Clinical trial NCT04150861
Conditions: Infertility
Keywords: In vitro fertilisation Controlled ovarian stimulation
Sponsor: Ferring Pharmaceuticals
Start date: 2019-06-23; Completion date: 2019-12-16
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
FE 999049 is a gonadotropin preparation containing recombinant human follicle stimulating hormone (rhFSH) under development by Ferring Pharmaceuticals. It is intended for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle. In previous trials the exposure to and dose proportionality of FE 999049 in a clinically relevant dose range in Caucasian and Japanese healthy women have been shown to be very similar. This is a trial in healthy Chinese women investigating the pharmacokinetics, safety, and tolerability of a single subcutaneous dose of FE 999049.

Detailed description:

Arms: arm 1: Participants received single subcutaneous abdominal injection of Follitropin delta 12 μg on Day 1. arm 2: Participants received single subcutaneous abdominal injection of Follitropin delta 18 μg on Day 1. arm 3: Participants received single subcutaneous abdominal injection of Follitropin delta 24 μg on Day 1.
Interventions: intervention 1: Follitropin Delta
Intervention descriptions: intervention 1: Solution for Injection, subcutaneous administration

Protocol documents:
Prot_000.pdf: 
Protocol 
Title of trial 
An open-label trial investigating the pharmacokinetics of FE 999049 given 
as a single subcutaneous dose in gonadotropin down-regulated healthy 
Chinese women 
NCT number: 
NCT04150861 
Sponsor trial code: 
000152  
Date:  
20 Sep 2018 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 1 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
 
CLINICAL TRIAL PROTOCOL 
 
An open-label trial investigating the pharmacokinetics of FE 999049 
given as a single subcutaneous dose in gonadotropin down-regulated 
healthy Chinese women 
000152  
 
EudraCT Number: 
Not applicable 
IND Number: 
Investigational Medicinal Product: 
FE 999049 
Indication: 
Controlled ovarian stimulation for the development of 
multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro 
fertilisation (IVF) or intracytoplasmic sperm injection 
(ICSI) cycle  
Phase: 
1 
Name and Address of Global 
Sponsor: 
Ferring Pharmaceuticals 
Global Clinical R&D 
International PharmaScience Center  
Kay Fiskers Plads 11  
DK-2300 Copenhagen S  
Denmark  
Tel: +45 88 33 88 34 
Fax: +45 88 33 88 80 
Local Sponsor 
Ferring Pharmaceuticals (Asia) Company Limited 
19/F Century Link Tower One 
1198 Century Avenue, Shanghai 
China 200122 
Tel: +86-21-80303001  
Fax: +86-21-80303010 
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. 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 2 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
SYNOPSIS 
TITLE OF TRIAL  
An open-label trial investigating the pharmacokinetics of FE 999049 given as a single 
subcutaneous dose in gonadotropin down-regulated healthy Chinese women 
SIGNATORY INVESTIGATOR  
 
TRIAL SITE  
One trial site in China. 
PLANNED TRIAL PERIOD  
The first subject is expected to be enrolled in 2019 with a total 
duration of the trial of approximately 7 months. 
CLINICAL PHASE 
1 
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE 
TRIAL 
FE 999049 is a gonadotropin preparation containing recombinant human follicle stimulating 
hormone (rhFSH) under development by Ferring Pharmaceuticals for controlled ovarian 
stimulation for the development of multiple follicles in women undergoing assisted reproductive 
technologies (ART) such as in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) 
cycle. In previous trials the exposure to and dose proportionality of FE 999049 in a clinically 
relevant dose range in Caucasian and Japanese healthy women have been shown to be very 
similar.This is a trial in healthy Chinese women investigating the pharmacokinetics, safety, and 
tolerability of a single subcutaneous dose of FE 999049.  
OBJECTIVES 
The objectives of the trial are to: 
• Investigate the single-dose pharmacokinetics of FE 999049 administered as a 
subcutaneous abdominal injection in healthy Chinese women 
• Investigate the safety and tolerability of a single dose of FE 999049 administered as a 
subcutaneous abdominal injection in healthy Chinese women 
METHODOLOGY 
This is an open-label, randomised parallel group trial investigating the pharmacokinetics of 
FE 999049 after a single subcutaneous abdominal injection of 12, 18, or 24 µg, with 8 healthy 
Chinese women in each dose group.  
Blood samples for analysis of FE 999049 concentration will be collected during 10 days.  


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
Premenopausal women are chosen as trial population to mimic the target patient population. In 
order to minimise the interference by endogenous FSH with the pharmacokinetic assessment of 
the recombinant FSH, a gonadotropin releasing hormone (GnRH) receptor agonist, 
DECAPEPTYL Depot, will be administered throughout the trial period to suppress the 
endogenous release of FSH.  
The doses in the trial are chosen to cover a possible range of clinical dosing of FSH in the 
targeted indications, however restricted at the lower end due to analytical constraints. 
NUMBER OF SUBJECTS  
24 healthy Chinese women will be included and dosed. 
CRITERIA FOR INCLUSION / EXCLUSION 
Healthy Chinese women, 21-40 years of age with a normal menstrual cycle (24-35 days), may be 
included in this trial. The complete list of inclusion and exclusion criteria is provided below. 
Inclusion Criteria 
1. Signed written Informed Consent Form 
2. Female of Chinese origin, with two ethnic Chinese parents and four ethnic Chinese 
grandparents 
3. 21–40 years of age (both inclusive) 
4. Willing to stop using combined oral contraceptives (COC) in relation to the first 
DECAPEPTYL Depot administration on Day -28 
5. Agrees to use a double barrier method of contraception between Day -63 and Day 28, if 
not abstinent. A double barrier method of contraception should also be used after Day 28 
until menses resumes or until another contraceptive method has been established 
6. Normal menstrual cycles with a range of 24-35 days in the absence of oral contraceptives 
7. Serum follicle-stimulating hormone (FSH) 5 IU/L on Day -3 and Day -1 
8. Body mass index (BMI) of 18.5 -25 kg/m2 (both inclusive)  
9. Negative serology for human immunodeficiency virus (HIV) antibody, hepatitis B 
(surface antigen), hepatitis C antibody, and syphilis bacteria 
10. Healthy according to medical history, physical examination, gynaecological examination, 
electrocardiogram (ECG), blood pressure, and laboratory profile of blood and urine 
11. Negative urine drug screen and alcohol breath test at screening and on Day -1 
12. Non-smoker or light smoker (≤ 5 cigarettes/day) for at least 6 months prior to trial start 
 


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
Exclusion Criteria 
1. Presence or a history of clinically significant diseases of the renal, hepatic, 
gastrointestinal, cardiovascular, or musculoskeletal systems, or presence or history of 
clinically significant reproductive, psychiatric, immunological, endocrine or metabolic 
diseases 
2. Cancer within the last 5 years except for adequately managed basal cell carcinoma and 
squamous cell carcinoma of the skin 
3. Pregnancy or breastfeeding 
4. Current or a history of endocrine abnormalities such as hyperprolactinaemia, polycystic 
ovary syndrome or other ovarian dysfunction, tumours of the pituitary gland or 
hypothalamus, thyroid or adrenal disease 
5. Clinically significant findings on the trans-vaginal ultrasound, cytology, gynaecological 
or breast examination at screening or on Day –1 including ovarian cysts or tumours of the 
ovaries or uterus 
6. Contraindications for the use of gonadotropins and gonadotropin-releasing hormone 
(GnRH) agonists 
7. Previously treated with gonadotropins within the last 6 months prior to screening 
8. History within the last two years or current abuse of alcohol or drugs 
9. Presence or history of severe allergy or anaphylactic reactions 
10. Intake of prescribed medication, over-the-counter (OTC) medication, or herbal medicines, 
with the exceptions of COC, cromoglycate, and paracetamol according to the labelling, 
within 2 weeks or 5 half-lives of the drug, whichever is longer, prior to first dose of 
DECAPEPTYL Depot. Topical treatments of bacterial or fungal infection are allowed if 
stopped before first dose of IMP. 
11. Intake of any non-registered investigational drug within the last 12 weeks preceding 
screening, or longer if judged by the investigator to possibly influence the outcome of the 
current trial 
12. High daily consumption of caffeine-containing beverages (e.g. more than five cups of 
coffee or equivalent) with a risk of withdrawal symptoms arising during the trial that may 
confound the safety evaluation 
13. Blood donation or major blood loss (≥500 mL) within the last 8 weeks, or plasma 
donation with the last 4 weeks preceding the first day of IMP dosing 
14. Current non-smokers or light smoker with a history of long-term, heavy smoking 
(>10 pack-years) 
15. Previously dosed in this trial 
16. Mental incapacity or language barrier precluding adequate understanding or co-operation 


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
17. Considered by the investigator to be unsuitable to participate in the trial for any other 
reason 
MEDICINAL PRODUCTS 
Investigational medicinal product 
• 
FE 999049 is provided as a cartridge with 72 µg rhFSH in 2.16 mL and an injection pen  
Non-investigational product 
• 
DECAPEPTYL Depot 3.75 mg 
DURATION OF TREATMENT  
Each subject is planned to receive a single injection of FE 999049. For each subject, the duration 
of the trial including screening and follow-up visits will not exceed 13 weeks. 
ENDPOINTS 
• Pharmacokinetics (AUC, AUCt, Cmax, tmax, CL/F, Vz/F, t½) 
• Safety (ECG, vital signs, laboratory parameters, adverse events)  
• Injection site reactions 
• Presence of anti-FSH antibodies 
TRIAL PROCEDURES / ASSESSMENTS 
Before inclusion into the trial, all subjects will undergo a general physical and a gynaecological 
examination, including vital signs, ECG, transvaginal ultrasonography and cytology as well as 
laboratory assessments including haematology, clinical chemistry, and urinalysis. 
The subjects will receive two administrations of a 1-month depot formulation of DECAPEPTYL 
Depot 3.75 mg to down-regulate endogenous release of FSH during the trial. The first 
DECAPEPTYL Depot administration will be given 28±1 days prior to the first dose of IMP. In 
women not receiving hormonal contraceptives, the first DECAPEPTYL Depot administration 
should take place in the time interval 7 days before to 3 days after the expected start of 
menstruation. In women discontinuing combined oral contraceptives, the first DECAPEPTYL 
Depot administration should take place after the subjects have discontinued the hormonal 
contraception and within 5 days of commencement of bleeding. A second administration will be 
given 10±1 days prior to the first IMP administration.  
To verify low stable endogenous hormones, serum FSH will be measured at Day -3 and Day -1. 
If any of the measurements is >5 mIU/mL, the subject will be excluded. 


Date: 20 Sep 2018 
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Supersedes: None 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
Subjects will come for a residential stay, lasting between Day -1 and Day 3, and ambulatory 
visits or, if agreed between investigator and subject, a residential stay from Day 4 to Day 10. A 
follow-up visit will be performed on Day 11. Blood samples for pharmacokinetic (PK) analysis 
of FE 999049 will be collected from Day 1 to Day 10, every 4 hours during the first 48 hours and 
then once daily.  
Safety and tolerability will be assessed in terms of AEs, vital signs, ECG, and safety laboratory 
parameters up to and including Day 11. On Day 1, Day 7 and Day 28, assessment of the presence 
of anti-FSH antibodies will be performed. 
STATISTICAL METHODS 
Pharmacokinetic analysis 
Pharmacokinetic parameters will be calculated using non-compartmental methods and evaluated 
using descriptive statistics. Dose proportionality will be investigated for AUC and Cmax. 
Safety 
Safety endpoints will be evaluated by data listings and descriptive statistics.  


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................................. 13 
1.1 
Background ............................................................................................................................. 13 
1.2 
Scientific Justification for Conducting the Trial ..................................................................... 14 
1.3 
Benefit / Risk Aspects ............................................................................................................. 14 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 16 
2.1 
Objectives ............................................................................................................................... 16 
2.2 
Endpoints ................................................................................................................................ 16 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 17 
3.1 
Overall Trial Design................................................................................................................ 17 
3.1.1 
Trial Design Diagram................................................................................................. 17 
3.1.2 
Overall Design and Control Methods ........................................................................ 17 
3.1.3 
Trial Schedule ............................................................................................................ 18 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 18 
3.3 
Interim Analysis ...................................................................................................................... 18 
3.4 
Data Monitoring Committee ................................................................................................... 18 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 18 
3.5.1 
Trial Design ............................................................................................................... 18 
3.5.2 
Selection of Endpoints ............................................................................................... 18 
3.5.3 
Blinding...................................................................................................................... 18 
3.5.4 
Selection of Doses in the Trial ................................................................................... 19 
3.5.5 
Selection and Timing of Dose for Each Subject ........................................................ 19 
3.5.6 
Withdrawal Criteria ................................................................................................... 19 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 20 
4.1 
Trial Population....................................................................................................................... 20 
4.1.1 
Inclusion Criteria ....................................................................................................... 20 
4.1.2 
Exclusion Criteria ...................................................................................................... 20 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 21 
4.2.1 
Recruitment ................................................................................................................ 21 
4.2.2 
Randomisation ........................................................................................................... 22 
4.3 
Restrictions ............................................................................................................................. 22 
4.3.1 
Prior and Concomitant Therapies .............................................................................. 22 
4.3.2 
Other Restrictions ...................................................................................................... 22 
4.3.3 
Subsequent Therapy ................................................................................................... 22 
4.4 
Withdrawal Criteria................................................................................................................. 23 
4.5 
Subject Replacement ............................................................................................................... 23 
5 
TREATMENTS ................................................................................................................................. 24 
5.1 
Treatments Administered ........................................................................................................ 24 
5.2 
Medicinal Products ................................................................................................................. 24 
5.2.1 
Characteristics and Source of Supply ........................................................................ 24 
5.2.2 
Packaging and Labelling ............................................................................................ 24 
5.2.3 
Conditions for Storage and Use ................................................................................. 24 
5.3 
Blinding/Unblinding ............................................................................................................... 24 
5.4 
Treatment Compliance, Dispensing and Accountability......................................................... 25 
5.5 
Return and Destruction of Medicinal Products and Auxiliary Supplies ................................. 25 


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
6 
TRIAL PROCEDURES .................................................................................................................... 26 
7 
TRIAL ASSESSMENTS ................................................................................................................... 29 
7.1 
Assessments Related to Endpoints .......................................................................................... 29 
7.1.1 
Pharmacokinetics ....................................................................................................... 29 
7.1.2 
Safety Assessments .................................................................................................... 29 
7.1.3 
Other Assessments related to Endpoints .................................................................... 30 
7.2 
Other Assessments .................................................................................................................. 31 
7.2.1 
FSH Determination Day -3 and Day -1...................................................................... 31 
7.2.2 
Serology/Virology ...................................................................................................... 31 
7.2.3 
Pregnancy Test ........................................................................................................... 31 
7.2.4 
Gynaecological Examination and Transvaginal Ultrasound ...................................... 31 
7.2.5 
Physical Examination ................................................................................................. 31 
7.2.6 
Drug Screen and Alcohol Breath Test ....................................................................... 32 
7.3 
Handling of Biological Samples ............................................................................................. 32 
7.4 
Laboratory Analyses ............................................................................................................... 32 
8 
ADVERSE EVENTS ......................................................................................................................... 33 
8.1 
Adverse Events ....................................................................................................................... 33 
8.1.1 
Definitions .................................................................................................................. 33 
8.2 
Collection and Recording of Adverse Events ......................................................................... 34 
8.2.1 
Collection of Adverse Events .................................................................................... 34 
8.2.2 
Recording of Adverse Events .................................................................................... 34 
8.3 
Adverse Events of Special Interest ......................................................................................... 37 
8.4 
Pregnancy and Pregnancy Outcome........................................................................................ 37 
8.5 
Serious Adverse Events .......................................................................................................... 38 
8.5.1 
Serious Adverse Event Definitions ............................................................................ 38 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ............................. 39 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .................................................... 40 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ........................................ 40 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit ................... 40 
9 
STATISTICAL METHODS ............................................................................................................. 41 
9.1 
Determination of Sample Size ................................................................................................ 41 
9.2 
Subject Disposition ................................................................................................................. 41 
9.3 
Protocol Deviations ................................................................................................................. 41 
9.4 
Analysis Sets ........................................................................................................................... 41 
9.4.1 
Full Analysis Dataset ................................................................................................. 41 
9.4.2 
Per Protocol Dataset ................................................................................................... 41 
9.4.3 
Safety Dataset ............................................................................................................ 41 
9.5 
Trial Population....................................................................................................................... 42 
9.5.1 
Demographics and other Baseline Characteristics ..................................................... 42 
9.5.2 
Medical History, Concomitant Medication and Physical Examination ..................... 42 
9.6 
Treatment Compliance ............................................................................................................ 42 
9.7 
Endpoint Assessments............................................................................................................. 42 
9.7.1 
General Considerations .............................................................................................. 42 
9.7.2 
Endpoints ................................................................................................................... 42 
9.7.3 
Safety Assessments .................................................................................................... 43 
10 
DATA HANDLING ........................................................................................................................... 46 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
10.1 
Source Data and Records ........................................................................................................ 46 
10.2 
Electronic Case Report Form .................................................................................................. 46 
10.3 
Data Management ................................................................................................................... 47 
10.4 
Provision of Additional Information ....................................................................................... 47 
11 
MONITORING PROCEDURES ..................................................................................................... 48 
11.1 
Periodic Monitoring ................................................................................................................ 48 
11.2 
Audit and Inspection ............................................................................................................... 48 
11.3 
Confidentiality of Subject Data ............................................................................................... 48 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................ 49 
12.1 
Protocol Amendments ............................................................................................................. 49 
12.2 
Deviations from the Protocol .................................................................................................. 49 
12.3 
Premature Trial Termination ................................................................................................... 49 
13 
REPORTING AND PUBLICATION .............................................................................................. 50 
13.1 
Clinical Trial Report ............................................................................................................... 50 
13.2 
Confidentiality and Ownership of Trial Data .......................................................................... 50 
13.3 
Publication and Public Disclosure .......................................................................................... 50 
13.3.1 Publication Policy ...................................................................................................... 50 
13.3.2 Public Disclosure Policy ............................................................................................ 50 
14 
ETHICAL AND REGULATORY ASPECTS ................................................................................. 51 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .......................... 51 
14.2 
Regulatory Authority Authorisation / Approval / Notification ............................................... 51 
14.3 
End-of-Trial Notification ........................................................................................................ 51 
14.4 
Ethical Conduct of the Trial .................................................................................................... 51 
14.5 
Subject Information and Consent ............................................................................................ 51 
14.6 
Subject Participation Card ...................................................................................................... 51 
14.7 
Compliance Reference Documents ......................................................................................... 52 
15 
LIABILITIES AND INSURANCE .................................................................................................. 53 
15.1 
ICH-GCP Responsibilities ...................................................................................................... 53 
15.2 
Liabilities and Insurance ......................................................................................................... 53 
16 
ARCHIVING ...................................................................................................................................... 54 
16.1 
Investigator File ...................................................................................................................... 54 
16.2 
Trial Master File...................................................................................................................... 54 
17 
REFERENCES ................................................................................................................................... 55 
 
LIST OF TABLES INCLUDED IN THE TEXT 
Table 1 
Trial flow chart ............................................................................................................................ 28 
Table 2 
Safety laboratory parameters ....................................................................................................... 30 
 
LIST OF FIGURES INCLUDED IN THE TEXT 
Figure 1 
Overall trial design: sequence and timing of trial events for each subject .................................. 17 
 


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
AMH 
anti-Müllerian hormone 
ANOVA 
analysis of variance 
ART 
assisted reproductive technology(ies) 
ATC 
anatomical therapeutic chemical classification system 
βhCG 
beta unit of human chorionic gonadotropin 
BMI 
body mass index 
CFDA 
China Food and Drug Administration 
CHO 
Chinese hamster ovary 
COC 
combined oral contraceptive 
COS 
controlled ovarian stimulation 
CRO 
clinical research organisation 
CV 
coefficient of variation 
ECG 
electrocardiogram 
e-CRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration, USA 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
gonadotropin-releasing hormone 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICSI 
intracytoplasmic sperm injection 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IVF 
in vitro fertilisation 
LLQ 
lower limit of quantification 
MCH 
mean corpuscular haemoglobin content 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean cellular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
non-compartmental analysis 
NIMP 
non-investigational medicinal product 
OHSS 
ovarian hyperstimulation syndrome 
OTC 
over-the-counter 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
rhFSH 
recombinant human follicle stimulating hormone 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
WHO 
World Health Organization 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
DEFINITION OF TERMS 
Definition of general terms  
Enrolled 
When subject and investigator have signed the Informed Consent Form 
Included 
When the subject has been dosed with investigational medicinal product 
(IMP) 
Pre-dose 
Before dosing on the day of IMP dosing 
Treatment period 
Time from administration of the IMP until discharge from the clinic at 
Visit 12  
End-of-trial 
The last visit (Visit 14) for the last subject 
 
Pharmacokinetic terms and definitions 
AUC 
Area under the concentration-time curve from dosing to infinity  
AUCt 
Area under the concentration-time curve from dosing up to time t, where t is 
the last time point at which the concentration is above the lower limit of 
quantification.  
% Extrap AUC 
Percentage of AUC that is due to extrapolation from the last measurable 
concentration 
CL/F 
Apparent total systemic clearance 
Cmax 
Maximum concentration observed  
z 
First-order rate constant associated with the terminal (log-linear) portion of the 
concentration-time curve 
NCA 
Non-compartmental analysis 
t½ 
Terminal elimination half-life 
tmax 
Time of maximum observed concentration (Cmax)  
Vz/F 
Apparent volume of distribution associated with the terminal phase 
 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
1 
INTRODUCTION 
1.1 
Background 
FE 999049 is a gonadotropin preparation containing recombinant human follicle-stimulating 
hormone (rhFSH) under development by Ferring Pharmaceuticals. It is intended for controlled 
ovarian stimulation for the development of multiple follicles in women undergoing assisted 
reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm 
injection (ICSI) cycle.  
FE 999049 is developed from a human cell line, in contrast to the commercially available rFSH 
products that are derived from Chinese hamster ovary (CHO) cell lines. In December 2016, Ferring 
received Marketing Authorisation approval from the European Commission for FE 999049 under 
the trade name REKOVELLE. During 2017, FE 999049 was approved in Australia, Brazil, Israel, 
and Switzerland, and in 2018, also in Mexico and Canada. 
Before the current trial, Ferring has completed four phase 1 trials (CS01, CS02, CS03 and 000020, 
all conducted in US), two phase 2 dose-response trials (000009 conducted in EU and 000124 
conducted in Japan) and two phase 3 trials (000004 and 000071 conducted in Europe and Rest of 
World) as part of the clinical development programme for FE 999049. A total of 1,927 subjects 
have been included in the completed clinical trials, of whom 1,112 subjects were exposed to 
FE 999049. Momentarily, two phase 3 trials are ongoing (a Pan-Asian trial conducted in China, 
Taiwan, South Korea, and Vietnam and one conducted in Japan) including approximately 1,328 
subjects in total of whom approximately 664 subjects will be randomised to treatment with 
FE 999049.   
Of the four previous phase 1 trials, CS01, CS03, and 000020 were single dose trials conducted in 
healthy female subjects.1,2,3 These trials showed that FE 999049 is absorbed slowly after single 
subcutaneous administration, with the median tmax ranging from 10 to 24 hours. Mean absolute 
bioavailability of FE 999049 given subcutaneously was determined to be 64%.3 Single 
subcutaneous administration of increasing doses to healthy female subjects indicated dose 
proportionality of Cmax and AUC over a wide dose range of 8.8 to 26.3 μg (based on conversion 
from IU to μg for the specific batch used).1 Thus, the data demonstrated that the exposure to 
FE 999049 increased proportionally with doses across the whole therapeutic dose range up to 24 μg 
FE 999049 (24 μg being the maximum dose in the phase 3 programme and in the proposed 
posology for repeated cycles). The fraction of FE 999049 excreted unchanged in urine was 
approximately 11%.3 Comparisons between Japanese and Caucasian women following 
administration of 450 IU FE 999049 demonstrated similar exposure by means of AUC and Cmax.2 
Also the PK parameters tmax, t½, CL/F, and Vz/F were similar for the Japanese and Caucasian 
women. Single dose administration of FE 999049 was safe and well tolerated as assessed by AEs, 
vital signs, ECG, clinical laboratory measurements, and physical examination. There were no signs 
of any anti-FSH antibody formation or allergic reactions. No serious adverse event or death 
occurred during the trials.  


Date: 20 Sep 2018 
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Page 14 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
One previous phase 1 trial, CS02, evaluated daily subcutaneous administration of 225 IU 
FE 999049 in healthy female subjects.4 This trial showed that a steady-state level of FSH was 
reached on treatment day 6-7 at which time the Cmax concentrations were 2.5- to 3-fold higher than 
those obtained after a single dose. The terminal half-life of FE 999049 was 28 hours after multiple 
subcutaneous administrations, which was shorter than the average of 40 hours after single 
subcutaneous administration. The time to maximal concentration was also shorter after multiple 
compared to single subcutaneous administration, with medians of 10 hours versus 24 hours, 
respectively.1,2,3,4 The reason for this is as yet unknown, but these differences have also been 
observed for other FSH preparations.5 
The two phase 2 trials 000009 and 000124 were randomised, controlled, assessor-blind, multi-
centre dose-response trials in which randomisation was stratified according to the subject’s anti-
Müllerian hormone (AMH) level at screening. In both trials, a statistically significant dose-response 
relationship for FE 999049 with respect to the number of oocytes retrieved was observed. 
Furthermore, the dose-response relationship observed in Japanese and European subjects was 
similar. The similarity of the dose-response relationship between Japanese and European subjects 
supported the pharmacological rationale of the individualised treatment regimen.6,7 
During the two phase 3 trials 000004 and 000071, 665 IVF/ICSI subjects were treated with 
FE 999049 in 1,012 treatment cycles. The two trials supported the efficacy and safety of FE 999049 
in the proposed indication with the individualised FE 999049 dosing regimen based on AMH level 
(measured by Elecsys® AMH Immunoassay, Roche Diagnostics) and body weight.8,9  
The ongoing phase 3 trial in Pan Asia is a randomised, controlled, assessor-blind, parallel groups, 
multicentre, non-inferiority trial comparing the efficacy and safety of FE 999049 and GONAL-F.  
The ongoing phase 3 trial in Japan is a randomised, controlled, assessor-blind, parallel groups, 
multicentre, non-inferiority trial assessing the efficacy and safety of FE 999049 versus 
FOLLISTIM.  
1.2 
Scientific Justification for Conducting the Trial 
This is a trial with the overall objective to obtain data on the pharmacokinetics of FE 999049 in 
healthy Chinese women. The trial will support the registration of FE 999049 in China. 
1.3 
Benefit / Risk Aspects 
This is a phase 1 trial in healthy subjects and does not entail any medical benefit for the trial 
participants. 


Date: 20 Sep 2018 
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Page 15 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
FE 999049 is a recombinant human FSH, and it is expected that the pharmacological effects and 
side effects of FE 999049 resemble those reported for other FSH products. The most frequently 
reported AEs in a previous single dose trial with FE 999049 in Caucasian women at doses ranging 
from 37.5 IU to 450 IU were headache and injection site reactions, the latter of short duration and 
possibly related to the volume administered.1 In another previous single dose trial with FE 999049 
in Japanese and Caucasian women at doses ranging from 75 IU to 450 IU, the most frequently 
reported AEs were lower abdominal pain, vaginal haemorrhage and injection site reactions.2 In both 
trials a limited number of other AEs were sporadically reported in all treatment groups, including 
the placebo groups, and FE 999049 was regarded well tolerated. In the third previous single dose 
trial with FE 999049 in Caucasian women receiving 450 IU, the most frequently reported AEs were 
headache, breast tenderness and pelvic discomfort.3 Common side effects reported for other FSH 
products are ovarian enlargement, breast complaints, abdominal pain, pelvic pain, headache, 
gastrointestinal symptoms, injection site reactions (swelling, pain, redness), hypersensitivity 
reactions, and ovarian cysts. Cases of ovarian hyperstimulation syndrome (OHSS), characterised by 
large ovarian cysts, abdominal pain, abdominal distension, vascular leakage, and rarely associated 
with thromboembolic events, have occurred in multiple dose trials with other FSH products, but no 
signs of OHSS were observed in the previous phase 1 trials.1,2,3,4  
Adverse drug reactions following treatment with GnRH agonists such as DECAPEPTYL Depot 
include, but are not restricted to, hot flushes, decreased libido, mood changes, headache, abdominal 
pain and menstrual disorders that may be related to the induced transient oestrogen deficiency. 
Functional follicular cysts may occur upon treatment with GnRH agonists, the incidence being up 
to 9.3 %.10 In this trial, the subjects will undergo an ultrasound examination prior to the 
administration of the investigational medicinal product (IMP), and those who have developed cysts 
will be withdrawn from the trial. Without gonadotropin stimulation, these cysts have virtually no 
clinical significance in a healthy woman.  
Overall, the risks posed to the subjects participating in the trial are deemed low and ethically 
justifiable. For more detailed information on FE 999049 please refer to the Investigator’s 
Brochure.11 


Date: 20 Sep 2018 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objectives of the trial are to: 
• 
Investigate the single-dose pharmacokinetics of FE 999049 administered as a subcutaneous 
abdominal injection in healthy Chinese women 
• 
Investigate the safety and tolerability of a single dose of FE 999049 administered as a 
subcutaneous abdominal injection in healthy Chinese women 
2.2 
Endpoints 
• 
Pharmacokinetics (AUC, AUCt, Cmax, tmax, CL/F, Vz/F, t½) 
• 
Safety (ECG, vital signs, laboratory parameters, adverse events)  
• 
Injection site reactions 
• 
Presence of anti-FSH antibodies 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
 
 
 
Figure 1 
Overall trial design: sequence and timing of trial events for each subject 
 
3.1.2 
Overall Design and Control Methods 
This is an open-label, randomised parallel group trial investigating the pharmacokinetics of a single 
subcutaneous abdominal injection of FE 999049. There will be 3 dose panels with 8 healthy 
Chinese women in each dose panel. 
After testing negative in pregnancy tests, the subjects will receive two subcutaneous 
administrations of a 1-month depot formulation of the GnRH agonist DECAPEPTYL Depot 
3.75 mg to down-regulate endogenous release of FSH during the trial. The first DECAPEPTYL 
Depot administration will be given 28±1 days prior to the first dose of IMP. In women not 
receiving hormonal contraceptives, the first DECAPEPTYL Depot administration should take place 
in the time interval 7 days before to 3 days after the expected start of menstruation. In women 
discontinuing combined oral contraceptives, the first DECAPEPTYL Depot administration should 
take place after the subjects have discontinued the hormonal contraception and within 5 days of 
commencement of bleeding. A second administration will be given 10±1 days prior to the first IMP 
administration. 
To verify low stable endogenous hormones, serum FSH will be measured at Day -3 and Day -1. If 
any of the measurements is >5 mIU/mL, the subject will be excluded. 
The doses to be administered are 12, 18, and 24 µg at a concentration of 33.3 µg/mL. 
Screening
visit
Day -63
Day -29
Day -28
Day 1
Run-in period 
Treatment period 
Day 10
Follow-up
visit
Subcutaneous injection 
of IMP
Day 11
Administration of DECAPEPTYL Depot 
on Day -28 1 and Day -10 1
Day -10
Antibody 
assessment
Day 28


Date: 20 Sep 2018 
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Page 18 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
For each subject the treatment period is 10 days, and the total duration of the trial from screening to 
the last follow-up visit after treatment will not exceed 13 weeks. 
3.1.3 
Trial Schedule 
The first subject is expected to be enrolled in 2019 with a total duration of the trial of 
approximately 7 months. The end of the trial is defined as the last visit (Visit 14, Day 28) for the 
last subject. 
3.2 
Planned Number of Trial Sites and Subjects 
The trial will be conducted at a single site, including 24 healthy women receiving active treatment. 
3.3 
Interim Analysis 
No interim analysis is planned.  
3.4 
Data Monitoring Committee 
No Data Monitoring Committee will be established for this trial. During the trial, the internal Safety 
Management Team at the sponsor will evaluate safety data on a regular basis.  
3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
Premenopausal women are chosen as trial population to mimic the target patient population. These 
women have endogenous biosynthesis and release of gonadotropin hormones. In order to minimise 
the interference of the endogenous FSH with the PK assessment of FE 999049, the GnRH agonist 
DECAPEPTYL Depot will be administered throughout the trial.  
Subcutaneous injection has been selected as the route of administration for the trial since this is the 
intended route of administration in the clinical setting. The duration of the treatment period is 
governed by the expected half-life of FE 999049, which after a single subcutaneous administration 
is reported to be 40-44 hours.1 Thus, more than five half-lives, which is generally considered to be 
sufficient for a drug to be regarded as eliminated, are likely to have elapsed at the follow-up visit. 
3.5.2 
Selection of Endpoints 
The selected endpoints focus on evaluating the PK, safety, and tolerability of FE 999049 in Chinese 
women. 
3.5.3 
Blinding 
This is an open-label trial. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
3.5.4 
Selection of Doses in the Trial 
The selection of doses is governed by the anticipated doses that may be considered in the clinical 
setting. The trial will include 3 dose groups of 12, 18, and 24 µg FE 999049. The doses will enable 
the single dose PK determination of FE 999049 at each dose level and investigate dose 
proportionality in Chinese women. The lowest dose of 12 µg FE 999049 will be the daily 
administered dose in any phase 3 trial for IVF patients with an AMH level < 15 pmol/L. The 18 and 
24 µg FE 999049 are the doses applied in a phase 3 safety trial in patients that require a higher 
FE 999049 dose in their second or third treatment cycle. The 24 µg dose will be the highest dose of 
FE 999049 applied for controlled ovarian stimulation (COS) prior to ART. 
3.5.5 
Selection and Timing of Dose for Each Subject 
All subjects will be dosed in the morning not less than 2 hours subsequent to a light standardised 
breakfast. This is assumed to minimise the possible analysis interference and variance caused by 
the intake of food just prior to sampling. 
3.5.6 
Withdrawal Criteria 
In order to ensure down-regulation and minimise any interference from endogenous FSH, any 
subject that does not have a FSH concentration ≤5 IU/L on Day -3 and Day -1 will be withdrawn 
from the trial before randomisation. The Day -3 assessment may be repeated up to 5 days later if 
the first FSH measurement is >5 IU/L (subsequent visits will be postponed accordingly). The 
second assessment and the Day -1 assessment must be within acceptable ranges. No other specific 
withdrawal criteria are defined. 
Since this trial comprises a single subcutaneous injection, no specific withdrawal criteria are 
defined that will arrest the treatment. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
4 
SELECTION OF TRIAL POPULATION  
4.1 
Trial Population 
Healthy Chinese women, 21-40 years of age and with a body mass index (BMI) of 18.5-25 kg/m2, 
with a normal menstrual cycle, may be included in this trial.  
4.1.1 
Inclusion Criteria 
All of the following inclusion criteria must be met before the subject can enter into the trial: 
1. Signed written Informed Consent Form 
2. Female of Chinese origin, with two ethnic Chinese parents and four ethnic Chinese 
grandparents 
3. 21–40 years of age (both inclusive) 
4. Willing to stop using combined oral contraceptives (COC) in relation to the first 
DECAPEPTYL Depot administration on Day -28 
5. Agrees to use a double barrier method of contraception between Day -63 and Day 28, if not 
abstinent. A double barrier method of contraception should also be used after Day 28 until 
menses resumes or until another contraceptive method has been established 
6. Normal menstrual cycles with a range of 24-35 days in the absence of oral contraceptives 
7. Serum follicle-stimulating hormone (FSH) 5 IU/L on Day -3 and Day -1 
8. Body mass index (BMI) of 18.5 -25 kg/m2 (both inclusive)  
9. Negative serology for human immunodeficiency virus (HIV) antibody, hepatitis B (surface 
antigen), hepatitis C antibody, and syphilis bacteria 
10. Healthy according to medical history, physical examination, gynaecological examination, 
electrocardiogram (ECG), blood pressure, and laboratory profile of blood and urine 
11. Negative urine drug screen and alcohol breath test at screening and on Day -1 
12. Non-smoker or light smoker (≤5 cigarettes/day) for at least 6 months prior to trial start 
4.1.2 
Exclusion Criteria 
Any subject meeting one or more of the following exclusion criteria cannot be included in the trial 
and will be withdrawn if occurring during the trial: 
1. Presence or a history of clinically significant diseases of the renal, hepatic, gastrointestinal, 
cardiovascular, or musculoskeletal systems, or presence or history of clinically significant 
reproductive, psychiatric, immunological, endocrine or metabolic diseases 
2. Cancer within the last 5 years except for adequately managed basal cell carcinoma and 
squamous cell carcinoma of the skin 
3. Pregnancy or breastfeeding 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
4. Current or a history of endocrine abnormalities such as hyperprolactinaemia, polycystic 
ovary syndrome or other ovarian dysfunction, tumours of the pituitary gland or 
hypothalamus, thyroid or adrenal disease 
5. Clinically significant findings on the trans-vaginal ultrasound, cytology, gynaecological or 
breast examination at screening or on Day –1 including ovarian cysts or tumours of the 
ovaries or uterus 
6. Contraindications for the use of gonadotropins and gonadotropin-releasing hormone 
(GnRH) agonists 
7. Previously treated with gonadotropins within the last 6 months prior to screening 
8. History within the last two years or current abuse of alcohol or drugs 
9. Presence or history of severe allergy or anaphylactic reactions 
10. Intake of prescribed medication, over-the-counter (OTC) medication, or herbal medicines, 
with the exceptions of COC, cromoglycate, and paracetamol according to the labelling, 
within 2 weeks or 5 half-lives of the drug, whichever is longer, prior to first dose of 
DECAPEPTYL Depot. Topical treatments of bacterial or fungal infection are allowed if 
stopped before first dose of IMP. 
11. Intake of any non-registered investigational drug within the last 12 weeks preceding 
screening, or longer if judged by the investigator to possibly influence the outcome of the 
current trial 
12. High daily consumption of caffeine-containing beverages (e.g. more than five cups of coffee 
or equivalent) with a risk of withdrawal symptoms arising during the trial that may 
confound the safety evaluation 
13. Blood donation or major blood loss (≥500 mL) within the last 8 weeks, or plasma donation 
with the last 4 weeks preceding the first day of IMP dosing 
14. Current non-smokers or light smoker with a history of long-term, heavy smoking 
(>10 pack-years) 
15. Previously dosed in this trial 
16. Mental incapacity or language barrier precluding adequate understanding or co-operation 
17. Considered by the investigator to be unsuitable to participate in the trial for any other reason 
4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
The subjects will be recruited from the healthy subject database of the clinical site conducting the 
trial, and by advertising.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
4.2.2 
Randomisation 
The subjects will be randomised into three dose groups (12, 18, and 24 µg) according to a 
computer-generated randomisation list provided by Global Biometrics, Ferring Pharmaceuticals. 
Randomisation will be carried out in the morning of the administration day. In case a withdrawn 
subject is replaced, she will receive the same dose as the subject she is replacing. 
4.3 
Restrictions 
4.3.1 
Prior and Concomitant Therapies 
No concomitant medication, including Chinese herbs, is allowed, except for treatment of AEs when 
necessary, cromoglycate, and paracetamol according to label. Combined oral contraceptives should 
be stopped prior to first dose of DECAPEPTYL Depot; this will be administered on Day -28 and 
within 5 days of commencement of bleeding, and may not be used during the trial. Topical 
treatment of bacterial or fungal infection is allowed if stopped before IMP administration. Any 
concomitant medication will be recorded in the electronic case report form (e-CRF), together with 
the main reason for its prescription. Also the dose and dosage regimen will be documented in the 
e-CRF. 
4.3.2 
Other Restrictions 
Subjects should abstain from drinking alcoholic beverages for 72 hours before the screening and all 
subsequent visits to the clinical investigation unit. In addition, subjects should abstain from 
drinking coffee and alcoholic beverages during the residential session in the treatment period. 
Intake of products containing poppy seeds (e.g. poppy cake) should be avoided for a period of at 
least 48 hours before screening and admission to the clinic in order to avoid analytical interference 
with the drug screen for opiates. 
The subjects should abstain from strenuous physical activity that is not within the subject’s normal 
weekly routine for 48 hours prior to screening, and from 48 hours prior to admission until the last 
safety examination. 
4.3.3 
Subsequent Therapy 
Since the trial population comprises healthy subjects only, no subsequent therapy is planned.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
4.4 
Withdrawal Criteria 
Since this is a single injection trial no specific withdrawal criteria are defined. The subject will be 
withdrawn from the trial if any of the inclusion or exclusion criteria during the conduct of the trial 
is violated in a way that invalidate subsequent assessments. The sponsor, and the investigator in 
agreement with the sponsor, reserves the right to discontinue the trial at any time for safety reasons 
or other reasons jeopardising the justification of the trial. Such a termination will be implemented in 
a time frame that is compatible with the subject’s well-being. If the trial is prematurely terminated 
or suspended, the investigator should promptly inform the subjects and assure appropriate follow-
up and treatment if required. Ferring Pharmaceuticals will notify the regulatory authorities of any 
plans to terminate the trial, and the investigator will notify the independent ethics committee 
(IEC)/institutional review board (IRB). 
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. 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.  
4.5 
Subject Replacement 
Subjects that are withdrawn may be replaced to reach 8 completed subjects at each dose level. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
5 
TREATMENTS  
5.1 
Treatments Administered 
Investigational Medicinal Product 
The subjects will receive a single subcutaneous abdominal injection of FE 999049 (follitropin 
delta). The doses administered will be 12, 18, and 24 µg according to randomisation.  
Non-investigational Medicinal Product 
The subjects will receive two subcutaneous abdominal injections of a 1-month depot formulation of 
the GnRH agonist DECAPEPTYL Depot 3.75 mg (Triptorelin). 
5.2 
Medicinal Products 
5.2.1 
Characteristics and Source of Supply 
Ferring Pharmaceuticals will provide the clinical site conducting the trial with FE 999049 and 
DECAPEPTYL Depot 3.75 mg in amounts sufficient for the trial. FE 999049 will be provided as 
cartridges with an isotonic phosphate buffered solution of pH 6.5 containing 33.3 µg/mL rhFSH 
(72 µg in 2.16 mL) and an injection pen. DECAPEPTYL Depot 3.75 mg will be provided as 
powder and solvent for suspension for injection. 
5.2.2 
Packaging and Labelling 
Packaging and labelling of the IMP and non-investigational medicinal product (NIMP) will be 
carried out under the responsibility of the Clinical Trial Supply (CTS) Department, Ferring 
Pharmaceuticals, Copenhagen, Denmark. The IMP and NIMP will be packed and labelled 
according to Good Manufacturing Practice (GMP), as well as any national regulatory requirements. 
All medicinal products will be labelled with trial specific labels, which contain a self- adhesive tear 
off portion to be affixed to the subject dispensing log maintained at trial site. 
5.2.3 
Conditions for Storage and Use 
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 to Ferring as instructed in the IMP/NIMP manual.   
In case of technical malfunction of an administration pen, all relevant details (including time, date, 
a description of the malfunction and whether dosing was affected) of the incidence should be 
reported in the e-CRF, the pen should be replaced and the treatment continued. Human errors such 
as misunderstanding of instructions or incorrect handling of the device should not be regarded as 
technical malfunctions. In case of adverse events caused by malfunction of the administration pen, 
these will be identified and described. 
5.3 
Blinding/Unblinding 
This is an open-label trial. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
5.4 
Treatment Compliance, Dispensing and Accountability 
The IMP will only be dispensed to subjects who meet the eligibility criteria and are randomised to a 
treatment group in the trial.  
The investigator (or his/her designated staff, e.g. trial nurse) will maintain a drug-dispensing log 
detailing the dates and quantities of IMPs/NIMPs dispensed to, and used by, each subject, as well 
as the batch numbers, IMP/NIMP numbers (or other identifier used in the trial).  
The monitor will verify the drug accountability during the trial and if applicable document any 
discrepancies. 
The IMP and NIMP will be administered by authorised staff at the clinical investigation unit. 
Compliance is assessed by recording the amount administered. 
5.5 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
All dispensed IMP and NIMP is to be destroyed at the trial site in accordance with local legislation 
after the drug accountability has been finalised and verified by the monitor.  
Any non-dispensed IMP and NIMP must be returned for destruction, as instructed by the Ferring 
CTS Department, after the drug accountability has been finalised and verified by the monitor. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
6 
TRIAL PROCEDURES  
The trial comprises 14 visits, 1 of which is the residential treatment visit. The duration of the trial 
including the screening period and the follow-up visits will not exceed 13 weeks. 
Assessments of AEs and concomitant medication will be performed throughout the trial. 
Visit 1 (Screening, Day -63 to Day -29) 
At the screening visit each subject will be informed about the trial and after signing the Informed 
Consent Form, assessments for eligibility will commence. The eligibility evaluation includes 
adherence to inclusion and exclusion criteria, collection of demographic data and medical history, 
physical examination, gynaecological examination with PAP smear (unless done within 6 months 
prior to screening) and transvaginal ultrasound, urine drug screen and alcohol breath test, 
assessment of vital signs, 12-lead ECG, blood sampling for clinical chemistry, haematology, 
serology, and pregnancy test, and urine sampling for urinalysis. 
Visit 2 (Run-in Period, Day -28) 
All subjects found eligible at the screening will be asked to return for the run-in period Visit 2. On 
Day -28±1, the subject will do a urinary pregnancy test, and if negative, receive an administration 
of DECAPEPTYL Depot 3.75 mg. In women not receiving hormonal contraceptives the first 
DECAPEPTYL Depot administration should take place in the time interval 7 days before to 3 days 
after the expected start of menstruation. In women discontinuing combined oral contraceptives, the 
first DECAPEPTYL Depot administration should take place after the subjects have discontinued 
the hormonal contraception and within 5 days of commencement of bleeding. 
Visit 3 (Run-in Period, Day -10) 
A urinary pregnancy test will be repeated on Day -10±1, and if negative, the subject will receive a 
second administration of DECAPEPTYL Depot 3.75 mg. 
Visit 4 (Run-in Period, Day -3) 
On Day -3 a blood sample will be collected for analysis and eligibility check of the FSH 
concentration. The Day -3 assessment may be repeated up to 5 days later if the first FSH 
measurement is >5 IU/L (subsequent visits will be postponed accordingly). A gynaecological 
examination and transvaginal ultrasound may be performed. 
Visit 5 (Run-in Period and Treatment, Day -1 to Day 3) 
All subjects still found eligible after the FSH analysis will be asked to return for a treatment visit 
(residential stay). At the arrival to the clinic on the day before the administration day (Day -1 in the 
run-in period), blood sampling for analysis and eligibility check of the FSH concentration, clinical 
chemistry, haematology, and pregnancy test, and urine sampling for urinalysis will be performed. A 
limited general eligibility check (inclusion/exclusion criteria), urine drug screen, alcohol breath test, 
vital signs, and 12-lead ECG will also be performed. A gynaecological examination and 
transvaginal ultrasound will be performed if not done on Days -3 or -2.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
The next day (Day 1), a blood sample for assessment of the presence of anti-FSH antibodies will be 
collected prior to administration of FE 999049. The subject will then be randomised to and receive 
an abdominal subcutaneous injection of either 12, 18, or 24 µg FE 999049. Safety assessments will 
be performed, injection site reactions assessed, and blood samples for PK analysis collected at 
predetermined time-points (Table 1). On Day 3, subsequent to the 48-hour PK sampling, the blood 
sampling for assessment of clinical chemistry, haematology, urine sampling for urinalysis, and 
assessment of vital signs and ECG, the subjects will be discharged from the clinic. 
Visits 6 - 12 (Assessment, Day 4 to Day 10) 
The subjects will visit the clinic each day in the morning or, if agreed between investigator and 
subject, have a residential stay from Day 4 to Day 10 for assessment of serum concentration of 
FE 999049. Additionally, at Visit 9 (Day 7) a blood sample for assessment of the presence of anti-
FSH antibodies will be collected. 
Visit 13 (Follow-up, Day 11) 
A follow-up visit will be scheduled on Day 11, the day after the last assessment day. Blood samples 
for analysis of clinical chemistry and haematology and for a pregnancy test will be collected as well 
as urine samples for urinalysis. Physical examination, 12-lead ECG and vital signs will be assessed. 
A gynaecological examination with PAP smear and transvaginal ultrasound will also be performed. 
Depending on the results of the follow-up assessments, additional visits may be requested at the 
discretion of the investigator. Subjects should be advised to continue to use a double barrier method 
of contraception until menses resumes or until another contraceptive method has been established. 
Visit 14 (Anti-FSH Antibody Assessment, Day 28) 
A visit for the collection of a blood sample for assessment of the presence of anti-FSH antibodies 
will be scheduled on Day 28.  
The end of trial is defined as the last visit by the last subject. After this visit the subjects will be 
contacted once a month until return of normal menstruation. 
Subjects with a treatment-induced anti-FSH antibody response on Day 28 (both with and without 
neutralising capacity) will be asked to return after 1, 2, 3, 6, 9, and 12 months until two consecutive 
assessments indicate that the anti-FSH antibody level has become negative or has returned to the 
baseline level. 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
Table 1 
Trial flow chart 
 
Screening 
Run-in period 
Treatment and Assessments 
Follow
-up 
Anti-
FSH 
ab 
 
Ambulatory visits 
Residential stay 
Ambulatory visits 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day -63 to -29 -28 -10 
-3 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
28 
Inclusion/exclusion 
criteria 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gynaecological exam. 
and transvaginal 
ultrasound 
X 
 
 
Xa 
Xa 
 
 
 
 
 
 
 
 
 
 
X 
 
Cytology 
 Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum pregnancy test  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test 
 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH for eligibility 
determination (local 
laboratory) 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PK 
determination 
 
 
 
 
 
Xd 
Xd Xd X 
X 
X 
X 
X 
X 
X 
 
 
Urine drugs screen 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
 
 
X 
Xf 
Xf 
Xf 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
X 
Xf 
Xf 
Xf 
 
 
 
 
 
 
 
X 
 
Clinical chemistry, 
haematology, and 
urinalysis 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
Injection site reactions 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for anti-
FSH antibody analysis 
 
 
 
 
 
Xh 
 
 
 
 
 
X 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of 
DECAPEPTYL Depot 
3.75 mg 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of IMP  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ab: antibody; ECG: electrocardiogram; FSH: follicle-stimulating hormone; IMP: investigational medicinal product; PK: pharmacokinetic;  
a) Between Day -3 and Day -1 
b) Cytology will be performed at screening if not done within 6 months prior to screening 
c) Before the Day -28±1 and Day -10±1 DECAPEPTYL Depot administration 
d) –1, –0.5, 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 48 hours post-dose 
e) Vital signs include systemic blood pressures, heart rate and body temperature 
f) 12, 24 and 48 hours post-dose 
g) Immediately, and 30 min and 24 hours after administration 
h) Before administration of FE 999049 


Date: 20 Sep 2018 
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Supersedes: None 
Page 29 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
7 
TRIAL ASSESSMENTS 
A laboratory manual will cover all blood and urine tests and describe sampling and shipment 
procedures including contact details, storage conditions, equipment, volume, analytical method, 
reference range, etc. The manual will be provided to the clinical investigational unit before the start 
of the trial. The total blood volume collected for clinical laboratory assessments and PK 
measurements will be less than 200 ml. If deemed necessary for safety reasons extra samples may 
be collected. 
7.1 
Assessments Related to Endpoints 
7.1.1 
Pharmacokinetics 
Blood samples for measurement of serum concentration of FSH will be collected 1 and 0.5 hours 
prior to IMP administration, immediately before administration, and at 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, and 48 hours, and 3, 4, 5, 6, 7, 8, and 9 days after administration. The actual sampling time 
at the ambulatory visits will be recorded. The serum concentrations of FSH will be analysed under 
the responsibility of the Department of Bioanalysis at Ferring Pharmaceuticals. 
7.1.2 
Safety Assessments 
7.1.2.1 
Adverse Events 
See Section 8. 
7.1.2.2 
Vital Signs 
Vital signs comprising systolic and diastolic blood pressure, heart rate, and body temperature will 
be assessed at screening, on Day -1, and 12, 24, and 48 hours after administration of FE 999049, 
and at the follow-up visit. Systolic and diastolic blood pressure will be measured after the subject 
has been in supine position for at least 5 minutes. All recordings will be performed using validated 
standard equipment. Clinically significant abnormal findings will be reported as AEs. 
7.1.2.3 
Electrocardiography 
The 12-lead ECGs will be recorded at screening, Day -1, and 12, 24, and 48 hours after 
administration of FE 999049, and at the follow-up visit after the subjects have rested for at least 
5 min in supine position. The ECG will be recorded with a validated ECG device.  
ECG recordings will capture at least four QRS complexes, i.e. 3 evaluable RR intervals. The 
investigator or a designate will evaluate whether the ECG is normal or abnormal and whether it is 
clinically significant, if abnormal. Any occurrence of de- or re-polarisation disorders, arrhythmic 
disorders or other abnormalities will be assessed and any changes compared to the pre-medication 
record will be commented. ECGs may be repeated for quality reasons and the repeat used for 
analysis. Clinically significant abnormal findings will be reported as AEs. 


Date: 20 Sep 2018 
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Supersedes: None 
Page 30 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
7.1.2.4 
Laboratory Parameters 
Clinical chemistry, haematology, and urinalysis 
Blood and urine samples will be collected at screening, on Day -1, Day 3, and at the follow-up visit 
for safety laboratory evaluations of clinical chemistry, haematology, and urinalysis parameters 
according to Table 2. The clinical chemistry and haematology analyses will be performed at a local 
laboratory. 
Urinalysis will be performed locally from a sample of mid-stream urine by means of a dip-stick 
test. In case any result of the dipstick is abnormal, a new urine test will be performed. If the 
abnormal result is confirmed, further examination may be initiated at the discretion of the 
investigator. Clinically significant abnormal findings will be reported as AEs.  
Table 2 
Safety laboratory parameters 
Clinical Chemistry 
Haematology 
Urinalysis 
Alanine aminotransferase 
Haematocrit 
Protein 
Albumin 
Haemoglobin 
Glucose 
Alkaline phosphatase 
Mean cellular volume (MCV) 
Bilirubin 
Aspartate aminotransferase 
Mean corpuscular haemoglobin (MCH) 
pH 
Glucose 
Mean corpuscular haemoglobin concentration 
(MCHC) 
Nitrite 
Calcium 
Platelet count 
Ketone 
Chloride 
Red blood cell count 
Urobilinogen 
Cholesterol 
Reticulocytes 
Blood 
Creatinine 
White blood cell count with differential count  
Leukocytes 
C-reactive protein 
Neutrophils, eosinophils, basophils, 
lymphocytes 
Specific gravity 
Gamma-glutamyltransferase 
Monocytes, large unclassified cells  
 
Phosphate 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin 
 
 
Triglycerides 
 
 
Urea (blood urea nitrogen) 
 
 
 
7.1.3 
Other Assessments related to Endpoints 
7.1.3.1 
Injection Site Reactions 
Injection site reactions will be assessed by the investigator immediately after injection, 30 minutes, 
and 24 hours after administration of the IMP. The injection site reactions to be assessed are redness, 
pain, itching, swelling, and bruising, each to be assessed as none, mild, moderate, or severe. These 
injection site reactions will not be recorded as AEs. 


Date: 20 Sep 2018 
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Supersedes: None 
Page 31 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
7.1.3.2 
Presence of Anti-FSH Antibodies 
Blood for assessment of the presence of anti-FSH antibodies in the serum will be collected on 
Day 1 before administration of FE 999049, Day 7 and Day 28. The samples will be analysed under 
the responsibility of the Department of Bioanalysis at Ferring Pharmaceuticals. Confirmed positive 
samples will subsequently be analysed for neutralising activity by a validated cell-based 
neutralising antibody assay.  
7.2 
Other Assessments 
7.2.1 
FSH Determination Day -3 and Day -1 
FSH for determination of down-regulation will be analysed on Day -3 and Day -1 using a validated 
standard method at a local laboratory. 
7.2.2 
Serology/Virology 
Determination of hepatitis B surface-antigen, hepatitis C virus antibodies, HIV antibodies and 
syphilis bacteria are performed at screening for eligibility purposes. 
7.2.3 
Pregnancy Test 
Serum β-human chorionic gonadotropin (β-hCG) will be determined at screening, and Day -1, and 
at the follow-up visit using validated standard methods. Urine β-hCG will be determined on Day -
28±1 and Day -10±1, prior to administration of DECAPEPTYL Depot 3.75 mg. 
7.2.4 
Gynaecological Examination and Transvaginal Ultrasound 
Gynaecological examination and transvaginal ultrasound will be performed at screening, before 
dosing (in the period Day -3 to Day -1), and at the follow-up visit. Cytology will be performed at 
screening if not done within 6 months prior to screening, and at the follow-up visit. 
7.2.5 
Physical Examination 
A complete physical examination will be performed at screening and at the follow-up visit. 
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 the follow-up visit, potential changes from screening to the follow-up visit 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 the follow-up visit must be recorded as adverse events. 
 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 32 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
7.2.6 
Drug Screen and Alcohol Breath Test 
To ensure that drugs are not abused, a urine dip stick drug screen and an alcohol breath test will be 
performed locally at screening and on Day -1. The drug screening will be performed using fresh 
mid-stream urine for the determination of amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, ecstasy, nortriptyline, opiates, phenacyclidine, and methadone.  
7.3 
Handling of Biological Samples 
A detailed description of all sample collections and shipment procedures will be included in a 
separate laboratory manual. The sponsor or third parties will store the PK and immunogenicity 
blood samples for a period of up to 2 years after the trial is finalised. 
7.4 
Laboratory Analyses 
All laboratory measurements, except for PK, anti-FSH antibodies and those that are assessed 
bed-side, will be analysed at a local laboratory. The investigator will review the laboratory results 
and evaluate and document whether the results are clinically significant or non-significant.  


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 33 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
8 
ADVERSE EVENTS 
8.1 
Adverse Events 
8.1.1 
Definitions 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes: 
• 
Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• 
Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP. 
• 
Any laboratory abnormality, vital sign or finding from physical or gynaecological 
examination assessed as clinically significant by the investigator [note: pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or during 
the screening period are not adverse events, but are recorded as medical history]. 
• 
Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures. 
• 
Overdoses and medication errors with and without clinical consequences. 
Pre-treatment Adverse Event 
A pre-treatment adverse event is any untoward medical occurrence arising or observed between 
informed consent and administration of the IMP. 
Treatment Emergent Adverse Event 
A treatment emergent adverse event is any adverse event occurring after the administration of the 
IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after start of IMP and within the time of residual drug 
effect.  
The time of residual drug effect is the estimated period of time after the administration of the IMP, 
where the effect of the product is still considered to be present based on pharmacokinetic, 
pharmacodynamic, or other IMP characteristics. The residual drug effect is generally accepted to be 
5 times the terminal half-life. The terminal half-life of FE 999049 after a single administration is 
expected to be approximately 40-44 hours.1 Thus, the time from the administration on Day 1 to 
Visit 13 on Day 11 is likely to cover more than 5 half-lives. All AEs occurring during the treatment 
and follow-up phase (i.e. including Day 11) are regarded as treatment emergent. 
Post-treatment Adverse Events 
A post-treatment adverse event is any adverse event occurring after the time of residual drug effect 
of the IMP, i.e. after the visit on Day 11 and until the anti-FSH antibody assessment on Day 28.  


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 34 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
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 or end of follow-up period as applicable. 
The sources of adverse events cover: 
• 
The subject’s response to questions about his/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 -eCRF with information about: 
• 
Adverse event 
• 
Date and time of onset (time can be omitted, if applicable) 
• 
Intensity 
• 
Causal relationship to the IMP 
• 
Action taken to IMP 
• 
Other action taken  
• 
Date and time of outcome (time can be omitted, if applicable) 
• 
Outcome 
• 
Seriousness 
Each of the items on the Adverse Event Log are 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 will be entered per record.  


Date: 20 Sep 2018 
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Supersedes: None 
Page 35 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
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. However, 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. 
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 and time of onset is the date and time 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 and time is the date and time the sample was taken or the examination 
was performed.  
Intensity 
The intensity of an adverse event must be classified using the following 3-point rating 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 the IMP 
The possibility of whether the IMP caused the AE 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 AE. The 
AE may occur as part of the pharmacological action of the IMP or may be unpredictable in its 
occurrence. 
Examples:  
• 
AEs that are uncommon but are known to be strongly associated with IMP exposure 
• 
AEs that are not commonly associated with IMP exposure, but the event occurs in 
association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge with the IMP 


Date: 20 Sep 2018 
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Supersedes: None 
Page 36 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and 
the AE. 
Examples: 
• 
Known consequences of the underlying disease or condition under investigation 
• 
AEs common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure 
Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:  
• 
No change (medication schedule maintained or no action taken) 
• 
Withdrawn 
• 
Interrupted 
• 
Dose reduced 
• 
Dose increased 
Other Action Taken  
AEs 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 recovers or dies. 
Outcome 
The outcome of an adverse event must be classified as one of the following: 
• 
Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• 
Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• 
Recovering (the event is improving) 
• 
Not recovered 
• 
Fatal 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 37 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
8.3 
Adverse Events of Special Interest 
Not applicable. 
8.4 
Pregnancy and Pregnancy Outcome 
If a pregnancy does occur, the subject will be withdrawn from the trial and Global 
Pharmacovigilance at Ferring Pharmaceuticals informed, using an SAE Report Form. Note, that 
pregnancy itself is not an SAE. The mother and the foetus will be followed up at least until the birth 
of the infant and one month after the birth of the infant. In general, the follow-up will include the 
course, duration and the outcome of the pregnancy and the health of the infant. If a pregnancy 
results in an abnormal outcome (birth defect/congenital anomaly) this must be reported as an SAE 
to Global Pharmacovigilance at Ferring Pharmaceuticals. 
 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 38 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
8.5 
Serious Adverse Events 
8.5.1 
Serious Adverse Event Definitions 
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 AE in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an 
event, which may have caused death if it were more severe. 
requires 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 an SAE. Hospital admissions and/or 
surgical operations planned before trial inclusion are not considered 
adverse events, if the illness or disease existed before the subject was 
enrolled in the trial, provided that the condition did not deteriorate 
during the trial. 
results in persistent or significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s 
ability to conduct normal life functions. In doubt, the decision should 
be left to medical judgement by the investigator. 
is 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 
Medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as 
important medical events that might not be immediately life-
threatening or result in death or hospitalisation but might jeopardise 
the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse. 
 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 39 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs 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 an SAE. The investigator is responsible for submitting the completed SAE Report 
Form with the fullest possible details within 3 calendar days of his/her knowledge of the SAE. 
 
SAE Report Form 
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Global Pharmacovigilance using the contact details below. 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
E-mail: 
 
Fax: 
 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Global Pharmacovigilance to access the information. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the 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 IEC/IRB with any additional requested information 
such as results of post-mortem examinations and hospital records. 
Expedited Reporting by Ferring 
Ferring will report all AEs that are serious, unexpected and with a reasonable possible causality 
to the IMP as judged by either the investigator or Ferring to the relevant parties within the 
stipulated timelines. The expectedness is assessed by Ferring Pharmaceuticals according to the 
Investigator’s Brochure for FE 99904911 and the label for DECAPEPTYL.12  
SAEs 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. 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 40 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
8.6 
Follow-up of Adverse Events and Serious Adverse Events 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable. 
After the subject’s last visit, the investigator must follow-up on any AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the 
medical condition of the subject is stable. All such relevant follow-up information must be reported 
to Ferring. If the event is a chronic condition, the investigator and Ferring may agree that further 
follow-up is not required. 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Trial Visit 
If an investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the 
SAE to have a reasonable possible causality to the IMP, the case will have to be reported to Ferring, 
regardless how long after the end of the trial this takes place. 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 41 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
9 
STATISTICAL METHODS 
The final statistical analyses will be detailed in a statistical analysis plan (SAP) prepared under the 
responsibility of Global Biometrics, Ferring Pharmaceuticals. The pharmacokinetic parameters 
specified will be computed by the Department of Translational Medicine, Ferring Pharmaceuticals. 
Statistical analysis of PK at end of trial will be performed under the responsibility of Global 
Biometrics. 
9.1 
Determination of Sample Size 
No formal sample size calculation has been performed for this phase 1 trial. Eight subjects 
receiving active treatment in each dose panel is considered sufficient to provide adequate 
information about the pharmacokinetic parameters at each dose level for the purposes of this trial. 
9.2 
Subject Disposition 
All subjects screened and exposed will be accounted for. The number of subjects screened but not 
dosed will be stated in the trial report but otherwise not accounted for. All post-dosing 
discontinuations will be summarised by time of and reason for discontinuation. 
9.3 
Protocol Deviations 
Major protocol violations, such as significant non-compliance or other serious unforeseen 
violations deemed to invalidate the data collected for the purpose of the trial will lead to exclusion 
of the data from analysis. In case of minor protocol violations, data will not be excluded from the 
data analysis. The rating of protocol violations in ‘minor’ and ‘major’ will be decided on the basis 
of a review of the data before declaration of ‘clean file’ and lock of database. 
9.4 
Analysis Sets 
9.4.1 
Full Analysis Dataset 
The full analysis data set (FAS) comprises data from all dosed subjects. The FAS will be used for 
presentation of compliance and all baseline characteristics (demographics, medical history, prior 
and concomitant medication, and physical examination). 
9.4.2 
Per Protocol Dataset 
The per protocol (PP) data set comprises data from all dosed subjects except data excluded as a 
result of major protocol violations as defined in Section 9.3. The PP analysis set will be used for 
presentation of PK endpoints.  
9.4.3 
Safety Dataset 
The safety analysis dataset comprises data from all dosed subjects and will be used for safety 
analysis. 


Date: 20 Sep 2018 
E-Study Protocol-23085; Ver.1.0 
Supersedes: None 
Page 42 of 56 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
9.5 
Trial Population 
9.5.1 
Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented by dose 
group for the FAS.  
9.5.2 
Medical History, Concomitant Medication and Physical Examination 
Medical history and concomitant medication will be presented by descriptive statistics for the FAS 
by dose group. The results of the physical examination will be listed. 
9.6 
Treatment Compliance 
Treatment compliance in terms of the number of subjects that were dosed in each dose group and 
the individual dose received will be presented for the FAS. 
9.7 
Endpoint Assessments 
9.7.1 
General Considerations 
The statistical analyses will include descriptive statistics reflecting the explorative nature of the 
trial. In general, the data will be presented by dose group.  
Continuous data will be summarised by dose using number, mean, standard deviation, median, 
minimum, and maximum. Categorical data will be summarised by dose using the number and 
percentage of subjects in each category. 
9.7.2 
Endpoints 
9.7.2.1 
Pharmacokinetics 
The statistical analysis of PK will be performed by Department of Translational Medicine, Ferring 
Pharmaceuticals. The PK parameters will be calculated for non-corrected as well as baseline 
corrected data by non-compartmental analysis (NCA) using the software Phoenix WinNonlin® 
(Certara, US). The baseline value is the mean of the values obtained prior to the administration of 
the IMP. Actual sampling time points relative to dosing will be used for the NCA and on the 
individual plots of serum concentration versus time. Serum concentration values below lower limit 
of quantification (LLQ) and missing values (e.g. no blood sample collected or no value obtained at 
analysis) will be excluded from the NCA. Values below LLQ will be represented as LLQ/2 in the 
plots. 
PK parameters will be estimated based on measurements from Day 1 to Day 10. From the serum 
concentration-time data of FE 999049 the following parameters will be estimated, if possible: 
AUC, AUCt, % Extrap AUC, Cmax, tmax, z, t½, CL/F, and Vz/F.  
Selection of data points for calculation of t½ via z will be based on the following considerations: 
• The automatic range selection used in Phoenix WinNonlin® will be used to propose an 
optimal number of time points to use for the calculation of z. 


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CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
• The time range of samples used to estimate z should preferably exceed the derived terminal 
half-life t½ (= ln 2/z). 
• All the samples used to calculate z should ideally fall in the log-linear elimination phase.  
• At least three samples above LLQ obtained during the log-linear elimination phase will if 
possible be included in the calculation of the z. 
• The final selection of samples for calculation of z will be based on visual inspection of log-
concentration-time plots of individual profiles. 
AUC will be calculated by the linear trapezoidal method. PK parameters will be presented by dose 
with number of measurements, number of missing data, mean, standard deviation, median, 
minimum, maximum, geometric mean, and %CV (based on untransformed data) for geometric 
mean (for AUC and Cmax). For t½, the harmonic mean will be listed in addition to the geometric 
mean. For tmax the geometric mean and the %CV will be omitted. 
Dose proportionality will be investigated for each of AUC and Cmax using a multiplicative analysis 
of variance model with log(dose) as covariate. In this model, a covariate coefficient of 1 would 
indicate dose proportionality. 
9.7.3 
Safety Assessments 
9.7.3.1 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be presented by time for each 
parameter and summarised by treatment. Shift tables will be presented for changes from baseline 
(i.e. the last assessment prior to administration) to the follow-up visit, and will be summarised by 
dose group.  
9.7.3.2 
Clinical Chemistry, Haematology, and Urinalysis  
Clinical chemistry and haematology parameters will be presented as the vital signs parameters. 
Urinalysis parameters will be summarised by dose group and visit. 
9.7.3.3 
ECG 
ECGs will be categorised as “normal”, “abnormal, not clinically significant”, or “abnormal, 
clinically significant” (as judged by the investigator) and summarised by treatment.  
9.7.3.4 
Adverse Events 
AEs will be coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). All data will be listed by subject. Only treatment emergent AEs will be 
presented in summary tables. Separate data listing will be provided for AEs that are classified as 
pre-treatment or post-treatment AEs. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
9.7.3.4.1 Overview of Treatment Emergent Adverse Events 
A treatment emergent AEs summary table will be presented including for each treatment the 
number of subjects reporting an AE, the percentage of subjects with an AE, and the number of 
events reported, for the following categories:  
• All AEs 
• Severe adverse events  
• Serious AEs  
• Adverse drug reactions 
• AEs leading to withdrawal  
• Deaths 
Adverse drug reactions will be defined as events considered having a reasonable possible 
relationship to the IMP as judged by the investigator. 
9.7.3.4.2 Incidence of Treatment Emergent Adverse Events 
Summary tables will be prepared for the incidence of treatment emergent AEs by treatment and 
MedDRA system organ class (SOC) and preferred term, presenting number of subjects reporting an 
AE, the percentage of subjects (%) with an AE, and the number of events reported. Summary tables 
will be prepared for:  
• All treatment emergent AEs 
• AEs by causality 
• AEs by intensity 
• ADRs by intensity 
Missing values will be treated as missing except for causality, intensity, seriousness, and outcome 
of an AE, at which occurrence a “worst case” approach will be taken. Thus, if causality is missing 
the AE will be regarded as related to the IMP, if the intensity is missing the intensity of the AE will 
be regarded as severe, if seriousness is missing the AE will be regarded as an SAE, and if the 
outcome is missing and no date of outcome is present the outcome is regarded as “not yet 
recovered”. 
9.7.3.4.3 Serious Adverse Events, Deaths, and other Significant Adverse Events 
Separate listings will be provided for SAEs, deaths, and other significant adverse events, if any. 
9.7.3.5 
Injection Site Reactions 
Injection site reactions will be summarised by dose group with the number and percentage of 
subjects experiencing none, mild, moderate, or severe grade of redness, pain, itching, swelling, and 
bruising immediately after injection, 30 minutes after injection, 24 hours after injection, or at any of 
these time points.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
9.7.3.6 
Anti-FSH Antibodies 
The proportion of subjects with anti-FSH antibodies as well as the proportion of subjects with 
anti-FSH antibodies with neutralising capacity will be tabulated for each dose group in total and for 
each time point.  
9.7.3.7 
Physical Examination 
Physical examination at the screening and the follow-up visits will be listed by subject. 
9.7.3.8 
Gynaecological Examination, Cytology, and Transvaginal Ultrasound 
Results of gynaecological examination, cytology, and transvaginal ultrasound at the screening and 
the follow-up visit, including changes from baseline, will be listed by subject. Observations 
categorised as “abnormal” will be flagged. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
10 
DATA HANDLING 
10.1 
Source Data and Records 
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 
Any trial-specific source data and the primary source location of the same will be described in the 
source data agreement and in the monitoring manual produced for this trial. 
10.2 
Electronic Case Report Form 
An electronic CRF (e-CRF) system will be used for data collection. The system is fully validated 
and access at all levels to the system is granted/revoked following Ferring and vendor procedures, 
in accordance with regulatory requirements and system requirements. 
After the trial database is declared clean and is released to the statistician, a final copy of the 
database will be stored at Ferring. The investigator will also receive a copy of the site’s final and 
locked data, including audit trail, electronic signature, queries, and management reports, as write-
protected PDF-files. The PDF-files will be stored in an electronic format and will be provided to 
the investigator before access to the e-CRF is revoked. The investigator will approve/authorise the 
e-CRF entries for each subject with an electronic signature which equals a handwritten signature. 
The signer must log in with his or her username and password and then re-enter this password on 
the page(s) requiring a signature. Trial data will be entered into the system in a timely manner, i.e. 
within 2 working days. 
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. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
10.3 
Data Management 
All data management activities will be specified in a data management plan prepared under the 
responsibility of Global Biometrics, Ferring Pharmaceuticals. 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. A trial database will be created according to the data 
management standard operating procedures and data validation programmes will be developed to 
check for data completion and validity.  
Data entry will be performed in accordance with standard operating procedures. For medical coding 
of AEs, medical history and concomitant medication the most recent versions of MedDRA and 
WHO Drug will be used. When all data have been processed, queries resolved, medical coding 
completed and any issues from review of protocol violations and data listings resolved, the database 
will be locked and any further update will be denied. A final quality assurance audit of the locked 
database will take place prior to transfer of the final database structured according to Ferring’s data 
transfer specifications. 
10.4 
Provision of Additional Information 
On request, the investigator will provide Ferring with additional data relating to the trial, or copies 
of relevant source records, duly anonymised and protected in accordance with applicable 
requirements.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
Monitoring of the clinical trial will occur both by on-site visits as well as by central (i.e. remote or 
in-house) review of e-CRF forms and the data management reports.  
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. A monitoring visit will take place in connection with the first 
dosing day to ensure that subjects are correctly included and procedures are correctly understood. 
11.2 
Audit and Inspection 
The investigator will make all the trial-related source data and records available at any time to a 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from the IEC/IRB 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 GCP including the Declaration of Helsinki 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 IECs/IRBs 
may wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the screening 
number will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IEC/IRB. 
11.3 
Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
e-CRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Form, will be maintained by the investigator in strict confidence. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
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 IEC/IRB 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 IEC/IRB approval/favourable opinion. 
12.2 
Deviations from the Protocol 
If deviations from the protocol occur, the investigator must inform the monitor, and the 
implications of the deviation must be reviewed and discussed. Any deviation must be documented, 
either as answer to a query in the e-CRF, in a protocol deviation report or a combination of both. A 
log of protocol deviation reports will be maintained by Ferring. Protocol deviation reports and 
supporting documentation must be kept in the Investigator’s File and in the Trial Master File. 
12.3 
Premature Trial Termination 
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the 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 the IEC/IRB will be informed. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
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 investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring. 
13.3 
Publication 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 offered authorship and Ferring. 
Any external contract research organisation or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial. 
13.3.2 
Public Disclosure Policy 
It is the responsibility of Ferring to register the trial in an appropriate registry, i.e. at 
www.cde.org.cn, which is designated by the China Food and Drug Administration (CFDA). 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
An IEC/IRB will review the protocol and any amendments and advertisements used for 
recruitment. The IEC/IRB will review the Subject Information Sheet and the Informed Consent 
Form, their updates (if any), and any written materials given to the subjects. The IEC/IRB, to which 
the protocol has been submitted, and the name of the committee chairman will be denoted in the 
clinical trial report. 
14.2 
Regulatory Authority Authorisation / Approval / Notification 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
14.3 
End-of-Trial Notification 
End-of-trial notification will be reported according to local regulations. In addition, a summary of 
the clinical trial report, e.g. the synopsis, will be provided when available and within one year of 
the trial completion (last subject last visit). 
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 must be signed and dated by the 
subject and the investigator who has provided information to the subject regarding the trial before 
the subject is exposed to any trial-related procedure, including screening tests for eligibility. 
The investigator (or the person delegated by the investigator) will explain that the subject is free to 
completely refuse to enter the trial or to withdraw from it at any time, without any consequences for 
his/her further care and without the need to justify his/her decision. 
The subject will receive a copy of the Subject Information and his/her signed Informed Consent 
Form. 
14.6 
Subject Participation Card 
The subject will be provided with a Subject Information Card bearing the following information: 
• 
That she is participating in a clinical trial 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
• 
That she is treated with FE 999049 
• 
The name and phone number of the investigator 
• 
Name and address of Ferring (if required by local regulations) 
The subject will be asked to return the Subject Information Card at the last trial visit, if applicable. 
Additionally, each subject’s primary care physician will be notified of their participation in the trial 
by the investigator, if the subject agrees and if applicable.  
14.7 
Compliance Reference Documents 
The Declaration of Helsinki, the consolidated ICH-GCP, and the CFDA regulations 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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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
15 
LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of Ferring, the monitor and the investigator will be as defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigator is responsible for adhering to the ICH-GCP responsibilities of investigators, 
for dispensing the IMP in accordance with the approved protocol or an approved amendment, and 
for its secure storage and safe handling throughout the trial. 
15.2 
Liabilities and Insurance 
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
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 the 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, the 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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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
17 
REFERENCES 
1  
FE 999049 CS01. A randomized, double-blind, placebo controlled, sequential dose 
escalation trial investigating the safety, tolerability and pharmacokinetics of FE 999049 
given as single subcutaneous doses in gonadotrophin down-regulated healthy women. 
Ferring Pharmaceuticals A/S Report, 12 Feb 2010. 
2  
FE 999049 CS03. A randomised, double-blind, placebo controlled, sequential dose 
escalation trial investigating the safety, tolerability and pharmacokinetics of FE 999049 
given as single subcutaneous doses in gonadotrophin down-regulated healthy Japanese and 
Caucasian women. Ferring Pharmaceuticals A/S Report, 23 May 2011. 
3  
FE 999049 000020. An open-label, randomised, parallel group trial investigating the 
absolute bioavailability and other pharmacokinetic parameters of FE 999049 and GONAL-F 
administered as single subcutaneous and intravenous doses in healthy women. Ferring 
Pharmaceuticals A/S Report, 14 Feb 2013. 
4  
FE 999049 CS02. A randomized, double-blind, active control, multiple dose study 
investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and 
immunogenicity of FE 999049 in comparison to GONAL-F in gonadotrophin down-
regulated healthy women. Ferring Pharmaceuticals A/S Report, 31 Mar 2011. 
5  
le Contonnec JY, Porchet HC, Beltrami V, Khan A, Toon S, Rowland M. Clinical 
pharmacology of recombinant human follicle-stimulation hormone. II. Single doses and 
steady state pharmacokinetics. Fertil Steril 1994; 61: 679-686.  
6  
FE 999049 000009. A randomised, controlled, assessor-blind, parallel groups, 
multinational, multicentre trial assessing the dose-response relationship of FE 999049 in 
controlled ovarian stimulation in women undergoing an assisted reproductive technology 
programme. Ferring Pharmaceuticals A/S Report, 29 Apr 2015. 
7  
FE 999049 000124. A randomised, controlled, assessor-blind, parallel groups, multicentre 
trial assessing the dose-response relationship of FE 999049 in controlled ovarian stimulation 
in Japanese women undergoing an assisted reproductive technology programme. Ferring 
Pharmaceuticals A/S Report, 16 Sep 2016. 
8  
Nyboe Andersen A, Nelson SM, Fauser BCJM, Garcia-Velasco JA, Klein BM, Arce J-C on 
behalf of the ESTHER-1 study group. Individualized versus conventional ovarian 
stimulation for in vitro fertilization: a multicentre, randomized, controlled, assessor-blinded, 
phase 3 noninferiority trial. Fertil Steril 2017; 107: 387-396. 
9  
Buur Rasmussen B, Mannaerts B, Klein BM, Helmgaard L, Arce J-C on behalf of the 
ESTHER-1 and ESTHER-2 trial group. Low immunogenicity potential of follitropin delta, a 
recombinant FSH preparation produced from a human cell line: Results from phase 3 trials 
(ESTHER-1 and ESTHER-2). Poster presented at the 32nd Annual Meeting of ESHRE; 
2016 Jul 3-6; Helsinki, Finland. 
10  
Qublan HS, Amarin Z, Tahat YA, Smadi AZ, Kilani M. Ovarian cyst formation following 
GnRH agonist administration in IVF cycles: incidence and impact. Hum Reprod. 2006, 
21:640-644. 
11  
Investigator’s Brochure FE 999049, Edition 6. Ferring Pharmaceuticals A/S, Mar 2017.  
 


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Ferring Pharmaceuticals 
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Follitropin Delta, FE 999049 
Trial Code: 000152  
Solution for Injection 
Clinical Trial Protocol 
 
12  
DECAPEPTYL Product Labelling. Last revision: 8 Jan 2018. 

SAP_001.pdf: 
Statistical Analysis Plan 
Title of trial 
An open-label trial investigating the pharmacokinetics of FE 999049 given 
as a single subcutaneous dose in gonadotropin down-regulated healthy 
Chinese women 
NCT number: 
NCT04150861 
Sponsor trial code: 
000152  
Date:  
15 Jan 2020 


Date: 15 JAN 2020 
E-Statistical Analysis Plan-23977; Ver. 1.0 
Supersedes: None 
Page 1 of 18 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
An open-label trial investigating the pharmacokinetics of FE 999049 given 
as a single subcutaneous dose in gonadotropin down-regulated healthy 
Chinese women 
 
000152 
 
 
Investigational Product: 
FE 999049 
 
Indication: 
Controlled ovarian stimulation for the development of 
multiple follicles in women undergoing assisted reproductive 
technologies (ART) such as an in vitro fertilisation (IVF) or 
intracytoplasmic sperm injection (ICSI) cycle  
 
Phase: 
1 
 
Author: 
 
 
Date of issue: 
15JAN2020 
 
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 


Date: 15 JAN 2020 
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Page 2 of 18 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
 
 
Change log 
 
Version 
No. 
 
Effective 
Date 
 
Reason for the Change / Revision 
 
Supersedes 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15JAN2020 
 
First version 
 
 
None 
 
 
 


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Page 3 of 18 
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
Review and Approval of Statistical Analysis Plan 
 
 
Author (e-signed in REAL):   
 
 
 
Project Statistician 
Global Biometrics 
Ferring Pharmaceuticals A/S 
 
Reviewers (Review using PleaseReview and stored in LSAF):  
 
                        
 
 
 
  
Lead Programmer 
Global Biometrics 
Ferring Pharmaceuticals A/S 
 
  
Pharmacovigilance physician 
Global Pharmacovigilance 
Ferring Pharmaceuticals A/S 
 
  
 
 
Medical Writer  
Medical Writing 
Ferring Pharmaceuticals A/S 
 
 
 
 
Project Statistician 
Global Biometrics 
Ferring Pharmaceuticals A/S 
 
 
 
Senior Medical Director 
Translational Medicine 
Ferring Pharmaceuticals A/S 
 
 
 
 
 
 
 
Senior Modelling and Simulation Scientist  
R&D, Translational Medicine, Pharmacokinetics & Modelling 
Ferring Pharmaceuticals A/S 
 
Approval by (e-signed in REAL):   
 
 
 
 
 
 
Director of Biostatistics 
Global Biometrics 
Ferring Pharmaceuticals A/S 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................................... 6 
1.1 
Definitions/ Abbreviations ........................................................................................................ 7 
1.1.1 
Definition of Terms ................................................................................................... 7 
1.1.2 
Abbreviations ............................................................................................................ 7 
1.2 
Presentation of results................................................................................................................ 9 
1.2.1 
Presentation of descriptive results ............................................................................. 9 
1.2.2 
Presentation of inferential results .............................................................................. 9 
1.2.3 
Subject data listings by domain ................................................................................ 9 
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 
Sample Size ............................................................................................................. 10 
3.1.2 
Visits ....................................................................................................................... 10 
4 
Protocol Violations ............................................................................................................................. 11 
5 
Analysis sets ........................................................................................................................................ 11 
5.1 
Full Analysis Set ..................................................................................................................... 11 
5.2 
Per Protocol Analysis Set ........................................................................................................ 11 
5.3 
Safety Analysis Set .................................................................................................................. 11 
6 
Trial population .................................................................................................................................. 12 
6.1 
Demographics and Other Baseline Characteristics ................................................................. 12 
6.2 
Medical History ....................................................................................................................... 12 
6.3 
Prior and Concomitant medication .......................................................................................... 12 
7 
Subject Disposition ............................................................................................................................. 12 
8 
Exposure and Treatment Compliance .............................................................................................. 12 
9 
Pharmacokinetics ............................................................................................................................... 13 
9.1 
General considerations ............................................................................................................ 13 
9.1.1 
Pharmacokinetic Endpoints ..................................................................................... 13 
10 
Safety ................................................................................................................................................... 15 
10.1 
Vital Signs ............................................................................................................................... 15 
10.2 
Clinical Chemistry, Haematology, and Urinalysis .................................................................. 15 
10.3 
ECG ......................................................................................................................................... 16 
10.4 
Adverse Events ........................................................................................................................ 16 
10.4.1 
Overview of Treatment Emergent Adverse Events ................................................ 16 
10.4.2 
Incidence of Treatment Emergent Adverse Events ................................................. 17 
10.4.3 
Serious Adverse Events, Deaths and Other Significant Adverse Events ................ 17 
10.5 
Injection Site Reactions ........................................................................................................... 17 
10.6 
Technical Malfunctions of the Administration Device ........................................................... 18 
10.7 
Anti-FSH Antibodies ............................................................................................................... 18 
10.8 
Physical Examination .............................................................................................................. 18 
10.9 
Gynaecological Examination, Cytology, and Transvaginal Ultrasound ................................. 18 


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
11 
Interim analyses .................................................................................................................................. 18 
12 
Deviations from the protocol ............................................................................................................. 18 
 
 


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
1 
Introduction 
This document describes the planned statistical analyses for trial 000152 and is based on the final 
protocol version 1.0 dated 20SEP2018. No changes to the analyses described in the trial protocol 
are introduced, but additional details and descriptions have been added.   


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
1.1 
Definitions/ Abbreviations 
1.1.1 
Definition of Terms 
Terms 
Definitions 
Prior medication  
Medication taken prior to treatment (i.e. the stop date is 
before the first IMP administration) 
Concomitant medication 
Medication that is not stopped before the first IMP administration, or is started 
between IMP administration and the follow-up visit (visit 13) 
Post-treatment medication  
Medication with start date after the follow-up visit (visit 13) 
Pre-treatment Adverse 
Event 
An Adverse Event with start time after signing of informed consent and before 
administration of IMP 
Treatment Emergent 
Adverse Event 
An Adverse Event that has start time or worsens in intensity after administration of 
IMP until the follow-up visit (visit 13) 
Post-treatment Adverse 
Event 
An Adverse Event that has start time after the follow-up visit (visit 13) 
AUC 
Area under the concentration-time curve from dosing to infinity  
AUCt 
Area under the concentration-time curve from dosing up to time t, where t is the 
last time point at which the concentration is above the lower limit of quantification.  
% Extrap AUC 
Percentage of AUC that is due to extrapolation from the last measurable 
concentration 
CL/F 
Apparent total systemic clearance 
Cmax 
Maximum concentration observed  
z 
First-order rate constant associated with the terminal (log-linear) portion of the 
concentration-time curve 
NCA 
Non-compartmental analysis 
t½ 
Terminal elimination half-life 
tmax 
Time of maximum observed concentration (Cmax)  
Vz/F 
Apparent volume of distribution associated with the terminal phase 
 
1.1.2 
Abbreviations 
Abbreviations 
Meaning of abbreviations in document 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ATC  
Anatomic Therapeutic Chemical  
CV  
Coefficient of Variation 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
HLGT 
High Level Group Term 
HLT 
High Level Term 
IMP 
Investigational Medicinal Product 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
LLQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIMP 
Non-investigational Medicinal Product 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
 


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
1.2 
Presentation of results 
1.2.1 
Presentation of descriptive results 
Categorical data will be summarised using frequency (n) and relative frequency as percentage (i.e. 
n/N*100). 
Continuous data will be summarised using the number of subjects (N), mean and standard deviation 
(SD), median and range (minimum to maximum). For PK parameters the descriptive statistics will 
additionally include the geometric mean and the CV. For t½, the harmonic mean will be included in 
addition to the geometric mean. For tmax the geometric mean and the CV will be omitted. 
1.2.2 
Presentation of inferential results 
Inferential results will be presented using point estimates, two-sided 95% confidence intervals, and 
two-sided p-values.  
1.2.3 
Subject data listings by domain  
All subject data will be presented in listings organised in accordance with the ICH E3 guideline. 
 
2 
Trial Objectives and Endpoints 
2.1 
Objectives 
The objectives of the trial are to: 
• 
Investigate the single-dose pharmacokinetics of FE 999049 administered as a subcutaneous 
abdominal injection in healthy Chinese women 
• 
Investigate the safety and tolerability of a single dose of FE 999049 administered as a 
subcutaneous abdominal injection in healthy Chinese women 
2.2 
Endpoints 
• 
Pharmacokinetics (AUC, AUCt, Cmax, tmax, CL/F, Vz/F, t½) 
• 
Safety (ECG, vital signs, laboratory parameters, adverse events)  
• 
Injection site reactions 
• 
Presence of anti-FSH antibodies 
 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
3 
Trial design 
3.1 
General Design Considerations 
This is an open-label, randomised parallel group trial investigating the pharmacokinetics of a single 
subcutaneous abdominal injection of FE 999049. Subjects will be randomised to 3 dose groups with 
8 healthy Chinese women in each group. 
After testing negative in pregnancy tests, the subjects will receive two subcutaneous administrations 
of a 1-month depot formulation of the GnRH agonist DECAPEPTYL Depot 3.75 mg to down-
regulate endogenous release of FSH during the trial. The first DECAPEPTYL Depot administration 
will be given 28±1 days prior to the first dose of IMP. In women not receiving hormonal 
contraceptives, the first DECAPEPTYL Depot administration should take place in the time interval 
7 days before to 3 days after the expected start of menstruation. In women discontinuing combined 
oral contraceptives, the first DECAPEPTYL Depot administration should take place after the 
subjects have discontinued the hormonal contraception and within 5 days of commencement of 
bleeding. A second administration will be given 10±1 days prior to the first IMP administration. 
To verify low stable endogenous hormones, serum FSH will be measured at Day -3 and Day -1. If 
any of the measurements is >5 mIU/mL, the subject will be excluded. 
The doses to be administered are 12, 18, and 24 µg at a concentration of 33.3 µg/mL. For each 
subject the treatment period is 10 days, and the total duration of the trial from screening to the last 
follow-up visit after treatment will not exceed 13 weeks. 
3.1.1 
Sample Size 
No formal sample size calculation has been performed for this phase 1 trial. Eight subjects receiving 
active treatment in each dose panel is considered sufficient to provide adequate information about 
the pharmacokinetic parameters at each dose level for the purposes of this trial. 
3.1.2 
Visits  
The trial comprises 14 visits. Visit 1 is a screening visit and visits 2-5 belong to the run-in period. 
Visit 5 is the end of the run-in period and the start of the treatment period. It starts the day before 
IMP administration and ends two days after IMP administration. During this time the subjects are 
residential at the clinic. At visits 6-12 the subjects come to the clinic in the morning for PK serum 
sampling. Visit 13 is a follow-up visit that takes place the day after the last PK sample was taken 
(10 days after IMP administration). This visit is regarded as the end of the treatment period. Visit 14 
takes place 27 days after IMP administration and has the purpose of collecting blood samples for 
assessment of the presence of anti-FSH antibodies. The sequence and timing of trial events are 
shown in Figure 1.  


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
 
Figure 1 Sequence and timing of trial events 
4 
Protocol Violations 
Major protocol violations, such as significant non-compliance or other serious unforeseen violations 
deemed to invalidate the data collected for the purpose of the trial will lead to exclusion of the data 
from analysis. In case of minor protocol violations, data will not be excluded from the data analysis. 
The rating of protocol violations in ‘minor’ and ‘major’ will be decided based on a review of the 
data before declaration of ‘clean file’ and lock of database. 
5 
Analysis sets 
5.1 
Full Analysis Set  
The full analysis set (FAS) includes data from all dosed subjects. The FAS will be used for 
presentation of compliance and all baseline characteristics (demographics, medical history, prior 
and concomitant medication). Subjects will be analysed according to the actual treatment received. 
5.2 
Per Protocol Analysis Set 
The per protocol (PP) analysis set includes data from all dosed subjects except data excluded 
because of major protocol violations as discussed in Section 4. The PP analysis set will be used for 
presentation of PK data. Subjects will be analysed according to the actual treatment received. 
5.3 
Safety Analysis Set  
The safety analysis set includes data from all dosed subjects and will be used for safety analysis. 
Subjects will be analysed according to the actual treatment received. The safety analysis set will be 
identical to the FAS. 
 
 
Screening
visit
Day -63
Day -29
Day -28
Day 1
Run-in period 
Treatment period 
Day 10
Follow-up
visit
Subcutaneous injection 
of IMP
Day 11
Administration of DECAPEPTYL Depot 
on Day -28 1 and Day -10 1
Day -10
Antibody 
assessment
Day 28


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
6 
Trial population 
6.1 
Demographics and Other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics (e.g. FSH for eligibility 
determination) will be presented by dose group and in total.  
6.2 
Medical History 
Medical history recorded at the screening visit will be coded using MedDRA and summarised by 
dose group and in total. The version of MedDRA will be documented.  
6.3 
Prior and Concomitant medication 
Prior and concomitant medication will be summarised by ATC classification (1st and 2nd level). 
Medications will be tabulated separately for: 
• Prior medication; i.e. medication taken exclusively prior to treatment (i.e. the stop date is before 
the first IMP administration) 
• Concomitant medication; i.e. medication that is not stopped before the first IMP administration 
or is started between IMP administration and the follow-up visit (visit 13). 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. 
• Post-treatment medication; i.e. medication with start date after the follow-up visit (visit 13). 
7 
Subject Disposition 
All post randomisation discontinuations will be summarised by time of and reason for 
discontinuation. The number of subjects screened but not found eligible will be stated in the trial 
report, and the reason for screening failure will be summarised. 
8 
Exposure and Treatment Compliance 
Times for administration of NIMP and IMP will be listed. Potential non-compliances with NIMP or 
IMP administration will be listed. 


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
9 
Pharmacokinetics 
9.1 
General considerations 
All individual concentration data (both baseline adjusted and unadjusted) and PK parameters will be 
listed by treatment and summarised by treatment with descriptive statistics. Individual and mean 
serum concentration (both baseline adjusted and unadjusted) vs. time curves will be presented for 
each treatment both on linear and logarithmic concentration axes. 
For serum concentrations the descriptive statistics will include number of subjects, arithmetic mean, 
standard deviation, median, minimal value and maximal value. For PK parameters the descriptive 
statistics will additionally include the geometric mean and the between-subject CV (i.e. the 
coefficient of variation based on the total variability, calculated as 100 ∙√𝑒𝑠2 −1 , where 𝑠 is the 
standard deviation calculated for the log-transformed data). 
9.1.1 
Pharmacokinetic Endpoints 
The calculation of PK parameters will be performed by Department of Translational Medicine, 
Ferring Pharmaceuticals. The PK parameters will be calculated for non-corrected as well as baseline 
corrected data by non-compartmental analysis (NCA) using the software Phoenix WinNonlin® 
(Certara, US). The baseline value is the mean of the three values obtained prior to the 
administration of the IMP (-1h, -30 min, 0 min). Baseline corrected values below LLQ will be set to 
zero. Actual sampling time points relative to dosing will be used for the NCA and on the individual 
plots of serum concentration versus time. Serum concentration values below lower limit of 
quantification (LLQ) and missing values (e.g. no blood sample collected or no value obtained at 
analysis) will be excluded from the estimation of z. Values below LLQ will be represented as 
LLQ/2 in the plots and in descriptive statistics. 
PK parameters will be estimated based on measurements from Day 1 to Day 10. From the serum 
concentration-time data of FE 999049 the following parameters will be estimated: AUC, AUCt,      
% Extrap AUC, Cmax, tmax, z, t½, CL/F, and Vz/F.  
Selection of data points for calculation of t½ via z will be based on the following considerations: 
• The automatic range selection used in Phoenix WinNonlin® will be used to propose an 
optimal number of time points to use for the calculation of z. 
• The time range of samples used to estimate z should preferably exceed the derived terminal 
half-life t½ (= ln 2/z). 
• All the samples used to calculate z should ideally fall in the log-linear terminal phase.  
• At least three samples above LLQ obtained during the log-linear terminal phase will if 
possible be included in the calculation of the z. 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
• The final selection of samples for calculation of z will be based on visual inspection of log-
concentration-time plots of individual profiles. 
AUC will be calculated by the linear trapezoidal method. PK parameters will be summarised by 
treatment (i.e. dose group) using descriptive statistics.  
Dose proportionality will be investigated for each of AUC and Cmax using a multiplicative analysis 
of variance model (i.e. AUC and Cmax will be log-transformed before analysis) with log(dose) as 
covariate. In this model, a covariate coefficient of 1 would indicate dose proportionality. 
 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
10 
Safety 
10.1 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be presented by time and 
treatment. Values at screening (visit 1), pre-administration (visit 5, day -1), post-administration 
(visit 5: 12, 24 and 48h post-administration), changes from pre-administration to 12, 24 and 48h 
post-administration, and at follow-up (visit 13) will be summarised for each variable by treatment.  
Individual and mean values for the six measurements will be plotted for all variables. 
Changes relative to normal ranges will be presented in shift tables with total number of subjects, 
and number and percent of subjects who experienced a shift from pre-administration (visit 5, day -
1), to post-administration (visit 5: 12, 24 and 48h post-administration). The following categories are 
defined for these shift tables: 
• Low:   
Values which are below the lower reference range limit; 
• Normal:  
Values which are within the lower and upper reference range; 
• High:   
Values which are above the upper reference range limit. 
 
The reference limits for vital signs will be 90-180 mmHg for systolic blood pressure, 50-105 mmHg 
for diastolic blood pressure, 50-120 bpm for pulse, and <38.3○C for body temperature. 
 
10.2 
Clinical Chemistry, Haematology, and Urinalysis  
Clinical chemistry, haematology and urinalysis parameters will be presented by time and treatment. 
Values at screening (visit 1), pre-administration (visit 5, day -1), post-administration (visit 5, day 3), 
the change from pre- to post-administration, and follow-up (visit 13) will be summarised for each 
laboratory variable by treatment.  
Individual and mean values for the four measurements will be plotted for all numerical lab 
variables. 
Changes relative to normal ranges will be presented in shift tables with total number of subjects, 
and number and percent of subjects who experienced a shift from pre-administration (visit 5, 
day -1), to post-administration (visit 5, day 3). The following categories are defined for these shift 
tables: 
• Low:   
Values which are below the lower reference range limit; 
• Normal:  
Values which are within the lower and upper reference range; 
• High:   
Values which are above the upper reference range limit. 
• Absent:  
No value for measured variable (for urinalysis) 
• Present:  
Any value obtained for measured variable (for urinalysis) 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
The reference range limits will be the ones used by the analysing lab. 
10.3 
ECG 
12-lead ECGs are categorised as “normal”, “abnormal, not clinically significant” or “abnormal 
clinically significant”. Data will be summarised by treatment. Shift tables will be presented for 
changes from pre-administration (visit 5, day -1) to 12, 24 and 48h post-administration (visit 5, day 
1, 2, and 3).  
10.4 
Adverse Events 
AEs will be coded according to the latest version of the MedDRA. All data will be listed by subject. 
For treatment emergent AEs, the listings will include the number of days from administration of 
IMP until the start of the AE. Only treatment emergent AEs (TEAEs) will be presented in summary 
tables. All summary tables will include columns for each treatment and a total column. Separate 
data listing will be provided for AEs that are defined as pre-treatment or post-treatment. The 
following definitions will be used: 
• A pre-treatment Adverse Event is an Adverse Event with start time after signing of informed 
consent and before administration of IMP 
• A Treatment Emergent Adverse Event (TEAE) is an Adverse Event that has start time or 
worsens in intensity after administration of IMP and until the follow-up visit (visit 13) 
• A post-treatment Adverse Event is an Adverse Event that has start time after the follow-up visit 
(visit 13) 
 
If the start date of an AE is completely or partially missing, the AE will be considered treatment 
emergent unless it can be excluded that it was treatment emergent based on the incomplete date. 
 
10.4.1 
Overview of Treatment Emergent Adverse Events 
The summary table for treatment emergent adverse events will include the number of subjects 
reporting an AE, the percentage of subjects (%) with an AE and the number of events reported, for 
each treatment and in total, for the following categories: 
• All TEAEs 
• Deaths 
• Serious TEAEs 
• Non-serious TEAEs 
• Severe TEAEs 
• Moderate TEAEs 
• Mild TEAEs 
• Adverse drug reactions (ADRs, i.e. TEAEs with reasonable possible causal relationship to 
IMP) 
• AEs leading to withdrawal 
• Other significant AEs 


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
10.4.2 
Incidence of Treatment Emergent Adverse Events 
Summary tables will be prepared for the incidence of treatment emergent adverse events per 
treatment and in total by MedDRA system organ class (SOC) and preferred term (PT), presenting 
number of subjects reporting an AE, the percentage of subjects (%) with an AE and the number of 
events reported. Summary tables will be prepared for: 
• All TEAEs  
• SAEs  
• TEAEs by causality (reasonable possibility/no reasonable possibility) 
• TEAEs by intensity (mild/moderate/severe) 
• ADRs by intensity 
 
Supporting data listings will be provided for: 
 
• All adverse events 
• Serious adverse events 
• ADRs 
• Adverse events leading to death 
• Adverse events leading to withdrawal 
• Pre-treatment adverse events 
• Post-treatment adverse events 
 
Missing values will be treated as missing except for causality, intensity, and seriousness of an AE, 
at which occurrence a “worst case” approach will be taken. Thus, if causality is missing the AE will 
be regarded as related to the IMP, if the intensity is missing the intensity of the AE will be regarded 
as severe, if seriousness is missing the AE will be regarded as an SAE, and if the outcome is 
missing and no date of outcome is present the outcome is regarded as “not yet recovered”. 
10.4.3 
Serious Adverse Events, Deaths and Other Significant Adverse Events 
Separate listings will be provided for SAEs, deaths and other significant AEs if any such event 
occurs. 
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
withdrawal. 
10.5 
Injection Site Reactions 
Injection site reactions will be summarised by treatment with the number and percentage of subjects 
experiencing none, mild, moderate, or severe grade of redness, pain, itching, swelling, and bruising, 
or any of these symptoms, immediately after injection, 30 minutes after injection, 24 hours after 
injection, or at any of these time points.  


Date: 15 JAN 2020 
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Ferring Pharmaceuticals 
CONFIDENTIAL 
Follitropin Delta, FE 999049 
Trial Code: 000152  
Statistical Analysis Plan 
10.6 
Malfunctions of the Administration Device 
The frequency of malfunctions of the administration device will be tabulated and the details of each 
malfunction will be listed. 
10.7 
Anti-FSH Antibodies 
The proportion of subjects with anti-FSH antibodies as well as the proportion of subjects with 
anti-FSH antibodies with neutralising capacity will be tabulated for each dose group in total and for 
each time point.  
10.8 
Physical Examination 
Physical examination at the screening (visit 1) and the follow-up visit (visit 13) will be listed by 
subject. Shift tables will be presented for changes from screening to follow-up.  
10.9 
Gynaecological Examination, Cytology, and Transvaginal Ultrasound 
Results of gynaecological examination, cytology, and transvaginal ultrasound at the screening (visit 
1), pre-administration (visit 5), and the follow-up visit (visit 13) will be listed by subject. Shift 
tables will be presented for changes from screening to follow-up. 
11 
Interim analyses 
There will be no interim analyses. 
12 
Deviations from the protocol 
No changes to the analyses described in the trial protocol are introduced, but additional details and 
descriptions have been added.