
place as soon as reaching the criterion for triggering of final follicular maturation. Should the 
subject not reach triggering criteria after a maximum of 20 days of stimulation, the end-of-
stimulation visit is to occur.  
Criterion for triggering of final follicular maturation with hCG:  
• 3 follicles of ≥17 mm 
 
Criterion for cancellation of the cycle due to excessive ovarian response:  
• >30 follicles of ≥12 mm each and/or E2 levels ≥5000 pg/mL (local laboratory) 
 
The following must take place at the end-of-stimulation visit: 
• Vital signs 
• Transvaginal ultrasound of uterus and ovaries (number and size of follicles) 
• Blood collection for central laboratory analysis of: 
- 
Clinical chemistry and hematology parameters 
- 
Endocrine parameters (AMH, FSH, hCG, LH, E2 and P4) 
• Blood collection for local laboratory analysis of [note: optional assessment; performed as 
per the site’s standard practice]: 
- 
Endocrine parameters (E2 and P4)  
• Dispensing of hCG (NOVAREL) (applicable to subjects reaching criterion for triggering 
only) 
• Collection of injection site reaction data (diary pages) 
• Drug accountability of IMP and GnRH agonist 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
For subjects with hCG administration, the oocyte retrieval visit must be scheduled 36±2 hours after 
the administration of hCG. Subjects will self-inject hCG (NOVAREL) at home. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 52 of 103 
 
 
 
 
 
 
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Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
For subjects with cycle cancellation, a visit for the first post-dosing anti-MENOPUR antibody 
assessment 7-10 days after the last IMP dose must be scheduled. 
 
6.3 
Oocyte Retrieval 
Oocyte retrieval must take place 36±2 hours after hCG administration. All oocytes from follicles 
with an estimated diameter ≥12 mm should be retrieved. Oocytes will be inseminated using partner 
or donor sperm by ICSI 4±2 hours after retrieval. 
Below are listed the procedures related to the subjects attending the oocyte retrieval visit, while 
procedures related to the oocytes are described in section 6.3.1. 
The following must take place at the oocyte retrieval visit: 
• Oocyte retrieval 
• Progesterone (ENDOMETRIN) for luteal phase support dispensed [note: progesterone must 
be started the day after oocyte retrieval and continued up to menses, negative βhCG, 
pregnancy loss or for a maximum of 10 weeks total if pregnancy is confirmed] 
• Blood collection for central laboratory analysis of endocrine parameters (FSH only) 
• 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 no oocytes retrieved, the next visit is the first post-dosing anti-MENOPUR 
antibody assessment visit (section 6.4.2). 
 
6.3.1 
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 until transfer at the blastocyst stage.  
The flow of the trial procedures for embryos is shown in Table 6-2. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 53 of 103 
 
 
 
 
 
 
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Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 6-2 
Trial Flow Chart – Oocyte / Embryo / Blastocyst Procedures 
 
Day 0 (OR) 
Day 1  
after OR 
Day 5 
after OR 
Timing 
-4h  
(±2h) 
0h 
19h 
(±2h) 
Day 5 
Oocyte retrieval (OR) 
X 
 
 
 
Assessment of maturity stage 
X 
 
 
Insemination by ICSI 
 
X 
 
 
Assessment of oocyte fertilization 
 
 
X 
 
Assessment of embryo / blastocyst quality 
 
 
 
X 
Transfer of blastocyst(s) of the highest quality availablea  
 
 
 
X 
Cryopreservation of blastocysts by vitrification, as applicable  
 
 
 
Xb 
a In the absence of viable blastocysts, morulae can be used if deemed suitable for transfer.  
b In case the investigator judges that a blastocyst/morula is still developing, cryopreservation on day 6 or later is allowed. 
OR: Oocyte retrieval; ICSI: intracytoplasmic sperm injection  
 
Day 0 (Oocyte Retrieval) 
• Oocyte retrieval at 4±2 hours before start of the insemination procedure 
• Assessment of maturity stage after oocyte retrieval and before insemination 
• Insemination at 0 hours using ICSI using ejaculated sperm (fresh or frozen) from partner or 
donor 
 
Day 1 after Oocyte Retrieval 
• Assessment of fertilization (number of pronuclei) at 19±2 hours after insemination. Only 
embryos with 2 pronuclei should continue with subsequent quality assessments. 
 
Day 5 after Oocyte Retrieval 
• Assessment of embryo developmental stage / blastocyst quality 
• Transfer of blastocyst(s) (section 6.4). Transfer on day 6 (or later) is not allowed. 
• Cryopreservation of blastocysts by vitrification, as applicable (section 6.4). 
Cryopreservation on day 6 (or later) is allowed in those instances where continued culture is 
judged necessary/beneficial by the embryologist. 
 
6.4 
Transfer 
6.4.1 
Blastocyst Transfer 
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. Transfer of day 6 (or later) 
blastocysts is not allowed. The subject-related procedures are described below. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 54 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies (first post-
dosing assessment)  
• Ultrasound for image acquisition of the uterus (applicable for a subset of trial sites) 
• Ultrasound-guided transfer of blastocyst(s) of the highest quality available according to this 
policy:  
Subjects with at least one good-quality 
blastocyst (i.e. grade 3BB or above): 
➢ single blastocyst transfer 
Subjects with absence of a good-quality 
blastocyst (i.e. lower than grade 3BB): 
➢ option of single blastocyst 
transfer 
➢ option of double blastocyst 
transfer if at least two blastocysts 
are available 
 
Note: in the absence of viable blastocysts, morulae can be used if deemed suitable for 
transfer. 
 
• Cryopreservation of blastocysts by vitrification, as applicable 
• Dispensing of progesterone for luteal phase support, if applicable  
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
For subjects with blastocyst transfer, the next visit is the βhCG test visit which must be scheduled 
10-14 days after transfer. 
 
6.4.2 
First Post-dosing Anti-MENOPUR Antibody Assessment (7-10 Days after Last IMP 
Dose) 
Subjects who have been exposed to MENOPUR liquid or MENOPUR powder must have the first 
post-dosing anti-MENOPUR antibody assessment performed 7-10 days after the last MENOPUR 
liquid or MENOPUR powder dose. This may coincide with the transfer visit (section 6.4.1). 
For subjects who do not attend the transfer visit, a separate visit must be scheduled, at which the 
following must take place: 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 55 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6.5 
βhCG Test 
6.5.1 
βhCG Test 
Subjects who have undergone transfer must attend a visit 10-14 days after transfer. 
The following must take place: 
• Blood collection for local laboratory analysis of βhCG 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies (second post-
dosing assessment (section 6.5.2)) 
• Dispensing of progesterone, if applicable  
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
The blood sample for βhCG will be analyzed by the local laboratory and evaluated according to the 
local reference ranges. In case of doubtful / inconclusive βhCG result, a second test will be 
performed, preferably within 2 days. Subjects with a positive βhCG test must attend a clinical 
pregnancy visit 5-6 weeks after transfer (section 6.6). Subjects with a negative βhCG test must 
proceed to the end-of-trial assessments (section 6.8). 
 
6.5.2 
Second Post-dosing Anti-MENOPUR Antibody Assessment (21-28 Days after Last 
IMP Dose) 
Subjects who have been exposed to MENOPUR liquid or MENOPUR powder must have the 
second post-dosing anti-MENOPUR antibody assessment performed 21-28 days after the last 
MENOPUR liquid or MENOPUR powder dose. This may coincide with the βhCG visit 
(section 6.5.1). 
For subjects who do not attend the βhCG test visit, a separate visit must be scheduled, at which the 
following must take place: 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
For subjects who do not attend the βhCG test visit, this second post-dosing anti-MENOPUR 
antibody assessment may be done in connection with the end-of-trial visit (section 6.8). 
 
6.6 
Clinical Pregnancy 
Subjects with a positive βhCG test must attend a visit 5-6 weeks after transfer. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 56 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
The following must take place: 
• Transvaginal ultrasound of uterus to assess any clinical pregnancy 
• Dispensing of progesterone for luteal phase support if a vital pregnancy is confirmed 
• Recording of use of any concomitant medication 
• Recording of adverse events 
 
If at least one intrauterine gestational sac with fetal heart beat is observed, vital pregnancy is 
confirmed. For subjects with a vital pregnancy, the next visit is the ongoing pregnancy visit 
(section 6.7). Subjects with no vital pregnancy must undergo end-of-trial assessments (section 6.8). 
 
6.7 
Ongoing Pregnancy 
If a vital pregnancy has been documented, the subject must attend a visit 8-9 weeks after transfer.  
The following procedures / assessments must take place: 
• Ultrasound (transvaginal or abdominal) of uterus to assess any intrauterine viable fetus 
• Recording of use of any concomitant medication  
• Recording of adverse events 
 
If at least one intrauterine viable fetus is identified, this confirms an ongoing pregnancy. 
 
6.8 
End-of-trial 
If a subject attends the scheduled trial visits, the end-of-trial assessments should take place at the 
last scheduled trial visit. 
Due to the timing of the mandatory anti-MENOPUR antibody assessments, the end-of-trial 
assessments can at the earliest be performed 21-28 days after the last MENOPUR liquid or 
MENOPUR powder dose. This may coincide with the βhCG visit for subjects with a negative 
βhCG test. 
The following end-of-trial procedures / assessments must take place, irrespective of whether the 
subject discontinues the trial prematurely or completes it:  
• Blood collection for central laboratory analysis of: 
- 
Clinical chemistry and hematology parameters 
- 
Endocrine parameters (AMH) 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 57 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
- 
anti-MENOPUR antibodies (second post-dosing assessment) [note: only applicable for 
subjects who have not already had a blood sample taken for the second post-dosing anti-
MENOPUR antibodies assessment as described in section 6.5.2] 
• Vital signs 
• Physical examination (including weight) 
• Gynecological examination 
• Drug accountability, if applicable 
• Recording of use of any concomitant medication 
• Recording of adverse events 
• End-of-trial form (completion of trial or premature discontinuation, date and reason for 
discontinuation, if applicable) 
 
These assessments serve to document the subject’s physical health at the end of the trial. 
 
6.9 
Post-trial Activities 
6.9.1 
Pregnancy Outcome and Neonatal Health Follow-up 
Pregnancy outcome will be gathered for all subjects with an ongoing pregnancy. Neonatal health 
data will also be collected. In addition, data on neonatal SAEs will be collected at 4 weeks and 
minimum 6 months after birth. These data will be reported separately. 


Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 58 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Primary Endpoint 
7.1.1 
Number of Fertilized Oocytes 
The number of fertilized oocytes will be assessed at 19±2 hours after insemination. Fertilized 
oocytes with 2 pronuclei will be regarded as correctly fertilized. 
 
7.2 
Assessments Related to Secondary Endpoints 
7.2.1 
βhCG Test 
A blood serum βhCG test must be obtained 10-14 days after blastocyst transfer. If the test is 
positive according to the local laboratory’s reference ranges, this confirms a positive βhCG. In case 
of doubtful / inconclusive βhCG result, a second test will be performed, preferably within 2 days, 
and the conclusive result recorded. 
 
7.2.2 
Clinical Pregnancy 
Clinical pregnancy will be based on detection of at least 1 intrauterine gestational sac with fetal 
heart movement on transvaginal ultrasound at 5-6 weeks after blastocyst transfer. For clinical 
pregnancies, the number of intrauterine sacs and fetal heart beats will be recorded. 
 
7.2.3 
Ongoing Pregnancy 
Ongoing pregnancy will be based on detection of at least 1 intrauterine viable fetus by transvaginal 
or abdominal ultrasound at 8-9 weeks after blastocyst transfer. For ongoing pregnancies, the 
number of intrauterine viable fetuses will be recorded. 
 
7.2.4 
Early Pregnancy Loss 
Early pregnancy loss will be defined as a positive βhCG tests but no ongoing pregnancy at 
8-9 weeks after blastocyst transfer, as described in sections 7.2.1 and 7.2.3 above. 
 
7.2.5 
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. 
The total number of follicles and number of follicles with a diameter of ≤9 mm, 10-11 mm, 
12-14 mm, 15-16 mm, and ≥17 mm on stimulation day 6 and last day of stimulation will be 
recorded. Data will be recorded separately for the right and left ovary. 
 


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Date: 14 Oct 2019 
E-Study Protocol-21539; Ver. 6.0 
Supersedes: 5.0 
Page 61 of 103 
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
all OHSS cases will be graded as mild, moderate or severe. 
 
7.2.13 
Adverse Events 
Adverse events will be recorded from the time of signed informed consent for participation in the 
trial until the end-of-trial visit. For each adverse event the following parameters are recorded by the 
investigator on the Adverse Event Log: description of event, date and time of onset, intensity, 
causal relation to IMP, action taken to IMP, other actions taken, seriousness of the adverse event, 
date and time of outcome, and outcome. Definitions of adverse events are provided in section 8. 
 
7.2.14 
Injection Site Reactions 
Every day throughout the stimulation period, the subjects will assess the local tolerability of 
subcutaneous injections of MENOPUR liquid or MENOPUR powder 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 subject will be informed to always inject MENOPUR liquid or Placebo to 
MENOPUR liquid using the pre-filled injection pen on the same side of the navel and MENOPUR 
powder or Placebo to MENOPUR powder using the syringe on the other side in order to be able to 
distinguish between injection site reactions related to MENOPUR liquid / Placebo to MENOPUR 
liquid and those related to MENOPUR powder / Placebo to MENOPUR powder. 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 e-CRF. 
 
7.2.15 
Anti-MENOPUR Antibodies 
Blood samples for assessment of anti-MENOPUR antibodies in the individual subjects in the trial 
will be drawn pre-dosing and post-dosing:  
• Screening [Note; this sample is exclusively used to re-establish the anti-drug antibody 
assays (e.g. screening- and confirmatory cut-points)] 
• Stimulation day 1, prior to dosing (baseline; pre-dosing sample) 
• 7-10 days after the last MENOPUR liquid or MENOPUR powder dose 
This may coincide with the transfer visit. Subjects not reaching transfer must be called in for 
this extra visit. 
• 21-28 days after the last MENOPUR liquid or MENOPUR powder dose 
This may coincide with the βhCG visit. In case of discontinuation before the βhCG visit, 
this assessment should be done at the end-of-trial visit scheduled 21-28 days after the last 


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MENOPUR liquid or MENOPUR powder dose. 
 
Ferring has developed the following assays for evaluating the immunogenicity of MENOPUR 
liquid or MENOPUR powder: 
Assay 1) 
A screening immunoassay, using labelled MENOPUR as capturing component, 
assessing the presence in serum of anti-MENOPUR antibodies, using a parametric cut-
point approach with a 5% false positive rate. 
Assay 2) 
A confirmatory immunoassay, using unlabeled MENOPUR for quenching of signal, 
confirming or disconfirming the specificity of any positive results in assay 1), using a 
parametric cut-point approach with a 1% false positive rate. 
Assay 3) 
A titer immunoassay determining the antibody response titer of any anti-MENOPUR 
antibodies confirmed in assay 2). 
Assay 4) 
A characterization step where any confirmed anti-MENOPUR antibodies will be tested 
for cross-reactivity towards FSH, hCG, LH and the structurally related TSH using the 
parametric cut-point with 1% false positive rate determined for assay 2). 
Assay 5) 
Neutralizing capacity of the antibodies confirmed positive in assay 2) and characterized 
for cross-reactivity in assay 4) will be assessed with three individual cell-based 
neutralizing antibody (NAb) assays (NAb FSH, NAb hCG and NAb LH) using a 
parametric cut-point approach with a 1% false positive rate. Samples that show cross-
reactivity only to individual drug components (i.e. either to FSH, to hCG or to LH) will 
be tested only in the corresponding NAb assay. In case a confirmed positive sample 
show cross-reactivity to all drug components, it will be tested in all three NAb assays. 
 
In subjects with a negative pre-dosing sample, a treatment-induced anti-MENOPUR antibody 
response will be defined as any post-dosing sample being positive in the confirmatory assay (i.e. 
assay 2). 
In subjects with a positive pre-dosing sample, a treatment-induced anti-MENOPUR antibody 
response will be defined as a statistically determined fold increase in titers from the pre-dosing 
assessment to a post-dosing assessment.a  
A subject is defined to have treatment-induced anti-MENOPUR antibodies with neutralizing 
capacity, if the subject has any post-dosing sample being positive in assay 5) and the pre-dosing 
sample was negative in assay 5) [this also includes the scenario of pre-dosing sample negative in 
assays 1) or 2) and therefore not tested in assay 5)].  
 
a The fold increase in titres will be determined by minimum significant ratio (MSR) experiments during assay 
validation and will be stated in the validation report and the clinical trial report. 


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Subjects with a treatment-induced anti-MENOUPUR antibody response (both with and without 
neutralizing capacity) will be followed until the response becomes negative or has returned to pre-
dosing level. These subjects will be called in for assessments at 2 months after the last post-dosing 
anti-MENOPUR antibody sampling. If required, further assessments will be made at 3, 4, 6, 9 and 
12 months after the last post-dosing anti-MENOPUR antibody sampling. The assessments will be 
terminated when two consecutive assessments are negative or indicate that the pre-dosing level has 
been reached, with a maximum follow-up period of one year. The assessments will also be 
terminated if the subject commences a new treatment cycle with any gonadotropin preparation. 
 
7.3 
Other Assessments 
7.3.1 
Demographics 
Demographic information will be obtained during the screening period, including the following: 
date of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White). 
 
7.3.2 
Medical History 
Any relevant medical history will be recorded during the screening period. This includes diagnosis / 
symptoms, and start and end dates (or marked ongoing in case it has not been resolved). 
 
7.3.3 
Menstrual History 
Information about the menstrual history (average cycle length) will be obtained during the 
screening period. 
 
7.3.4 
Reproductive History 
Information about the reproductive history will be obtained during the screening period. This will 
include number of clinical pregnancies, number of fetuses and outcome. Information on primary 
versus secondary infertility will be derived. 
 
7.3.5 
Infertility History 
Information about the causes of infertility and duration of infertility will be obtained during the 
screening period. This will also cover information about any previous treatment for infertility, 
including type of treatment and gonadotropin preparations used. 
 


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7.3.6 
Confirmation of Downregulation 
Pituitary downregulation should be confirmed after minimum 10 days but no more than 20 days of 
GnRH agonist administration during the screening / downregulation period. 
Downregulation is confirmed by a serum E2 level ≤20 pg/mL and transvaginal ultrasound showing 
no ovarian cysts. 
 
7.3.7 
Vital Signs 
Systolic and diastolic blood pressure, pulse, and temperature will be measured at screening, on 
day 1, on the last day of stimulation and at end-of-trial. Assessments of blood pressure and heart 
rate are to be measured while the subject is seated after resting for 3 minutes. All blood pressure 
measurements should be made using the same arm and prior to any scheduled blood draws. 
 
7.3.8 
Physical Examinations 
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. 
In addition, height and weight, will be measured at screening for calculation of BMI, and body 
weight will be measured as part of the end-of-trial assessments. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log. 
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to end-of-
trial must be recorded as adverse events. 
 
7.3.9 
Gynecological Examinations 
A complete gynecological examination will be performed at screening and at end-of-trial. 
Information will be recorded for breast, external genitalia, vagina, cervix, uterus, ovaries and 
fallopian tubes.  
Each category will be evaluated as normal, abnormal not clinically significant or abnormal 
clinically significant. Abnormal clinically significant findings at screening must be reported on the 
Medical History Log. 
 


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7.3.10 
Clinical Laboratory Variables 
Central Laboratory Tests 
The following laboratory tests will be performed by a central laboratory: 
• Screening, last day of stimulation and end-of-trial visit: serum chemistry: non-fasting 
glucose, blood urea nitrogen, creatinine, potassium, sodium, chloride, calcium, aspartate 
aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase. 
• Screening, last day of stimulation and end-of-trial visit: hematology: red blood cell count, 
white blood cell count, hematocrit, hemoglobin, platelet count, and differential count. 
• Screening, day 1, last day of stimulation and end-of-trial visit: AMH. An AMH level greater 
than 1.0 ng/mL should be documented at screening. 
• Downregulation, day 6, and last day of stimulation: E2. An E2 level of ≤20 pg/mL should 
be documented to confirm downregulation prior to randomization. 
• Day 1, day 6, last day of stimulation and oocyte retrieval: FSH. 
• Day 1, day 6, and last day of stimulation: hCG, LH and P4. 
 
The samples for AMH, FSH, LH, hCG and P4 on stimulation day 1 (baseline) will be collected 
prior to the first dose of MENOPUR liquid or MENOPUR powder. For E2, the sample confirming 
downregulation will be used as baseline. Samples drawn on stimulation day 6 and on the last day of 
stimulation will be collected at least 8 hours after the previous MENOPUR liquid, MENOPUR 
powder or GnRH agonist administration. 
The investigator will review the laboratory results and evaluate and document whether the results 
are normal or abnormal and whether or not abnormal results are clinically significant. The 
laboratory report will be signed and dated by the investigator. 
 
Local Laboratory Tests 
The following laboratory tests prior to randomization will be performed at each site’s local or 
reference laboratory per standard practice if results are not already available in the subject’s chart. 
Furthermore, analysis of hormones after randomization may also be performed locally. Results will 
be reviewed by the investigator and documented in the subject’s chart and e-CRF (if applicable). 
• Hormones prior to randomization: total testosterone, prolactin, and TSH should be drawn at 
screening or within 12 months prior to screening and documented to be within normal limits 
or considered not clinically significant by the investigator. In addition, the early follicular 
phase (cycle day 2-4) serum FSH level should be between 1-12 IU/L within 3 months prior 
to randomization.  


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• Other laboratory assessments prior to randomization: serum hepatitis B surface antigen, 
hepatitis C antibody, HIV antibody, and rapid plasma reagin tests are to be done at 
screening, if not done within 6 months prior to screening, and documented to be negative.  
• Hormones after randomization: E2 and P4 may be analyzed at various time points during 
stimulation (optional), and serum βhCG is to be analyzed for pregnancy monitoring. 
 
7.3.11 
Blastocyst Transfer Procedure 
Any difficulty or eventuality during the transfer procedure will be noted. 
 
7.3.12 
Malfunction of Pen 
In case of technical malfunction of a pen, that results in a replacement of the pen, all relevant 
details (including time, date, a description of the malfunction and whether dosing was affected) of 
the incidence should be reported in a blinded manner in the e-CRF, the pen should be replaced and 
the treatment continued. Human errors such as misunderstanding of instructions or incorrect 
handling of the pen should not be regarded as technical malfunctions. 
In case of adverse events caused by malfunction of the pen, these will be identified and described. 
 
7.3.13 
Concomitant Medication 
The use of any concomitant medication within the last 3 months prior to informed consent for 
participation in the trial (except medication used in previous infertility treatment cycles which will 
be recorded as part of the infertility history) and throughout the trial will be recorded. Recording of 
concomitant medication will be performed at all visits. Any changes in concomitant medications or 
treatments must be recorded at each visit. 
 
7.3.14 
Ultrasound for Image Acquisition of the Uterus 
At a subset of trial sites, ultrasound for image acquisition of the uterus will be carried out at the 
transfer visit. Details on equipment and procedures related to this exploratory assessment will be 
provided in a trial-specific manual. 
Resultant images may be analyzed to identify features that correlate with subject response to 
treatment and/or clinical outcomes, such as ongoing pregnancy. These data will be reported 
separately. 
 


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7.4 
Assessments Related to Post-trial Information 
7.4.1 
Pregnancy Outcome and Neonatal Health Follow-up 
All subjects with an ongoing pregnancy will be followed as part of the post-trial follow-up. Live 
birth rate and neonatal health data at birth covering gestational age, gender, birth weight and length, 
and Apgar scores after 1, 5 and 10 minutes will be collected. In addition, data on neonatal SAEs 
will be collected at 4 weeks and minimum 6 months after birth (see section 8.5.1). These data will 
be reported separately. 
 
7.4.2 
Late Pregnancy Loss 
The occurrence of late pregnancy losses defined as an ongoing pregnancy (i.e. at least 1 intrauterine 
viable fetus at 8-9 weeks after blastocyst transfer), but no live birth will be evaluated as part of the 
post-trial follow-up. These data will be reported separately. 
 
7.5 
Handling of Biological Samples and Other Material 
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. All biological 
samples will be analyzed 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 are the blood samples analyzed by a local 
laboratory at the trial clinic / hospital 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 the required approvals. The processes related to handling of biological 
samples will be described in the informed consent documents, and biobank / data protection 
legislation including local legislation will be adhered to. 
With respect to the image recordings of the uterus, a trial-specific manual will be provided to the 
subset of sites participating in this exploratory assessment, describing in detail the equipment and 
procedures. All recordings will be stored. 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 unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP. 
• Any laboratory abnormality, vital sign or finding from physical or gynecological 
examination assessed as clinically significant by the investigator [note: pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or during 
the screening period are not adverse events, but are recorded as medical history]. 
• Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures. 
 
All adverse events will be coded by Ferring Global Pharmacovigilance using the Medical 
Dictionary for Regulatory Activities (MedDRA) (the version effective at trial start). 
 
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the end-of-trial visit. 
The sources of adverse events cover: 
• The subject’s response to questions about her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit). 
• Symptoms spontaneously reported by the subject. 
• Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
• Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization). 
 
8.2.2 
Recording of Adverse Events 
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s e-CRF with information about: 


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• 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.b 
Note: a procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalization is not an adverse event; the reason for hospitalization is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event). 
 
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. 
 
 
b  
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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Intensity 
The intensity of an adverse event must be classified using the following 3-point scale: 
Mild: 
Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate: 
Event sufficient to affect usual activity (disturbing). 
Severe: 
Inability to work or perform usual activities (unacceptable). 
 
Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following: 
Reasonable possibility:  
There is evidence or argument to suggest a causal relationship between the IMP and the adverse 
event. The adverse event may occur as part of the pharmacological action of the IMP or may be 
unpredictable in its occurrence. 
Examples:  
• Adverse events that are uncommon but are known to be strongly associated with IMP 
exposure. 
• Adverse events that are not commonly associated with IMP exposure, but the event occurs 
in association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge with the IMP. 
 
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and 
the adverse event. 
Examples: 
• Known consequences of the underlying disease or condition under investigation. 
• 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 recognized standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log. 
 
Date and Time of Outcome 
The date and time the subject recovered or died. 
 
Outcome 
The outcome of an adverse event must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering (the event is improving) 
• Not recovered 
• Fatal. 
 


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8.3 
Adverse Events of Special Interest 
8.3.1 
Ovarian Hyperstimulation Syndrome 
Symptoms and Classification 
OHSS is an adverse event of special interest during controlled ovarian stimulation. Investigators 
will record OHSS symptoms using a classification system based on Golan’s classification system13 
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 (Golan’s Classification 
System) 
Mild OHSS 
 
Grade 1 
Abdominal distension and discomfort  
 
Grade 2  
Features of grade 1 plus nausea/vomiting and/or diarrhea. Ovaries enlarged to 
5-12 cm.a) 
Moderate OHSS 
 
Grade 3  
Features of mild OHSS plus ultrasonic evidence of ascites.b)  
Severe OHSS 
 
Grade 4  
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax (or 
breathing difficulties). Paracentesis due to OHSS symptoms. c) 
 
Grade 5  
All of the above plus change in blood volume, increased blood viscosity due to 
hemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d) Hospitalization due to OHSS symptoms.e) 
a)  For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded.  
b)  For subjects with transvaginal evidence of ascitis, the size of the fluid pockets in the pelvis (Douglas pouch, vesico-
uterine pouch, etc.) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, 
and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid pockets in the 
pelvis.  
c)  In case of paracentesis, the volume of fluid drained should be measured. 
d)  Hemoconcentration is defined as hematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded. 
e)    Hospitalization is defined as admission exceeding 24 hours. 
 
All cases of OHSS must be reported as adverse events and followed until the adverse event has an 
outcome of recovered. Any case of OHSS that requires hospitalization or surgical/medical 
intervention should be considered severe. All cases of severe OHSS should be reported as a SAE.  


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Please note, that the classification of ‘mild OHSS’, ‘moderate OHSS’ and ‘severe OHSS’ does not 
refer to the classification of an adverse event’s intensity (also rated mild, moderate, or severe), but 
to the grades in Golan’s Classification System described above.  
Subject narratives will be prepared for all OHSS cases.  
Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of 
final follicular maturation and late OHSS will be defined as OHSS with onset >9 days after 
triggering of final follicular maturation. 
 
Preventive Interventions of Early OHSS 
Preventive interventions of early OHSS include the following:  
• Cycle cancellation due to excessive ovarian response 
• Administration of dopamine agonist (only in subjects with ≥20 follicles of ≥12 mm) 
• Investigator requested reduction in gonadotropin dose to prevent OHSS 
 
Investigations in case of OHSS 
The investigator should report signs, symptoms and laboratory assessments used to diagnose and 
classify all cases of OHSS in the e-CRF. The following investigations must be conducted when 
OHSS symptoms are first observed and repeated when there are clinically relevant changes in the 
OHSS presentation:  
• Body weight and maximum abdominal circumference 
• Ultrasound of ovarian size and if applicable, measurement of pelvic/abdominal/thoracic 
fluid  
• Vital signs 
• Blood sample for central lab analysis of the following: 
- 
Progesterone and estradiol 
- 
Red blood cell count, white blood cell count, hemoglobin, hematocrit, platelet count and 
differential count  
- 
Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, calcium, 
chloride, creatinine, gamma-glutamyl transferase, non-fasting glucose, potassium and 
sodium 
- 
Coagulation parameters (prothrombin time, activated partial thrombin time) 
 


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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. 
 
8.4 
Other Events of Special Interest 
8.4.1 
Injection Site Reactions 
Injection site reactions after administration of IMP (MENOPUR liquid including Placebo to 
MENOPUR powder and MENOPUR powder including Placebo to MENOPUR liquid) are only to 
be reported as adverse events if they require active management, i.e. discontinuation of IMP, 
additional investigations or treatment of the injection site reaction. Local tolerability of IMP 
constitutes a secondary endpoint and will be evaluated in detail based on the subjects’ recordings in 
the diary.  
Local tolerability reactions after administration of NIMP are to be reported as adverse events if they 
fulfil the definition of an adverse event. 
 
8.4.2 
Treatment-induced Anti-MENOPUR Antibodies 
Presence of treatment-induced anti-MENOPUR antibodies is not to be reported as an adverse event. 
These data will be described as part of the secondary endpoints. 
 
8.4.3 
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. 
 
8.4.4 
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 at least one intrauterine 
gestational sac with or without heart beat in a pregnancy 
where one viable fetus remains as documented by ultrasound 


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Ectopic pregnancy: 
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery 
 
Concerning timing, a pregnancy loss occurring before ongoing pregnancy (i.e. a positive βhCG 
tests but no ongoing pregnancy at 8-9 weeks after blastocyst transfer) will be defined as an early 
pregnancy loss, while a pregnancy loss occurring after ongoing pregnancy (i.e. at least 
1 intrauterine viable fetus at 8-9 weeks after blastocyst transfer but no live birth) during the post-
trial follow-up will be defined as a late pregnancy loss. 
 
8.4.5 
Multiple Pregnancies 
Multi-fetal gestations are not to be reported as adverse events.  
 


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8.5 
Serious Adverse Events 
8.5.1 
Serious Adverse Event Definition 
Serious Adverse Events during the Trial 
An event is defined a serious 
adverse event (SAE) if it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented and 
reported, including deaths occurring within four weeks after the treatment 
ends and irrespective of the causal relationship to the IMP. The death of a 
subject enrolled in a trial is per se not an event, but an outcome. 
is life-threatening 
The term life-threatening refers to an adverse event in which the subject was 
at immediate risk of death at the time of the event. It does not refer to an 
event, which may have caused death if it were more severe. 
requires in-patient 
hospitalization or 
prolongation of existing 
hospitalization 
The term hospitalization means that the subject was admitted to hospital or 
that existing hospitalization was extended as a result of an event. 
Hospitalization describes a period of at least 24 hours. Over-night stay for 
observation, stay at emergency room or treatment on an out-patient basis do 
not constitute a hospitalization. However, medical judgement must always 
be exercised and when in doubt the case should be considered serious (i.e. if 
case fulfils the criterion for a medically important event). Hospitalizations 
for administrative or social purposes do not constitute an SAE. Hospital 
admissions and/or surgical operations planned before trial inclusion are not 
considered adverse events, if the illness or disease existed before the subject 
was enrolled in the trial, provided that the condition did not deteriorate 
during the trial. 
results in persistent or 
significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to 
medical judgement by the investigator. 
is an important medical 
event 
Medical and scientific judgment should be exercised in deciding whether 
other situations should be considered serious such as important medical 
events that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the patient or might require intervention 
to prevent one of the other outcomes listed in the definition above. Examples 
of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
 


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Elective Termination in the Time between Clinical and Ongoing Pregnancy 
In connection with elective termination due to a congenital anomaly observed at or after the clinical 
pregnancy visit (i.e. 5-6 weeks after transfer), but before ongoing pregnancy has been established 
(i.e. 8-9 weeks after transfer), the congenital anomaly of the fetus should be reported as a SAE.  
The congenital anomaly leading to elective termination will be coded using both MedDRA and 
ICD-10 and classified as minor or major.c 
 
Serious Adverse Events during Post-trial Activities 
Pregnancy outcome and neonatal health data (i.e. gestational age, gender, birth weight and length, 
and Apgar scores after 1, 5 and 10 minutes) will be gathered for all subjects with an ongoing 
pregnancy. These data will be collected at birth. In addition, data on neonatal SAEs will be 
collected at 4 weeks and minimum 6 months after birth. These data will be reported separately. 
The following untoward medical occurrences reported as part of this post-trial follow-up 
information will be recorded as SAEs: 
• Death of mother in connection with pregnancy or labor 
• Death of neonate / infant 
• Stillbirthd 
• Neonate admitted to the neonatal intensive care unit (NICU) regardless of duration, or 
neonate / infant admitted to the neonatal care unit (NCU) / pediatric care unit (PCU) for 
more than 2 hours 
• Congenital anomaly / birth defect 
• Medically important event 
 
In case of admission to NICU or NCU / PCU, the reason for admission must be reported as an SAE, 
rather than just the act of hospitalization. 
Congenital anomalies will be coded by Ferring using both MedDRA and ICD-10 and classified as 
minor or major. 
 
 
c 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. 
d Stillbirth: ≥ gestational age 24 weeks + 0 days, calculated from the day of transfer + 19 days 


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8.5.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported immediately to Ferring Pharmacovigilance as soon as it becomes 
known to the investigator and not later than within 24 hours of their knowledge of the occurrence of 
an SAE. 
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE. 
SAE Report Form 
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Pharmacovigilance using the contact details below. 
Ferring Pharmacovigilance 
E-mail: 
US Fax: 
 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Pharmacovigilance to access the information. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the e-CRF), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring Pharmacovigilance 
using the contact details in the section above. In any case this information must be supplied by the 
investigator upon request from Ferring. On any copies provided, such details such as subject’s 
name, address, and hospital ID number should be concealed and instead subject number should be 
provided.
The investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records. 
Overdose and medication errors of IMP with and without clinical consequences will be tracked in 
the e-CRF and reviewed by Ferring Pharmacovigilance on an ongoing basis. 
Ferring will report SAEs according to local regulations. 


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8.6 
Follow-up of Adverse Events and Serious Adverse Events 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable. 
After the subject’s last visit, the investigator must follow-up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. Follow-up should continue until the outcome of recovered, recovered with 
sequelae or fatal, has been reached. Further, if the event is a chronic condition, the investigator and 
Ferring may agree that further follow-up is not required. 
 
8.6.2 
Follow-up of Serious Adverse Events with Onset during the Post-Trial 
For post-trial SAEs in neonates, where the neonate has not recovered at the 6 month follow-up 
assessment, the investigator must follow up until the SAE has resolved. If the SAE is a chronic 
condition or the medical condition of the neonate is stable, the investigator and Ferring may agree 
that further follow-up is not required. 
 
8.6.3 
Collection of Serious Adverse Events with Onset after End-of-trial 
If an investigator becomes aware of an SAE after the subject’s last visit in the trial, and he/she 
assesses the SAE to have a reasonable possible causality to the IMP, the case will have to be 
reported to Ferring Pharmacovigilance, regardless how long after the end of the trial this takes 
place. 
 


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9 
STATISTICAL METHODS 
This section details the planned statistical analyses for the primary endpoint and outlines the 
analysis plan for the secondary endpoints. All analyses and further descriptions of the statistical 
methodology for the primary and secondary endpoints will be included in the Statistical Analysis 
Plan (SAP). The SAP will be available before breaking the blind. A separate SAP will be prepared 
to cover the post-trial information. 
 
9.1 
Determination of Sample Size 
The present trial is a pharmacodynamic comparison of a marketed product to a new formulation of 
the same. With 188 subjects per treatment group, the trial has at least 85% power to demonstrate 
the non-inferiority of MENOPUR liquid to MENOPUR powder in the number of fertilized oocytes 
at the 1-sided significance level of 0.025. This is based on the results for MENOPUR powder from 
the COMBINE trial conducted in a similar setting (GnRH agonist protocol, MENOPUR starting 
dose of 225 IU for the first five days, insemination by ICSI etc.) and in a similar population 
(infertile women between 18 and 42 years). The mean (SD) of the number of fertilized oocytes 
were 7.88 (5.15) with similar results in the two age groups (7.92 in the <35 years age group vs. 7.80 
in the ≥35 years age group). The non-inferiority margin of -1.60 will retain 80% of the expected 
comparator effect.  
After adjusting for 5% missing data, approximately 400 subjects will be randomized (1:1) into this 
trial, stratified by trial site and age (<35years and ≥35years). 
A blinded sample size reassessment will be done when data on the primary endpoint are available 
for 70% of the planned subjects or when 300 subjects are randomized, whichever comes first. The 
sample size reassessment will be done without breaking the blind and without inflating the type I 
error of the trial, in line with current regulatory guidelines. The expected maximum number of 
subjects to be randomized is 500 (250 subjects per treatment group), corresponding to a blinded 
one-sample (both groups pooled) standard deviation estimate of 5.8 and 85% power. 
 
9.2 
Subject Disposition 
The number and percentage of subjects within each analysis set, randomized subjects treated with 
IMP (MENOPUR liquid including Placebo to MENOPUR powder or MENOPUR powder 
including Placebo to MENOPUR liquid), and subjects prematurely discontinued from the trial will 
be summarized. All post-baseline discontinuations will be summarized by reason for 
discontinuation. The number of subjects screened and not randomized will be presented. 
 
9.3 
Protocol Deviations 
The rating of protocol deviations as ‘minor’ and ‘major’, as well as the criteria for major protocol 
deviations with the implication of exclusions from the per-protocol analysis set will be decided by 


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the Ferring clinical team on the basis of a blinded review of data before declaration of clean file and 
lock of database.  
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be summarized and listed by subject. 
 
9.4 
Analysis Sets 
9.4.1 
Intention-to-Treat Analysis Set  
The intention-to-treat (ITT) analysis set comprises all randomized (as planned) subjects. 
 
9.4.2 
Modified Intention-to-Treat Analysis Set  
The modified intention-to-treat (mITT) analysis set comprises all randomized (as planned) subjects 
who received at least 1 dose of IMP (MENOPUR liquid including Placebo to MENOPUR powder 
or MENOPUR powder including Placebo to MENOPUR liquid). 
 
9.4.3 
Per Protocol Analysis Set 
The per protocol (PP) analysis set comprises all mITT subjects except those excluded as a result of 
major protocol deviations. 
  
9.4.4 
Safety Analysis Set 
The safety analysis set comprises all treated subjects and is analyzed according to the actual 
treatment received. 
 
9.5 
Trial Population 
9.5.1 
Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for the 
subjects in the mITT, PP, and safety analysis sets by treatment group, separately. 
 
9.5.2 
Medical History, Concomitant Medication and Other Population Characteristics 
All medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarized for each medical item. 
Concomitant medications will be coded using the World Health Organization Drug Reference List. 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
classification first level (alphabetically) and Anatomical Therapeutic Chemical classification 
second level (in decreasing order of frequency). 


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Infertility history, menstrual history and reproductive history will be listed by subject and presented 
in summary tables. 
 
9.6 
Efficacy Endpoint Assessments 
9.6.1 
General Considerations 
All primary and secondary efficacy analyses will be conducted for the mITT analysis set. 
Furthermore, sensitivity analyses will be conducted for the PP and ITT analysis sets as appropriate.  
Continuous variables will be described with the number of non-missing values, mean, standard 
deviation, median, and minimum/maximum values. Categorical variables will be described with the 
number and percentage of subjects with each level. Missing values will not be included in the 
calculation of percentages unless otherwise specified. All individual subject data will be listed. 
 
9.6.2 
Primary Endpoint 
The primary objective of the trial is to demonstrate the non-inferiority of MENOPUR liquid versus 
MENOPUR powder with respect to the number of fertilized oocytes in women undergoing 
controlled ovarian stimulation powder. The non-inferiority limit for the difference between 
treatments (MENOPUR liquid minus MENOPUR powder) is set as -1.60. The non-inferiority 
hypothesis to be tested for the primary endpoint will be: 
H0: µMENOPUR liquid - µMENOPUR powder ≤ -1.60 
against the alternative 
H1: µMENOPUR liquid - µMENOPUR powder > -1.60 
where µMENOPUR liquid and µMENOPUR powder denote the mean numbers of fertilized oocytes in subjects 
treated with MENOPUR liquid and MENOPUR powder, respectively. 
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in the least squares mean number of fertilized oocytes 
between the two treatment groups. If the lower-limit of the 95% confidence interval is greater than 
the non-inferiority limit (-1.60), the null hypothesis will be rejected and it will be claimed that 
MENOPUR liquid is non-inferior to MENOPUR powder with respect to the number of fertilized 
oocytes. 
Due to the expected large sample size, the primary endpoint will be analyzed using a mixed effects 
two-way analysis of variance (ANOVA) model, based on the asymptotic normal approximation. 
The model will include the treatment group and the age group as fixed factors, as well as the trial 
site as a random effect. The least squares mean estimate of the treatment difference in the number 
of fertilized oocytes and the associated 95% confidence interval will be derived through an 


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LSMEANS statement in the SAS PROC GLM procedure. For subjects who do not have any 
oocytes retrieved, or do not have fertilization assessment due to early withdrawal, or any other 
reason, the number of fertilized oocytes will be considered as zero. 
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority 
limit (-1.60) but also above zero then there is evidence of superiority in terms of statistical 
significance at the 2-sided 5% level. With evidence of superiority, the corresponding 2-sided p-
value will be reported. There is no need for a multiplicity adjustment since it is a simple closed test 
procedure. 
The primary efficacy analysis will be conducted for the mITT population. Sensitivity analyses for 
the primary endpoint will be conducted for both the ITT analysis set and the PP analysis set. 
 
9.6.3 
Secondary Endpoints 
All secondary efficacy endpoints will be summarized using tables and figures, as appropriate. 
Additional details will be specified in the Statistical Analysis Plan. The secondary efficacy 
endpoints include: 
• Positive βhCG rate, clinical pregnancy rate and ongoing pregnancy rate will be presented by 
descriptive statistics by treatment group. 
• Early pregnancy loss will be presented by descriptive statistics by treatment group. 
• The follicle cohort on stimulation day 6 and last day of stimulation will be summarized by 
treatment on the follicle level (number of follicles ≤9 mm, 10-11 mm, 12-14 mm, 
15-16 mm, and ≥17 mm) and subject level (largest follicle size and average number of 
follicles ≥17 mm, ≥15 mm, and ≥12 mm). Tables will be produced for all subjects and for 
subjects with oocytes retrieved. 
• The endocrine profile will be summarized using descriptive statistics by scheduled visit, as 
well as for the change from baseline, if appropriate. The analyses will be based on the 
central laboratory values. 
• The number of oocytes retrieved, the number of metaphase II oocytes, and the number of 
oocytes undergoing ICSI will be summarized by frequency distribution and by descriptive 
statistics for each treatment group. 
• The fertilization rate will be expressed as a percentage for each subject and calculated as 
100 times the ratio of the number of fertilized 2PN oocytes to the number of oocytes 
retrieved. Descriptive statistics will be provided by treatment group. 


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• The number and quality of blastocysts 5 days after oocyte retrieval will be summarized by 
frequency distribution and by descriptive statistics for each treatment group. 
 
Based on the serum FSH concentrations, a population pharmacokinetic model will be developed. 
The modelling will be detailed in a modelling analysis plan and reported separately. 
 
9.7 
Extent of Exposure and Treatment Compliance 
The number of days exposed and the total amount of IMP and NIMP administered will be 
summarized and listed per subject and treatment. Subjects that deviate from the planned treatment 
will also be listed. 
 
9.8 
Safety 
9.8.1 
General Considerations 
Analyses for the safety analysis set will be conducted according to the actual treatment received. 
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of adverse events. A worst-case approach will be used: if causality is missing, the adverse event 
will be regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse 
event will be regarded as severe; if seriousness is missing, the adverse event will be regarded as 
serious; if outcome is missing, and no date of outcome is present, the outcome is regarded as 
‘ongoing’. 
Data will be presented by summary tables and listings only. Categorical data will be summarized by 
treatment using the number and percentage of subjects in each category. For calculation of 
percentages, the denominator will be the total number of subjects in the respective treatment group 
in the safety analysis set. Continuous data will be summarized by treatment using number, mean, 
standard deviation, median, minimum, and maximum. 
All individual subject data will be listed per subject and treatment as observed including any 
derived values. 
 
9.8.2 
Adverse Events 
Adverse events will be coded using MedDRA. 
A treatment-emergent adverse event is defined as an adverse event that emerges during treatment 
having been absent pre-treatment, or worsens relative to the pre-treatment state. Only treatment-
emergent adverse events will be presented in summary tables. 
All data will be listed per subject and adverse event. 


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Written narratives will be issued for all SAEs and adverse events leading to discontinuation.  
Adverse events judged by the investigator as being reasonably possibly related to IMP will be 
termed adverse drug reactions. 
 
Overview of Treatment Emergent Adverse Events 
A summary table for treatment-emergent adverse event will be presented, including for each 
treatment, 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 event. 
• Severe adverse events. 
• Adverse drug reactions. 
• Adverse events leading to discontinuation. 
• SAEs. 
• Deaths. 
 
Incidence of Adverse Events 
Treatment-emergent adverse events in each treatment group will be tabulated by system organ class 
(SOC) and preferred term. 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. 
For each treatment the following counts are done: 
• For number of subjects experiencing a particular event, counting will be done by subject 
and not by event. This is valid for both the SOC and preferred term, i.e. a subject will only 
be counted once in each SOC and once within each preferred term. 
• For total number of events counting will be done by event. This is valid for both the SOC 
and preferred term, i.e. an event occurring more than once for the same subject will be 
counted for each occurrence. 
 
This counting and data presentation will be applied for the various incidences of adverse event 
tables described below. 
 


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Incidence of Adverse Events by Relationship to IMP 
Treatment-emergent adverse events for each treatment group will be tabulated by SOC, preferred 
term, and relationship to IMP. 
 
Incidence of Adverse Events by Intensity 
Treatment-emergent adverse events for each treatment group will be tabulated by SOC, preferred 
term, and intensity. 
 
Incidence of Adverse Drug Reactions by Intensity 
Adverse drug reactions for each treatment group will be tabulated by SOC, preferred term and 
intensity for all IMP-related adverse events. 
 
Adverse Events Leading to Discontinuation 
Adverse events leading to discontinuation for each treatment group will be listed and tabulated by 
SOC and preferred term. 
 
Serious Adverse Events 
SAEs for each treatment group will be listed and tabulated by SOC and preferred term. 
 
Deaths 
A separate data listing will be provided for all deaths, if any. 
Furthermore, treatment-emergent adverse events occurring in ≥5% in any treatment group will be 
tabulated by SOC and preferred term. 
 
9.8.3 
OHSS 
Frequency of OHSS is a secondary endpoint. OHSS for each treatment group will be tabulated by 
classification (mild, moderate, severe) and grade (1, 2, 3, 4, 5). The tabulation will be made for 
OHSS overall as well as separately for early OHSS and late OHSS. 
 
9.8.4 
Injection Site Reactions 
Frequency and intensity of injection site reactions is a secondary endpoint. 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), 


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reaction and intensity (none, mild, moderate and severe). 
 
9.8.5 
Anti-MENOPUR Antibodies 
Frequency of anti-MENOPUR antibodies is a secondary endpoint. The proportion of subjects with 
treatment-induced anti-MENOPUR antibodies as well as the proportion of subjects with treatment-
induced anti-MENOPUR antibodies with neutralizing capacity will be tabulated. 
 
9.8.6 
Technical Malfunctions of the Pen 
Technical malfunctions of the pen is a secondary endpoint. The frequency of technical malfunctions 
of the pen will be tabulated. 
 
9.8.7 
Vital Signs 
Vital signs will be summarized by treatment group. All vital signs values will be listed per subject, 
treatment group, and time point. Values outside the reference range will be flagged. 
 
9.8.8 
Physical Examination 
Physical examinations will be summarized and all subjects with any abnormal finding will be listed 
per subject for the safety analysis set. 
 
9.8.9 
Gynecological Examination 
Gynecological examinations will be summarized and all subjects with any abnormal finding will be 
listed by subject for the safety analysis set. 
 
9.8.10 
Safety Laboratory Variables 
Baseline, last day of stimulation and end-of-trial safety laboratory values for each subject will be 
listed by test and all values outside the normal range will be identified. Mean changes from baseline 
to last day of stimulation and from baseline to end-of-trial will be summarized by treatment group 
using descriptive statistics. 
 
9.8.11 
Additional Endpoints 
All post-trial endpoints will be summarized using tables and figures, as appropriate. Additional 
details will be specified in the separate Statistical Analysis Plan for the post-trial endpoints. The 
post-trial endpoints include: 
• Live birth rate 


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• Late pregnancy loss rate (defined as an ongoing pregnancy but no live birth). 
• Neonatal health including SAEs at birth, and SAEs at 4 weeks and minimum 6 months after 
birth. 
Descriptive statistics will be provided in each of the respective post-trial endpoints.  
 
9.9 
Interim Analyses and Administrative Review 
No interim analysis is planned. 
A sample size reassessment (see section 9.1) will be performed without breaking the blind and 
without inflating the type I error of the trial, in line with the current regulatory guidelines for non-
inferiority trials by FDA. This monitoring will be performed by the project statistician who will 
evaluate the one-sample standard deviation of the primary efficacy endpoint in a blinded manner in 
relation to the assumptions underlying the sample size calculation. 
A restricted recalculation rule for the sample size reassessment will be used. Accordingly, 
400 subjects should be randomized to achieve sufficient power if the blinded one-sample standard 
deviation estimate of the primary efficacy endpoint is 5.15. If the estimated standard deviation is 
above the assumed value of 5.15, the sample size can be adjusted up to a maximum of 500 subjects 
(250 subjects per treatment group), corresponding to a standard deviation of 5.80. If the blinded 
one-sample standard deviation estimate is below the expected 5.15, the sample size will not be 
decreased below the planned 400 subjects. 
Blinded monitoring of the assumptions underlying the sample size is recommended specifically for 
non-inferiority trials by FDA14 and in general by EMA.15 


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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 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 
• Body weight measurements 
• Visit dates 
• Dates of administration of IMP 
• Dates and daily doses of NIMP 
• Dates and daily doses of concomitant medication 
• Date of oocyte retrieval and number of oocytes retrieved 
• Date of transfer and number and quality of blastocysts transferred 
• Number and quality of blastocysts cryopreserved 


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• Results of βhCG test and ultrasound at clinical and ongoing pregnancy visits 
• Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth 
• Injection site reactions after IMP administration – diary 
• Adverse events (description as well as start/stop date and time) 
• OHSS symptoms, preventive interventions, investigations and treatments 
• Follow-up on treatment-induced anti-MENOPUR antibody response 
• Reason for discontinuation 
• Event of unblinding, including the reason for unblinding 
 
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record. 
If the trial sites use electronic patient record systems, the sponsor will decide if the electronic 
patient records qualify for the trial and document the decision. If the electronic patient records 
system does not qualify for the trial, it may be considered to utilize paper data sheets for source 
data as an exception. 
The source data for the endocrine parameters, clinical chemistry and hematology parameters as well 
as anti-MENOPUR antibodies will be available at the central laboratory. Laboratory reports will be 
available at the sites for endocrine parameters, clinical chemistry and hematology parameters. 
 
10.2 
e-CRF/Electronic Case Report Form 
An e-CRF system provided by an independent third-party contract research organization (CRO) 
will be used for data capture. The system is validated and access at all levels to the system is 
granted/revoked following Ferring and vendor procedures, in accordance with regulatory and 
system requirements. 
Trial data should be entered into the e-CRF in a timely manner. The time-frame will be specified in 
the investigator agreement. 
The investigator will approve/authorize the e-CRF entries for each subject, with the exception of 
the treatment allocation module which is un-accessible to the investigator to maintain the assessor-
blinding, with an electronic signature which is equivalent to a handwritten signature.  
The e-CRF system and the database will be hosted at the independent third party CRO. After the 
trial database is declared clean and released to the statistician, a final copy of the database will be 
stored at Ferring. The investigator will also receive a copy of the trial site’s final and locked data 
(including audit trail, electronic signature and queries) as write-protected pdf-files produced by the 


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independent third party CRO. The pdf-files will be stored in an electronic format and will be 
provided to the investigator before access to the e-CRF is revoked. 
Entry errors occurring in the e-CRF will be corrected electronically. Such corrections or 
modifications will be automatically tracked by an audit trail detailing the date and time of the 
correction and the name of the person making the correction. 
 
10.3 
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
Department, Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection, cleaning and validation. 
The data management plan will also include information about the intended use of computerised 
systems, a description of the security measures employed to protect the data and a description of the 
electronic data flow. 
 
10.4 
Provision of Additional Information 
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements. 


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11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Council for Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions.  
The investigator will permit the monitor direct access to all source data, including electronic 
medical records, and/or documents in order to facilitate data verification. The investigator will 
cooperate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
investigator is expected to be able to meet the monitor during these visits. When the first subject is 
randomized at the trial site, a monitoring visit will take place shortly afterwards. For this trial, the 
frequency of the monitoring visits per site will be determined by the enrolment rate. 
The source data verification process and definition of key variables to be monitored and the 
monitoring strategy will be described in detail in the Monitoring Plan for the trial. 
 
11.2 
Audit and Inspection 
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic / foreign regulatory inspectors or 
representatives from IRBs who may audit / inspect the trial. 
The main purposes of an audit or inspection are to evaluate trial conduct and compliance with the 
trial protocol, ICH-GCP, the applicable regulatory requirements, and standard operating 
procedures.  
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorized Ferring representatives and representatives from regulatory authorities and IRBs may 
wish to inspect their medical records. During audits/inspections the auditors / inspectors may copy 
relevant parts of the medical records. No personal identification apart from the 
screening/randomization number will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by regulatory authorities 
or IRB. 
 
11.3 
Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
e-CRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 


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and the signed Informed Consent Documents, will be maintained by the investigator in strict 
confidence. 
 


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12 
CHANGES IN THE CONDUCT OF THE TRIAL 
12.1 
Protocol Amendments 
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRBs and regulatory authorities, in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to IRBs approval or favorable opinion. 
 
12.2 
Deviations from the Protocol 
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
sponsor, and the implications of the deviation must be reviewed and discussed. All deviations must 
be documented, and a record of protocol deviations should be retained by the investigator and 
sponsor.  
 
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 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. Furthermore, the data and information collected during the post-trial follow-up 
activities will be reported in clinical trial report addendums, including live birth, neonatal health at 
birth, and neonatal SAEs at 4 weeks and minimum 6 months after birth. 
 
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 


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invention. 
 
13.3.2 
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
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 at the US 
National Institutes of Health. 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 
Institutional Review Board 
An IRB will review the protocol and any amendments and advertisements used for recruitment. The 
IRB will review the Subject Information Sheet and the Informed Consent Form, their updates (if 
any), and any written materials given to the subjects. A list of all IRBs to which the protocol has 
been submitted and the name of the committee chairmen will be included in the Clinical Trial 
Report. 
 
14.2 
Regulatory Authority Approval 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
 
14.3 
End-of-Trial and End-of-Trial Notification 
The end of the trial is defined as the date of LSLV, i.e. when the last subject completes the end-of-
trial visit. Post-trial activities will cover the period until collection of the last pregnancy outcome 
and neonatal health data at birth, and safety follow-up data on neonates for a minimum of 6 months 
after birth. 
In the case of early termination, Ferring must notify the end of the trial to the relevant regulatory 
authorities and the concerned IRBs as soon as possible, clearly explain the reasons, and describe 
follow-up measures, if any, taken for safety reasons. 
Within one year of the end of the trial, Ferring shall send the final Clinical Trial Report to the 
relevant regulatory authorities. 
 
14.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
 
14.5 
Subject Information and Consent 
Informed Consent Documents regarding Participation in the Trial – Subject 
The investigator (or the person delegated by the investigator) will obtain a freely given written 
consent from each subject after an appropriate explanation of the aims, methods, sources of 
funding, any possible conflicts of interest, anticipated benefits, potential risks of the trial and the 
discomfort it may entail, post-trial provisions and any other aspects of the trial which are relevant to 


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


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The child-custody holders will be informed that the monitor(s), quality assurance auditor(s) 
mandated by Ferring, ethics committee representatives or FDA inspector(s), in accordance with 
applicable regulatory requirements, may review the neonate’s source records and data. Data 
protection will be handled in compliance with national / local regulations. 
 
14.6 
Subject Participation Card 
The subject will be provided with a Subject Participation Card bearing the following information: 
• That she is participating in a clinical trial. 
• That she is treated with menotropins for assisted reproductive technologies. 
• The name and phone number of the investigator. 
• The name, address and phone number of Ferring contact (as required by local regulations). 
 
The subjects will be asked to keep the Subject Participation Card in their possession at all times 
during the trial. 
In addition, each subject’s primary care physician will be notified of the subject’s 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, and other national law(s) in the US where 
the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct. 
 


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


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


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17 
REFERENCES 
 
1. 
MENOPUR – menotropins for injection. Ferring Pharmaceuticals. 
Prescribing Information, Version: February 2014. 
2. 
Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. 
Hum Reprod 2003; 18: 1000-1004. 
3. 
Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 
2003; 18: 1005-1009. 
4. 
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. 
5. 
Csokmay JM, Hill MJ, Chason RJ, Hennessy S, James AN, Cohen J, DeCherney AH, Segars 
JH, Payson MD. Experience with a patient-friendly, mandatory, single-blastocyst transfer 
policy: the power of one. Fertil Steril 2011; 96: 580-584. 
6. 
Kresowik JD, Stegmann BJ, Sparks AE, Ryan GL, van Voorhis BJ. Five-years of a 
mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate without 
lowering pregnancy rates. Fertil Steril 2011; 96: 1367-1369. 
7. 
Practice Committee of Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Elective single-embryo 
transfer. Fertil Steril 2012; 97: 835-842. 
8. 
Practice Committee of the Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Criteria for number of 
embryos to transfer: a committee opinion. Fertil Steril 2013; 99: 44-46. 
9. 
Rehman KS, Bukulmez O, Langley M, Carr BR, Nackley AC, Doody KM, Doody KJ. Late 
stages of embryo progression are a much better predictor of clinical pregnancy than early 
cleavage in intracytoplasmic sperm injection and in vitro fertilisation cycles with blastocyst-
stage transfer. Fertil Steril 2007; 87: 1041-1052. 
10. 
Practice Committee of the Society for Assisted Reproductive Technology and Practice 
Committee of the American Society for Reproductive Medicine. Endometriosis and 
infertility: a committee opinion. Fertil Steril 2012; 98:591-8. 
11. 
Menopur (FE 999906) Investigator’s Brochure, Ferring Pharmaceuticals, Edition 5, August 
2017. 
12. 
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards 
reproductive certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th 
world congress on in vitro fertilisation and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388. 


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13. 
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. 
14. 
U.S. Department of Health and Human Services Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), Draft guidance November 2016, Non-inferiority Clinical Trials to Establish 
Effectiveness. 
15. 
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP). Points to consider on switching between 
superiority and non-inferiority. CPMP/EWP/482/99. 


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CLINICAL TRIAL PROTOCOL 
SUMMARY OF CHANGES 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program 
Trial 000303 
CLARA 
(Comparison of MENOPUR Liquid and Powder in Women Undergoing ART) 
IND Number: 
Investigational 
Medicinal Product: 
Indication: 
Phase: 
Name and Address of 
Sponsor: 
053954 
MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL 
MENOPUR powder and solvent for solution for injection, 75 IU 
Development of multiple follicles and pregnancy in ovulatory women 
undergoing controlled ovarian stimulation as part of an assisted 
reproductive technology (ART) cycle 
3 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
________________________________________________________________________________ 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. 


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RATIONALE FOR CHANGES: 
This present document describes the changes made to the clinical trial protocol, version 3.0, dated 
28 March 2018.  
The following aspects have been changed:  
• Addition of image acquisition of the uterus at the blastocyst transfer visit, which will be 
performed at a subset of trial sites 
• Update of trial timelines 
• Correction of an inconsistency related to the blood sampling schedule 
• Correction of typos in a sentence related to the sample size considerations 
• Clarification of trial-specific source data requirements 
 
IMPLICATIONS OF CHANGE: 
This protocol update has implications for the informed consent form, and the revised text is 
included in the present document.  
There are no immediate implications to the trial as recruitment has not started.  
The changes do not affect the safety of subjects, scope of investigation, or scientific rigor of the 
trial. The present summary of changes as well as an updated protocol (version 4.0) will be 
submitted to IRBs and approval will be obtained prior to the respective sites starting the trial. 


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AMENDED TEXT: 
Superseded wording is marked as strike through, and new wording is shown in italics. 
 
1 
SYNOPSIS – PLANNED TRIAL PERIOD 
Superseded Prior Wording 
First subject first visit (FSFV): 
Q3 2018 
Last subject last visit (LSLV): 
Q3 2019 
New Protocol Wording 
First subject first visit (FSFV): 
Q3 2019 
Last subject last visit (LSLV): 
Q3 2020 
 
2 
SYNOPSIS – METHODOLOGY 
Superseded Prior Wording 
Blood samples…  Clinical chemistry and hematology are assessed at screening and at end-of-trial 
…   
New Protocol Wording 
Blood samples…  Clinical chemistry and hematology are assessed at screening, last day of 
stimulation, and end-of-trial …  
 
3 
SYNOPSIS – STATISTICAL METHODS 
Superseded Prior Wording 
… This is based on the results for MENOPUR powder from the COMBINE trial in a similar setting 
…  
New Protocol Wording 
… This is based on the results for MENOPUR powder from the COMBINE trial conducted in a 
similar setting …  
 


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4 
SECTION 3.1.3 – METHODOLOGY 
Superseded Prior Wording 
Blood samples…  Clinical chemistry and hematology are assessed at screening and at end-of-trial 
…   
New Protocol Wording 
Blood samples…  Clinical chemistry and hematology are assessed at screening, last day of 
stimulation, and end-of-trial …  
 
5 
SECTION 3.1.3 – TRIAL SCHEDULE 
Superseded Prior Wording 
First subject first visit (FSFV) is planned to Q3 2018 
Last subject last visit (LSLV) is planned to Q3 2019 
 
New Protocol Wording 
First subject first visit (FSFV) is planned to Q3 2019 
Last subject last visit (LSLV) is planned to Q3 2020 
 
6 
TABLE 6-1 – TRIAL FLOW CHART 
Superseded Prior Wording 
 
Screening 
and Down-
regulation 
Stimulation 
Oocyte 
retrieval 
Transfer 
Pregnancy monitoring 
End 
Pre-
stimulation 
period 
During stimulation 
End of 
stimula
-tion 
OR 
Transfer 
βhCG Clinical Ongoing End-of-
trial 
Timing 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound sonographyp 
X 
Xb 
X 
X 
X 
 
 
 
X 
X 
 
… 
 
 
 
 
 
 
 
 
 
 
 
p) Transvaginal ultrasound with exception of the ongoing pregnancy visit, where it can be either transvaginal or abdominal examination 


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New Protocol Wording 
 
Screening 
and Down-
regulation 
Stimulation 
Oocyte 
retrieval 
Transfer 
Pregnancy monitoring 
End 
Pre-
stimulation 
period 
During stimulation 
End of 
stimula
-tion 
OR 
Transfer 
βhCG Clinical Ongoing End-of-
trial 
Timing 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound sonographyp 
X 
Xb 
X 
X 
X 
 
X 
 
X 
X 
 
… 
 
 
 
 
 
 
 
 
 
 
 
p) Transvaginal ultrasound with exception of the transfer and ongoing pregnancy visits, where it can be either transvaginal or abdominal 
examination. 
 
7 
SECTION 6.4.1 – BLASTOCYST TRANSFER 
Superseded Prior Wording 
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. Transfer of day 6 (or later) 
blastocysts is not allowed. The subject-related procedures are described below. 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies (first post-
dosing assessment)  
• Transfer of blastocyst(s) of the highest quality available according to this policy: …  
 
New Protocol Wording 
Transfer is performed on day 5 (blastocyst stage) after oocyte retrieval. Transfer of day 6 (or later) 
blastocysts is not allowed. The subject-related procedures are described below. 
• Blood collection for central laboratory analysis of anti-MENOPUR antibodies (first post-
dosing assessment)  
• Ultrasound for image acquisition of the uterus (applicable for a subset of trial sites) 
• Ultrasound-guided transfer of blastocyst(s) of the highest quality available according to this 
policy: … 
 


Date: 01 Mar 2019 
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CONFIDENTIAL 
8 
SECTION 7.3.10 – CLINICAL LABORATORY VALUES 
Superseded Prior Wording 
• Screening and end-of-trial visit: serum chemistry: non-fasting glucose, blood urea nitrogen, 
creatinine, potassium, sodium, chloride, calcium, aspartate aminotransferase, alanine 
aminotransferase, and gamma-glutamyl transferase. 
• Screening and end-of-trial visit: hematology: red blood cell count, white blood cell count, 
hematocrit, hemoglobin, platelet count, and differential count. 
 
New Protocol Wording 
• Screening, last day of stimulation and end-of-trial visit: serum chemistry: non-fasting 
glucose, blood urea nitrogen, creatinine, potassium, sodium, chloride, calcium, aspartate 
aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase. 
• Screening, last day of stimulation and end-of-trial visit: hematology: red blood cell count, 
white blood cell count, hematocrit, hemoglobin, platelet count, and differential count. 
 
9 
SECTION 7.3.14 – ULTRASOUND FOR IMAGE ACQUISITION OF THE UTERUS 
New Protocol Wording 
7.3.14 Ultrasound for Image Acquisition of the Uterus 
At a subset of trial sites, ultrasound for image acquisition of the uterus will be carried out at the 
transfer visit. Details on equipment and procedures related to this exploratory assessment will be 
provided in a trial-specific manual. 
Resultant images may be analyzed to identify features that correlate with subject response to 
treatment and/or clinical outcomes, such as ongoing pregnancy. These data will be reported 
separately. 
 


Date: 01 Mar 2019 
E-Protocol Amendment-23428; Ver.1.0 
Supersedes: None 
Page 7 of 10 
 
 
 
 
 
 
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Solution for Injection  
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Ferring Pharmaceuticals 
CONFIDENTIAL 
10 
SECTION 7.5 – HANDLING OF BIOLOGICAL SAMPLES 
Superseded Prior Wording 
7.5 Handling of Biological Samples  
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. ... The processes 
related to handling of biological samples will be described in the informed consent documents, and 
biobank / data protection legislation including local legislation will be adhered to. 
 
New Protocol Wording 
7.5 Handling of Biological Samples and Other Material  
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. ... The processes 
related to handling of biological samples will be described in the informed consent documents, and 
biobank / data protection legislation including local legislation will be adhered to. 
With respect to the image recordings of the uterus, a trial-specific manual will be provided to the 
subset of sites participating in this exploratory assessment, describing in detail the equipment and 
procedures. All recordings will be stored. Data protection legislation including local legislation 
will be adhered to. 
 
11 
SECTION 9.1 – DETERMINATION OF SAMPLE SIZE 
Superseded Prior Wording 
… This is based on the results for MENOPUR powder from the COMBINE trial in a similar 
conducted in a similar setting …  
 
New Protocol Wording 
… This is based on the results for MENOPUR powder from the COMBINE trial conducted in a 
similar setting … 
 


Date: 01 Mar 2019 
E-Protocol Amendment-23428; Ver.1.0 
Supersedes: None 
Page 8 of 10 
 
 
 
 
 
 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
12 
SECTION 9.8.10 – SAFETY LABORATORY VALUES 
Superseded Prior Wording 
Baseline and end-of-trial safety laboratory values for each subject will be listed by test and all 
values outside the normal range will be identified. Mean changes from baseline to end-of-trial will 
be summarized by treatment group using descriptive statistics. 
 
New Protocol Wording 
Baseline, last day of stimulation and end-of-trial safety laboratory values for each subject will be 
listed by test and all values outside the normal range will be identified. Mean changes from baseline 
to last day of stimulation and from baseline to end-of-trial will be summarized by treatment group 
using descriptive statistics. 
 
13 
SECTION 10.1 – SOURCE DATA AND SOURCE DOCUMENTS 
Superseded Prior Wording 
Trial-specific Source Data Requirements – Ferring 
…  
• 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) 
…  
 
New Protocol Wording 
…  
• Informed consent (date and time of obtaining written informed consent) 
…  
 


Date: 01 Mar 2019 
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Supersedes: None 
Page 9 of 10 
 
 
 
 
 
 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
14 
MASTER INFORMED CONSENT DOCUMENTS – BLASTOCYST TRANSFER 
VISIT 
Superseded Prior Wording 
... During this visit, you will have the following tests and procedures performed: 
• have a transvaginal ultrasound as part of the blastocyst transfer process and 
• ...  
 
New Informed Consent Wording 
... During this visit, you will have the following tests and procedures performed: 
• have a transvaginal or abdominal ultrasound as part of the blastocyst transfer process (and 
might include collection of ultrasound images of the uterus) and 
• ...  
 
15 
MASTER INFORMED CONSENT DOCUMENTS – RETENTION OF SAMPLES 
Superseded Prior Wording 
Blood samples ... 
The samples will be labeled with your study subject ID (not your name), and your identity will 
remain confidential. When all the needed information from the study has been gathered, the 
samples will be destroyed. Destruction for all blood samples will take place within 2 years after 
reporting of the study results, except blood samples analyzed by the local laboratory which are 
destroyed sooner. 
... 
 
New Informed Consent Wording 
Blood samples ... 
The samples will be labeled with your study subject ID (not your name), and your identity will 
remain confidential. When all the needed information from the study has been gathered, the 
samples will be destroyed. Destruction for all blood samples will take place within 2 years after 
reporting of the study results or when methods / results have been adequately validated, except 
blood samples analyzed by the local laboratory which are destroyed sooner. 
... 


Date: 01 Mar 2019 
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Supersedes: None 
Page 10 of 10 
 
 
 
 
 
 
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Solution for Injection  
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Ferring Pharmaceuticals 
CONFIDENTIAL 
If images of your uterus are collected, these recordings will be labeled with your study subject ID 
(not your name), and your identity will remain confidential.  
 


Date: 03 Jun 2019
E-Protocol Amendment-23614; Ver. 1.0
Supersedes: None
Page 1 of 4
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #02 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
SUMMARY OF CHANGES #02 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program 
Trial 000303 
CLARA 
(Comparison of MENOPUR Liquid and Powder in Women Undergoing ART) 
IND Number: 
053954 
Investigational 
Medicinal Product: 
MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL 
MENOPUR powder and solvent for solution for injection, 75 IU 
Indication: 
Development of multiple follicles and pregnancy in ovulatory women 
undergoing controlled ovarian stimulation as part of an assisted 
reproductive technology (ART) cycle 
Phase: 
3 
Name and Address of 
Sponsor: 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
________________________________________________________________________________ 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. 


Date: 03 Jun 2019
E-Protocol Amendment-23614; Ver. 1.0
Supersedes: None
Page 2 of 4
 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #02 
Ferring Pharmaceuticals 
CONFIDENTIAL 
DOCUMENT INFORMATION: 
This present document describes the changes made to the clinical trial protocol, version 4.0, and the 
master informed consent form, version 2.0; both dated 01 March 2019.  
 
IMPLICATIONS OF CHANGE: 
There are no immediate implications to the trial as recruitment has not started.  
The changes do not affect the safety of subjects, scope of investigation, or scientific rigor of the 
trial. The present summary of changes as well as an updated protocol (version 5.0) will be 
submitted to IRBs and approval will be obtained prior to the respective sites starting the trial. 
Moreover, an updated master informed consent form (version 3.0) will be issued.  


Date: 03 Jun 2019
E-Protocol Amendment-23614; Ver. 1.0
Supersedes: None
Page 3 of 4
 
 
 
 
 
 
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Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #02 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SUMMARY OF MAIN CHANGES TO CLINICAL TRIAL PROTOCOL: 
• The combined oral contraceptive used as part of the pituitary downregulation protocol has 
been changed from CYCLAFEM 1/35 to NORTREL 1/35 due to lack of availability. Both 
products contain 1 mg norethindrone and 0.035 mg ethinyl estradiol per tablet. 
• The previous inclusion criterion on serum AMH and FSH levels has been split into two 
separate criteria. The AMH sample can be taken at any time during the cycle and will be 
analyzed by the central laboratory. The FSH sample must be taken at cycle days 2-4 and 
will be analyzed by the local laboratory.  
• The previous inclusion criterion on normal Pap smear has been replaced by a new exclusion 
criterion on known abnormal cervical cytology with the purpose of consistency across 
ongoing Ferring trials. The original criterion was aligned to the Ferring 000293 protocol 
under the assumption that the present trial would be started during the conduct of that trial, 
but has been changed to match the Ferring 000001 and 000002 trials which will be ongoing 
when the present trial starts. This change should make it simpler for sites participating in 
multiple Ferring trials at the same time. 
• Eligibility criteria that may be assessed based on information in the subject’s chart have 
been omitted as individual assessments at the screening visit.  
• The blood sampling schedule on stimulation day 1 has been simplified. Serum E2 is 
analyzed by the central laboratory as part of the confirmation of downregulation, which 
occurs within 3 days before stimulation day 1. Serum E2 will therefore not be analyzed 
again on stimulation day 1. Furthermore, the optional local analysis of serum E2 and P4 on 
stimulation day 1 has been left out. 
• A typo in the flow chart regarding the timing of stimulation day 1 has been corrected. 
• The timing of the oocyte maturity stage assessment has been expanded. 
• The data collection on follicle size has been simplified leading to omission of average 
follicle size and average size of the 3 largest follicles from the display of follicular 
development. 
• The general term ‘administration device’ has been replaced with the specific term ‘pen’. 
• Neonatal SAEs will be assessed also at 4 weeks after birth. 
• Trial timelines have been updated. 
 
The affected sections, tables, and figures have been revised in accordance with the above changes 
and have been implemented in version 5.0 of the clinical trial protocol.  


Date: 03 Jun 2019
E-Protocol Amendment-23614; Ver. 1.0
Supersedes: None
Page 4 of 4
 
 
 
 
 
 
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Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #02 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SUMMARY OF MAIN CHANGES TO MASTER INFORMED CONSENT FORM: 
The protocol changes summarized on the previous page have been applied in the master informed 
consent form as applicable. In addition, the following revision has been made:  
• Text added to mention that the blood samples taken in connection with anti-MENOPUR 
antibodies may also be used to qualify the antibody assays. 
 
The changes have been implemented in version 3.0 of the master informed consent form.  
 


Date: 14 Oct 2019 
E-Protocol Amendment-23858; Ver.1.0 
Supersedes: None 
Page 1 of 3 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303
Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #03 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
SUMMARY OF CHANGES #03 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program 
Trial 000303 
CLARA 
(Comparison of MENOPUR Liquid and Powder in Women Undergoing ART) 
IND Number: 
053954 
Investigational 
Medicinal Product: 
MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL 
MENOPUR powder and solvent for solution for injection, 75 IU 
Indication: 
Development of multiple follicles and pregnancy in ovulatory women 
undergoing controlled ovarian stimulation as part of an assisted 
reproductive technology (ART) cycle 
Phase: 
3 
Name and Address of 
Sponsor: 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
________________________________________________________________________________ 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. 


Date: 14 Oct 2019 
E-Protocol Amendment-23858; Ver.1.0 
Supersedes: None 
Page 2 of 3 
 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303
Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #03 
Ferring Pharmaceuticals 
CONFIDENTIAL 
DOCUMENT INFORMATION: 
This present document describes the changes made to the clinical trial protocol, version 5.0, dated 
03 June 2019.  
 
IMPLICATIONS OF CHANGE: 
There are no immediate implications to the trial as recruitment has not started.  
The changes do not affect the safety of subjects, scope of investigation, or scientific rigor of the 
trial. The present summary of changes as well as an updated protocol (version 6.0) will be 
submitted to IRBs and approval will be obtained prior to the respective sites starting the trial. The 
revisions are considered administrative changes. 
This protocol update does not have implications for the informed consent form.  


Date: 14 Oct 2019 
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Supersedes: None 
Page 3 of 3 
 
 
 
 
 
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Solution for Injection  
Clinical Trial Protocol Amendment - Summary of Changes #03 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SUMMARY OF MAIN CHANGES TO CLINICAL TRIAL PROTOCOL: 
• It has been clarified that the reduction in GnRH agonist (LEUPROLIDE ACETATE) dose 
from 0.1 mL (500 µg)/day to 0.05 mL (250 µg)/day should occur on stimulation day 1. The 
previous wording “once downregulation has been confirmed” has been considered too 
unspecific and therefore changed to “stimulation day 1”.  
• The template statement on how to record instances of accidental unblinding has been 
customized by removing “(e.g. the subject tells the investigator)” as this scenario is not 
applicable for the present trial with a double-blind, double-dummy design.  
• The request for subjects to return the Subject Participation Card at the end-of-trial visit has 
been omitted in line with revisions made to Ferring’s clinical trial protocol template.  
• The explanation of IMP/NIMP destruction has been deleted, as this process is described in a 
manual outside the protocol.  
• The description of the functions included in the Ferring clinical trial team has been 
expanded to include the field monitors, as monitoring of this trial will be conducted by 
Ferring employees and not a Contract Research Organization.  
• Exclusion criterion 12 has been corrected from UK English spelling (“gonadotrophin”) to 
US English spelling (“gonadotropin”).  
• A typo has been rectified; “MENOPUR powder (including Placebo to MENOPUR 
powder)” has been corrected to “MENOPUR powder (including Placebo to MENOPUR 
liquid)”.  
 
The affected sections and figures have been revised in accordance with the above changes and have 
been implemented in version 6.0 of the clinical trial protocol.  


Date: 19 Mar 2020 
E-Protocol Amendment-24122; Ver.1.0 
Supersedes: None 
Page 1 of 4 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment – Summary of Changes #04 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
SUMMARY OF CHANGES #04 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program 
Trial 000303 
CLARA 
(Comparison of MENOPUR Liquid and Powder in Women Undergoing ART) 
IND Number: 
053954 
Investigational Medicinal Product: 
MENOPUR solution for injection in pre-filled pen, 
1200 IU/1.92 mL 
MENOPUR powder and solvent for solution for 
injection, 75 IU 
Indication: 
Development of multiple follicles and pregnancy in 
ovulatory women undergoing controlled ovarian 
stimulation as part of an assisted reproductive 
technology (ART) cycle 
Phase: 
3 
Name and Address of Sponsor: 
Ferring Pharmaceuticals, Inc. 
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
Tel: 
 
Amendment Number: 
04 
Sites where Effective: 
All trial sites 
Date of Protocol: 
Original: 18 Dec 2017 / Current: 14 Oct 2019 
________________________________________________________________________________ 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or another company 
within the Ferring Group.  


Date: 19 Mar 2020 
E-Protocol Amendment-24122; Ver.1.0 
Supersedes: None 
Page 2 of 4 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment – Summary of Changes #04 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
This Protocol Amendment  
- temporary halt of recruitment and implications for continued trial conduct -  
is issued as urgent safety measures due to COVID-19 required to protect subjects against 
immediate hazard to their health and safety and is implemented immediately  
 
 
DOCUMENT INFORMATION: 
Protocol change intended to eliminate an apparent immediate hazard to subjects. 
 
REASON FOR CHANGE TO THE CLINICAL TRIAL PROTOCOL: 
• The COVID-19 pandemic has caused extensive restrictions on the movement of local 
populations in countries worldwide and recommendations to focus health care resources on 
essential activities only. Subsequently, clinical trial participants are experiencing increased 
difficulty in attending scheduled visits and trial sites are operating at reduced capacity. 
 
• On 17 March 2020, the American Society for Reproductive Medicine (ASRM) issued a 
guidance on patient management and clinical recommendations, including: “Suspend 
initiation of new treatment cycles…. Strongly consider cancellation of all embryo transfers 
whether fresh or frozen… Continue to care for patients who are currently “in-cycle””.  
 
• On 18 March 2020, the Food and Drug Administration (FDA) issued a guidance on conduct 
of clinical trials of medicinal products during the COVID-19 pandemic, including general 
considerations for how to ensure the safety of trial participants, maintain compliance with 
GCP and minimize risks to trial integrity. 
Ferring has conducted a risk assessment, which led to this change to the clinical trial protocol. This 
document outlines the deliberations and decisions.  


Date: 19 Mar 2020 
E-Protocol Amendment-24122; Ver.1.0 
Supersedes: None 
Page 3 of 4 
 
 
 
 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment – Summary of Changes #04 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SUMMARY OF MAIN CHANGES TO CLINICAL TRIAL PROTOCOL: 
Ferring is issuing a temporary halt of recruitment, i.e. a pause of screening and randomization. 
Ferring is issuing guidance for continued trial conduct and management of subjects already 
included in the trial. The table below provides guidance for how to manage the subjects according 
to stage in the trial.  
Temporary halt of recruitment  
Continued trial conduct for management of subjects 
already included in the trial  
• Pause screening 
• Pause randomization 
• Screened subjects (not yet initiated downregulation): 
downregulation will not be initiated; the screening period 
will be extended by the approximate duration of this 
COVID-19 related temporary recruitment halt 
• Subjects in downregulation (not yet randomized):  
stop downregulation and do not proceed to 
randomization; these subjects will be allowed to initiate a 
new downregulation phase when this COVID-19 related 
temporary recruitment halt is lifted   
• Randomized subjects:  
continue per protocol and document any deviations  
 
In case subjects are prevented from attending scheduled visits, the investigator (or designee) will 
attempt to contact the subject by phone or other ways to inquire about potential adverse events and 
changes to concomitant medication. 
 
IMPLICATIONS OF CHANGE: 
The implications of these changes to the protocol are summarized below. The actions are 
considered urgent safety measures due to COVID-19 required to protect subjects against immediate 
hazard to their health and safety and are therefore implemented immediately.  
 
• Trial sites, regulatory authorities and independent research boards will be informed.  
• Subjects will be verbally informed by the investigator of potential changes to the course of 
action, as applicable for the individual subject. This will be documented in the subject’s 
medical records. 


Date: 19 Mar 2020 
E-Protocol Amendment-24122; Ver.1.0 
Supersedes: None 
Page 4 of 4 
 
 
 
 
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Trial Code: 000303 
Solution for Injection  
Clinical Trial Protocol Amendment – Summary of Changes #04 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Protocol deviations (including deviations to the aspects described in this ‘change to 
protocol’) should be avoided whenever possible except where necessary to eliminate an 
immediate hazard to the subject. If deviations occur they will be documented as per 
standard practice, with additional specification whether they were related to the COVID-19 
situation.  
• Ferring will continuously monitor the situation and will lift the temporary halt of 
recruitment (screening and randomization) and resume the trial activities as per protocol 
when it is judged that the situation allows for this. Ferring will notify sites, regulatory 
authorities and independent research boards accordingly.  

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Cover page for Statistical Analysis Plan 
 
 
Sponsor name 
Ferring Pharmaceuticals Inc. 
NCT Number: 
NCT04163458 
Sponsor trial ID: 
000303 
Official title of trial: 
A randomized, double-blind double-dummy trial 
comparing MENOPUR solution for injection in a pre-
filled pen and MENOPUR powder and solvent for 
solution for injection (menotropins for injection) in a 
GnRH agonist cycle in women aged 18-42 years 
undergoing an assisted reproductive technology 
program 
Document Date:  
17 Aug 2021 
 
 
 
 
 


Date: 17 Aug 2021 
E-Statistical Analysis Plan-24512; Ver. 2.0 
Supersedes: None 
Page 1 of 45 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind double-dummy trial comparing MENOPUR solution for 
injection in a pre-filled pen and MENOPUR powder and solvent for solution for injection 
(menotropins for injection) in a GnRH agonist cycle in women aged 18-42 years undergoing 
an assisted reproductive technology program  
000303 
Investigational Product: 
MENOPUR solution for injection in pre-filled pen, 
1200 IU/1.92mL 
MENOPUR powder and solvent for solution for injection, 
75 IU 
Indication: 
Development of multiple follicles and pregnancy in ovulatory 
women undergoing controlled ovarian stimulation as part of 
an assisted reproductive technology (ART) cycle 
Phase: 
3 
Author: 
 Ph.D. 
Date: 
17 Aug 2021 
Version: 
2.0 
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 


Date: 17 Aug 2021 
E-Statistical Analysis Plan-24512; Ver. 2.0 
Supersedes: None 
Page 2 of 45 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Change log 
Version 
No. 
Effective 
Date 
Reason for the Change / Revision 
Supersedes 
1.0 
31 Aug 
2020 
Original version 
None 
2.0 
17 Aug 
2021 
The following describes the changes that have been made to 
the SAP between versions 1.0 and 2.0. 
The following edits were made to correct mistakes in V1.0 
of the SAP. 
•
Transfer policy deviations will not be considered
during the assessment of major or minor deviations.
Because transfer occurs after the primary endpoint
assessment, a transfer policy deviation cannot
impact the primary endpoint.
•
There were cases where “Stimulation Day 5” was
used. These cases have been updated to reflect that
measurement occurs on “Stimulation Day 6”.
•
In V1.0 of the SAP, for the multiple imputation
sensitivity analysis, the imputation model (negative
binomial) and the analysis model (ANOVA) did not
align. In V2.0 of the SAP, the imputation model has
been changed to align to the analysis model (both
are now an ANOVA model).
The following edits were made to clarify the original intent 
of SAP V1.0. 
•
For a subset of inferences, the within-treatment
group 95% confidence intervals (adjusted for
stratification factors) will be displayed. The subset
of inferences is now better defined in V2.0 of the
SAP.
•
If the Safety analysis set is identical to the mITT
analysis set, tables based on the mITT analysis set
will be produced. (The identical tables based on the
Safety analysis set will be suppressed.)
•
Trial population, efficacy, and safety summaries will
be produced that are broken out by age strata.
1.0 


Date: 17 Aug 2021 
E-Statistical Analysis Plan-24512; Ver. 2.0 
Supersedes: None 
Page 3 of 45 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
•
Presentation of NIMPs taken prior to randomization
will include a summary for all subjects exposed,
whether or not they were randomized.
•
A listing of protocol deviations due to COVID-19
will be included.
•
In V1.0 of the SAP, the primary endpoint model was
described as a ‘linear model’. In V2.0 of the SAP,
the primary endpoint model has been explicitly
defined as an ANOVA model.
•
In V1.0 of the SAP, the analysis method for the
secondary pregnancy endpoints and any other
dichotomous endpoint was omitted. In V2.0 of the
SAP, these secondary efficacy analyses have been
defined to use the Mantel-Haenszel method.
•
In several sections, the presentation of subgroup
summaries is requested. V2.0 of the SAP clarifies
that these subgroups begin with the mITT analysis
set prior to subsetting. Inference is performed on
complete analysis sets and not on subgroups.
•
The categories for the frequency table summary of
the number of 2PN and the number of MII have
been aligned with the same for oocytes retrieved.
•
The analysis of inseminated oocytes has been
removed as this was never listed as an endpoint.
•
Additional details have been added for the modeling
of change from baseline in endocrine laboratory
parameters.
•
Ranges for markedly abnormal vital signs and
laboratory parameters have been added as an
appendix.
•
The production of within-treatment group Clopper-
Pearson confidence intervals for the proportion of
anti-MENOPUR antibodies has been added in V2.0
of the SAP.
•
Early pregnancy losses are now described as a
subgroup display within the Safety section. This had
previously been in the Efficacy section.
•
Added summaries of AEs and ADRs that occur in at
least 2% of subjects.
•
Additional details have been added regarding the
summary and analysis of post-trial endpoints.
Additionally, the following minor edits have been made: 
•
The SAP reviewers have been updated.
•
Minor typos have been corrected throughout.


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Agreement on Statistical Analysis Plan 
Author:  
 
 
Biostatistics 
Ferring Pharmaceuticals, Inc. 
Reviewers: 
 
 
Statistical Programming 
Ferring Pharmaceuticals, Inc. 
 
 
US Pharmacovigilance 
Ferring Pharmaceuticals, Inc. 
 
 
Global Medical Writing 
Ferring Pharmaceuticals, A/S 
 
 
Reproductive Health and Urology, Clinical Development 
Ferring Pharmaceuticals, Inc. 
 
 
Reproductive Medicine and Maternal Health 
Ferring Pharmaceuticals, Inc. 
 
 
Clinical Operations 
Ferring Pharmaceuticals, Inc. 
 
 
Clinical Operations 
Ferring Pharmaceuticals, Inc. 
Approval: 
 
 
Biometrics 
Ferring Pharmaceuticals, Inc. 


Date: 17 Aug 2021 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................................... 8 
1.1 
Definitions/ Abbreviations ........................................................................................................ 8 
1.1.1 
Definition of Terms ................................................................................................... 8 
1.1.2 
Abbreviations ............................................................................................................ 8 
1.2 
Presentation of results.............................................................................................................. 10 
1.2.1 
Presentation of descriptive results ........................................................................... 10 
1.2.2 
Presentation of inferential results ............................................................................ 10 
1.2.3 
Subject data listings by domain .............................................................................. 10 
2 
Trial Objectives and Endpoints ........................................................................................................ 11 
2.1 
Objectives ................................................................................................................................ 11 
2.2 
Endpoints ................................................................................................................................. 11 
3 
Trial design ......................................................................................................................................... 14 
3.1 
General Design Considerations ............................................................................................... 14 
3.2 
Sample Size ............................................................................................................................. 15 
4 
Subject Disposition ............................................................................................................................. 17 
5 
Protocol Deviations ............................................................................................................................ 18 
6 
Analysis sets ........................................................................................................................................ 19 
6.1 
Intention-to-Treat Analysis Set ............................................................................................... 19 
6.2 
Modified Intention-to-Treat Analysis Set................................................................................ 19 
6.3 
Per Protocol Analysis Set ........................................................................................................ 19 
6.4 
Safety Analysis Set .................................................................................................................. 19 
7 
Trial Population .................................................................................................................................. 20 
7.1 
Display of Trial Population Characteristics............................................................................. 20 
7.2 
Demographics .......................................................................................................................... 20 
7.3 
Medical History ....................................................................................................................... 20 
7.4 
Menstrual History .................................................................................................................... 20 
7.5 
Reproductive History............................................................................................................... 20 
7.6 
Infertility History ..................................................................................................................... 21 
7.7 
Vital Signs ............................................................................................................................... 21 
7.8 
Physical Examination .............................................................................................................. 21 
7.9 
Endocrine Parameters .............................................................................................................. 22 
7.10 
Gynecological Examination .................................................................................................... 22 
7.11 
Follicles ................................................................................................................................... 22 
7.12 
Endometrial Thickness ............................................................................................................ 22 
7.13 
Prior and Concomitant Medication.......................................................................................... 22 
8 
Exposure and Treatment Compliance .............................................................................................. 23 
8.1 
Extent of Exposure .................................................................................................................. 23 
8.1.1 
IMP ......................................................................................................................... 23 
8.1.2 
NIMPs ..................................................................................................................... 23 
8.1.3 
Treatment Compliance ............................................................................................ 24 
9 
Efficacy ................................................................................................................................................ 25 
9.1 
General Considerations ........................................................................................................... 25 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
9.1.1 
Analysis Sets ........................................................................................................... 25 
9.1.2 
Analysis Methods .................................................................................................... 25 
9.2 
Primary Endpoint..................................................................................................................... 25 
9.2.1 
Primary Endpoint Analysis ..................................................................................... 25 
9.2.2 
Sensitivity Analyses ................................................................................................ 26 
9.3 
Secondary Efficacy Endpoints ................................................................................................ 28 
9.3.1 
Positive βhCG Rate ................................................................................................. 28 
9.3.2 
Clinical Pregnancy Rate .......................................................................................... 28 
9.3.3 
Ongoing Pregnancy Rate ........................................................................................ 28 
9.3.4 
Number and Size of Follicles During Stimulation .................................................. 28 
9.3.5 
Levels of Endocrine Parameters.............................................................................. 29 
9.3.6 
Number of Oocytes Retrieved ................................................................................. 29 
9.3.7 
Number of Metaphase II Oocytes ........................................................................... 29 
9.3.8 
Fertilization Rate ..................................................................................................... 30 
9.3.9 
Number and Quality of Blastocysts on Day 5 ......................................................... 30 
10 
Safety ................................................................................................................................................... 32 
10.1 
General Considerations ........................................................................................................... 32 
10.1.1 
Imputation rules ...................................................................................................... 32 
10.2 
Safety endpoints ...................................................................................................................... 32 
10.2.1 
Adverse Events ....................................................................................................... 32 
10.2.1.1 
Overview of Treatment Emergent Adverse Events ............................ 33 
10.2.1.2 
Incidence of Adverse Events .............................................................. 33 
10.2.2 
OHSS ...................................................................................................................... 34 
10.2.3 
Early Pregnancy Loss .............................................................................................. 34 
10.2.4 
Injection Site Reactions .......................................................................................... 34 
10.2.5 
Treatment-induced Anti-MENOPUR Antibodies ................................................... 35 
10.2.6 
Technical Malfunction of the Pen ........................................................................... 35 
10.2.7 
Vital Signs ............................................................................................................... 35 
10.2.7.1 
Summary Statistics ............................................................................. 35 
10.2.7.2 
Changes Relative to Normal Range .................................................... 35 
10.2.7.3 
Markedly Abnormal Changes ............................................................. 35 
10.2.7.4 
Data Listings ....................................................................................... 35 
10.2.8 
Physical Examination .............................................................................................. 35 
10.2.9 
Gynecological Examination .................................................................................... 35 
10.2.10 
Safety Laboratory Variables ................................................................................... 36 
10.2.10.1 
Summary Statistics ............................................................................. 36 
10.2.10.2 
Changes Relative to Normal Range .................................................... 36 
10.2.10.3 
Markedly Abnormal Changes ............................................................. 36 
10.2.10.4 
Data Listings ....................................................................................... 36 
11 
Post-trial Assessments ........................................................................................................................ 37 
11.1 
Live Birth Rate ........................................................................................................................ 37 
11.2 
Late Pregnancy Loss................................................................................................................ 37 
11.3 
Neonatal Health ....................................................................................................................... 37 
12 
Interim analyses .................................................................................................................................. 38 
13 
Deviations from the protocol ............................................................................................................. 39 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
14 
Tables, Listings and Figures .............................................................................................................. 40 
15 
References ........................................................................................................................................... 41 
Appendix 1 ..................................................................................................................................................... 42 
Appendix 2 ..................................................................................................................................................... 45 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
1 
Introduction 
This document describes the planned statistical analyses for Trial 000303 based on the protocol 
Version 6.0 dated 14 Oct 2019.  
1.1 
Definitions/ Abbreviations 
1.1.1 
Definition of Terms 
Terms 
Definitions 
Baseline 
The last available assessed value prior to the first exposure to IMP. 
1.1.2 
Abbreviations 
Abbreviations 
Meaning of abbreviations in document 
AE 
Adverse Event 
AMH 
Anti-Müllerian Hormone 
ART 
Assisted Reproductive Technology 
ATC 
Anatomic Therapeutic Chemical 
βhCG 
Beta-Human Chorionic Gonadotropin 
BMI 
Body Mass Index 
CRF 
Case Report Form 
E2 
Estradiol 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GnRH 
Gonadotropin-releasing Hormone 
hCG 
Human Chorionic Gonadotropin 
ICSI 
Intracytoplasmic Sperm Injection 
IMP 
Investigational Medicinal Product 
ITT 
Intention-To-Treat 
IU 
International Unit 
IUI 
Intrauterine Insemination 
LH 
Luteinizing Hormone 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-To-Treat 
NIMP 
Non-Investigational Medicinal Product 
OI 
Ovulation Induction 
P4 
Progesterone 
PP 
Per-Protocol 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 
ULOQ 
Upper Limit of Quantification 
WHO 
World Health Organization 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
1.2 
Presentation of results 
1.2.1 
Presentation of descriptive results 
Categorical data will be summarized, unless otherwise stated, using the frequency (n) and relative 
frequencies as a percentage (i.e.; 100*n/N). 
Continuous data will be presented for observed values, unless otherwise stated, using the number of 
subjects (N), number of observations (n), mean and standard deviation (SD), median and 
interquartile range (IQR), and range (minimum to maximum). 
1.2.2 
Presentation of inferential results 
Inferential results will include confidence intervals for the treatment difference. For a subset of 
analyses, a within-treatment group confidence interval will be presented. 
1.2.3 
Subject data listings by domain 
Individual subject data will be presented in listings in accordance to ICH E3. Included will be 
listings of: 
•
Discontinued subjects
•
Protocol deviations
•
Subjects excluded from the efficacy analysis
•
Demographic data
•
Non-investigational medicinal product (NIMP) and investigational medicinal product (IMP)
use (with indication of compliance and concentration)
•
Individual efficacy response data
•
Adverse events by subject (with indication of deaths and serious adverse events [SAEs])
•
Individual laboratory measurements by subject (with indication of abnormal values)


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
2 
Trial Objectives and Endpoints 
2.1 
Objectives 
Primary Objective 
•
To demonstrate non-inferiority of MENOPUR liquid versus MENOPUR powder with
respect to the number of fertilized oocytes in women undergoing controlled ovarian
stimulation.
Secondary Objectives 
•
To evaluate the pregnancy rates after stimulation with MENOPUR liquid and MENOPUR
powder.
•
To evaluate the follicular development during stimulation with MENOPUR liquid and
MENOPUR powder.
•
To evaluate the serum endocrine profile during stimulation with MENOPUR liquid and
MENOPUR powder.
•
To evaluate the number of oocytes retrieved, the number and quality of embryos, and the
number and quality of blastocysts, associated with MENOPUR liquid and MENOPUR
powder.
•
To evaluate treatment efficiency of MENOPUR liquid and MENOPUR powder.
•
To evaluate the safety profile of MENOPUR liquid and MENOPUR powder, including
adverse events, routine safety laboratory parameters, local tolerability and immunogenicity.
2.2 
Endpoints 
Primary Endpoint 
•
Number of fertilized (2 pronuclei [2PN]) oocytes at 19±2 hours after insemination.
Secondary Endpoints 
•
Positive βhCG rate (positive βhCG test 10-14 days after blastocyst transfer).
•
Clinical pregnancy rate (transvaginal ultrasound showing at least 1 intrauterine gestational
sac with fetal heart beat 5-6 weeks after blastocyst transfer).
•
Ongoing pregnancy rate (at least one intrauterine viable fetus 8-9 weeks after blastocyst
transfer).


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Ferring Pharmaceuticals 
CONFIDENTIAL 
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Trial Code: 000303  
Statistical Analysis Plan 
• Early pregnancy loss (defined as a positive βhCG test but no ongoing pregnancy at 8-9 
weeks after blastocyst transfer). 
• Follicular development as assessed by transvaginal ultrasound on stimulation day 6 and last 
day of stimulation. 
• Endocrine profile: 
o Serum follicle-stimulating hormone (FSH) on day 6, last day of stimulation and at 
oocyte retrieval, and corresponding population pharmacokinetics (PK) analysis. 
o Serum Anti-Müllerian hormone (AMH) on last day of stimulation and at end-of-trial. 
o Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) on day 6 and 
last day of stimulation. 
o Estradiol (E2) and progesterone (P4) on day 6 and last day of stimulation. 
• Number of oocytes retrieved, number of metaphase II oocytes, fertilization rate, and number 
and quality of blastocysts 5 days after oocyte retrieval. 
• Total gonadotropin dose and number of stimulation days. 
• Frequency of OHSS (early OHSS if the onset is ≤9 days after triggering of final follicular 
maturation and late OHSS if the onset is >9 days after triggering of final follicular 
maturation). 
• Frequency and intensity of adverse events. 
• Changes in circulating levels of clinical chemistry and hematology parameters and 
proportion of subjects with markedly abnormal changes. 
• Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject during the stimulation period. 
• Frequency of treatment-induced anti-MENOPUR antibodies, overall as well as with 
neutralizing capacity. 
• Technical malfunctions of the pen. 
Post-trial Endpoints 
• Live birth rate. 
• Late pregnancy loss rate (defined as an ongoing pregnancy but no live birth). 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
•
Neonatal health including SAEs at birth, and SAEs at 4 weeks and minimum 6 months after
birth.


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
3 
Trial design 
3.1 
General Design Considerations 
Overview of Design Elements 
This is a phase 3, randomized, double-blind double-dummy, parallel-group, multicenter non-
inferiority trial. Approximately 400 females aged 18-42 years undergoing controlled ovarian 
stimulation as a part of a gonadotropin-releasing hormone (GnRH) agonist protocol at infertility 
centers in the US will be randomized 1:1 to receive either MENOPUR liquid (including Placebo to 
MENOPUR powder) or MENOPUR powder (including Placebo to MENOPUR liquid). 
Randomization will be stratified by trial site and age strata (<35 years and ≥35 years). 
The primary endpoint is the number of fertilized oocytes. Positive βhCG, clinical pregnancy and 
ongoing pregnancy are included as secondary endpoints in the trial. The secondary endpoints also 
cover commonly investigated pharmacodynamic parameters such as endocrine profile and ovarian 
response as well as standard evaluations of safety profile. Furthermore, oocyte and embryo quality 
will be assessed and a detailed evaluation of blastocyst quality is also included in the trial. 
A blinded sample size reassessment will be done when data on the primary endpoint are available 
for 70% of the planned subjects or when 300 subjects are randomized, whichever comes first. The 
number of randomized subjects may be adjusted up to a maximum of 500 subjects, corresponding to 
a blinded one-sample standard deviation estimate of 5.8 and 85% power. No interim analyses 
intended to compare treatment groups with respect to efficacy or safety are planned. 
Subjects are followed through the assessment of ongoing pregnancy. Post-trial follow-up extends to 
collection of delivery information (live birth and neonatal health), which will be collected for all 
subjects with an ongoing pregnancy. In addition, data on neonatal SAEs will be collected at 4 weeks 
and minimum 6 months after birth. Subjects with a treatment-induced anti-MENOPUR antibody 
response will be followed until the response has become negative or returned to the pre-dosing 
level, or for a maximum of 1 year. 
Additional Design Considerations 
Within 3 days of downregulation confirmation (serum E2 ≤20 pg/mL [central laboratory] and 
transvaginal ultrasound showing no ovarian cysts), subjects will be randomized to receive either 
MENOPUR liquid (including Placebo to MENOPUR powder) or MENOPUR powder (including 
Placebo to MENOPUR liquid) initiated at 225 international units (IU) for 5 days. From stimulation 
day 6 onward, based on follicular response assessed by transvaginal ultrasound, dosing can be 
adjusted every second day as needed by 75 IU per adjustment. However, the maximum 
gonadotropin dose will be 450 IU/day and the minimum dose will be 75 IU/day; gonadotropin 
dosing can continue for a maximum of 20 days, and coasting is not allowed. 
Oocyte retrieval will take place 36±2 hours after triggering of final follicular maturation, and 
oocytes will be inseminated by intracytoplasmic sperm injection (ICSI) 4±2 hours after retrieval; 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
oocyte maturity will be recorded. Fertilization (number of pronuclei) will be assessed 19±2 hours 
following ICSI. Blastocyst quality will be assessed on day 5 following oocyte retrieval. 
All subjects will have single blastocyst transfer if they have at least one good-quality (i.e. grade 
3BB or above) blastocyst available on day 5 following oocyte retrieval. If no good-quality 
blastocyst is available, they may have double blastocyst transfer, if at least two blastocysts are 
available. Transfer of day 6 (or later) blastocyst(s) is not allowed. 
Blood samples will be collected throughout the trial for the purpose of evaluating the endocrine 
profile, clinical chemistry and hematology parameters as well as anti-MENOPUR antibodies. 
Endocrine parameters (FSH, LH, hCG, E2 and P4) are assessed at baseline (E2 at confirmation of 
downregulation and FSH, LH, hCG and P4 on stimulation day 1), day 6, and at end-of-stimulation 
(day of trigger), and furthermore, FSH is also assessed at oocyte retrieval. In addition, AMH is 
assessed on stimulation day 1, on the last day of stimulation, and at end-of-trial. Clinical chemistry 
and hematology are assessed at screening, last day of stimulation, and end-of-trial. Anti-
MENOPUR antibodies are assessed at four occasions. The first sample is taken at the screening 
visit and is exclusively used to re-establish the anti-drug antibody analytical assays. The subsequent 
three samples are used for analysis of anti-MENOPUR antibodies in the individual subjects in the 
trial, and are taken prior to dosing on stimulation day 1 and at two occasions post-dosing: 7-10 days 
after the last MENOPUR liquid or MENOPUR powder dose (this may coincide with the transfer 
visit) and 21-28 days after the last MENOPUR liquid or MENOPUR powder dose (this may 
coincide with the βhCG test visit). Subjects with a treatment-induced anti-MENOPUR antibody 
response will be followed until the response has become negative or returned to the pre-dosing 
level. 
Local tolerability of MENOPUR liquid or MENOPUR powder following subcutaneous 
administration will be assessed by the subject three times daily: immediately, 30 minutes and 24 
hours after each injection. The assessment of injection site reactions will be made throughout the 
stimulation period and recorded by the subject in a diary. 
Concerning post-trial follow-up, all subjects with an ongoing pregnancy will be followed. Data will 
be gathered on delivery information (live birth and neonatal health). In addition, data on neonatal 
SAEs will be collected at 4 weeks and minimum 6 months after birth. 
3.2 
Sample Size 
The present trial is a pharmacodynamic comparison of a marketed product to a new formulation of 
the same. With 188 subjects per treatment group, the trial has at least 85% power to demonstrate the 
non-inferiority of MENOPUR liquid to MENOPUR powder in the number of fertilized oocytes at 
the 1-sided significance level of 0.025. This is based on the results for MENOPUR powder from the 
COMBINE trial (data on file) conducted in a similar setting (GnRH agonist protocol, MENOPUR 
starting dose of 225 IU for the first five days, insemination by ICSI etc.) and in a similar population 
(infertile women between 18 and 42 years). The mean (SD) of the number of fertilized oocytes were 
7.88 (5.15) with similar results in the two age groups (7.92 in the <35 years age group vs. 7.80 in 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
the ≥35 years age group). The non-inferiority margin of -1.60 will retain 80% of the expected 
comparator effect. 
After adjusting for 5% missing data, approximately 400 subjects will be randomized (1:1) into this 
trial, stratified by trial site and age (<35 years and ≥35 years). 
A blinded sample size reassessment will be done when data on the primary endpoint are available 
for 70% of the planned subjects or when 300 subjects are randomized, whichever comes first. The 
sample size reassessment will be done without breaking the blind and without inflating the type I 
error of the trial, in line with current regulatory guidelines. The expected maximum number of 
subjects to be randomized is 500 (250 subjects per treatment group), corresponding to a blinded 
one-sample (both groups pooled) standard deviation estimate of 5.8 and 85% power. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
4 
Subject Disposition 
All subjects screened will be accounted for. The number of subjects screened but not randomized to 
treatment will be presented with the reason for screen failure. 
Subject disposition with respect to each analysis set will be tabulated. The number of subjects in the 
intention-to-treat (ITT) analysis set will be used as the denominator when calculating percentages. 
Randomized subjects, randomized subjects treated with investigational medicinal product (IMP; 
MENOPUR liquid including Placebo to MENOPUR powder or MENOPUR powder including 
Placebo to MENOPUR liquid), and randomized subjects prematurely discontinued from the trial 
will be summarized. Randomized subjects prematurely discontinued from the trial will have the 
reason for premature discontinuation summarized. 
Subject disposition with respect to the start of the COVID-19 pandemic trial hold will be tabulated 
and listed using the ITT analysis set. Subject disposition will be summarized by whether a subject 
had exited the trial before or after the start of the COVID-19 pandemic trial hold. Of the subjects 
that had not yet exited the trial, the subject status (i.e.; not yet recruited, in screening, or 
randomized) will be summarized.  
Subjects that were in screening but had not yet been randomized prior to the COVID-19 pandemic 
trial hold were considered screen failures. Subjects that were screen failed due to the COVID-19 
pandemic trial hold could re-enter the trial, beginning again the screening process. All subjects that 
were screen failed due to the COVID-19 pandemic trial hold will be listed along with an indicator 
of whether the subject re-entered the trial or not. Those subjects that re-entered the trial will have 
two screening identification numbers. Both identification numbers will be included in the listing. 
For subjects that were already randomized but had not yet exited the trial at the start of the COVID-
19 pandemic trial hold, the last visit completed prior to the trial hold will be summarized. 
A detailed listing of selected trial assessments will be created. Included will be an indicator of 
whether the corresponding visit took place, an indicator of whether the visit was expected to occur 
before, during, or after the COVID-19 pandemic trial hold, and an indicator of whether the 
missingness was due to the COVID-19 pandemic. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
5 
Protocol Deviations 
The rating of protocol deviations as ‘minor’ and ‘major’, as well as the criteria for major protocol 
deviations with the implication of exclusions from the per-protocol (PP) analysis set will be decided 
on the basis of a blinded review of data before declaration of clean file and lock of database. 
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release. Major protocol deviations will be summarized and listed by subject. 
Major protocol deviations, such as significant non-compliance with the IMP regimen, NIMP 
regimens, or other serious unforeseen deviations that may affect the conclusions for the primary 
endpoint of the trial, will lead to exclusion of data from the PP analysis set. Other protocol 
deviations will not lead to the exclusion from the PP analysis set.  
Protocol deviations due to COVID-19 will be listed. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
6 
Analysis sets 
6.1 
Intention-to-Treat Analysis Set 
The intention-to-treat (ITT) analysis set comprises of all randomized (as planned) subjects. 
6.2 
Modified Intention-to-Treat Analysis Set 
The modified intention-to-treat (mITT) analysis set comprises all randomized (as planned) subjects 
who received at least 1 dose of IMP (MENOPUR liquid including Placebo to MENOPUR powder 
or MENOPUR powder including Placebo to MENOPUR liquid).  
6.3 
Per Protocol Analysis Set 
The per protocol (PP) analysis set comprises all mITT subjects except those excluded as a result of 
major protocol deviations.  
6.4 
Safety Analysis Set 
The safety analysis set comprises all treated subjects and is analyzed according to the actual 
treatment received. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
7 
Trial Population 
7.1 
Display of Trial Population Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented by 
treatment group as detailed in Section 1.2.1 for the subjects in the mITT, PP, and Safety analysis 
sets, unless otherwise noted. In the case that the Safety analysis set is identical to the mITT analysis 
set, presentations will use the mITT and PP analysis sets.  Summaries will be made using all 
subjects, subjects in the <35 years age strata, and subject in the ≥35 years age strata. 
In the case of multiple assessments prior to the first exposure to IMP, the baseline value is defined 
as described in Section 1.1.1. 
All demographic and baseline characteristics will also be presented in listings. Listings will be 
produced for the mITT analysis set only. 
Unless otherwise noted, missing data will not be imputed. 
7.2 
Demographics 
Descriptive statistics of baseline demographic variables (e.g.; race and ethnic origin, height, weight, 
BMI, and age at randomization) will be tabulated.  
In addition, for age strata and trial site, the as-randomized stratification factors (according to the 
actual randomization) and the actual stratification factors (according to the eCRF demographic 
data), will also be summarized. 
7.3 
Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) using the version effective at trial start or later. The version of MedDRA will be 
documented. Medical history will be tabulated by System Organ Class sorted alphabetically and 
Preferred Term sorted in decreasing order of frequency. Medical history will only be tabulated for 
the mITT analysis set. 
Medical history will be listed by treatment group and subject number for the mITT analysis set. 
7.4 
Menstrual History 
The average duration of the menstrual cycle (days) will be tabulated. 
7.5 
Reproductive History 
The following data on reproductive history following natural conception obtained at the screening 
visit will be tabulated: Number of subjects with at least one previous clinical pregnancy, number of 
clinical pregnancies per subject, number of subjects with at least one live birth, and number of live 
births per subject. In addition, the number of fetuses on a clinical pregnancy level and the outcome 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
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Trial Code: 000303  
Statistical Analysis Plan 
on a fetus level (live birth, still birth, ectopic pregnancy, miscarriages by trimester, and 
terminations) will be tabulated. 
Information on reproductive history will be listed by treatment group, subject number and previous 
clinical pregnancy from natural conception number for the mITT analysis set. 
7.6 
Infertility History 
The following data on infertility history obtained at the screening visit will be tabulated: The 
primary reason for infertility, (all applicable) reasons for infertility, and duration of infertility 
(months). 
The following data on previous fertility treatment cycles obtained at the screening visit will be 
tabulated: Number of subjects with at least one previous fertility treatment cycle, number of 
previous fertility treatment cycles per subject, number of subjects with at least one positive βhCG, 
number of positive βhCG per subject, number of subjects with at least one clinical pregnancy, 
number of clinical pregnancies per subject, number of subjects with at least one live birth, number 
of live births per subject. In addition, the type of treatment (OI/IUI/Both, assisted reproductive 
technology [ART]), and medications used on the cycle level, the number of fetuses on the clinical 
pregnancy level and the outcome on the fetus level (live birth, still birth, ectopic pregnancy, 
miscarriages by trimester, and terminations) will be tabulated. 
Information on previous fertility treatment cycles will be listed by treatment group, subject number, 
and previous fertility cycle number for the mITT analysis set. The listing will include information 
on the start date, type of treatment, medication used, βhCG assessment, clinical pregnancy 
assessment, and outcome for each fetus. 
7.7 
Vital Signs 
Blood pressure (systolic and diastolic), pulse, and temperature measured on stimulation day 1 will 
be summarized. 
Vital signs on stimulation day 1 will be listed as part of the safety listings (Section 10.2.7.4). 
7.8 
Physical Examination 
Each category of the physical examination is evaluated as normal, abnormal not clinically 
significant, abnormal clinically significant, or not done.  Physical examinations at screening will be 
summarized by category. 
Physical examinations with abnormal findings at screening will be listed as part of the safety 
listings (Section 10.2.8). 


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Statistical Analysis Plan 
7.9 
Endocrine Parameters 
Blood samples will be collected for analysis of the following endocrine parameters: AMH, FSH, 
hCG, LH, E2, and P4. The baseline values will be calculated as described in Section 1.1.1 and 
summarized as described in Section 1.2.1. 
Endocrine parameters will be listed as part of the safety listings (Section 10.2.10.4). 
7.10 
Gynecological Examination 
Each category of the gynecological examination is evaluated as normal, abnormal not clinically 
significant, or abnormal clinically significant. Gynecological examination at screening will be 
summarized by category. 
Gynecological examination with abnormal findings will be listed as part of the safety listings 
(Section 10.2.9). 
7.11 
Follicles 
The number of follicles at baseline will be summarized. 
7.12 
Endometrial Thickness 
The endometrial thickness at baseline will be summarized. 
7.13 
Prior and Concomitant Medication 
Prior and concomitant medication will be coded using the World Health Organization (WHO) Drug 
Reference List. They will be summarized by Anatomic Therapeutic Chemical (ATC) classification 
1st level (alphabetically) and ATC classification 2nd level (in decreasing order of frequency). These 
medications will be tabulated separately for: 
1) Prior medication; i.e. medication taken exclusively prior to treatment (i.e.; with stop 
date/time before date/time of first IMP administration); 
2) Concomitant medication; i.e. medication taken during the treatment period (i.e.; medication 
that was not stopped before date/time of first IMP administration and not started after the 
end of trial). 
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication. 
Prior and concomitant medication will be listed by treatment group and subject number for the 
mITT analysis set. 
 


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8 
Exposure and Treatment Compliance 
Summaries will be produced for the mITT, PP, and Safety analysis sets. In the case that the Safety 
analysis set is identical to the mITT analysis set, presentations will use the mITT and PP analysis 
sets. For NIMP used prior to randomization (i.e.; oral contraceptives and GnRH agonist), a 
summary will be created that uses all screened subjects that received the corresponding NIMP.  
8.1 
Extent of Exposure 
For any IMP or NIMP, duration of treatment (days) is defined as the number of days from first 
exposure to the day of last exposure (both inclusive). 
Listings associated with the IMP and NIMP summaries will be presented. 
8.1.1 
IMP 
Exposure to MENOPUR liquid or MENOPUR powder will be summarized by treatment group as 
the duration of stimulation, the total dose, the maximum and minimum daily doses, and the average 
daily dose defined as the total dose administered divided by the number of stimulation days. 
Frequency tables will be included to describe the duration of treatment by categories (<7, 7-8, 9-10, 
11-12, and ≥13 days).
Investigator-requested decreases and increases of the IMP dose will be captured during the 
stimulation period. The requested dose change (decrease / increase / no change) on stimulation day 
6 will be tabulated. Furthermore, the total number of dose increase requests and dose decrease 
requests per subject will be tabulated. 
8.1.2 
NIMPs 
Oral Contraceptives 
The total dose and duration of treatment will be summarized. 
GnRH Agonist 
The total dose and duration of treatment will be summarized. In addition, the summary of the 
starting day of the GnRH agonist, relative to the last day of oral contraceptive use, will be 
presented. 
hCG 
The number of subjects that had hCG administered as well as the total dose administered for those 
subjects that had hCG administered will be summarized. 
Luteal Phase Support 


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The total dose, average total daily dose, the duration of treatment, and the number of subjects that 
stopped due to menstrual bleeding will be summarized. 
8.1.3 
Treatment Compliance 
Subjects that deviate from the planned treatment will be listed, including non-compliance to both 
IMP and NIMP. 


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Statistical Analysis Plan 
9 
Efficacy 
9.1 
General Considerations 
The presentation of results for each analysis set will proceed as outlined in Section 1.2. Summaries 
will be made using all subjects, subjects in the <35 years age strata, and subject in the ≥35 years age 
strata. 
9.1.1 
Analysis Sets 
All primary and secondary efficacy analyses will be conducted for the mITT analysis set. 
Furthermore, for the primary endpoint, sensitivity analyses will be conducted for the PP and ITT 
analysis sets as appropriate.  
9.1.2 
Analysis Methods 
Because randomization is stratified by age strata and center, all statistical analyses of efficacy 
endpoints will incorporate fixed effects for both age strata and center. Except when specifically 
stated otherwise, all confidence intervals will be 2-sided 95% confidence intervals. 
For the primary endpoint and other continuous secondary endpoints (excluding endocrine labs), an 
ANOVA model will be used and, in SAS, the confidence interval for the treatment difference may 
be produced either through an LSMEANS statement (with the PDIFF option) or an appropriately 
formulated ESTIMATE statement. Within-treatment group confidence intervals will also be 
produced using an LSMEANS statement. 
For secondary pregnancy endpoints and other binary secondary endpoints, the Mantel-Haenszel 
method will be used to combine risk differences across the age strata and center stratification 
variables to produce the common risk difference. The common risk difference and associated 
confidence interval will be reported. 
Recruitment within strata will be assessed. In the case where one or more strata have too small of a 
membership to perform inference, centers will be pooled together. Centers with the smallest 
membership will be pooled together into one or more pooled centers until inference is possible, 
taking care that no pooled center contains a membership larger than the median enrollment among 
the remaining centers and the pooled center(s). 
9.2 
Primary Endpoint 
The primary endpoint is defined as the number of fertilized (2 pronuclei [2PN]) oocytes at 19±2 
hours after insemination. In addition to the primary endpoint analysis, a frequency table with 
subjects grouped according to their number of fertilized oocytes will be prepared using these 
categories: ≤2, 3-5, 6-10, 11-15, and ≥16 2PN. 
9.2.1 
Primary Endpoint Analysis 
The primary objective of the trial is to demonstrate the non-inferiority of MENOPUR liquid versus 
MENOPUR powder with respect to the number of fertilized oocytes in women undergoing 


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controlled ovarian stimulation. The null hypothesis is that MENOPUR liquid is inferior to 
MENOPUR powder where the non-inferiority limit for the difference between treatments 
(MENOPUR liquid minus MENOPUR powder) is set as -1.60. Therefore, the non-inferiority 
hypothesis to be tested for the primary endpoint will be: 
𝐻0: 𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑙𝑖𝑞𝑢𝑖𝑑−𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑝𝑜𝑤𝑑𝑒𝑟≤−1.60 
against the alternative 
𝐻1: 𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑙𝑖𝑞𝑢𝑖𝑑−𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑝𝑜𝑤𝑑𝑒𝑟> −1.60 
where 𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑙𝑖𝑞𝑢𝑖𝑑 and 𝜇𝑀𝐸𝑁𝑂𝑃𝑈𝑅 𝑝𝑜𝑤𝑑𝑒𝑟 denote the mean numbers of fertilized oocytes in 
subjects treated with MENOPUR liquid and MENOPUR powder, respectively. 
The null hypothesis (𝐻0) will be tested against the alternative by constructing a 2-sided 95% 
confidence interval for the difference in the least squares mean number of fertilized oocytes 
between the two treatment groups. If the lower-limit of the 95% confidence interval is greater than 
the non-inferiority limit (-1.60), the null hypothesis will be rejected and it will be claimed that 
MENOPUR liquid is non-inferior to MENOPUR powder with respect to the number of fertilized 
oocytes. 
Due to the expected large sample size, the primary endpoint will be analyzed using an ANOVA 
model. The model will include the treatment group, the age strata, and the center as factors. The 
least squares mean estimate of the treatment difference in the number of fertilized oocytes and the 
associated 95% confidence interval will be derived as described in Section 9.1.2.  For subjects who 
do not have any oocytes retrieved, or do not have fertilization assessment due to early withdrawal, 
or any other reason, the number of fertilized oocytes will be considered as zero. 
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority 
limit (-1.60) but also above zero then there is evidence of superiority in terms of statistical 
significance at the 2-sided 5% level. With evidence of superiority, the corresponding 2-sided p-
value will be reported. There is no need for a multiplicity adjustment since it is a simple closed test 
procedure. 
The primary endpoint analysis will be conducted for the mITT population. 
9.2.2 
Sensitivity Analyses 
Four sensitivity analyses will be conducted. The first two sensitivity analyses will repeat the 
primary analysis but will use the ITT and PP analysis sets.  
The third sensitivity analysis will repeat the primary analysis using the mITT analysis set, but will 
apply a different method of imputation for missing data. The primary analysis treats all missing 
primary endpoints as having observed zero 2PN. There are instances, however, where the number 


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Statistical Analysis Plan 
of 2PN for a subject with a missing primary endpoint could theoretically have been greater than 
zero. Such instances may include: withdrawal of consent, being lost to follow-up, having the study 
terminated by the sponsor, not attending key visits, due to the COVID-19 pandemic trial hold, or 
other reasons that would cause a subject with a potential non-zero 2PN count to have a missing 
value. The temporal nature of the above stated reasons for missing a non-zero 2PN count are such 
that a subject would need to have taken one or more doses of IMP and have a missing primary 
endpoint. A sensitivity analysis for the primary endpoint will be performed by using the multiple 
imputation approach which could impute a non-zero value for missing primary endpoints where it 
can be reasonably expected that the true value would have been non-zero. The following steps will 
be taken to implement the multiple imputation method: 
•
Imputation phase – An ANOVA model with factors for treatment group, age strata, and
center will be fitted to data from subjects in the mITT analysis set, less those subjects with
missing primary endpoints. For each missing primary endpoint, a total of 1000 draws will be
made from a normal distribution that is characterized by the estimated parameters from the
fitted model and the factor values associated with the missing record. A total of 1000
complete datasets will be constructed.
•
Analysis phase – Each of the 1000 complete datasets will be analyzed using the ANOVA
model described in Section 9.1.2.
•
Pooling phase – The estimated mean differences and standard errors from the analysis phase
will be combined using Rubin’s formula (Rubin 1987):
𝑚𝑀𝐼=
1
1000 ∑𝑚𝑖
1000
𝑖=1
 
𝑠𝑒𝑀𝐼= √
1
1000 ∑𝑠𝑒𝑖
2
1000
𝑖=1
+ (1 +
1
1000) (
1
1000 −1) ∑(𝑚𝑖−𝑚𝑀𝐼)2
1000
𝑖=1
where 𝑚𝑖 and 𝑠𝑒𝑖 are the estimated mean treatment difference and standard error for the 
treatment difference from the 𝑖𝑡ℎ complete dataset and 𝑚𝑀𝐼 and 𝑠𝑒𝑀𝐼 are the pooled
estimates. The mean difference in the number of 2PN between the MENOPUR liquid and 
the MENOPUR powder groups will be estimated as 𝑚𝑀𝐼 and the associated 95% confidence 
interval will be calculated as 𝑚𝑀𝐼± 1.96 ∗𝑠𝑒𝑀𝐼. 
The fourth sensitivity analysis will again repeat the primary endpoint analysis using the mITT 
analysis set but will instead use a 95.08% two-sided confidence interval to assess non-inferiority. 
This sensitivity analysis assesses the impact of any Type I error inflation incurred due to performing 
a blinded sample size recalculation during a non-inferiority study. See Appendix 1 for more details. 


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Furthermore, the number of fertilized oocytes will be summarized for several subgroups: 
•
By reason for infertility
•
By center
•
By number of oocytes retrieved (<4, 4-7, 8-14, 15-19, and ≥20)
•
By AMH level on stimulation day 1 (<7.5, 7.5-<15, 15-<25, ≥25 pmol/L; ≤ median, >
median)
9.3 
Secondary Efficacy Endpoints
Secondary efficacy endpoints will be analyzed based on the mITT analysis set and summarized 
based on both the mITT and PP analysis sets. For several endpoints, summaries consisting of 
subgroups of the mITT analysis set will be presented. Descriptive summaries will be tabulated as 
described in Section 1.2.1. 
9.3.1 
Positive βhCG Rate 
The positive βhCG rate will be presented by treatment group and analyzed using the method 
described for secondary pregnancy endpoints in Section 9.1.2. Subjects who do not have a 
confirmed positive βhCG test will be counted as not having positive βhCG unless a positive clinical 
or ongoing pregnancy outcome is observed later. For example, if the outcome βhCG is missing, but 
the clinical pregnancy outcome is ‘positive’ then βhCG will be imputed as ‘positive’. 
9.3.2 
Clinical Pregnancy Rate 
The clinical pregnancy rate will be presented by treatment group and analyzed using the method 
described for secondary pregnancy endpoints in Section 9.1.2. Subjects who do not have at least 1 
intrauterine gestational sac, confirmed by TVUS, with a fetal heart beat at 5-6 weeks after 
blastocyst transfer will be counted as not having clinical pregnancy unless a positive ongoing 
pregnancy outcome is observed later. For example, if the clinical pregnancy assessment is missing, 
but the ongoing pregnancy outcome is ‘positive’ then clinical pregnancy will be imputed as 
‘positive’. 
9.3.3 
Ongoing Pregnancy Rate 
The ongoing pregnancy rate will be presented by treatment group and analyzed using the method 
described for secondary pregnancy endpoints in Section 9.1.2.  
9.3.4 
Number and Size of Follicles During Stimulation 
The follicle cohort on stimulation day 6 and the last day of stimulation will be summarized by 
treatment on the follicle level (number of follicles ≤9 mm, 10-11 mm, 12-14 mm, 15-16 mm, and 
≥17 mm) and the subject level (largest follicle size and average number of follicles ≥17 mm, ≥15 


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Statistical Analysis Plan 
mm, and ≥12 mm). The subject level parameters will be analyzed as described in Section 9.1.2 for 
the primary endpoint. 
9.3.5 
Levels of Endocrine Parameters 
The levels of endocrine parameters will be presented by treatment group for both the scheduled visit 
and the change from baseline for post-baseline visits. Baseline values for endocrine parameters are 
calculated as defined in Section 1.1.1. 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. 
The following list describes which post-baseline visits (and, consequently, change from baseline 
calculations) are summarized for each of the endocrine parameters. 
• AMH: End-of-stimulation and end-of-trial. 
• FSH: Stimulation day 6, end-of-stimulation, and oocyte retrieval. 
• hCG, LH, Estradiol, and Progesterone: Stimulation day 6 and end-of-stimulation. 
For each parameter the change from baseline will be compared between treatment groups using a 
log-normal model. In this model, the follow-up measurement will be the dependent variable and the 
linear predictors will include treatment, age strata, and center as factors as well as the baseline 
measurement (log-transformed) as a covariate. Inferential results will be presented as described in 
Section 1.2.2. 
9.3.6 
Number of Oocytes Retrieved 
The number of oocytes retrieved will be presented by descriptive statistics by treatment group and 
analyzed as described in Section 9.1.2 for the primary endpoint. Furthermore, a frequency table 
with subjects grouped according to their number of oocytes retrieved will be prepared using these 
categories: ≤3, 4-7, 8-14, 15-19, and ≥20 oocytes. Subjects without oocyte retrieval will be imputed 
to have 0 oocytes retrieved. For example, if the cycle is cancelled due to poor ovarian response, the 
number of oocytes retrieved is imputed as 0. Additional subgroup summaries of the number and 
distribution of oocytes retrieved for subjects with oocytes retrieved will also be presented. 
9.3.7 
Number of Metaphase II Oocytes 
Oocytes will have their maturity stage assessed prior to insemination. Maturity stage will be 
categorized as germinal vesicle, metaphase I, metaphase II, degenerated, or other. For subjects that 
have oocytes retrieved, but are missing maturity stage information, the maturity stage of their 
oocytes will be regarded as unknown (i.e.; not metaphase II). 
The number and distribution (≤3, 4-6, 7-12, 13-17, and ≥18) of MII oocytes will be presented by 
descriptive statistics by treatment group. Furthermore, the number of inseminated oocytes, the 
sperm source, and the sperm type will also be presented by descriptive statistics by treatment group. 


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Statistical Analysis Plan 
9.3.8 
Fertilization Rate 
For subjects with >0 oocytes retrieved, the rate of fertilized oocytes to oocytes retrieved will be 
presented by descriptive statistics by treatment group. Furthermore, for subjects with >0 metaphase 
II oocytes, the rate of fertilized oocytes to metaphase II oocytes will be presented by descriptive 
statistics by treatment group. Fertilization rates will be summarized based on the subset of the mITT 
analysis set. 
9.3.9 
Number and Quality of Blastocysts on Day 5 
The embryos on Day 5 after oocyte retrieval will be summarized on both the embryo level and on 
the subject level. 
Embryo Level 
At the embryo level all embryos evaluated will be included in the tables when reporting embryo 
stage, destiny, and grading. Frequency tables will be produced for the embryo stage, destiny at day 
5, blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm 
grading. 
Subject Level 
At the subject level the following variables will be derived for all subjects in the analysis set. For 
any subject that did not have a blastocyst, did not have oocyte retrieval, or otherwise had a missing 
subject-level endpoint, a value of ‘NO’ or 0 will be imputed, as appropriate. 
•
At least one blastocyst available
•
At least one good-quality blastocyst available
•
Number of blastocysts
•
Number of good quality blastocysts
•
Number of blastocysts transferred
Among the above variables, the number of blastocysts and the number of good quality blastocysts 
will be analyzed as described in Section 9.1.2 for the primary endpoint. The dichotomous variables 
of having at least one blastocyst available and of having at least one good quality blastocyst 
available will be analyzed as described in Section 9.1.2 for secondary pregnancy endpoints. No 
analysis will be performed for the remaining variables in this section. 
At the subject level the following variables will be derived for mITT analysis set subjects that had 
oocytes retrieved: 
•
Rate of blastocysts to oocytes retrieved


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• Rate of good-quality blastocysts to oocytes retrieved 
At the subject level the following variables will be derived for mITT analysis set subjects that had 
at least one fertilized oocyte: 
• Rate of blastocysts to fertilized oocytes 
• Rate of good quality blastocysts to fertilized oocytes 
 
 


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10 
Safety 
10.1 
General Considerations 
Safety summaries, unless otherwise stated, will be performed using the Safety analysis set and will 
be summarized as described in Section 1.2.1. Summaries will be made using all subjects, subjects in 
the <35 years age strata, and subject in the ≥35 years age strata. 
All individual subject data will be listed per subject and treatment as observed including any 
derived values. Adverse event listings will also include an indicator of whether the adverse event 
occurred before, during, or after the COVID-19 pandemic trial hold. 
10.1.1 
Imputation rules 
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of adverse events. A worst-case approach will be used: if causality is missing, the adverse event will 
be regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse event 
will be regarded as severe; if seriousness is missing, the adverse event will be regarded as serious; if 
outcome is missing, and no date of outcome is present, the outcome is regarded as ‘ongoing’. 
10.2 
Safety endpoints 
10.2.1 
Adverse Events 
Adverse events will be coded using MedDRA. Adverse events will be grouped according to the 
start of both NIMP and IMP as follows: 
•
Pre-NIMP adverse event, i.e. any adverse event occurring after signed informed consent and
before start of NIMP, or a pre-existing medical condition that worsens in intensity after
signed informed consent but before start of NIMP.
•
Pre-treatment adverse event, i.e. any adverse event occurring after the start of NIMP and
before start of IMP, or a pre-existing medical condition that worsens in intensity after start
of NIMP 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, or a pre-existing medical condition that worsens in intensity after
start of IMP and before end-of-trial.
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-NIMP and 
pre-treatment adverse events will be presented in a listing only. 
Written narratives will be issued for all SAEs and adverse events leading to discontinuation. 
Adverse events judged by the investigator as being reasonably possibly related to IMP will be 
termed adverse drug reactions. 


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Statistical Analysis Plan 
10.2.1.1 
Overview of Treatment Emergent Adverse Events 
A summary table for treatment-emergent adverse events will be presented, including for each 
treatment, the number of subjects reporting an adverse event, the percentage of subjects (%) with an 
adverse event, and the number of events (E) reported, for the following categories: 
• Treatment-emergent adverse events. 
• Treatment-emergent severe adverse events. 
• Treatment-emergent non-serious adverse events. 
• Treatment-emergent serious adverse events. 
• Treatment-emergent adverse drug reactions. 
• Treatment-emergent adverse events leading to discontinuation. 
• Treatment-emergent deaths. 
10.2.1.2 
Incidence of Adverse Events 
Treatment-emergent adverse events in each treatment group will be tabulated by system organ class 
(SOC) and preferred term (PT). 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 (E) 
reported. AEs will be presented by SOC sorted alphabetically and PT sorted in decreasing 
frequency of occurrence. 
Summary tables will be prepared for: 
• All treatment-emergent adverse events. 
• Treatment-emergent adverse events occurring in ≥2% and ≥5% of subjects in any treatment 
group. 
• Treatment-emergent adverse drug reactions occurring in ≥2% and ≥5% of subjects in any 
treatment group. 
• Treatment-emergent adverse events by causality. 
• Treatment-emergent adverse events by intensity. 
• Treatment-emergent adverse drug reactions by intensity. 
• Treatment-emergent adverse events leading to discontinuation. 


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Statistical Analysis Plan 
•
Treatment-emergent serious adverse events.
•
Treatment-emergent adverse events leading to death.
Supporting data listings will be provided for: 
•
All pre-NIMP adverse events sorted by SOC and PT.
•
All pre-treatment adverse events sorted by SOC and PT.
•
All treatment-emergent adverse events sorted by SOC and PT.
•
All treatment-emergent adverse events sorted by center and subject number.
•
All unique verbatim and coded terms.
•
All SAEs.
•
All non-Serious adverse events.
•
All adverse events leading to discontinuation.
•
All adverse events leading to death.
10.2.2 
OHSS 
OHSS for each treatment group will be tabulated by classification (mild, moderate, severe) and 
grade (1, 2, 3, 4, 5). These tabulations will be made for OHSS overall as well as separately for early 
OHSS and late OHSS. 
10.2.3 
Early Pregnancy Loss 
Early pregnancy loss is defined as a positive βhCG test but no ongoing pregnancy at 8-9 weeks after 
blastocyst transfer. The early pregnancy loss rate will be presented by treatment group. The 
denominator for the early pregnancy loss rate consists of those subjects with a positive βhCG. 
10.2.4 
Injection Site Reactions 
For each injection site reaction (redness, pain, itching, swelling, and bruising), the number of events 
and the number of subjects experiencing those events will be tabulated by time (immediately, 30 
minutes, and 24 hours), reaction type, and intensity (none, mild, moderate, and severe). Because of 
the double-dummy design, injection site reactions for IMP (MENOPUR liquid and MENOPUR 
powder) will be summarized together and injection site reactions for Placebo (Placebo to 
MENOPUR liquid and Placebo to MENOPUR powder) will be summarized together. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
10.2.5 
Treatment-induced Anti-MENOPUR Antibodies 
The proportion of subjects with treatment-induced anti-MENOPUR antibodies as well as the 
proportion of subjects with treatment-induced anti-MENOPUR antibodies with neutralizing 
capacity will be tabulated. Within each treatment group, a 95% Clopper-Pearson confidence interval 
will be constructed for both the proportion of subjects with treatment-induced anti-MENOPUR 
antibodies and for the proportion of subjects with treatment-induced anti-MENOPUR antibodies 
with neutralizing capacity. 
10.2.6 
Technical Malfunction of the Pen 
The frequency of reported malfunctions of the administration pen will be presented in a summary 
table. 
10.2.7 
Vital Signs 
The baseline for the vital sign analyses will be calculated as described in Section 1.1.1. 
10.2.7.1 
Summary Statistics 
Mean change from baseline at each time point will be presented for each vital sign variable using 
the process outlined in Section 1.2.1. 
10.2.7.2 
Changes Relative to Normal Range 
Each vital sign variable value is classified as either ‘Low’, ‘Normal’, or ‘High’. Shift tables will be 
prepared to show the number and percentage of subjects that experience a shift from baseline to the 
end-of-stimulation visit and from baseline to the end-of-trial visit. 
10.2.7.3 
Markedly Abnormal Changes 
Summary tables 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 vital signs are specified in Appendix 2. 
10.2.7.4 
Data Listings 
Data listings will be prepared by treatment group, center, subject number, and time point for all 
vital sign values (including screening and baseline) and abnormal values will be flagged. 
10.2.8 
Physical Examination 
Physical examination at the end-of-trial visit will be compared to baseline (as defined in Section 
1.1.1) and summarized in shift tables. All subjects with any abnormal finding will be listed per 
subject. 
10.2.9 
Gynecological Examination 
Gynecological examination at the end-of-trial visit will be compared to baseline (as defined in 
Section 1.1.1) and summarized in shift tables. All subjects with any abnormal finding will be listed 
per subject. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
10.2.10 
Safety Laboratory Variables 
The baseline for the safety laboratory variable analyses will be calculated as described in Section 
1.1.1. 
10.2.10.1 
Summary Statistics 
The circulating levels of clinical chemistry and hematology parameters, including change from 
baseline, will be tabulated for each time point for each laboratory variable. Mean change from 
baseline to the end-of-stimulation visit and to the end-of-trial visit will be presented for each 
laboratory variable using the process outlined in Section 1.2.1. 
10.2.10.2 
Changes Relative to Normal Range 
Each safety laboratory variable value is classified as either ‘Low’, ‘Normal’, or ‘High’. Shift tables 
will be prepared to show the number and percentage of subjects that experience a shift from 
baseline to the end-of-stimulation visit and from baseline to the end-of-trial visit. 
10.2.10.3 
Markedly Abnormal Changes 
Summary tables 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 clinical chemistry and hematology variables are specified 
in Appendix 2. 
10.2.10.4 
Data Listings 
Data listings will be prepared by treatment group, center, subject number, and time point for all 
safety laboratory values (including screening) and abnormal values will be flagged along with their 
determination of clinically significant or not clinically significant. Laboratory variables will be 
grouped under “Hematology” and “Clinical Chemistry”. 


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CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
11 
Post-trial Assessments 
The post-trial assessments will be reported as an addendum to the 000303 clinical study report. 
11.1 
Live Birth Rate 
The live birth rate will be presented by treatment group and analyzed using the method described 
for secondary pregnancy endpoints in Section 9.1.2. Subjects with no information on live birth will 
be defaulted to a negative response. 
11.2 
Late Pregnancy Loss 
Late pregnancy loss is defined as an ongoing pregnancy but no live birth. The rate of late pregnancy 
loss will be presented by treatment group. 
11.3 
Neonatal Health 
The gestational age, gender, weight, length, and Apgar scores (1 minute, 5 minutes, and 10 minutes) 
will be presented by treatment group. Furthermore, admissions to care units (NICU, NCU, or PCU), 
admissions to care units for longer than 2 hours, malformations or congenital anomalies, neonatal 
death, and important medical events will be presented by treatment group at birth, at 4 weeks after 
live birth, and after 6 months following live birth. 
Neonatal SAEs will be summarized from birth through a minimum of 6 months after birth. Written 
narratives will be issued for all SAEs.  
Parameters relating to maternal health will also be presented by treatment group. These will include 
clinically relevant pregnancy, labor, or delivery complications, COVID-19 infection, exposure to 
risk factors of congenital anomalies or malformations, and maternal death in connection with 
pregnancy or labor. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
12 
Interim analyses 
A sample size reassessment will be performed without breaking the blind and without meaningful 
inflation of the Type I error of the trial (see Appendix 1), in line with the current regulatory 
guidelines for non-inferiority trials by the Food and Drug Administration (FDA). The one-sample 
standard deviation of the primary efficacy endpoint will be evaluated in a blinded manner in 
relation to the assumptions underlying the sample size calculation. 
The sample size reassessment is to take place when 70% of the planned sample size has provided a 
primary endpoint (280 primary endpoints) or when 300 subjects have been randomized, whichever 
occurs first. 
A restricted recalculation rule for the sample size reassessment will be used. The trial will originally 
target 400 randomized subjects. At the time of the interim analysis, the estimated one-sample 
standard deviation will be used to recalculate the required sample size. If the recalculated sample 
size is less than 400, then the targeted sample size will remain at 400 (i.e.; the sample size will 
never decrease below 400). If the recalculated sample size is greater than 400, however, then the 
targeted sample size will be increased to either the recalculated sample size or 500, whichever is 
smaller. 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
13 
Deviations from the protocol 
There is one deviation from the planned analysis in the protocol. Center will be incorporated into 
statistical analyses as a fixed effect instead of a random effect. 
Because randomization is stratified by age strata and center, it was planned in the protocol to 
perform analyses by adjusting for both age strata and center. Age strata was to be incorporated as a 
fixed effect and center was to be incorporated as a random effect. 
In this statistical analysis plan, however, we incorporate center as a fixed effect. The reason for 
doing so is twofold. First, centers are rarely chosen at random. Second, the interpretation of an 
interaction between center and any other variable of interest would be complicated by the use of a 
random effect. Interactions between fixed effects are much more readily interpretable. While there 
are no pre-planned analyses that incorporate an interaction that includes center, it is possible that a 
post-hoc analysis could. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
14 
Tables, Listings and Figures 
Tables, listings, and figures (TLF) will be presented in a separate document.  
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
15 
References 
1. Rubin, D.B. (1987) Multiple imputation for nonresponse in surveys. New York: John Wiley
& Sons.


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Appendix 1  
Assessment of Type I Error Inflation 
In November 2019, the FDA released a guidance for industry document titled, “Adaptive Designs 
for Clinical Trials of Drugs and Biologics.” Of relevance for the present trial, Section IV: Adaptive 
Designs Based on Non-Comparative Data states, “These adaptations generally do not inflate the 
Type I error probability. However, there is the potential for limited Type I error probability inflation 
in trials incorporating hypothesis tests of non-inferiority or equivalence (Friede and Kieser 2003). 
Sponsors should evaluate the extent of inflation in these scenarios.” The present trial is a non-
inferiority study that includes a form of non-comparative adaptive design, namely a blinded sample 
size recalculation. 
Using the methods described in Appendix 1 of Friede and Kieser (2003), a simulation study was 
performed. The simulation study assessed the potential Type I error of the present trial given the 
design considerations for the sample size recalculation (See Section 3.2). The ‘true’ pooled standard 
deviation was set to range from 3.0 to 15.0 using increments of 0.1. For each increment, 10,000,000 
simulations were performed. Based upon the design considerations of the present trial, the 
minimum sample size was set to 400, the maximum sample size was set to 500, and the sample size 
recruited at the time of the sample size recalculation was set to 280. Likewise, when recalculating 
the sample size during each simulation rep, an alternative treatment difference of 0 was assumed, 
the non-inferiority margin was set to -1.6, a two-sided alpha of 0.05 was used, and the power was 
set to 85%. 
The results of the simulation can be seen in Figure 0-1 below. For true pooled standard deviations 
that are less than 5 and greater than 6, the Type I error is well controlled. For true pooled standard 
deviations between 5 and 6, there is a small amount of Type I error inflation. The maximum Type I 
error observed was 0.0253705, which occurred at a true pooled standard deviation of 5.6. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Figure 0-1: Actual Type I error of the 000303 trial given the true pooled standard deviation. 
One conservative method for controlling the maximum Type I error inflation was illustrated by 
Friede and Stammer (2010). An iterative procedure is performed, adjusting alpha until the 
maximum observed Type I error is within a certain distance, epsilon, of the predefined desirable 
level of Type I error. This method was applied to the present trial by setting epsilon equal to 0.0001 
(i.e.; a maximum Type I error no greater than 0.0251). 
The results of applying the procedure can be seen in Figure 0-2 below. When adjusting the one-
sided Type I error from 0.025 to 0.0246 (or, equivalently, the two-sided Type I error from 0.05 to 
0.0492), the maximum observed Type I error is within 0.0001 of the pre-specified Type I error of 
0.025. The maximum observed Type I error was 0.0250291 and again occurred at a standard 
deviation of 5.6. 


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CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Figure 0-2: Adjusted Type I error after applying an alpha correction. 
The Type I error inflation observed in Figure 0-1 is considered to be small and inconsequential. 
Therefore, no adjustments to the primary analysis are taken. A sensitivity analysis, however, is 
added. As described in Section 9.2.2, the primary analysis will be repeated using the same analysis 
set and imputation approach, but a different alpha level when constructing the two-sided confidence 
interval. Instead of a two-sided 95% confidence interval, a two-sided 95.08% confidence interval 
will be constructed. This confidence interval reflects the adjustment necessary to contain the 
maximum Type I error to be within 0.0001 of the pre-specified desired level of Type I error. 
Below are the references made in the appendix. 
1. Friede, T. & Kieser, M. (2003) Blinded sample size reassessment in non-inferiority and
equivalence trials. Statistics in Medicine, 22:995-1007. DOI: 10.102/sim.1456.
2. Friede, T. & Stammer, H. (2010) Blinded sample size recalculation in noninferiority trials:
A case study in dermatology. Drug Information Journal, 44:598-608.


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Menotrophin HP, FE 999906, FE 999911 
Trial Code: 000303  
Statistical Analysis Plan 
Appendix 2 
Table 1 
Markedly Abnormal Criteria for Laboratory Tests 
Variable Code 
Variable 
Units 
Low 
High 
RBC 
Erythocytes 
10^12/L 
< 3.0 
N.A
WBC 
Leukocytes 
10^9/L 
< 2.5 
> 15.0
HGB 
Haemoglobin 
g/L 
< 100 
> 190
HCT 
Haematocrit 
RATIO 
< 0.28 
> 0.5
EOSLE 
Eosinophils/Leukocytes 
% 
N.A
≥ 10 
NEUTLE 
Neutrophils/Leukocytes 
% 
≤ 15 
≥ 90 
LYMLE 
Lymphocytes/Leukocytes 
% 
≤ 10 
≥ 80 
MONOLE 
Monocytes/Leukocytes 
% 
N.A
≥ 20 
BASOLE 
Basophils 
% 
N.A
≥ 5 
PLAT 
Platelets 
10^9/L 
< 110 
> 600
AST 
AST 
IU/L 
N.A
> 3xULN
BUN 
Blood urea nitrogen 
mmol/L 
N.A
> 12.5
CA 
Calcium 
mmol/L 
< 1.75 
> 2.74
CL 
Chloride 
mmol/L 
N.A
N.A
ALT 
ALT 
IU/L 
N.A
> 3xULN
CREAT 
Creatinine 
umol/L 
N.A
> 3xULN
GGT 
GGT 
IU/L 
N.A
> 3xULN
GLUC 
Glucose 
mmol/L 
< 2.5 
> 16.7
K 
Potassium 
mmol/L 
< 3.0 
> 5.8
SODIUM 
Sodium 
mmol/L 
< 125 
> 155
ALP 
Alkaline phosphatase 
IU/L 
N.A
> 3xULN
LH 
Luteinizing hormone 
IU/L 
N.A
>10
Table 2 Markedly Abnormal Criteria for Vital Signs* 
Variable 
Criterion Value 
Change from Baseline 
Systolic blood pressure 
≥ 180 mmHg 
≤ 90 mmHg 
Increase of ≥ 20 mmHg 
Decrease of ≥ 20 mmHg 
Diastolic blood pressure 
≥ 105 mmHg 
≤ 50 mmHg 
Increase of ≥ 15 mmHg 
Decrease of ≥ 15 mmHg 
Pulse 
≥ 120 bpm 
≤ 50 bpm 
Increase of ≥ 15 bpm 
Decrease of ≥ 15 bpm 
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the specified change from baseline.