Trial Outcomes & Findings for Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 1 (NCT NCT01956110)

NCT ID: NCT01956110

Last Updated: 2022-01-13

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1329 participants
• Primary outcome timeframe: 10-11 weeks after blastocyst transfer
• Results posted on: 2022-01-13

Participant Flow

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.

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.

Participant milestones

Measure	FE 999049 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.	GONAL-F 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.
Overall Study STARTED	665	661
Overall Study COMPLETED	630	639
Overall Study NOT COMPLETED	35	22

Reasons for withdrawal

Measure	FE 999049 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.	GONAL-F 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.
Overall Study Protocol Violation	25	11
Overall Study Adverse Event	9	10
Overall Study Personal reasons	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	FE 999049 n=665 Participants 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 n=661 Participants 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 n=1326 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	665 Participants n=5 Participants	661 Participants n=7 Participants	1326 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	665 Participants n=5 Participants	661 Participants n=7 Participants	1326 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 10-11 weeks after blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Ongoing Pregnancy Rate	31.6 Percentage of subjects	30.7 Percentage of subjects

PRIMARY outcome

Timeframe: 10-11 weeks after blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=560 Participants 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.	FE 999049 n=562 Participants 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.
Ongoing Implantation Rate	35.8 Percentage	35.2 Percentage

SECONDARY outcome

Timeframe: 5-6 weeks after blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Vital Pregnancy Rate	33.4 Percentage of subjects	31.7 Percentage of subjects

SECONDARY outcome

Timeframe: 5-6 weeks after blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=560 Participants 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.	FE 999049 n=562 Participants 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.
Implantation Rate	41.3 Percentage	39.8 Percentage

SECONDARY outcome

Timeframe: Day of oocyte retrieval

Population: Subjects who underwent triggering of final follicular maturation.

Outcome measures

Measure	GONAL-F n=643 Participants 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.	FE 999049 n=635 Participants 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.
Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved <4 or >=15 oocytes retrieved	31.3 Percentage of subjects	26.6 Percentage of subjects
Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved <4 or >=20 oocytes retrieved	18.4 Percentage of subjects	14.5 Percentage of subjects

SECONDARY outcome

Timeframe: ≤9 days after triggering of final follicular maturation

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

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.

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS Any preventive intervention	4.5 Percentage of subjects	2.3 Percentage of subjects
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS Early OHSS (any grade) / preventive interventions	6.2 Percentage of subjects	4.7 Percentage of subjects
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS Early OHSS (mod/severe) / preventive interventions	5.1 Percentage of subjects	3.6 Percentage of subjects
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS Early OHSS (any grade)	3.0 Percentage of subjects	2.6 Percentage of subjects
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS Early OHSS (moderate/severe)	1.4 Percentage of subjects	1.4 Percentage of subjects

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response Cycle cancelled due to poor ovarian response	2.7 Percentage of subjects	3.8 Percentage of subjects
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response Cycle cancelled due to excessive ovarian response	0 Percentage of subjects	0 Percentage of subjects
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response Triggering with GnRH agonist	3.5 Percentage of subjects	1.5 Percentage of subjects

SECONDARY outcome

Timeframe: Day of oocyte retrieval

Population: Subjects who underwent triggering of final follicular maturation.

Outcome measures

Measure	GONAL-F n=643 Participants 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.	FE 999049 n=636 Participants 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.
Number of Oocytes Retrieved	10.4 Oocytes retrieved Standard Deviation 6.5	10.0 Oocytes retrieved Standard Deviation 5.6

SECONDARY outcome

Timeframe: Day of oocyte retrieval

Population: Subjects who underwent triggering of final follicular maturation.

Outcome measures

Measure	GONAL-F n=643 Participants 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.	FE 999049 n=635 Participants 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.
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved Low response (<4 oocytes)	9.6 Percentage of subjects	8.0 Percentage of subjects
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved Moderate response (4-7 oocytes)	30.3 Percentage of subjects	30.1 Percentage of subjects
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved Targeted response (8-14 oocytes)	38.4 Percentage of subjects	43.3 Percentage of subjects
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved Hyperresponse (15-19 oocytes)	12.9 Percentage of subjects	12.1 Percentage of subjects
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved Severe hyperresponse (≥ 20 oocytes)	8.7 Percentage of subjects	6.5 Percentage of subjects

SECONDARY outcome

Timeframe: Prior to insemination

Population: Subjects with all oocytes inseminated using ICSI.

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

Outcome measures

Measure	GONAL-F n=522 Participants 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.	FE 999049 n=531 Participants 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.
Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])	7.7 Number of oocytes Standard Deviation 5.2	7.4 Number of oocytes Standard Deviation 4.3

SECONDARY outcome

Timeframe: Day 1 after insemination

Population: Subjects with oocytes retrieved.

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

Outcome measures

Measure	GONAL-F n=640 Participants 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.	FE 999049 n=634 Participants 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.
Fertilisation Rate	57 Percentage of oocytes Standard Deviation 23.8	56 Percentage of oocytes Standard Deviation 24.5

SECONDARY outcome

Timeframe: On day 3 after oocyte retrieval

Population: Subjects with oocytes retrieved.

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.

Outcome measures

Measure	GONAL-F n=640 Participants 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.	FE 999049 n=634 Participants 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.
Number and Quality of Embryos on Day 3 Number of embryos	5.7 Number of embryos Standard Deviation 4.3	5.4 Number of embryos Standard Deviation 3.7
Number and Quality of Embryos on Day 3 Number of good-quality embryos	4.5 Number of embryos Standard Deviation 3.7	4.2 Number of embryos Standard Deviation 3.3

SECONDARY outcome

Timeframe: On day 5 after oocyte retrieval

Population: Subjects with oocytes retrieved.

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.

Outcome measures

Measure	GONAL-F n=640 Participants 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.	FE 999049 n=634 Participants 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.
Number and Quality of Blastocysts on Day 5 Number of blastocysts	3.5 Number of blastocytss Standard Deviation 3.2	3.3 Number of blastocytss Standard Deviation 2.8
Number and Quality of Blastocysts on Day 5 Number of good-quality blastocysts	2.1 Number of blastocytss Standard Deviation 2.4	2.0 Number of blastocytss Standard Deviation 2.2

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

The total gonadotropin dose was recorded.

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Total Gonadotropin Dose	103.7 µg of dose Standard Deviation 33.6	90 µg of dose Standard Deviation 25.3

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Number of Stimulation Days	8.6 Days Standard Deviation 1.7	8.9 Days Standard Deviation 1.9

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments	36.8 Percentage of subjects	33.2 Percentage of subjects

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

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.

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period	3.5 Percentage of events	3.4 Percentage of events

SECONDARY outcome

Timeframe: End-of-stimulation and day of blastocyst transfer

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

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).

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) End of stimulation visit	15.9 Millimeter Standard Deviation 17.36	16.1 Millimeter Standard Deviation 18.14
Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) Transfer visit	16.1 Millimeter Standard Deviation 19.37	17.2 Millimeter Standard Deviation 20.02

SECONDARY outcome

Timeframe: End-of-stimulation and day of blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Changes in Body Weight Transfer visit	0.0 Kg Standard Deviation 0.98	0.0 Kg Standard Deviation 1.03
Changes in Body Weight End of stimulation visit	0.2 Kg Standard Deviation 0.78	0.3 Kg Standard Deviation 1.11

SECONDARY outcome

Timeframe: End-of-stimulation and day of blastocyst transfer

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Changes in Maximum Abdominal Circumference End of stimulation visit	0.1 Centimeter Standard Deviation 5.03	0.3 Centimeter Standard Deviation 4.41
Changes in Maximum Abdominal Circumference Transfer visit	-0.1 Centimeter Standard Deviation 5.23	0.6 Centimeter Standard Deviation 4.79

SECONDARY outcome

Timeframe: 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

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

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

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies	0.76 Percentage of subjects Interval 0.25 to 1.76	1.05 Percentage of subjects Interval 0.42 to 2.16

SECONDARY outcome

Timeframe: >9 days after triggering of final follicular maturation

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

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.

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Proportion of Subjects With Late OHSS Late OHSS (any grade)	1.8 Percentage of subjects	0.9 Percentage of subjects
Proportion of Subjects With Late OHSS Late OHSS (moderate/severe)	1.5 Percentage of subjects	0.8 Percentage of subjects

SECONDARY outcome

Timeframe: End-of-stimulation (up to 20 stimulation days)

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

Confirmed technical malfunction of administration pen.

Outcome measures

Measure	GONAL-F n=661 Participants 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.	FE 999049 n=665 Participants 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.
Technical Malfunctions of the Administration Pen	0.00 Percentage of subjects	0.15 Percentage of subjects

Adverse Events

FE 999049

Serious events: 16 serious events

Other events: 168 other events

Deaths: 0 deaths

GONAL-F

Serious events: 10 serious events

Other events: 159 other events

Deaths: 0 deaths

Serious adverse events

Measure	FE 999049 n=665 participants at risk 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 n=661 participants at risk 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.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.30% 2/665 • Number of events 2 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.00% 0/661 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Haemorrhage in pregnancy	0.75% 5/665 • Number of events 5 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.15% 1/661 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.30% 2/665 • Number of events 2 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.15% 1/661 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Biochemical pregnancy	0.15% 1/665 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.30% 2/661 • Number of events 2 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Abortion threatened	0.15% 1/665 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.00% 0/661 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Pregnancy, puerperium and perinatal conditions Hyperemesis gravidarum	0.00% 0/665 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.15% 1/661 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Psychiatric disorders Affect lability	0.15% 1/665 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.00% 0/661 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Gastrointestinal disorders Colitis ulcerative	0.15% 1/665 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.00% 0/661 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Ovarian hyperstimulation syndrome	0.45% 3/665 • Number of events 3 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.91% 6/661 • Number of events 6 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Adnexal torsion	0.15% 1/665 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.00% 0/661 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Infections and infestations Post procedural infection	0.00% 0/665 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	0.15% 1/661 • Number of events 1 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.

Other adverse events

Measure	FE 999049 n=665 participants at risk 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 n=661 participants at risk 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.
Injury, poisoning and procedural complications Procedural pain	7.4% 49/665 • Number of events 51 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	7.9% 52/661 • Number of events 54 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Nervous system disorders Headache	14.6% 97/665 • Number of events 131 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	13.3% 88/661 • Number of events 110 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Pelvic pain	6.9% 46/665 • Number of events 54 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	6.2% 41/661 • Number of events 59 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.
Reproductive system and breast disorders Pelvic discomfort	5.7% 38/665 • Number of events 46 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.	3.8% 25/661 • Number of events 31 • Adverse events (AEs) were recorded from signed informed consent to the end-of-trial (up to approximately 5.5 months). AEs with onset after start of first administration of IMP were considered treatment-emergent and are presented for the safety analysis set.

Additional Information

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Ferring Pharmaceuticals

Email: DK0-Disclosure@ferring.com

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