Trial Outcomes & Findings for An Observational Study of Follitropin Alpha Biosimilar: the Real-world Data (NCT NCT04854707)

Last Updated: 2021-10-22

Results Overview

The total number of retrieved oocytes at the day of ovum pick-up. No more than 37 hours from the introduction of the ovulation inducer (HCG or GnRH-agonist). Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) the analysed population was: (1) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH - 2625 participants (lack of efficacy: 78 participants, the analysed population was 2547 participants); (2) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH - 2859 participants (lack of efficacy: 89, the analysed population was 2770); (3) Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH - 2183 participants (lack of efficacy: 59, the analysed population was 2124) and (4) Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH - 676 participants (lack of efficacy: 30, the analysed population was 646).

Recruitment status

COMPLETED

Target enrollment

5484 participants

Primary outcome timeframe

From date of start of ovarian stimulation with follitropin alpha up to 15 days

Results posted on

2021-10-22

Participant Flow

All of the analysed subjects underwent OS using GnRH antagonist/agonist protocols, with no restrictions on the OS protocol or food supplements/vitamins.

Participant milestones

Participant milestones
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression.
Overall Study STARTED	2625	2183	676
Overall Study COMPLETED	2547	2124	646
Overall Study NOT COMPLETED	78	59	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression.
Overall Study Lack of Efficacy	78	59	30

Baseline Characteristics

An Observational Study of Follitropin Alpha Biosimilar: the Real-world Data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=2625 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=2183 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=676 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression.	Total n=5484 Participants Total of all reporting groups
Age, Continuous	34.9 years STANDARD_DEVIATION 4.8 • n=5 Participants	32.9 years STANDARD_DEVIATION 4.6 • n=7 Participants	33.1 years STANDARD_DEVIATION 4.9 • n=5 Participants	33.9 years STANDARD_DEVIATION 4.8 • n=4 Participants
Sex: Female, Male Female	2625 Participants n=5 Participants	2183 Participants n=7 Participants	676 Participants n=5 Participants	5484 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	2625 Participants n=5 Participants	2183 Participants n=7 Participants	676 Participants n=5 Participants	5484 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment Russia	2625 participants n=5 Participants	2183 participants n=7 Participants	676 participants n=5 Participants	5484 participants n=4 Participants
Body Mass Index (BMI), kg/m^2	23.9 kg/m^2 STANDARD_DEVIATION 4.7 • n=5 Participants	23.7 kg/m^2 STANDARD_DEVIATION 4.6 • n=7 Participants	23.1 kg/m^2 STANDARD_DEVIATION 4.5 • n=5 Participants	23.8 kg/m^2 STANDARD_DEVIATION 5.7 • n=4 Participants
Duration of infertility, years	5.7 years STANDARD_DEVIATION 4.1 • n=5 Participants	5.4 years STANDARD_DEVIATION 4.3 • n=7 Participants	5.6 years STANDARD_DEVIATION 3.8 • n=5 Participants	5.6 years STANDARD_DEVIATION 4.2 • n=4 Participants
IVF attempt	1.4 number of IVF attempts STANDARD_DEVIATION 0.7 • n=5 Participants	1.2 number of IVF attempts STANDARD_DEVIATION 0.5 • n=7 Participants	1.4 number of IVF attempts STANDARD_DEVIATION 0.9 • n=5 Participants	1.3 number of IVF attempts STANDARD_DEVIATION 0.7 • n=4 Participants

PRIMARY outcome

Timeframe: From date of start of ovarian stimulation with follitropin alpha up to 15 days

Population: Arm "Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH" is combined group for primary and secondary outcome measures and consist of patients from "Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH" and "Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH".

Outcome measures

Outcome measures
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=2547 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 78 participants (or 3%), the analysed population was 2547 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH n=2770 Participants The ovarian stimulation (OS) protocols included monotherapy protocols with using follitropin alpha biosimilar only and antagonists/agonists of of gonadotropin-releasing hormone (GnRH): ganirelix, cetrorelix, triptorelin, buserelin. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 89 participants (or 3,1%), the analysed population was 2770 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=2124 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 59 participants (or 2,7%), the analysed population was 2124 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=646 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 30 participants (or 4,4%), the analysed population was 646 participants.	The Overall Protocols n=5317 Participants The OS protocols included: (1) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH, (2) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH Follicle Stimulating Hormone/Luteinizing Hormone: Overall ovarian stimulation protocols with follitropin alpha biosimilar for at least 5 days+other recombinant and menotropins and short (antagonists of GnRH) or long protocol (agonist of GnRH).
Number of Oocytes Retrieved	8.6 The total number of retrieved oocytes Standard Deviation 6.8	10.3 The total number of retrieved oocytes Standard Deviation 7.4	10.5 The total number of retrieved oocytes Standard Deviation 7.5	9.6 The total number of retrieved oocytes Standard Deviation 7.0	9.5 The total number of retrieved oocytes Standard Deviation 7.2

PRIMARY outcome

Timeframe: At least 6 weeks after embryo transfer

Ongoing clinical pregnancy per embryo transfer (detection of gestational sac and heartbeat from 6 weeks after transfer), n (ongoing pregnancy rate per transfer with known outcome, %). Due to delayed embryo transfers, the analysed population for "Ongoing clinical pregnancy per embryo transfer" was: (1) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH - 2007 embryo transfers (1542 with known outcome); (2) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH - 2213 embryo transfers (1800 with known outcome); (3) Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH - 1809 embryo transfers (1466 with known outcome) and (4) Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH - 404 embryo transfers (334 with known outcome).

Outcome measures

Outcome measures
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=1542 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 78 participants (or 3%), the analysed population was 2547 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH n=1800 Participants The ovarian stimulation (OS) protocols included monotherapy protocols with using follitropin alpha biosimilar only and antagonists/agonists of of gonadotropin-releasing hormone (GnRH): ganirelix, cetrorelix, triptorelin, buserelin. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 89 participants (or 3,1%), the analysed population was 2770 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=1466 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 59 participants (or 2,7%), the analysed population was 2124 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=334 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 30 participants (or 4,4%), the analysed population was 646 participants.	The Overall Protocols n=3342 Participants The OS protocols included: (1) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH, (2) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH Follicle Stimulating Hormone/Luteinizing Hormone: Overall ovarian stimulation protocols with follitropin alpha biosimilar for at least 5 days+other recombinant and menotropins and short (antagonists of GnRH) or long protocol (agonist of GnRH).
Percentage of Participants With Ongoing Clinical Pregnancy Per Embryo Transfer	39.3 Percetnage of patients (%) Interval 36.9 to 41.7	37.6 Percetnage of patients (%) Interval 35.3 to 39.8	37.9 Percetnage of patients (%) Interval 35.5 to 40.5	35.9 Percetnage of patients (%) Interval 30.8 to 41.1	38.4 Percetnage of patients (%) Interval 35.9 to 40.2

SECONDARY outcome

Timeframe: From date of start of ovarian stimulation with follitropin alpha up to 15 days

Mature oocytes (MII stage of development). Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) the analysed population was: (1) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH - 2625 participants (lack of efficacy: 78 participants, the analysed population was 2547 participants); (2) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH - 2859 participants (lack of efficacy: 89, the analysed population was 2770); (3) Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH - 2183 participants (lack of efficacy: 59, the analysed population was 2124) and (4) Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH - 676 participants (lack of efficacy: 30, the analysed population was 646).

Outcome measures

Outcome measures
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=2547 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 78 participants (or 3%), the analysed population was 2547 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH n=2770 Participants The ovarian stimulation (OS) protocols included monotherapy protocols with using follitropin alpha biosimilar only and antagonists/agonists of of gonadotropin-releasing hormone (GnRH): ganirelix, cetrorelix, triptorelin, buserelin. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 89 participants (or 3,1%), the analysed population was 2770 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=2124 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 59 participants (or 2,7%), the analysed population was 2124 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=646 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 30 participants (or 4,4%), the analysed population was 646 participants.	The Overall Protocols n=5317 Participants The OS protocols included: (1) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH, (2) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH Follicle Stimulating Hormone/Luteinizing Hormone: Overall ovarian stimulation protocols with follitropin alpha biosimilar for at least 5 days+other recombinant and menotropins and short (antagonists of GnRH) or long protocol (agonist of GnRH).
Number of Mature Oocytes	6.7 Number of mature oocytes Standard Deviation 6.2	7.7 Number of mature oocytes Standard Deviation 6.9	7.6 Number of mature oocytes Standard Deviation 6.9	6.7 Number of mature oocytes Standard Deviation 5.7	6.8 Number of mature oocytes Standard Deviation 6.6

SECONDARY outcome

Timeframe: From date of start of ovarian stimulation with follitropin alpha up to 16 days

Fertilization rate (FR) is percentage of transformation of oocytes into two pronuclei (presence of two pronuclei: zygotes with 2PN). Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) the analysed population was: (1) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH - 2625 participants (lack of efficacy: 78 participants, the analysed population was 2547 participants); (2) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH - 2859 participants (lack of efficacy: 89, the analysed population was 2770); (3) Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH - 2183 participants (lack of efficacy: 59, the analysed population was 2124) and (4) Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH - 676 participants (lack of efficacy: 30, the analysed population was 646).

Outcome measures

Outcome measures
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=2547 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 78 participants (or 3%), the analysed population was 2547 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH n=2770 Participants The ovarian stimulation (OS) protocols included monotherapy protocols with using follitropin alpha biosimilar only and antagonists/agonists of of gonadotropin-releasing hormone (GnRH): ganirelix, cetrorelix, triptorelin, buserelin. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 89 participants (or 3,1%), the analysed population was 2770 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=2124 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 59 participants (or 2,7%), the analysed population was 2124 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=646 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 30 participants (or 4,4%), the analysed population was 646 participants.	The Overall Protocols n=5317 Participants The OS protocols included: (1) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH, (2) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH Follicle Stimulating Hormone/Luteinizing Hormone: Overall ovarian stimulation protocols with follitropin alpha biosimilar for at least 5 days+other recombinant and menotropins and short (antagonists of GnRH) or long protocol (agonist of GnRH).
Number of Fertilized Oocytes	5.8 zygotes with 2PN Standard Deviation 5.2	7.2 zygotes with 2PN Standard Deviation 6.2	7.3 zygotes with 2PN Standard Deviation 6.3	5.7 zygotes with 2PN Standard Deviation 5.0	6.1 zygotes with 2PN Standard Deviation 5.8

SECONDARY outcome

Timeframe: From date of start of ovarian stimulation with follitropin alpha up to 16 days

Mean dose of follitropin alpha biosimilar for ovarian stimulation. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) the analysed population was: (1) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH - 2625 participants (lack of efficacy: 78 participants, the analysed population was 2547 participants); (2) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH - 2859 participants (lack of efficacy: 89, the analysed population was 2770); (3) Monoprotocols: follitropin alpha biosimilar only and antagonists of GnRH - 2183 participants (lack of efficacy: 59, the analysed population was 2124) and (4) Monoprotocols: follitropin alpha biosimilar only and agonist of GnRH - 676 participants (lack of efficacy: 30, the analysed population was 646).

Outcome measures

Outcome measures
Measure	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH n=2547 Participants The OS protocols included: mixed protocols (recombinant with addition of urinary-derived gonadotropins) and antagonists/agonists of GnRH (ganirelix, cetrorelix, triptorelin, buserelin), where follitropin alpha biosimilar used for at least 5 days during OS. Follicle Stimulating Hormone/Luteinizing Hormone: Subcutaneous injection of follitropin alpha biosimilar, with daily dose 100-300 IU for at least 5 days, than added another gonadotropin for a maximum of 10 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 78 participants (or 3%), the analysed population was 2547 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH n=2770 Participants The ovarian stimulation (OS) protocols included monotherapy protocols with using follitropin alpha biosimilar only and antagonists/agonists of of gonadotropin-releasing hormone (GnRH): ganirelix, cetrorelix, triptorelin, buserelin. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH or agonist of GnRH. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 89 participants (or 3,1%), the analysed population was 2770 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH n=2124 Participants The OS protocols included: monotherapy protocols with using only follitropin alpha biosimilar and antagonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using antagonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 59 participants (or 2,7%), the analysed population was 2124 participants.	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH n=646 Participants The OS protocol included: monotherapy protocols with using only follitropin alpha biosimilar and agonists of GnRH. Follitropin Alfa: Subcutaneous injection of follitropin alpha biosimilar only, with daily dose 100-300 IU for 10 days, maximum of 15 days, using agonists of GnRH only for suppression. Due to lack of efficacy of the therapy (ovarian stimulation was not completed and oocytes were not retrieved) in 30 participants (or 4,4%), the analysed population was 646 participants.	The Overall Protocols n=5317 Participants The OS protocols included: (1) Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH, (2) Mixed protocols: recombinant and urinary-derived gonadotropins and antagonists/agonists of GnRH Follicle Stimulating Hormone/Luteinizing Hormone: Overall ovarian stimulation protocols with follitropin alpha biosimilar for at least 5 days+other recombinant and menotropins and short (antagonists of GnRH) or long protocol (agonist of GnRH).
Total Dose of Follitropin Alpha Biosimilar Protocol, IU	1672 IU (International Units) Standard Deviation 568	1919 IU (International Units) Standard Deviation 639	1952 IU (International Units) Standard Deviation 621	1711 IU (International Units) Standard Deviation 680	1825 IU (International Units) Standard Deviation 647

Adverse Events

The Overall Protocols

Serious events: 0 serious events

Other events: 657 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	The Overall Protocols n=5484 participants at risk The overall protocols (groups) were combined and analysed for Serious Adverse Events and other (not including serious) adverse events. Due to overall ovarian stimulation protocols consist of follitropin alpha biosimilar treatment for at least 5 days, the adverse events were combined in one group to analyse the safety of follitropin alpha biosimilar treatment not in relation to protocol of ovarian stimulation and other medication.
Skin and subcutaneous tissue disorders Injection site pain	12.0% 657/5484 • Number of events 657 • The time frame was 20 days: ovarian stimulation (up to 15 days) till the day of embryo transfer (up to 5 days). Serious adverse events collection (hospitalizations). Due to overall ovarian stimulation protocols consist of follitropin alpha biosimilar treatment for at least 5 days, the adverse events were combined in one group ("Overall protocols"). The questionary was not include the enquiry for exact description of ovarian stimulation protocol (or treatment).

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Principal investigator is a sponsor employee
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