Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women

Sponsor

Ferring Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT03228680

Collaborator

(none)

373

Enrollment

Locations

Arms

23.3

Actual Duration (Months)

21.9

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: Follitropin delta Drug: Follitropin beta	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

373 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial Assessing the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women Undergoing an Assisted Reproductive Technology Programme

Actual Study Start Date :

Jul 29, 2017

Actual Primary Completion Date :

Jun 10, 2019

Actual Study Completion Date :

Jul 8, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Follitropin delta FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	Drug: Follitropin delta Single daily subcutaneous administration through pre-filled injection pen Other Names: FE 999049 REKOVELLE
Active Comparator: Follitropin beta FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	Drug: Follitropin beta Single daily subcutaneous injection in the abdomen Other Names: FOLLISTIM

Arm

Intervention/Treatment

Experimental: Follitropin delta

FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.

Drug: Follitropin delta

Single daily subcutaneous administration through pre-filled injection pen

Other Names:

FE 999049

REKOVELLE

Active Comparator: Follitropin beta

FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.

Drug: Follitropin beta

Single daily subcutaneous injection in the abdomen

Other Names:

FOLLISTIM

Outcome Measures

Primary Outcome Measures

Number of Oocytes Retrieved [36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)]
The number of oocytes retrieved was recorded at the oocyte retrieval visit.

Secondary Outcome Measures

Clinical Pregnancy Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]
Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate [13-15 days after transfer (up to approximately 1.5 months after start of stimulation)]
Defined as positive serum beta-hCG test 13-15 days after transfer.
Vital Pregnancy Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
Implantation Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response [End-of-stimulation (up to 20 stimulation days)]
Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk [End-of-stimulation (up to 20 stimulation days)]
Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved [On the day of oocyte retrieval (up to 22 days after start of stimulation)]
Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population [On the day of oocyte retrieval (up to 22 days after start of stimulation)]
Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) [≤9 days after triggering of final follicular maturation]
Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS [Up to 9 days after triggering of final follicular maturation]
Defined as proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.
Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) [>9 days after triggering of final follicular maturation]
Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.
Number of Follicles on Stimulation Day 6 [At Day 6 of stimulation]
Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
Number of Follicles at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
Size of Follicles on Stimulation Day 6 [At Day 6 of stimulation]
Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint.
Size of Follicles at End-of-Stimulation [End-of-stimulation (up to 20 stimulation days)]
Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint.
Fertilization Rate [Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)]
The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Number and Quality of Embryos [Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)]
Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
Number and Quality of Blastocysts [Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)]
Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 [At Day 6 of stimulation]
The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
The median and IQR of FSH and LH levels at end-of-stimulation are presented.
Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 [At Day 6 of stimulation]
The median and IQR of estradiol levels on stimulation Day 6 are presented.
Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
The median and IQR of estradiol levels at end-of-stimulation are presented.
Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 [At Day 6 of stimulation]
The median and IQR of progesterone levels on stimulation Day 6 are presented.
Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
The median and IQR of progesterone levels at end-of-stimulation are presented.
Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 [At Day 6 of stimulation]
The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
The median and IQR of Inhibin A levels at end-of-stimulation are presented.
Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 [At Day 6 of stimulation]
The median and IQR of inhibin B levels on stimulation Day 6 are presented.
Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
The median and IQR of inhibin B levels at end-of-stimulation are presented.
Number of Stimulation Days [End-of-stimulation (up to 20 stimulation days)]
Total Gonadotropin Dose of FE 999049 [End-of-stimulation (up to 20 stimulation days)]
Total Gonadotropin Dose of FOLLISTIM [End-of-stimulation (up to 20 stimulation days)]
Number of Participants With Adverse Events (AEs) Stratified by Intensity [From signed informed consent up to 5-6 weeks after transfer]
The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]
Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial [Up to 5-6 weeks after transfer]
Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial [Up to 5-6 weeks after transfer]
Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Frequency and Intensity of Injection Site Reactions [End-of-stimulation (up to 20 stimulation days)]
The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
Technical Malfunctions of the Administration Pens [End-of-stimulation (up to 20 stimulation days)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Informed Consent Documents signed prior to any trial-related procedures.
In good physical and mental health.
Japanese females between the ages of 20 and 40 years.
Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine (ASRM) classification) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from male partner.
Infertility for at least 1 year before randomization (not applicable in case of tubal or severe male factor infertility).
The trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF/ICSI.
Hysterosalpingography, hysteroscopy, saline infusion sonography or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior to screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening.
Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and fallopian tubes and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
Early follicular phase (cycle day 2-4) serum levels of follicle stimulating hormone (FSH) between 1 and 15 IU/L (results obtained within 3 months prior to screening).
Body mass index (BMI) between 17.5 and 32.0 kg/m^2 (both inclusive) at screening.

Exclusion Criteria:

Known endometriosis stage III-IV (defined by the revised ASRM classification).
One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomization is allowed).
Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy).
Known abnormal karyotype of subject or of her partner. In case the sperm production is severely impaired (concentration <1 million/mL), normal karyotype, including no Y chromosome microdeletion, must be documented.
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease.
Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.

Contacts and Locations

Locations

	Site	City	State	Country
1	Yachiyo Hospital	Anjo	Aichi	Japan
2	Investigational Site 8121	Chiba-shi	Chiba	Japan
3	Yokota Maternity Hospital	Maebashi	Gunma	Japan
4	Sophia Ladies Clinic	Sagamihara	Kanagawa	Japan
5	Investigational Site 8122	Sendai-shi	Miyagi	Japan
6	Investigational Site 8123	Higashiōsaka-shi	Osaka	Japan
7	Investigational Site 8120	Osaka-Shi	Osaka	Japan
8	Ladies Clinic Kitahama	Osaka-shi	Osaka	Japan
9	Investigational Site 8125	Saitama-shi	Saitama	Japan
10	Investigational Site 8124	Shinjuku-Ku	Tokyo	Japan
11	Akita University Hospital	Akita		Japan
12	Yamashita Ladies' Clinic	Hyogo		Japan
13	Investigational Site 8126	Saitama		Japan
14	Omiya Ladies Clinic	Saitama		Japan
15	Saint Women's Clinic	Saitama		Japan
16	Women's Clinic Fujimino	Saitama		Japan
17	Tokushima University Hospital	Tokushima		Japan

Sponsors and Collaborators

Ferring Pharmaceuticals

Investigators

Study Director: Global Clinical Compliance, Ferring Pharmaceuticals

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Ferring Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT03228680

Other Study ID Numbers:

000273

First Posted:

Jul 25, 2017

Last Update Posted:

Jan 14, 2022

Last Verified:

Apr 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Infertility

Follicle Stimulating Hormone

Study Results

Participant Flow

Recruitment Details	A total of 17 investigational sites in Japan randomized participants to the trial between 29 July 2017 to 08 July 2019.
Pre-assignment Detail	A total of 373 participants were screened. Of these, 25 were screening failures and 348 participants were randomized: 170 participants were exposed to FE 999049 & 177 participants were exposed to FOLLISTIM. One participant was randomized to FOLLISTIM but not exposed to investigational medicinal product (IMP) was considered a randomization failure.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Period Title: Overall Study
STARTED	170	178
COMPLETED	147	143
NOT COMPLETED	23	35

Baseline Characteristics

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)	Total
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	Total of all reporting groups
Overall Participants	170	177	347
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.2 (3.5)	34.0 (3.4)	34.1 (3.5)
Sex: Female, Male (Count of Participants)
Female	170 100%	177 100%	347 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	170 100%	177 100%	347 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	170 100%	177 100%	347 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Japan	170 100%	177 100%	347 100%

Outcome Measures

1. Primary Outcome

Title	Number of Oocytes Retrieved
Description	The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Time Frame	36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)

Outcome Measure Data

Analysis Population Description
The full analysis set (FAS) comprised all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [Oocytes retrieved]	9.3 (5.4)	10.5 (6.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Mean number of oocytes retrieved.
	Type of Statistical Test	Non-Inferiority
	Comments	The pre-specified non-inferiority (NI) margin was -3.0 oocytes. The NI was evaluated based on the two-sided 95% CI from the ANOVA on 'number of oocytes retrieved' with treatment and AMH stratum as fixed factors.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95% -2.3 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	If the lower bound of 95% CI was well above pre-specified NI limit of -3.0 oocytes, then NI of FE 999049 to FOLLISTIM with respect to number of oocytes retrieved in women undergoing controlled ovarian stimulation would be demonstrated

2. Secondary Outcome

Title	Clinical Pregnancy Rate
Description	Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
Time Frame	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [percentage of participants]	25.3 14.9%	23.7 13.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Percentage of participants with at least one gestational sac 5-6 weeks after transfer.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95% -7.5 to 10.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.

3. Secondary Outcome

Title	Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate
Description	Defined as positive serum beta-hCG test 13-15 days after transfer.
Time Frame	13-15 days after transfer (up to approximately 1.5 months after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [percentage of participants]	29.4 17.3%	29.4 16.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Percentage of participants with positive beta-hCG.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% -9.5 to 9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.

4. Secondary Outcome

Title	Vital Pregnancy Rate
Description	Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
Time Frame	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [percentage of participants]	23.5 13.8%	21.5 12.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Percentage of participants with vital pregnancy.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95% -6.7 to 10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.

5. Secondary Outcome

Title	Implantation Rate
Description	Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
Time Frame	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants with blastocyst transfer.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Measure Embryos transferred	135	141
Number [% of sacs/blastocysts transferred]	31.9	29.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Percentage of implanted embryos 5-6 weeks after transfer.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95% -8.9 to 12.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference (FE 999049-FOLLISTIM) in rates was estimated and a two-sided 95% Cl was constructed using the Mantel-Haenszel method to combine results across AMH strata.

6. Secondary Outcome

Title	Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Cycle cancelled due to poor ovarian response	1.2 0.7%	0.6 0.3%
Cycle cancelled due to excessive ovarian response	0 0%	1.1 0.6%

7. Secondary Outcome

Title	Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [percentage of participants]	7.6 4.5%	11.3 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with blastocyst transfer cancellation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.244
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

8. Secondary Outcome

Title	Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Description	Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
Time Frame	On the day of oocyte retrieval (up to 22 days after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	173
Low response (<4 oocytes)	8.3 4.9%	5.2 2.9%
Moderate response (4-7 oocytes)	36.1 21.2%	26.6 15%
Targeted response (8-14 oocytes)	40.8 24%	42.8 24.2%
Hyperresponse (15-19 oocytes)	10.1 5.9%	14.5 8.2%
Severe hyperresponse (≥ 20 oocytes)	4.7 2.8%	11.0 6.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with <4 oocytes retrieved (low response).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.254
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with 4-7 oocytes retrieved (moderate response).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.041
	Comments	P-value was based on likelihood ratio test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with 8-14 oocytes retrieved (targeted response).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.705
	Comments	P-value was based on likelihood ratio test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with 15-19 oocytes retrieved (hyperresponse).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.183
	Comments	P-value was based on likelihood ratio test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with >= (more than equal to) 20 oocytes retrieved (severe hyperresponse).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.030
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

9. Secondary Outcome

Title	Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population
Description
Time Frame	On the day of oocyte retrieval (up to 22 days after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	173
AMH < 15 pmol/L (<4 oocytes retrieved)	11.6 6.8%	12.3 6.9%
AMH >= 15 pmol/L (>=15 oocytes retrieved)	22.0 12.9%	42.0 23.7%
AMH >= 15 pmol/L (>=20 oocytes retrieved)	8.0 4.7%	19.0 10.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with extreme ovarian responses: AMH < 15 pmol/L (<4 oocytes retrieved)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.893
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with extreme ovarian responses: AMH >= 15 pmol/L (>=15 oocytes retrieved)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with extreme ovarian responses: AMH >= 15 pmol/L (>=20 oocytes retrieved)
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.021
	Comments	P-value based on likelihood ratio chi-square test.
	Method	Chi-squared
	Comments

10. Secondary Outcome

Title	Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)
Description
Time Frame	≤9 days after triggering of final follicular maturation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all participants randomized or exposed.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Cycle cancellation	0 0%	1.1 0.6%
Triggering with GnRH agonist	1.2 0.7%	1.1 0.6%
Administration of dopamine agonist	0.6 0.4%	1.7 1%

11. Secondary Outcome

Title	Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS
Description	Defined as proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.
Time Frame	Up to 9 days after triggering of final follicular maturation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all participants randomized and exposed.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Early OHSS (any grade)	10.0 5.9%	18.6 10.5%
Early OHSS (moderate/severe)	6.5 3.8%	13.0 7.3%
Early OHSS (any grade) and/or preventive	10.6 6.2%	20.9 11.8%
Early OHSS (moderate/severe) and/or preventive	7.6 4.5%	16.4 9.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportions of participants with early OHSS (any grade).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.017
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with early OHSS (moderate/severe).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.035
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with early OHSS (any grade) and/or preventive interventions.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.006
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportion of participants with early OHSS (moderate/severe) and/or preventive interventions.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.009
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

12. Secondary Outcome

Title	Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade)
Description	Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.
Time Frame	>9 days after triggering of final follicular maturation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all participants randomized or exposed.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Late OHSS (any grade)	1.2 0.7%	1.1 0.6%
Late OHSS (moderate/severe)	0.6 0.4%	1.1 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportions of participants with late OHSS (any grade).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.968
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Proportions of participants with late OHSS (moderate/severe).
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.582
	Comments	P-value was based on likelihood ratio chi-square test.
	Method	Regression, Logistic
	Comments	The model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors.

13. Secondary Outcome

Title	Number of Follicles on Stimulation Day 6
Description	Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized or exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [Follicles]	12.8 (7.2)	13.3 (7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of follicles on stimulation Day 6 was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.198
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

14. Secondary Outcome

Title	Number of Follicles at End-of-stimulation
Description	Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized or exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [Follicles]	14.9 (8.0)	16.3 (8.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of follicles at end-of-stimulation was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.036
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

15. Secondary Outcome

Title	Size of Follicles on Stimulation Day 6
Description	Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [mm]	12.7 (2.1)	12.8 (2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The average size of 3 largest follicles was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.592
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

16. Secondary Outcome

Title	Size of Follicles at End-of-Stimulation
Description	Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [mm]	19.2 (1.5)	19.4 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The average size of 3 largest follicles was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.286
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

17. Secondary Outcome

Title	Fertilization Rate
Description	The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time Frame	Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised all randomized and exposed participants

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [percentage of fertilized oocytes]	54.5 (26.1)	57.1 (23.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The fertilization rate (number of oocytes with 2 pronuclei divided by the number of oocytes retrieved) was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.395
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

18. Secondary Outcome

Title	Number and Quality of Embryos
Description	Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
Time Frame	Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number of embryo	5.8 (4.2)	7.0 (4.3)
Number of good-quality embryo	3.9 (3.3)	4.6 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of embryos on Day 3 was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.001
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of good-quality embryos on Day 3 was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.004
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

19. Secondary Outcome

Title	Number and Quality of Blastocysts
Description	Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Time Frame	Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number of blastocysts	3.1 (2.7)	4.2 (3.4)
Number of good-quality blastocysts	2.3 (2.3)	3.0 (2.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of blastocysts on Day 5 was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<.001
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of good-quality blastocysts on Day 5 was analyzed.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

20. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6
Description	The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	166	175
FSH	15.4	14.7
LH	2.6	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of FSH on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.228
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95% 0.98 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of LH on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.777
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.81 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

21. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation
Description	The median and IQR of FSH and LH levels at end-of-stimulation are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	172
FSH	14.3	16.4
LH	1.6	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of FSH at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.84 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of LH at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.057
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95% 1.00 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

22. Secondary Outcome

Title	Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6
Description	The median and IQR of estradiol levels on stimulation Day 6 are presented.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	166	175
Median (Inter-Quartile Range) [pmol/L]	2277.1	2680.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of estradiol on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.71 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

23. Secondary Outcome

Title	Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation
Description	The median and IQR of estradiol levels at end-of-stimulation are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	172
Median (Inter-Quartile Range) [pmol/L]	6517.0	7438.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of estradiol at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.003
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.76 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

24. Secondary Outcome

Title	Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6
Description	The median and IQR of progesterone levels on stimulation Day 6 are presented.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	166	175
Median (Inter-Quartile Range) [nmol/L]	1.7	1.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of progesterone on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.814
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.89 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

25. Secondary Outcome

Title	Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation
Description	The median and IQR of progesterone levels at end-of-stimulation are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	168	172
Median (Inter-Quartile Range) [nmol/L]	2.5	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of progesterone levels at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.68 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

26. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6
Description	The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	166	175
Median (Inter-Quartile Range) [ng/L]	113.1	129.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of Inhibin A on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.73 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

27. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation
Description	The median and IQR of Inhibin A levels at end-of-stimulation are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	172
Median (Inter-Quartile Range) [ng/L]	323.8	390.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of Inhibin A at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% 0.72 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

28. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6
Description	The median and IQR of inhibin B levels on stimulation Day 6 are presented.
Time Frame	At Day 6 of stimulation

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	166	175
Median (Inter-Quartile Range) [ng/L]	570.5	686.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of Inhibin B on stimulation Day 6.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.75 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

29. Secondary Outcome

Title	Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation
Description	The median and IQR of inhibin B levels at end-of-stimulation are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The FAS comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	169	172
Median (Inter-Quartile Range) [ng/L]	686.0	734.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	Circulating levels of Inhibin B at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.027
	Comments	The P-value corresponds to the two-sided F-test of treatment effect.
	Method	ANCOVA
	Comments	The ANCOVA model included treatment and AMH stratum (<15 pmol/L and ≥15 pmol/L) as fixed factors and log-baseline as covariate.

Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.79 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean ratio is equal to FE 999049/FOLLISTIM.

30. Secondary Outcome

Title	Number of Stimulation Days
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Mean (Standard Deviation) [Days]	8.9 (1.9)	8.8 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049 (Follitropin Delta), FOLLISTIM (Follitropin Beta)
	Comments	The number of stimulation days at end-of-stimulation.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.694
	Comments	2-sided
	Method	van Elteren test
	Comments	P-value was based on van Elteren test adjusted for AMH strata.

31. Secondary Outcome

Title	Total Gonadotropin Dose of FE 999049
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170
Mean (Standard Deviation) [μg]	83.5 (28.9)

32. Secondary Outcome

Title	Total Gonadotropin Dose of FOLLISTIM
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	177
Mean (Standard Deviation) [IU]	1499 (514)

33. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) Stratified by Intensity
Description	The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).
Time Frame	From signed informed consent up to 5-6 weeks after transfer

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Any AE	73 42.9%	92 52%
Mild AE	69 40.6%	86 48.6%
Moderate AE	8 4.7%	12 6.8%
Severe AE	0 0%	1 0.6%

34. Secondary Outcome

Title	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation
Description	Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
ALT (IU/L): Normal to markedly high (>3xULN)	0 0%	1 0.6%
AST (IU/L): Normal to markedly high (>3xULN)	0 0%	1 0.6%

35. Secondary Outcome

Title	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation
Description	Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [participants]	0 0%	0 0%

36. Secondary Outcome

Title	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial
Description	Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
Time Frame	Up to 5-6 weeks after transfer

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [participants]	0 0%	0 0%

37. Secondary Outcome

Title	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial
Description	Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Time Frame	Up to 5-6 weeks after transfer

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Leukocytes (10^9/L) Normal to markedly high (>=16)	0 0%	1 0.6%
Hemoglobin (g/L) Normal to markedly low	0 0%	1 0.6%
Hematocrit (ratio) Normal to markedly low (>=0.56)	0 0%	1 0.6%

38. Secondary Outcome

Title	Frequency and Intensity of Injection Site Reactions
Description	The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Any mild injection site reaction	271	719
Any moderate injection site reaction	7	19
Any severe injection site reaction	1	0
Mild redness	140	174
Moderate redness	2	0
Severe redness	0	0
Mild itching	4	5
Moderate itching	1	0
Severe itching	0	0
Mild pain	19	411
Moderate pain	1	16
Severe pain	0	0
Mild swelling	6	10
Moderate swelling	0	0
Severe swelling	0	0
Mild bruising	102	119
Moderate bruising	3	3
Severe bruising	1	0

39. Secondary Outcome

Title	Technical Malfunctions of the Administration Pens
Description
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description
The safety analysis set comprised of all randomized and exposed participants.

Arm/Group Title	FE 999049 (Follitropin Delta)	FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.	FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
Measure Participants	170	177
Number [percentage of participants]	0 0%	0 0%

Adverse Events

	FE 999049 (Follitropin Delta)		FOLLISTIM (Follitropin Beta)
Time Frame	Adverse events were monitored from the time of obtaining informed consent until the last visit (end-of-trial) (up to approximately 2 years) .
Adverse Event Reporting Description	Adverse events with onset after start of first administration of IMP were considered treatment -emergent and are presented for the safety analysis set.

Arm/Group Title	FE 999049 (Follitropin Delta)		FOLLISTIM (Follitropin Beta)
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.		FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/170 (0%)		0/177 (0%)
Serious Adverse Events
	FE 999049 (Follitropin Delta)		FOLLISTIM (Follitropin Beta)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/170 (0%)		2/177 (1.1%)
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome	0/170 (0%)	0	2/177 (1.1%)	2
Other (Not Including Serious) Adverse Events
	FE 999049 (Follitropin Delta)		FOLLISTIM (Follitropin Beta)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/170 (42.9%)		92/177 (52%)
Gastrointestinal disorders
Constipation	4/170 (2.4%)	4	5/177 (2.8%)	6
General disorders
Injection site erythema	13/170 (7.6%)	14	15/177 (8.5%)	15
Injection site pruritus	0/170 (0%)	0	5/177 (2.8%)	5
Infections and infestations
Viral upper respiratory tract infection	6/170 (3.5%)	6	6/177 (3.4%)	6
Nervous system disorders
Headache	4/170 (2.4%)	4	4/177 (2.3%)	4
Pregnancy, puerperium and perinatal conditions
Biochemical pregnancy	6/170 (3.5%)	6	10/177 (5.6%)	10
Abortion spontenous	3/170 (1.8%)	3	4/177 (2.3%)	4
Haemorrhage in pregnancy	4/170 (2.4%)	4	0/177 (0%)	0
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome	19/170 (11.2%)	19	35/177 (19.8%)	35
Ovarian cyst	5/170 (2.9%)	5	7/177 (4%)	7
Ovarian enlargement	5/170 (2.9%)	5	5/177 (2.8%)	5
Pelvic fluid collection	4/170 (2.4%)	4	4/177 (2.3%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.

Results Point of Contact

Name/Title	Clinical Development Support
Organization	Ferring Pharmaceuticals
Phone
Email	DK0-Disclosure@ferring.com

Responsible Party:

Ferring Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT03228680

Other Study ID Numbers:

000273

First Posted:

Jul 25, 2017

Last Update Posted:

Jan 14, 2022

Last Verified:

Apr 1, 2021