ESTHER-1: Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 1

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01956110
• Collaborator: (none)
• Enrollment: 1,329
• Locations: 13
• Arms: 2
• Duration (Months): 39.1
• Patients Per Site: 102.2
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

This trial investigates the effects of FE 999049 compared to GONAL-F.

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: Follitropin Delta (FE 999049); Drug: Follitropin Alfa (GONAL-F)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1329 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre, Multinational Trial Comparing the Efficacy and Safety of FE 999049 With Follitropin Alfa (GONAL-F) in Controlled Ovarian Stimulation in Women Undergoing an Assisted Reproductive Technology Programme
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: Jan 3, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Follitropin Delta (FE 999049)	Drug: Follitropin Delta (FE 999049)
Active Comparator: B Follitropin Alfa (GONAL-F)	Drug: Follitropin Alfa (GONAL-F)

Outcome Measures

Primary Outcome Measures

1. Ongoing Pregnancy Rate [10-11 weeks after blastocyst transfer]

   Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.

2. Ongoing Implantation Rate [10-11 weeks after blastocyst transfer]

   Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.

Secondary Outcome Measures

1. Vital Pregnancy Rate [5-6 weeks after blastocyst transfer]

   Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.

2. Implantation Rate [5-6 weeks after blastocyst transfer]

   Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.

3. Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved [Day of oocyte retrieval]

4. Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS [≤9 days after triggering of final follicular maturation]

   The proportion of subjects 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.

5. Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response [End-of-stimulation (up to 20 stimulation days)]

   Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.

6. Number of Oocytes Retrieved [Day of oocyte retrieval]

7. Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved [Day of oocyte retrieval]

8. Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) [Prior to insemination]

   Number of oocytes in metaphase II prior to ICSI insemination is presented.

9. Fertilisation Rate [Day 1 after insemination]

   Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.

10. Number and Quality of Embryos on Day 3 [On day 3 after oocyte retrieval]

    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.

11. Number and Quality of Blastocysts on Day 5 [On day 5 after oocyte retrieval]

    Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.

12. Total Gonadotropin Dose [End-of-stimulation (up to 20 stimulation days)]

    The total gonadotropin dose was recorded.

13. Number of Stimulation Days [End-of-stimulation (up to 20 stimulation days)]

14. Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments [End-of-stimulation (up to 20 stimulation days)]

15. Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period [End-of-stimulation (up to 20 stimulation days)]

    Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.

16. Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) [End-of-stimulation and day of blastocyst transfer]

    The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort).

17. Changes in Body Weight [End-of-stimulation and day of blastocyst transfer]

    Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.

18. Changes in Maximum Abdominal Circumference [End-of-stimulation and day of blastocyst transfer]

    Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.

19. Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies [Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose]

    The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.

20. Proportion of Subjects With Late OHSS [>9 days after triggering of final follicular maturation]

    Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented.

21. Technical Malfunctions of the Administration Pen [End-of-stimulation (up to 20 stimulation days)]

    Confirmed technical malfunction of administration pen.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed Consent Documents signed prior to screening evaluations

• In good physical and mental health

• Pre-menopausal females between the ages of 18 and 40 years

• Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor

• Infertility for at least one year before randomisation for subjects ≤37 years or for at least 6 months for subjects ≥38 years (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 randomisation

• Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.

• Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomisation)

• Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening

Exclusion Criteria:

• Known endometriosis stage III-IV

• One or more follicles ≥10 mm observed on the transvaginal ultrasound prior to randomisation on stimulation day 1

• 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/sperm donor, as applicable, depending on source of sperm used for insemination in this trial.

• 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	Postal Code
1	UZ Brussel (there may be other sites in this country)	Brussels		Belgium
2	Fertilitat and PUC-RS (there may be other sites in this country)	Porto Alegre		Brazil
3	Pacific Centre for Reproductive Medicine	Burnaby	British Columbia	Canada
4	Olive Fertility Centre	Vancouver	British Columbia	Canada
5	Ottawa Fertility Centre	Ottawa	Ontario	Canada
6	IVF CUBE SE (there may be other sites in this country)	Prague		Czechia
7	Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)	Copenhagen		Denmark
8	Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)	Lille		France
9	Centro Natalità San Raffaele (there may be other sites in this country)	Milano		Italy
10	The nOvum Clinic (there may be other sites in this country)	Warszawa		Poland
11	IVF & Reproductive Genetics Center (there may be other sites in this country)	Moscow		Russian Federation
12	IVI Sevilla (there may be other sites in this country)	Sevilla		Spain
13	Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)	Glasgow		United Kingdom

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support, Ferring Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01956110
• Other Study ID Numbers: 000004; 2013-001669-17; U1111-1147-6826
• First Posted: Oct 8, 2013
• Last Update Posted: Jan 13, 2022
• Last Verified: Sep 1, 2018

• Additional relevant MeSH terms: Infertility; Follicle Stimulating Hormone

Study Results

Participant Flow

Recruitment Details	A total of 37 sites randomised subjects into the trial : 3 in Belgium, 3 in Brazil, 3 in Canada, 4 in the Czech Republic, 2 in Denmark, 2 in France, 2 in Italy, 2 in Poland, 4 in Russia, 10 in Spain and 2 in United Kingdom.
Pre-assignment Detail	A total of 1501 subjects were screened in the trial, of whom 1329 subjects were randomised: 666 subjects to FE 999049 and 663 subjects to GONAL-F. Three subjects were randomisation failures and did not receive investigational medicinal product (IMP); 1 in the FE 999049 group and 2 in the GONAL-F group.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised 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 randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	Follitropin Alfa (GONAL-F) was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F was 150 international units (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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Period Title: Overall Study
STARTED	665	661
COMPLETED	630	639
NOT COMPLETED	35	22

Baseline Characteristics

Arm/Group Title	FE 999049	GONAL-F	Total
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	Total of all reporting groups
Overall Participants	665	661	1326
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	665 100%	661 100%	1326 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	665 100%	661 100%	1326 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Ongoing Pregnancy Rate
Description	Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
Time Frame	10-11 weeks after blastocyst transfer

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat (mITT) analysis set (all randomised and exposed subjects). This is equivalent to full analysis set (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number [Percentage of subjects]	30.7	31.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% confidence interval (CI) derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
	Type of Statistical Test	Non-Inferiority
	Comments	The lower bound of the 95% CI was well above the pre-specified non-inferiority limit of -8.0%. Thus, non-inferiority of FE 999049 to GONAL-F with regard to ongoing pregnancy rate was demonstrated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -5.9 to 4.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Ongoing Implantation Rate
Description	Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.
Time Frame	10-11 weeks after blastocyst transfer

Outcome Measure Data

Analysis Population Description

Subjects with blastocyst transfer (a total of 585 and 584 blastocysts were transferred in the FE999049 and GONAL-F groups, respectively).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	562	560
Number [Percentage]	35.2	35.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	The pre-specified non-inferiority margin was -8.0% (absolute). Non-inferiority was evaluated based on a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
	Type of Statistical Test	Non-Inferiority
	Comments	The lower bound of the 95% CI was well above the pre-specified non-inferiority limit of -8.0%. Thus, non-inferiority of FE 999049 to GONAL-F with regard to ongoing implantation rate was demonstrated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -6.1 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. 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 blastocyst transfer.
Time Frame	5-6 weeks after blastocyst transfer

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number [Percentage of subjects]	31.7	33.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment groups were compared using a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
	Type of Statistical Test	Non-Inferiority
	Comments	The lower bound of the 95% CI was well above -8.0% (pre-specified non-inferiority limit for the co-primary endpoints). Thus, the result was supportive of the co-primary endpoint analyses.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -6.7 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Implantation Rate
Description	Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
Time Frame	5-6 weeks after blastocyst transfer

Outcome Measure Data

Analysis Population Description

Subjects with blastocyst transfer (a total of 585 and 584 blastocysts were transferred in the FE999049 and GONAL-F groups, respectively).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	562	560
Number [Percentage]	39.8	41.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment groups were compared using a two-sided 95% CI derived based on the asymptotic normal distribution. The treatment comparison was adjusted for age (<35, 35-37 and 38-40 years) by using the Mantel-Haenszel method to combine results across age-strata.
	Type of Statistical Test	Non-Inferiority
	Comments	The lower bound of the 95% CI was well above -8.0% (pre-specified non-inferiority limit for the co-primary endpoints). Thus, the result was supportive of the co-primary endpoint analyses.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -7.0 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved
Time Frame	Day of oocyte retrieval

Outcome Measure Data

Analysis Population Description

Subjects who underwent triggering of final follicular maturation.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	635	643
<4 or >=15 oocytes retrieved	26.6	31.3
<4 or >=20 oocytes retrieved	14.5	18.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: <4 or >=15 oocytes retrieved
	Type of Statistical Test	Other
	Comments	A logistic regression model was fitted to the data including AMH, log(AMH)^2, treatment group and interactions between treatment group and AMH and treatment group and log(AMH)^2 in the linear predictor. A second logistic regression model (nested within the first model) was fitted including AMH and log(AMH)^2 in the linear predictor.
Statistical Test of Hypothesis	p-Value	=0.001
	Comments	Inclusion of treatment provides a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: <4 or >=20 oocytes retrieved
	Type of Statistical Test	Other
	Comments	A logistic regression model was fitted to the data including AMH, log(AMH)2, treatment group and interactions between treatment group and AMH and treatment group and log(AMH)^2 in the linear predictor. A second logistic regression model (nested within the first model) was fitted including AMH and log(AMH)^2 in the linear predictor.
Statistical Test of Hypothesis	p-Value	=0.002
	Comments	Inclusion of treatment provides a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

6. Secondary Outcome

Title	Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS
Description	The proportion of subjects 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	≤9 days after triggering of final follicular maturation

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Early OHSS (any grade)	2.6	3.0
Early OHSS (moderate/severe)	1.4	1.4
Any preventive intervention	2.3	4.5
Early OHSS (any grade) / preventive interventions	4.7	6.2
Early OHSS (mod/severe) / preventive interventions	3.6	5.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Early OHSS (any grade)
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	=0.291
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Early OHSS (moderate/severe)
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	=0.644
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Preventive interventions
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	=0.005
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Early OHSS (any grade) and/or preventive interventions
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	=0.046
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Early OHSS (moderate/severe) and/or preventive interventions
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	=0.019
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

7. Secondary Outcome

Title	Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
Description	Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Cycle cancelled due to poor ovarian response	3.8	2.7
Cycle cancelled due to excessive ovarian response	0	0
Triggering with GnRH agonist	1.5	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Cycle cancelled due to poor response
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using a logistic regression model with treatment and age (<35, 35- 37, and 38-40 years) as factors.
Statistical Test of Hypothesis	p-Value	=0.302
	Comments	P-value corresponds to test for treatment difference.
	Method	Likelihood ratio test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.74 to 2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison:Triggering with GnRH agonist
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using a logistic regression model with treatment and age (<35, 35-37, and 38-40 years) as factors.
Statistical Test of Hypothesis	p-Value	0.019
	Comments	P-value corresponds to test for treatment difference.
	Method	Likelihood ratio test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.2 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Oocytes Retrieved
Time Frame	Day of oocyte retrieval

Outcome Measure Data

Analysis Population Description

Subjects who underwent triggering of final follicular maturation.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	636	643
Mean (Standard Deviation) [Oocytes retrieved]	10.0 (5.6)	10.4 (6.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Number of oocytes retrieved
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	=0.692
	Comments
	Method	van Elteren
	Comments

9. Secondary Outcome

Title	Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Time Frame	Day of oocyte retrieval

Outcome Measure Data

Analysis Population Description

Subjects who underwent triggering of final follicular maturation.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	635	643
Low response (<4 oocytes)	8.0	9.6
Moderate response (4-7 oocytes)	30.1	30.3
Targeted response (8-14 oocytes)	43.3	38.4
Hyperresponse (15-19 oocytes)	12.1	12.9
Severe hyperresponse (≥ 20 oocytes)	6.5	8.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	The relation between ovarian response potential (AMH at screening) and probability of achieving the targeted response was modelled using logistic regression models.
	Type of Statistical Test	Other
	Comments	A logistic regression model was fitted to the data including AMH, log(AMH)^2, treatment group and interactions between treatment group and AMH and treatment group and log(AMH)^2 in the linear predictor. A second logistic regression model (nested within the first model) was fitted including AMH and log(AMH)^2 in the linear predictor.
Statistical Test of Hypothesis	p-Value	=0.019
	Comments	Inclusion of treatment provides a better fit to the data
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

10. Secondary Outcome

Title	Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])
Description	Number of oocytes in metaphase II prior to ICSI insemination is presented.
Time Frame	Prior to insemination

Outcome Measure Data

Analysis Population Description

Subjects with all oocytes inseminated using ICSI.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	531	522
Mean (Standard Deviation) [Number of oocytes]	7.4 (4.3)	7.7 (5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Number of metaphase II oocytes
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	=0.909
	Comments
	Method	van Elteren
	Comments

11. Secondary Outcome

Title	Fertilisation Rate
Description	Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time Frame	Day 1 after insemination

Outcome Measure Data

Analysis Population Description

Subjects with oocytes retrieved.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	634	640
Mean (Standard Deviation) [Percentage of oocytes]	56 (24.5)	57 (23.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Fertilisation rate
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	van Elteren
	Comments

12. Secondary Outcome

Title	Number and Quality of Embryos on Day 3
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	On day 3 after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Subjects with oocytes retrieved.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	634	640
Number of embryos	5.4 (3.7)	5.7 (4.3)
Number of good-quality embryos	4.2 (3.3)	4.5 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Number of embryos
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	=0.59
	Comments
	Method	van Elteren
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Good quality embryos
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	=0.414
	Comments
	Method	van Elteren
	Comments

13. Secondary Outcome

Title	Number and Quality of Blastocysts on Day 5
Description	Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
Time Frame	On day 5 after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Subjects with oocytes retrieved.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	634	640
Number of blastocysts	3.3 (2.8)	3.5 (3.2)
Number of good-quality blastocysts	2.0 (2.2)	2.1 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Number of blastocysts
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	= 0.344
	Comments
	Method	van Elteren
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Good-quality blastocysts
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	= 0.58
	Comments
	Method	van Elteren
	Comments

14. Secondary Outcome

Title	Total Gonadotropin Dose
Description	The total gonadotropin dose was recorded.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Mean (Standard Deviation) [µg of dose]	90 (25.3)	103.7 (33.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Total gonadotropin dose
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	van Elteren
	Comments

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Mean (Standard Deviation) [Days]	8.9 (1.9)	8.6 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Number of stimulation days
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using the van Elteren test adjusted for age (<35, 35-37, and 38-40 years).
Statistical Test of Hypothesis	p-Value	=0.062
	Comments
	Method	van Elteren
	Comments

16. Secondary Outcome

Title	Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description

mITT analysis set (all randomised and exposed subjects). This is equivalent to the FAS.

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number [Percentage of subjects]	33.2	36.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Investigator-requested gonadotropin dose adjustments
	Type of Statistical Test	Equivalence
	Comments	Treatment groups were compared using a chi-square test.
Statistical Test of Hypothesis	p-Value	=0.178
	Comments
	Method	Chi-squared
	Comments

17. Secondary Outcome

Title	Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period
Description	Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency 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

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number [Percentage of events]	3.4	3.5

18. Secondary Outcome

Title	Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS)
Description	The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort).
Time Frame	End-of-stimulation and day of blastocyst transfer

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
End of stimulation visit	16.1 (18.14)	15.9 (17.36)
Transfer visit	17.2 (20.02)	16.1 (19.37)

19. Secondary Outcome

Title	Changes in Body Weight
Description	Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time Frame	End-of-stimulation and day of blastocyst transfer

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
End of stimulation visit	0.3 (1.11)	0.2 (0.78)
Transfer visit	0.0 (1.03)	0.0 (0.98)

20. Secondary Outcome

Title	Changes in Maximum Abdominal Circumference
Description	Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time Frame	End-of-stimulation and day of blastocyst transfer

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
End of stimulation visit	0.3 (4.41)	0.1 (5.03)
Transfer visit	0.6 (4.79)	-0.1 (5.23)

21. Secondary Outcome

Title	Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies
Description	The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.
Time Frame	Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number (95% Confidence Interval) [Percentage of subjects]	1.05	0.76

22. Secondary Outcome

Title	Proportion of Subjects With Late OHSS
Description	Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented.
Time Frame	>9 days after triggering of final follicular maturation

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Late OHSS (any grade)	0.9	1.8
Late OHSS (moderate/severe)	0.8	1.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Late OHSS (any grade)
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	0.320
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FE 999049, GONAL-F
	Comments	Treatment comparison: Late OHSS (moderate/severe)
	Type of Statistical Test	Other
	Comments	Nested logistic regression models were compared using the likelihood ratio test. The full logistic regression model included treatment as factor, log(AMH) as covariate and the interaction term. The nested model did not include treatment and the interaction term.
Statistical Test of Hypothesis	p-Value	0.390
	Comments	Inclusion of treatment does not provide a better fit to the data.
	Method	Likelihood ratio test
	Comments	Likelihood ratio test comparing the reduced model including only AMH to the full model including AMH, treatment group and interactions.

23. Secondary Outcome

Title	Technical Malfunctions of the Administration Pen
Description	Confirmed technical malfunction of administration pen.
Time Frame	End-of-stimulation (up to 20 stimulation days)

Outcome Measure Data

Analysis Population Description

Safety analysis set (all randomised and exposed subjects). This is equivalent to the mITT (FAS).

Arm/Group Title	FE 999049	GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.	GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
Measure Participants	665	661
Number [Percentage of subjects]	0.15	0.00

Adverse Events

Time Frame	Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months).
Adverse Event Reporting Description	AEs 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		GONAL-F
Arm/Group Description	FE 999049 was administered as single daily subcutaneous injections in the abdomen. Subjects randomised to FE 999049 had their individual dose determined on the basis of their AMH level at screening and their body weight at randomisation. The daily FE 999049 dose was fixed throughout the stimulation period and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.		GONAL-F was administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F 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 450 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Subjects could be treated for a maximum of 20 days.
All Cause Mortality
	FE 999049		GONAL-F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	FE 999049		GONAL-F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/665 (2.4%)		10/661 (1.5%)
Gastrointestinal disorders
Colitis ulcerative	1/665 (0.2%)	1	0/661 (0%)	0
Infections and infestations
Post procedural infection	0/665 (0%)	0	1/661 (0.2%)	1
Injury, poisoning and procedural complications
Post procedural haemorrhage	2/665 (0.3%)	2	0/661 (0%)	0
Pregnancy, puerperium and perinatal conditions
Haemorrhage in pregnancy	5/665 (0.8%)	5	1/661 (0.2%)	1
Abortion spontaneous	2/665 (0.3%)	2	1/661 (0.2%)	1
Biochemical pregnancy	1/665 (0.2%)	1	2/661 (0.3%)	2
Abortion threatened	1/665 (0.2%)	1	0/661 (0%)	0
Hyperemesis gravidarum	0/665 (0%)	0	1/661 (0.2%)	1
Psychiatric disorders
Affect lability	1/665 (0.2%)	1	0/661 (0%)	0
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome	3/665 (0.5%)	3	6/661 (0.9%)	6
Adnexal torsion	1/665 (0.2%)	1	0/661 (0%)	0
Other (Not Including Serious) Adverse Events
	FE 999049		GONAL-F
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	168/665 (25.3%)		159/661 (24.1%)
Injury, poisoning and procedural complications
Procedural pain	49/665 (7.4%)	51	52/661 (7.9%)	54
Nervous system disorders
Headache	97/665 (14.6%)	131	88/661 (13.3%)	110
Reproductive system and breast disorders
Pelvic pain	46/665 (6.9%)	54	41/661 (6.2%)	59
Pelvic discomfort	38/665 (5.7%)	46	25/661 (3.8%)	31

Limitations/Caveats

[Not Specified]

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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.