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

• Sponsor: IVFarma LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04854707
• Collaborator: Institute for Preventive and Social Medicine (Other)
• Enrollment: 5,484
• Locations: 35
• Actual Duration (Months): 12.3
• Patients Per Site: 156.7
• Patients Per Site Per Month: 12.8

Study Details

Study Description

Brief Summary

Aim to investigate the efficacy of follitropin alpha biosimilar therapy (Primapur®) in nonselected real-world population.

Condition or Disease	Intervention/Treatment	Phase
Reproductive Issues; Reproductive Disorder; Fertility Disorders; Fertility Issues; Gynecologic Disease; IVF	Drug: Follitropin Alfa; Drug: Follicle Stimulating Hormone/Luteinizing Hormone; Drug: Follitropin Alfa; Drug: Follitropin Alfa; Drug: Follicle Stimulating Hormone/Luteinizing Hormone

Detailed Description

A retrospective observational anonymized cohort study of follitropin alpha biosimilar (Primapur®) as a pre-filled pen injector with a dose adjustment of 5 IU, aimed to investigate its efficacy and safety in a nonselected population with indications to assisted reproductive technologies (ART) was carried out. The ovarian stimulation (OS) protocols included:

monotherapy protocols with using only Primapur®; mixed protocols (recombinant and urinary-derived gonadotropins); short protocols with using antagonists of gonadotropin-releasing hormone (GnRH) and long protocols with GnRH agonists. The stimulation protocols were analyzed with Primapur® application for at least 5 days.

Study Design

• Study Type: Observational
• Actual Enrollment: 5484 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: An Observational Study "FOLLITROPIN" Comparing the Efficacy of Follitropin Alpha Biosimilar: the Real-world Data
• Actual Study Start Date: Jan 12, 2020
• Actual Primary Completion Date: Dec 20, 2020
• Actual Study Completion Date: Jan 20, 2021

Arms and Interventions

Arm	Intervention/Treatment
Monoprotocols: follitropin alpha biosimilar only and antagonists/agonists of GnRH 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.	Drug: 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.; Other Names: Primapur Biosimilar
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.	Drug: 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.; Other Names: Follitropin beta Follitropin alfa + Lutropin alfa Corifollitropin alfa Menotropins Follitropin alfa Follitropin alfa biosimilar
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.	Drug: 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.; Other Names: Primapur Biosimilar Follitropin alfa biosimilar
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.	Drug: 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.; Other Names: Primapur Biosimilar Follitropin alfa biosimilar
The overall protocols 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	Drug: 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).; Other Names: Follitropin beta Corifollitropin alfa Follitropin alfa + Lutropin alfa Menotropins Follitropin alfa biosimilar Follitropin alfa

Outcome Measures

Primary Outcome Measures

1. Number of Oocytes Retrieved [From date of start of ovarian stimulation with follitropin alpha up to 15 days]

   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).

2. Percentage of Participants With Ongoing Clinical Pregnancy Per Embryo Transfer [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).

Secondary Outcome Measures

1. Number of Mature Oocytes [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).

2. Number of Fertilized Oocytes [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).

3. Total Dose of Follitropin Alpha Biosimilar Protocol, IU [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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 43 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women with established causes of infertility and indications for the use of ART methods, according to the Order of the Ministry of Health of the Russian Federation "On the use of assisted reproductive technologies, contraindications and limitations to their use" No. 107 n dated August 30, 2012.

• Infertility due to female and/or male factor.

• Presence of ovaries accessible for aspiration of follicles.

• Anatomical and functional capability of uterus to bear pregnancy.

Exclusion Criteria:

• Women with established contraindications to the use of ART methods, according to the Order of the Ministry of Health of the Russian Federation "On the use of assisted reproductive technologies, contraindications and limitations to their use" No. 107 n dated August 30, 2012.

• Presence of pregnancy

• Hypersensitivity to follitropin alfa or excipients.

• Ovarian cysts (not associated with polycystic ovarian syndrome), uterine hemorrhage of unclear etiology

• Premature ovarian failure

• Presence of clinically significant systemic disease

• Presence of chronic cardiovascular, hepatic, renal or pulmonary disease

• Neoplasia

• Narcomania, alcoholism

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for reproductive medicine, Barnaul	Barnaul		Russian Federation
2	Clinical Institute of Reproductive Medicine	Ekaterinburg		Russian Federation
3	Center for reproductive medicine, Irkutsk	Irkutsk		Russian Federation
4	Clinic "Mother and Child" Kazan	Kazan		Russian Federation
5	Clinic "Mother and Child" Kostroma	Kostroma		Russian Federation
6	Clinic "Mother and Child" Krasnodar	Krasnodar		Russian Federation
7	Center for reproductive medicine, Krasnoyarsk	Krasnoyarsk		Russian Federation
8	Clinical Hospital Lapino	Moscow Oblast		Russian Federation
9	AltraVita IVF clinic	Moscow		Russian Federation
10	Center of Reproductive Medicine and Genetics "Nova Clinic"	Moscow		Russian Federation
11	Clinic "Mather and Child" Lefortovo	Moscow		Russian Federation
12	Clinic "Mather and Child" Savelovskaya	Moscow		Russian Federation
13	Clinic "Mother and Child" Khodynskoe Pole	Moscow		Russian Federation
14	Clinic "Mother and Child" Kuntsevo	Moscow		Russian Federation
15	Clinic "Mother and Child" South-West	Moscow		Russian Federation
16	Clinical Hospital MD GROUP (Perinatal Center on Sevastopolskiy)	Moscow		Russian Federation
17	Clinic "Mother and Child"	Nizhny Novgorod		Russian Federation
18	Medika-2	Novokuznetsk		Russian Federation
19	Center for reproductive medicine, Novosibirsk	Novosibirsk		Russian Federation
20	Clinical Hospital "Avicenna"	Novosibirsk		Russian Federation
21	Ceter for reproductive medicine, Omsk	Omsk		Russian Federation
22	Clinic "Mother and Child" Perm	Perm		Russian Federation
23	Clinic "Mother and Child" Rostov-on-Don	Rostov-on-Don		Russian Federation
24	Clinic "Mather and Child"	Ryazan'		Russian Federation
25	"Genesis" Reproduction Centre	Saint Petersburg		Russian Federation
26	Clinic "Mother and Child" Saint-Petersburg	Saint Petersburg		Russian Federation
27	Clinical Hospital "Mother and Child"	Samara		Russian Federation
28	Clinic "Mather and Child" Tula	Tula		Russian Federation
29	Clinical Hospital "Mother and Child"	Tyumen		Russian Federation
30	Clinical Hospital "Mother and Child"	Ufa		Russian Federation
31	Clinic "Mother and Child" Vladimir	Vladimir		Russian Federation
32	Clinic "Mather and Child" Vladivostok	Vladivostok		Russian Federation
33	Clinic "Mother and Child" Volgograd	Volgograd		Russian Federation
34	Clinic "Mother and Child" Voronezh	Voronezh		Russian Federation
35	Clinic "Mother and Child" Yaroslavl	Yaroslavl		Russian Federation

Sponsors and Collaborators

• IVFarma LLC
• Institute for Preventive and Social Medicine

Investigators

• Principal Investigator: Dilorom Kamilova, PhD, MD Medical Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 10, 2021

More Information

Publications

None provided.

• Responsible Party: IVFarma LLC
• ClinicalTrials.gov Identifier: NCT04854707
• Other Study ID Numbers: IVF-2020
• First Posted: Apr 22, 2021
• Last Update Posted: Oct 22, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by IVFarma LLC: follitropin alpha; follicle-stimulating hormone; in vitro fertilization; assisted reproductive technologies; biosimilar; follitropin alfa; real-world data
• Additional relevant MeSH terms: Infertility; Disease; Menotropins; Hormones; Follicle Stimulating Hormone

Study Results

Participant Flow

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

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	2625	2183	676
COMPLETED	2547	2124	646
NOT COMPLETED	78	59	30

Baseline Characteristics

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	Total
Arm/Group Description	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.	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.	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 of all reporting groups
Overall Participants	2625	2183	676	5484
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.9 (4.8)	32.9 (4.6)	33.1 (4.9)	33.9 (4.8)
Sex: Female, Male (Count of Participants)
Female	2625 100%	2183 100%	676 100%	5484 100%
Male	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	2625 100%	2183 100%	676 100%	5484 100%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Russia	2625 100%	2183 100%	676 100%	5484 100%
Body Mass Index (BMI), kg/m^2 (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.9 (4.7)	23.7 (4.6)	23.1 (4.5)	23.8 (5.7)
Duration of infertility, years (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.7 (4.1)	5.4 (4.3)	5.6 (3.8)	5.6 (4.2)
IVF attempt (number of IVF attempts) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [number of IVF attempts]	1.4 (0.7)	1.2 (0.5)	1.4 (0.9)	1.3 (0.7)

Outcome Measures

1. Primary Outcome

Title	Number of Oocytes Retrieved
Description	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).
Time Frame	From date of start of ovarian stimulation with follitropin alpha up to 15 days

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	The Overall Protocols
Arm/Group Description	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.	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.	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.	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 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).
Measure Participants	2547	2770	2124	646	5317
Mean (Standard Deviation) [The total number of retrieved oocytes]	8.6 (6.8)	10.3 (7.4)	10.5 (7.5)	9.6 (7.0)	9.5 (7.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Percentage of Participants With Ongoing Clinical Pregnancy Per Embryo Transfer
Description	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).
Time Frame	At least 6 weeks after embryo transfer

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	The Overall Protocols
Arm/Group Description	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.	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.	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.	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.	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).
Measure Participants	1542	1800	1466	334	3342
Number (95% Confidence Interval) [Percetnage of patients (%)]	39.3	37.6	37.9	35.9	38.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH
	Comments	95% Confidence intervals (CIs) of point estimates were calculated using the exact binominal distribution (Clopper-Pearson method) for proportions
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.314
	Comments
	Method	Chi-squared
	Comments	z-value = 1
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.0161 to 0.0501
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH
	Comments	95% Confidence intervals (CIs) of point estimates were calculated using the exact binominal distribution (Clopper-Pearson method) for proportions
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.482
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0207
	Confidence Interval	(2-Sided) 95%; -0.0369 to 0.0782
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Mature Oocytes
Description	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).
Time Frame	From date of start of ovarian stimulation with follitropin alpha up to 15 days

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	The Overall Protocols
Arm/Group Description	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.	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.	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.	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.	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).
Measure Participants	2547	2770	2124	646	5317
Mean (Standard Deviation) [Number of mature oocytes]	6.7 (6.2)	7.7 (6.9)	7.6 (6.9)	6.7 (5.7)	6.8 (6.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Number of Fertilized Oocytes
Description	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).
Time Frame	From date of start of ovarian stimulation with follitropin alpha up to 16 days

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	The Overall Protocols
Arm/Group Description	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.	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.	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.	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.	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).
Measure Participants	2547	2770	2124	646	5317
Mean (Standard Deviation) [zygotes with 2PN]	5.8 (5.2)	7.2 (6.2)	7.3 (6.3)	5.7 (5.0)	6.1 (5.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Total Dose of Follitropin Alpha Biosimilar Protocol, IU
Description	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).
Time Frame	From date of start of ovarian stimulation with follitropin alpha up to 16 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH	Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH	The Overall Protocols
Arm/Group Description	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.	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.	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.	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.	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).
Measure Participants	2547	2770	2124	646	5317
Mean (Standard Deviation) [IU (International Units)]	1672 (568)	1919 (639)	1952 (621)	1711 (680)	1825 (647)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mixed Protocols: Recombinant and Urinary-derived Gonadotropins and Antagonists/Agonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists/Agonists of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Monoprotocols: Follitropin Alpha Biosimilar Only and Antagonists of GnRH, Monoprotocols: Follitropin Alpha Biosimilar Only and Agonist of GnRH
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	The time frame was 20 days: ovarian stimulation (up to 15 days) till the day of embryo transfer (up to 5 days).
Adverse Event Reporting Description	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).
Arm/Group Title	The Overall Protocols
Arm/Group Description	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.
All Cause Mortality
	The Overall Protocols
	Affected / at Risk (%)	# Events
Total	0/5484 (0%)
Serious Adverse Events
	The Overall Protocols
	Affected / at Risk (%)	# Events
Total	0/5484 (0%)
Other (Not Including Serious) Adverse Events
	The Overall Protocols
	Affected / at Risk (%)	# Events
Total	657/5484 (12%)
Skin and subcutaneous tissue disorders
Injection site pain	657/5484 (12%)	657

Limitations/Caveats

The real-world patient data analysed in this study were representative, showing the ability of follitropin biosimilars to develop both folliculogenesis and clinical pregnancy in a nonselected population. Additional comparative studies are needed to confirm the efficacy of the biosimilars in patients with classified types of infertility causes, including unexplained infertility.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.