Conditions: Infertility
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 620
Healthy volunteers: no

Brief summary:
The purpose of this trial is to demonstrate non-inferiority of MENOPUR® versus recombinant Follicle Stimulating Hormone (rFSH) (Gonal-f®) with respect to ongoing pregnancy rate in women undergoing controlled ovarian stimulation (COS) following GnRH treatment.

Detailed description:

Arms:
arm 1: menotropins for injection arm 2: None

Interventions: intervention 1: menotropin intervention 2: recombinant FSH
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
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CLINICAL TRIAL PROTOCOL
A Randomized, Assessor-blind Trial Comparing MENOPUR® (menotropins for injection) 
and Recombinant FSH (Follicle Stimulating Hormone) in a GnRH Antagonist Cycle with 
Single-Blastocyst Transfer in a High Responder Subject Population
000205
EudraCT Number:
2008-006775-67
IND Number:
053954
Investigational Medicinal Product:
MENOPUR® (menotropins for injection) 
Indication:
Development of multiple follicles and pregnancy in 
ovulatory women as part of an Assisted Reproductive 
Technology (ART)
Cycle with ICSI 
Phase:
4
Name and Address of Sponsor:
Ferring International PharmaScience Center US Inc.
Reproductive Health & Urology
100 Interpace Parkway
Parsippany, NJ  07054
973-796-1600
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group.  It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A Randomized, Assessor-blind Trial Comparing MENOPUR® and Recombinant FSH in a GnRH 
Antagonist Cycle with Single-Blastocyst Transfer in a High Responder Subject Population
TRIAL SITES
25-30 infertility centers in the United States (US)
PLANNED TRIAL PERIOD
First subject first visit:
August/September 2015
Last subject last visit:
December 2016
CLINICAL PHASE
4
OBJECTIVES
Primary Objective

To demonstrate non-inferiority of MENOPUR® versus recombinant follicle-stimulating 
hormone (Gonal-f®) with respect to ongoing pregnancy rate in women undergoing 
controlled ovarian stimulation (COS) following a gonadotropin-releasing hormone (GnRH)
antagonist protocol.
Secondary Objectives

To evaluate the positive β-human chorionic gonadotropin (hCG) rates and clinical 
pregnancy rates after stimulation with MENOPUR® and Gonal-f® following a GnRH 
antagonist protocol.

To evaluate follicular development during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the serum endocrine profile during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the number of oocytes retrieved, the fertilization rate, and embryo quality, 
associated with MENOPUR® and Gonal-f® following a GnRH antagonist protocol.

To evaluate the live birth rate associated with MENOPUR® and Gonal-f® following a 
GnRH antagonist protocol.

To evaluate the adverse event (AE) profile of MENOPUR®  and Gonal-f®


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ENDPOINTS
The primary endpoint is the ongoing pregnancy rate, defined as the presence of at least 
1 intrauterine pregnancy with a detectable fetal heartbeat at 10-11 weeks gestation (8-9 weeks after 
blastocyst transfer in the fresh cycle).
Secondary Endpoints

Positive β-hCG rate (2 positive β-hCG tests; the first approximately 10-14 days after 
blastocyst transfer in the fresh cycle and a second confirmatory test approximately 2 days 
later).

Clinical pregnancy rate (transvaginal ultrasound [TVUS] showing at least 1 intrauterine 
gestational sac with fetal heart beat at 6-7 weeks gestation, 4-5 weeks after blastocyst 
transfer in the fresh cycle).

Early pregnancy loss (defined as 2 positive -hCG tests but no ongoing pregnancy at 
10-11 weeks gestation in the fresh cycle).

Follicular development as assessed by TVUS (total number of follicles and number of 
follicles with a diameter of ≤9mm, 10-11 mm, 12-14 mm, 15-16 mm, and ≥17 mm on 
stimulation Day 6 and last day of stimulation).

Endocrine profile:
o
Serum follicle-stimulating hormone (FSH), hCG, luteinizing hormone (LH), 
androstenedione, total testosterone, dehydroepiandrosterone:  Day 1, Day 6, and last 
day of stimulation.
o
Progesterone (P4), estradiol (E2):  Day 1, Day 6, last day of stimulation, and Visit 4 
(morning following hCG trigger).

Oocytes retrieved metaphase II oocytes, number of oocytes undergoing ICSI, fertilization 
rate, quality of embryos 3 days after oocyte retrieval, and the quality of blastocysts 5 days 
after oocyte retrieval.

Aneuploidy rate.

Endometrial assessment by TVUS (endometrial thickness in mm and echogenicity pattern 
on stimulation Day 6, last day of stimulation, and at the time of blastocyst transfer in the 
fresh cycle [transabdominal pelvic ultrasound or TVUS]).
Post-trial Endpoints

Cumulative live birth rate for fresh and frozen blastocyst transfers (viable live birth greater 
>21 weeks gestation).

Live birth rate for fresh blastocyst transfers (viable live birth greater >21 weeks gestation).

Early pregnancy loss rate in frozen blastocyst transfer, defined as 2 positive -hCG tests but 
no ongoing pregnancy at 10-11 weeks gestation in the frozen cycle.


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
Late pregnancy loss rate (defined as a confirmed ongoing pregnancy but no live birth).

Positive β-hCG rate, clinical pregnancy rate, and ongoing pregnancy rate for frozen 
blastocyst transfers.
Safety Endpoints

AEs.

Frequency of ovarian hyperstimulation syndrome (OHSS) (early OHSS if the onset is 
≤9 days after hCG administration and late OHSS if the onset is >9 days after hCG 
administration).
METHODOLOGY
This is a Phase 4, randomized, open-label, assessor-blind, parallel-group, multicenter 
non-inferiority trial with the option for superiority.  Approximately 600 females undergoing COS 
following a GnRH antagonist protocol at approximately 25-30 infertility centers in the US will be 
randomized 1:1 to receive either MENOPUR® or Gonal-f®.  The primary endpoint is ongoing 
pregnancy rate.  
On the second or third day of spontaneous menses, gonadotropins (either MENOPUR® or Gonal-
f®) will be initiated at 150 IU for 5 days.  From stimulation Day 6 onward, based on follicular 
response assessed by TVUS, dosing can be adjusted every day as needed by 75 IU per adjustment.  
However, the maximum gonadotropin dose will be 300 IU/day; gonadotropin dosing can continue 
for a maximum of 20 days.
Once the lead follicle measures ≥14 mm and/or serum E2 levels are ≥300 pg/mL, the GnRH 
antagonist (ganirelix acetate) will be initiated at a daily dose of 0.25 mg and continued throughout 
the gonadotropin treatment period. The stimulation day of the antagonist start will be recorded in 
the electronic case report form.  A single injection of 250 μg hCG (Ovidrel®) will be administered 
to induce final follicular maturation as soon as 3 follicles of ≥17 mm are observed on TVUS.  In the 
case of excessive ovarian response (>30 follicles of ≥12 mm each and/or E2 levels ≥5000 pg/mL), 
the hCG trigger will be replaced with a GnRH agonist trigger (4 mg leuprolide acetate) and the 
fresh blastocyst transfer cancelled, with cryopreservation of all resultant viable blastocysts
following biopsy.  Oocyte retrieval will take place roughly 36 hours after hCG administration, and 
oocytes will be inseminated by intracytoplasmic sperm injection (ICSI) 4±1 hours after retrieval; 
oocyte maturity will be recorded.  Fertilization (number of pronuclei) will be checked on Day 1 
following oocyte retrieval.  Embryo quality will be assessed on Days 3 and 5 following oocyte 
retrieval; in the case of late blastulation, assessments will be made on Day 6 or Day 7, as needed.  
On Day 5 following ICSI, a single blastocyst of the best quality available will be transferred; all 
remaining blastocysts will be frozen using the vitrification method.  Laser-assisted trophectoderm
biopsy for preimplantation genetic screening will be done on expanded blastocysts on Day 5; in the 
case of late blasulation, biopsy will be performed on Day 6 or Day 7, as needed.  The PGS results 
will not be used to determine blastocyst selection for fresh transfer on Day 5.  The evening of the 


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day after oocyte retrieval, vaginal progesterone inserts (ENDOMETRIN®; Ferring) will be initiated 
for luteal phase support and will continue until the day of the -hCG test (10-14 days after 
blastocyst transfer).  On the day that the progesterone inserts are initiated, only a single, 100 mg 
dose of ENDOMETRIN® will be given.  On subsequent days, two (2) doses of ENDOMETRIN®
(100 mg/BID for a total of 200 mg/day) will be given.  ENDOMETRIN® will be continued for a 
maximum of 10 weeks total if pregnancy is confirmed.  For subjects with no ongoing pregnancy in 
the fresh cycle, single frozen blastocyst transfer can be initiated within 6 months of a subject’s date 
of randomization.  
NUMBER OF SUBJECTS
Approximately 600 infertile females are to be randomized (300 subjects per group).
MAIN CRITERIA FOR INCLUSION/EXCLUSION
Subjects are to be aged 21 to 35 years with regular ovulatory menstrual cycles of 21 to 45 days, 
with a body mass index between 18 and 30 kg/m2, infertility for a period of ≥1 year (≥6 months if 
receiving donor sperm), and who have a serum anti-Müllerian hormone (AMH) ≥5 ng/mL at 
screening.  Key exclusion criteria include endometriosis stage III-IV, history of recurrent 
miscarriage, and previous poor response to a COS cycle.
MEDICINAL PRODUCTS
Investigational Medicinal Products (IMPs):
Each IMP will be administered subcutaneously once daily for up to 20 days at a dose of 75 IU to 
300 IU.

MENOPUR® (menotropins for injection) manufactured by Ferring Pharmaceuticals Inc.,
will be provided as a vial with powder (75 IU FSH activity and 75 IU LH activity) and a vial 
with diluent.  After reconstitution, each vial delivers 75 IU of FSH activity and 75 IU of LH 
activity.  

Gonal-f®, (follitropin alpha for injection) a human follicle stimulating hormone (FSH) 
preparation of recombinant DNA origin manufactured by EMD Serono Inc., will be 
provided as pen and cartridges filled with either 300 or 450 IU of FSH activity. 
Concomitant Therapy (Non-investigational Medicinal Products [NIMPs]):
The NIMPs include the following:

Ganirelix® (ganirelix acetate injection), manufactured by Merck, will be provided as a pre-
filled syringe (0.5 mL) delivering 0.25 mg Ganirelix.  A daily dose of 0.25 mg will be 
continued throughout the gonadotropin treatment period.

Ovidrel® (choriogonadotropin alfa), manufactured by EMD Serono Inc., will be provided as 
a pre-filled syringe (0.5 mL) delivering 250 μg choriogonadotropin alfa, to be administered 
as a single injection as soon as 3 follicles of ≥17 mm are observed on TVUS.

ENDOMETRIN® (progesterone), manufactured by Ferring Pharmaceuticals Inc., will be 


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provided as inserts to be administered vaginally. On the day that the progesterone inserts are 
initiated, only a single, 100 mg dose of ENDOMETRIN® will be given.  On subsequent 
days, ENDOMETRIN® will be administered 2 times daily, each delivering 100 mg of 
progesterone (200 mg/day).  ENDOMETRIN® will be initiated the evening of the day after 
oocyte retrieval and will continue until the day of the second -hCG test (if negative) or if 
pregnancy is confirmed by the second -hCG test for a maximum of 10 weeks total.
DURATION OF TREATMENT
Subjects are treated with IMPs (either HP-hMG or Gonal-f®) for a maximum of 20 days.
STATISTICAL METHODS
Sample Size Calculation
The study has at least 80% power, with 275 subjects per treatment group, to demonstrate the non-
inferiority of MENOPUR® to Gonal-f® in the ongoing clinical pregnancy rate at the 1-sided 
significance level of 0.025 with a 12% non-inferiority margin, by assuming an ongoing pregnancy 
rate of 50% for both treatment groups (Yeh et al. 2014). Assuming that 8% of the subjects may not 
be eligible for the per protocol analysis set, approximately 600 subjects will be randomized (1:1) 
into this study.
Efficacy:
The primary objective of the trial is to demonstrate the non-inferiority of MENOPUR® versus
Gonal-f® with respect to ongoing pregnancy rate in women undergoing COS following a GnRH 
antagonist protocol.  The non-inferiority limit for the difference between treatments (MENOPUR®
minus Gonal-f®) will be -12% (absolute).  The non-inferiority hypothesis to be tested for the 
primary endpoint will be:
H0: MENOPUR - Gonal-f -12% 
against the alternative 
H1: MENOPUR - Gonal-f > -12%, where
MENOPUR and Gonal-f denote the ongoing pregnancy rate of subjects treated with MENOPUR® and 
Gonal-f®, respectively, in a single fresh blastocyst transfer following a GnRH antagonist protocol.
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 
95% confidence interval for the difference in ongoing pregnancy rates.  Subjects who do not have at 
least 1 intrauterine pregnancy with a detectable fetal heartbeat at 10-11 weeks gestation (8-9 weeks 
after blastocyst transfer in the fresh cycle), due to missing data, early withdrawal, or any other 
reason will be considered treatment failures (i.e., not having ongoing pregnancy).  If the lower-limit 
of the 95% confidence interval is greater than the non-inferiority limit (-12%), the null hypothesis 
will be rejected and it will be claimed that MENOPUR® is non-inferior to Gonal-f® with respect to 
ongoing pregnancy rate.  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.


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TABLE OF CONTENTS
Page
SYNOPSIS .......................................................................................................................................................2
1
INTRODUCTION..............................................................................................................................13
1.1
Background .............................................................................................................................13
1.2
Scientific Justification for Conducting the Trial .....................................................................13
1.3
Benefit/Risk Aspects...............................................................................................................14
2
TRIAL OBJECTIVES AND ENDPOINTS.....................................................................................15
2.1
Objectives................................................................................................................................15
2.2
Endpoints.................................................................................................................................15
3
INVESTIGATIONAL PLAN............................................................................................................17
3.1
Overall Trial Design................................................................................................................17
3.1.1
Trial Design Diagram.................................................................................................17
3.1.2
Overall Design and Control Methods.........................................................................17
3.2
Planned Number of Trial Sites and Subjects...........................................................................19
3.3
Discussion of Overall Trial Design and Choice of Control Groups........................................19
3.3.1
Trial Design................................................................................................................19
3.3.2
Selection of Endpoints................................................................................................20
3.3.3
Blinding......................................................................................................................20
3.3.4
Selection of Doses in the Trial ...................................................................................20
3.3.5
Selection and Timing of Dose for Each Subject.........................................................20
3.3.6
Withdrawal Criteria....................................................................................................20
3.3.7
Follow-up Procedures.................................................................................................21
4
SELECTION OF TRIAL POPULATION.......................................................................................22
4.1
Trial Population.......................................................................................................................22
4.1.1
Inclusion Criteria........................................................................................................22
4.1.2
Exclusion Criteria.......................................................................................................23
4.2
Method of Assigning Subjects to Treatment Groups ..............................................................24
4.2.1
Recruitment ................................................................................................................24
4.2.2
Randomization............................................................................................................24
4.3
Restrictions..............................................................................................................................24
4.3.1
Prior and Concomitant Therapies...............................................................................24
4.3.2
Prohibited Therapy.....................................................................................................24
5
TREATMENTS..................................................................................................................................25
5.1
Treatments Administered ........................................................................................................25
5.1.1
Investigational Medicinal Products............................................................................25
5.1.2
Non-Investigational Medicinal Products (NIMPs).....................................................25
5.2
Characteristics and Source of Supply......................................................................................25
5.3
Packaging and Labeling ..........................................................................................................25
5.4
Conditions for Storage and Use...............................................................................................26
5.5
Blinding/Unblinding................................................................................................................26
5.6
Treatment Compliance ............................................................................................................26
5.6.1
Dispensing and Accountability...................................................................................26
5.6.2
Return and Destruction of Investigational Medicinal Products..................................26


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5.7
Auxiliary Supplies...................................................................................................................27
6
TRIAL PROCEDURES.....................................................................................................................28
6.1
Visit 1 - Screening and Pre-stimulation Period .......................................................................31
6.2
Visit 2 - Randomization and Start of Controlled Ovarian Stimulation, Cycle Day 2-3 ..........31
6.3
Visit 3 - Stimulation Follow-up (Day 6) and Unscheduled Visits ..........................................31
6.4
Visit 4 - Day Following Administration of Ovidrel® ..............................................................33
6.5
Visit 5 - Oocytes Retrieval/Insemination ................................................................................33
6.6
Visit 6 - Blastocyst Transfer....................................................................................................34
6.7
Visits 7, 8, and 9 - Pregnancy Monitoring...............................................................................34
6.8
End of Trial (EOT) Visit .........................................................................................................35
6.9
Pregnancy Follow-Up..............................................................................................................35
7
TRIAL ASSESSMENTS....................................................................................................................37
7.1
Assessments Related to Endpoints..........................................................................................37
7.1.1
Pregnancy Tests and Pregnancy Monitoring..............................................................37
7.1.2
Oocyte Retrieval and Blastocyst Transfer..................................................................37
7.1.3
Transvaginal Ultrasounds...........................................................................................37
7.1.4
Central Laboratory Tests............................................................................................37
7.1.5
Local Laboratory Tests...............................................................................................38
7.1.6
Ovarian Hyperstimulation Syndrome Monitoring......................................................38
7.1.7
Concomitant Medications...........................................................................................39
7.2
Other Assessments ..................................................................................................................40
7.2.1
Physical and Gynecological Examinations ................................................................40
7.2.2
Medical History/Menstrual History............................................................................40
7.2.3
Vital Signs..................................................................................................................40
7.2.4
Number of Oocytes Retrieved....................................................................................40
7.2.5
Metaphase II Oocytes.................................................................................................40
7.2.6
Fertilization Rate........................................................................................................40
7.2.7
Number and Quality of Embryos on Day 3................................................................40
7.2.8
Number and Quality of Blastocysts on Day 5............................................................41
7.2.9
Overall Blastocyst Quality on Day 5..........................................................................42
7.2.10 Compaction Assessment in Morulas ..........................................................................42
8
ADVERSE EVENTS..........................................................................................................................43
8.1
Adverse Event Definition........................................................................................................43
8.2
Collection and Recording of Adverse Events..........................................................................43
8.2.1
Collection of Adverse Events.....................................................................................43
8.2.2
Recording of Adverse Events.....................................................................................43
8.3
Pregnancy and Pregnancy Outcome........................................................................................46
8.4
Serious Adverse Events...........................................................................................................47
8.4.1
Serious Adverse Event Definition..............................................................................47
8.4.2
Collection, Recording and Reporting of Serious Adverse Events..............................48
8.5
Follow-up of Adverse Events and Serious Adverse Events....................................................49
8.5.1
Follow-up of Adverse Events with Onset during the Trial ........................................49
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial.............................49
9
STATISTICAL METHODS..............................................................................................................50
9.1
Determination of Sample Size.................................................................................................50


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9.2
Subject Disposition..................................................................................................................50
9.3
Protocol Deviations.................................................................................................................50
9.4
Analysis Sets ...........................................................................................................................50
9.4.1
Intent-to-Treat (ITT) Analysis Dataset.......................................................................50
9.4.2
Modified Intent-to-Treat (mITT) Analysis Dataset....................................................50
9.4.3
Per Protocol (PP) Analysis Dataset............................................................................50
9.4.4
Safety Analysis Dataset..............................................................................................50
9.5
Trial Population.......................................................................................................................51
9.5.1
Demographics and other Baseline Characteristics .....................................................51
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations ................51
9.6
Efficacy Endpoint Assessments ..............................................................................................51
9.6.1
General Considerations ..............................................................................................51
9.6.2
Primary Efficacy Endpoint.........................................................................................51
9.6.3
Secondary Endpoints..................................................................................................53
9.6.4
Post-Trial Endpoints...................................................................................................54
9.7
Extent of Exposure and Treatment Compliance......................................................................54
9.8
Safety.......................................................................................................................................54
9.8.1
General Considerations ..............................................................................................54
9.8.2
Adverse Events...........................................................................................................55
9.8.3
Vital Signs..................................................................................................................56
9.8.4
Physical Examination.................................................................................................56
9.8.5
Gynecological Examination .......................................................................................57
9.8.6
Clinical Laboratory Variables ....................................................................................57
9.9
Interim Analyses......................................................................................................................57
10
DATA HANDLING............................................................................................................................58
10.1
Source Data and Source Documents .......................................................................................58
10.2
eCRF/Case Report Form .........................................................................................................58
10.3
Data Management....................................................................................................................59
10.4
Provision of Additional Information .......................................................................................59
11
MONITORING PROCEDURES......................................................................................................60
11.1
Periodic Monitoring ................................................................................................................60
11.2
Audit and Inspection ...............................................................................................................60
11.3
Confidentiality of Subject Data...............................................................................................60
12
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................61
12.1
Protocol Amendments .............................................................................................................61
12.2
Deviations from the Protocol...................................................................................................61
12.3
Premature Trial Termination...................................................................................................61
13
REPORTING AND PUBLICATION...............................................................................................62
13.1
Clinical Trial Report................................................................................................................62
13.2
Confidentiality and Ownership of Trial Data..........................................................................62
13.3
Publications and Public Disclosure .........................................................................................62
13.3.1 Publication Policy.......................................................................................................62
13.3.2 Public Disclosure Policy ............................................................................................63
14
ETHICAL AND REGULATORY ASPECTS .................................................................................64
14.1
Institutional Review Board......................................................................................................64


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14.2
Regulatory Authority Authorization/Approval/Notification...................................................64
14.3
End-of-Trial and End-of-Trial Notification.............................................................................64
14.4
Ethical Conduct of the Trial ....................................................................................................64
14.5
Subject Information and Consent............................................................................................64
14.6
Compliance Reference Documents .........................................................................................65
15
LIABILITIES AND INSURANCE...................................................................................................66
15.1
ICH-GCP Responsibilities.......................................................................................................66
15.2
Liabilities and Insurance..........................................................................................................66
16
ARCHIVING......................................................................................................................................67
16.1
Investigator File.......................................................................................................................67
16.2
Trial Master File......................................................................................................................67
17
REFERENCES...................................................................................................................................68
PROTOCOL DOCUMENT APPROVAL ..................................................................................................69
LIST OF TABLES
Table 1
Trial Assessments............................................................................................................29
Table 2
Classification of Mild, Moderate, and Severe OHSS......................................................39
LIST OF FIGURES
Figure 1
Trial Flow Diagram.........................................................................................................17


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
AMH
anti-Müllerian hormone
ART
assisted reproductive technology
BMI
body mass index
COS
controlled ovarian stimulation
CRO
contract research organization
DHEA
dehydroepiandrosterone
E2
estradiol
eCRF
electronic case report form
EOT
end of treatment
EudraCT
European Union Clinical Trial Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin-releasing hormone
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
ICSI
intracytoplasmic sperm injection
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT
intent-to-treat
IVF
in vitro fertilization
LH
luteinizing hormone
MedDRA
Medical Dictionary for Regulatory Activities
MERiT
Menotrophin vs. Recombinant FSH in vitro Fertilization Trial
mITT
modified intent-to-treat
NIMP
Non-Investigational Medicinal Product
OHSS
ovarian hyperstimulation syndrome
P4
progesterone
PGS
preimplantation genetic screening
PP
per protocol
rFSH
recombinant follicle-stimulating hormone
SAE
serious adverse event


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SOC
system organ class
TSH
thyroid stimulating hormone
TVUS
transvaginal ultrasound
US
United States 


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1
INTRODUCTION
1.1
Background
The Menotrophin vs. Recombinant FSH in vitro Fertilization Trial (MERiT) study was a large, 
randomized, open-label, multicenter, multinational study comparing treatment outcomes of 
controlled ovarian stimulation (COS) using MENOPUR® (n=363) with those using recombinant 
follicle-stimulating hormone (rFSH) α (Gonal-f®, Merck KGaA, Darmstadt, Germany, n=368) in in 
vitro fertilization (IVF) cycles using a long gonadotropin-releasing hormone (GnRH) agonist down-
regulation protocol (Andersen, 2006). The results of this study conducted in 2005 demonstrated 
non-inferiority of MENOPUR® to Gonal-f® in ongoing pregnancy rates.  Meta-analyses have 
indicated that menotropins provide higher live birth rates than Gonal-f® in the long GnRH agonist
protocol (van Wely et al. 2011).  A randomized, open-label, assessor-blind, parallel-group,
multicenter trial comparing the efficacy of MENOPUR® and rFSH (Puregon®: Schering-Plough 
Organon) was conducted in subjects undergoing COS following a GnRH antagonist protocol; this 
study, called MEGASET, randomized 749 subjects in Europe (Belgium, Czech Republic, Denmark, 
Poland, Spain, Sweden, and Turkey) (Devroey, 2012).  The ongoing pregnancy rates in the 
MENOPUR® and Puregon® groups were 28.9% and 26.7%, respectively, in the intent-to-treat (ITT) 
population and 30.0% and 27.0%, respectively, in the per protocol (PP) population.  The non-
inferiority of MENOPUR® to Puregon®, with respect to the ongoing pregnancy rate, was 
demonstrated for both the ITT and PP populations.
A retrospective analysis of data from both MERiT and MEGASET evaluated the impact of 
gonadotropin treatment on ovarian response and clinical outcome in women at risk of a high 
response and who were undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment (Arce, 
2014). Women at risk of a high response were defined as those with anti-Müllerian hormone 
(AMH) levels >75th percentile (i.e., equivalent to >5.2 ng/mL [37.4 pmol/L] in both studies), 
corresponding to 155 women in the MERiT study and 188 women in the MEGASET study.  High 
ovarian response was defined as ≥15 oocytes retrieved.  Treatment with MENOPUR® versus rFSH 
was associated with a lower median number of oocytes retrieved in women at risk of a high 
response, irrespective of the down-regulation protocol (Arce, 2014).  When the data of women with 
high AMH from both protocols were integrated, MENOPUR® treatment was associated with a 
significantly lower incidence of high response (32% versus 49%, p=0.001) and increased live birth 
rate per started cycle (34% versus 22%, p=0.012) compared with rFSH treatment (Arce, 2014).
1.2
Scientific Justification for Conducting the Trial
The current study has a similar design as the MEGASET study conducted in Europe.  The aim of 
this study is to demonstrate non-inferiority of MENOPUR® versus rFSHα (Gonal-f®) with respect 
to ongoing pregnancy rate in potential high-responders undergoing IVF/ICSI treatment, using an 
initial gonadotropin dose of 150 IU within a GnRH antagonist-controlled protocol.  Subjects will be 
classified as high ovarian responders based on a serum level of AMH ≥5ng/mL. The AMH 


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measurements will be determined at a single reference laboratory (ReproSource, Inc., Woburn, MA) 
utilizing materials and reagents from Beckman Coulter-DSL (Chaska, MN).
1.3
Benefit/Risk Aspects
This study will be conducted using approved drugs with well-established efficacy and safety 
profiles; thus, the benefit/risk aspects are expected to be similar to what is outlined in the package 
insert for MENOPUR® (menotropins for injection [package insert] 2014) and Gonal-f RFF® Redi-
ject™ (follitropin alfa injection [package insert] 2014).


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To demonstrate non-inferiority of MENOPUR® versus recombinant follicle-stimulating 
hormone (Gonal-f®) with respect to ongoing pregnancy rate in women undergoing 
controlled ovarian stimulation (COS) following a gonadotropin-releasing hormone (GnRH)
antagonist protocol.
Secondary Objectives

To evaluate the positive β-human chorionic gonadotropin (hCG) and clinical pregnancy 
rates after stimulation with MENOPUR® and Gonal-f® following a GnRH antagonist 
protocol.

To evaluate follicular development during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the serum endocrine profile during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the number of oocytes retrieved, the fertilization rate, and embryo quality 
associated with MENOPUR® and Gonal-f® following a GnRH antagonist protocol.

To evaluate the live birth rate associated with MENOPUR® and Gonal-f® following a GnRH 
antagonist protocol.

To evaluate the adverse event (AE) profile of MENOPUR® and Gonal-f®
2.2
Endpoints
Primary Endpoint

Ongoing pregnancy rate, defined as the presence of at least 1 intrauterine pregnancy with a 
detectable fetal heartbeat at 10–11 weeks of gestation (8-9 weeks after blastocyst transfer in 
the fresh cycle).
Secondary Endpoints

Positive β-hCG rate (2 positive β-hCG tests; the first approximately 10-14 days after 
blastocyst transfer in the fresh cycle and a second confirmatory test approximately 2 days 
later).

Clinical pregnancy rate (transvaginal ultrasound [TVUS] showing at least 1 intrauterine 
gestational sac with fetal heart beat at 6-7 weeks gestation, 4-5 weeks after blastocyst 
transfer in the fresh cycle).

Early pregnancy loss (defined as 2 positive -hCG tests but no ongoing pregnancy at 
10-11 week’s gestation in the fresh cycle).


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
Follicular development as assessed by TVUS (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 the last day of stimulation).

Endocrine profile:

Serum follicle-stimulating hormone (FSH), hCG, luteinizing hormone (LH), 
androstenedione, total testosterone, dehydroepiandrosterone (DHEA):  Day 1, Day 6, 
and last day of stimulation.

Progesterone (P4), estradiol (E2):  Day 1, Day 6, last day of stimulation, and Visit 4 
(morning following hCG administration).

Oocytes retrieved metaphase II oocytes, number of oocytes undergoing ICSI, fertilization 
rate, quality of embryos 3 days after oocyte retrieval, and the quality of blastocysts 5 days 
after oocyte retrieval.

Aneuploidy rate.

Endometrial assessment by TVUS (endometrial thickness in mm and echogenicity pattern 
on stimulation Day 6, the last day of stimulation, and at the time of blastocyst transfer in the 
fresh cycle [transabdominal pelvic ultrasound or TVUS]).
Post-trial Endpoints

Cumulative live birth rate for fresh and frozen blastocyst transfers (viable live birth 
>21 weeks gestation).

Live birth rate for fresh blastocyst transfers (viable live birth >21 weeks gestation).

Early pregnancy loss rate in frozen blastocyst transfer, defined as 2 positive -hCG tests but 
no ongoing pregnancy at 10-11 weeks gestation in the frozen cycle.

Late pregnancy loss rate (defined as a confirmed ongoing pregnancy but no live birth).

Positive β-hCG rate, clinical pregnancy rate, and ongoing pregnancy rate for frozen 
blastocyst transfers.
Safety Endpoints

AEs.

Frequency of ovarian hyperstimulation syndrome (OHSS) (early OHSS if the onset is 
≤9 days after hCG administration and late OHSS if the onset is >9 days after hCG 
administration).


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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 1.
Figure 1
Trial Flow Diagram
3.1.2
Overall Design and Control Methods
This is a Phase 4, randomized, open-label, assessor-blind, parallel-group, multicenter study to be 
conducted at approximately 25-30 infertility centers in the United States (US).  Approximately 600 
females undergoing COS following a GnRH antagonist protocol will be randomized to receive 
either MENOPUR® or Gonal-f®.  The study is designed to demonstrate non-inferiority of 
MENOPUR® versus Gonal-f® for ongoing pregnancy rates in a predefined high-responder subject 
population.  High responders will be defined as subjects who have a serum AMH ≥5 ng/mL.  All 
AMH measurements will be determined at a single reference laboratory (ReproSource, Inc., 
Woburn, MA), utilizing materials and reagents from Beckman Coulter-DSL (Chaska, MN).
Subjects will be randomized 1:1 to undergo COS with either MENOPUR® or Gonal-f® in a GnRH 
antagonist cycle.  Gonadotropins (either MENOPUR® or Gonal-f®) will be started on the second or 
third day of spontaneous menses.  The gonadotropin dose will be initiated at 150 IU for the first 
5 days.  From stimulation Day 6 onward, based on follicular response assessed by TVUS, dosing 
can be adjusted every day as needed by 75 IU per adjustment.  However, the maximum 
gonadotropin dose will be 300 IU/day; gonadotropin dosing can continue for a maximum of 
20 days.  Coasting is prohibited.


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If the lead follicle measures ≥14 mm and/or serum E2 levels are ≥300 pg/mL, the GnRH antagonist 
Ganirelix® (ganirelix acetate) will be initiated at a daily dose of 0.25 mg and continued throughout 
the gonadotropin treatment period. The stimulation day of the antagonist start will be recorded in 
the electronic case report form (eCRF). A single injection of 250 μg hCG (Ovidrel®) will be 
administered to induce final follicular maturation as soon as 3 follicles of ≥17 mm are observed on 
TVUS.  If a subject has >30 follicles that are ≥12 mm each, she will receive 4 mg of leuprolide 
acetate administered subcutaneously at least 12 hours after the last dose of the GnRH antagonist.  If 
the GnRH agonist trigger was required, TVUS-guided oocyte retrieval will be performed 
approximately 36 hours later, and all resultant viable blastocysts will be vitrified after 
trophectoderm biopsy, with no fresh blastocyst transfer to decrease risk of OHSS.
In order to minimize the risk of empty follicle syndrome, the subject will return the morning after 
hCG trigger to draw serum hCG, E2, and P4 levels.  If the hCG level is <50 IU/L and/or P4 is 
<3.5 ng/mL, then a booster/rescue second dose of hCG must be given on that day as soon as 
possible.  If the subject received the GnRH agonist trigger, the bloods drawn will be LH, E2, and P4
levels.  If, after the GnRH agonist trigger, the LH is <15 IU/L and/or the P4 <3.5 ng/mL, a 
rescue/booster dose of hCG (Ovidrel®) should be given as soon as possible.  Delay of oocyte 
retrieval will be left to the clinician’s discretion and will be based on the time at which the rescue 
dose was administered.
Oocyte retrieval will take place approximately 36 hours after hCG administration.  Oocytes will be 
inseminated using partner sperm by ICSI 4±1 hours after retrieval; oocyte maturity will be 
recorded.  Fertilization (number of pronuclei) will be checked on Day 1 following oocyte retrieval.  
Embryo quality will be assessed on Days 3 and 5 following oocyte retrieval; in the case of late 
blastulation, assessments will be made on Day 6 or 7, as needed. On Day 5 following ICSI, a single 
blastocyst of the best quality available will be transferred; all remaining biopsied blastocysts will be 
frozen using the vitrification method. Laser-assisted trophectoderm biopsy for preimplantation 
genetic screening (PGS) will be done on Day 5; in the case of late blasulation, biopsy will be 
performed on Day 6 or Day 7, as needed. PGS results will not be used to select the blastocyst for 
fresh transfer.  No fresh transfers will be done on Day 6 or Day 7 blastocysts.
The evening of the day after oocyte retrieval, vaginal progesterone inserts (ENDOMETRIN®; 
Ferring) will be initiated for luteal phase support.  On the day that the progesterone inserts are 
initiated, only a single, 100 mg dose of ENDOMETRIN® will be given.  On subsequent days, two 
(2) doses of ENDOMETRIN® (100 mg / BID for a total of 200 mg/day) will be given.  
ENDOMETRIN® will be continued until the day of the -hCG test (10-14 days after blastocyst
transfer) if negative for pregnancy or if pregnancy is confirmed, will be continued for a maximum 
of 10 weeks.
Positive β-hCG will be confirmed by 2 positive -hCG tests, the first performed approximately 10-
14 days after blastocyst transfer with a second positive test 2 days later.  Clinical pregnancy will be 
confirmed by TVUS, indicating at least 1 intrauterine gestational sac with fetal heart beat at 6-7


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weeks gestation (4-5 weeks after blastocyst transfer).  Ongoing pregnancy will be confirmed by at 
least 1 intrauterine viable fetus at 10-11 weeks gestation (8-9 weeks after blastocyst transfer). 
For subjects with no ongoing pregnancy in the fresh cycle or for those receiving agonist trigger, 
single frozen blastocyst transfer cycles can be initiated within 6 months of a subject’s initial date of 
randomization.  Single blastocyst transfer is mandatory.  The PGS results can be used to select a
euploid blastocyst for frozen blastocyst transfer.  Frozen-thawed blastocyst transfer cycle data will 
be collected, including blastocyst transfer information (to include embryo grade, euploid status, 
endometrial thickness, presence of blood/mucus on transfer catheter tip, and whether blastocyst is 
retained in the catheter requiring a second pass), -hCG test results, clinical pregnancy, ongoing 
pregnancy, and live birth.
In women undergoing COS, an excessive response to follicular-stimulating agents may lead to the 
development of OHSS, which represents a spectrum that can be categorized as mild, moderate, or 
severe. Subjects who have an excessive response to ovarian stimulation (>30 follicles that are ≥12 
mm each and/or serum E2 ≥5000 pg/mL) will have the cycle cancelled and converted to freeze all 
with GnRH agonist trigger.  That is, the subject will receive 4 mg of leuprolide acetate administered 
subcutaneously at least 12 hours after the last dose of the GnRH antagonist; TVUS-guided oocyte 
retrieval will be performed approximately 36 hours later, and all resultant blastocysts will be 
vitrified after trophectoderm biopsy, with no fresh blastocyst transfer, to decrease the risk of OHSS.
All cases of OHSS will be considered AEs and will be recorded in the source documents for that 
subject and on the AE page in the eCRF.  Severe OHSS that requires medical or surgical 
intervention (i.e., paracentesis, hospitalization) is considered a serious adverse event (SAE).  
See Section 7.1.6 for definitions of mild, moderate, and severe OHSS.
Post-trial follow-up extends to collection of delivery information (live birth and neonatal health to 
include APGAR scores, birth weight, gestational age at birth, presence of congenital anomaly/birth 
defect, and cause of neonatal death, if applicable), which will be collected for all subjects with an 
ongoing pregnancy in the fresh cycle or the 6-month post-randomization frozen-thawed blastocyst 
transfer cycles.  Live birth rate after the fresh cycle and cumulative live birth rate after fresh and 6-
month post-randomization frozen-thawed blastocyst transfer cycles will be evaluated as part of the 
post-trial follow-up.
3.2
Planned Number of Trial Sites and Subjects
The study is planned to be conducted in 25-30 infertility centers in the US.  Approximately 
600 infertile females are to be randomized (1:1).
3.3
Discussion of Overall Trial Design and Choice of Control Groups
3.3.1
Trial Design
This is a multicenter, randomized, open-label, assessor-blind, parallel-group study to be conducted 
in female subjects undergoing COS following a GnRH antagonist protocol.  Each study center will 


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follow the study center’s standard practice for assisted reproductive technology (ART) unless 
otherwise noted in this protocol.  Subjects who are potential high ovarian responders will be 
enrolled; high ovarian responders will be classified based on a high serum level of AMH ≥5 ng/mL 
at the start of stimulation.  Eligible subjects will be randomly assigned to 1 of 2 treatment arms, 
either MENOPUR® or Gonal-f®; COS will continue for up to 20 days.
The primary objective of the trial is to demonstrate the non-inferiority of MENOPUR® versus 
Gonal-f® with respect to ongoing pregnancy rate in women undergoing COS following a GnRH 
antagonist protocol. The non-inferiority limit for the difference between treatments (MENOPUR®
minus Gonal-f®) will be -12% (absolute).
3.3.2
Selection of Endpoints
The efficacy endpoints in this study (ongoing pregnancy rate, positive β-hCG rate, clinical 
pregnancy rate, live birth rate, fertilization rate, number of oocytes retrieved, embryo quality, 
aneuploidy rate, and pregnancy loss) are typical endpoints to demonstrate the effectiveness of 
products used for ovarian stimulation and pregnancy in infertile subjects.  Safety endpoints of AEs, 
laboratory results, and OHSS are also typical.
3.3.3
Blinding
MENOPUR® is provided in a vial (powder), while Gonal-f® is provided in a pen and cartridge 
system. Therefore, a double-blind design is not feasible. The trial; however, is assessor-blind, 
ensuring unbiased evaluation by the individual performing the ultrasound monitoring,
embryologists, and central laboratory personnel. Furthermore, the primary endpoint for this trial is 
ongoing pregnancy rate, a clinically objective assessment.
3.3.4
Selection of Doses in the Trial
Either MENOPUR® or Gonal-f® will be administered subcutaneously once daily for up to 20 days 
at a dose of 75 IU to 300 IU.
3.3.5
Selection and Timing of Dose for Each Subject
The dose of the investigational medicinal product (IMP) (MENOPUR® or Gonal-f®) will be 
initiated at 150 IU for the first 5 days.  From stimulation Day 6 onward, based on follicular response 
assessed by TVUS, dosing can be adjusted every day, as needed, by 75 IU per adjustment.  
However, the maximum gonadotropin dose will be 300 IU/day; gonadotropin dosing can continue 
for a maximum of 20 days.
3.3.6
Withdrawal Criteria
A subject that withdraws from the study will not be replaced.  Every subject has the right to refuse 
further participation in the study at any time and without providing reasons.  A subject's 
participation is to terminate immediately upon her request.  The Investigator should seek to obtain 
the reason and record this in the source documents and eCRF.


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If, at the time of refusal, a dose of the study product has already been administered, the subject must 
be advised to consider follow-up safety investigations that will include all procedures outlined for 
the end of treatment (EOT) Visit.
The subject can also be withdrawn from the study at any time at the discretion of the Investigator; 
the reason should be discussed with the Sponsor prior to discontinuation and fully documented in 
the source documents and eCRF.
3.3.7
Follow-up Procedures
Subjects will return to the study center for regular scheduled clinic visits as required per protocol 
for measurement of hormone levels, TVUS, 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; subjects with a 
positive test result will have a second confirmatory test performed 2 days later.
Clinical pregnancy will be confirmed by TVUS, indicating at least 1 intrauterine gestational sac 
with fetal heart beat at 6-7 weeks gestation (4-5 weeks after blastocyst transfer).  Ongoing 
pregnancy will be confirmed by at least 1 intrauterine viable fetus at 10-11 weeks of gestation 
(8-9 weeks after blastocyst transfer).
For subjects with no ongoing pregnancy in the fresh cycle, single frozen blastocyst transfers can be 
initiated within 6 months of the date of the subject’s initial randomization.  The PGS results can be 
used to select a euploid blastocyst for frozen transfer(s).
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 the fresh cycle or the 6-month 
post-randomization frozen-thawed blastocyst transfer cycles.  Frozen-thawed blastocyst transfer 
cycle data will be collected, including blastocyst transfer information, β-hCG test results, clinical 
pregnancy, and ongoing pregnancy.  Live birth rate after the fresh cycle and cumulative live birth 
rate following the fresh and 6-month post randomization start frozen-thawed cycles (if applicable) 
will be evaluated as part of the post-trial follow-up.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
To be eligible for participating in the trial, subjects must satisfy the following criteria:
1.
Signed informed consent, prior to any study-related procedure.
2.
Females aged 21 to 35 years with regular ovulatory menstrual cycles of 21 to 45 days, with 
a BMI between 18 and 30 kg/m2 who desire pregnancy.
3.
Subjects must be high responders, defined as subjects who have a serum AMH ≥5 ng/mL at
screening.
4.
Documented history of infertility (e.g., unable to conceive for at least 12 months or for at 
least 6 months if receiving donor sperm) with a Day 2 or Day 3 serum FSH level between 1 
and 12 IU/L (inclusive), the results of which should be obtained within 6 months prior to 
screening. The highest FSH result within 6 months prior to screening will be considered for 
inclusion.  Patients with documented bilateral tubal occlusion established as a cause of 
infertility are eligible at diagnosis.
5.
Male partner with semen analysis that is at least adequate for ICSI at screening or within 6 
months prior to the screening date.  Partners with severe male factors requiring invasive or 
surgical sperm retrieval may not be used.  Use of donor sperm is allowed.
6.
Willing to accept transfer of 1 blastocyst per cycle.
7.
At least 1 cycle with no fertility medication immediately prior to screening.
8.
Hysterosalpingography, hysteroscopy, or saline hysterosonogram documenting uterine 
anatomy appropriate for ART at screening or within 12 months prior to screening.
9.
TVUS documenting presence and adequate visualization of at least 1 ovary, without 
evidence of abnormality (e.g., no endometrioma, no dermoid cysts) and normal adnexa 
(e.g., no hydrosalpinx) at screening.
10. Total testosterone, prolactin, and thyroid-stimulating hormone (TSH) within the normal 
limits for the clinical laboratory or considered not clinically significant by the Investigator
at screening or within 12 months prior to screening.  Note: Subjects with high TSH levels 
who receive replacement therapy and are considered adequately controlled can be enrolled 
at the discretion of the Investigator.
11. Pap smear test results that are appropriate for ART, in the opinion of the Investigator, at 
screening or within the last 24 months prior to screening.
12. Negative serum hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency 
virus (HIV) antibody, and rapid plasma reagin tests at screening or within 6 months prior to 
screening.
13. Willing and able to comply with the protocol for the duration of the study.


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4.1.2
Exclusion Criteria
Subjects with any of the following are to be excluded from study participation:
1.
Known stage III-IV endometriosis (American Society for Reproductive Medicine, 2012).
2.
Oocyte donor or embryo recipient; gestational or surrogate carrier.
3.
History of recurrent miscarriage not followed by a live birth (recurrent is defined as two (2) 
or more consecutive miscarriages)
4.
Previous IVF or ART failure due to a poor response to gonadotropins.  Poor response is 
defined as development of ≤2 mature follicles or history of 2 previous failed cycle 
cancellations prior to oocyte retrieval due to poor response.
5.
Inadequate number of oocytes, defined as fewer than 5 oocytes retrieved in previous ART 
attempts.
6.
Early follicular phase total antral follicle count (diameter 2-10 mm) <10 for both ovaries 
combined (results obtained at screening or within 12 months prior to screening).
7.
Subject’s male partner, with obvious leukospermia (>2 million white blood cells/mL) or 
signs of infection in semen sample within 6 months of the subject’s screening.  If either of 
these conditions exists, the male should be treated with antibiotics and retested prior to the 
subject’s randomization.
8.
Known abnormal karyotype of subject or her partner.
9.
The use of hormonal birth control within 3 months prior to screening.
10. Use or plan to use any of the following medications during the pre-treatment and treatment 
phase: hormonal drug products (including estrogen, androgen supplementation, i.e., DHEA, 
androgen patch) progesterone creams, progesterone in oil injections, hydrocortisone, and 
other steroid drug products, and fertility modifiers such as insulin sensitizers.  Occasional 
use of inhaled or topical corticosteroids may be permitted.
11. The presence of any uncontrolled systemic disease.
12. Currently breastfeeding, pregnant, or has a contraindication to pregnancy that would 
preclude participation in the trial.
13. Presence of abnormal uterine bleeding of undetermined origin.
14. Findings at the gynecological examination that preclude gonadotropin therapy, in the 
opinion of the Investigator.
15. History of chemotherapy (except for gestational conditions) or radiotherapy.
16. Current or recent substance abuse, including alcohol.
17. Current or recent (3 months prior to screening) smoking more than 3 cigarettes per day.
18. Documented intolerance or allergy to any of the medications used, including the study 
medication.
19. Participation in any experimental drug study within 30 days prior to screening.


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20. Refusal or inability to comply with the requirements of the protocol for any reason, 
including scheduled clinic visits and laboratory tests.
21. Known mental incapacity or language barrier precluding adequate understanding of the 
informed consent information and the study activities.
22. Clinic staff member directly involved in the conduct of the study.  Any other staff member 
interested in participating must obtain Institutional Review Board (IRB) approval prior to 
participation.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The site will recruit subjects based on the inclusion/exclusion criteria and local recruitment 
practices.  Recruitment materials cannot be used prior to IRB approval.
4.2.2
Randomization
Randomization list will be generated by the study statistician prior to the first subject’s first visit.  
Each subject will be randomized to 1 of the 2 treatment arms, MENOPUR® or Gonal-f®,
immediately prior to administration of study drug.  Randomization numbers will be allocated 
sequentially to the subjects in the order in which the subjects are randomized.
Under no circumstances will subjects be permitted to re-randomize for a second time in this study.
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Any concomitant therapies used during the study or within 1 month prior to screening will be 
recorded in the source documents and eCRF, along with the main reason for their prescription/use.
4.3.2
Prohibited Therapy
Use of any medications other than the study medication provided for this study should be avoided 
from the screening period until completion of the study.  Occasional use of over-the-counter 
medications or prescription drugs may be allowed, except for those listed in Section 4.1.2.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Products
Each IMP will be administered subcutaneously once daily for up to 20 days at a dose of 75 IU to 
300 IU.

MENOPUR® (menotropins for injection) manufactured by Ferring Pharmaceuticals Inc.,
will be provided as a vial with powder (75 IU FSH activity and 75 IU LH activity) and a vial 
with diluent.  After reconstitution, each vial delivers 75 IU of FSH activity and 75 IU of LH 
activity.

Gonal-f® (follitropin alpha for injection) a human follicle stimulating hormone (FSH) 
preparation of recombinant DNA origin manufactured by EMD Serono Inc., will be 
provided as pen and cartridges filled with either 300 or 450 IU of FSH activity.
5.1.2
Non-Investigational Medicinal Products (NIMPs)
The NIMPs include the following.

Ganirelix® (ganirelix acetate injection), manufactured by Merck, will be provided as a pre-
filled syringe (0.5 mL) delivering 0.25 mg Ganirelix.  A daily dose of 0.25 mg will be 
continued throughout the gonadotropin treatment period.

Ovidrel® (choriogonadotropin alfa), manufactured by EMD Serono Inc., will be provided as 
a pre-filled syringe (0.5 mL) delivering 250 μg choriogonadotropin alfa, to be administered 
as a single injection as soon as 3 follicles of ≥17 mm are observed on TVUS.

ENDOMETRIN® (Progesterone), manufactured by Ferring Pharmaceuticals Inc., will be 
provided as inserts to be administered vaginally. On the day that the progesterone inserts are 
initiated, only a single, 100 mg dose of ENDOMETRIN® will be given.  On subsequent 
days, ENDOMETRIN® will be administered 2 times daily, each delivering 100 mg of 
Progesterone (200 mg/day).  ENDOMETRIN® will be initiated the evening of the day after 
oocyte retrieval and will continue until the day of the second -hCG test (if negative) or if 
pregnancy is confirmed by the second -hCG test for a maximum of 10 weeks total.
5.2
Characteristics and Source of Supply
All medicinal (IMP and NIMP) products will be provided by Ferring Pharmaceuticals Inc. and will 
be handled according to the principles of Good Manufacturing Practice.
5.3
Packaging and Labeling
Packaging and labeling of the medicinal products will be performed under the responsibility of the 
IMP department at Ferring Pharmaceuticals A/S in accordance with Good Manufacturing Practice
and national regulatory requirements.


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All IMP will be provided to the investigational site as vials with powder and prefilled syringes with 
solvent MENOPUR® or as pen and cartridges filled with solution (Gonal-f®) in its original 
packaging.  Subjects will self-administer study drug subcutaneously once daily for up to 20 days.  
The label of the IMP and NIMP will contain 1 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 as per the label for each drug.  The storage compartment shall 
be monitored regularly with a minimum-maximum thermometer and the values shall be 
documented.  Deviations in storage temperature must be reported to the Sponsor without delay and 
the IMP must not be used until acceptance from the Sponsor is received.  See package inserts for 
specific storage and use instructions of MENOPUR® (menotropins for injection [package insert] 
2014), Gonal-f RFF® Redi-ject™ (follitropin alfa injection [package insert] 2014), Ganirelix®
(ganirelix acetate injection [package insert 2013]), Ovidrel® (choriogonadotropin alfa [package 
insert] 2014), and ENDOMETRIN® (Progesterone) [package insert] 2014).
The IMPs (MENOPUR® or Gonal-f®) will only be administered to subjects who meet the eligibility 
criteria and are randomized to a treatment group in the study.
5.5
Blinding/Unblinding
The study is assessor blind trial to individuals performing the ultrasound monitoring, embryologists, 
and central laboratory personnel.
5.6
Treatment Compliance
5.6.1
Dispensing and Accountability
The IMP will only be dispensed to subjects who meet the eligibility criteria and are randomized to a 
treatment arm in the study.
The Investigator or designee will maintain a drug-dispensing log detailing the dates and quantities 
of IMPs dispensed to, and used by, each subject.  The monitor will verify drug accountability 
during the study.  In order to monitor compliance, the subjects are to return the empty, partially 
used, and unused vials to the Investigator at each visit.  The Investigator or designee 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.
5.6.2
Return and Destruction of Investigational Medicinal Products 
The Monitor will check the supplies, the drug accountability, and inventory records.  Following this 
check, the Investigator or designee will sign off the records.


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The Sponsor must issue a written approval prior to any destruction of IMP/NIMP.  Any destruction 
document must clearly identify the study code, batch number, subject numbers involved, and the 
quantities of IMP/NIMP destroyed, including treatment visits, if applicable.
All used IMP/NIMP can be destroyed at the study site after the drug accountability has been 
finalized and signed off by the Investigator.  This includes residual liquid in a vial or ampoule 
(where no second dose can be withdrawn).
Used syringes and needles should be destroyed immediately after usage according to normal 
procedures at each study site. 
Any unused IMP/NIMP will be returned for destruction, as instructed by the IMP Department, 
Ferring Pharmaceuticals A/S, 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 the Sponsor. 
5.7
Auxiliary Supplies
Sponsor will provide the site with syringes and needles for administration of MENOPUR® 75 IU.


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6
TRIAL PROCEDURES
The trial procedures for subjects are shown in Table 1.


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Table 1
Trial Assessments
Timing
Screening
Pre-treatment
Stimulation
Post 
Trigger
Oocyte 
retrieval
Transfer
Pregnancy monitoring
End
β-hCG
Clinical
Ongoing
EOT1
<90 days before 
Visit 2
Day 1
(Cycle 
Day 2-3)
Day 6
Protocol stimulation 
monitoring, Ovidrel®
hCG injection
Post-hCG
dose
36 h (±2 h) 
after hCG
5 days after 
oocyte 
retrieval
10-14 days after
blastocyst transfer
4-5 weeks 
after 
blastocyst
transfer
8-9 weeks 
after 
blastocyst 
transfer
Visit
Visit 1
Visit 2
Visit 3
Unscheduled
Visit 4
Visit 5
Visit 6
Visit 7a
Visit 7b
Visit 8
Visit 9
Written informed consent
X
Inclusion/exclusion criteria
X
X
Demographics, medical/infertility history
X
Physical examination, vital signs
X
X
Gynecological examination with 
Pap smear2
X
Pregnancy test 
X
X
X
X3
Local laboratory (standard of care E2, P4, 
hCG, LH)
X
X
X
X4
Central laboratory (E2, P4, hCG, 
testosterone, androstenedione, DHEA, 
FSH, LH)
X5
X
X6
X7
Central laboratory (AMH, chemistry, 
hematology)
X
X11
Screening laboratory
X8
Randomization, dispense IMP
X9
TVUS (study-specific)
X
X
X
X
X
X12
X
X
Oocyte retrieval
X
Blastocyst transfer/freezing
X
Drug accountability (IMP only)
X
X
X
X
Concomitant medications
X10
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X


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1.
EOT 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 study.
2.
Pap smear if not done in the previous 24 months.
3.
For subjects who have a positive serum β-hCG at visit 7a.  If conflicting results are obtained in the first 2 tests (visits 7a & 7b), a third test will be performed 2 days after the second test.
4. 
Including hCG or LH (if leuprolide acetate is given) in the morning.
5.
No hCG on Day 1 of stimulation.
6.
Blood samples for central and local laboratory testing must be drawn on the last day of stimulation.  Since the final day of stimulation may not be known until the late afternoon or evening of the hCG trigger dose, an extra 
blood sample/tube will be collected and stored onsite for each day of stimulation monitoring to ensure the final day of stimulation is collected.
7.
Only P4 and E2 will be collected and sent to the central laboratory for the post trigger/Visit 4.
8.
Screening labs: total testosterone, TSH, prolactin within 12 months prior to screening; FSH (Day 2/3), HIV, rapid plasma reagin, hepatitis B antigen, and hepatitis C antibody within 6 months prior to screening.
9.
The gonadotropin starting dose is 150 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.
10.
Collect/document all medications taken within 30 days prior to screening.
11.
No AMH to be drawn at EOT.
12.
At Visit 6, a transabdominal or transvaginal ultrasound will be performed to assess endometrial thickness and echogenicity.


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6.1
Visit 1 - Screening and Pre-stimulation Period
Screening can take place within 90 days prior to Visit 2.
After giving written informed consent, the subject will be screened based on the following:
- inclusion/exclusion criteria
- medical and infertility history (including well documented gynecological and menstrual 
history)
- complete physical examination, including vital signs and BMI
- gynecological examination (including Pap smear if not performed within the previous 24 
months )
- record concomitant medications taken within 1 month of screening
- uterine cavity appropriate for ART on hysterosalpingography, hysteroscopy, or saline 
sonohysterogram within 12 months prior to screening
- normal ovaries and adnexa on TVUS (at screening)
- total antral follicle count (diameter 2-10 mm) ≥10 for both ovaries combined
- serum pregnancy, chemistry, hematology, AMH levels via the central laboratory, and FSH. 
Screening will also be based on total testosterone, prolactin and TSH within 12 months of screening
and FSH (Day 2/3), HIV, hepatitis B antigen, hepatitis C antibody, and rapid plasma reagin within 
6 months of screening.
Copies of all reports must be filed in the subject’s chart. 
Each study center will follow its standard of practice guidelines for ICSI within the study 
parameters noted in this protocol.  Evaluation of the partner's fertility potential (semen analysis)
should be included in the work-up if it was not done within the previous 6 months. 
Re-screens are not allowed.
6.2
Visit 2 - Randomization and Start of Controlled Ovarian Stimulation, Cycle Day 2-3 
After all inclusion/exclusion criteria are met, subjects will be randomized to undergo COS with 
either MENOPUR® or Gonal-f® in a GnRH antagonist cycle.  The study medication will be 
initiated on the second or third day of spontaneous bleeding, after documentation of a negative 
urine or serum pregnancy test completed at the local onsite laboratory.  The starting total daily dose 
for subjects in both arms will be 150 IU for the first 5 days.  A review of concomitant medications 
and updated medical history will also be completed and a TVUS will be performed. E2, P4, 
testosterone, androstenedione, DHEA, FSH, LH will be drawn. 
6.3
Visit 3 - Stimulation Follow-up (Day 6) and Unscheduled Visits
After 5 days of treatment with a dose of 150 IU (Day 6 of stimulation), the subject will return to the 
clinic for monitoring and adjustment of gonadotropin dose, as needed.  A TVUS will be performed 
and serum hormone levels (E2, P4) will be collected and evaluated via the local laboratory.  The 
start/stop dates, dosages, duration of treatment, and results of all ultrasounds and blood analyses 


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obtained during the stimulation will be documented in the eCRF as well as concomitant 
medications and AEs.
Based on follicular response assessed by TVUS, dosing can be adjusted daily as needed by 75 IU 
per adjustment.  However, the minimum daily total dose is 75 IU and the maximum total daily dose
of study drug may not exceed 300 IU.  Dosing with HP-hMG or Gonal-f® can continue for a 
maximum of 20 days.
When the lead follicle measures ≥14 mm and/or serum E2 levels are ≥300 pg/mL, the GnRH 
antagonist (ganirelix acetate) will be initiated at a daily dose of 0.25 mg and continued throughout 
the gonadotropin treatment period and the exact stimulation day of administration will be 
documented in the eCRF. 
Subjects will be monitored per the center’s standard practice during the stimulation dosing between 
Days 7 to 20 or until the stimulation phase is complete or study treatment is discontinued.  
Although these visits are not protocol-specific and can vary based on each centers standard of care, 
the results of the TVUS, E2 levels, P4 levels, concomitant medications, and AEs will be 
documented in the eCRF as unscheduled stimulation visits.  The TVUS and blood results from the 
final day of stimulation (day of hCG trigger administration) will be documented in the eCRF and 
blood samples sent to the central laboratory.  Since the final day of stimulation may not be known 
until the late afternoon or evening of the hCG trigger dose, an extra blood sample/tube will be 
collected and stored onsite for each day of stimulation monitoring to ensure the final day of 
stimulation is collected. Subjects will receive a single subcutaneous injection of Ovidrel®
(choriogonadotropin alfa, r-hCG) to induce final follicular maturation when ≥3 follicles of ≥17 mm 
are detected on TVUS.  
The time between two Ganirelix® injections as well as the time between the last Ganirelix injection 
and the hCG injection should not exceed 30h.

When injecting Ganirelix in the morning, treatment with Ganirelix should be continued 
throughout the gonadotropin treatment period including the day of triggering final follicular 
maturation.

When injecting Ganirelix in the afternoon, the last Ganirelix injection should be given in the 
afternoon prior to the day of triggering final follicular maturation.
Important Note: coasting is prohibited.  If the criteria for hCG administration is not met after 
20 days of treatment (i.e., subject does not have ≥3 follicles ≥17 mm in size), the subject will be 
discontinued from study treatment.  An EOT Visit will be scheduled or completed at this time and 
the information will be documented in the eCRF.
Subjects are to return the pens and empty, partially used, and unused vials/cartridges of the IMP to 
the site in order to monitor compliance.  The coordinator or designee will reconcile and document 
the returned drug product in the drug accountability log.


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6.4
Visit 4 - Day Following Administration of Ovidrel®
The subject will return to the center (in the morning) the day following the Ovidrel® injection for 
P4 and E2 samples to be submitted to the central laboratory; serum hCG will be analyzed at the 
local lab.  A TVUS will be performed.  The date, time, and dosage of Ovidrel® will be recorded as 
well as study medication compliance.  Adverse events and concomitant medications will be 
assessed and documented.  Any symptoms of OHSS will be closely monitored.
The cycle will be cancelled in case of poor ovarian response (if the Investigator judges that 
≥3 follicles of ≥17 mm cannot be reached after a minimum of 10 days of stimulation).  
Subjects who have an excessive response to ovarian stimulation (>30 follicles of ≥12 mm and/or E2 
≥5000 pg/mL) will have the fresh transfer cancelled, and the hCG trigger will be replaced with a 
GnRH agonist trigger (4 mg leuprolide acetate). If leuprolide acetate is administered, a blood 
sample for LH will be collected and analyzed at the local lab. All resultant expanded blastocysts 
will be vitrified after trophectoderm biopsy, with no fresh blastocyst transfer in order to decrease
the risk of OHSS.  Following oocyte retrieval and blastocyst evaluation, an End of Trial (EOT)
Visit will be scheduled or completed and the information will be documented in the eCRF.
In order to minimize the risk of empty follicle syndrome, the subject will return the morning after 
hCG trigger to draw serum hCG, E2, and P4 levels.  If the hCG level is <50 IU/L and/or P4 is 
<3.5 ng/mL, then a booster/rescue second dose of hCG must be given on that day as soon as 
possible.  If the subject received the GnRH agonist trigger, the bloods drawn will be LH, E2, and 
P4 levels.  If, after the GnRH agonist trigger, the LH is <15 IU/L and/or the P4 <3.5 ng/mL, a 
rescue/booster dose of hCG (Ovidrel®) should be given as soon as possible.  Delay of oocyte 
retrieval will be left to the clinician’s discretion and will be based on the time at which the rescue 
dose was administered.
6.5
Visit 5 - Oocytes Retrieval/Insemination
A TVUS will be performed and oocytes retrieved roughly 36 hours after hCG administration.  
Oocytes will be inseminated using partner or donor sperm by ICSI 4±1 hours after retrieval.  
Oocyte maturity will be assessed at the time of ICSI.  Fertilization (number of pronuclei) will be 
checked on Day 1 following oocyte retrieval.  Embryos must be cultured individually in separate 
dishes/droplets following the Day 1 assessment.  Embryo quality will be assessed on Days 3 and 5
following oocyte retrieval; in the case of late blasulation, assessment will be performed on Day 6 or 
Day 7, as needed.  A standardized embryo grading system will be used and documented in the 
eCRF.  Adverse events and concomitant medications will be assessed and documented.
Each subject will be provided with vaginal progesterone inserts (200 mg/day – ENDOMETRIN®) 
to begin luteal support on the evening of the day after oocyte retrieval.  The dose will be 
administered following the instructions provided in the package insert.  Luteal phase support will 
continue until negative -hCG (10-14 days after blastocyst transfer) or 8-9 weeks gestation, if 
pregnant.


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6.6
Visit 6 - Blastocyst Transfer
On Day 5 following ICSI, a single blastocyst of the best quality available will be transferred; all 
remaining blastocysts will be frozen using the vitrification method.  A transabdominal pelvic 
ultrasound or transvaginal ultrasound will be performed to assess the endometrial thickness and 
echogenicity pattern.  Laser-assisted trophectoderm biopsy for preimplantation genetic screening 
(PGS) will be done on Day 5; in the case of late blasulation, biopsy will be performed on Day 6 or 
Day 7, as needed.  All expanded blastocysts with Blastocyst Expansion and Hatching Status 3-6, 
Inner Cell Mass grading A or B, and Trophoectoderm Grading A, B, or C. (Gardner & Schoolcraft, 
1999) should be biopsied.  The results of the PGS will not be available prior to the fresh blastocyst 
transfer, but can be used for subsequent frozen blastocyst transfer cycles, if needed. Adverse events 
and concomitant medications will be assessed and documented.
The residual cells obtained from ART (including granulosa cells, immature eggs, eggs that do not 
fertilize, sperm that is left over after fertilization, or embryos that stop developing, developed 
abnormally, are aneuploid or that would be discarded after other embryos are selected for embryo 
transfer or freezing) may be considered for use for further research in a future sub-study.  Some of 
the research may be genetic and/or may be used for some of the following reasons.  
•
To further our understanding of how patients’ genetics affect the response to medications 
designed for ovarian stimulation.
•
To develop new techniques to optimize our understanding of genetic and chromosomal 
regulation in eggs, sperm, and embryos.
•
To improve embryonic efficiency by assessing genes, DNA, RNA, proteins, chromosomes
and cellular pathologies.
•
To characterize normal and abnormal expression of genes and their functions, as well as 
downstream effects of transcription and translation.
•
To determine the frequency of embryo mosaicism and chromosomal irregularities 
(inversions, translocations, deletions, etc.) 
•
To study proteins and their structure, functions, and interactions. 
Subjects who wish to participate in such a sub-study will be asked to consent to the donation of this 
material.
6.7
Visits 7, 8, and 9 - Pregnancy Monitoring

Visit 7: All subjects will be required to return to the clinic approximately 10-14 days after 
blastocyst transfer for β-hCG assessment. If the first serum β-hCG is positive, a second 
confirmatory test will be performed approximately 2 days later. If the pregnancy test is 
negative, ENDOMETRIN® will be discontinued and EOT procedures completed.  If 
conflicting results are obtained in the first 2 tests, a third test will be performed 2 days after 
the second test.  If a positive β-hCG is confirmed, ENDOMETRIN ® will continue up to 
10 weeks from the time it was initiated until the EOT Visit.

Visit 8: Subjects who are pregnant will return to the clinic 4-5 weeks after blastocyst 
transfer for clinical pregnancy assessment (TVUS showing at least 1 intrauterine gestational 
sac with fetal heartbeat).


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
Visit 9: Subjects with clinical pregnancy will return to the clinic 8-9 weeks after blastocyst 
transfer for assessment of ongoing pregnancy (presence of at least 1 intrauterine pregnancy 
with a viable fetus with a detectable fetal heartbeat).
An End of Trial (EOT) Visit will be scheduled or completed for non-pregnant subjects and 
the information will be documented in the eCRF.
Non-pregnant subjects: Subjects without 2 positive β-hCG tests, clinical pregnancy, or ongoing 
pregnancy in the fresh cycle, may undergo a single frozen blastocyst transfer within 6 months of 
each subject’s date of randomization.  The PGS results can be used to select the euploid blastocyst 
for frozen transfer.  Frozen-thawed blastocyst transfer cycle data will be collected, including 
blastocyst transfer information (endometrial thickness and echogenicity, grade of blastocyst, ploidy 
of blastocyst, presence of blood, or mucus within catheter tip), -hCG serum results, clinical 
pregnancy, and ongoing pregnancy for the first frozen blastocyst transfer cycle following negative 
pregnancy.
Subjects may also return to the study center for regularly scheduled clinic visits as required per 
study center standard of care.  The data collected during these visits will not be documented in the 
eCRF unless it is new or is a change in concomitant medications, pregnancy, or AEs.
6.8
End of Trial (EOT) Visit
EOT assessments will be performed at the subject’s last scheduled visit.  If the EOT visit cannot be 
scheduled on the same day as the last scheduled visit, it can be done the following day.  In the case 
of premature discontinuation from the study, an EOT visit will be completed within 2 weeks after 
the subject’s last scheduled visit.
A physical examination will be done and vital signs will be recorded.  The following laboratory 
tests will be performed by a central laboratory (no AMH will be drawn):

Serum chemistry: non-fasting glucose, blood urea nitrogen, creatinine, potassium, sodium, 
chloride, calcium, aspartate aminotransferase, alanine aminotransferase, and gamma-
glutamyl transferase.

Hematology:  red blood cell count, white blood cell count, hematocrit, hemoglobin, platelet 
count, and differential count.
Adverse events and concomitant medications will be assessed and documented and drug 
accountability will be performed.
6.9
Pregnancy Follow-Up
After confirmation of ongoing pregnancy in the fresh cycle or the 6-month post-treatment frozen-
thawed blastocyst transfer cycle, the site will be required to collect delivery information (live birth 
and neonatal health).  The follow-up will be conducted by the study center via telephone or mail
and recorded in the eCRF.  The site will also document miscarriage/pregnancy loss (spontaneous 
and/or induced), date of live birth, number of deliveries, gestational age at delivery, birth weight at 
deliveries, gender, and congenital anomalies/birth defects.  Live birth rate after the fresh cycle and 


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cumulative live birth rate after fresh and 6-month post-treatment frozen-thawed transfer cycles will 
be evaluated as part of the pregnancy follow-up.


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
7.1.1
Pregnancy Tests and Pregnancy Monitoring
Positive β-hCG will be based on the detection of 2 positive β-hCG tests in serum via central 
laboratory.  -hCG pregnancy tests will be performed for all subjects 10-14 days after blastocyst
transfer, with a second test approximately 2 days later, if the first test is positive.  If conflicting 
results are obtained in the first 2 tests, a third test will be performed 2 days after the second test. 
Subjects who achieve pregnancy (2 positive serum pregnancy tests) will be followed up for clinical
and ongoing pregnancy at 2 additional study visits.
Clinical pregnancy will be based on detection of intrauterine gestational sac and/or fetal heart 
movement on TVUS at approximately 4-5 weeks post-blastocyst transfer.  Ongoing pregnancy will 
be based on detection of at least 1 intrauterine viable fetus at 10-11 weeks gestation (8-9 weeks 
after blastocyst transfer).
7.1.2
Oocyte Retrieval and Blastocyst Transfer
Information regarding the total number of oocytes retrieved, the number of mature oocytes 
obtained, number of oocytes undergoing ICSI, and number of fertilized (2PN) oocytes will be 
documented in the eCRF. Blastocyst transfer cycle data will be collected and documented in the 
eCRF including: endometrial thickness in mm, grade of blastocyst transferred, and presence of 
blood or mucus within the catheter tip after transfer is completed.
7.1.3
Transvaginal Ultrasounds
Transvaginal ultrasounds (including ovaries, adnexa, endometrial thickness in mm, follicular 
development - diameter of each follicle in mm, hyper- or hypo-echogenicity will be documented 
and recorded in the eCRF), and if pregnant, presence of  intrauterine gestational sac, fetal pole, 
and/or fetal heartbeat, will be collected.  Other ultrasounds may be performed throughout the ICSI 
treatment per standard practice but will not be documented in the eCRF.
7.1.4
Central Laboratory Tests
The following laboratory tests will be performed by a central laboratory:

Screening and EOT Visit:  serum chemistry: non-fasting glucose, blood urea nitrogen, 
creatinine, potassium, sodium, chloride, calcium, aspartate aminotransferase, alanine 
aminotransferase, and gamma-glutamyl transferase.

Screening and EOT Visit: hematology: red blood cell count, white blood cell count, 
hematocrit, hemoglobin, platelet count, and differential count.

Screening:  AMH (all subjects will have an AMH sample taken).  This must be at least 3 
months after the cessation of any hormonal birth control and may be repeated 1 additional 
time to determine eligibility.


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
Day 1, Day 6, final day of stimulation:  FSH, hCG, LH, androstenedione, total testosterone, 
and DHEA.

Day 1, Day 6, final day of stimulation, and Visit 4 (in the morning following hCG 
administration):  E2, P4.
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.
7.1.5
Local Laboratory Tests
The following laboratory tests will be performed at each site’s local or reference laboratory per 
standard practice and will be reviewed by the Investigator.  All blood draws should be non-fasting.  
The results must be available and documented in the subject’s chart and eCRF (if applicable).

Hormones: 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. Early follicular phase (Day 2/3) serum levels of 
FSH should be documented between 1- 12 IU/L (inclusive) at screening or in the preceding 
6 months prior to screening. 

Other laboratory assessments: negative serum hepatitis B surface antigen, hepatitis C 
antibody, HIV antibody, and rapid plasma reagin tests are to be done at screening or within 
6 months prior to screening and documented to be within normal limits. 

FSH (cycle Day 2-3) within 6 months of screening.

E2, P4, LH, and serum β-hCG tests collected at various time points during stimulation and 
luteal support.
7.1.6
Ovarian Hyperstimulation Syndrome Monitoring
In women undergoing COS, an excessive response to follicular stimulating agents may lead to the 
development of OHSS, which has a spectrum that can be categorized as mild, moderate, or severe.  
If OHSS is suspected, the subject should have a TVUS to document ovarian size and presence of 
ascites, as well as serum chemistry and hematology (see screening laboratories).


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Table 2
Classification of Mild, Moderate, and Severe OHSS
Mild OHSS
Grade 1: Abdominal distension and discomfort
Grade 2: Features of Grade 1 plus nausea/vomiting and/or diarrhea.  Ovaries enlarged to 5-12 cm.1
Moderate OHSS
Grade 3: Features of mild OHSS plus ultrasonic evidence of ascites.2
Severe OHSS
Grade 4: Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax 
(or breathing difficulties).  Paracentesis due to OHSS symptoms.3
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.4  
Hospitalization due to OHSS symptoms.
1.
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.
2.
For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, vesicouterine
pouch, etc.) should be estimated by measuring the greatest diameter and its greatest perpendicular diameter, and multiplying 
these 2 numbers (the unit will be cm2).  Peritoneal fluid is the total size of all fluid pockets in the pelvis.
3.
In case of paracentesis, the volume of fluid drained should be measured.
4.
Hemoconcentration is defined as hematocrit >45 %.  Electrolyte disturbances are
defined as hyponatremia 
(sodium <135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L).  Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time, or abnormal activated partial thrombin time.  Diminished renal perfusion 
is defined as creatinine >1.2 mg/dL.  Oliguria is defined as urine output less than 500 mL/24 hours.  Anuria is defined as failure 
to produce urine.  If applicable, actual volume of urine output will be recorded.
All cases of OHSS will be considered AEs and will be recorded in the source documents for that 
subject and on the AE page in the eCRF.  Severe OHSS that requires medical or surgical 
intervention (i.e., paracentesis or hospitalization) is considered an SAE (see Section 8.4).
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation.  
Classification of grade is according to Golan’s classification system (Golan, 1989) and all OHSS 
cases will be graded as mild, moderate, or severe.  Preventive interventions for early OHSS cover 
cycle cancellation due to excessive ovarian response, triggering of final follicular maturation with 
GnRH agonist, and administration of dopamine agonist (the latter is only considered as preventive 
intervention in subjects with ≥20 follicles of ≥12 mm).
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation.
7.1.7
Concomitant Medications
At each study visit, subjects will be queried regarding use of any medication other than study drug 
since the last visit.  Any use of prior medication or concomitant medication will be recorded in the 
source documents and eCRF and include the following information:  name of medication, total 
daily dose, route of administration, start and stop dates, and reason for use.  If the reason for the use 
of concomitant medication meets the definition of an AE, the AE should be recorded in the source 
documents for that subject and on the AE page in the eCRF.


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7.2
Other Assessments
7.2.1
Physical and Gynecological Examinations
A complete physical and gynecological examination will be performed at screening (including 
height, weight, BMI calculation, and pelvic and breast examinations).  In addition, a Pap smear will 
be performed at screening if not done in the previous 24 months.  If done in the previous 24 
months, a copy of the report must be filed in the subject’s chart.
7.2.2
Medical History/Menstrual History
A complete medical and gynecological history will be obtained at screening and will include a 
review of prior medical history, menstrual history, concurrent conditions by body system, history of 
alcohol, tobacco, and drug use, and female reproductive status.  Medical history findings will be 
recorded in the subject’s chart and eCRF.
7.2.3
Vital Signs
Blood pressure, heart rate, and temperature will be measured at screening.  Blood pressure and 
heart rate are to be measured while the subject is seated under resting conditions.
7.2.4
Number of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit.
7.2.5
Metaphase II Oocytes
Maturity stage will be assessed prior to undergoing ICSI.  Maturity stage will be categorized as 
germinal vesicle, metaphase I, metaphase II, degenerated, or other.
7.2.6
Fertilization Rate
The number of pronuclei will be counted on Day 1 post-insemination and recorded.  Fertilization 
rate is the number of 2PN oocytes divided by the number of oocytes retrieved.
7.2.7
Number and Quality of Embryos on Day 3
Each embryo will be evaluated on Day 3 post-insemination. The quality evaluation will consist of 
assessment of cleavage stage and embryo morphology parameters (blastomere uniformity, cell size, 
degree of fragmentation, and visual signs of multinucleation).
Cleavage stage will be defined by the number of blastomeres.
Blastomere uniformity will be classified as equally sized blastomeres or unequally sized 
blastomeres (largest blastomere >25% larger in average diameter compared to the smallest 
blastomere).
Cell size will be classified as stage-specific cell size or not stage-specific cell size.


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Degree of fragmentation will be classified as 1 of the following: 0%, 1-10%, 11-20%, 21-25%, 26-
30%, 31-50%, or >50% fragmentation, or totally fragmented (no blastomeres recognized).
Visual sign of multinucleation will be evaluated as a yes or no.
7.2.8
Number and Quality of Blastocysts on Day 5
Blastocyst Expansion and Hatching Status, Blastocyst Inner Cell Mass Grading, and 
Trophectoderm Grading
The quality evaluation of blastocysts on Day 5 after oocyte retrieval will consist of assessment of 3
parameters: blastocyst expansion and hatching status, blastocyst inner cell mass grading, and 
trophectoderm grading. The scoring is based on the classification system by
Gardner & Schoolcraft, 1999, with the addition of D-categories for inner cell mass and 
trophectoderm.
Blastocyst expansion and hatching status will be assessed as 1 of the following:
1:  An early blastocyst, blastocoel being less than half volume of that of the embryo.
2:  A blastocyst with a blastocoel whose volume is half of, or greater than half of, that of the 
embryo.
3:  A blastocyst with a blastocoel completely filling the embryo.
4:  An expanded blastocyst with a blastocoel volume larger than that of the early embryo, with a 
thinning zona.
5:  A hatching blastocyst with the trophectoderm starting to herniate through the zona.
6:  A hatched blastocyst, in which the blastocyst has completely escaped from the zona.
For blastocysts with expansion and hatching status 3-6, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as 1 of the following:
A:  Tightly packed, many cells.
B:  Loosely grouped, several cells.
C:  Very few cells.
D:  Degenerative or no inner cell mass.
Trophectoderm grading will be assessed as 1 of the following:
A:  Many cells forming a cohesive epithelium.
B:  Few cells forming a loose epithelium.
C:  Very few, large cells.
D:  Degenerative or very large cells.


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Blastocysts with expansion and hatching status 3-6 will have a score combining the 3 parameters 
(blastocyst expansion and hatching status, inner cell mass, and trophectoderm); e.g., 4AB for a 
blastocyst with blastocyst expansion and hatching status 4, inner cell mass grading A, and 
trophectoderm grading B.
7.2.9
Overall Blastocyst Quality on Day 5
The overall blastocyst quality on Day 5 is based on the blastocyst expansion and hatching status, 
inner cell mass grading, and trophectoderm grading.
Excellent-quality blastocysts are defined as those with blastocyst expansion and hatching status 4, 
5, or 6, inner cell mass grading A, and trophectoderm grading A or B.  The number and percentage 
of excellent-quality blastocysts on Day 5 is a secondary endpoint.  This will be based on the best 
overall quality score of the Day 5 post-insemination assessments.
Good-quality blastocysts are defined as those with blastocyst expansion and hatching status 3, 4, 5, 
or 6, inner cell mass grading B, and trophectoderm grading A or B.  The number and percentage of 
good-quality blastocysts on Day 5 will be based on the best overall quality score.  The number and 
percentage of excellent-quality blastocysts and good-quality blastocysts on Day 5 will be 
calculated. The best blastocyst based on Day 5 morphology will be transferred.
All expanded blastocysts with Blastocyst Expansion and Hatching Status 3-6, Inner Cell Mass 
grading A or B, and Trophoectoderm Grading A, B, or C. should be biopsied.
7.2.10 Compaction Assessment in Morulas
Embryos that have not reached the blastocyst stage on Day 5, but are morulas, will also be 
evaluated. Morulas will be categorized as 1 of the following 3 options:

Compacted: complete compaction. Tightly compacted cells. Individual cell membranes are 
no longer visible.

Compacting: early stage. Cells can be distinguished.
Abnormal compaction: regional or partial compaction, or few cells (<8) in compaction
Day 5 morulas may be considered for extended culture as per the investigator/site standard of care.  
Day 6 or Day 7 viable blastocysts can then undergo trophectoderm biopsy and vitrification.  All 
expanded blastocysts with Blastocyst Expansion and Hatching Status 3-6, Inner Cell Mass grading 
A or B, and Trophoectoderm Grading A, B, or C. should be biopsied.
The quality of Day 6 or Day 7 embryos should be assessed and recorded on the eCRF according to 
the criteria specified in section 7.2.9. 


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An AE 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.

AEs commonly observed and AEs 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 (findings from assessments 
and examinations done during screening are not AEs, 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.

Overdoses and medication errors with and without clinical consequences.
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The Investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit (EOT).
The sources of AEs 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 AEs in the AE Log provided in each subject’s eCRF with 
information about:

AE description.

Date and time of onset (time can be omitted, if not applicable).

Intensity.

Causal relationship to IMP.


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Action taken to IMP.

Other action taken.

Date and time of outcome (time can be omitted, if not applicable).

Outcome.

Seriousness.
Each of the items in the AE 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 AE more than once and the subject recovers in between the 
events, the AEs should be recorded separately.  If an AE 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.a
Note the following: a procedure is not an AE; the reason for conducting the procedure is.  
Hospitalization is not an AE; the reason for hospitalization is.  Death is not an AE, but the cause of 
death is (an exception is sudden death of unknown cause, which is an AE).
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 AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the 
date the sample was taken or the examination was performed.  
Intensity
The intensity of an AE 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).
                                                
a
Exception: if an AE with onset before the first IMP administration (i.e., a pre-treatment AE) changes in 
intensity, this must be recorded as 2 separate events.  The initial AE should be recorded with outcome “not yet 
recovered” and the date and time of outcome is when the intensity changed.  The second AE should be 
recorded with date and time of onset when the intensity changed.


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Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as 1 of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship 
between the IMP and the AE.  The AE may occur as part of the 
pharmacological action of the IMP or may be unpredictable in its 
occurrence.
Examples: 

AEs that are uncommon but are known to be strongly associated with IMP exposure.

AEs that are not commonly associated with IMP exposure, but the event occurs in 
association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge.
No reasonable possibility:
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the AE.
Examples:

Known consequences of the underlying disease or condition under investigation.

AEs common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure.
Action Taken to IMP
The action taken to the IMP in response to an AE must be classified as 1 of the following:

No change (medication schedule maintained or no action taken).

Withdrawn.

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 AE, this medication should be entered in the Concomitant 
Medication Log.


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Date and Time of Outcome
The date and time (time can be deleted/omitted, if not applicable) the subject recovered or died.
Outcome
The outcome of an AE must be classified as 1 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.

Not yet recovered.

Fatal.
8.3
Pregnancy and Pregnancy Outcome
Subjects who achieve pregnancy (2 positive β-hCG tests) will be followed for clinical pregnancy 
(intrauterine gestational sac and/or fetal heart movement approximately 4-5 weeks after embryo 
transfer) and ongoing pregnancy (approximately 8-9 weeks after embryo transfer).  Pregnant 
subjects will complete their final study visit approximately 8-9 weeks after embryo transfer
(or sooner, if there is a loss of pregnancy).  Subjects with ongoing pregnancy will be followed by 
telephone or mail for live birth data and information will be recorded in the eCRF.  Pregnancy loss 
will be recorded on a pregnancy follow-up form in the eCRF. 


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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
An event is defined an SAE if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within 4 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 AE 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 inpatient 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.  An overnight stay for observation, a stay 
at an emergency room, or treatment on an outpatient basis does not constitute a 
hospitalization.  However, medical judgment must always be exercised and 
when in doubt the case should be considered serious (i.e., if the case fulfills 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 AEs 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.  If in doubt, the decision should be left to 
medical judgment by the Investigator.
is a congenital anomaly/birth 
defect
Congenital anomaly/birth defect observed in any offspring of the subject 
conceived during treatment with the IMP.
is an important medical event
Important medical events are events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in 
the definition above.  Examples of important medical events include AEs that 
suggest a significant hazard, contraindication or precaution, occurrence of 
malignancy, or development of drug dependency or drug abuse.  Medical and 
scientific judgment should be exercised in deciding whether events qualify as 
medically important.
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product.  Any organism virus or infectious particle 
(e.g., prion protein transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent.  A 
transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings indicating an infection in a subject exposed to a medicinal 
product.


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8.4.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to the contract research organization (CRO) and/or Ferring 
Pharmaceuticals 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 to the CRO and/or the local safety officer at Ferring Pharmaceuticals, Inc. by fax 
within 24 hours of his/her knowledge of the SAE and submit all related follow-up information no 
later than 3 calendar days using the contact details below:
 
Completion of the Demographics Log, AE Log, Medical History Log, and Concomitant Medication
Log is mandatory for initial reports and for follow-up reports if any changes have been made since 
the initial report.
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g., laboratory parameters (that are not already uploaded in the eCRF), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring Pharmacovigilance 
using the contact details in the section above.  In any case, this information must be supplied by the
Investigator upon request from Ferring.  On any copies provided, details such as the subject’s name, 
address, and hospital identification number should be concealed and instead the 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.
Expedited Reporting by Ferring
Ferring will report all AEs that are serious, unexpected, and with a reasonable possible causality to 
the IMP, as judged by either the Investigator or Ferring, to the relevant parties within the stipulated 
timelines.
The expectedness is assessed by Ferring according to the Package Inserts for both the IMP and Non 
IMP products.
Serious AEs will be considered reportable regardless of whether or not the IMP or Non IMP was 
used in accordance with the provisions in the protocol, Package Inserts, and labeling.


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8.5
Follow-up of Adverse Events and Serious Adverse Events 
8.5.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the Investigator must follow-up on each AE 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 AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the 
medical condition of the subject is stable.  All such relevant follow-up information must be reported 
to Ferring.  If the event is a chronic condition, the Investigator and Ferring may agree that further 
follow-up is not required.
8.5.2
Collection of Serious Adverse Events with Onset after Last Trial
If an Investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the 
SAE to have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, 
regardless how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
This section details the planned statistical analyses for the primary endpoint and outlines 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 available before 
the first subject signs their informed consent.  Any deviations from the protocol-specified statistical 
analysis will be described in the Statistical Analysis Plan or final report, as appropriate. A separate 
Statistical Analysis Plan will be prepared to cover the post-trial information.
9.1
Determination of Sample Size
The study has at least 80% power, with 275 subjects per treatment group, to demonstrate the non-
inferiority of MENOPUR® to Gonal-f® in the ongoing clinical pregnancy rate at the 1-sided 
significance level of 0.025 with a 12% non-inferiority margin, by assuming an ongoing pregnancy 
rate of 50% for both treatment groups (Yeh et al. 2014). Assuming that 8% of the subjects may not 
be eligible for the PP analysis set, approximately 600 subjects will be randomized (1:1) into this 
study.
9.2
Subject Disposition
The number and percentage of subjects within each analysis set, randomized subjects treated with 
IMP, and subjects prematurely discontinued from the study 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
Major protocol deviations will be defined and documented prior to database lock.  Details will be 
provided in the Statistical Analysis Plan and/or in the Clean File document.
9.4
Analysis Sets
9.4.1
Intent-to-Treat (ITT) Analysis Dataset
The ITT analysis set comprises all randomized (as planned) subjects.
9.4.2
Modified Intent-to-Treat (mITT) Analysis Dataset
The mITT analysis set comprises all randomized (as planned) subjects who received at least 1 dose 
of IMP.
9.4.3
Per Protocol (PP) Analysis Dataset
The PP analysis set comprises all mITT subjects except those excluded as a result of major protocol 
deviations.
9.4.4
Safety Analysis Dataset
All subjects who received at least 1 dose of IMP will be included in the safety population.


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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 Safety Evaluations
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
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).
9.6
Efficacy Endpoint Assessments
9.6.1
General Considerations
All primary, secondary, and post-trial efficacy analyses will be conducted for the mITT  analysis 
set. Analyses for the mITT, PP, and ITT analysis sets will be conducted according to the 
randomized treatment.  Analyses for the safety analysis set will be conducted according to the
actual treatment received.  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 Efficacy Endpoint
The primary objective of the trial is to demonstrate that MENOPUR® is non-inferior to recombinant 
FSH with respect to ongoing pregnancy rate in a single fresh treatment cycle following a GnRH 
antagonist protocol.  Ongoing pregnancy is defined as presence of at least 1 intrauterine pregnancy 
with a detectable fetal heartbeat at 10-11 weeks gestation (8-9 weeks after blastocyst transfer in the 
fresh cycle).  The non-inferiority limit for the difference between treatments (MENOPUR® versus 
Gonal-f®) is -12% (absolute). The non-inferiority hypothesis to be tested for the primary endpoint 
is:
H0: MENOPUR - Gonal-f
® -12% 
against the alternative 
H1: MENOPUR - Gonal-f
® > -12%,
where MENOPUR and Gonal-f
® denote the ongoing pregnancy rate of subjects randomized and treated 
with MENOPUR® and Gonal-f®, respectively, in a single fresh embryo transfer following a GnRH 
antagonist protocol.
The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 
95% confidence interval for the difference in ongoing pregnancy rates. If the lower-limit of the 
95% confidence interval is greater than the non-inferiority limit (-12%), the null hypothesis will be 


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rejected and it would be claimed that MENOPUR® is non-inferior to Gonal-f® with respect to 
ongoing pregnancy rate in a single fresh embryo transfer following a GnRH antagonist protocol. 
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority 
limit (-12%) 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. 
Due to the expected large sample size, the confidence interval will be established based on the 
asymptotic normal distribution as follows:
f
Gonal
f
Gonal
f
Gonal
MENOPUR
MENOPUR
MENOPUR
f
Gonal
MENOPUR
N
N
Z










)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ
)
2
/
1
(







where
MENOPUR
ˆ
: is the observed ongoing pregnancy rate of subjects randomized to MENOPUR®
in a single fresh treatment cycle following a GnRH antagonist protocol.
f
Gonal
ˆ
: is the observed ongoing pregnancy rate of subjects randomized to Gonal-f®
in a single fresh treatment cycle following a GnRH antagonist protocol.
MENOPUR
N
: is the number of subjects randomized to MENOPUR®.
f
Gonal
N

: is the number of subjects randomized to Gonal-f®.
)
2
/
1
(


Z
   : is the 1-α/2 percentile in the standard normal distribution.
α
: is the significance level, i.e., 0.05.
Subjects who do not have at least 1 intrauterine pregnancy with a detectable fetal heartbeat at 10–11 
weeks gestation (8-9 weeks after blastocyst transfer in the fresh cycle), due to missing data, early 
withdrawal, or any other reason will be considered treatment failures (i.e., not having ongoing 
pregnancy).
The primary endpoint analysis will be based on the mITT analysis set. 
Sensitivity analyses for the primary endpoint will be conducted for both the ITT analysis set and the 
PP analysis set.


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9.6.3
Secondary Endpoints
All secondary endpoints will be summarized using tables and figures, as appropriate. Additional 
details will be specified in the Statistical Analysis Plan.  The secondary endpoints include:

Positive β-hCG rate and clinical pregnancy rate in the fresh cycle will be analyzed using the 
same method that is applied to the primary efficacy analysis.

Early pregnancy loss is defined as 2 positive -hCG tests but no ongoing pregnancy at 
10-11 week’s gestation in the fresh cycle.  Descriptive statistics will be provided 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 ≤9mm, 10-11 mm, 12-14 mm, 15-16 mm, 
and ≥17 mm) and subject level (largest follicle size, average follicle size, average size of 3 
largest follicles, 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. Any subject who receives antagonist 
earlier than Day 6 will be excluded from Day 6 endocrine analysis.

Serum FSH, hCG, LH, androstenedione, total testosterone, DHEA:  Day 1, Day 6, and 
final day of stimulation.

P4, E2: Day 1, Day 6, final day of stimulation, and Visit 4 (in the morning following 
hCG trigger).

The number of oocytes retrieved, the number of metaphase II oocytes, and the number of 
normally fertilized (2PN) oocytes 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.

The quality of embryos 3 days after oocyte retrieval will be assessed by cleavage stage, 
blastomere uniformity, cell size, the degree of fragmentation, and visual signs of 
multinucleation.  Frequency distributions and descriptive statistics will be provided for each 
treatment group at the embryo level, as appropriate.

The quality of blastocysts 5 days after oocyte retrieval will be assessed by blastocyst 
expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm
grading.  Frequency distributions will be provided for each treatment group at the blastocyst 
level.

The best quality blastocyst 5 days after oocyte retrieval at the subject level will be 
summarized for excellent-quality blastocysts and good-quality blastocysts separately by 
treatment using descriptive statistics.

The aneuploidy rate will be expressed as a percentage for each subject and calculated as 100 
times the ratio of the number of aneuploid blastocysts to the total number of blastocysts. 
Descriptive statistics will be provided by treatment group.


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
Endometrial thickness and the echogenicity pattern will be summarized by frequency 
distribution and by descriptive statistics, as appropriate, for each treatment group at 
stimulation Day 6, the last day of stimulation, and at the time of blastocyst transfer in the 
fresh cycle.
9.6.4
Post-Trial 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:

Cumulative live birth rate for fresh and frozen blastocyst transfer (defined as the proportion 
of subjects with at least 1 viable live birth greater >21 weeks gestation).

Live birth rate for fresh blastocyst transfer (defined as the proportion of subjects with at 
least 1 viable live birth greater >21 weeks gestation).

Early pregnancy loss rate in frozen blastocyst transfer is defined as 2 positive -hCG tests
but no ongoing pregnancy at 10-11 weeks gestation in the frozen cycle.

Late pregnancy loss rate (defined as a confirmed ongoing pregnancy but no viable live birth 
greater >21 weeks gestation).

Positive β-hCG rate, clinical pregnancy rate, and ongoing pregnancy rate for frozen 
blastocyst transfers.
Descriptive statistics will be provided in each of the respective post-trial endpoints.
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
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of AEs. A worst-case approach will be used: if causality is missing, the AE will be regarded as 
related to the IMP; if the intensity of an AE is missing, the AE will be regarded as severe; if 
seriousness is missing, the AE 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. 


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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 AE is defined as an AE that emerges during treatment having been absent 
pre-treatment, or worsens relative to the pre-treatment state. Only treatment-emergent AEs will be 
presented in summary tables. 
All data will be listed per subject and AE. 
Written narratives will be issued for all SAEs and AEs leading to withdrawal. If causality is 
missing, the AE will be regarded as being reasonably possibly related to IMP. Related AEs (judged 
as being reasonably possibly related to IMP) will be termed adverse drug reactions.
Overview of Treatment Emergent Adverse Events
A treatment-emergent AE summary table will be presented, including for each treatment, the 
number of subjects reporting an AE, the percentage of subjects with an AE, and the number of 
events reported, for the following categories: 

All AE.

Severe AEs.

Adverse drug reactions.

AEs leading to discontinuation.

SAEs.

Deaths.
Incidence of Adverse Events
Treatment-emergent AEs 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 AE, the 
percentage of subjects with an AE, 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.


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This counting and data presentation will be applied for the various incidences of AE tables 
described below.
Incidence of OHSS
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. 
Incidence of AEs by Relationship to IMP
Treatment-emergent AEs for each treatment group will be tabulated by SOC, preferred term, and 
relationship to IMP. One summary table will be prepared per type of relationship 
(related/not related). 
Incidence of AEs by Intensity
Treatment-emergent AEs for each treatment group will be tabulated by SOC, preferred term, and 
intensity. One summary table will be prepared per type of intensity (mild/moderate/severe).
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 AEs. 
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
Serious AEs 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 (deaths occurring at any time during the trial, 
i.e., pre-treatment, during treatment, or post-treatment), if any.
9.8.3
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.
9.8.4
Physical Examination
Physical examinations will be summarized and all subjects with any abnormal finding will be listed 
per subject for the safety analysis set.


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9.8.5
Gynecological Examination
Gynecological examinations will be summarized and all subjects with any abnormal finding will be 
listed by subject for the safety analysis set.
9.8.6
Clinical Laboratory Variables
Baseline and EOT 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 the EOT will be summarized by 
treatment group using descriptive statistics.
9.9
Interim Analyses
No interim analysis is planned.


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10 DATA HANDLING
10.1 Source Data and Source Documents
Source Data – International Conference on Harmonization (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
Any study specific source data will be described and defined in the monitoring manual produced 
for this study. 
10.2 eCRF/Case Report Form
An electronic data capture system provided by an independent third-party will be used.  The system 
is validated and access at all levels to the system is granted/revoked following Ferring and vendor 
procedures, in accordance with regulatory and system requirements.
Data should be entered into the system within 3 working days after the subject has attended a visit 
or after the data become available, as applicable.
The eCRF system and the database will be hosted at the independent third party CRO.  After the 
trial database is declared clean and released to the statistician, a final copy of the database will be 
stored at Ferring.  The Investigator will also receive a copy of the trial site’s final and locked data 
(including audit trail, electronic signature, and queries) as write-protected PDF files produced by 
the independent third party CRO.  The PDF files will be stored on a CD and will be provided to the 
Investigator before access to the eCRF is revoked.
Errors occurring in the eCRF will be corrected electronically.  Such corrections/modifications will 
be automatically tracked by an audit trail detailing the date and time of the correction and the name 
of the person making the correction.
The Investigator will approve/authorize the eCRF entries for each subject with an electronic 
signature that is equivalent to a handwritten signature.


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10.3 Data Management 
A data management plan will be created under the responsibility of the Biometrics department.  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 describe captured methods, who is authorized to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including 
timing of transfers), the origin and destination of the data, and who will have access to the data at 
all times.
10.4 Provision of Additional Information
On request, the Investigator will provide the Sponsor with additional data relating to the study, or 
copies of relevant source records, 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, 
ICH-Good Clinical Practice (GCP), standard operating procedures and applicable regulatory 
requirements, maintenance of trial-related source records, completeness, accuracy and verifiability 
of eCRF entries compared to source data, verification of drug accountability, and compliance to 
safety reporting instructions.  The Investigator will permit the monitor direct access to all source 
data, including electronic medical records, and/or documents in order to facilitate data verification.  
The Investigator will 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.
11.2 Audit and Inspection
The Investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP, including the Declaration of Helsinki, and all other relevant regulations.
The subjects must be informed by the Investigator and in the informed consent documents that 
authorized Ferring representatives and representatives from regulatory authorities and IRBs may 
wish to inspect their medical records.  During audits/inspections, the auditors/inspectors may copy 
relevant parts of the medical records.  No personal identification, apart from the 
screening/randomization number, will appear on these copies.
The Investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IRB.
11.3 Confidentiality of Subject Data
The Investigator will ensure that the confidentiality of the subjects’ data will be preserved.  In the 
eCRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial.  
Documents that are not for submission to Ferring, e.g., the confidential subject identification code 
and the signed informed consent documents, will be maintained by the Investigator in strict 
confidence.


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12 CHANGES IN THE CONDUCT OF THE TRIAL
12.1 Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
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 IRB approval.
12.2 Deviations from the Protocol
If deviations from the protocol occur, the Investigator must inform the monitor and the implications 
of the deviation must be reviewed and discussed.  Any deviation must be documented, either as an 
answer to a query in the eCRF, in a protocol deviation report in the eCRF, or a combination of both.  
A log of significant protocol deviation reports will be maintained by Ferring.  Protocol deviation 
reports and supporting documentation must be kept in the Investigator’s File and in the trial master 
file.
12.3 Premature Trial Termination
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 2 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 and submitted for comments and signature(s) to the signatory Investigator(s).  
The name of the signatory Investigator and contact details are specified in the contact list 
attachment in the protocol.
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, 1 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 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 comment prior to submission.  
Comments will be given within 4 weeks from receipt of the draft manuscript.  This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property.  If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published.  Under such conditions, the publication will be modified or delayed at the 
Investigator’s discretion, to allow sufficient time for Ferring to seek patent protection of the 
invention.


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Clinical Trial Protocol - Amendment 4
Ferring Pharmaceuticals
CONFIDENTIAL
13.3.2 Public Disclosure Policy 
International Committee of Medical Journal Editors 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 registry, i.e., www.ClinicalTrials.gov, which is sponsored by the National 
Institutes of Health.


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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 Authorization/Approval/Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements.  All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3 End-of-Trial and End-of-Trial Notification
At the end of the trial the IRBs will be notified in writing. 
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
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, anticipated 
benefits, potential hazards, and any other aspects of the trial which are relevant to the subject’s 
decision to participate. The trial subject must be given ample time to consider participation in the 
trial, before the consent is obtained.  The informed consent documents must be signed and dated by 
the subject and the Investigator who has provided information to the subject regarding the trial 
before the subject is exposed to any trial-related procedure, including screening tests for eligibility.
The Investigator (or the person delegated by the Investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for her further care and without the need to justify her decision.
The subject will receive a copy of the subject information and her signed informed consent form.
If new 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.


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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.
14.6 Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, and 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 will be as 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
In case of any damage or injury occurring to a subject in association with the IMP or the 
participation in the trial, Ferring has contracted an insurance company, which covers the liability of 
Ferring, the Investigator, and other persons involved in the trial in compliance with the laws in the 
countries involved.


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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 2 years after the 
completion or discontinuation of the study, 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 case report form/eCRF data for Ferring.  The Investigator must arrange for the retention 
of this subject Identification Log and signed informed consent documents 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.  Documents may be transferred to Ferring 
Global Quality Assurance, for example, if the Investigator retires and the documents no longer can 
be archived by the site.
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
American Society for Reproductive Medicine. Endometriosis: a guide for patients. 2012.
Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified 
hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. 
Hum Reprod. 2006;21(12):3217-27.
Devroey P, Pellicer A, Andersen AN, Arce JC; Menopur in GnRH Antagonist Cycles with Single 
Embryo Transfer Trial Group. A randomized assessor-blind trial comparing highly purified hMG 
and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer. Fertil 
Steril. 2012;97(3):561-71.
Arce JC, Klein BM, La Marca A. The rate of high ovarian response in women identified at risk by a 
high serum AMH level is influenced by the type of gonadotropin. Gynecol Endocrinol. 
2014;30(6):444-50.
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian Hyperstimulation 
Syndrome: An Update Review. Obstetrical and Gynecological Survey. 1989;44:6:430-440.
MENOPUR® (menotropins for injection) [package insert] Parsippany, NJ: 
Ferring Pharmaceuticals Inc.; February, 2014.
Gonal-f RFF® Redi-ject™ (follitropin alfa injection) [package insert] Rockland, MA: EMD Serono 
Inc.; January, 2014.
Ganirelix acetate injection [package insert] Whitehouse Station, NJ: Merck & Co. Inc.; December, 
2013.
Ovidrel® (choriogonadotropin alfa) [package insert] Rockland, MA: EMD Serono Inc.; September, 
2014.
ENDOMETRIN® (progesterone) [package insert] Parsippany, NJ: Ferring Pharmaceuticals Inc.; 
June, 2014.
van Wely M, Kwan I, Burt AL, et al. Recombinant versus urinary gonadotropin for ovarian 
stimulation in assisted reproductive technology cycles. Cochrane Database Syst Rev. 
2011;(2):CD005354.
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards reproductive 
certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th world congress on in 
vitro fertilization and human reproductive genetics. The Parthenon Publishing Group. 1999. 378-
88.
Yeh JS, Steward RG, Dude AM, et al. Pregnancy outcomes decline in recipients over age 44: an 
analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society for Assisted 
Reproductive Technology. Fertil Steril. 2014;101(5):1331-6.


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PROTOCOL DOCUMENT APPROVAL
The Principal Investigator and Ferring agree to conduct the trial as outlined in this Protocol with 
reference to national/local regulations and in accordance with current Good Clinical Practice (GCP) 
guidelines. Any modification to the Protocol must be agreed upon by both the Principal Investigator 
and Ferring and be documented in writing. By written agreement to this Protocol, the Principal 
Investigator agrees to allow direct access to all documentation, including source data, to authorized 
individuals representing Ferring (including monitoring staff and auditors) to Institutional Review 
Boards (IRBs) and/or to domestic and foreign regulatory authorities. 
FERRING REPRESENTATIVE 
___________________________________________
_________________
Date
 Reproductive Health and Urology
PRINCIPAL INVESTIGATOR
  
___________________________________________
            _________________
                                                                                                                         Date
Print Name:  ________________________________
Site Name:    ________________________________
Address:       ________________________________
                     ________________________________
                     ________________________________

SAP_000.pdf: 
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12%
STATISTICAL ANALYSIS PLAN
A Randomized, Assessor-blind Trial Comparing MENOPUR® (menotropins for injection) 
and Recombinant FSH (Follicle Stimulating Hormone) in a GnRH Antagonist Cycle with 
Single-Blastocyst Transfer in a High Responder Subject Population
000205
Investigational Product:
MENOPUR® (menotropins for injection)
Indication:
Development of multiple follicles and pregnancy in ovulatory 
women as part of an Assisted Reproductive Technology 
(ART) Cycle with ICSI
Phase:
4
Author:
Yodit Seifu, PhD
Date of issue:
March 8, 2017
Version:
4.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes


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2.0
3.0
4.0
21SEP2015
16Feb2017
SAP based on Protocol dated 22JUL2015 

For some baseline characteristics 
the analysis based on the safety 
population has been removed. The 
summaries based on the mITT 
and PP populations were
considered to be sufficient.

For the primary analysis, the 
sensitivity analysis based on ITT 
population was removed. 
Furthermore, sub-group analysis 
by genetic testing was added.

Clarification on protocol 
deviation analysis.

Added forest plots and boxplots.

Removed the logistic regression.

Other minor clarification and
corrections were made.
In the conduct of the study, it was 
observed that there were a number of 
patients that had their primary endpoint 
visit too early (up to 4 weeks early). 
Initially, it was planned to use the visit 
assessment for this analysis however, 
because of this observation visit windows 
were considered to be a more accurate 
assessment for the endpoint.  In Section 
9, the visit window has now been 
defined. Furthermore, if a patient has 
pregnancy assessment beyond this visit 
she will also be considered as responder.
To make it consistent, this type of 
window was also applied to the clinical 
pregnancy endpoint. 
Version 1
Version 2
Version 3


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Author, Reviewers, and Approver of the Statistical Analysis Plan
Author:  
Yodit Seifu, PhD.
             
Senior Project Statistician, Biometrics
             
Ferring International Pharmascience Center US, Inc.
Reviewers:
Vladimir Yankov, M.D.
                             
Vice President, Reproductive Health & Urology
Ferring International Pharmascience Center US, Inc.
Ralph Bobo, M.D.
Associate Vice President, US Pharmacovigilance
Ferring Pharmaceuticals Inc.
Kinesha O’Brien
Manger, Clinical Operations
Ferring International Pharmascience Center US, Inc.
Approver:
Masakazu Ando, PhD. 
Director, Biostatistics
Ferring International Pharmascience Center US, Inc.


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 5
1
Introduction.......................................................................................................................................... 8
1.1
Definitions/ Abbreviations...................................................................................................... 8
1.1.1
Definition of Terms.................................................................................................... 8
1.1.2
Abbreviations ............................................................................................................. 8
2
Trial Objectives and Endpoints.......................................................................................................... 9
2.1
Objectives................................................................................................................................. 9
2.2
Endpoints................................................................................................................................. 9
3
Trial design......................................................................................................................................... 11
3.1
General Design Considerations............................................................................................ 11
3.2
Determination of Sample Size.............................................................................................. 11
4
Subject Disposition ............................................................................................................................ 12
5
Protocol Deviations............................................................................................................................ 13
6
Analysis sets........................................................................................................................................ 14
6.1
Intention-To-Treat Analysis Set .......................................................................................... 14
6.2
Modified Intention-To-Treat Analysis Set.......................................................................... 14
6.3
Per Protocol Analysis Set ..................................................................................................... 14
6.4
Safety Analysis Set ................................................................................................................ 14
7
Trial population ................................................................................................................................. 15
7.1
Demographics and Other Baseline Characteristics ........................................................... 15
7.1.1
Demographics........................................................................................................... 15
7.1.2
AMH.......................................................................................................................... 15
7.1.3
Endocrine Profile ..................................................................................................... 15
7.1.4
Gynecological History and Infertility Diagnosis ................................................... 15
7.1.5
Obstetric History...................................................................................................... 15
7.1.6
Gynecological Examination..................................................................................... 15
7.1.7
Uterine Cavity and Pregnancy Test ....................................................................... 15
7.1.8
Transvaginal Ultrasound......................................................................................... 15
7.1.9
Semen Analysis......................................................................................................... 15
7.1.10 Tobacco and Alcohol................................................................................................ 16
7.2
Medical and Surgical History .............................................................................................. 16
7.3
Prior and Concomitant Medication..................................................................................... 16


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7.4
Physical Examination ........................................................................................................... 16
7.5
Other Procedures During the Study.................................................................................... 16
8
Exposure and Treatment Compliance ............................................................................................. 17
8.1
Extent of Exposure................................................................................................................ 17
8.1.1
IMP (Gonadotropins) .............................................................................................. 17
8.1.2
GnRH Antagonist..................................................................................................... 17
8.1.3
hCG ........................................................................................................................... 17
8.1.4
Progesterone............................................................................................................. 17
8.2
Treatment Compliance......................................................................................................... 17
9
Efficacy ............................................................................................................................................... 19
9.1
General Considerations........................................................................................................ 19
9.1.1
Tabulations............................................................................................................... 19
9.1.2
Listings...................................................................................................................... 19
9.1.3
Handling of Drop-Outs and Missing Values.......................................................... 19
9.2
Primary Endpoint ................................................................................................................. 19
9.2.1
Sensitivity Analyses.................................................................................................. 21
9.3
Secondary Endpoints............................................................................................................ 21
9.3.1
Positive β-hCG rate in the fresh cycle.................................................................... 21
9.3.2
Clinical pregnancy rate in the fresh cycle.............................................................. 22
9.3.3
Early pregnancy loss in the fresh cycle .................................................................. 22
9.3.4
Follicles...................................................................................................................... 22
9.3.5
Endocrine Profile ..................................................................................................... 22
9.3.6
Oocytes...................................................................................................................... 23
9.3.7
Fertilization Rate ..................................................................................................... 23
9.3.8
Quality of Embryos 3 Days after Oocyte Retrieval............................................... 23
9.3.9
Quality of Blastocysts 5 Days after Oocyte Retrieval ........................................... 23
9.3.10 Best Quality Blastocysts 5 Days after Oocyte Retrieval ....................................... 23
9.3.11 Aneuploidy Rate....................................................................................................... 23
9.3.12 Endometrial Thickness and Echogenicity Pattern................................................ 24
9.4
Post-Trial Endpoints............................................................................................................. 24
10
Safety................................................................................................................................................... 25
10.1
General Considerations........................................................................................................ 25
10.2
Adverse Events...................................................................................................................... 25
10.2.1 Overview of Treatment-Emergent Adverse Events.............................................. 25
10.2.2 Incidence of Treatment-Emergent Adverse Events.............................................. 26


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10.3
Chemistry and Hematology Laboratory Variables ........................................................... 26
10.4
Vital Signs.............................................................................................................................. 27
10.4.1 Vital Signs................................................................................................................. 27
10.4.2 Summary Statistics .................................................................................................. 27
10.4.3 Data Listings............................................................................................................. 27
10.5
Other Safety Variables ......................................................................................................... 27
10.5.1 OHSS......................................................................................................................... 27
10.5.2 Signs of Excessive Response.................................................................................... 27
11
Interim analyses................................................................................................................................. 28
12
Deviations from protocol analysis .................................................................................................... 29
13
References........................................................................................................................................... 30
14
Tables, Listings and Figures Shells .................................................................................................. 31
Appendix 1
Markedly Abnormal Laboratory Safety Values and Vital Sign.......................... 32


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1
Introduction
This document describes the planned statistical analyses for 000205 based on the protocol dated 10
December 2015.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Randomized
Subject randomized to trial treatment
Screened
Subject who enters the screening phase
1.1.2
Abbreviations
Abbreviation
Meaning of abbreviation in document
AE
adverse event
AMH
anti-Müllerian hormone
ATC
Anatomical Therapeutic Chemical Classification System
-hCG
Beta unit of human chorionic gonadotropin 
BMI
body mass index
COS
controlled ovarian stimulation
E2
estradiol
FSH
follicle-stimulating hormone
GnRH
gonadotropin-releasing hormone
hCG
human chorionic gonadotrohin
hMG
human menopausal gonadotrohin / menotrohin
HP-hMG
highly purified hMG
ICSI
intracytoplasmic sperm injection
IMP
investigational medicinal product
ITT
intention-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
NIMP
non-investigational medicinal product
OHSS
ovarian hyper stimulation syndrome
PP
per-protocol
PT
preferred term
SAE
serious adverse event
SOC
system organ class
TVUS
transvaginal ultrasound


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2
Trial Objectives and Endpoints
2.1
Objectives 
Primary Objective

To demonstrate non-inferiority of MENOPUR® versus recombinant follicle-stimulating 
hormone (Gonal-f®) with respect to ongoing pregnancy rate in women undergoing 
controlled ovarian stimulation (COS) following a gonadotropin-releasing hormone (GnRH) 
antagonist protocol.
Secondary Objectives

To evaluate the positive β-human chorionic gonadotropin (hCG) and clinical pregnancy 
rates after stimulation with MENOPUR® and Gonal-f® following a GnRH antagonist 
protocol.

To evaluate follicular development during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the serum endocrine profile during stimulation with MENOPUR® and Gonal-f®
following a GnRH antagonist protocol.

To evaluate the number of oocytes retrieved, the fertilization rate, and embryo quality 
associated with MENOPUR® and Gonal-f® following a GnRH antagonist protocol.

To evaluate the live birth rate associated with MENOPUR® and Gonal-f® following a 
GnRH antagonist protocol.

To evaluate the adverse event (AE) profile of MENOPUR® and Gonal-f®
2.2
Endpoints
Primary Endpoint

Ongoing pregnancy rate, defined as the presence of at least 1 intrauterine pregnancy with a 
detectable fetal heartbeat at 10–11 weeks of gestation (8-9 weeks after blastocyst transfer in 
the fresh cycle)
Secondary Endpoints

Positive β-hCG rate (2 positive β-hCG tests; the first approximately 10-14 days after 
blastocyst transfer in the fresh cycle and a second confirmatory test approximately 2 days 
later)

Clinical pregnancy rate (transvaginal ultrasound [TVUS] showing at least 1 intrauterine 
gestational sac with fetal heart beat at 5-6 weeks gestation, 3-4 weeks after blastocyst 
transfer in the fresh cycle)

Early pregnancy loss (defined as 2 positive -hCG tests but no ongoing pregnancy at 
10-11 week’s gestation in the fresh cycle)


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
Follicular development as assessed by TVUS (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 the last day of stimulation)

Endocrine profile:

Serum follicle-stimulating hormone (FSH), hCG, luteinizing hormone (LH), 
androstenedione, total testosterone, dehydroepiandrosterone (DHEA):  Day 1, Day 6, 
and last day of stimulation

Progesterone (P4), estradiol (E2):  Day 1, Day 6, last day of stimulation, and Visit 4 
(morning following hCG administration)

Oocytes retrieved, metaphase II oocytes, fertilization rate, quality of embryos 3 days after 
oocyte retrieval, and the quality of blastocysts 5 days after oocyte retrieval

Aneuploidy rate

Endometrial assessment by TVUS (endometrial thickness in mm and echogenicity pattern 
on stimulation Day 6, the last day of stimulation, and at the time of blastocyst transfer in the 
fresh cycle)
Post-trial Endpoints

Cumulative live birth rate for fresh and frozen blastocyst transfers (viable live birth 
>21 weeks gestation)

Live birth rate for fresh blastocyst transfers (viable live birth >21 weeks gestation)

Early pregnancy loss rate in frozen blastocyst transfer, defined as 2 positive -hCG tests but 
no ongoing pregnancy at 10-11 weeks gestation in the frozen cycle

Late pregnancy loss rate (defined as a confirmed ongoing pregnancy but no live birth)

Positive β-hCG rate, clinical pregnancy rate, and ongoing pregnancy rate for frozen 
blastocyst transfers
Safety Endpoints

Adverse Events

Frequency of ovarian hyperstimulation syndrome (OHSS) (early OHSS if the onset is 
≤9 days after hCG administration and late OHSS if the onset is >9 days after hCG 
administration)


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3
Trial design
3.1
General Design Considerations
This is a Phase 4, randomized, open-label, assessor-blind, parallel-group, multicenter study to be 
conducted in the United States (US).  Approximately 600 females undergoing COS following a 
GnRH antagonist protocol will be randomized (1:1) to receive either MENOPUR® or Gonal-f®.  
The study is designed to demonstrate non-inferiority of MENOPUR® versus Gonal-f® for ongoing 
pregnancy rates in a predefined high-responder subject population.  High responders will be defined 
as subjects who have a serum AMH ≥5 ng/mL.  
3.2
Determination of Sample Size
The study has at least 80% power, with 275 subjects per treatment group, to demonstrate the non-
inferiority of MENOPUR® to Gonal-f® in the ongoing clinical pregnancy rate at the 1-sided 
significance level of 0.025 with a -12% non-inferiority margin, by assuming an ongoing pregnancy 
rate of 50% for both treatment groups [ 1].  As the sensitivity analysis to the primary analysis is also 
deemed important, sufficient power is required for that analysis as well, and hence, assuming that 
8% of the subjects may not be eligible for the PP analysis set, approximately 600 subjects will be 
randomized (1:1) into this study.


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4
Subject Disposition
The number and percentage of subjects within each analysis set, randomized subjects treated with 
IMP, subjects who underwent a fresh cycle, and subjects prematurely discontinued from the study 
will be summarized.  All post-baseline discontinuations will be summarized by reason for 
discontinuation.  The subjects screened and not randomized will be presented in a separate data 
listing.


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5
Protocol Deviations
Major protocol deviations are a subset of protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a 
subject's rights, safety, or well-being. A subset of these major protocol deviations will lead to 
exclusion of the data from the PP analysis set.
Some of the criteria for major protocol deviation are listed below:

Actual treatment taken not in accordance with randomized treatment

Significant non-compliance of the protocol specified visits, treatments, and/or procedures

Violation of inclusion criteria 3 (AMH ≥5 ng/mL at screening)

Violation of inclusion criteria 9 (at least 1 ovary)
Violation of exclusion criteria 14 (findings at the gynecological examination that preclude 
gonadotropin therapy)
Blinded review of protocol deviations will be conducted prior to data base lock. The rating of 
protocol deviations as ‘minor’ or ‘major’  and  exclusion from PP analyses will be completed prior 
to the declaration of ‘clean file’ and lock of database.
The number and percentage of subjects with major protocol deviations will be summarized.


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6 Analysis sets
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set comprises all randomized  subjects and subjects will be
analyzed according to their randomized treatment.
6.2
Modified Intention-To-Treat Analysis Set
The modified intention-to-treat (mITT) analysis set comprises all randomized subjects who 
received at least 1 dose of IMP and will be analyzed according to their randomized treatment.
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 and will be analyzed according to their randomized treatment.
6.4
Safety Analysis Set 
The safety analysis set comprises all treated subjects and will be analyzed according to the actual 
treatment received.  


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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for the 
subjects in the mITT and PP analysis sets by treatment group. For patients demographic  and 
tobacco and alcohol history  this summary will also be repeated using the safety analysis set..
Categorical data will be summarised using numbers and percentages. The percentages are based on 
the total number of subjects within the given analysis set. Continuous data will be presented with
the number of subjects, mean, standard deviation, median, interquartile range, minimum, and 
maximum. All demographic and baseline characteristics will also be presented in  listings.
7.1.1
Demographics
Baseline demographics variables, including age, sex, race, ethnicity, height, weight, and Body Mass 
Index (BMI), will be summarized by treatment group.  Age will be calculated as (Date of Informed 
Consent – Date of Birth)/365.25, rounded down to the nearest integer.  BMI will be calculated as 
body weight (kg)/(height (m))2, rounded to one decimal place.
7.1.2
AMH 
Baseline AMH will be summarized by treatment group.  
7.1.3
Endocrine Profile
The baseline endocrine profile (FSH, hCG, LH, P4, E2, androstenedione, total testosterone, 
dehydroepiandrosterone) will be summarized by treatment group by whether the samples were 
analyzed locally and centrally as appropriate.
7.1.4
Gynecological History and Infertility Diagnosis
Baseline gynecological history, infertility diagnosis, and the proportion subjects who have not had a 
previous clinical pregnancy will be summarized by treatment group.    
7.1.5
Obstetric History
Baseline obstetric history will be summarized by treatment group.
7.1.6
Gynecological Examination
Baseline gynecological examination will be summarized by treatment group.
7.1.7
Uterine Cavity and Pregnancy Test
Baseline uterine cavity assessment and pregnancy test will be summarized by treatment group.
7.1.8
Transvaginal Ultrasound
Baseline transvaginal ultrasound will be summarized by treatment group.
7.1.9
Semen Analysis 
Baseline semen analysis will be summarized by treatment group.


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7.1.10
Tobacco and Alcohol  
Tobacco and Alcohool Habits will be summarized by treatment group.
7.2
Medical and Surgical History
Medical and Sugical history recorded at screening visit will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 19.1 or later.  Medical and Surgical history will be listed 
by treatment and subject and summarized by treatment group, system organ class (SOC), and 
preferred term (PT) for the subjects in the mITT and safety analysis sets, separately.   
7.3
Prior and Concomitant Medication
Prior and concomitant medications will be coded using World Health Organisation Drug 
(WHODrug) Dictionary version 01SEP2013 or later. Medications will be listed by treatment and 
subject as well as summarized by treatment group, Anatomical Therapeutic Chemical (ATC) 
classification 1st level (alphabetically), and ATC classification 2nd level (in decreasing order of 
frequency) for the subjects in the mITT and safety analysis sets, separately. Medications will be 
tabulated separately for:
1) Prior medication; i.e. medication taken exclusively prior to first IMP administration, i.e.
with stop date before date of first IMP administration
2) Concomitant medication, i.e. medication taken after IMP administration (regardless of 
whether the drug began before first IMP administration) i.e. medication that was not 
stopped before date of first IMP administration and not started after the end-of-trial visit
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
7.4
Physical Examination
Abnormal physical examination results will be listed by treatment, subject, visit, and body system
for the Safety analysis set. 
7.5
Other Procedures During the Study
Information regarding other procedures logged during the study will be listed by treatment, subject, 
and start date for the Safety analysis set.


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8
Exposure and Treatment Compliance
8.1
Extent of Exposure 
All tabulations will be prepared for the Safety analysis set.
8.1.1
IMP (Gonadotropins)
Exposure to gonadotropins will be summarized as the total gonadotropin dose administered, dose 
administered from day 6 to last stimulation day, duration of treatment (days). Frequency tables will 
be included to describe the duration of treatment, the maximum dose, the dose on stimulation day 6, 
the final dose, and the number of dose adjustments.
This table will be produced overall and for subjects who completed the stimulation cycle, i.e. 
underwent triggering of final follicular maturation.
8.1.2
GnRH Antagonist
Once both the lead follicle measures ≥14 mm and serum E2 levels are ≥300 pg/mL, the GnRH 
antagonist (ganirelix acetate) will be initiated at a daily dose of 0.25 mg and continued throughout 
the gonadotropin treatment period.
The total dose, starting day of GnRH antagonist, and duration of treatment (days) will be tabulated. 
This table will be produced overall and for subjects who completed the stimulation cycle, i.e. 
underwent triggering of final follicular maturation.
8.1.3
hCG
A single injection of 250 μg hCG (Ovidrel®) will be administered to induce final follicular 
maturation as soon as 3 follicles of ≥17 mm are observed on TVUS. The following will be 
tabulated: number of subjects who met the hCG criteria, number of subjects that had hCG 
administered, number of subjects who met the hCG criteria and had hCG administered, the number 
of days from when the hCG criteria was met to when the hCG administered, and the number of 
subjects who had the hCG trigger replaced with a GnRH agonist trigger.
8.1.4
Progesterone
Vaginal progesterone inserts (200 mg/day – ENDOMETRIN®; Ferring) will be initiated for luteal 
phase support and will continue until the day of the -hCG test (10-14 days after blastocyst
transfer) if negative for pregnancy or if pregnancy is confirmed, will be continued for a maximum 
of 10 weeks.
The total dose and duration of treatment (days) will be tabulated for all subjects, for subjects with 
two positive -hCG, and for subjects that do not have two positive -hCG results.
8.2
Treatment Compliance 
As treatment compliance is assumed to be high, only subjects not receiving the scheduled dose will 
be listed by center and subject number.


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Separate listings will be prepared for  

violations of the IMP schedule 

violations of the antagonist schedule

hCG not administered according to the protocol

Agonist not administered according to the protocol

Progesterone not administered according to the protocol
In addition, a summary table displaying the number and frequency of subjects with violations of the 
IMP schedule, violations of the antagonist schedule, hCG not administered according to the 
protocol, agonist not administered according to the protocol and progesterone not administered 
according to the protocol will be presented.


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9
Efficacy
9.1
General Considerations
Efficacy analysis will be conducted for the mITT population unless otherwise specified. All 
statistical tests will be performed using a two-sided test at a 5% significance level. No adjustments 
will be made for multiple tests. Baseline for all efficacy analyses will be the values obtained at the 
last assessment prior to the first dose of IMP.  
9.1.1
Tabulations
All summaries will be presented by treatment group and overall. Categorical data will be 
summarized using numbers and percentages. The percentages are based on the total number of 
subjects with a corresponding assessment. Continuous data will be presented using the number of 
subjects with an observation, mean and standard deviation, median, interquartile range, minimum,
and maximum.
9.1.2
Listings
All primary and secondary endpoints will be listed sorted by center, treatment, and subject id.
9.1.3
Handling of Drop-Outs and Missing Values
  For the primary and secondary endpoints positive β-hCG and clinical pregnancy missing 
observations will be imputed to negative unless a positive result is observed at a later pregnancy 
assessment. For example, if the outcome of β-hCG is missing but clinical pregnancy is ‘positive’ 
then β-hCG will be imputed as ‘positive’.
Missing values will not be imputed for the any of the other secondary endpoints.
9.2
Primary Endpoint
The primary objective of the trial is to demonstrate that MENOPUR® is non-inferior to recombinant 
FSH with respect to ongoing pregnancy rate in a single fresh treatment cycle following a GnRH 
antagonist protocol.  Ongoing pregnancy is defined as presence of at least 1 intrauterine pregnancy 
with a detectable fetal heartbeat at 10-11 weeks gestation (8-9 weeks after blastocyst transfer in the 
fresh cycle).  The non-inferiority limit for the difference between treatments (MENOPUR® minus
Gonal-f®) is -12% (absolute).  The non-inferiority hypothesis to be tested for the primary endpoint 
is:
H0: MENOPUR - Gonal-f
® -12% 
against the alternative 
H1: MENOPUR - Gonal-f
® > -12%,
where MENOPUR and Gonal-f
® denote the ongoing pregnancy rate of subjects treated with 
MENOPUR® and Gonal-f®, respectively, in a single fresh embryo transfer following a GnRH 
antagonist protocol.


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The null hypothesis (H0) will be tested against the alternative by constructing a 2-sided 
95% confidence interval for the difference in ongoing pregnancy rates.  If the lower-limit of the 
95% confidence interval is greater than the non-inferiority limit (-12%), the null hypothesis will be 
rejected and it would be claimed that MENOPUR® is non-inferior to Gonal-f® with respect to 
ongoing pregnancy rate in a single fresh embryo transfer following a GnRH antagonist protocol. 
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority 
limit (-12%) 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. 
Due to the expected large sample size, the confidence interval will be established based on the 
asymptotic normal distribution as follows:
f
Gonal
f
Gonal
f
Gonal
MENOPUR
MENOPUR
MENOPUR
f
Gonal
MENOPUR
N
N
Z










)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
ˆ
ˆ
)
2
/
1
(







where
MENOPUR
ˆ
: is the observed ongoing pregnancy rate of subjects randomized to MENOPUR®
in a single fresh treatment cycle following a GnRH antagonist protocol.
f
Gonal
ˆ
: is the observed ongoing pregnancy rate of subjects randomized to Gonal-f® in a 
single fresh treatment cycle following a GnRH antagonist protocol.
MENOPUR
N
: is the number of subjects randomized to MENOPUR®.
f
Gonal
N

: is the number of subjects randomized to Gonal-f®.
)
2
/
1(


Z
   : is the 1-α/2 percentile in the standard normal distribution.
α
: is the significance level, i.e., 0.05.
Subjects who do not have at least 1 intrauterine pregnancy with a detectable fetal heartbeat at 10–11 
weeks gestation (8-9 weeks after blastocyst transfer in the fresh cycle) due to missing data, early 
withdrawal, or any other reason will be considered treatment failures (i.e., not having ongoing 
pregnancy) unless they have an assessment of detectable fetal heartbeat at a later date. Hence, for 
the analysis of this endpoint all positive (detectable fetal heartbeat) ultrasound assessments that 
occur in the interval from the end of 7th week from fresh tranfer  till the end of study will be 
considered as responder for the primary endpoint (i.e., ultrasound assessment date – fresh transfer 
date + 1  ≥  7 *7 = 49).  Forty nine days was used because the 8-9 weeks visit window included 50 


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(beginning of the 8th week) to 63 days after fresh transfer.  The primary endpoint analysis will be 
based on the mITT analysis set.
9.2.1
Sensitivity Analyses 
Sensitivity analyses for the primary endpoint analysis will be conducted for the PP analysis set in 
the same manner as the mITT analysis set.
In addition, the ongoing pregnancy rate will be presented by center for the mITT analysis set, for 
subjects in the mITT analysis set with oocytes retrieved, and for subjects in the mITT analysis set 
with an embryo transfer.
Furthermore, the ongoing pregnancy rate will be presented for the following break downs for all 
mITT subjects, for mITT subjects with oocytes retrieved and for mITT subjects with a blastocyst 
transfer:

By reason for infertility 

By center

By number of oocytes retrieved (<=3, 4-7, 8-10, 11-14, >=15)

By quality of blastocyst transferred.

By AMH level at screening

For patients that received fresh blastocyst, by results of the genetic testing
For these sub-group analyses, treatment differences and associated 95% CIs will be generated. 
Furthermore, these summaries will be displayed in a forest plot. 
9.3
Secondary Endpoints
All secondary endpoints will be based on the mITT analysis set unless otherwise specified.  
Positive β-hCG rate and clinical pregnancy rate, in the fresh cycle, will be presented by treatment 
group with the corresponding 95% confidence intervals of the treatment difference.  This will be 
calculated in the same manner as the primary endpoint.
9.3.1
Positive β-hCG rate in the fresh cycle
Positive β-hCG in the fresh cycle is defined as 2 positive β-hCG tests; the first performed 
approximately 10-14 days after the fresh blastocyst transfer with a second positive test at least 2 
days later.  The positive β-hCG rate in the fresh cycle will be presented by treatment group with the 
corresponding 95% confidence intervals of the treatment difference. This analysis will also be 
repeated for the PP set.
Subjects who do not have 2 positive β-hCG tests due to missing data, early withdrawal, or any other 
reason will be counted as not having positive β-hCG unless a positive result is observed at a later 
pregnancy assessment. For example, if the outcome of β-hCG is missing but clinical pregnancy is 
‘positive’ then β-hCG will be imputed as ‘positive’.


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9.3.2
Clinical pregnancy rate in the fresh cycle
Clinical pregnancy in the fresh cycle is defined as at least 1 intrauterine gestational sac, confirmed 
by TVUS, with a fetal heart beat at 5-6 weeks gestation (3-4 weeks after the fresh blastocyst
transfer).  The clinical pregnancy rate in the fresh cycle will be presented by treatment group with 
the corresponding 95% confidence intervals of the treatment difference. This analysis will also be 
repeated for the PP set.
Subjects who do not have at least 1 intrauterine gestational sac, confirmed by TVUS, with a fetal 
heart beat at 5-6 weeks gestation (3-4 weeks after the fresh blastocyst transfer) due to missing data, 
early withdrawal, or any other reason will be counted as not having clinical pregnancy unless a 
positive result is observed at a later pregnancy assessment. For example, if TVUS test at 5-6 weeks 
is missing but clinical pregnancy is ‘positive’ at 10-11 weeks of gestation, it will be imputed as 
‘positive’. Hence, for the analysis of this endpoint all positive (detectable fetal heartbeat) 
ultrasound assessments that occur in the interval from the end of 2nd week from fresh tranfer  till 
the end of study will be consdered as responder for this secondary endpoint (i.e., ultrasound 
assessment date – fresh transfer date + 1  ≥  2 *7 = 14).  Fourteen days was used because the 3-4 
weeks visit window included 15 (beginning of the 3th week) to 28 days after fresh transfer.
9.3.3
Early pregnancy loss in the fresh cycle
Early pregnancy loss in the fresh cycle is defined as 2 positive -hCG tests, but no ongoing 
pregnancy at 10-11 week’s gestation, in the fresh cycle.  The early pregnancy loss rate in the fresh 
cycle will be calculated for mITT subjects with 2 positive -hCG tests and presented by descriptive 
statistics for each treatment group. Furthermore,  the difference  in event rates between the two 
treatments will be presented together with the associated 95% CI.
9.3.4
Follicles
The follicles within each treatment group on stimulation day 6 and last day of stimulation will be 
summarized by frequency at the follicle level (i.e. the number of follicles within the treatment 
group that are ≤9mm, 10-11 mm, 12-14 mm, 15-16 mm, and ≥17 mm).  The follicles for each 
subject within each treatment group on stimulation day 6 and last day of stimulation will also be 
summarized by the largest follicle size, average follicle size, average size of the 3 largest follicles, 
and the rate of follicles ≥17 mm, ≥15 mm, and ≥12 mm.  Tables will be produced for all mITT 
subjects and for all mITT subjects with oocytes retrieved.
9.3.5
Endocrine Profile
The endocrine profile will be summarized using descriptive statistics by scheduled visit, as well as 
for the change from baseline for post-baseline visits;  

Serum follicle-stimulating hormone (FSH), hCG, luteinizing hormone (LH), 
androstenedione, total testosterone, dehydroepiandrosterone will be summarized on Day 1, 
Day 6, and last day of stimulation.


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
Progesterone (P4), estradiol (E2) will be summarized on Day 1, Day 6, last day of 
stimulation, and Visit 4 (morning following hCG trigger)  
Any subject who receives an antagonist earlier than Day 6 will be excluded from Day 6 endocrine 
analysis. Associated box-plots will also be generated.
9.3.6
Oocytes
The number of oocytes retrieved, the number of metaphase II oocytes, the number of oocytes 
undergoing ICSI, and the number of normally fertilized (2PN) oocytes will be summarized by 
frequency distribution and by descriptive statistics for each treatment group.
9.3.7
Fertilization Rate
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.  In addition for 
subjects undergoing ICSI 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 
metaphase II oocytes.  Descriptive statistics will be provided by treatment group.
9.3.8
Quality of Embryos 3 Days after Oocyte Retrieval
The quality of embryos 3 days after oocyte retrieval will be assessed by cleavage stage, blastomere 
uniformity, cell size, the degree of fragmentation, and visual signs of multinucleation.  Frequency 
distributions and descriptive statistics will be provided for each treatment group at the embryo 
level.
9.3.9
Quality of Blastocysts 5 Days after Oocyte Retrieval
The quality of blastocysts 5 days after oocyte retrieval will be assessed by blastocyst expansion and 
hatching status, blastocyst inner cell mass grading, and trophectoderm grading. Blastocyst 
information collected on day 6 and 7 will be summarized similarly. Furthermore,  the overall 
quality of the  blastocysts on day 5 will also be summarized. Frequency distributions will be 
provided for each treatment group at the blastocyst level.
9.3.10
Best Quality Blastocysts 5 Days after Oocyte Retrieval
The best quality blastocyst 5 days after oocyte retrieval at the subject level will be summarized for 
excellent-quality blastocysts and good-quality blastocysts separately by treatment using descriptive 
statistics.
9.3.11
Aneuploidy Rate
The aneuploidy rate will be expressed as a percentage for each subject and calculated as 100 times 
the ratio of the number of aneuploid blastocysts to the total number of blastocysts..Descriptive 
statistics will be provided by treatment group.


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9.3.12
Endometrial Thickness and Echogenicity Pattern
Endometrial thickness will be summarized by descriptive statistics and the echogenicity pattern will 
be summarized by frequency distribution , at stimulation Day 6, the last day of stimulation, and at 
the time of blastocyst transfer.  
9.4
Post-Trial 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:

Cumulative live birth rate for fresh and frozen blastocyst transfer (defined as the proportion 
of subjects with at least 1 viable live birth greater >21 weeks gestation).

Live birth rate for fresh blastocyst transfer (defined as the proportion of subjects with at 
least 1 viable live birth greater >21 weeks gestation).

Early pregnancy loss rate in frozen blastocyst transfer is defined as 2 positive -hCG tests 
but no ongoing pregnancy at 10-11 weeks gestation in the frozen cycle.

Late pregnancy loss rate (defined as a confirmed ongoing pregnancy but no viable live birth 
greater >21 weeks gestation).

Positive β-hCG rate, clinical pregnancy rate, and ongoing pregnancy rate for frozen 
blastocyst transfers.
Descriptive statistics will be provided for each of the respective post-trial endpoints.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis set and subjects will be included in 
tabulations according to actual treatment received.
10.2 Adverse Events
Adverse events will be recorded from signed informed consent until the end-of-trial visit.
Adverse events (AEs) are classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.1 or later.
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of AE. A ‘worst case’ approach will be used: 

if causality is missing, the AE will be regarded as related to the IMP

if the intensity of an AE is missing, the AE will be regarded as severe

if seriousness is missing, the AE will be regarded as serious

if outcome is missing and no date of outcome is present, the outcome is regarded as ‘Not 
yet recovered’
Missing event start and event stop dates will be imputed in the most conservative way, i.e. the event 
should start as early as possible based on the (partially) missing start date while remaining 
treatment emergent (if relevant), and last as long as possible, i.e. until last visit or one day prior to 
the next event with the same preferred term, if any. In the latter case both consecutive AEs (with 
the same PT) will remain to be regarded as two separate events (despite being adjacent).
A treatment emergent adverse event is any adverse event occurring in the period from first 
administration of IMP till end-of-trial visit.
Pre-treatment adverse events will be reported in a listing only. This listing will be sorted by center
and subject ID and date of onset.
10.2.1
Overview of Treatment-Emergent Adverse Events
An AE overview summary table will be prepared including the number of subjects reporting an AE, 
the percentage of subjects (%) with an AE, and the number of events (E) reported, for the following 
categories: 

Treatment-emergent adverse events

Deaths 

Serious adverse events 

Adverse events leading to withdrawal 

Severe and life threatening adverse events 

Adverse drug reactions


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10.2.2
Incidence of Treatment-Emergent Adverse Events
Treatment-emergent adverse events will be summarized in summary tables. The tables will display 
the total number of subjects reporting an AE and the percentage of subjects (%) with an AE. AEs 
will be presented alphabetically by system organ class (SOC) and in decreasing frequency of 
occurrence by preferred term (PT).
Summary tables will be prepared for:

All adverse events

Adverse events with an incidence [≥ 5%] of subjects in any treatment group

Adverse events by causality (related/unrelated)

Adverse events leading to death

Adverse events by intensity (mild/moderate/severe)

Serious adverse events 

Adverse events leading to withdrawal
A supporting data listings will be provided for:

All adverse events sorted by center, subject number, and date of onset 

Adverse drug reactions 

Adverse events leading to death

Severe adverse events 

Serious adverse events

Adverse events leading to withdrawal
Supporting data listing by SOC sorted alphabetically and PT sorted in decreasing frequency of 
occurrence will be provided for:

All adverse events
The all adverse events table will summarize all the treatment-emergent AEs by SOC and Preferred
Term displaying the total number of subjects (N) reporting an AE, the percentage of subjects (%) 
with an AE, and the number of events (E) reported will also be provided.
10.3 Chemistry and Hematology Laboratory Variables
Mean change and mean percentage (%) change from baseline at the end of trial will be presented 
for each laboratory variable. In addition, descriptive statistics, i.e., the number of subjects with 
data, mean, standard deviation, median, minimum, and maximum values, will be presented for 
observed values at screening and end of treatment for each laboratory variable.


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Data listings will also be prepared by center for all subjects with any markedly abnormal laboratory
safety values at any time-point (including screening/baseline) (appendix 1).
10.4 Vital Signs 
10.4.1
Vital Signs
Baseline for all vital signs analyses will be the values obtained at the screening visit. The only 
planned post-baseline assessment of vital signs is at the End of trial visit.
10.4.2
Summary Statistics
Mean change and mean percentage (%) change from baseline at end of trial will be presented for 
each vital signs variable. In addition, descriptive statistics, i.e., the number of subjects with data, 
mean, standard deviation, median, minimum, and maximum values, will be presented for observed 
values and change from baseline at screening and end of treatment for each vital signs variable. 
10.4.3
Data Listings
Data listings will be prepared by center for all subjects with any markedly abnormal vital signs 
value at any time-point (including screening/baseline) (appendix 1).
10.5 Other Safety Variables
10.5.1
OHSS
A summary table will be prepared showing the incidence and severity of early OHSS, late OHSS, 
and overall OHSS. This table will display the number and percentage of subjects (%) and the 
number of events. Early OHSS is defined as OHSS with onset ≤9 days after triggering of final 
follicular maturation. Note this includes OHSS with onset before triggering and OHSS with onset 
during stimulation where triggering is not performed.
10.5.2
Signs of Excessive Response
A table will be prepared summarizing signs of excessive response. The table will present the 
number of subjects in following categories:

OHSS early onset defined as at most 9 days after hCG administration

Cancellation of cycle due to excessive response

Preventive action (leuprolide acetate)

Received a medical or surgical intervention for OHSS


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Interim analyses
No interim analysis is planned.


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Deviations from protocol analysis
For some of the baseline characteristics, the analysis based on the safety population has been 
removed. The summaries based on mITT and PP populations were considered to be sufficient.
For the primary analysis, the sensitivity analysis based on ITT populations was removed.
Furthermore, sub-group analysis by genetic testing was added.
For the primary analysis, it was added that patients that have positive pregnancy test at any time 
after the 8-9 week window post-fresh transfer will also be considered as positive for this primary 
endpoint. 


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References
1. Yeh JS, Steward RG, Dude AM, et al. Pregnancy outcomes decline in recipients over age 
44: an analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society 
for Assisted Reproductive Technology. Fertil Steril. 2014;101(5):1331-6.


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Tables, Listings and Figures Shells
The document with tables, figures and listings (TLF) shells presented in a separate 
document.


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Appendix 1
Markedly Abnormal Laboratory Safety Values and Vital 
Sign
Table 1:
Markedly abnormal Criteria for Laboratory Tests
Markedly abnormal Criteria
Variable
Units
Low
High
Haematology
Haemoglobin
g/L
115
Not applicable
Haematocrit
Ratio
0.37
0.56
Total WBC
109/L
2.8
16.0
Eosinophils
%
Not applicable
10
Neutrophils
%
15
90
Lymphocytes
%
10
80
Monocytes
%
Not applicable
20
Basophils
%
Not applicable
5
Bands
%
Not applicable
20
Platelets
109/L
75
700
Total RBC
1012/L
3.5
Not applicable
Clinical Chemistry
AST 
IU/L
Not applicable
> 3xULN
ALT 
IU/L
Not applicable
> 3xULN
Alkaline 
phosphatase
IU/L
Not applicable
> 3xULN and 25% increase from 
baseline
GGT
IU/L
Not applicable
> 3xULN
LDH
IU/L
Not applicable
> 3xULN
Total bilirubin
μmol/L
Not applicable
1.5xULN
Urea nitrogen
mmol/L
Not applicable
10.7
Creatinine
μmol/L
Not applicable
177
Total protein
g/L
45
90
Albumin
g/L
25
65
Sodium
mmol/L
130
155
Potassium
mmol/L
3.0
5.8
Chloride
mmol/L
90
115
Phosphorus
mmol/L
0.5
1.9
Calcium
mmol/L
1.8
3.9
Uric acid
mmol/L
Not applicable
0.62
Glucose
mmol/L
2.8
10
Total cholesterol
mmol/L
Not applicable
8.0
Urinalysis: Quantitative


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Markedly abnormal Criteria
Variable
Units
Low
High
pH
None
4
Not applicable
Specific gravity
None
1.005
Not applicable
Urinalysis: Dipstick Chemistries
Glucose
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Casts
Not applicable
Increase of 2 or more units from baseline
Protein
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Ketones
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Blood (Hgb)
0 - 4+
Not applicable
Increase of 2 or more units from baseline
Urinalysis: Microscopic Variables
RBC
no./hpf
Not applicable
10
WBC
no./hpf
Not applicable
20
Casts
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Bacteria
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Cells
no./hpf
Not applicable
Neg at baseline to positive on-treatment
Crystals
no./hpf
Not applicable
Neg at baseline to positive on-treatment
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 rate
120 bpm
50 bpm
Increase of 15 bpm
Decrease of 15 bpm
Body weight
None
Increase of 7%
Decrease of 7%
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the 
specified change from baseline.