Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-1)

Infertility Clinical Trial

— RITA-1  

Official title:

A Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Trial Investigating the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Women Aged 18-34 Years Undergoing Assisted Reproductive Technology

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03740737
• Other study ID #: 000001
• Status: Completed
• Phase: Phase 3
• Start date: October 26, 2018
• Est. completion date: November 11, 2020

Study information

• Verified date: August 2023
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial investigates the effects of FE 999049 compared to placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 579
• Est. completion date: November 11, 2020
• Est. primary completion date: November 11, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 34 Years

Eligibility

Inclusion Criteria:

• Informed Consent Documents signed prior to any trial-related procedure.
• In good physical and mental health in the judgement of the investigator.
• Pre-menopausal females between the ages of 18 and 34 years. The participants must be at least 18 years (including the 18th birthday) when they sign the informed consent and no more than 34 years (up to the day before the 35th birthday) at the time of randomization.
• Body mass index (BMI) between 17.5 and 38.0 kg/m2 (both inclusive) at screening.
• Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
• Documented history of infertility for at least 12 months before randomization (not applicable in case of tubal or severe male factor infertility, or when the use of donor sperm is indicated).
• Regular menstrual cycles of 24-35 days (both inclusive).
• Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous fibroids of any size or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) at screening or within 1 year prior to screening.
• Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) at screening. Both ovaries must be accessible for oocyte retrieval.
• Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomization).
• Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests at screening or within 6 months prior to screening.
• Willing to accept single blastocyst transfer in the fresh cycle and in the cryopreserved cycles initiated within 12 months from the start of COS using blastocysts obtained in this trial.

Exclusion Criteria:

• More than one previous COS cycle for IVF/ICSI.
• Known endometriosis stage III-IV (defined by the revised ASRM classification, 2012 ).
• Known history of anovulation.
• One or more follicles greater than or equal to 10 mm (including cysts) observed on the transvaginal ultrasound prior to randomization on stimulation day 1.
• Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy [excluding ectopic pregnancy] and before week 24 of pregnancy).
• Known abnormal karyotype of participant or of her partner / sperm donor, as applicable, depending on source of sperm used for insemination in this trial. In case partner sperm will be used and the sperm production is severely impaired (concentration <1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented.
• Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
• Known inherited or acquired thrombophilia.
• Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
• Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of pharmacologically controlled sub-clinical hypothyroidism.
• Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.
• Known moderate or severe impairment of renal or hepatic function.
• Any abnormal finding of clinical chemistry, hematology, thyroid-stimulating hormone (TSH) or prolactin, or vital signs at screening, which is judged clinically significant by the investigator.
• Known abnormal cervical cytology of clinical significance observed within three years prior to randomization (unless the clinical significance has been resolved).
• Findings at the gynecological examination at screening which preclude gonadotropin stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine device.
• Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to randomization) or contraindication to pregnancy.
• Known current active pelvic inflammatory disease.
• Use of fertility modifiers during the last menstrual cycle before randomization, including dehydroepiandrosterone (DHEA), metformin or cycle programming with oral contraceptives, progestogen or estrogen preparations.

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• Follitropin delta
FE 999049 was administered as single daily subcutaneous injections in the abdomen at a starting dose of 12 µg daily that was fixed for the first four stimulation days. Based on ovarian response, the dose could be adjusted by 3 µg, with dose increases implemented not more frequently than once every 2 days and dose decreases implemented per investigator's judgement. The minimum daily dose was 6 µg, and the maximum daily dose was 24 µg. Participants could be treated for a maximum of 20 days. Coasting, use of dopamine agonist or any other drug to prevent early ovarian hyperstimulation syndrome (OHSS) with the exception of gonadotropin-releasing hormone (GnRH) agonist for triggering of final follicular maturation, was not allowed.

Other:
• Placebo
Placebo was administered as single daily subcutaneous injection dialed to the same value (dose) as FE 999049. Participants could be treated for a maximum of 20 days. Coasting, use of dopamine agonist or any other drug to prevent early OHSS with the exception of GnRH agonist for triggering of final follicular maturation, was not allowed.

Locations

Country	Name	City	State
United States	Abington Reproductive Medicine	Abington	Pennsylvania
United States	Center for Assisted Reproduction	Bedford	Texas
United States	Main Line Fertility Center	Bryn Mawr	Pennsylvania
United States	Reproductive Endocrinology Associates of Charlotte (REACH) S. Corporation	Charlotte	North Carolina
United States	Fertility Centers of Illinois (RH)	Chicago	Illinois
United States	Institute for Reproductive Health	Cincinnati	Ohio
United States	Women's Medical Research Group, LLC	Clearwater	Florida
United States	HRC Fertility	Encino	California
United States	Center for Advanced Reproductive Services PC	Farmington	Connecticut
United States	InVia Fertility	Hoffman Estates	Illinois
United States	Fertility Institute of Hawaii, INC	Honolulu	Hawaii
United States	Houston Fertility Institute	Houston	Texas
United States	Fertility Associates of Memphis, PLLC	Memphis	Tennessee
United States	Reproductive Associates of Delaware	Newark	Delaware
United States	Eastern Virginia Medical School | EVMS Obstetrics & Gynecology	Norfolk	Virginia
United States	Utah Fertility Center	Pleasant Grove	Utah
United States	Carolina Conceptions	Raleigh	North Carolina
United States	Mayo Clinic	Rochester	Minnesota
United States	Seattle Reproductive Medicine WA	Seattle	Washington
United States	Fertility Treatment Center	Tempe	Arizona
United States	Boston IVF	Waltham	Massachusetts
United States	Center of Reproductive Medicine	Webster	Texas
United States	Center for Reproductive Medicine	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative Ongoing Pregnancy Rate After the Fresh Cycle and Cryopreserved Cycles Initiated Within 12 Months From the Start of COS	Defined as at least one intrauterine viable fetus 8-9 weeks after transfer. Data in this endpoint are presented for the fresh cycle and the cryopreserved cycles.	8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary	Ongoing Pregnancy Rate in the Fresh Cycle and in the Cryopreserved Cycles	Defined as at least one intrauterine viable fetus 8-9 weeks after transfer. Data in this endpoint are presented for the fresh cycle and the cryopreserved cycles.	8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary	Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles	Time from start of COS to ongoing pregnancy, including both the fresh and cryopreserved cycles.; In the placebo group, no participants achieved an ongoing pregnancy either after 12 calendar months or after 12 study months.	8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary	Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Measured in Number of Cycles Before Achieving Ongoing Pregnancy	Time from start of COS to ongoing pregnancy, including both the fresh and cryopreserved cycles, measured in number of cycles before achieving ongoing pregnancy.; In the placebo group, no participants achieved an ongoing pregnancy either after 12 calendar months or after 12 study months.	8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary	Ongoing Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively	Defined as the number of intrauterine viable fetuses 8-9 weeks after transfer divided by number of blastocysts transferred. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.; One participant can contribute with a range from zero to multiple blastocysts.; Data is not shown for placebo arm because no blastocyst transfer was performed in the fresh cycle or cryopreserved cycles.; '%' in the unit of measure refers to 'percentage'.	8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary	Clinical Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively	Defined at least one gestational sac 5-6 weeks after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.	5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
Secondary	Vital Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively	Defined at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.	5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
Secondary	Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively	Defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.; One participant can contribute with a range from zero to multiple blastocysts.; Data is not shown for placebo arm because no subjects underwent blastocyst transfer in the fresh cycle or cryopreserved cycles.; '%' in the unit of measure refers to 'percentage'.	5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
Secondary	Positive Beta Human Chorionic Gonadotropin (ßhCG) Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively	Defined as positive serum ßhCG test 10-14 days after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.	10-14 days after transfer (up to approximately 14 months after start of stimulation)
Secondary	Proportion of Subjects in the Fresh Cycle With Triggering of Final Follicular Maturation (hCG, With GnRH Agonist, and in Total), Cycle Cancellation and Transfer Cancellation	Data in this endpoint are presented for the fresh cycle.	Up to 5 days after oocyte retrieval (up to 27 days after start of stimulation)
Secondary	Number of Follicles on Stimulation Day 5	The total number of follicles and the number of follicles per size category are presented	On stimulation day 5
Secondary	Number of Follicles at End-of-stimulation	The total number of follicles and the number of follicles per size category is reported.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Size of Follicles on Stimulation Day 5	Counted by ultrasound for the right and left ovary for each participant.	On stimulation day 5
Secondary	Size of Follicles at End-of-stimulation	Counted by ultrasound for the right and left ovary for each participant.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Number of Oocytes Retrieved	The number of oocytes retrieved was recorded at the oocyte retrieval visit.	On day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Proportion of Subjects With <4, 4-7, 8-14, 15-19 and =20 Oocytes Retrieved	Grouped according to the number of oocytes retrieved. Participants with cycle cancellation due to poor ovarian response are included in the <4 oocytes group.	On day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Number of Metaphase II Oocytes	The number of MII oocytes to oocytes retrieved for participants where all oocytes were inseminated using ICSI are presented.	On day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Number of Fertilized Oocytes	An oocyte was defined as fertilized if it had 2 pronuclei (2PN) at 19h (±2h).	On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
Secondary	Fertilization Rate	The fertilization rate was defined as the number of 2PN oocytes divided by the number of oocytes retrieved.; Fertilization rate relative to oocytes retrieved has been reported.; Data is not shown for placebo arm because the mean number of fertilized oocytes was 0 in all subjects, since no subjects had oocytes retrieved or fertilized.	On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
Secondary	Number and Quality of Blastocysts on Day 5 After Oocyte Retrieval	Number of blastocysts (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.	On day 5 after oocyte retrieval
Secondary	Endometrial Thickness on Stimulation Day 5	Mean endometrial thickness is reported.	On stimulation day 5
Secondary	Endometrial Thickness at End-of-stimulation	Mean endometrial thickness is reported.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Echogenicity Pattern on Stimulation Day 5	The distribution of participants with hypoechogenic, isoechogenic, or hyperechogenic endometrium is reported.	On stimulation day 5
Secondary	Echogenicity Pattern at End-of-stimulation	The distribution of participants with hypoechogenic, isoechogenic, or hyperechogenic endometrium is reported.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Oocyte Utilization Rate	Defined as the number of blastocysts transferred or cryopreserved divided by the number of oocytes retrieved.; Data in this endpoint are presented for the cryopreserved cycles.	On day of oocyte retrieval up to 12 months after start of COS
Secondary	Oocyte Efficiency Index	Defined as the cumulative number of ongoing pregnancies per oocyte retrieved.; Data in this endpoint are presented for the cryopreserved cycles.; The unit of measure for this endpoint is 'cumulative ongoing pregnancies/oocyte retrieved'.	8-9 weeks after transfer
Secondary	Percentage of Blastocysts Surviving Cryopreservation	Data in this endpoint are presented for the cryopreserved cycles.; The unit is number of blastocysts with observations. One participant can contribute with a range from zero to multiple blastocysts.	0 hour (+0.5 hour) after thawing
Secondary	Percentage of Blastocysts With Re-expansion After Cryopreservation	Data in this endpoint are presented for the cryopreserved cycles.; The unit is number of blastocysts with observations. One participant can contribute with a range from zero to multiple blastocysts.	2.5 hour (±0.5 hour) after thawing
Secondary	Number of Cryopreserved Cycles Initiated Within 12 Months From the Start of COS	The total number of cryopreserved cycles initiated are reported.; One participant can contribute with multiple cycles.; Data in this endpoint are presented for the cryopreserved cycles.	Up to 12 months after start of stimulation
Secondary	Number of Cryopreserved Cycles With Blastocyst Transfer	The total number of cryopreserved cycles with blastocyst transfer are reported.; One participant can contribute with multiple cycles.; Data in this endpoint are presented for the cryopreserved cycles.	Up to 12 months after start of stimulation
Secondary	Circulating Concentrations of Anti-mullerian Hormone (AMH)	Blood samples for analysis of circulating concentrations of AMH were drawn. The median and inter-quartile range (IQR) of AMH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Follicle-stimulating Hormone (FSH)	Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Luteinizing Hormone (LH)	Blood samples for analysis of circulating concentrations of LH were drawn. The median and IQR of LH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Estradiol	Blood samples for analysis of circulating concentrations of estradiol were drawn. The median and IQR of estradiol levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Progesterone	Blood samples for analysis of circulating concentrations of progesterone were drawn. The median and IQR of progesterone levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Inhibin A	Blood samples for analysis of circulating concentrations of inhibin A were drawn. The median and IQR of inhibin A levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Circulating Concentrations of Inhibin B	Blood samples for analysis of circulating concentrations of inhibin B were drawn. The median and IQR of inhibin B levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.	From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Total Gonadotropin Dose	Calculated by start dates, end dates and daily dose of IMP.	Up to 20 stimulation days
Secondary	Number of Stimulation Days	Calculated by start dates and end dates.	Up to 20 stimulation days
Secondary	Proportion of Participants With Investigator-requested Gonadotropin Dose Adjustments	Investigator-requested decreases and increases of the gonadotropin dose.	Stimulation Day 5
Secondary	Percentage of Participants With Adverse Events (AEs)	Any AE occurring after start of IMP and before the end-of-trial visit, or a pre-treatment AE or pre-existing medical condition that worsens in intensity after start of IMP and before the end-of-trial visit was considered treatment-emergent, and is presented for this endpoint.; Data in this endpoint are presented for the fresh cycle.	From time of signing informed consent until the end-of-cycle visit in the fresh cycle (up to approximately 6 months)
Secondary	Intensity of AEs	The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity; moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).; Data in this endpoint are presented for the fresh cycle.	From time of signing informed consent until the end-of-cycle visit in the fresh cycle (up to approximately 6 months)
Secondary	Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Albumin, Protein	Blood samples were collected for the analysis of clinical chemistry parameters including: Albumin and protein.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase and Gamma Glutamyl Transferase	Blood samples were collected for the analysis of clinical chemistry parameters including: Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and gamma glutamyl transferase.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Cholesterol, Glucose, Phosphate, Potassium and Sodium	Blood samples were collected for the analysis of clinical chemistry parameters including: Bicarbonate, blood urea nitrogen, calcium, chloride, cholesterol, glucose, phosphate, potassium and sodium.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Direct Bilirubin, Total Bilirubin, Creatinine, Urate	Blood samples were collected for the analysis of clinical chemistry parameters including: Direct bilirubin, total bilirubin, creatinine, urate.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Lactate Dehydrogenase	Blood samples were collected for the analysis of clinical chemistry parameters including: Lactate dehydrogenase.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Proportion of Subjects With Markedly Abnormal Changes of Clinical Chemistry Parameters: Phosphate, Potassium	The table represents the percentage of participants in each group with normal baseline values and markedly abnormal end-of-stimulation or end-of-cycle visit values for phosphate and potassium.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Erythrocytes	Blood samples were collected for the analysis of haematology parameter including: Erythrocytes.; Data in this endpoint are presented for the fresh cycle.	From screening to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Leukocytes and Platelets	Blood samples were collected for the analysis of haematology parameters including: Leukocytes and platelets.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Haemoglobin	Blood samples were collected for the analysis of haematology parameters including: Haemoglobin.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Haematocrit	Blood samples were collected for the analysis of haematology parameter including: Haematocrit.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Volume	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular volume.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Hemoglobin	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular hemoglobin.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Haemoglobin Concentration	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular haemoglobin concentration.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Changes in Haematology Parameters Compared to Baseline: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes	Blood samples were collected for the analysis of haematology parameters including: Basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes and neutrophils/leukocytes.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Proportion of Subjects With Markedly Abnormal Changes of Haematology Parameters: Leukocytes and Lymphocytes/Leukocytes.	The table represents the percentage of participants in each group with normal baseline values and markedly abnormal end-of-stimulation or end-of-cycle visit values for Leukocytes and lymphocytes/leukocytes.; Data in this endpoint are presented for the fresh cycle.	From screening (baseline) to the end-of-stimulation visit and end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period	Assessed by the participant during the stimulation period. Participants assessed the injection site reactions (redness, pain, itching, swelling and bruising) three times daily: immediately after the injection, 30 minutes after the injection and 24 hours after the injection.	End-of-stimulation (up to 20 stimulation days)
Secondary	Intensity of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period	Assessed by the participant during the stimulation period as mild, moderate or severe.	End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralizing Capacity	Measured by presence of anti-FSH antibodies.; 95% Clopper-Pearson confidence interval has been reported in this endpoint.	Up to 28 days after end of the stimulation period
Secondary	Frequency and Intensity of Immune-related AEs	Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs).	From time of signing informed consent until the end-of-cycle visit in the fresh cycle (approximately 6 months)
Secondary	Proportion of Subjects With Cycle Cancellations Due to an AE, Including Immune-related AEs, or Due to Technical Malfunctions of the Administration Pen	For each participant the reason for cycle cancellation is recorded.; Data in this endpoint are presented for the fresh cycle.	Up to 20 stimulation days
Secondary	Proportion of Subjects With OHSS, Overall and by Grade, and Proportion of Subjects With Moderate/Severe OHSS	Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe.; Data in this endpoint are presented for the fresh cycle.	=9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation until 21-28 days after last IMP dose or up to ongoing pregnancy 8-9 weeks after transfer in pregnant participants (late OHSS)
Secondary	Proportion of Subjects Hospitalized Due to OHSS and Proportion of Subjects Undergoing Paracentesis Due to OHSS	Percentage of participants hospitalized or undergoing paracentesis due to OHSS are reported.	=9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation until 21-28 days after last IMP dose or up to ongoing pregnancy 8-9 weeks after transfer in pregnant participants (late OHSS)
Secondary	Proportion of Participants With Multi-fetal Gestation in the Fresh Cycle	Defined as pregnancy with more than one fetus. Among participants with ongoing pregnancy, percentage of participants with twin pregnancies are presented.; '%' in the unit of measure refers to 'percentage'.	Up to 8-9 weeks after transfer
Secondary	Proportion of Cryopreserved Cycles With Multi-fetal Gestation	Defined as pregnancy with more than one fetus. Among cryopreserved cycles with ongoing pregnancy, percentage of cycles with twin pregnancies are presented.; '%' in the unit of measure refers to 'percentage'.	Up to 8-9 weeks after transfer
Secondary	Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy (With and Without Medical/Surgical Intervention) and Vanishing Twins in the Fresh Cycle	The percentage of participants with biochemical pregnancy, spontaneous abortion, ectopic pregnancy (with and without medical/surgical intervention) and vanishing twins in the fresh cycle are presented.; The overall number of participants analyzed is the number of participants with positive ßhCG.; Data is not shown for placebo arm because no participants had a positive ßhCG.; '%' in the unit of measure refers to 'percentage'.; Unit: Percentage of participants with early pregnancy loss.	Up to 8-9 weeks after transfer
Secondary	Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy (With and Without Medical/Surgical Intervention) and Vanishing Twins in the Cryopreserved Cycles	The percentage of cryopreserved cycles with biochemical pregnancy, spontaneous abortion, ectopic pregnancy (with and without medical/surgical intervention) and vanishing twins are presented.; '%' in the unit of measure refers to 'percentage'.; Data is not shown for placebo arm because no participants had a positive ßhCG.	Up to 8-9 weeks after transfer
Secondary	Proportion of Participants With Technical Malfunctions of the Administration Pen	Incidences of technical malfunctions of the administration pen were recorded.	Up to 20 stimulation days