Clinical trial NCT02449889
Conditions: Infertility
Sponsor: Ferring Pharmaceuticals
Start date: 2016-04-01; Completion date: 2018-03-01
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is investigating the efficacy and safety of highly purified human chorionic gonadotropin (HP-hCG) and recombinant human chorionic gonadotropin (rhCG) for triggering of final follicular maturation in women undergoing controlled ovarian stimulation

Detailed description:

Arms: arm 1: highly purified human chorionic gonadotropin, intramuscularly (IM) arm 2: highly purified human chorionic gonadotropin, subcutaneously (SC) arm 3: recombinant human chorionic gonadotropin
Interventions: intervention 1: highly purified human chorionic gonadotropin intervention 2: recombinant human chorionic gonadotropin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Date: 30 Jan 2015
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Supersedes: None
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FE 999086, HP-hCG (CHORAPUR)
Trial Code: 000191 
Solution for Injection
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A randomised, controlled, assessor-blind, parallel groups, multicentre trial comparing the efficacy 
and safety of highly purified human chorionic gonadotropin (HP-hCG) and recombinant human 
chorionic gonadotropin (rhCG) for triggering of final follicular maturation in women undergoing 
controlled ovarian stimulation
FASHION
(Efficacy and safety of HP-hCG and rhCG for triggering of final follicular maturation)
Trial 000191
Investigational Medicinal Product:
FE 999086, HP-hCG (CHORAPUR)
Indication:
For Assisted Reproductive Technology (ART) programme
such as in vitro fertilisation: triggering of final follicular 
maturation and luteinisation after stimulation of follicle 
growth 
Phase:
III
Name and Address of Sponsor:
Laboratórios Ferring Ltda
Praça São Marcos 624 
Alto de Pinheiros 
05455-050 São Paulo 
Brazil
Tel: (+55) 11 3024 7500
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group.


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Trial Code: 000191 
Solution for Injection
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CONFIDENTIAL
SYNOPSIS
TITLE OF TRIAL
A randomised, controlled, assessor-blind, parallel groups, multicentre trial comparing the efficacy 
and safety of highly purified human chorionic gonadotropin (HP-hCG) and recombinant human 
chorionic gonadotropin (rhCG) for triggering of final follicular maturation in women undergoing 
controlled ovarian stimulation
SIGNATORY INVESTIGATOR
 University of Sao Paulo, Ribeirão Preto, Brazil
TRIAL SITES
5 sites in Brazil
PLANNED TRIAL PERIOD
Estimated FPFV: Q4 2015
Estimated LPLV / end-of-trial: Q4 2016
CLINICAL PHASE
III
OBJECTIVES
Primary 
!
To demonstrate non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 μg for 
triggering of final follicular maturation with respect to number of oocytes retrieved in 
women undergoing controlled ovarian stimulation
Secondary 
!
To evaluate HP-hCG and rhCG with respect to oocyte fertilisation
!
To evaluate HP-hCG and rhCG with respect to pregnancy 
!
To compare HP-hCG with rhCG with respect to endocrine profile
!
To compare HP-hCG with rhCG with respect to safety profile 
ENDPOINTS
Primary 
!
Number of oocytes retrieved
Secondary 
!
Number of metaphase II oocytes (only applicable for insemination using ICSI)
!
Number of fertilised (2PN) oocytes 
!
Fertilisation rate (the rate of fertilised oocytes to oocytes retrieved for subjects with oocytes 
retrieved and also the rate of fertilised oocytes to metaphase II oocytes for subjects with 
oocytes inseminated using ICSI)


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FE 999086, HP-hCG (CHORAPUR)
Trial Code: 000191 
Solution for Injection
Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
!
Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)
!
Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
!
Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer)
!
Circulating concentrations of estradiol, progesterone and hCG at transfer and 13-15 days 
after transfer
!
Frequency and intensity of adverse events
!
Early and late OHSS rates
!
Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject after hCG administration
Post-trial Information
!
Live birth rate and neonatal health at birth for subjects who have achieved a vital pregnancy
METHODOLOGY
This is a randomised, assessor-blind, parallel groups, multicentre trial comparing the efficacy and 
safety of highly purified human chorionic gonadotropin (HP-hCG, CHORAPUR, Ferring 
Pharmaceuticals) and recombinant human chorionic gonadotropin (rhCG, OVIDREL, Merck 
Serono) for triggering of final follicular maturation in women undergoing controlled ovarian 
stimulation. The trial procedures are in line with routine clinical practice, i.e. controlled ovarian 
stimulation following a GnRH antagonist protocol, triggering of final follicular maturation, oocyte 
retrieval, embryo / blastocyst transfer and pregnancy monitoring. 
On day 2-3 of the menstrual cycle, subjects will start controlled ovarian stimulation with highly 
purified menotrophin (HP-hMG, MENOPUR, Ferring Pharmaceuticals). The initial daily dose of 
HP-hMG is 150 IU SC, followed by potential dose adjustments based on the subject’s response as 
observed on transvaginal ultrasound, depending on the centre’s practice and the investigator’s 
judgement. During stimulation, subjects will be monitored by transvaginal ultrasound on 
stimulation day 1, 6 and hereafter at least every other day until the end of stimulation. Coasting is 
prohibited. GnRH antagonist (cetrorelix acetate, CETROTIDE, Merck Serono) will be initiated on 
stimulation day 6 at a daily dose of 0.25 mg and continued throughout the controlled ovarian 
stimulation.
The criterion for triggering of final follicular maturation is ≥3 follicles with a diameter ≥17 mm and 
<25 follicles with a diameter ≥12 mm observed on transvaginal ultrasound. Randomisation and 
administration of hCG will take place on the day of reaching the criterion for triggering of final 
follicular maturation. Subjects will be randomised in a 1:1:1 ratio to either HP-hCG 5,000 IU IM, 
HP-hCG 5,000 IU SC, or rhCG 250 μg SC. Randomisation will be stratified by the number of 
follicles ≥12 mm at the end of stimulation (two strata: <10 follicles and ≥10 follicles). Subjects who 
do not meet the criterion for triggering of final follicular maturation will not proceed to 
randomisation and are considered screening failures.
Oocyte retrieval will take place 36h (±2h) after hCG administration. All oocytes from follicles with 
an estimated diameter ≥12 mm should be retrieved. Oocytes will be inseminated within 6h after 
retrieval using IVF or ICSI. In case of ICSI, maturity stage should be assessed. On day 1 after 


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Trial Code: 000191 
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CONFIDENTIAL
oocyte retrieval, fertilisation will be assessed, and the correct fertilisation will be defined as oocytes 
with 2 pronuclei (2PN). On day 3 after oocyte retrieval, the number of embryos and good-quality 
embryos (≥6 blastomeres and ≤20% fragmentation) will be assessed. In case of continued culture, 
the number of blastocysts and good-quality blastocysts (grade 3BB or above) will be assessed on 
day 5 after oocyte retrieval. Subjects will undergo transfer of 1-2 embryos or blastocysts on day 3 
or day 5 after oocyte retrieval. 
Vaginal progesterone capsules (UTROGESTAN, Besins Healthcare) 3 × 200 mg/day will be 
provided for luteal phase support starting the day of or the day after oocyte retrieval, depending on 
the centre’s practice, and continuing until the clinical pregnancy visit (can be discontinued earlier in 
case of no embryo / blastocyst transfer, a negative βhCG test or pregnancy loss). 
Pregnancy monitoring consists of a visit 13-15 days after transfer where a serum βhCG test will be 
taken and a visit 5-6 weeks after transfer assessing clinical and vital pregnancy via transvaginal 
ultrasound. 
Blood samples will be collected at the end of stimulation, the embryo / blastocyst transfer visit and 
the βhCG visit for analysis of endocrine profile (estradiol, progesterone and hCG) and potential 
analysis of anti-hCG antibodies. 
Local tolerability of the hCG preparations will be assessed by the subject three times after the hCG 
administration: immediately, 30 minutes and 24 hours after.
Post-trial Activities
All subjects with a vital pregnancy will be followed till delivery to gather information on pregnancy 
outcome, e.g. live birth. Furthermore, data will be gathered on neonatal health at birth, including 
minor/major congenital anomalies.
NUMBER OF SUBJECTS
It is planned to randomise 258 subjects from 5 sites in Brazil. It is estimated that up to 300 subjects 
should be screened to achieve 258 subjects eligible for randomisation. 
The assumptions underlying the sample size estimation will be evaluated by the Data Monitoring 
Committee (DMC) in a blinded manner and the number of randomised subjects may be adjusted up 
to a maximum of 348 subjects.
CRITERIA FOR INCLUSION / EXCLUSION
This trial will include women aged 18-39 years, diagnosed with infertility and considered eligible 
for IVF/ICSI treatment. Women with more than 3 previous controlled ovarian stimulation cycles, 
with poor response in a previous cycle at a gonadotropin starting dose of 150 IU/day or higher, or 
with excessive response in a previous cycle at a gonadotropin starting dose of 150 IU/day or lower 
are excluded from participation.
The complete list of inclusion and exclusion criteria is provided below.
Inclusion criteria 
1. Informed Consent Form signed prior to screening evaluations.


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Trial Code: 000191 
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CONFIDENTIAL
2. Willing and able to comply with the protocol for the duration of the trial.
3. In good physical and mental health.
4. Pre-menopausal females between the ages of 18 and 39 years. The subjects must be at least 
18 years (including the 18th birthday) when they sign the informed consent and no more 
than 39 years (up to the day before the 40th birthday) at the time of randomisation.
5. Documented history of infertility (e.g. unable to conceive for at least 1 year for subjects
<35 years of age; or unable to conceive for at least 6 months for subjects ≥35 years of age, 
subjects with bilateral tubal occlusion or absence of fallopian tubes, or subjects who require 
donor sperm).
6. Use of fresh or frozen ejaculated sperm from male partner or donor. If partner sperm will be 
used, male partner should have a semen analysis that is at least adequate for ICSI based on 
analysis within 6 months prior to randomisation. 
7. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or 
enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa 
(e.g. no hydrosalpinx) at screening. Both ovaries must be accessible for oocyte retrieval.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no endometrial or endocervical polyps and no congenital structural 
abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior 
to randomisation.
9. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
10. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening.
11. Follicular development with ≥3 follicles with a diameter ≥17 mm and <25 follicles with a 
diameter ≥12 mm observed on transvaginal ultrasound at the end of stimulation in the trial 
cycle.
12. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 12 IU/L (results 
obtained within 6 months prior to randomisation).
13. Negative urine pregnancy test at screening and negative urine pregnancy test on the day of 
stimulation day 1 prior to administration of gonadotropin for controlled ovarian stimulation.
14. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV), Human 
Immunodeficiency Virus (HIV), syphilis, Human T-Cell Lymphotropic Virus (HTLV) 1 
and 2 antibody tests within 2 years prior to randomisation.
15. Willing to accept transfer of 1-2 embryos / blastocysts.
Exclusion Criteria
1. Known mental incapacity or language barrier precluding adequate understanding of the 
informed consent information and the trial activities.


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2. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
3. Known endometriosis stage III and IV according to the revised classification of the 
American Society for Reproductive Medicine (ASRM).
4. Known polycystic ovarian syndrome (PCOS) according to the revised Rotterdam consensus.
5. History of more than three previous controlled ovarian stimulation cycles.
6. Poor response in a previous controlled ovarian stimulation cycle using a gonadotropin
starting dose of 150 IU/day or higher. Poor response is defined as <4 oocytes retrieved, or 
cycle cancellation prior to oocyte retrieval due to inadequate follicular development.
7. Excessive response in a previous controlled ovarian stimulation cycle using a gonadotropin
starting dose of 150 IU/day or lower. Excessive response is defined as ≥20 oocytes retrieved 
or cycle cancellation prior to oocyte retrieval due to excessive follicular development, 
including risk of ovarian hyperstimulation syndrome (OHSS).
8. OHSS leading to hospitalisation in a previous controlled ovarian stimulation cycle.
9. At risk of developing moderate / severe OHSS in the current controlled ovarian stimulation 
cycle, as judged by the investigator at the end of stimulation (i.e. on the day of 
randomisation).
10. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy and before week 24 of pregnancy, excluding ectopic pregnancy).
11. Known surgical or medical condition that may interfere with absorption, distribution, 
metabolism, or excretion of the drugs to be used.
12. Undiagnosed vaginal bleeding.
13. Currently breast-feeding.
14. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial. In case partner sperm will 
be used and the sperm production is severely impaired (concentration <1 million/mL), 
normal karyotype, including no Y-chromosome microdeletion, must be documented.
15. Use of epididymis and testicular sperm from partner or donor.
16. Known inherited or acquired thrombophilia disease.
17. Known active arterial or venous thromboembolism or severe thrombophlebitis, or a history 
of these events.
18. Known porphyria.
19. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
20. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
21. Known moderate or severe impairment of renal or hepatic function.
22. Findings at the gynaecological examination at screening which preclude gonadotropin 


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CONFIDENTIAL
stimulation or are associated with a reduced chance of pregnancy, e.g. retained intrauterine 
device.
23. Known current active pelvic inflammatory disease.
24. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
25. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
26. Use of fertility modifiers during the last menstrual cycle before start of controlled ovarian 
stimulation, including oral contraceptives, clomiphene citrate, gonadotropins, 
dehydroepiandrosterone (DHEA) or insulin sensitisers.
27. Any concomitant medications that would interfere with evaluation of trial medications. 
Specifically, any non-trial hormonal therapy (except for thyroid medication and
non-systemic steroids) or continuous use of prostaglandin inhibitors (non-steroid 
anti-inflammatory drugs (NSAIDs), including aspirin) within 4 weeks prior to start of 
controlled ovarian stimulation.
28. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
29. Hypersensitivity to any drug substance or excipients in a GnRH or any GnRH analogue / 
derivative.
30. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
31. Addictive substance abuse, defined as current or past (1 year prior to randomisation) abuse 
of alcohol or drugs, and/or current (1 month prior to randomisation) intake of more than 
14 units of alcohol per week, and/or current or past (3 months prior to randomisation) 
smoking habit of more than 20 cigarettes per day.
32. Previous participation in the trial.


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Trial Code: 000191 
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MEDICINAL PRODUCTS
Investigational Medicinal Products (IMPs)
IMP
Trade name
Dose
HP-hCG 
CHORAPUR
A single 5,000 IU IM or SC injection on the day of reaching 
the criterion for triggering of final follicular maturation.
rhCG
OVIDREL
A single 250 μg SC injection on the day of reaching the 
criterion for triggering of final follicular maturation.
Concomitant Therapy / Non-investigational Medicinal Products (NIMPs)
NIMP
Trade name
Dose
HP-hMG
MENOPUR
150 IU SC injection once daily as starting dose on day 2-3 of 
the menstrual cycle. Potential dose adjustments based on the 
subject’s response as observed on transvaginal ultrasound, 
depending on the centre’s practice and the investigator’s 
judgement.
GnRH 
antagonist 
(cetrorelix 
acetate)
CETROTIDE
0.25 mg SC injection once daily, starting on stimulation day 6 
and continued throughout the stimulation period.
Progesterone
UTROGESTAN
3 × 200 mg daily as vaginal capsules, starting on the day of or 
the day after oocyte retrieval, depending on the centre’s 
practice, and continued until the clinical pregnancy visit. 
Progesterone support can be terminated earlier in case of no 
transfer, a negative βhCG test or pregnancy loss. 
DURATION OF TREATMENT
IMP will be administered as a single injection.
STATISTICAL METHODS
The non-inferiority margin for the difference between treatments (HP-hCG 5,000 IU versus rhCG 
250 μg) is set to -3.0 oocytes. Non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 μg
will be established by doing the comparisons in sequential order as follows:
1) HP-hCG 5,000 IU IM vs. rhCG 250 μg SC
2) HP-hCG 5,000 IU SC vs. rhCG 250 μg SC
This will only be evaluated if the first comparison establishes non-inferiority
It is assumed that the three treatments are equivalent with respect to number of oocytes retrieved. 
The number of oocytes retrieved is assumed to follow a normal distribution with a mean of 10-12 


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and a standard deviation of 6.0. Under these assumptions, a sample size of 258 subjects (86 subjects 
per group) will result in approximately 90% power to establish non-inferiority for the first 
comparison and approximately 80% power to establish non-inferiority for both comparisons. The 
number of subjects with major protocol deviations affecting the primary endpoint is assumed to be 
negligible. Therefore the sample size has not been adjusted to account for major protocol deviations 
affecting the primary endpoint.
Sample Size Monitoring
The standard deviation of the number of oocytes retrieved will be evaluated in a blinded manner. If 
the standard deviation is larger than 6.0, the sample size may be increased to a maximum of 
348 subjects (116 subjects per group) corresponding to a standard deviation of 7.0.
Primary Endpoint
The non-inferiority hypothesis to be tested for the primary endpoint is 
H0: ORHP-hCG – ORrhCG ≤ -3.0 against the alternative HA: ORHP-hCG – ORrhCG > -3.0 
where ORHP-hCG and ORrhCG  denotes the number of oocytes retrieved with HP-hCG 5,000 IU (IM or 
SC) and rhCG 250 μg SC, respectively.
For each comparison, the null hypothesis (H0) will be tested against the alternative (HA) by 
constructing a two-sided 95% confidence interval for the difference in number of oocytes retrieved. 
The confidence interval will be based on analysis of variance (ANOVA) model including treatment, 
randomisation stratum and trial site as factors. The primary endpoint will be analysed for the 
intention-to-treat (ITT) and the per-protocol (PP) analysis sets. Since this is a non-inferiority trial,
the ITT and the PP analysis sets will have equal importance and should lead to similar conclusions
for a robust interpretation.
Evaluation of the Primary Objective
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority
limit but also above zero, there is evidence of superiority in terms of statistical significance at the 
two-sided 5% level. In this case, the p-value from the test for superiority will be reported. There is 
no need for a multiplicity adjustment, since it is a simple closed test procedure. This interpretation 
is in line with European Medicines Agency (EMA) “Points to consider on switching between 
superiority and non-inferiority”.
The result of the analysis of the primary endpoint (number of oocytes retrieved) is essential for the 
non-inferiority claim. The number of metaphase II oocytes (only applicable for insemination using 
ICSI) and the number of fertilised oocytes are considered the key secondary endpoints supportive 
of the primary endpoint. The analyses of the remaining secondary endpoints are intended to provide 
additional characterisation of the treatment effect.


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Solution for Injection
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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 14
LIST OF FIGURES ...................................................................................................................................... 14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 15
1
INTRODUCTION ............................................................................................................................. 17
1.1
Background............................................................................................................................. 17
1.2
Scientific Justification for Conducting the Trial..................................................................... 17
1.3
Benefit / Risk Aspects............................................................................................................. 18
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 20
2.1
Objectives ............................................................................................................................... 20
2.2
Endpoints ................................................................................................................................ 20
3
INVESTIGATIONAL PLAN ........................................................................................................... 21
3.1
Overall Trial Design................................................................................................................ 21
3.1.1
Trial Design Diagram ................................................................................................ 21
3.1.2
Overall Design and Control Methods ........................................................................ 22
3.1.3
Trial Schedule............................................................................................................ 23
3.2
Planned Number of Trial Sites and Subjects........................................................................... 23
3.3
Interim Analysis...................................................................................................................... 23
3.4
Data Monitoring Committee (DMC) ...................................................................................... 23
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 23
3.5.1
Trial Design ............................................................................................................... 23
3.5.2
Selection of Endpoints ............................................................................................... 25
3.5.3
Blinding ..................................................................................................................... 25
3.5.4
Selection of Doses in the Trial................................................................................... 25
3.5.5
Selection and Timing of Dose for Each Subject........................................................ 26
3.5.6
Selection of the Trial Population ............................................................................... 26
3.5.7
Follow-up Procedures ................................................................................................ 27
4
SELECTION OF TRIAL POPULATION ...................................................................................... 28
4.1
Trial Population ...................................................................................................................... 28
4.1.1
Inclusion Criteria ....................................................................................................... 28
4.1.2
Exclusion Criteria ...................................................................................................... 29
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 31
4.2.1
Recruitment................................................................................................................ 31
4.2.2
Randomisation ........................................................................................................... 31
4.3
Restrictions ............................................................................................................................. 31
4.3.1
Prohibited Therapy..................................................................................................... 31
4.3.2
Other Restrictions ...................................................................................................... 32
4.4
Withdrawal Criteria................................................................................................................. 32
4.5
Subject Replacement............................................................................................................... 32
5
TREATMENTS ................................................................................................................................. 33
5.1
Treatments Administered........................................................................................................ 33
5.1.1
Investigational Medicinal Products (IMPs) ............................................................... 33
5.1.2
Non-Investigational Medicinal Products (NIMPs) .................................................... 33


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5.2
Characteristics and Source of Supply ..................................................................................... 34
5.3
Packaging and Labelling......................................................................................................... 34
5.4
Conditions for Storage and Use .............................................................................................. 35
5.5
Blinding / Unblinding ............................................................................................................. 36
5.5.1
Blinding ..................................................................................................................... 36
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 37
5.6
Dispensing and Accountability, Return and Destruction........................................................ 37
5.7
Auxiliary Supplies .................................................................................................................. 37
6
TRIAL PROCEDURES .................................................................................................................... 38
6.1
At All Visits ............................................................................................................................ 39
6.2
Screening................................................................................................................................. 39
6.3
Controlled Ovarian Stimulation.............................................................................................. 39
6.4
Randomisation / hCG Administration..................................................................................... 40
6.5
Oocyte Retrieval ..................................................................................................................... 41
6.6
Day of Transfer (Day 3 or 5 after Oocyte Retrieval).............................................................. 42
6.7
βhCG Test............................................................................................................................... 42
6.8
Clinical Pregnancy.................................................................................................................. 43
6.9
End-of-trial.............................................................................................................................. 43
6.10
Post-trial Activities ................................................................................................................. 43
7
TRIAL ASSESSMENTS ................................................................................................................... 44
7.1
Assessments Related to Primary Endpoint ............................................................................. 44
7.1.1
Number of Oocytes Retrieved.................................................................................... 44
7.2
Assessments Related to Secondary Endpoints........................................................................ 44
7.2.1
Number of Metaphase II Oocytes.............................................................................. 44
7.2.2
Number of Fertilised Oocytes.................................................................................... 44
7.2.3
Fertilisation Rate........................................................................................................ 44
7.2.4
Positive βhCG Rate.................................................................................................... 44
7.2.5
Clinical Pregnancy Rate............................................................................................. 44
7.2.6
Vital Pregnancy Rate ................................................................................................. 45
7.2.7
Circulating Levels of Endocrine Parameters ............................................................. 45
7.2.8
Number and Quality of Embryos on Day 3 ............................................................... 45
7.2.9
Number and Quality of Blastocysts on Day 5............................................................ 45
7.2.10 Frequency and Intensity of Adverse Events .............................................................. 46
7.2.11 Early and Late OHSS Rates....................................................................................... 46
7.2.12 Frequency and Intensity of Injection Site Reactions.................................................. 47
7.3
Other Assessments.................................................................................................................. 47
7.3.1
Demographics ............................................................................................................ 47
7.3.2
Medical History ......................................................................................................... 47
7.3.3
Infertility History ....................................................................................................... 47
7.3.4
Menstrual History ...................................................................................................... 47
7.3.5
Reproductive History................................................................................................. 47
7.3.6
Body Measurements................................................................................................... 47
7.3.7
Physical Examination................................................................................................. 48
7.3.8
Gynaecological Examination..................................................................................... 48
7.3.9
Number and Size of Follicles during Stimulation...................................................... 48
7.3.10 Anti-hCG Antibodies................................................................................................. 48


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7.3.11 Concomitant Medication............................................................................................ 49
7.3.12 Drug Dispensing and Accountability......................................................................... 49
7.3.13 End-of-Trial Form...................................................................................................... 49
7.4
Assessments Related to Post-trial Information ....................................................................... 49
7.5
Handling of Biological Samples ............................................................................................. 49
8
ADVERSE EVENTS ......................................................................................................................... 50
8.1
Adverse Event Definition........................................................................................................ 50
8.2
Collection and Recording of Adverse Events......................................................................... 50
8.2.1
Collection of Adverse Events .................................................................................... 50
8.2.2
Recording of Adverse Events .................................................................................... 50
8.3
Adverse Events of Special Interest ......................................................................................... 53
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)........................................................... 53
8.3.2
Local Tolerability....................................................................................................... 54
8.3.3
Menstrual Bleeding.................................................................................................... 55
8.3.4
Pregnancy Loss .......................................................................................................... 55
8.4
Serious Adverse Events .......................................................................................................... 56
8.4.1
Serious Adverse Event Definition.............................................................................. 56
8.4.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 57
8.5
Follow-up of Adverse Events and Serious Adverse Events.................................................... 58
8.5.1
Follow-up of Adverse Events with Onset during the Trial........................................ 58
8.5.2
Collection of Serious Adverse Events with Onset after End-of-Trial........................ 58
9
STATISTICAL METHODS ............................................................................................................. 59
9.1
Determination of Sample Size ................................................................................................ 59
9.2
Subject Disposition ................................................................................................................. 60
9.3
Protocol Deviations................................................................................................................. 60
9.4
Analysis Sets........................................................................................................................... 61
9.4.1
Intention-to-Treat (ITT) Analysis Set........................................................................ 61
9.4.2
Full Analysis Set (FAS)............................................................................................. 61
9.4.3
Per-Protocol (PP) Analysis Set .................................................................................. 61
9.4.4
Safety Analysis Set .................................................................................................... 61
9.5
Trial Population ...................................................................................................................... 61
9.5.1
General Considerations.............................................................................................. 61
9.5.2
Demographics ............................................................................................................ 62
9.5.3
Body Measurements................................................................................................... 62
9.5.4
Number and Size of Follicles during Stimulation...................................................... 62
9.5.5
Endocrine Parameters ................................................................................................ 62
9.5.6
Medical History ......................................................................................................... 62
9.5.7
Infertility History ....................................................................................................... 62
9.5.8
Menstrual History ...................................................................................................... 62
9.5.9
Reproductive History................................................................................................. 62
9.5.10 Physical Examination and Gynaecological Examination .......................................... 63
9.5.11 Concomitant Medication............................................................................................ 63
9.6
Extent of Exposure and Treatment Compliance ..................................................................... 63
9.7
Endpoint Assessments............................................................................................................. 63
9.7.1
General Considerations.............................................................................................. 63
9.7.2
Primary Endpoint....................................................................................................... 64


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9.7.3
Secondary Endpoints ................................................................................................. 65
9.8
Safety ...................................................................................................................................... 67
9.8.1
General Considerations.............................................................................................. 67
9.8.2
Adverse Events .......................................................................................................... 67
9.8.3
Early and Late OHSS................................................................................................. 68
9.8.4
Injection Site Reactions ............................................................................................. 68
10
DATA HANDLING ........................................................................................................................... 69
10.1
Source Data and Source Documents....................................................................................... 69
10.2
e-CRF...................................................................................................................................... 70
10.3
Data Management ................................................................................................................... 70
10.4
Provision of Additional Information....................................................................................... 71
11
MONITORING PROCEDURES ..................................................................................................... 72
11.1
Periodic Monitoring................................................................................................................ 72
11.2
Audit and Inspection............................................................................................................... 72
11.3
Confidentiality of Subject Data............................................................................................... 72
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 73
12.1
Protocol Amendments............................................................................................................. 73
12.2
Deviations from the Protocol .................................................................................................. 73
12.3
Premature Trial Termination................................................................................................... 73
13
REPORTING AND PUBLICATION .............................................................................................. 74
13.1
Clinical Trial Report ............................................................................................................... 74
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 74
13.3
Publications and Public Disclosure......................................................................................... 74
13.3.1 Publication Policy ...................................................................................................... 74
13.3.2 Public Disclosure Policy............................................................................................ 74
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 76
14.1
National Ethics Committee ..................................................................................................... 76
14.2
Regulatory Authority Authorisation ....................................................................................... 76
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 76
14.4
Ethical Conduct of the Trial.................................................................................................... 76
14.5
Subject Information and Consent............................................................................................ 76
14.6
Subject Information Card........................................................................................................ 77
14.7
Compliance Reference Documents......................................................................................... 77
15
LIABILITIES AND INSURANCE .................................................................................................. 78
15.1
ICH-GCP Responsibilities...................................................................................................... 78
15.2
Liabilities and Insurance......................................................................................................... 78
16
ARCHIVING...................................................................................................................................... 79
16.1
Investigator File ...................................................................................................................... 79
16.2
Trial Master File ..................................................................................................................... 79
17
REFERENCES................................................................................................................................... 80


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LIST OF TABLES 
Table 5-1
Investigational Medicinal Products (IMPs) ....................................................................33
Table 5-2
Non-Investigation Medicinal Products (NIMPs)............................................................33
Table 5-3
Characteristics and Source of Supply of Medicinal Products.........................................34
Table 5-4
Packaging of Medicinal Products ...................................................................................35
Table 5-5
Conditions for Storage of Medicinal Products................................................................36
Table 6-1
Trial Flow Chart..............................................................................................................38
Table 8-1
Classification of Mild, Moderate and Severe OHSS ......................................................54
LIST OF FIGURES
Figure 3-1 Trial Diagram..................................................................................................................21


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
ANOVA
analysis of variance
ATC
Anatomical Therapeutic Chemical Classification System
ART
assisted reproductive technology
ASRM
American Society for Reproductive Medicine
AUC
area under curve
βhCG
beta unit of human chorionic gonadotropin
BMI
body mass index
COS
controlled ovarian stimulation
DHEA
dehydroepiandrosterone
DMC
Data Monitoring Committee
EC
ethics commitee
e-CRF
electronic Case Report Form
EMA
European Medicines Agency
FAS
full analysis set
FDA
Food and Drug Administration 
FSH
follicle-stimulating hormone 
FPFV
first patient first visit
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH
gonadotropin-releasing hormone
h
hour(s)
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HP-hCG
highly purified human chorionic gonadotropin
HP-hMG
highly purified menotrophin
HTLV
human T-cell lymphotropic virus
ICD-10
International Statistical Classification of Diseases and Related Health Problems, 
10th revision
ICH
International Conference on Harmonisation
ICMART
International Committee Monitoring Assisted Reproductive Technologies
ICMJE
International Committee of Medical Journal Editors
ICSI
intracytoplasmic sperm injection
IM
intramuscular(ly)
IMP
investigational medicinal product
ITT
intention-to-treat
IU
international units
IVF
in vitro fertilisation
L
litre
LH
luteinising hormone
LLOQ
lower limit of quantification
LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MII
metaphase II


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mL
millilitre
NCU
neonatal care unit
NICU
neonatal intensive care unit
NIMP
non-investigational medicinal product
nmol
nanomol
NSAID
non-steroidal anti-inflammatory drug
OHSS
ovarian hyperstimulation syndrome
OR
oocyte retrieval
PCOS
polycystic ovarian syndrome 
pmol
picomol
2PN
2 pronuclei 
PP
per-protocol
PT
preferred term
rhCG
recombinant hCG
SAE
serious adverse event
SC
subcutaneous(ly) 
SOC
system organ class
SPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction 
TVU
transvaginal ultrasound
μg
microgram
ULOQ
upper limit of quantification
WHO
World Health Organization


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1
INTRODUCTION
1.1
Background
Human chorionic gonadotropin (hCG) belongs to the gonadotropins, Anatomical Therapeutic 
Chemical (ATC) code G03GA01, and is a glycoprotein hormone produced by the human placenta. 
It is comprised of an alpha subunit that is common to luteinising hormone (LH) and 
follicle-stimulating hormone (FSH), and a beta subunit that is unique to hCG. The action of hCG is 
qualitatively the same as that of the pituitary gonadotropin LH. However, hCG has a significantly
longer half-life and thus has a greater effect compared to LH.1
Exogenous human chorionic gonadotropin (hCG) has been used for treatment of female and male 
infertility for many years. In females, hCG mimics LH surge and thereby is used to induce 
ovulation in anovulatory or oligo-ovulatory women or to trigger final follicular maturation in 
women undergoing assisted reproductive technology (ART) programmes.1
CHORAPUR is a highly purified hCG (HP-hCG) obtained from the urine of pregnant women. An 
identical product to CHORAPUR is currently marketed by Ferring in some countries under the 
trade name BREVACTID. Additionally, for nearly 20 years Ferring has marketed another 
urine-derived hCG product CHORAGON, which used to be available in Brazil. Both CHORAPUR 
and CHORAGON have a dosage form of 5000 IU for intramuscular (IM) administration, but have 
different drug substance suppliers. Due to the cease of drug substance supply for CHORAGON, 
Ferring intends to replace CHORAGON with CHORAPUR worldwide. CHORAPUR 
(BREVACTID) 5,000 IU has been demonstrated to be bioequivalent with CHORAGON 5,000 IU
in terms of pharmacokinetic and pharmacodynamic properties after IM administration in healthy 
volunteers in a phase I trial.1 In addition, comparability studies of hCG drug substances from the 
two suppliers have shown that the drug substance of CHORAPUR has higher purity than that of 
CHORAGON,1 and therefore CHORAPUR as a more purified product may be suitable also for 
subcutaneous (SC) administration. 
Choriogonadotropin alfa (OVIDREL, Merck Serono) is a recombinant hCG (rhCG) expressed by a 
Chinese hamster ovarian cell line.2 It is commercially available as a pre-filled pen containing 
250 μg hCG to be administered SC for triggering of final follicular maturation in an ART setting. 
To support the registration of CHORAPUR, the present phase III trial is conducted with the
primary objective of documenting the non-inferiority of HP-hCG 5,000 IU compared with rhCG 
250 μg for triggering of final follicular maturation with respect to number of oocytes retrieved in 
women undergoing controlled ovarian stimulation.
1.2
Scientific Justification for Conducting the Trial
A number of studies2,3,4,5 have compared the efficacy and safety of urine-derived hCG administered 
IM and rhCG administered SC for triggering of final follicular maturation in women undergoing 
ART. All concluded that there were no statistically significant differences between the two 
preparations in clinical outcomes including the number of oocytes retrieved and the clinical 
pregnancy rate. A recent trial compared another HP-hCG product against rhCG and demonstrated 
that the two products were equally efficient and safe for triggering of final follicular maturation
when administered SC.6


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The present trial intends to complement and expand the prior comparison of HP-hCG and rhCG by 
having a three-arm design to compare rhCG 250 μg SC to both HP-hCG (CHORAPUR) 5,000 IU 
IM and HP-hCG (CHORAPUR) 5,000 IU SC. CHORAPUR is approved for the intended indication 
in several countries based on the available data, but for registration purpose in other countries 
(including Brazil), there is a need to document in a phase III trial with adequate power that HP-hCG 
5,000 IU IM is not inferior to rhCG 250 μg SC with respect to number of oocytes retrieved in 
women undergoing controlled ovarian stimulation. 
With improved purification, HP-hCG is now possible to be administered SC in addition to the 
approved IM route of administration. The SC route of administration for another, less purified 
urine-derived hCG product 10,000 IU was demonstrated to be bioequivalent to the IM route with 
respect to hCG exposure as assessed by the area under the curve (AUC); meanwhile, it was shown 
to be well tolerated in healthy pituitary-suppressed women.7 Supported by all the evidence above, 
this trial will also examine the efficacy and safety of HP-hCG 5,000 IU SC versus rhCG 250 μg 
SC.
1.3
Benefit / Risk Aspects
Benefits
The treatment cycle is provided to the participating subjects free of charge, as Ferring compensates 
the investigational clinics for their expenses. Subjects participating in this trial may benefit by 
achieving a pregnancy. In addition, the data obtained from the treatment cycle may provide useful 
information for optimising the ovarian response and for clinical planning of subsequent treatment 
cycles.
Risks
Participating in the trial does not imply extra risks for the subjects in comparison to routine practice 
for triggering of final follicular maturation. The risks associated with ART treatment, including the 
risk of controlled ovarian stimulation and clinical and laboratory procedures, are explained to the 
subjects as part of the counselling prior to starting treatment.
CHORAPUR and OVIDREL are both approved products (although CHORAPUR is approved in
other countries than Brazil) and the treatment regimen applied in this trial is in line with the 
standard posology. Based on the available data, the most frequently reported adverse events in 
relation to CHORAPUR include headache and injection site reactions (both reported to occur in
more than 10% of patients), nausea, abdominal pain, vomiting, mild or moderate ovarian 
hyperstimulation syndrome (OHSS) and breast swelling (all reported to occur in 1-10% of 
patients).8 The most common adverse events in relation to use of OVIDREL are headache, injection 
site reactions, tiredness, nausea, abdominal pain, vomiting and mild or moderate OHSS (all 
reported to occur in 1-10% of patients).9
As part of the ART treatment in this trial, subjects will receive concomitant fertility medications 
including gonadotropin, GnRH antagonist and progesterone. The concomitant fertility medications
are approved products and are considered generally well tolerated. The most frequently reported
adverse events with these concomitant medication products are similar to those reported for hCG
preparations, such as headache, injection site reactions, abdominal pain, nausea and mild or 


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moderate OHSS. Furthermore, the vaginal progesterone has been associated with local intolerance 
(burning, pruritus or fatty discharge) but incidences are very low.
Most commonly observed adverse events in ART treatment are related to overstimulation of the 
ovaries, e.g. OHSS. They are mainly dose dependent and dependent on the individual subject’s 
response to the treatment. OHSS manifests itself with increasing degree of severity. Moderate /
severe OHSS is associated with marked ovarian enlargement, fluid accumulation and other 
complications. Subjects are closely monitored throughout the trial and the risk of developing early 
OHSS can be prevented by withholding gonadotropins and withholding hCG. Very rare cases of 
serious allergic reactions to hormone preparations have been reported.
The number of embryos / blastocysts transferred will for each subject depend on the availability of 
embryos / blastocysts of good morphological quality, local regulations and clinical practice. 
Transfer of 2 embryos / blastocysts is associated with increased risk of multiple pregnancies / births 
and the related neonatal health problems, compared to transfer of a single embryo / blastocyst.
Participation in this trial does not imply transfer of more embryos / blastocysts than what is judged 
appropriate by the subject, the investigator and local regulations. The incidence of miscarriage is 
higher in women undergoing controlled ovarian stimulation than in women conceiving 
spontaneously, and also the risk of ectopic pregnancy is higher but mainly in patients with a history 
of tubal obstruction.
Subjects will also undergo standard ART treatment procedures, e.g. transvaginal ultrasound, blood 
sampling, oocyte retrieval and transfer. The transvaginal ultrasound examinations may be 
associated with mild discomfort and a very rare risk of infection. The blood sampling might be 
associated with mild discomfort, bruising and a very rare risk of infection. The oocyte retrieval 
procedure is associated with discomfort and very rarely infections and bleeding. The transfer 
procedure is associated with mild discomfort and very rarely infections and mild bleeding.
Benefits / Risks
Participation in this trial is not expected to have a negative influence on the subject’s likelihood of 
conceiving compared to normal clinical practice. Furthermore, participation does not imply extra 
risks for the subjects in comparison to routine IVF/ICSI treatment. In conclusion, the evaluation of 
benefits and risks indicates that participation in this trial is associated with a favourable benefit-risk 
ratio. 


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective
!
To demonstrate non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 μg for 
triggering of final follicular maturation with respect to number of oocytes retrieved in 
women undergoing controlled ovarian stimulation 
Secondary Objectives
!
To evaluate HP-hCG and rhCG with respect to oocyte fertilisation
!
To evaluate HP-hCG and rhCG with respect to pregnancy 
!
To compare HP-hCG with rhCG with respect to endocrine profile
!
To compare HP-hCG with rhCG with respect to safety profile 
2.2
Endpoints
Primary Endpoint
!
Number of oocytes retrieved
Secondary Endpoints
!
Number of metaphase II oocytes (only applicable for insemination using ICSI)
!
Number of fertilised (2PN) oocytes 
!
Fertilisation rate (the rate of fertilised oocytes to oocytes retrieved for subjects with oocytes 
retrieved and also the rate of fertilised oocytes to metaphase II oocytes for subjects with 
oocytes insemination using ICSI)
!
Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)
!
Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)
!
Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer)
!
Circulating concentrations of estradiol, progesterone and hCG at transfer and 13-15 days 
after transfer
!
Frequency and intensity of adverse events
!
Early and late OHSS rates
!
Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject after hCG administration
Post-trial Information
!
Live birth rate and neonatal health at birth for subjects who have achieved a vital pregnancy


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A diagram illustrating the trial period is shown in Figure 3-1.
a
Starting dose of 150 IU/day SC; followed by potential dose adjustments according to individual response. 
b
Progesterone can start on the day of or the day after oocyte retrieval and should continue until clinical pregnancy 
visit (can be discontinued earlier in case of no embryo / blastocyst transfer, a negative βhCG test or pregnancy loss).   
c
Stimulation day 1, 6 and hereafter at least every other day until the end of stimulation.
Abbreviations: GnRH=gonadotropin-releasing hormone, hCG=human chorionic gonadotropin, HP-hCG=highly 
purified hCG, IM=intramuscular(ly), OR=oocyte retrieval, rhCG=recombinant hCG, SC=subcutaneous(ly), 
TVU=transvaginal ultrasound.
Figure 3-1 Trial Diagram 
Controlled ovarian stimulation
MENOPUR a
OR+
3/5 days
Screening
Stimulation day 1
hCG  +
36±2h
Oocyte retrieval (OR)
Transfer
Progesterone UTROGESTAN 3 × 200 mg/day b
βhCG test
Transfer + 
13-15 days
Clinical 
pregnancy
Randomisation / 
hCG administration 
Transfer + 
5-6 weeks
Blood 
Local 
tolerability
HP-hCG
5,000 IU IM
HP-hCG
5,000 IU SC
rhCG
250 μg SC
Medicinal products
Main procedures/assessments
Oocyte/embryo 
assessments
End of 
stimulation
Stimulation day 6
GnRH antagonist
CETROTIDE 
0.25 mg/day
c
TVU
TVU
TVU
TVU
Blood 
Blood 


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3.1.2
Overall Design and Control Methods
Trial Design 
This is a randomised, assessor-blind, parallel groups, multicentre trial comparing the efficacy and 
safety of HP-hCG (CHORAPUR, Ferring Pharmaceuticals) and rhCG (OVIDREL, Merck Serono) 
for triggering of final follicular maturation in women undergoing controlled ovarian stimulation. 
The trial procedures are in line with routine clinical practice, i.e. controlled ovarian stimulation 
following a GnRH antagonist protocol, triggering of final follicular maturation, oocyte retrieval, 
embryo / blastocyst transfer and pregnancy monitoring. 
On day 2-3 of the menstrual cycle, subjects will start controlled ovarian stimulation with highly 
purified menotrophin (HP-hMG, MENOPUR, Ferring Pharmaceuticals). The initial daily dose of 
HP-hMG is 150 IU SC, followed by potential dose adjustments based on the subject’s response as 
observed on transvaginal ultrasound, depending on the centre’s practice and the investigator’s 
judgement. During stimulation, subjects will be monitored by transvaginal ultrasound on 
stimulation day 1, 6 and hereafter at least every other day until the end of stimulation. Coasting is 
prohibited. GnRH antagonist (cetrorelix acetate, CETROTIDE, Merck Serono) will be initiated on 
stimulation day 6 at a daily dose of 0.25 mg and continued throughout the controlled ovarian 
stimulation.
The criterion for triggering of final follicular maturation is ≥3 follicles with a diameter ≥17 mm and 
<25 follicles with a diameter ≥12 mm observed on transvaginal ultrasound. Randomisation and 
administration of hCG will take place on the day of reaching the criterion for triggering of final 
follicular maturation. Subjects will be randomised in a 1:1:1 ratio to either HP-hCG 5,000 IU IM, 
HP-hCG 5,000 IU SC, or rhCG 250 μg SC. Randomisation will be stratified by the number of 
follicles ≥12 mm at the end of stimulation (two strata: <10 follicles and ≥10 follicles). Subjects who 
do not meet the criterion for triggering of final follicular maturation will not proceed to 
randomisation and are considered screening failures.
Oocyte retrieval will take place 36h (±2h) after hCG administration. All oocytes from follicles with 
an estimated diameter ≥12 mm should be retrieved. Oocytes will be inseminated within 6h after 
retrieval using IVF or ICSI. In case of ICSI, maturity stage should be assessed. On day 1 after oocyte 
retrieval, fertilisation will be assessed, and the correct fertilisation will be defined as oocytes with 
2 pronuclei (2PN). On day 3 after oocyte retrieval, the number of embryos and good-quality embryos 
(≥6 blastomeres and ≤20% fragmentation) will be assessed. In case of continued culture, the number 
of blastocysts and good-quality blastocysts (grade 3BB or above) will be assessed on day 5 after 
oocyte retrieval. Subjects will undergo transfer of 1-2 embryos or blastocysts on day 3 or day 5 after 
oocyte retrieval. 
Vaginal progesterone capsules (UTROGESTAN, Besins Healthcare) 3 × 200 mg/day will be 
provided for luteal phase support starting the day of or the day after oocyte retrieval, depending on the
centre’s practice, and continuing until the clinical pregnancy visit (can be discontinued earlier in case 
of no embryo / blastocyst transfer, a negative βhCG test or pregnancy loss). 
Pregnancy monitoring consists of a visit 13-15 days after transfer where a serum βhCG test will be 
taken and a visit 5-6 weeks after transfer assessing clinical pregnancy via transvaginal ultrasound. 
Blood samples will be collected at the end of stimulation, the embryo / blastocyst transfer visit and 
the βhCG visit for analysis of endocrine profile (estradiol, progesterone and hCG) and potential 
analysis of anti-hCG antibodies. 


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Local tolerability of the hCG preparations will be assessed by the subject three times after the hCG 
administration: immediately, 30 minutes and 24 hours after.
Post-trial Activities
All subjects with a vital pregnancy will be followed till delivery to gather information on pregnancy 
outcome, e.g. live birth. Furthermore, data will be gathered on neonatal health at birth, including 
minor/major congenital anomalies.
3.1.3
Trial Schedule
Estimated First patient first visit (FPFV):
Q4 2015
Estimated Last patient last visit (LPLV) / end-of-trial:
Q4 2016
3.2
Planned Number of Trial Sites and Subjects
It is planned to randomise 258 subjects from 5 sites in Brazil. It is estimated that up to 300 subjects 
should be screened to achieve 258 subjects (86 subjects per group) eligible for randomisation. 
The assumptions underlying the sample size estimation will be evaluated by the Data Monitoring 
Committee (DMC) in a blinded manner and the number of randomised subjects may be adjusted up 
to a maximum of 348 subjects.
3.3
Interim Analysis
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned. 
3.4
Data Monitoring Committee (DMC)
An internal DMC consisting of the sponsor’s Medical Officer at Ferring Global Clinical R&D, the 
sponsor’s Medical Officer in Brazil and the project-responsible statistician at Ferring Global
Biometrics will be established. 
The assumptions underlying the sample size estimation will be evaluated by the DMC in a blinded 
manner and the number of randomised subjects may be adjusted up to a maximum of 348 subjects. 
The charter of the DMC will specify the relevant details.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
The primary objective of the trial is to demonstrate the non-inferiority of HP-hCG 5,000 IU 
compared with rhCG 250 μg for triggering of final follicular maturation with respect to number of 
oocytes retrieved in women undergoing controlled ovarian stimulation.
This is a randomised controlled trial using an approved hCG product as an active comparator. It is a 
parallel group design restricted to a single treatment cycle. The trial will be assessor-blind, as a


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double-blind design is not considered feasible for the present trial for various practical reasons, 
which are described in detail in section 3.5.3. The assessor-blinding will ensure unbiased evaluation 
by the investigators, embryologists and central laboratory personnel. Similarly, Ferring staff will 
also remain blinded to individual subject treatment allocation during the conduct of the trial. The 
trial will be a multicentre trial. This set-up ensures that the required number of subjects can be 
recruited within a reasonable time and also has the advantage that it should facilitate subsequent 
generalisation of the results.
The trial is designed with adequate power to demonstrate non-inferiority of HP-hCG IM versus 
rhCG SC with respect to number of oocytes retrieved. The non-inferiority margin for this primary 
endpoint has been set at -3.0. A non-inferiority margin of -3.0 has been recommended by the Food 
and Drug Administration (FDA) and European Medicines Agency (EMA) and follows regulatory 
precedence for the approval of infertility indications with the number of oocytes retrieved as 
primary endpoint. 10,11,12,13 The margin has also been used in previous clinical trials comparing the 
efficacy and safety of different hCG products.2,3,4 The number of oocytes retrieved is assumed to 
follow a normal distribution with a mean of 10-12 and a standard deviation of 6.0. With a sample 
size of 86 subjects per group, it is expected that the difference in the number of oocytes retrieved 
between the HP-hCG groups and the rhCG group has to be less than 1.2 in order to meet the non-
inferiority margin of -3.0. As an example, if the average number of oocytes retrieved in the rhCG 
group is 12.0, the average number of oocytes retrieved in the HP-hCG groups has to be at least 10.8 
in order to establish non-inferiority.
Strict criteria have been incorporated in the design of this comparative efficacy trial to properly 
assess the effect of different hCG products on treatment outcome. In general, treatment and 
procedures before hCG administration have been standardised to minimise variation of follicular 
development. After screening, eligible subjects will undergo a standardised controlled ovarian 
stimulation by receiving the same gonadotropin at the same starting dose. All subjects will follow
the GnRH antagonist protocol by using the same GnRH antagonist at the same dose and starting at 
the same time. In addition, transvaginal ultrasound will be performed regularly to monitor the 
follicular development and only subjects with adequate follicular development can be randomised 
and proceed to receive hCG for triggering of final follicular maturation. To further control for the 
confounding of follicular development, randomisation is stratified by the number of follicles 
≥12 mm at the end of stimulation (two strata: <10 follicles and ≥10 follicles). 
The retrieval of all oocytes from follicles with an estimated diameter ≥12 mm and the following 
insemination of oocytes by either IVF or ICSI reflect the procedures used in the target population 
for the proposed indication. To account for the different transfer policies across clinics and across 
individuals in the same clinic, the present protocol allows transfer on day 3 or day 5 after oocyte 
retrieval. A maximum of 2 embryos / blastocysts can be transferred, as this is in line with the 
current clinical practices taken for maintaining efficacy (i.e. pregnancy) and minimising risks (i.e. 
multiple pregnancies) of the controlled ovarian stimulation cycle. Meanwhile, some flexibility has 
been given regarding the choice of single or double transfer of embryos / blastocysts, as the transfer 
takes place after assessment of the primary endpoint. 
Subjects who achieve a vital pregnancy will be followed up till delivery to collect information on 
pregnancy outcome. In addition, neonatal health data will be gathered at birth.


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3.5.2
Selection of Endpoints
The primary endpoint of this trial, the number of oocytes retrieved, is an objective and measurable
parameter. The number of oocytes retrieved is a direct measure of the main pharmacological action 
of hCG preparations, as it integrates a cascade of intrafollicular events necessary for oocyte release 
from the follicle.2 The number of oocytes retrieved has also been used as the primary endpoint in 
other trials comparing the efficacy and safety of hCG products of different origins.2,3,4,6
Secondary endpoints will explore the qualitative and quantitative impact of HP-hCG and rhCG with 
regard to oocyte maturity, fertilisation rate and pregnancy. To investigate the pharmacodynamic 
effect, endocrine profile represented by estradiol and progesterone will be evaluated at the end of 
stimulation, the embryo / blastocyst transfer visit and the βhCG visit. Safety endpoints cover 
adverse events, early and late OHSS rates, and injection site reactions. Pre-defined injection site 
reactions, i.e. redness, pain, itching, swelling and bruising, will be assessed by the subjects at three
occasions spanning from immediately after injection to 24 hours after. 
Post-trial activities cover follow-up of subjects who have achieved a vital pregnancy to collect data 
on pregnancy outcome and neonatal health at birth.
In conclusion, the primary and secondary endpoints are appropriate for this trial.
3.5.3
Blinding
The investigational medicinal products (IMPs) in this trial differ in presentation, as HP-hCG is 
provided as a pair of powder vial and solvent ampoule to be administered either SC or IM after 
reconstitution, whereas rhCG is provided as a pre-filled pen to be administered SC only. 
Furthermore, rhCG is manufactured by Merck Serono and bought commercially for use in this trial. 
Therefore, a double-blind, double-dummy design is not feasible.
Previous trials comparing the efficacy and safety of rhCG and urine-derived hCG have been 
open-label studies with no blinding of investigators, other assessors or sponsor.2,6 This trial is 
assessor-blind, however, ensuring unbiased evaluation by the investigators, embryologists and 
laboratory personnel. The trial staff dispensing and/or administering IMP, the trial coordinator 
(person entering data into the electronic case report form (e-CRF); can be the same person who 
dispense and/or administer IMP), the in-field monitors and the participating subjects will know the 
treatment allocation once the subjects are randomised. Precaution will be taken to ensure that the 
treatment allocations are not available to the investigators or other assessors throughout the trial. 
Subjects will be clearly instructed not to discuss their treatment allocation with the investigator.
The Ferring clinical trial team (except IMP Department members) will be blinded to individual and 
group treatment allocation until breaking of the blind.
3.5.4
Selection of Doses in the Trial
Each subject meeting the criterion for triggering of final follicular maturation will receive a single 
dose of 5,000 IU HP-hCG IM, 5,000 IU HP-hCG SC or 250 μg rhCG SC. 
The doses are selected to be consistent with the posology of the respective products for the 
indication of triggering of final follicular maturation in women undergoing ART.8,9 The approved 
rhCG (OVIDREL) dose is 250 μg, which has been suggested to be equivalent to approximately 


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6,500 IU.12 Standard dose of urine-derived hCG for triggering of final follicular maturation is either 
5,000 or 10,000 IU. The lowest effective dose of 5,000 IU is selected for HP-hCG in this trial, as 
this would be a reasonable approach in clinical practice.
OVIDREL (rhCG) has been approved for SC administration, while CHORAPUR (HP-hCG) is
approved for IM administration only. With improved purification, HP-hCG is now possible to be 
administered SC in addition to the approved IM route of administration. The SC route of 
administration for another, less purified urine-derived hCG product 10,000 IU was demonstrated to 
be bioequivalent to the IM route with respect to hCG exposure as assessed by AUC and was shown 
to be well tolerated in healthy pituitary-suppressed women.7 Supported by all the evidence above, 
this trial will also examine the efficacy and safety of HP-hCG 5,000 IU SC.
The treatment regimen in this trial for HP-hMG (MENOPUR), the GnRH antagonist 
(CETROTIDE) and progesterone (UTROGESTAN) is according to the respective products’ 
labelling for the indication of ART and/or standard clinical practice supported by literature.
3.5.5
Selection and Timing of Dose for Each Subject
Administration of hCG will take place when there is adequate follicular development for triggering 
of final follicular maturation, i.e. when ≥3 follicles with a diameter ≥17 mm and <25 follicles with 
a diameter ≥12 mm are observed on transvaginal ultrasound. While the follicular development 
criterion may vary slightly across clinics and individual situation, a standardised criterion must be 
established for the purpose of the trial. Subjects having <3 follicles with a diameter ≥17 mm at the 
end of stimulation are at risk of having no available embryos / blastocysts for transfer, whereas 
subjects having ≥25 follicles with a diameter ≥12 mm are at risk of developing early moderate /
severe OHSS.
3.5.6
Selection of the Trial Population
The trial population is representative of patients undergoing IVF/ICSI treatment. The subjects are 
women with documented history of infertility, including tubal infertility, unexplained infertility, 
infertility related to endometriosis stage I/II according to the revised classification of the American
Society for Reproductive Medicine (ASRM)14 or infertility due to male factor, eligible for IVF 
and/or ICSI treatment. Patients with polycystic ovary syndrome (PCOS) by the revised Rotterdam 
consensus15 or patients with endometriosis stage III-IV by the revised ASRM classification14 are 
excluded from participation. Women having contraindications to controlled ovarian stimulation 
with gonadotropins will be excluded from participation in this trial. 
For the purpose of this trial, considerations have been given to ensure the trial population is suitable 
for triggering of final follicular maturation and that the trial population is relatively homogeneous 
in relation to ovarian response. To minimise the number of potential poor and excessive responders 
in the trial, eligibility for participation is based on ovarian response defined by the number and size 
of follicles in this controlled ovarian stimulation cycle and in previous cycles. 
This trial includes women within the age group of 18-39 years, as increasing female age is 
associated with fewer oocytes and a reduction in oocyte or embryo quality. The allowed body mass 
index (BMI) is 17.5-32.0 kg/m2, thus covering underweight, normal weight, overweight and obese 
patients.


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Altogether, the population selected for this trial would be expected to be representative for patients 
undergoing controlled ovarian stimulation in IVF/ICSI cycles.
3.5.7
Follow-up Procedures
Post-Trial Activities
Post-trial activities cover follow-up of pregnancy outcome and neonatal health at birth for subjects 
who have achieved a vital pregnancy. 
Access to Therapy after End-of-Trial
HP-hCG is for single use in one treatment cycle. Concerning access to therapy after completion of 
the trial, HP-hCG is not currently approved in Brazil and cannot be offered to patients for future 
treatment cycles. However, the comparator rhCG is approved for triggering of final follicular 
maturation and is commercially available in Brazil. 


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Subjects must meet all of the criteria listed below to be eligible for participation in the trial.
1. Informed Consent Form signed prior to screening evaluations.
2. Willing and able to comply with the protocol for the duration of the trial.
3. In good physical and mental health.
4. Pre-menopausal females between the ages of 18 and 39 years. The subjects must be at least 
18 years (including the 18th birthday) when they sign the informed consent and no more 
than 39 years (up to the day before the 40th birthday) at the time of randomisation.
5. Documented history of infertility (e.g. unable to conceive for at least 1 year for subjects 
<35 years of age; or unable to conceive for at least 6 months for subjects ≥35 years of age, 
subjects with bilateral tubal occlusion or absence of fallopian tubes, or subjects who require 
donor sperm).
6. Use of fresh or frozen ejaculated sperm from male partner or donor. If partner sperm will be 
used, male partner should have a semen analysis that is at least adequate for ICSI based on
analysis within 6 months prior to randomisation. 
7. Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, 
without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or 
enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa 
(e.g. no hydrosalpinx) at screening. Both ovaries must be accessible for oocyte retrieval.
8. Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal 
ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence 
of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger 
than 3 cm in diameter, no endometrial or endocervical polyps and no congenital structural 
abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior 
to randomisation.
9. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory.
10. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening.
11. Follicular development with ≥3 follicles with a diameter ≥17 mm and <25 follicles with a 
diameter ≥12 mm observed on transvaginal ultrasound at the end of stimulation in the trial 
cycle.
12. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 12 IU/L (results 
obtained within 6 months prior to randomisation).
13. Negative urine pregnancy test at screening and negative urine pregnancy test on the day of 
stimulation day 1 prior to administration of gonadotropin for controlled ovarian stimulation.


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14. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV), Human 
Immunodeficiency Virus (HIV), syphilis, Human T-Cell Lymphotropic Virus (HTLV) 1 
and 2 antibody tests within 2 years prior to randomisation.
15. Willing to accept transfer of 1-2 embryos / blastocysts.
4.1.2
Exclusion Criteria
Subjects meeting any of the criteria listed below will not be eligible for participation in the trial.
1. Known mental incapacity or language barrier precluding adequate understanding of the 
informed consent information and the trial activities.
2. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
3. Known endometriosis stage III and IV according to the revised classification of the 
American Society for Reproductive Medicine (ASRM).14
4. Known polycystic ovarian syndrome (PCOS) according to the revised Rotterdam 
consensus.15
5. History of more than three previous controlled ovarian stimulation cycles.
6. Poor response in a previous controlled ovarian stimulation cycle using a gonadotropin 
starting dose of 150 IU/day or higher. Poor response is defined as <4 oocytes retrieved, or 
cycle cancellation prior to oocyte retrieval due to inadequate follicular development.
7. Excessive response in a previous controlled ovarian stimulation cycle using a gonadotropin 
starting dose of 150 IU/day or lower. Excessive response is defined as ≥20 oocytes retrieved 
or cycle cancellation prior to oocyte retrieval due to excessive follicular development, 
including risk of OHSS.
8. OHSS leading to hospitalisation in a previous controlled ovarian stimulation cycle.
9. At risk of developing moderate / severe OHSS in the current controlled ovarian stimulation 
cycle, as judged by the investigator at the end of stimulation (i.e. on the day of 
randomisation).
10. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound 
confirmation of pregnancy and before week 24 of pregnancy, excluding ectopic pregnancy).
11. Known surgical or medical condition that may interfere with absorption, distribution, 
metabolism, or excretion of the drugs to be used.
12. Undiagnosed vaginal bleeding.
13. Currently breast-feeding.
14. Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, 
depending on source of sperm used for insemination in this trial. In case partner sperm will 
be used and the sperm production is severely impaired (concentration <1 million/mL), 
normal karyotype, including no Y-chromosome microdeletion, must be documented.
15. Use of epididymis and testicular sperm from partner or donor.
16. Known inherited or acquired thrombophilia disease.


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17. Known active arterial or venous thromboembolism or severe thrombophlebitis, or a history 
of these events.
18. Known porphyria.
19. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or 
kidney) with the exception of controlled thyroid function disease.
20. Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which 
would contraindicate the use of gonadotropins.
21. Known moderate or severe impairment of renal or hepatic function.
22. Findings at the gynaecological examination at screening which preclude gonadotropin 
stimulation or are associated with a reduced chance of pregnancy, e.g. retained intrauterine 
device. 
23. Known current active pelvic inflammatory disease.
24. Known abnormal cervical cytology of clinical significance observed within three years prior 
to randomisation (unless the clinical significance has been resolved).
25. Known history of chemotherapy (except for gestational conditions) or radiotherapy.
26. Use of fertility modifiers during the last menstrual cycle before start of controlled ovarian 
stimulation, including oral contraceptives, clomiphene citrate, gonadotropins, 
dehydroepiandrosterone (DHEA) or insulin sensitisers.
27. Any concomitant medications that would interfere with evaluation of trial medications. 
Specifically, any non-trial hormonal therapy (except for thyroid medication and non-
systemic steroids) or continuous use of prostaglandin inhibitors (non-steroid anti-
inflammatory drugs (NSAIDs), including aspirin) within 4 weeks prior to start of controlled 
ovarian stimulation.
28. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the 
trial.
29. Hypersensitivity to any drug substance or excipients in a GnRH or any GnRH analogue / 
derivative.
30. Use of any non-registered investigational drugs during the last 3 months prior to 
randomisation.
31. Addictive substance abuse, defined as current or past (1 year prior to randomisation) abuse 
of alcohol or drugs, and/or current (1 month prior to randomisation) intake of more than 
14 units of alcohol per week, and/or current or past (3 months prior to randomisation) 
smoking habit of more than 20 cigarettes per day.
32. Previous participation in the trial.


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4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
The participating subjects will be recruited among the patients attending the clinics included in the 
trial. Advertisements may be used if approved by Brazil’s National Ethics Committees (ECs) and 
regulatory authorities, as applicable, according to local regulations and the clinic’s practices.
A screening number is allocated to each subject who has given written informed consent to 
participate in the trial. A subject must always be assigned to the lowest available screening number 
at each site. A subject screening / enrolment log for all screened subjects must be maintained by the 
investigator.
4.2.2
Randomisation
Subjects who meet the criterion for triggering of final follicular maturation will be randomised in a 
1:1:1 ratio to treatment with either HP-hCG 5,000 IU IM, HP-hCG 5,000 IU SC, or rhCG 250 μg 
SC. Randomisation is performed centrally through the e-CRF and will be stratified by the number 
of follicles ≥12 mm on the last day of stimulation (two strata: <10 follicles and ≥10 follicles). The 
randomisation number will be allocated to the subject together with the treatment allocation. When 
a subject is randomised to the trial, she will always be assigned to the lowest available 
randomisation number. An independent statistician at the Ferring Global Biometrics Department 
will prepare a computer-generated randomisation list and randomisation is performed in blocks. 
Blocks will be maintained within trial sites, i.e. the randomisation will be stratified by trial site. The 
block size will only be revealed when the trial database is declared clean and locked. An overview 
of recruitment will be recorded on a subject identification code list for all randomised subjects kept 
by the investigator. 
4.3
Restrictions
4.3.1
Prohibited Therapy
Prohibited Therapy before and during the Trial 
Subjects must not use any fertility modifiers during the last menstrual cycle before start of 
controlled ovarian stimulation, including oral contraceptives, clomiphene citrate, gonadotropins, 
DHEA or insulin sensitisers.
Subjects must not use any concomitant medications that would interfere with evaluation of trial
medications within 4 weeks before start of controlled ovarian stimulation. These prohibited 
concomitant medications include any non-trial hormonal therapy (except for thyroid medication
and non-systemic steroids) and continuous use of prostaglandin inhibitors (NSAIDs, including 
aspirin). 
It is prohibited to administer other hCG preparations than HP-hCG/rhCG or to administer other
concomitant fertility medications than those provided throughout the trial.


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Prohibited Therapy after the Trial
It is prohibited to continue therapy outside the scope of the trial with medicinal products provided 
specifically for the trial.
4.3.2
Other Restrictions
Subjects participating in the trial are not allowed to have any of the following addictive substance 
abuse as listed below:
!
Any current or past (1 year prior to randomisation) abuse of alcohol or drugs
!
Any current or past (3 months prior to randomisation) smoking habit of more than 
20 cigarettes per day
!
Any current (1 month prior to randomisation) intake of more than 14 units of alcohol per 
week
4.4
Withdrawal Criteria
Withdrawal from Trial
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. The investigator also has the right to withdraw subjects. For any 
discontinuation, the investigator will obtain all the required details and document the date of the 
premature termination and the main reason in the e-CRF.
Withdrawal of Consent
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analysed. This will be described in the informed consent. The subject can request 
destruction of samples which would otherwise have been kept in storage.
4.5
Subject Replacement
A subject can only be assigned one screening number and one randomisation number. Subjects who 
discontinue prematurely from the trial after randomisation are not to be replaced, i.e. randomisation 
numbers are uniquely linked to each subject and cannot be re-used.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Products (IMPs)
Subjects who meet the criterion for triggering of final follicular maturation will be randomised in a 
1:1:1 ratio to either HP-hCG 5,000 IU IM, HP-hCG 5,000 IU SC, or rhCG 250 μg SC (Table 5-1).
Administration of hCG will take place on the day of reaching the criterion for triggering of final 
follicular maturation (≥3 follicles with a diameter ≥17 mm and <25 follicles with a diameter 
≥12 mm).  
Table 5-1
Investigational Medicinal Products (IMPs)
IMP
Trade name
Dose
HP-hCG 
CHORAPUR
A single 5,000 IU IM or SC injection on the day of 
reaching the criterion for triggering of final follicular 
maturation.
rhCG
OVIDREL/
OVITRELLE a)
A single 250 μg SC injection on the day of reaching the 
criterion for triggering of final follicular maturation.
a)
OVIDREL is the trade name in Brazil and OVITRELLE is the trade name in Europe.
5.1.2
Non-Investigational Medicinal Products (NIMPs)
As concomitant therapy in the controlled ovarian stimulation cycle, subjects will use the following 
non-investigational medicinal products (NIMPs) as illustrated in Table 5-2.
Table 5-2
Non-Investigation Medicinal Products (NIMPs)
NIMP
Trade name
Dose
HP-hMG
MENOPUR
150 IU SC injection once daily as starting dose on 
day 2-3 of the menstrual cycle. Potential dose adjustments 
based on the subject’s response as observed on 
transvaginal ultrasound, depending on the centre’s practice 
and the investigator’s judgement.
GnRH antagonist
(cetrorelix acetate)
CETROTIDE
0.25 mg SC injection once daily, starting on stimulation 
day 6 and continued throughout the stimulation period.
Progesterone
UTROGESTAN
3 × 200 mg daily as vaginal capsules, starting on the day 
of or the day after oocyte retrieval, depending on the 
centre’s practice, and continued until the clinical 
pregnancy visit. Progesterone support can be terminated
earlier in case of no transfer or a negative βhCG test or 
pregnancy loss.


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All NIMPs are used in line with the recommendations in the respective products’ labelling for the 
indication of ART and/or standard clinical practice supported by literature.
5.2
Characteristics and Source of Supply
All medicinal products are provided by Ferring and will be handled according to the principles of 
Good Manufacturing Practice (GMP). Table 5-3 provides an overview of the presentation and 
manufacturer of each medicinal product.
Table 5-3
Characteristics and Source of Supply of Medicinal Products
IMP / NIMP
Presentation
Manufacturer
CHORAPUR
(HP-hCG)
CHORAPUR is provided as 1 vial with white lyophilised
powder and 1 ampoule with 1 mL solvent. After 
reconstitution, 1 mL solvent contains 5,000 IU hCG.
Ferring 
Pharmaceuticals
OVIDREL/ 
OVITRELLE a)
(rhCG)
OVIDREL/OVITRELLE a) (choriogonadotropin alfa) is 
provided as a pre-filled pen (0.5 mL) for single use 
delivering 250 μg choriogonadotropin alfa.
Merck Serono
MENOPUR
(HP-hMG)
MENOPUR is provided in 1 vial with white lyophilised
powder and 1 ampoule with 1 mL solvent containing 
0.9% sodium chloride. After reconstitution, 1 mL solvent 
contains 75 IU of FSH activity and 75 IU of LH activity.
Ferring 
Pharmaceuticals
CETROTIDE
(GnRH 
antagonist)
CETROTIDE (cetrorelix acetate) is provided as powder 
and solvent for solution for injection. After reconstitution, 
1 mL solvent contains 0.25 mg cetrorelix. 
Merck Serono
UTROGESTAN 
(progesterone)
UTROGESTAN is provided as vaginal capsules, each 
containing 200 mg of progesterone.
Besins Healthcare
a)
OVIDREL is the trade name in Brazil and OVITRELLE is the trade name in Europe.
5.3
Packaging and Labelling
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
IMP Department at Ferring in accordance with GMP and national regulatory requirements. Details 
on the packaging of each medicinal product are provided in Table 5-4. 


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Table 5-4
Packaging of Medicinal Products
IMP / NIMP
Packaging
CHORAPUR
(HP-hCG)
CHORAPUR is provided in boxes containing 1 vial with white 
lyophilised powder and 1 ampoule with solvent for single use. The dry 
substance must be reconstituted with the solvent prior to use.
OVIDREL/ 
OVITRELLE a)
(rhCG)
OVIDREL/OVITRELLE a) is provided in commercial boxes containing 
1 pre-filled pen and 1 needle for single use.
MENOPUR
(HP-hMG)
MENOPUR is provided in commercial boxes containing 5 vials with
white lyophilised powder and 5 ampoules with 1 mL solvent each.
CETROTIDE
(GnRH antagonist)
CETROTIDE is provided in commercial boxes containing 1 vial with 
powder, 1 pre-filled syringe with 1 mL solvent, 1 mixing needle and 
1 injection needle for single use. 
UTROGESTAN
(progesterone)
UTROGESTAN is provided in commercial boxes containing 21 capsules; 
each capsule contains 200 mg micronized progesterone.
a)
OVIDREL is the trade name in Brazil and OVITRELLE is the trade name in Europe.
All IMPs and NIMPs will be labelled with trial-specific labels, which contain a self-adhesive 
tear-off portion to be affixed to the Drug Accountability Form maintained at the trial site. 
The content of the labels will be in accordance with Annex 13, EudraLex, volume 4 and national 
requirements.
5.4
Conditions for Storage and Use
A trial medication delegate, typically a trial nurse, will be identified at each site for handling trial 
medication related issues, including dispensing and/or administering IMP. The trial medication 
delegate will ensure that the medicinal products will be stored in appropriate conditions in a secure 
location with controlled access. The storage compartment shall be monitored regularly and the 
temperature shall be documented.
Deviations in storage temperature must be reported without delay and the medicinal products must 
not be used until further instructions from Ferring are received.
Conditions for storage of the medicinal products before and after dispensing to the subjects are 
listed in Table 5-5.


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Table 5-5
Conditions for Storage of Medicinal Products
IMP / NIMP
Before dispensing to subject
After dispensing to subject
CHORAPUR
(HP-hCG)
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
OVIDREL/
OVITRELLE a)
(hCG)
Store in refrigerator at 2-8ºC. 
Do not freeze. Store in original 
package to protect from light.
Store in refrigerator at 2-8ºC. 
Do not freeze. Store in original 
package to protect from light. 
MENOPUR
(HP-hMG)
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
CETROTIDE 
(GnRH antagonist)
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
Do not store above 25°C. Do not 
freeze. Store in original package to 
protect from light.
UTROGESTAN
(progesterone)
Do not freeze. Store in original 
package. No other special storage 
conditions required.
Do not freeze. Store in original 
package. No other special storage 
conditions required.
a)
OVIDREL is the trade name in Brazil and OVITRELLE is the trade name in Europe.
Depending on the storage facilities at the clinic, more restrictive temperature requirements (e.g.  
storage in refrigerator at 2-8ºC) than those listed in Table 5-5 may be implemented. 
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for CHORAPUR and the Summary of Product Characteristics (SPC) for 
OVIDREL, MENOPUR, CETROTIDE and UTROGESTAN.
5.5
Blinding / Unblinding
5.5.1
Blinding
The trial is assessor-blind, and all investigators, embryologists and laboratory personnel will be 
blinded to treatment allocation throughout the trial. The trial staff dispensing and/or administering 
IMP, the trial coordinators, the in-field monitors and the participating subjects will know the 
treatment allocation once the subjects are randomised. Precaution must be taken to ensure that the 
treatment allocations are not available to the investigators or other assessors throughout the trial. 
Subjects must be clearly instructed to only discuss their treatment allocation with the trial staff 
dispensing and/or administering IMP and not to mention it to the investigator.
The randomisation list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and locked. Likewise, the treatment allocation 
information on the e-CRF will not be accessible to assessors or the Ferring clinical trial team or 
laboratory personnel during the trial. 


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Solution for Injection
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The Ferring clinical trial team (except IMP Department members) will be blinded to treatment 
allocation until breaking of the blind. The blind will be broken when the trial database is declared 
clean and locked. 
5.5.2
Unblinding of Individual Subject Treatment
Emergency decoding envelopes will be available to the investigator and designated persons at 
Ferring. Breaking of the blind for individual subjects in emergency situations is only permitted in 
case of a suspected unexpected serious adverse reaction (SUSAR) or in case of an important 
adverse event where the knowledge of the IMP in question is required for therapeutic decisions for 
the management of the subject.
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
Ferring. The person who opens a code envelope must record on it the reason and the date of 
opening, and then sign and date the opened envelope. It should be recorded in the e-CRF that the 
code is broken, why, when and by whom. The investigator must record the event of unblinding in 
the subject’s medical record, including the reason for unblinding.  
In case of accidental unblinding (e.g. the subject tells the investigator), the same documentation as 
for emergency unblinding must be obtained, i.e. the code envelope must be opened and why, when 
and by whom must be noted both on the code envelope and in the e-CRF, and the event must also 
be recorded in the subject’s medical record.
It may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the authorities and/or EC. In that situation, every effort will be made to maintain 
blinding of Ferring personnel involved in data analysis and interpretation. Other personnel may be 
unblinded for SUSARs, including trial site staff as well as staff acting on behalf of Ferring.
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and locked.
5.6
Dispensing and Accountability, Return and Destruction
To maintain blinding, the investigator will not be involved in any handling of medicinal products 
(neither IMP nor NIMP). The trial medication delegate will maintain subject dispensing logs, 
detailing the dates, quantities and batch numbers of dispensed and returned IMP and NIMP for each 
subject. The trial medication delegate will also manage the overall drug accountability at the site. 
The monitor will verify drug accountability of IMP and NIMP throughout the trial and will 
document any discrepancies.
Concerning destruction, the trial medication delegate at the site must ensure destruction of used 
IMPs and NIMPs in accordance with local legislation after drug accountability has been verified by 
the monitor and signed off by the trial medication delegate, while un-used IMPs and NIMPs will be 
returned for destruction as instructed by the IMP Department of Ferring.
5.7
Auxiliary Supplies
Ferring will supply safety containers for the collection of used pens, syringes, vials and needles 
under request from the clinics. 


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Solution for Injection
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6
TRIAL PROCEDURES
The flow chart of the trial procedures for subjects is shown in Table 6-1.
Table 6-1
Trial Flow Chart 
Screening
Pre-
treatment
Treatment
Post-treatment
End
Eligibility
COS
Triggering
Randomisation/
hCG administration a)
Oocyte 
retrieval
(OR)
Trans-
fer
Pregnancy monitoring
End-
of-
trial
βhCG
Clinical
Timing
<90 days before 
randomisation
The day of reaching the 
triggering criterion
36h ±2h 
after 
triggering
Day 3/5 
after OR
13-15 days after 
transfer
5-6 weeks after 
transfer
b)
Written informed consent
X
Inclusion/exclusion 
criteria
X
  X c)
X d)
Demographics
X
Medical history 
X
Infertility history
X
Menstrual history
X
Reproductive history
X
Body measurements
X
X
Physical examination
X
X
Gynaecological 
examination
X
X
Urinary pregnancy test
X
  X c)
Transvaginal ultrasound
X
  X e)
  X d)
X
Blood collection
(endocrine and anti-hCG 
antibodies) 
  X d)
  X f)
  X f)
HP-hMG for COS
X
GnRH antagonist 
X g)
Randomisation
X
IMP administration 
X 
Local tolerability
X
Oocyte retrieval
X
Progesterone for luteal 
phase support h)
X
X
  X 
X
Embryo / blastocyst
transfer
X
βhCG test 
X
Drug accountability
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
End-of-trial form 
X
a)
Randomisation and administration of hCG take place on the day of reaching the criterion for triggering of final follicular maturation, i.e. 
≥3 follicles with a diameter ≥17 mm and <25 follicles with a diameter ≥12 mm observed on transvaginal ultrasound. 
b)
End-of-trial form must be completed at the subject’s last scheduled visit or within 2 weeks after last scheduled visit in case of premature 
discontinuation. All subjects with a vital pregnancy will be followed up after the end of trial. 
c)
Performed before start of stimulation. 
d)
Performed at the end of stimulation visit before randomisation. 
e)
Performed on stimulation day 1, 6 and hereafter at least every other day until the end of stimulation. 
f)
Blood collection for anti-hCG antibodies is only performed for subjects who have attended the transfer and βhCG visits.
g)
GnRH antagonist will be initiated on stimulation day 6 and continued throughout stimulation.
h)
Progesterone can start on the day of or the day after oocyte retrieval and should continue until clinical pregnancy visit (can be discontinued earlier 
in case of no embryo / blastocyst transfer, a negative βhCG test or pregnancy loss).
Abbreviations: COS=controlled ovarian stimulation, h=hour(s), hCG=human chorionic gonadotropin, HP-hMG=highly purified menotropin, 
IMP=investigational medicinal product, OR=oocyte retrieval 


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Trial Code: 000191 
Solution for Injection
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6.1
At All Visits
The following will be done at all visits throughout the trial:
!
Drug accountability, if applicable 
!
Recording of use of any concomitant medication (for screening visit: within the last 
3 months prior to signing informed consent for participation in the trial)
!
Recording of adverse events (for screening visit: from the date of signed informed consent 
for participation in the trial)
6.2
Screening
Potential participants will be scheduled to come to the clinic for the screening assessments. 
Screening must be initiated within 90 days before randomisation (corresponding to around 75 days 
before stimulation day 1). 
The following must take place during the screening period:
!
Signed and dated written informed consent, obtained prior to any trial-related procedures
!
Allocation of a screening number
!
Check of inclusion and exclusion criteria (those which are possible to check at screening)
!
Demographics (age, ethnicity, race)
!
Collection of the following data:
-
Medical history
-
Infertility history
-
Menstrual history
-
Reproductive history
!
Body measurements (body weight, height) [note: these are used for calculation of BMI]
!
Physical examination
!
Gynaecological examination and transvaginal ultrasound
!
Urinary pregnancy test – must be negative
Subjects considered eligible for the trial based on the inclusion and exclusion criteria assessed at 
this time point may proceed to the next visit, scheduled on day 2-3 of the menstrual cycle.
6.3
Controlled Ovarian Stimulation
On day 2-3 of the menstrual cycle, subjects will attend the stimulation day 1 visit. GnRH antagonist 
must be started on stimulation day 6. The other visits during the stimulation period will be 
scheduled according to individual’s response, the investigator’s judgement and the clinic’s practice; 
however, transvaginal ultrasound must be performed on stimulation day 1, 6 and hereafter at least 
every other day until the end of stimulation.


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The following must take place: 
At stimulation day 1 visit
Prior to start of HP-hMG administration
!
Ensure that the subject is still eligible for participation in the trial
!
Check those inclusion and exclusion criteria that were not possible during screening 
!
Urinary pregnancy test – must be negative
!
Transvaginal ultrasound of ovaries (number and size of follicles; in case one of more 
follicles ≥10 mm are observed on the transvaginal ultrasound, these functional cysts may be 
punctured prior to start of HP-hMG, or the start of controlled ovarian stimulation may be 
delayed to the next cycle)
After confirmation of eligibility for HP-hMG administration
!
Dispense and/or administer HP-hMG (starting from stimulation day 1; the starting dose of 
HP-hMG is 150 IU once daily, followed by potential dose adjustments according to 
individual response; the first administration of HP-hMG takes place at the clinic and can be 
done by the trial medication delegate, another qualified trial staff, or by the subject herself 
under supervision of the aforementioned person)
At stimulation day 6 visit and visits hereafter until the end of stimulation
!
Dispense and/or administer GnRH antagonist (starting from stimulation day 6; the first 
administration of GnRH antagonist takes place at the clinic and can be done by the trial 
medication delegate, another qualified trial staff or by the subject herself under supervision 
of the aforementioned person)
!
Transvaginal ultrasound must be performed on stimulation day 6 and hereafter at least every 
other day until the end of stimulation
6.4
Randomisation / hCG Administration
Randomisation occurs at the end of stimulation visit when the subject reaches the following
criterion (hCG criterion) for triggering of final follicular maturation as observed on transvaginal 
ultrasound: 
!
≥3 follicles with a diameter ≥17 mm and
!
<25 follicles with a diameter ≥12 mm
Subjects who do not meet the hCG criterion are considered screening failures and will not proceed 
to randomisation. 
Subjects who meet the hCG criterion will have the following procedures / assessments prior to 
randomisation:
!
Ensure that the subject is still eligible for participation in the trial
!
Check the inclusion and exclusion criteria that were not possible during stimulation


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Solution for Injection
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!
Blood collection for analysis of endocrine profile (estradiol, progesterone and hCG) and 
potential analysis of anti-hCG antibodies
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation:
!
Randomisation, i.e. assignment to the lowest available subject number within stratum and 
thereby allocation to either 5,000 IU HP-hCG IM, 5,000 IU HP-hCG SC or 250 μg rhCG SC
!
Dispense IMP according to randomisation 
!
Hand out the diary to the subject for local tolerability assessment
The IM administration of IMP should be done by the trial medication delegate or another qualified 
trial staff, while the SC administration of IMP can also be done by the subject under supervision of 
the trial medication delegate or another qualified trial staff. In either administration route, the 
subject should be under observation by the trial medication delegate or another qualified trial staff
in the immediate period after the administration. Care must be taken to ensure blinding of the 
investigator and other assessors.
After the administration of IMP, the subject must do the following:
!
Assessment of local tolerability (recorded in a diary) – the first evaluation of injection site 
reactions (redness, pain, itching, swelling and bruising) is done immediately after the 
injection of IMP, followed by the second evaluation 30 minutes after injection of IMP and 
the third evaluation 24 hours after injection of IMP 
The next visit is the oocyte retrieval visit, which must be scheduled 36h (±2h) after the hCG
administration.
6.5
Oocyte Retrieval
Oocyte retrieval must take place 36h (±2h) after hCG administration. All oocytes from follicles 
with an estimated diameter ≥12 mm should be retrieved.
The following must take place at the oocyte retrieval visit:
!
Oocyte retrieval. Oocytes must be cultured individually in separate dishes / droplets.
!
Assessment of maturity stage (applicable for oocytes undergoing ICSI)
!
Insemination within 6h after retrieval using IVF or ICSI using ejaculated sperm (fresh or 
frozen) from partner or donor
!
Dispensing of progesterone for luteal support – should be started on the day of or the day 
after oocyte retrieval, depending on the clinic’s practice, and continued until the clinical 
pregnancy visit (can be discontinued earlier in case of no embryo / blastocyst transfer, a 
negative βhCG test or pregnancy loss)
!
Collection of diary pages
For subjects with no oocytes retrieved, the next visit is the end-of-trial visit (section 6.9).


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Day 1 after Oocyte Retrieval
Fertilisation of oocytes will be assessed on day 1 after oocyte retrieval by counting the number of 
pronuclei in oocytes. Correct fertilisation is defined as oocytes with 2PN. For subjects with oocytes 
retrieved, the next visit is the transfer visit 3 or 5 days after oocyte retrieval (section 6.6).
6.6
Day of Transfer (Day 3 or 5 after Oocyte Retrieval)
Transfer can be performed on day 3 (embryo stage) or on day 5 (blastocyst stage) after oocyte 
retrieval, depending on the investigator’s judgement and local clinical practice. On day 3 after 
oocyte retrieval, the total number of embryos and the number of good-quality embryos defined as 
≥6 blastomeres and ≤20% fragmentation will be assessed. In case of continued oocyte culture, the 
total number of blastocysts and the number of good-quality blastocysts defined as at least 3BBa
according to the classification system by Gardner and Schoolcraft16 will be assessed on day 5 after 
oocyte retrieval.
The subject-related procedures are described below:
!
Blood collection for analysis of endocrine profile (estradiol, progesterone and hCG) and 
potential analysis of anti-hCG antibodies
!
Transfer of 1-2 embryos on day 3 or transfer of 1-2 blastocysts on day 5
!
Dispensing of progesterone for luteal phase support – should be continued until the clinical 
pregnancy visit (can be discontinued earlier in case of no embryo / blastocyst transfer, a 
negative βhCG test or pregnancy loss)
Assisted hatching is prohibited.
The actual number of embryos / blastocysts transferred for each subject depends on the availability 
of embryos / blastocysts, local regulations and clinical practice for the subject’s age. Any surplus
embryos / blastocysts can be managed according to local practices.
For subjects with embryo or blastocyst transfer, the next visit is the βhCG test visit which must be 
scheduled 13-15 days after transfer (section 6.7).
For subjects with no embryo or blastocyst transfer, the next visit is the end-of-trial visit 
(section 6.9).
6.7
βhCG Test
Subjects who have undergone transfer must attend a visit 13-15 days after transfer. 
The following must take place:
!
Blood collection for local laboratory analysis of ∀hCG 
!
Blood collection for analysis of endocrine profile (estradiol, progesterone and hCG) and 
potential analysis of anti-hCG antibodies
                                                
a
At least 3BB: Blastocyst expansion and hatching status 4, 5, 6 (independent of inner cell mass and trophectoderm) 
and blastocyst expansion and hatching status 3 with inner cell mass and tropectoderm gradings of A or B. 


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Trial Code: 000191 
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!
Dispensing of progesterone for luteal phase support – should be continued until the clinical 
pregnancy visit (can be discontinued earlier in case of no embryo / blastocyst transfer, a 
negative βhCG test or pregnancy loss)
The blood sample for βhCG will be analysed by the local laboratory and evaluated according to the 
local reference ranges. In case of a doubtful ∀hCG result, the test may be repeated. Subjects with a 
positive ∀hCG test must attend a clinical pregnancy visit 5-6 weeks after transfer (section 6.8). 
Subjects with a negative ∀hCG test must proceed to the end-of-trial assessments (section 6.9).
6.8
Clinical Pregnancy
Subjects with a positive ∀hCG test must attend a visit 5-6 weeks after transfer. 
The following must take place:
!
Transvaginal ultrasound of uterus to assess any clinical pregnancy 
If at least one gestational sac (either intrauterine or ectopic) is observed, this confirms a clinical 
pregnancy. If at least one intrauterine gestational sac with fetal heart beat is observed, this confirms 
a vital pregnancy. All subjects, irrespective of the result of the pregnancy monitoring, will proceed 
to the end-of-trial assessments (section 6.9). In addition, subjects with a vital pregnancy will be 
followed up (section 6.10). 
6.9
End-of-trial
If a subject attends the scheduled trial visits, the end-of-trial assessments should take place at the 
subject’s last scheduled trial visit or within 2 weeks after last scheduled visit in case of premature 
discontinuation.
The following procedures / assessments must take place at the end-of-trial visit, irrespective of 
whether the subject discontinues the trial prematurely or completes it: 
!
Body measurements (body weight)
!
Physical examination
!
Gynaecological examination
!
Completion of end-of-trial form 
6.10
Post-trial Activities
All subjects with a vital pregnancy will be followed up until delivery for pregnancy outcome data. 
Furthermore, data will be gathered on neonatal health at birth. These data will be reported 
separately.


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Primary Endpoint
7.1.1
Number of Oocytes Retrieved
The number of oocytes retrieved will be recorded at the oocyte retrieval visit.
7.2
Assessments Related to Secondary Endpoints
7.2.1
Number of Metaphase II Oocytes
Maturity stage will be assessed prior to insemination for oocytes that will undergo ICSI. Maturity 
stage will be categorised as germinal vesicle, metaphase I, metaphase II (MII), degenerated or 
other.
7.2.2
Number of Fertilised Oocytes
On day 1 after oocyte retrieval, fertilisation will be assessed by counting the number of pronuclei,
which will be recorded as 0, 1, 2 or >2. Correct fertilisation is defined as oocytes with 2PN.
7.2.3
Fertilisation Rate
Fertilisation rate is calculated as the rate of fertilised oocytes to oocytes retrieved for subjects with 
oocytes retrieved and the rate of fertilised oocytes to MII oocytes for subjects with ICSI 
insemination.
7.2.4
Positive βhCG Rate
A blood ∀hCG test must be obtained 13-15 days after transfer. If the test is positive according to the 
local laboratory’s reference ranges, this confirms a positive ∀hCG.
7.2.5
Clinical Pregnancy Rate
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Clinical 
pregnancy will be defined as at least one gestational sac, either intrauterine or ectopic. The 
inclusion of ectopic pregnancies and the lack of specification of heart beat in the definition of 
clinical pregnancy is in line with the current International Committee Monitoring Assisted 
Reproductive Technologies (ICMART) and World Health Organization (WHO) glossary on ART 
terminology.b,17 For intrauterine and ectopic pregnancies, the number of gestational sacs with fetal 
heart beat as well as without fetal heart beat will be recorded. 
                                                
b
ICMART and WHO glossary on ART terminology: Clinical pregnancy – a pregnancy diagnosed by 
ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes 
ectopic pregnancy.


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7.2.6
Vital Pregnancy Rate
A transvaginal ultrasound of the uterus will be performed 5-6 weeks after transfer. Vital pregnancy 
will be defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after 
transfer. 
7.2.7
Circulating Levels of Endocrine Parameters 
A blood sample will be collected at the end-of-stimulation visit prior to randomisation, at transfer
and at the βhCG visit for analysis of endocrine profile (estradiol, progesterone and hCG). These
samples will be analysed at a central laboratory. The investigator will review and evaluate the 
laboratory results. The laboratory report will be signed and dated by the investigator. 
7.2.8
Number and Quality of Embryos on Day 3
On day 3 after oocyte retrieval, the total number of embryos and the number of good-quality 
embryos will be assessed and recorded.
The quality evaluation of embryos will consist of the following morphological parameters: 
!
number of blastomeres (1, 2, 3, 4, 5, 6, 7, 8…) 
!
degree of fragmentation (≤20%, >20%)
A good-quality embryo is defined as  ≥6 blastomeres and ≤20% fragmentation.
For the transferred embryos, the two quality parameters above (number of blastomeres and degree 
of fragmentation) must be recorded.
7.2.9
Number and Quality of Blastocysts on Day 5
On day 5 after oocyte retrieval, the total number of blastocysts and the number of good-quality 
blastocysts will be assessed and recorded.
The quality evaluation of blastocysts will consist of the following morphological 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.16
Blastocyst expansion and hatching status will be assessed as one of the following:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, 
that of the embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early 
embryo, with a thinning zona
5. A hatching blastocyst with the trophectoderm starting to herniate through the 
zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the 
zona


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For blastocysts with expansion and hatching status 3-6, blastocyst inner cell mass grading and 
trophectoderm grading will be evaluated.
Blastocyst inner cell mass grading will be assessed as one of the following:
A. Tightly packed, many cells
B. Loosely grouped, several cells
C. Very few cells
Trophectoderm grading will be assessed as one of the following:
A. Many cells forming a cohesive epithelium
B. Few cells forming a loose epithelium
C. Very few, large cells 
Blastocysts with expansion and hatching status 3-6 will have a score combining the three 
parameters (blastocyst expansion and hatching status, inner cell mass and trophectoderm); e.g. 4AB 
for a blastocyst with blastocyst expansion and hatching status 4, inner cell mass grading A and 
trophectoderm grading B.
A good-quality blastocyst is defined as at least 3BB: blastocyst expansion and hatching status 4, 5, 
6 (independent of inner cell mass and trophectoderm gradings) and blastocyst expansion and 
hatching status 3 with inner cell mass and trophectoderm gradings of A or B.
For the transferred blastocysts, the three quality parameters above (blastocyst expansion and 
hatching status, inner cell mass and trophectoderm) must be recorded. 
7.2.10
Frequency and Intensity of Adverse Events
Adverse events (see definition in section 8.1) will be recorded from signing the informed consent 
for participation in the trial until the end-of-trial visit. For each adverse event, the following 
parameters are recorded by the investigator on the Adverse Event Log: description of event, date 
and time of onset, intensity, causal relation to IMP, action taken to IMP, other actions taken, 
seriousness of the adverse event, date and time of outcome, and outcome. Furthermore, the pattern 
(e.g. the frequency, time of onset, intensity, seriousness and outcome) of the most frequent /
relevant adverse events will be tabulated (see section 9.8.2).
7.2.11
Early and Late OHSS Rates
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation
and late OHSS as OHSS with onset >9 days after triggering of final follicular maturation.
Classification of grade is according to Golan’s classification system18 (see section 8.3.1 for details)
and all OHSS cases will be graded as mild, moderate or severe (note: the classification “mild 
OHSS”, “moderate OHSS” and “severe OHSS” does not refer to the classification of an adverse 
event’s intensity that is also rated mild, moderate, or severe).


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7.2.12
Frequency and Intensity of Injection Site Reactions
The subjects will assess the local tolerability of the injections of IMP at three time points relative to 
the administration: immediately after the injection, 30 minutes after the injection and 24 hours after 
the injection. The following injection site reactions will be assessed: redness, pain, itching, swelling 
and bruising. The presence and intensity of each injection site reaction will be rated as one of the 
following: none, mild, moderate or severe.
The subject will record the assessments in a diary and the diary data will subsequently be 
transcribed to the e-CRF.
7.3
Other Assessments
7.3.1
Demographics
Demographic information will be obtained during the screening period, including the following: 
date of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White).
7.3.2
Medical History
Any relevant medical history will be recorded at screening. This includes diagnoses / symptoms 
and whether it is a past or ongoing occurrence.
7.3.3
Infertility History
Information about the reasons of infertility and duration of infertility will be obtained during the 
screening period. This will also cover information about any previous treatment for infertility, 
including type of treatment and gonadotropin preparations used.
7.3.4
Menstrual History
Information about the menstrual history (average cycle length) will be obtained during the 
screening period.
7.3.5
Reproductive History
Information about the reproductive history regarding natural conception will be obtained during the 
screening period. This will include number of clinical pregnancies, number of fetuses and outcome. 
Information on primary versus secondary infertility will be derived.
7.3.6
Body Measurements
Body measurements will be made at screening and end-of-trial. Body weight will be measured at 
both visits, and will be done without shoes and overcoat and using a calibrated scale. Height will 


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only be measured at screening and will be used to calculate BMI. 
7.3.7
Physical Examination
A complete physical examination will be performed at screening and end-of-trial. Information will 
be recorded for general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth and throat), respiratory system, cardiovascular system, 
gastrointestinal system, lymphatic system, urinary system, musculoskeletal system and skin. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to 
end-of-trial must be recorded as adverse events.
7.3.8
Gynaecological Examination
A complete gynaecological examination will be performed at screening and end-of-trial. 
Information will be recorded for breast, external genitalia, vagina, cervix, uterus, ovaries and 
fallopian tubes. 
At screening, each category will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant findings at screening must be 
reported on the Medical History Log.
At end-of-trial, potential changes from screening to end-of-trial will be evaluated for each category. 
In case of changes, these will be evaluated as normal, abnormal not clinically significant or 
abnormal clinically significant. Abnormal clinically significant changes from screening to 
end-of-trial must be recorded as adverse events.
7.3.9
Number and Size of Follicles during Stimulation
Transvaginal ultrasound will be performed during the stimulation period to count the number of 
follicles and measure the size of follicles. Data on the number and size of follicles will be collected 
prior to start of stimulation on stimulation day 1, stimulation day 6 and at the end of stimulation.
Data will be recorded separately for the right and left ovary.
7.3.10
Anti-hCG Antibodies
Blood samples for potential analysis of anti-hCG antibodies will be collected at the 
end-of-stimulation visit prior to randomisation, the transfer visit and the βhCG visit. Samples are 
taken only for subjects who have attended the transfer and βhCG visits.


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7.3.11
Concomitant Medication
The use of any concomitant medication within the last 3 months prior to signing the informed 
consent for participation in the trial (except medication used in previous infertility treatment cycles) 
and throughout the trial will be recorded. Recording of concomitant medication will be performed 
at all visits. Any changes in concomitant medications or treatments must be recorded at each visit.
7.3.12
Drug Dispensing and Accountability
For all medicinal products, dates of administration and dose administered will be recorded. 
Furthermore, time of administration will also be recorded for IMP, HP-hMG and GnRH antagonist. 
Details on drug dispensing and accountability are provided in section 5.6.
7.3.13
End-of-Trial Form
An end-of-trial form must be filled in at the subject’s last visit, irrespective of whether the subject 
completes the trial or not. Completion / discontinuation status will be recorded, as well as date and 
reason for discontinuation in case the subject did not complete the trial.
7.4
Assessments Related to Post-trial Information
All subjects with a vital pregnancy will be followed till delivery to gather information on pregnancy 
outcome, e.g. live birth. Furthermore, data will be gathered on neonatal health at birth, including 
gender, birth weight and length as well as information on minor/major congenital anomalies.
These data will be reported separately.
7.5
Handling of Biological Samples
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. All biological 
samples will be analysed at central laboratories and will be maintained in storage after the end of 
the trial. Destruction will take place within 2 years after reporting of the trial or when methods /
results have been adequately validated. An exception is the blood sample for βhCG, which is 
analysed by a local laboratory at the trial clinic and subsequently destroyed. For all biological 
samples collected in the trial, it applies that analyses beyond those described in the protocol can 
only be performed after obtaining the required approvals. The processes related to handling of
biological samples will be described in the informed consent, and biobank / data protection 
legislation including local legislation will be adhered to.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes:
! Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP.
! Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP.
! Any laboratory abnormality, vital sign or finding from physical or gynaecological
examination assessed as clinically significant by the investigator [note: findings from 
assessments and examinations done during screening are not adverse events, but are recorded 
as medical history.]
! Accidental injuries, reasons for any change in medication (drug and/or dose) (not applicable 
for HP-hMG dose adjustment), reasons for any medical, nursing or pharmacy consultation, 
or reasons for admission to hospital or surgical procedures.
! Overdoses and medication errors that relate to IMP with and without clinical consequences.
All adverse events will be coded by Ferring Global Pharmacovigilance using Medical Dictionary 
for Regulatory Activities (MedDRA, the version effective at trial start).
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the end-of-trial visit.
The sources of adverse events cover:
!
The subject’s response to questions about her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit).
!
Symptoms spontaneously reported by the subject.
!
Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities.
!
Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalisation).
8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s e-CRF with information about:


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!
Adverse event
!
Date and time of onset 
!
Intensity
!
Causal relationship to IMP
!
Action taken to IMP
!
Other action taken
!
Date and time of outcome 
!
Outcome
!
Seriousness
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Event
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis / symptom should be entered per record.
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event.c
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event).
Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
date is the date the sample was taken or the examination was performed.
                                                
c
Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
changes in intensity, this must be recorded as two separate events. The initial adverse event should be recorded with 
outcome “not yet recovered” and the date and time of outcome is when the intensity changed. The second adverse 
event should be recorded with date and time of onset when the intensity changed. 


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Intensity
The intensity of an adverse event must be classified using the following 3-point scale:
Mild:
Awareness of signs or symptoms, but no disruption of usual activity
Moderate:
Event sufficient to affect usual activity (disturbing)
Severe:
Inability to work or perform usual activities (unacceptable)
Causal Relationship to IMP
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following:
Reasonable possibility:
There is evidence or argument to suggest a causal relationship between 
the IMP and the adverse event. The adverse event may occur as part of 
the pharmacological action of the IMP or may be unpredictable in its 
occurrence.
Examples: 
!
adverse events that are uncommon but are known to be strongly 
associated with IMP exposure.
!
adverse events that are not commonly associated with IMP exposure, 
but the event occurs in association with other factors strongly 
suggesting causation, such as a strong temporal association or the 
event recurs on rechallenge.
No reasonable possibility: There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the adverse event.
Examples:
!
known consequences of the underlying disease or condition under 
investigation.
!
adverse events common in the trial population, which are also 
anticipated to occur with some frequency during the course of the 
trial, regardless of IMP exposure.
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:
!
No change (medication schedule maintained or no action taken)
!
Withdrawn
!
Interrupted


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Other Action Taken
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log.
Date and Time of Outcome
The date and time the subject recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:
!
Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment)
!
Recovered with sequelae (resulted in persistent or significant disability / incapacity)
!
Recovering
!
Not yet recovered
!
Fatal
8.3
Adverse Events of Special Interest
8.3.1
Ovarian Hyperstimulation Syndrome (OHSS)
Symptoms and Classification
OHSS is an adverse event of special interest during controlled ovarian stimulation. Investigators 
will record OHSS symptoms and will use Golan’s system18 as shown in Table 8-1 to grade (1, 2, 3, 
4 or 5) each OHSS case.


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Table 8-1
Classification of Mild, Moderate and Severe OHSS
Mild OHSS
Grade 1
Abdominal distension and discomfort 
Grade 2 
Features of grade 1 plus nausea/vomiting and/or diarrhoea. Ovaries enlarged to 
5-12 cm.a)
Moderate OHSS
Grade 3 
Features of mild OHSS plus ultrasonic evidence of ascites.b)
Severe OHSS
Grade 4 
Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax (or 
breathing difficulties). Paracentesis due to OHSS symptoms. c)
Grade 5 
All of the above plus change in blood volume, increased blood viscosity due to 
haemoconcentration, coagulation abnormalities, and diminished renal perfusion and 
function.d)
a) For each ovary, the size will be the average of the greatest diameter and its greatest perpendicular diameter. Ovarian 
enlargement will be based on the average size of the right and left ovaries. The sizes of both ovaries should be 
recorded. 
b) For subjects with transvaginal evidence of ascites, the size of the fluid pockets in the pelvis (Douglas pouch, 
vesico-uterine pouch, etc.) should be estimated by measuring the greatest diameter and its greatest perpendicular 
diameter, and multiplying these two numbers (the unit will be cm2). Peritoneal fluid is the total size of all fluid 
pockets in the pelvis. 
c) In case of paracentesis, the volume of fluid drained should be measured.
d) Heaemoconcentration is defined as haematocrit >45 %. Electrolyte disturbances is defined as hyponatremia (sodium 
<135 mEq/L) and/or hyperkalemia (potassium >5.0 mEq/L). Coagulation abnormalities are defined as presence of 
thromboembolic events, abnormal prothrombin time or abnormal activated partial thrombin time. Diminished renal 
perfusion is defined as creatinine >1.2 mg/dl. Oliguria is defined as urine output less than 500 mL / 24 hours. Anuria 
is defined as failure to produce urine. If applicable, actual volume of urine output will be recorded.
All cases of OHSS must be reported as adverse events. Those that fall under the category serious 
adverse events must be reported as such. Note that the classification ‘mild OHSS’, ‘moderate 
OHSS’ and ‘severe OHSS’ does not refer to the classification of an adverse event’s intensity (also 
rated mild, moderate, or severe). 
Concerning timing, early OHSS will be defined as OHSS with onset ≤9 days after triggering of 
final follicular maturation and late OHSS will be defined as OHSS with onset >9 days after 
triggering of final follicular maturation.
8.3.2
Local Tolerability
Injection site reactions after administration of IMP are only to be reported as adverse events if they 
require active management, i.e. additional investigations or treatment of the injection site reaction. 
Local tolerability of IMP constitutes a secondary endpoint and will be evaluated in detail based on 
the subjects’ recordings in the diary. 


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Local tolerability reactions after administration of NIMP are to be reported as adverse events if they 
fulfil the definition of an adverse event.
8.3.3
Menstrual Bleeding
Menstrual bleeding is only to be reported as an adverse event in case it is excessive, painful, 
delayed or in any other way deviating from the subject’s normal menstruation. Menstrual bleeding 
associated with lack of pregnancy will be reported as part of the efficacy evaluation. 
8.3.4
Pregnancy Loss
The following terminology should be used for reporting of pregnancy losses during the trial:
Biochemical pregnancy: 
Positive βhCG test but no gestational sac is observed on later 
transvaginal ultrasound, or menstruation is reported
Spontaneous abortion: 
Positive βhCG test but all intrauterine gestational sacs are 
without fetal heart beat as documented by ultrasound, or there 
are no viable fetuses observed by ultrasound
Vanishing twin:
Spontaneous disappearance of an intrauterine gestational sac 
with or without heart beat in a pregnancy where one viable 
fetus remains as documented by ultrasound
Ectopic pregnancy:
Extrauterine gestational sac with or without fetal heart beat as 
documented by ultrasound or surgery


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8.4
Serious Adverse Events
8.4.1
Serious Adverse Event Definition
Serious Adverse Events during the Trial
An event is defined a serious 
adverse event if it:
Guidance
results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a subject enrolled 
in a trial is per se not an event, but an outcome.
is life-threatening
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe.
requires in-patient hospitalisation 
or prolongation of existing 
hospitalisation
The term hospitalisation means that the subject was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation 
describes a period of at least 24 hours. Over-night stay for observation, stay at 
emergency room or treatment on an out-patient basis do not constitute a 
hospitalisation. However, medical judgement must always be exercised and when 
in doubt the case should be considered serious (i.e. if case fulfils the criterion for a 
medically important event). Hospitalisations for administrative or social purposes 
do not constitute a serious adverse event. Hospital admissions and/or surgical 
operations planned before trial inclusion are not considered adverse events, if the 
illness or disease existed before the subject was enrolled in the trial, provided that 
the condition did not deteriorate during the trial.
results in persistent or significant 
disability / incapacity
Disability / incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgement by the investigator.
is a congenital anomaly/birth 
defect
Congenital anomaly / birth defect observed in any offspring of the subject 
conceived during treatment with the IMP.
is an important medical event
Important medical events are events that may not be immediately life-threatening 
or result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include adverse events that suggest a 
significant hazard, contraindication or precaution, occurrence of malignancy or 
development of drug dependency or drug abuse. Medical and scientific judgement
should be exercised in deciding whether events qualify as medically important.
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product. Any organism virus or infectious particle (e.g. 
prion protein transmitting Transmissible Spongiform Encephalopathy), pathogenic 
or non-pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a subject exposed to a medicinal product.


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Serious Adverse Event during Post-trial Follow-up
The following untoward medical occurrences reported as part of the pregnancy outcome and
neonatal health data collection will be recorded as serious adverse events. Data will be collected at 
birth.
!
Death of mother in connection with pregnancy or labour
!
Death of neonate
!
Stillbirth
!
Neonate admitted to the neonatal intensive care unit (NICU) or neonatal care unit (NCU)
!
Congenital anomaly / birth defect
In case of admission to NICU or NCU, the reason for admission must be reported as a serious 
adverse event, rather than just the act of hospitalisation.
Congenital anomalies will be coded using both MedDRA and ICD-10 and classified as minor or 
majord in accordance with the EMA guideline.19
8.4.2
Collection, Recording and Reporting of Serious Adverse Events
Serious Adverse Event Reporting by the Investigator
All serious adverse events must be reported immediately to Ferring Global Pharmacovigilance as 
soon as it becomes known to the investigator and not later than within 24 hours of their knowledge 
of the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed Serious Adverse Event (SAE) Report 
Form with the fullest possible details within 3 calendar days of his/her knowledge of the serious 
adverse event.
Serious Adverse Event (SAE) Report Form
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE report from cannot be filled in within the e-CRF system, a paper SAE report form should 
be used and sent to Ferring Global Pharmacovigilance using the contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: safety.mailbox@ferring.com
Fax: (+45) 8838 0147
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Global Pharmacovigilance to access the information.
                                                
d
Major abnormalities: a life threatening structural anomaly or one likely to cause significant impairment of health or 
functional capacity and which needs medical or surgical treatment. 
Minor anomalies: relatively frequent structural anomaly not likely to cause any medical or cosmetic problems.


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Additional information relevant to the serious adverse events such as hospital records, results from 
investigations, e.g. laboratory parameters (that are not already uploaded in the e-CRF), invasive 
procedures, scans and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 
Global Pharmacovigilance using the contact details in the section above. In any case this 
information must be supplied by the investigator upon request from Ferring. On any copies 
provided, such details such as subject’s name, address, and hospital ID number should be concealed 
and instead subject number should be provided.
The investigator will supply Ferring and the EC with any additional requested information such as 
results of post-mortem examinations and hospital records.
Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.
The expectedness is assessed by Ferring according to the Investigator’s Brochure for CHORAPUR
and the SPC for OVIDREL. 
Serious adverse events will be considered reportable regardless of whether or not the IMP was used 
in accordance with the provisions in the protocol, Investigator’s Brochure and labelling.
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 subject’s participation of the trial, the investigator must follow up on each adverse event 
until it is resolved or until the medical condition of the subject is stable.
After the subject’s last visit, the investigator must follow up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. 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 End-of-Trial
If an investigator becomes aware of a serious adverse event after the end of the trial, and he/she 
assesses the serious adverse event to have a reasonable possible causality to the IMP (HP-hCG IM, 
HP-hCG SC or rhCG SC) or a NIMP where Ferring is Marketing Authorisation Holder (i.e.
HP-hMG), the case will have to be reported to Ferring Global Pharmacovigilance
(safety.mailbox@ferring.com), regardless how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
The Ferring Global Biometrics Department will be responsible for the statistical analyses of the 
primary and secondary endpoints. This section details the planned statistical analyses for the 
primary endpoint and outlines the planned statistical analyses for the secondary endpoints. All 
analyses and further descriptions of the statistical methodology for the primary and secondary 
endpoints will be included in the Statistical Analysis Plan (SAP) available before breaking the blind 
of the trial. A separate SAP will be prepared to cover reporting of the post-trial activities 
(pregnancy outcome and neonatal health at birth). 
9.1
Determination of Sample Size
The primary objective of this trial is to demonstrate non-inferiority of HP-hCG 5,000 IU compared 
with rhCG 250 μg for triggering of final follicular maturation with respect to number of oocytes 
retrieved in women undergoing controlled ovarian stimulation. The primary endpoint is the number 
of oocytes retrieved.
The trial has three arms: HP-hCG 5,000 IU IM, HP-hCG 5,000 IU SC, and rhCG 250 μg SC.
Non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 μg will be established by doing the 
comparisons in sequential order as follows:
1) HP hCG 5,000 IU IM vs. rhCG 250 μg SC
2) HP hCG 5,000 IU SC vs. rhCG 250 μg SC
This will only be evaluated if the first comparison establishes non-inferiority
The non-inferiority margin has been set at -3.0 oocytes (section 3.5.1). Non-inferiority will be 
evaluated using a two-sided 95% confidence interval for the difference between treatment groups. 
Non-inferiority will be claimed if the lower limit of this confidence interval is greater than the 
non-inferiority margin.
The trial is dimensioned to have 90% power of achieving the primary objective for the first 
comparison and approximately 80% power for establishing non-inferiority for both comparisons.
Since this is a non-inferiority trial, the per-protocol (PP) and the intention-to-treat (ITT) analyses 
are equally important, i.e. non-inferiority should be established for both populations in order to 
have a robust conclusion.20, 21
The primary analysis will be based on an analysis of variance (ANOVA) model including 
treatment, randomisation stratum and trial site as factors. It is assumed that the three treatments are 
equivalent with respect to number of oocytes retrieved. The number of oocytes retrieved is assumed 
to follow a normal distribution with a mean of 10-12 and a standard deviation of 6.0. Under these 
assumptions, a sample size of 86 subjects per group will result in approximately 90% power to
establish non-inferiority of the first comparison by using a non-inferiority margin of -3.0 oocytes. It 
is expected that the difference in the number of oocytes retrieved between the HP-hCG groups and 
the rhCG group has to be less than 1.2 in order to meet the non-inferiority margin of -3.0. As an 
example, if the average number of oocytes retrieved in the rhCG group is 12.0, the average number 
of oocytes retrieved in the HP-hCG groups has to be at least 10.8 in order to establish 
non-inferiority.


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The number of subjects with major protocol deviations affecting the primary endpoint is assumed to 
be negligible. Therefore the sample size has not been adjusted to account for major protocol 
deviations affecting the primary endpoint. 
The standard deviation of the number of oocytes retrieved will be evaluated in a blinded manner. If 
the standard deviation is larger than 6.0, the sample size may be increased to a maximum of 
348 subjects (116 subjects per group) corresponding to a standard deviation of 7.0. Blinded 
monitoring of the assumptions underlying the sample size is recommended specifically for 
non-inferiority trials by FDA20 and in general by EMA.21
9.2
Subject Disposition
All screened subjects will be accounted for. 
Screened subjects who discontinue from the trial prior to randomisation are regarded as screening
failures. Screening failures and their primary reason for screening failure will be tabulated. 
Screening failures will not otherwise be accounted for. 
Subject disposition with respect to analysis sets will be tabulated by treatment group overall and by 
randomisation stratum for all randomised subjects. This table will include the number of completed 
and discontinued subjects including reason for discontinuation. A separate table will summarise the 
subject disposition with respect to analysis sets by trial site overall and by stratum. 
The number of subjects completed and discontinued (including reason) will be tabulated by 
treatment group overall and by randomisation stratum for the following trial parts: triggering of 
final follicular maturation, oocyte retrieval, transfer, pregnancy monitoring and end-of-trial. This 
table will be produced for the ITT analysis set overall and by stratum. A separate table will 
summarise the details on embryo / blastocyst transfer including day of transfer and number of 
transferred embryos / blastocysts.
Subject disposition with respect to analysis sets will be listed for all randomised subjects including 
information on trial completion and reason for discontinuation for non-completers. Subjects who 
discontinued from the trial will also be listed separately.
9.3
Protocol Deviations
Protocol deviations will be rated as minor or major. Major protocol deviations impacting the 
primary endpoint and thereby affecting the conclusions will lead to exclusion of subjects from the 
PP analysis set. Subjects will not be excluded from the PP analysis set in case of only minor 
protocol deviations. 
The list of major protocol deviations impacting the primary endpoint includes, but is not restricted 
to the following:
1) hCG administered but triggering criterion is not met
2) Wrong dose of hCG administered
3) Oocyte retrieval not performed 36h (±2h) after hCG administration


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The sponsor’s Medical Officer at Ferring Global Clinical R&D, the sponsor’s Medical Officer in 
Brazil, and the project-responsible statistician at Ferring Global Biometrics will perform a blinded 
review of data before declaration of clean file and lock of database and rate protocol deviations as 
minor or major. The list of major protocol deviations will be detailed and documented in the clean 
file document prior to database release. Major protocol deviations impacting the primary endpoint 
will be tabulated and listed by subject for the ITT analysis set.
9.4
Analysis Sets
9.4.1
Intention-to-Treat (ITT) Analysis Set
The ITT analysis set is defined as all randomised subjects. Subjects will be analysed according to 
planned (randomised) treatment.
9.4.2
Full Analysis Set (FAS)
The full analysis set (FAS) is defined as all subjects randomised and exposed to IMP. Subjects will 
be analysed according to planned (randomised) treatment received.
9.4.3
Per-Protocol (PP) Analysis Set
The PP analysis set is defined as all subjects randomised and exposed to IMP except those excluded 
as a result of major protocol deviations as described in section 9.3. Subjects will be analysed 
according to actual treatment received.
9.4.4
Safety Analysis Set
The safety analysis set is defined as all subjects randomised and exposed to IMP. Subjects will be 
analysed according to actual treatment received.
9.5
Trial Population
9.5.1
General Considerations
All relevant baseline data will be tabulated by treatment group and overall. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, inter-quartile range, 
minimum, and maximum. Categorical variables will be presented with number and percentage of 
subjects within each specific category. The purpose of these tabulations is to characterise the 
treatment groups and assess the degree of similarity achieved by the randomisation. Baseline data 
will not be compared using statistical tests. Unless otherwise noted, tabulations will be produced 
overall and by randomisation stratum for both the ITT and the PP analysis sets. 
All baseline data will be listed by subject for the ITT analysis set. 
Unless otherwise noted, missing data will not be imputed.


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9.5.2
Demographics 
Age, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race (American Indian or Alaska 
Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White) will 
be tabulated.
9.5.3
Body Measurements
Height (m), weight (kg) and BMI (kg/m2) obtained at screening will be tabulated.
9.5.4
Number and Size of Follicles during Stimulation
The number of follicles and the average follicle size will be tabulated for stimulation day 1, 
stimulation day 6 and end of stimulation.
9.5.5
Endocrine Parameters
The following endocrine parameters obtained on the day of triggering before exposure to IMP will 
be tabulated: estradiol (pmol/L), progesterone (nmol/L), and hCG (IU/L). Values below the lower 
limit of quantification (LLOQ) will be included as LLOQ/2. Values above the upper limit of 
quantification (ULOQ) will be included as ULOQ.
9.5.6
Medical History
All recorded medical history will be coded using MedDRA. The version of MedDRA will be 
documented. Medical history will be summarised for each medical item. This summary table will 
only be produced overall (i.e. not by stratum) for the ITT.
9.5.7
Infertility History
Primary reason for infertility and duration of infertility will be tabulated. The table will also include 
the proportion of subjects with primary infertility. Primary infertility is defined as no previous 
clinical pregnancy. Information on previous fertility treatment will be summarised including type of 
treatment and outcome.
9.5.8
Menstrual History
The average cycle length (days) will be tabulated.
9.5.9
Reproductive History
Reproductive history regarding natural conception will be tabulated including number of clinical 
pregnancies, number of fetuses and outcome.


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9.5.10
Physical Examination and Gynaecological Examination
Physical examination and gynaecological examination will be listed by subject and summarised per 
category. These summary tables will only be produced overall (i.e. not by stratum) for the ITT 
analysis set.
9.5.11
Concomitant Medication 
Concomitant medications will be coded using the WHO Drug Reference List. Prior and 
concomitant medication will be summarised by ATC classification 1st level alphabetically and ATC 
classification 2nd level in decreasing order of frequency. These medications will be tabulated 
separately for:
!
Prior medication, i.e. medication taken exclusively prior to treatment (i.e. stopped before 
IMP administration)  
!
Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before IMP administration and not started after the end-of-trial visit)
These summary tables will only be produced overall (i.e. not by stratum) for the ITT analysis set.
If the timing of the dose of a medication cannot be established in relation to the administration IMP, 
it will be considered as concomitant medication. Concomitant medications will be listed by subject.
9.6
Extent of Exposure and Treatment Compliance
Treatment non-compliance will be presented in listings, as non-compliance is expected to be 
limited.
9.7
Endpoint Assessments
9.7.1
General Considerations
The result of the analysis of the primary endpoint (number of oocytes retrieved) is essential for the 
non-inferiority claim. The number of MII oocytes (only applicable for insemination using ICSI) and 
the number of 2PN oocytes are considered the key secondary endpoints supportive of the primary 
endpoint. The analyses of the remaining secondary efficacy endpoints are intended to provide 
additional characterisation of the treatment effect.
The randomisation is stratified by the number of follicles ≥12 mm at the end of stimulation (two 
strata: <10 follicles and ≥10 follicles). Summary tables for the primary endpoint and the secondary 
efficacy endpoints will be presented overall and by randomisation strata for both the ITT and the PP 
analysis sets.
All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will, where appropriate, be presented with two-sided 95% confidence intervals and 
p-values corresponding to the hypothesis of “equal effect” against the alternative “different effect”.
All primary and secondary efficacy endpoints will be listed for the ITT analysis set.


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Multiplicity
No adjustment for multiplicity is required for the primary analysis, since there is only one primary 
endpoint and the evaluation is performed in a sequential manner. Concerning the secondary 
endpoints, no formal adjustment for multiplicity will be utilised. Statistically significant results 
among these secondary endpoints will be interpreted cautiously.
Missing Observations
Missing observations for the primary endpoint (number of oocytes retrieved) will be imputed as 
zero irrespective of the reason why data is not recorded. 
Missing observations for the number of 2PN oocytes will be imputed as zero. This also includes 
subjects with no oocytes retrieved; these will have the number of 2PN oocytes set to zero.
For subjects who have all oocytes inseminated using ICSI, missing observations for the number of 
MII oocytes will be imputed as zero. For subjects who do not have any oocytes inseminated using 
ICSI, missing observations for the number of MII oocytes will not have a value imputed.
Missing observations for the βhCG assessment will be imputed as negative, unless a positive result 
is observed at the clinical pregnancy visit. For example, if the outcome of βhCG is missing but 
clinical pregnancy is “positive”,  βhCG will be imputed as “positive”.
Missing observations for the clinical pregnancy assessment and vital pregnancy assessment will be 
imputed as “negative” irrespective of why data were not recorded.
9.7.2
Primary Endpoint
The primary objective of this trial is to demonstrate non-inferiority of HP-hCG 5,000 IU compared 
with rhCG 250 μg for triggering of final follicular maturation with respect to number of oocytes 
retrieved in women undergoing controlled ovarian stimulation. The non-inferiority margin for the 
difference between treatments (HP-hCG 5,000 IU versus rhCG 250 μg) is set to -3.0 oocytes.
HP-hCG 5,000 IU is included in the trial using two different routes of administration, IM and SC. 
Non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 μg will be established by doing the 
comparisons in sequential order as follows:
1) HP-hCG 5,000 IU IM vs. rhCG 250 μg SC
2) HP-hCG 5,000 IU SC vs. rhCG 250 μg SC
This will only be evaluated if the first comparison establishes non-inferiority
The non-inferiority hypothesis to be tested for the primary endpoint is 
H0: ORHP-hCG – ORrhCG ≤ -3.0
against the alternative
HA: ORHP-hCG – ORrhCG > -3.0
where ORHP-hCG and ORrhCG  denotes the number of oocytes retrieved with HP-hCG 5,000 IU (IM or 
SC) and rhCG 250 μg SC, respectively.


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For each comparison, the null hypothesis (H0) will be tested against the alternative (HA) by 
constructing a two-sided 95% confidence interval for the difference in number of oocytes retrieved. 
The confidence interval will be based on ANOVA model including treatment, randomisation 
stratum and trial site as factors. The primary endpoint will be analysed for the ITT and the PP 
analysis sets. Since this is a non-inferiority trial, the ITT and the PP analysis sets will have equal 
importance and should lead to similar conclusions for a robust interpretation.
Comparison 1: HP-hCG 5,000 IU IM versus rhCG 250 μg SC
If the lower-limit of the 95% confidence interval is greater than the non-inferiority limit 
(-3.0 oocytes), the null hypothesis will be rejected and it would be claimed that HP-hCG 5,000 IU 
IM is non-inferior to rhCG 250 μg SC with respect to number of oocytes retrieved. 
Comparison 2: HP-hCG 5,000 IU SC versus rhCG 250 μg SC
If Comparison 1 establishes non-inferiority, the second comparison will be performed. If the 
lower-limit of the 95% confidence interval is greater than the non-inferiority limit (-3.0 oocytes), 
the null hypothesis will be rejected and it would be claimed that HP-hCG 5,000 IU SC is
non-inferior to rhCG 250 μg SC with respect to number of oocytes retrieved.
If the 95% confidence interval for the treatment difference not only lies above the non-inferiority
limit but also above zero, there is evidence of superiority in terms of statistical significance at the 
two-sided 5% level. In this case, the p-value from the test for superiority will be reported. There is 
no need for a multiplicity adjustment, since it is a simple closed test procedure. This interpretation 
is in line with EMA’s “Points to consider on switching between superiority and non-inferiority”.22
9.7.3
Secondary Endpoints
Number of Metaphase II Oocytes
Oocytes undergoing ICSI will have their maturity stage assessed prior to insemination. The number 
of MII oocytes per subject will be analysed in a similar manner as the primary endpoint. However, 
non-inferiority does not need to be formally established for this secondary endpoint. The number of 
MII oocytes per subject will be tabulated including both summary statistics and a frequency table.
The table will also summarise the percentage of MII oocytes to oocytes retrieved for subjects who 
have all oocytes inseminated using ICSI.
Number of Fertilised Oocytes 
The number of 2PN oocytes per subject will be tabulated including both summary statistics and a 
frequency table. The number of 2PN oocytes per subject will be analysed in a similar manner as the 
primary endpoint. However, non-inferiority does not need to be formally established for this 
secondary endpoint.
Fertilisation Rate
For subjects with oocytes retrieved, the rate of 2PN oocytes to oocytes retrieved will be tabulated.
For subjects with all oocytes inseminated using ICSI, the rate of 2PN oocytes to MII oocytes will 


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be tabulated.
Number and Quality of Embryos on Day 3
The number of embryos and the number of good quality embryos available on day 3 will be 
tabulated. For embryos transferred on day 3, the number of blastomeres and the degree of 
fragmentation will be tabulated. 
Number and Quality of Blastocysts on Day 5
The number of blastocysts and the number of good quality blastocysts available on day 5 will be 
tabulated. For blastocysts transferred on day 5, the blastocyst expansion and hatching status, 
blastocyst inner cell mass grading, trophectoderm grading and the combined score will be 
tabulated.
Positive βhCG Rate 
The positive βhCG rate is defined as the proportion of subjects with positive serum βhCG test 
13-15 days after transfer. No formal treatment comparison is planned since the trial is not powered 
for this secondary endpoint. The positive βhCG rate will be tabulated including two-sided 95% 
Clopper-Pearson confidence intervals for the within treatment effect. In addition, the positive βhCG 
rate may be presented by day of transfer (day 3 / day 5), number of embryos / blastocysts 
transferred (single transfer / double transfer) or quality of embryos / blastocysts transferred.
Clinical Pregnancy Rate
The clinical pregnancy rate is defined as the proportion of subjects with at least one gestational sac, 
either intrauterine or ectopic, 5-6 weeks after transfer. No formal treatment comparison is planned 
since the trial is not powered for this secondary endpoint. The clinical pregnancy rate will be 
tabulated including two-sided 95% Clopper-Pearson confidence intervals for the within treatment 
effect. For subjects with a positive clinical pregnancy assessment, the type of clinical pregnancy 
(intrauterine or ectopic) will be tabulated. In addition, the clinical pregnancy rate may be presented 
by day of transfer (day 3 / day 5), number of embryos / blastocysts transferred (single transfer / 
double transfer), or quality of embryos / blastocysts transferred. 
Vital Pregnancy Rate
The vital pregnancy rate is defined as the proportion of subjects with at least one intrauterine 
gestational sac with fetal heart beat 5-6 weeks after transfer. No formal treatment comparison is 
planned since the trial is not powered for this secondary endpoint. The vital pregnancy rate will be 
tabulated including two-sided 95% Clopper-Pearson confidence intervals for the within treatment 
effect. For subjects with a positive vital pregnancy assessment, the number of intrauterine 
gestational sacs with fetal heart beat and the number of fetuses with fetal heart beat will be 
tabulated. In addition, the vital pregnancy rate may be presented by day of transfer (day 3 / day 5) , 
number of embryos / blastocysts transferred (single transfer / double transfer), or quality of 
embryos / blastocysts transferred. 


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Circulating Concentrations of Endocrine Parameters
Blood samples drawn at end-of-stimulation, at transfer and at the βhCG visit (13-15 days after 
transfer) are analysed for estradiol, progesterone and hCG. Each parameter and the change from 
baseline for post-baseline measurements will be tabulated. Values below the lower limit of 
quantification (LLOQ) will be included as LLOQ/2. Values above the upper limit of quantification 
(ULOQ) will be included as ULOQ. 
For each parameter, the change from baseline will be compared between treatment groups using a 
linear normal model. In this model, change from baseline in ln-transformed measurements will be 
the dependent variable and the linear predictor will include treatment and randomisation stratum as 
factors and baseline measurement (ln-transformed) as covariate. The estimated treatment difference 
with two-sided 95% confidence interval will be presented on the scale of measurement (i.e. 
exp-transformed) and accompanied by the p-value for test of no treatment difference.
9.8
Safety
9.8.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set.
9.8.2
Adverse Events
Adverse events will be coded using MedDRA. The version of MedDRA will be documented. 
Adverse events will be grouped according to start of IMP as follows:
!
Pre-treatment adverse event, i.e. any adverse event occurring after signed informed consent 
and before administration of IMP, or a pre-existing medical condition that worsens in 
intensity after signed informed consent but before administration of IMP
!
Treatment-emergent adverse event, i.e. any adverse event occurring after administration of 
IMP and before the end-of-trial visit, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after administration of IMP and before the 
end-of-trial visit
Treatment-emergent adverse events will be presented in summary tables and listings. Pre-treatment 
adverse events will be presented in a listing only.
A treatment-emergent adverse event overview table will be prepared including the number of 
subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported, for the following categories: all adverse events, severe adverse events, 
adverse reactions, adverse events leading to discontinuation, serious adverse events and deaths. An 
adverse reaction is an adverse event judged by the investigator to be related to IMP with a 
reasonable possibility.
Treatment-emergent adverse events will be tabulated by system organ class (SOC) alphabetically 
and preferred term (PT) in decreasing order of frequency. The following will be presented: number 
of subjects reporting an adverse event, the percentage of subjects with an adverse event, and the 
number of events reported.


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Summary tables will be produced for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate / severe), adverse reactions by intensity (mild / moderate / severe), 
serious adverse events, adverse events leading to discontinuation, adverse events with an incidence 
of ≥5% in any treatment group, and non-serious adverse events with an incidence of ≥5% in any 
treatment group.
9.8.3
Early and Late OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation.
Late OHSS is defined as OHSS with onset >9 days after triggering of final follicular maturation. 
Early and late OHSS will be tabulated by classification (mild, moderate, severe) and grade (1, 2, 3, 
4, 5). 
9.8.4
Injection Site Reactions
For each injection site reaction (redness, pain, itching, swelling and bruising), the number of events 
will be tabulated by time (immediately, 30 minutes, 24 hours) and intensity (none, mild, moderate 
and severe).


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – ICH Definition
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial).
Trial-specific Source Data Requirements – Ferring
Source documents need to be preserved for the maximum period of time permitted by local 
requirements. For each subject enrolled, the investigator will indicate in the source documents that 
the subject participates in this trial, and will record at least the following information, if applicable: 
!
Existence of subject (initials, date of birth) 
!
Confirmation of participation in trial (trial ID, subject ID)
!
Informed consent(s) (date and time of oral information, date and time of handing out 
Informed Consent Form, date and time of obtaining written informed consent(s))
!
Eligibility for participation in the trial (documenting all inclusion / exclusion criteria)
!
Relevant medical history, infertility history, menstrual history and reproductive history
!
Visit dates
!
Dates of administration of IMP 
!
Injection site reactions after IMP administration – diary 
!
Dates and daily doses of NIMP
!
Dates and daily doses of concomitant medication 
!
Date of oocyte retrieval and number of oocytes retrieved
!
Number of MII oocytes (only applicable for insemination using ICSI)
!
Number of fertilised (2PN) oocytes 
!
Number and quality of embryos / blastocysts transferred and date of transfer
!
Number of embryos / blastocysts and number of good-quality embryos / blastocysts available 
on the day of transfer
!
Results of βhCG test and ultrasound at clinical pregnancy visit
!
Pregnancy outcome, i.e. live birth or pregnancy loss, and neonatal health at birth
!
Adverse events (description as well as start/stop date and time)


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!
OHSS symptoms and management
!
Reason for discontinuation
!
Event of unblinding, including the reason for unblinding
No specific protocol data can be recorded directly in the e-CRF without prior written or electronic 
record. 
If the trial sites use electronic patient record systems, the sponsor will decide if the electronic 
patient records qualify for the trial and document the decision. If the electronic patient records 
system does not qualify for the trial, certified copies of medical records will be used to capture 
source data as applicable.
The source data for the endocrine parameters as well as anti-hCG antibodies (if analysed) will be 
available at the central laboratory. Laboratory reports will be available at the sites.
10.2
e-CRF
An e-CRF system provided by an independent third-party contract research organisation, Target 
Health Inc., will be used for data capture. The system is validated and access at all levels to the 
system is granted/revoked following sponsor and vendor procedures, in accordance with regulatory 
requirements and system requirements.
Data should be entered into the system within a reasonable time after the subject has attended a 
visit or after the data become available, as applicable. 
The investigator will approve / authorise the e-CRF entries for each subject, with the exception of 
the treatment allocation module which is un-accessible to the investigator to maintain the 
assessor-blinding, with an electronic signature which is equivalent to a handwritten signature. 
The e-CRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and locked, a final copy of the database will be stored at Ferring. The investigator 
will also receive a copy of the trial site’s final and locked data (including audit trail, electronic 
signature and queries) as write-protected pdf-files produced by Target Health Inc. The pdf-files will 
be stored on a CD and will be provided to the investigator before access to the e-CRF is revoked.
Errors occurring in the e-CRF will be corrected electronically. Such corrections/modifications will 
be automatically tracked by an audit trail detailing the date and time of the correction and the name 
of the person making the correction. 
10.3
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
Department of Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection, cleaning and validation.
The data management plan will describe captured methods, who is authorised to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including 


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timing of data 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 Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference of Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions. The investigator will permit the 
monitor direct access to all source data, including electronic medical records, and/or documents in 
order to facilitate data verification. The investigator will co-operate with the monitor to ensure that 
any discrepancies that may be identified are resolved. The investigator is expected to be able to 
meet the monitor during these visits. The monitoring procedures are described in further detail in 
the Monitoring Plan.
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 EC 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 Helsinki23 and all other relevant regulations.
The subjects must be informed by the investigator and in the Informed Consent Form that 
authorised Ferring representatives and representatives from regulatory authorities and ECs may 
wish to inspect their medical records. During audits / inspections, the auditors / inspectors may 
copy relevant parts of the medical records. No personal identification apart from the screening /
randomisation number will appear on these copies.
The investigator should notify Ferring without any delay of any inspection by regulatory authorities
or ECs.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. On 
e-CRFs or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Form, will be maintained by the investigator in strict confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving ECs and regulatory authorities, in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to EC approval or favourable opinion.
12.2
Deviations from the Protocol
Protocol deviations should not occur. 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 in a protocol deviation report. A log of protocol deviation reports 
will be maintained by Ferring. Protocol deviation reports and supporting documentation must be 
kept in the Investigator’s File and the Trial Master File.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and ECs will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigators and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial.
Authorship is granted based on the criteria established by the International Committee of Medical 
Journal Editors (ICMJE).24 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 contract research organisation 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 four weeks from receipt of the draft manuscript. This statement 
does not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published. Under such conditions, the publication will be modified or delayed at the 
investigator’s discretion, to allow sufficient time for Ferring to seek patent protection of the 
invention.
13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in appropriate public registries, including


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www.ClinicalTrials.gov, which is sponsored by National Institutes of Health and the local registry 
Registro Brasileiro de Ensaios Clinicos (ReBEC). 


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14
ETHICAL AND REGULATORY ASPECTS
14.1
National Ethics Committee 
ECs will review the protocol and any amendments and advertisements used for recruitment. ECs
will also review the Subject Informed Consent Form, their updates (if any), and any written 
materials given to the subjects. A list of all ECs to which the protocol has been submitted and the 
name of the committee chairman will be included in the Clinical Trial Report.
14.2
Regulatory Authority Authorisation 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
The end of the trial is defined as the date of LPLV. 
At the end of the clinical trial, the sponsor shall notify the national regulatory authorities and the 
concerned ECs about the completion of the clinical trial. 
In the case of early termination, Ferring must notify the end of the trial to the national regulatory 
authorities and the concerned ECs immediately and at the latest within 15 days after the trial is 
halted, clearly explain the reasons, and describe follow-up measures, if any, taken for safety 
reasons. 
Within one year of the end of the trial, Ferring shall send a summary of the final Clinical Trial 
Report to the national regulatory authorities and the concerned ECs.
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 Form (a consolidated document 
consisting of subject information and signature sheet) 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.


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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 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 Informed Consent Form will be forwarded to the EC (and 
regulatory authorities, if required). The trial subjects will be informed about this new information 
and re-consent will be obtained.
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by 
Ferring, ECs’ representatives or regulatory authorities’ 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
Subject Information Card
The subject will be provided with a Subject Information Card bearing at least the following 
information:
! That she is participating in a clinical trial
! That the trial involves controlled ovarian stimulation for an IVF/ICSI cycle and thereby 
includes a treatment regimen with HP-hMG, a GnRH antagonist, a progesterone preparation, 
as well as randomisation to a single dose of either HP-hCG IM, HP-hCG SC or rhCG SC
! The name and phone number of the investigator
The subject will be asked to return the Subject Information Card at the end-of-trial visit.
14.7
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, and other national law(s) in the country
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing the IMP in accordance with the approved protocol or an approved amendment, and 
for its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
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 which covers the liability of Ferring, 
the investigator and other persons involved in the trial in compliance with the laws in the country 
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 15 years after the 
completion or discontinuation of the trial, if no further instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous e-CRF data for Ferring. The investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Form for at least 15 years after the completion or 
discontinuation of the trial.
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the Investigator File archived at an 
external archive.
16.2
Trial Master File
Ferring will archive the Trial Master File in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
REFERENCES
1
FE 999086, HP-hCG (CHORAPUR) Investigator’s Brochure. 1st Edition. January 2015
2
Chang P, Kenley S, Burns T, Denton G, Currie K, DeVane G, O’Dea Louis, The US 
Multicenter Study 7927 Investigator Group. Recombinant human chorionic gonadotropin 
(rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses 
of rhCG (Ovidrel) to urinary hCG (Profasi) for induction of final follicular maturation in in 
vitro fertilization-embryo transfer. Fertil Steril 2001; 76: 67-74.
3
Driscoll GL, Tyler JP, Hangan JT, Fisher PR, Birdsall MA, Knight DC. A prospective, 
randomized, controlled, double blind, double-dummy comparison of recombinant and 
urinary HCG for inducing oocyte maturation and follicular luteinization in ovarian 
stimulation. Hum Reprod 2000; 15: 1305-1310.
4
The European Recombinant Human Chorionic Gonadotrophin Study Group. Induction of 
final follicular maturation and early luteinization in women undergoing ovulation induction 
for assisted reproduction treatment-recombinant HCG versus urinary HCG. Hum Reprod 
2000; 15: 1446-1451.
5
The International Recombinant Human Chorionic Gonadotropin Study Group. Induction of 
ovulation in World Health Organization group II anovulatory women undergoing follicular 
stimulation with recombinant human follicle-stimulating hormone: a comparison of 
recombinant human chorionic gonadotropin (rhCG) and urinary hCG. Fertil Steril 2001; 75: 
111-1118.
6
Bellavia M, Geyter C, Streuli I, Ibecheole V, Birkhäuser MH, Cometti B, de Ziegler D.
Randomized controlled trial comparing highly purified (HPhCG) and recombinant hCG 
(r-hCG) for triggering ovulation in ART. Gynecol Endocrinol 2013; 29: 93-97.
7
Mannaerts BMJL, Geurts TBP, Odink J. A randomized three-way cross-over study in 
healthy pituitary-suppressed women to compare the bioavailability of human chorionic 
gonadotrophin (Pregnyl®) after intramuscular and subcutaneous administration. Hum 
Reprod 1998; 13(6): 1461-1464.
8
CHORAPUR’s proposed Summary of Product Characteristics.  January 2015
9
OVITRELLE Summary of Product Characteristics. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000320/WC500051458.pdf
10
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Bemfola Assessment Report. EMA/65507/2013 rev. 1. 26 June 2014. Pp 46-47, 
59. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002615/WC500166820.pdf
11
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). OVALEAP Assessment Report. EMA/CHMP/41467/2013. 31 July 2013. Pp 42.  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002608/WC500152908.pdf
12
European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). OVITRELLE Assessment Report – Scientific Discussion. Drafted in 2004, First 
published on 09 November 2011. Pp 15. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Scientific_Discussion/human/000320/WC500051449.pdf


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13
U.S. Department of Health and Human Services Food and Drug Administration (FDA), 
Center for Drug Evaluation and Research, Medical Review for OVIDREL (NDA number: 
21,149). 15 September 2000. Pp 41. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-149_Ovidrel_Medr.pdf
14
American Society for Reproductive Medicine. Revised American Society for Reproductive 
Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67: 817–821.
15
The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 
consensus on diagnostic criteria and longterm health risks related to polycystic ovary 
syndrome (PCOS). Hum Reprod 2004; 19: 41-47.
16
Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Towards 
reproductive certainty (Eds Jansen R & Mortimer D). The plenary proceedings of the 11th
world congress on in vitro fertilization and human reproductive genetics. The Parthenon 
Publishing Group. 1999. Pp 378-388.
17
Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, 
Sullivan E, van der Poel S on behalf of ICMART and WHO. The International Committee 
for Monitoring Assisted Reproductive Technology (ICMART) and the World Health 
Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod 2009; 24: 
2683-2687.
18
Golan A, Ron-El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation 
syndrome: an update review. Obstet Gynecol Survey 1989; 44: 430-440.
19
European Medicines Agency (EMA). Committee for medicinal products for human use 
(CHMP). Guideline on the exposure to medicinal products during pregnancy: need for 
postauthorisation data. EMEA/CHMP/313666/2005.
20
U.S. Department of Health and Human Services Food and Drug Administration (FDA), 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), Draft guidance March 2010, Non-inferiority Clinical Trials.
21
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP), ICH E9, Statistical Principles for Clinical Trials, 
CPMP/ICH/363/96. 
22
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for 
Proprietary Medicinal Products (CPMP). Points to consider on switching between 
superiority and non-inferiority. CPMP/EWP/482/99.
23
World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. 59th WMA General Assembly, Seoul, October 2008.
24
International Committee of Medical Journal Editors (ICMJE). Uniform requirements for 
manuscripts submitted to biomedical journals: ethical considerations in the conduct and 
reporting of research: authorship and contributorship. www.ICMJE.org

SAP_001.pdf: 
Date: 11 feb 2016
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Trial Code: 000191
Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
A randomised, controlled, assessor-blind, parallel groups, multicentre trial comparing the efficacy 
and safety of highly purified human chorionic gonadotropin (HP-hCG) and recombinant human 
chorionic gonadotropin (rhCG) for triggering of final follicular maturation in women undergoing 
controlled ovarian stimulation
FASHION
(Efficacy and safety of HP-hCG and rhCG for triggering of final follicular maturation)
Trial 000191
Investigational Product:
FE 999086, HP-hCG (CHORAPUR)
Indication:
For Assisted Reproductive Technology (ART) programme 
such as in vitro fertilisation: triggering of final follicular 
maturation and luteinisation after stimulation of follicle 
growth
Phase:
III
Author:
Date of issue:
11 FEB 2016
Version:
1.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1.0
11 FEB 2016
New document.
None


Date: 11 feb 2016
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Trial Code: 000191
Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
SignedI agreement on Statistical Analysis Plan
Author:  
              
Global Biometrics, Clinical R&D
Ferring Pharmaceuticals A/S
Review:
Reproductive Health, Clinical R&D
Ferring Pharmaceuticals A/S
Global Pharmacovigilance, Clinical R&D
Ferring Pharmaceuticals A/S
 
 Clinical R&D
Ferring Pharmaceuticals A/S
 
Global Biometrics, Clinical R&D
Ferring Pharmaceuticals A/
Global Biometrics, Clinical R&D
Ferring Pharmaceuticals A/S 
Approval:
 
Global Biometrics, Clinical R&D
Ferring Pharmaceuticals A/S
                                                
I Can be replaced by a list of reviewers/approvers if sign off can be performed in the REAL system


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Statistical Analysis Plan
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TABLE OF CONTENTS
1
Introduction.......................................................................................................................................... 7
1.1
Definitions/ Abbreviations...................................................................................................... 7
1.1.1
Definition of Terms.................................................................................................... 7
1.1.2
Abbreviations ............................................................................................................. 8
2
Trial Objectives and Endpoints.......................................................................................................... 9
2.1
Objectives................................................................................................................................. 9
2.2
Endpoints................................................................................................................................. 9
3
Trial Design ........................................................................................................................................ 10
3.1
General Design Considerations............................................................................................ 10
3.1.1
Overall Design and Control Methods..................................................................... 10
3.2
Determination of Sample Size.............................................................................................. 10
4
Subject Disposition ............................................................................................................................ 12
5
Protocol Deviations............................................................................................................................ 13
6
Analysis Sets....................................................................................................................................... 14
6.1
Intention-To-Treat Analysis Set .......................................................................................... 14
6.2
Full-Analysis Set.................................................................................................................... 14
6.3
Per Protocol Analysis Set ..................................................................................................... 14
6.4
Safety Analysis Set ................................................................................................................ 14
6.5
Additional Data Presentations ............................................................................................. 14
7
Trial Population................................................................................................................................. 15
7.1
Demographics and Other Baseline Characteristics ........................................................... 15
7.2
Transvaginal Ultrasound...................................................................................................... 15
7.2.1
Ovarian Volume....................................................................................................... 15
7.2.2
Endometrial Status .................................................................................................. 16
7.2.3
Follicular development ............................................................................................ 16
7.3
Endocrine Parameters.......................................................................................................... 16
7.4
Infertility History, Menstrual History and Reproductive History ................................... 16
7.5
Physical and Gynaecological Examination......................................................................... 17
7.6
Medical History..................................................................................................................... 17
7.7
Concomitant Medication...................................................................................................... 17
7.7.1
Concomitant Fertility Medication.......................................................................... 18


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7.7.2
Other Medications ................................................................................................... 18
8
Exposure and Treatment Compliance ............................................................................................. 20
8.1.1
Extent of Exposure................................................................................................... 20
8.1.2
Treatment Compliance............................................................................................ 20
9
Efficacy ............................................................................................................................................... 21
9.1
General Considerations........................................................................................................ 21
9.1.1
Primary and Secondary Endpoints ........................................................................ 21
9.1.2
Analysis and Presentation of Primary and Secondary Endpoints....................... 21
9.1.3
Multiplicity ............................................................................................................... 21
9.1.4
Missing Data............................................................................................................. 22
9.2
Primary Endpoint ................................................................................................................. 22
9.2.1
Primary Analysis...................................................................................................... 22
9.2.2
Additional Analyses ................................................................................................. 23
9.2.3
Summary Tables ...................................................................................................... 24
9.3
Secondary Endpoints............................................................................................................ 24
9.3.1
Metaphase II Oocytes and Fertilised Oocytes ....................................................... 24
9.3.2
Fertilisation Rate...................................................................................................... 24
9.3.3
Number and Quality of Embryos Day 3 ................................................................ 25
9.3.4
Number and Quality of Blastocysts Day 5............................................................. 25
9.3.5
Pregnancy Rates....................................................................................................... 26
9.3.6
Endocrine Parameters............................................................................................. 27
9.4
Other Assessments ................................................................................................................ 28
9.4.1
Insemination............................................................................................................. 28
9.4.2
Embryo or Blastocyst Transfer Procedure............................................................ 28
10
Safety................................................................................................................................................... 29
10.1
General Considerations........................................................................................................ 29
10.2
Adverse Events...................................................................................................................... 29
10.2.1 Overall Summary of Treatment-Emergent Adverse Events................................ 30
10.2.2 Incidence of Treatment-emergent Adverse Events............................................... 31
10.3
Treatment-emergent OHSS ................................................................................................. 32
10.4
Early Pregnancy Loss........................................................................................................... 32
10.5
Injection-site Reactions......................................................................................................... 32
10.6
Physical and Gynaecological Examinations........................................................................ 33


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10.7
Body Weight .......................................................................................................................... 33
10.8
Anti-drug Antibodies............................................................................................................ 33
11
Interim Analyses ................................................................................................................................ 34
12
Deviations from Protocol Analysis ................................................................................................... 35
13
Tables, Listings and Figures ............................................................................................................. 36
14
References........................................................................................................................................... 37


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1
Introduction
This statistical analysis plan (SAP) is based on the protocol for trial 000191 (Version 1.0, 30 
January 2015) and describes the planned statistical analyses for the period from screening up to 5-6 
weeks after transfer (end-of-trial). 
A separate SAP will be prepared covering post-trial information (live birth and neonatal health) for 
subjects with a vital pregnancy.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Gestational age
Days between date of embryo transfer and date of birth + 17 days 
or days between date of blastocyst transfer and date of birth + 19 
days 
Primary infertility
No previous clinical pregnancy
Randomised
Subject randomised to trial treatment
Randomisation stratum
Number of follicles ≥12 mm at the end of stimulation: <10 or ≥10 
based on the available data of the follicles (e.g. not necessarily 
the stratum that was used when the subject was randomised)
Screened
Subject who enters the screening phase
Screening failures
Screened subjects that are not randomised


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1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
adverse event
βhCG
beta unit of human chorionic gonadotropin
BMI
body mass index
DMC
Data Monitoring Committee
eCRF
electronic Case Report Form
FAS
full analysis set
GnRH
gonadotropin-releasing hormone
hCG
human chorionic gonadotropin
HP-hCG
highly purified human chorionic gonadotropin
ICSI
intracytoplasmic sperm injection
IM
intramuscular(ly)
ITT
intention-to-treat
IQ-range
inter quartile range 
LLOQ
lower limit of quantification 
MII
metaphase II
IMP
investigational medicinal product
OHSS
ovarian hyperstimulation syndrome
OR
oocyte retrieval
PN
pronuclei
PP
per-protocol
PT
preferred term
rhCG
recombinant hCG
SAE
serious adverse event
SC
subcutaneous(ly)
SOC
system organ class
ULOQ
upper limit of quantification


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2
Trial Objectives and Endpoints
2.1
Objectives
Primary Objective

To demonstrate non-inferiority of HP-hCG 5,000 IU compared with rhCG 250 µg for 
triggering of final follicular maturation with respect to number of oocytes retrieved in 
women undergoing controlled ovarian stimulation 
Secondary Objectives

To evaluate HP-hCG and rhCG with respect to oocyte fertilisation

To evaluate HP-hCG and rhCG with respect to pregnancy 

To compare HP-hCG with rhCG with respect to endocrine profile

To compare HP-hCG with rhCG with respect to safety profile
2.2
Endpoints
Primary Endpoint

Number of oocytes retrieved
Secondary Endpoints

Number of metaphase II oocytes (only applicable for insemination using ICSI)

Number of fertilised (2PN) oocytes 

Fertilisation rate (the rate of fertilised oocytes to oocytes retrieved for subjects with oocytes 
retrieved and also the rate of fertilised oocytes to metaphase II oocytes for subjects with 
oocytes insemination using ICSI)

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer)

Circulating concentrations of estradiol, progesterone and hCG at transfer and 13-15 days 
after transfer

Frequency and intensity of adverse events

Early and late OHSS rates 

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject after hCG administration
Post-trial Information

Live birth rate and neonatal health at birth for subjects who have achieved a vital pregnancy


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3
Trial Design
3.1
General Design Considerations
3.1.1
Overall Design and Control Methods
Trial Design
This is a randomised, assessor-blind, 3 parallel groups, multicentre phase III trial comparing 
efficacy and safety of HP-hCG (subcutaneous (SC) or intramuscular (IM) administration) and rhCG 
(SC) for triggering of final follicular maturation in women undergoing controlled ovarian 
stimulation.
Subjects who meet the criterion for triggering of final follicular maturation will be randomised in a 
1:1:1 ratio to either HP hCG 5,000 IU IM, HP hCG 5,000 IU SC, or rhCG 250 µg SC.
Randomisation will be stratified by the number of follicles ≥12 mm at the end of stimulation (two 
strata: <10 and ≥10). 
The end-of-trial assessments should take place at the subject’s last scheduled trial visit or within 2 
weeks after last scheduled visit in case of premature discontinuation. Subjects with a vital 
pregnancy at end-of-trial will be followed for post-trial information.
3.2
Determination of Sample Size
It is planned to randomise 258 subjects from 5 sites in Brazil. 
The trial is dimensioned as a non-inferiority trial based on the primary endpoint, ‘Number of 
oocytes retrieved’ and a non-inferiority margin of -3.0 oocytes, see protocol section 3.5.1 for the 
rational of the non-inferiority margin.
Non-inferiority of HP-hCG compared with rhCG will be established by doing the comparisons in 
sequential order as follows: 
1) HP-hCG IM vs. rhCG SC
2) HP-hCG SC vs. rhCG SC
This will only be evaluated if the first comparison establishes non-inferiority
In each step non-inferiority will be established if the respective 95% confidence interval lie entirely 
above -3.0 (the non-inferiority margin) for both the PP and the ITT analysis sets.
The sample size was determined for a 1:1:1 randomisation ratio based on a one-sided t-test at a 
2.5% significance level. Assuming all treatment are equally effective and a standard deviation of 
6.0 oocytes, a sample size of 68 subjects per treatment group would give 90% power to establish 


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non-inferiority for the first comparison. The number of subjects with major protocol deviations 
affecting the primary endpoint is assumed to be negligible. Therefore the sample size has not been 
adjusted to account for major protocol deviations affecting the primary endpoint.
The sample size needed to establish non-inferiority for the first comparison can be derived by 
solving the equation for the smallest integer n:
 = 
2 	
(2 −2) 
 + 
(2 −2)

 
( −)
where n=sample size for one group
t(df)p is the p percentile of the t-distribution with df degrees of freedom
s=assumed standard deviation
δ=non-inferiority margin
ε=actual difference between treatments (assumed to be zero)
α/2=significance level (one-sided)
β=1-power.
The power to establish non-inferiority for both comparisons, assuming the ITT and PP analysis set 
to be equal in addition to the suggested sequential testing procedure, was approximated to 80% via 
simulation.
The assumption regarding the standard deviation underlying the sample size estimation will be 
evaluated by an Internal Data Monitoring Committee (DMC) in a blinded manner and the number 
of randomised subjects may be adjusted up to a maximum of 348 subjects. See protocol and the 
DMC working procedures for more details.


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4
Subject Disposition
Screened subjects
All screened subjects will be accounted for. The total number of screened subjects will be 
summarised (n and % of total number of screened) by: Randomised, Reason for failure
(Inclusion/exclusion criteria not met, Withdrawal by subject, Other) and All.
Unless otherwise specified the disposition tables will be produced overall and by stratum and will 
include the treatment groups and a total column.
Subject disposition
Subject disposition with respect to analysis sets (n and % of ITT): ITT Analysis Set, Full Analysis 
Set, PP Analysis Set and Safety Analysis Set. 
Subject disposition by trial site
Subject disposition by trial site overall and by stratum (no treatment groups) (n and % of ITT with 
no percentage for the screened subjects): Screened, Analysis Sets (ITT, FAS, PP and Safety 
Analysis Set), Completed, Discontinued.
Subject completion/discontinuation - ITT
Subject completion by end-of-trial status (n and % of ITT): Completed, Discontinued (primary 
reason for premature discontinuation according to end-of-trial form).
Subject attendance at selected trial visits - ITT and PP
Subject attendance at selected visits (n and % of ITT or PP): Triggering visit, Oocyte retrieval visit, 
Transfer visit, βhCG visit, Clinical pregnancy visit and End-of-trial visit.
Subject attendance by trial procedure - ITT and PP
Subject attendance by selected trial procedures (Oocyte retrieval, Transfer, βhCG assessment, 
Clinical pregnancy and End-of-trial) including the detailed information of why the trial procedure
was not performed.
Listings - ITT
Subject disposition with respect to analysis sets will be listed including information on trial 
completion. Subjects who discontinued from the trial will be listed including information on date 
and reason for discontinuation, the last visit attended (excluding the end-of-trial visit). Both listings 
will be sorted by centre, stratum and subject number.


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5
Protocol Deviations
Protocol deviations will be rated as minor or major. Major protocol deviations impacting the 
primary endpoint and thereby affecting the conclusions will lead to exclusion of subjects from the 
PP analysis set. Subjects will not be excluded from the PP analysis set in case of only minor 
protocol deviations. 
The list of major protocol deviations impacting the primary endpoint includes, but is not restricted 
to the following:
hCG administered but triggering criterion is not met
1)
Wrong dose of hCG administered
2)
Oocyte retrieval not performed 36h (±2h) after hCG administration
3)
The sponsor’s Medical Officer at Ferring Global Clinical R&D, the sponsor’s Medical Officer in 
Brazil, and the project-responsible statistician at Ferring Global Biometrics will perform a blinded 
review of data before declaration of clean file and lock of database and rate protocol deviations as 
minor or major. The list of major protocol deviations will be detailed and documented in the clean 
file document prior to database release. Major protocol deviations impacting the primary endpoint 
will be tabulated and listed by subject for the ITT analysis set.
Major protocol deviations - ITT
Major protocol deviations leading to exclusion of subjects from the PP analysis set will be 
summarised overall (any major deviation) and by category (based on the coded terms) and 
produced overall and by stratum including the treatment groups and a total column (n and % of 
ITT).
Listings - ITT
The listing will include the planned (randomised) and actual treatment and details about the 
deviation.


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6
Analysis Sets
Four different analysis sets are defined in the protocol: ITT, FAS, PP and the safety analysis set. 
The ITT and PP analysis sets are the main analysis sets used for the primary efficacy evaluation. In 
addition, if FAS is different from ITT, (e.g. some subjects are randomised but not exposed to IMP) 
the FAS may also be used to describe the primary and key secondary efficacy endpoints. The safety 
analysis set will be used for the safety evaluation.
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set is defined as all randomised subjects. Subjects will be 
analysed according to planned (randomised) treatment.
6.2
Full-Analysis Set
The full analysis set (FAS) is defined as all subjects randomised and exposed to IMP. Subjects will 
be analysed according to planned (randomised) treatment received.
6.3
Per Protocol Analysis Set
The PP analysis set is defined as all subjects randomised and exposed to IMP except those excluded 
as a result of major protocol deviations as described in protocol section 9.3
.
Subjects will be 
analysed according to actual treatment received. 
6.4
Safety Analysis Set 
The safety analysis set is defined as all subjects randomised and exposed to IMP. Subjects will be 
analysed according to actual treatment received.
6.5
Additional Data Presentations
Efficacy (based on ITT) and safety (based on safety analysis set) will in some cases be reported 
using the following subgroups reflecting different aspects of the trial:

Subjects with oocyte retrieved (>=1 oocytes)

Fertilisation method (IVF, ICSI or IVF and ICSI)

Subjects with ICSI only

Subjects with transfer

Number of embryos/blastocysts transferred (single transfer or double transfer)

Quality of embryos/blastocysts transferred (good quality or not good quality)

Transfer Day (Day 3 or Day 5)

Subjects with positive βhCG


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7
Trial Population
Categorical data will be summarised using numbers and percentages (n and % of all observed) in 
addition to the sum ‘All’. The percentages are based on the total number of subjects with a 
corresponding assessment in the analysis set. Continuous data will be presented, using the number 
of subjects (n), mean and standard deviation, median, inter-quartile range (IQ-range), minimum and 
maximum. 
Missing data will not be imputed.
Summary tables will include the treatment groups and a total column. The purpose of these 
tabulations is to characterise the treatment groups and assess the degree of similarity achieved by 
randomisation. Tabulations will be produced overall and by stratum for the analysis set (ITT only 
or both ITT and PP as specified below). In case the ITT and PP analysis sets are identical duplicate 
tables will not be produced.
The data used to describe the trial population will be listed for the ITT analysis set.
7.1
Demographics and Other Baseline Characteristics
Demographics by stratum - ITT and PP
Demographics captured at screening: Age (years), Age grouped (<35, 35-37, >=38, All), Race, 
Ethnicity and Country.
Body measurements by stratum - ITT and PP
Body measurements captured at screening: Height (m), Weight (kg), BMI (kg/m2) and BMI 
grouped (<18.5, 18.5-<25.0, 25.0-<30.0,>=30.0, All).
7.2
Transvaginal Ultrasound
Transvaginal ultrasound is performed to assess the ovarian at stimulation Day 1, the endometrium 
at stimulation Day 1 and end of stimulation and the follicular development at stimulation Day 1, 6, 
subsequent stimulation days, and at end of stimulation. The data captured in the stimulation period 
will be presented as part of baseline characteristics.
7.2.1
Ovarian Volume
The average ovarian volume (cm3) will be calculated using the equation for an ellipsoid as: 
1000
1
2
2
6












l
l
l
r
r
r
d
w
l
d
w
l

where lx, wx, and dx are the length, width and depth in mm of the right (x=r) and left (x=l) ovary 
respectively. The total ovarian volume is then derived as twice the average volume. The total and 
average ovarian volume will only be reported if observations are available for both ovaries.


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Ovarian volume before stimulation by stratum - ITT and PP
Ovarian volumes stimulation Day 1: Total ovarian volume (cm3) and Average ovarian volume 
(cm3).
7.2.2
Endometrial Status
Endometrial status by stratum and visit - ITT and PP
Endometrial status by visit (Day 1 and end of stimulation): Endometrial thickness (mm), 
Endometrial thickness (categories) (<=6 mm, 7-9 mm, >=10 mm, All) and Endometrial 
echogenicity pattern (Hypoechogenic, Isoechogenic, Hyperechogenic, Not possible to evaluate, 
All).
7.2.3
Follicular development
Follicular development will combine the data from both the left and the right ovary and summaries 
will be made for stimulation Day 1, Day 6 and end of stimulation.
Follicles by stratum and visit - ITT and PP
By visit (Day 1, 6 and end of stimulation on subject level): Total number of follicles and Average 
follicle size (mm). 
7.3
Endocrine Parameters
Values below the lower limit of quantification (LLOQ) will be included as LLOQ/2. Values above 
the upper limit of quantification (ULOQ) will be included as ULOQ.
Endocrine parameters by stratum - ITT and PP
The endocrine profile at baseline: Estradiol (ρmol/L), Progesterone (nmol/L) and hCG (IU/L).
7.4
Infertility History, Menstrual History and Reproductive History
Infertility history by stratum - ITT and PP
Infertility history: Primary infertility (Yes, No, All), Duration of infertility (months) and Primary 
reason for infertility (Unexplained infertility, Tubal infertility, Mild male factor, Moderate male 
factor, Severe male factor, Anovulatory Infertility WHO Group I, Anovulatory Infertility WHO 
Group II, Endometriosis (Stage I/II), Endometriosis (Stage III/IV), Other, All).
Menstrual history by stratum - ITT and PP
Menstrual history: Average duration of menstrual cycle (days).
Obstetric history (natural conception) - ITT and PP
Obstetric history (all parameters should be treated as categorical): Previous clinical pregnancy
(Yes, No, All), Number of previous clinical pregnancies (0, 1, 2, 3, 4, All), Previous live birth (Yes, 
No, All), Number of previous live births (0, 1, 2, 3, All), Number of fetuses (pregnancy level) (1, 2, 


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All) and Outcome (fetus level) (Live birth, Still birth, Ectopic pregnancy, Miscarriage 1st trimester, 
Miscarriage 2nd trimester, Miscarriage 3rd trimester, Termination, All).
Previous fertility treatment by stratum - ITT and PP
Previous fertility treatment (all parameters should be treated as categorical): Previous fertility 
treatment (Yes, No, All), Number of previous fertility treatments (0, 1, 2, 3, 4, 5, 6, >6, All), 
Previous clinical pregnancy (Yes, No, All), Number of clinical pregnancies (0, 1, 2, 3, All), 
Previous live births (Yes, No, All), Number of previous live births (0, 1, 2, All), Number of fetuses 
(pregnancy level) (1, 2, All) and Outcome (fetus level) (Live birth, Still birth, Ectopic pregnancy, 
Miscarriage 1st trimester, Miscarriage 2nd trimester, Miscarriage 3rd trimester, Termination, All).
7.5
Physical and Gynaecological Examination
Physical and gynaecological examination will be summarised by the reported body system with 
responses ‘Normal’, ‘Abnormal, NCS’ and ‘Abnormal, CS’ (no total column for categories within 
body systems. These summary tables will only be produced overall (i.e. not by stratum) for the ITT 
analysis set.
Physical examination - ITT
Gynaecological examination - ITT
7.6
Medical History
Medical history recorded at screening visit will be coded using MedDRA. Medical history will be 
reported as ongoing if the diagnosis is present at the randomisation. The summaries will be made 
by SOC (alphabetically) and preferred term (in decreasing order of frequency based on the total 
column) including number of subjects with observation (n) and % of ITT. These summary tables 
will only be produced overall (i.e. not by stratum) for the ITT analysis set.
Incidence of ongoing medical history events by MedDRA system organ class and preferred 
term - ITT
The number of subjects with “Any ongoing medical history” will be included.
Incidence of past medical history events by MedDRA system organ class and preferred term -
ITT
The number of subjects with “Any past medical history” will be included.
7.7
Concomitant Medication
Concomitant medication include two categories; “concomitant fertility medication / non-
investigational medicinal products” and “other concomitant medication”. 


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7.7.1
Concomitant Fertility Medication
Concomitant fertility medication provided as non-investigational medicinal products are: 
gonadotropin, GnRH antagonist and progesterone.
Duration of a treatment (days) is defined as the number of days from first exposure to the day of 
last exposure (both inclusive). If a subject misses an intermediate dose she will still be considered 
as being under treatment.
Gonadotropin by stratum - ITT and PP
Duration of gonadotropin treatment (days), Total gonadotropin dose (IU), Dose on stimulation Day 
1 (IU/day), Dose on stimulation Day 6 (IU/day), Dose on last stimulation day (IU/day) and Average 
daily dose (IU/day).
GnRH antagonist by stratum - ITT and PP
Duration of GnRH antagonist treatment (days) and Total GnRH antagonist dose (mg).
Progesterone by stratum - ITT and PP
Progesterone by stratum - Subjects with positive beta-hCG - ITT and PP
Progesterone by stratum - Subjects with negative beta-hCG - ITT and PP
Duration of progesterone treatment (days) and Total progesterone dose (mg)
7.7.2
Other Medications
Concomitant medication (except for the treatments that are given as part of the protocol, such as the 
IMP, gonadotropin, GnRH antagonist and progesterone) will be summarised by ATC classification 
1st level (alphabetically) and ATC classification 2nd level (in decreasing order of frequency based 
on the total column). The tables are currently only planned for the ITT analysis set and without 
stratum.
The medications will be tabulated separately for:
1) Prior medication; i.e. medication taken exclusively prior to treatment (i.e. with stop date 
before date of IMP administration);
2) Concomitant medication, i.e. medication taken during the treatment period (i.e. medication 
that was not stopped before date of first IMP-administration and not started after the end-of-
trial visits.
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication.
Concomitant medication by ATC level 1 and ATC level 2 - ITT
The number of subjects with “Any concomitant medication” will be included.


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Prior medication by ATC level 1 and ATC level 2 - ITT
The number of subjects with “Any prior medication” will be included.


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8
Exposure and Treatment Compliance
The exposure data will be listed for the ITT analysis set.
8.1.1
Extent of Exposure 
Triggering of final follicular maturation by stratum - ITT
Triggering criteria met at last stimulation day (Yes, No, All), Triggering drug (the actual drug used 
HP-hCG, rhCG, Not triggered, All), Administration route (SC, IM) and dose (HP-hCG (IU), rhCG 
(µg)).
8.1.2
Treatment Compliance 
No summary tables are planned on compliance, since non-compliance is expected to be limited due 
to the fact that the IMP is administered as a single injection by the trial staff (or at the attendance of 
the trial staff for the SC administration).


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9
Efficacy
9.1
General Considerations
The efficacy endpoints will be listed for the ITT analysis set. The listings will be sorted by centre, 
stratum, subject number and visit.
In case the ITT and PP analysis sets are identical duplicate tables will not be produced.
If the FAS is different from the ITT analysis set, (e.g. some subjects are randomised but not 
exposed to IMP) tables for primary and key secondary efficacy endpoints will also be produced for 
the FAS.
9.1.1
Primary and Secondary Endpoints
The result of the analysis of the primary endpoint (number of oocytes retrieved) is essential for the 
non-inferiority claim. The number of MII oocytes (only applicable for subjects where all oocytes 
are intended to be inseminated using ICSI) and the number of 2PN oocytes are considered the key 
secondary endpoints supportive of the primary endpoint. However, non-inferiority does not need to 
be established for these secondary supportive endpoints. The analyses of the remaining secondary 
efficacy endpoints are intended to provide additional characterisation of the treatment effect.
9.1.2
Analysis and Presentation of Primary and Secondary Endpoints
Summary tables for the primary endpoint and the secondary efficacy endpoints will be presented 
overall and by stratum for both the ITT and the PP analysis sets.
All statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will, where appropriate, be presented with two-sided 95% confidence intervals and p-
values corresponding to the hypothesis of “equal effect” against the alternative “different effect”.
9.1.3
Multiplicity
Multiplicity needs to be addressed for the primary endpoints since it involves 2 hypotheses and 
each hypotheses needs to be demonstrated for 2 analysis sets. No adjustment for the multiple 
hypotheses is required, since there is only one primary endpoint and the evaluation is performed in 
a sequential manner as described in Section 9.2.1. No adjustment is needed for the 2 analysis sets
since non-inferiority has to be established for both. 
Concerning the superiority claim for the primary endpoint and the secondary endpoints, no formal 
adjustment for multiplicity will be utilised. Statistically significant results among these secondary 
endpoints will be interpreted cautiously.


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9.1.4
Missing Data
Missing observations for the primary endpoint (number of oocytes retrieved) will be imputed as 
zero irrespective of the reason why data was not recorded. 
Missing observations for the number of 2PN oocytes will be imputed as zero. This also includes 
subjects with no oocytes retrieved; these will have the number of 2PN oocytes set to zero.
For subjects where all oocytes are intended to be inseminated using ICSI, missing observations for 
the number of MII oocytes will be imputed as zero. For subjects who do not have any oocytes 
inseminated using ICSI, missing observations for the number of MII oocytes will not have a value 
imputed.
Missing observations for the βhCG assessment will be imputed as negative, unless a positive result 
is observed at the clinical pregnancy visit. For example, if the outcome of βhCG is missing but 
clinical pregnancy is “positive”, βhCG will be imputed as “positive”.
Missing observations for the clinical pregnancy assessment and vital pregnancy assessment will be 
imputed as “negative” irrespective of why data were not recorded.
9.2
Primary Endpoint
9.2.1
Primary Analysis
The primary endpoint ‘Number of oocytes retrieved’ captured 36h±2h after triggering will be 
analysed using an ANOVA model with treatment (HP-hCG 5.000 IU IM, HP-hCG 5.000 IU SC 
and rhCG 250 μg SC), stratum (<10 and >=10) and trial site (5 sites are planned) as fixed factors.
The model will be fitted for the PP and the ITT analysis sets. Since this is a non-inferiority trial, the 
PP and the ITT analysis sets have equal importance and should lead to similar conclusions for a 
robust interpretation. The 2-sided 95% confidence limits for the mean treatment differences (HP-
hCG IM - rhCG SC and HP-hCG SC - rhCG SC) will be calculated based on the fitted model for 
each analysis set. 
Non-inferiority of HP-hCG compared with rhCG will be established by doing the comparisons in 
sequential order as follows:
1) HP-hCG IM vs. rhCG SC
2) HP-hCG SC vs. rhCG SC
This will only be evaluated if the first comparison establishes non-inferiority
In each step non-inferiority will be established if the respective 95% confidence interval lie entirely 
above -3.0 (the non-inferiority margin) for both the PP and the ITT analysis sets. If the 95% 
confidence interval for the mean treatment difference not only lies above the non-inferiority limit 
but also above zero for the ITT analysis set, there is evidence of superiority in terms of statistical 


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significance at the two-sided 5% level. In this case, the p-value from the test for superiority will be 
reported.
Formally the model can be written as follows:
OR i = centre j(i) + stratum k(i) + treatment l(i) + ε i,
where:
OR i denotes the number of oocytes retrieved for subject i
centre j(i) denotes the centre for subject i
stratum k(i) denotes the stratification factor for subject i
treatment l(i) denotes the treatment for subject i
ε i  denotes an error term assumed to be normally distributed with mean zero and a common 
standard deviation across subjects.
The hypotheses to be tested in a in sequential order are: 
H10: ORHP-hCG IM - ORrhCG ≤ -3.0
H1A: ORHP-hCG IM - ORrhCG > -3.0
H20: ORHP-hCG SC - ORrhCG ≤ -3.0
H2A: ORHP-hCG SC - ORrhCG > -3.0
where ORHP-hCG IM, ORHP-hCG SC and ORrhCG denotes the number of oocytes retrieved with HP-hCG 
(IM or SC) and rhCG, respectively.
9.2.2
Additional Analyses
The amount of imputed data (missing observations for the primary endpoint imputed as zero) are
expected to be limited due to the trial design. Subjects with missing observations for the primary 
endpoint are likely to be excluded from the PP analysis set and hence the ITT analysis set can be 
used to assess the implication of the imputation method.
The fixed effects and the corresponding p-values will be presented for the following models:
the primary analysis model
1    
the model that also includes the treatment-by-stratum interaction 
2    
the model excluding stratum
3    
the model fitted to each stratum separately (subgroup analyses). 
4    


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In addition, more variables may be added to the primary ANOVA model in order to adjust for 
baseline differences or to investigate for a potential treatment interaction. 
9.2.3
Summary Tables
Oocytes retrieved by stratum - ITT/PP
Number of oocytes retrieved.
9.3
Secondary Endpoints
9.3.1
Metaphase II Oocytes and Fertilised Oocytes
An ANOVA model, similar to that used for the primary endpoint, will be fitted for the following 
endpoints:

Number of metaphase II oocytes (only applicable for insemination using ICSI)

Number of fertilised (2PN) oocytes
The model will be fitted for both the ITT and the PP analysis sets. The 2-sided 95% confidence 
limits for the mean treatment differences (HP-hCG IM - rhCG SC and HP-hCG SC - rhCG SC) and 
the corresponding p-value for no treatment difference will be presented for each comparison.
Subgroup analysis for stratum will be made by fitting the ANOVA to each stratum separately.
Summary Tables
Metaphase II oocytes(subject level) by insemination method (ICSI only) and stratum –
ITT/PP
Number of metaphase II oocytes, Metaphase II oocytes to oocytes retrieved (%) and Metaphase II 
oocytes continued.
Fertilised oocytes (subject level) by stratum – ITT/PP
Fertilised oocytes (subject level) by stratum - Subjects with oocytes retrieved – ITT/PP
Fertilised oocytes (subject level) by insemination method – ITT/PP
Number of fertilised oocytes and Oocytes continued.
9.3.2
Fertilisation Rate
The fertilisation rate is defined both based on oocytes retrieved and MII oocytes and expressed as 
percentages. The fertilisation rate will be summarised using descriptive statistics.
Fertilisation rate:

100*(Number of fertilised oocytes/Number of oocytes retrieved) for subjects with oocytes 
retrieved 


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
100*(Number of fertilised oocytes/Number of metaphase II oocytes) for subjects with all 
oocytes inseminated using ICSI
Summary Tables
Insemination Day 0 (embryo level) by stratum – ITT
Insemination Day 0 (embryo level) by insemination method – ITT
Oocyte maturity stage (Germinal vesicle (GV), Metaphase I (MI), Metaphase II (MII), 
Degenerated, Other and All), Destiny (Continue, Out of trial, All), Oocyte inseminated (Yes, No, 
All), Method of insemination (IVF; ICSI, All).
Fertilisation Day 1 (embryo level) by stratum – ITT
Fertilisation Day 1 (embryo level) by insemination method – ITT
Pronuclei at Day 1 (>2 pn, 2 pn, 1 pn, 0 pn, Damaged, All), Destiny (Continue, Out of trial, All).
Fertilisation (subject level) by stratum - Subjects with oocytes retrieved - ITT
Fertilisation (subject level) by insemination method - ITT
Fertilisation rate relative to oocytes retrieved and Fertilisation rate relative to MII oocytes.
9.3.3
Number and Quality of Embryos Day 3
The number of embryos and the number of good quality embryos (≥6 blastomeres and ≤20% 
fragmentation) available on day 3 will be tabulated. 
Embryo assessments Day 3 (embryo level) by stratum – ITT
Embryo assessments Day 3 (embryo level) by insemination method – ITT
Embryo stage (Cleavage stage, Compacting/Compaction, Degenerated, All), Degree of 
fragmentation (<=20%, >20%, All), Visual sign of multi-nucleation (Yes, No, All), Good-quality 
embryo (Yes, No, All), Destiny (Continue, Transferred, Cryopreserved, Out of trial, All).
Embryo quality Day 3 (subject level) by stratum – ITT
Embryo quality Day 3 (subject level) by day of transfer – ITT
Embryo quality Day 3 (subject level) by insemination method – ITT
Number of embryos, At least one embryo on Day 3 (Yes, No, All), Number of good-quality 
embryos, At least one good-quality embryo on Day 3 (Yes, No, All), Number of embryos
transferred (0, 1, 2, All).
9.3.4
Number and Quality of Blastocysts Day 5
The number of blastocysts and the number of good quality blastocysts (grade 3BB or above) 
available on day 5 will be tabulated. 


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Blastocyst assessments Day 5 (embryo level) by stratum – ITT
Blastocyst assessments Day 5 (embryo level) by insemination method – ITT
Embryo stage (Blastocysts, Morula, Degenerated, Cleavage stage, All), Blastocyst expansion and 
hatching status (1 to 6, as defined on the eCRF), Inner cell mass grading (A: Tightly packed, many 
cells, B: Loosely grouped, several cells, C: Very few cells, All), Trophectoderm grading (A: Many 
cells forming a cohesive epithelium, B: Few cells forming a loose epithelium, C: Very few, large 
cell, All), Quality of blastocyst (XAB combo), Good-quality blastocyst (Yes, No, All), Destiny 
(Transferred, Cryopreserved, Out of trial, All), Artificial shrinking (Yes, No, All).
Blastocyst quality Day 5 (subject level) by stratum – ITT
Blastocyst quality Day 5 (subject level) by insemination method – ITT
Number of blastocysts, At least one blastocyst on Day 5 (Yes, No, All), Number of good-quality 
blastocysts, At least one good-quality blastocyst on Day 5 (Yes, No, All).
Blastocyst destiny at day 5 (subject level) by stratum - ITT
Blastocyst destiny at day 5 (subject level) by insemination method – ITT
Number of blastocyst transferred (0, 1, 2, All), Blastocysts cryopreserved (0, 1, 2, >=3, All).
9.3.5
Pregnancy Rates
The following rates are defined as the proportion of subjects with the event of interest: 

Positive βhCG rate (positive serum βhCG test 13-15 days after transfer)

Clinical pregnancy rate (at least one gestational sac 5-6 weeks after transfer)

Vital pregnancy rate (at least one intrauterine gestational sac with fetal heart beat 5-6 weeks 
after transfer)
The proportions with the different denominators (all subjects, subjects with oocytes retrieved and
subjects with transfer) will be calculated as crude rates (without adjustment of stratum and centre) 
and presented for the different denominators (ITT and PP). 
In addition, the pregnancy rates will be summarised by day of transfer (Day 3 or Day 5), number of 
embryos/blastocysts transferred (single transfer or double transfer) and quality of 
embryos/blastocysts transferred (good quality or not good quality).
The pregnancy rates for each treatment (HP-hCG IM, HP-hCG SC and rhCG SC) will be presented 
together with the 2-sided 95% Clopper-Pearson confidence intervals based on the ITT analysis set. 
No formal treatment comparison are planned for the pregnancy rates since the trial is not powered 
for these secondary endpoints.


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Summary Tables
Beta-hCG by stratum – ITT/PP
Beta-hCG by stratum - Subjects with oocytes retrieved – ITT/PP
Beta-hCG by stratum - Subjects with transfer – ITT/PP
Beta-hCG (Positive, Negative, All).
Clinical pregnancy by stratum – ITT/PP
Clinical pregnancy by stratum - Subjects with oocytes retrieved – ITT/PP
Clinical pregnancy by stratum - Subjects with transfer – ITT/PP
Clinical pregnancy (Positive, Negative, All), Intrauterine pregnancy (Yes, No, All), Ectopic 
pregnancy (Yes, No, All).
Vital pregnancy by stratum – ITT/PP
Vital pregnancy by stratum - Subjects with oocytes retrieved – ITT/PP
Vital pregnancy by stratum - Subjects with transfer – ITT/PP
Vital pregnancy (Positive, Negative, All), Intrauterine gestational sacs with heart beat (1, 2, 3, All)
and Intrauterine fetal heart beats (1, 2, 3, All).
9.3.6
Endocrine Parameters
The endocrine parameters are measured at randomisation (end of stimulation), at the transfer visit 
and at the visit 13-15 days after transfer (pregnancy monitoring). Data will be evaluated based on 
the ITT analysis without any data imputation.
The endocrine parameters will be evaluated by fitting a separate ANCOVA model to the 
log(relative change) to the transfer visit and the pregnancy monitoring visit. The models will 
include treatment, centre, stratum and pregnancy status (positive or negative βhCG at the βhCG
visit) as fixed factors and log(baseline) as continuous covariate.
Subgroup analyses for stratum and positive/negative βhCG at the βhCG visit will be made by fitting 
the ANCOVA to each stratum separately. 
The endpoints are:

Circulating concentrations of estradiol, progesterone and hCG at transfer and 13-15 days 
after transfer
The 2-sided 95% confidence limits for the mean treatment ratios (HP-hCG IM / rhCG SC and HP-
hCG SC / rhCG SC) and the corresponding p-value for no treatment difference (ratio=1) will be 
presented for each visit and comparison, overall and by stratum.


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Exploratory analysis will be made to investigate if the ovarian response (number of oocytes 
retrieved) impact the circulating levels the endocrine parameters. 
Summary Statistics and Graphs
The actual measurements and the change from baseline will be summarised overall and by stratum.
In addition Box plots will be used to display the actual levels and the change from baseline over 
time. 
9.4
Other Assessments
9.4.1
Insemination
Insemination (subject level) by stratum – ITT
Method of insemination (n, %) (None, IVF, ICSI, IVF and ICSI and All).
9.4.2
Embryo or Blastocyst Transfer Procedure
Embryo or blastocyst transfer procedure (subject level) by stratum – ITT
Day of transfer (3, 5), Number of embryo/blastocyst transferred (0, 1, 2 or All), Method of transfer 
(Ultrasound guided, Clinical touch or All), Difficult transfer (Yes, No, All) and Any eventuality 
(Yes, No, All).


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10
Safety
10.1
General Considerations
The safety endpoints will be listed for the safety analysis set. The listings will be sorted by centre, 
stratum, subject number, visit or onset as applicable.
Safety parameters will be evaluated for the safety analysis set, i.e. data will be reported according 
to actual treatment received. The safety endpoints are:

Frequency and intensity of AEs

Early and late OHSS rates

Frequency and intensity of injection site reactions (redness, pain, itching, swelling and 
bruising) assessed by the subject after hCG administration
Post-trial Information

Live birth rate and neonatal health at birth for subjects who have achieved a vital pregnancy
In addition the following safety parameters are collected:

Physical examination at screening and end-of-trial

Gynaecological examination at screening and end-of-trial

Body weight at screening and end-of-trial
Blood collection is performed for potential analysis of anti hCG antibodies at end-of-stimulation 
(baseline), transfer and 13-15 days after transfer.
OHSS and injection site reactions are both recorded on specific eCRFs designed to include the 
relevant details for each event. OHSS is also reported on the standard AE form whereas injection 
site reactions are only reported on the standard AE form if they require active management. 
The AE/event tabulations will be prepared overall, i.e. not by stratum. The summaries will include 
the number of subjects reporting an AE/event, the percentage of subjects (%) with an AE/event, and 
the total number of AEs/events (E).
10.2
Adverse Events
AEs will be recorded from signed informed consent until the end-of-trial visit. In addition, serious 
adverse events (SAEs) reported as part of the pregnancy outcome and neonatal health will be 
recorded during the post-trial follow-up period.


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If a subject suffers from the same AE more than once and the subject recovers in between the 
events, the AEs will be reported separately. 
AEs are grouped according to exposure as follows:

Pre-treatment AE, i.e. any AE occurring after signed informed consent and before 
administration of the randomised treatment, or a pre-existing medical condition that worsens 
in intensity after signed informed consent but before administration of randomised 
treatment.

Treatment-emergent AE, i.e. any AE occurring after administration of randomised treatment 
and before the end-of-trial visit, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after administration of randomised treatment and before 
the end-of-trial visit.
If the timing of an AE cannot be established in relation to administration of randomised treatment, 
it will be considered as a treatment emergent AE.
Pre-treatment AEs will be listed only.
AEs are classified according to the MedDRA. The system organ class (SOC) and the preferred term 
(PT) will be used to categorise events. The version of MedDRA will be documented.
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of adverse events where a worst-case approach will be used: 

if causality is missing, the AE will be regarded as related to the randomised treatment with a 
reasonable possibility

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’
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
discontinuation.
10.2.1
Overall Summary of Treatment-Emergent Adverse Events
A summary table of treatment-emergent AEs will include the following categories: 

Adverse events

Severe adverse events

Adverse drug reactions (adverse events with causality to randomised treatment judged as a 
reasonable possibility)


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
Adverse events leading to discontinuation

Serious adverse events

Adverse events leading to death
10.2.2
Incidence of Treatment-emergent Adverse Events
Treatment-emergent adverse events will be summarised overall (“Any adverse event”), by SOC 
(alphabetically) and PT (in decreasing frequency of occurrence) for:

Adverse events

Adverse drug reactions

Adverse events leading to death 

Adverse events by intensity (mild, moderate or severe separately)

Adverse drug reactions by intensity (mild, moderate or severe separately)

Serious adverse events

Adverse events leading to discontinuation

Pregnancy loss
Treatment-emergent adverse events will be summarised overall (“Any adverse event”) and by PT 
(in decreasing frequency of occurrence) for:

Adverse events with an incidence of at least 5% (in any treatment group)

Non-serious adverse events with and incidence of at least 5% (in any treatment group)
Treatment-emergent adverse events will be summarised overall (“Any adverse event”), by SOC 
(alphabetically) and by High Level Group Term (HLGT) (in decreasing frequency of occurrence) 
for:

Adverse events
Supporting data listings sorted by SOC (alphabetically), PT (in decreasing frequency of 
occurrence), centre, stratum, treatment, subjects and onset will be provided for:

All adverse events

All adverse events sorted by PT (not SOC)

Adverse drug reactions

Adverse events leading to death

Severe adverse events

Serious adverse events 


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
Adverse events leading to discontinuation

Pregnancy loss
10.3
Treatment-emergent OHSS
Early OHSS is defined as OHSS with onset ≤9 days after triggering of final follicular maturation
and late OHSS as OHSS with onset >9 days after triggering. OHSS symptoms will be classified 
using Golan’s system (see protocol sec 8.3.1) 
Treatment-emergent OHSS by grade
A summary table (n, %) of treatment-emergent OHSS by severity classification and grade (Any 
Grade, Mild OHSS: Grade 1 and 2, Moderate OHSS: Grade 3, Severe OHSS: Grade 4 and 5 and 
Moderate/Severe) will be prepared for:

OHSS

Early OHSS

Late OHSS
10.4
Early Pregnancy Loss
An early pregnancy loss is defined by a positive βhCG testnot followed by a vital pregnancy. 
Number of subjects with early pregnancy loss will be summarised (n and % of patients with a 
positive βhCG test).
10.5
Injection-site Reactions
Overall summary of injection-site reactions
An overall summary table of subjects with injection-site reaction (n, %) will be prepared for the 
following categories: 

At least one injection-site reaction

At least one moderate/sever injection-site reaction
Injection-site reactions by symptom, time and severity
A summary table of “injection-site reaction by symptom, time and severity (n, %, E) will be 
prepared by symptom (redness, pain, itching, swelling and bruising), by time (All time points, 
Immediately after, 30 minutes, 24 hours) and intensity (None, Mild, Moderate, Severe and
Moderate/severe). 


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10.6
Physical and Gynaecological Examinations
Shift tables (baseline versus end-of-trial visit) will be made for physical examination and 
gynaecological examinations per body system/test. The tables will include subjects with non-
missing data at both visits for a body system/test.
Physical examination: change in evaluation at end-of-trial visit
Gynaecological examination: change in evaluation at end-of-trial visit
A summary table per body system/test, baseline versus end-of-trial visit with N1, n and % (N1=
number of subjects with non-missing value in available baseline category and at least one non-
missing value recorded at end-of-trial visit, n=number of subjects with non-missing value in each 
category for baseline and end-of-trial visit, % = percentage of subjects).
All data for the subjects with one or more abnormal findings (at baseline or end-of-trial for any of 
the body systems/tests) will be listed by body system/test and time point.
10.7
Body Weight
Body weight is measured at screening and end-of-trial. The actual measurements and the change 
from baseline will be summarised. 
10.8
Anti-drug Antibodies
Summaries will be made as applicable if the blood samples are analysed for anti hCG antibodies.


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11
Interim Analyses
No interim analysis intended to compare treatment groups with respect to efficacy or safety is 
planned.
The assumption underlying the sample size estimation (assuming a standard deviation of 6.0 
oocytes) will be evaluated by the internal DMC. The sample size reassessment will be done without 
breaking the blind and without inflating the type I error of the trial1, in line with the current 
regulatory guidelines2, 3. The details are explained in the working procedures for the internal DMC.


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12
Deviations from Protocol Analysis
There are no changes to the analyses outlined in the protocol.


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13
Tables, Listings and Figures
The planned summary tables, figures and listings (TLF) for the end-of-text are included in this 
SAP. No separate document will be prepared with shells.


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14
References
                                                
1
Kieser M, Friede T. Simple procedures for blinded sample size adjustemtn that do not affect 
the type error rate.. Statist. Med. 2003; 22:3571-3581.
2
U.S. Department of Health and Human Services Food and Drug Administration (FDA), 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), Draft guidance February 2010, Adaptive Design Clinical Trials for 
Drugs and Biologics.
3
Committee for Medicinal Products for Human Use (CHMP), Reflection paper on 
methodological issues in confirmatory clinical trials planned with an adaptive design. 
Adopted by CHMP 18 October 2007, CHMP/EWP/2459/02.