Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women

• Follitropin delta (Drug), also known as FE 999049, REKOVELLE: Single daily subcutaneous administration through pre-filled injection pen
• Follitropin beta (Drug), also known as FOLLISTIM: Single daily subcutaneous injection in the abdomen

Primary outcomes

• Number of Oocytes Retrieved [36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)]: The number of oocytes retrieved was recorded at the oocyte retrieval visit.

Secondary outcomes

• Clinical Pregnancy Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]: Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
• Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate [13-15 days after transfer (up to approximately 1.5 months after start of stimulation)]: Defined as positive serum beta-hCG test 13-15 days after transfer.
• Vital Pregnancy Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]: Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
• Implantation Rate [5-6 weeks after transfer (up to approximately 3 months after start of stimulation)]: Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
• Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response [End-of-stimulation (up to 20 stimulation days)]
• Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk [End-of-stimulation (up to 20 stimulation days)]
• Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved [On the day of oocyte retrieval (up to 22 days after start of stimulation)]: Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
• Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population [On the day of oocyte retrieval (up to 22 days after start of stimulation)]
• Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) [≤9 days after triggering of final follicular maturation]
• Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS [Up to 9 days after triggering of final follicular maturation]: Defined as proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.
• Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) [>9 days after triggering of final follicular maturation]: Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.
• Number of Follicles on Stimulation Day 6 [At Day 6 of stimulation]: Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
• Number of Follicles at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
• Size of Follicles on Stimulation Day 6 [At Day 6 of stimulation]: Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint.
• Size of Follicles at End-of-Stimulation [End-of-stimulation (up to 20 stimulation days)]: Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint.
• Fertilization Rate [Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)]: The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
• Number and Quality of Embryos [Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)]: Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
• Number and Quality of Blastocysts [Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)]: Number of embryos (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.
• Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 [At Day 6 of stimulation]: The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
• Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: The median and IQR of FSH and LH levels at end-of-stimulation are presented.
• Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 [At Day 6 of stimulation]: The median and IQR of estradiol levels on stimulation Day 6 are presented.
• Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: The median and IQR of estradiol levels at end-of-stimulation are presented.
• Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 [At Day 6 of stimulation]: The median and IQR of progesterone levels on stimulation Day 6 are presented.
• Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: The median and IQR of progesterone levels at end-of-stimulation are presented.
• Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 [At Day 6 of stimulation]: The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
• Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: The median and IQR of Inhibin A levels at end-of-stimulation are presented.
• Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 [At Day 6 of stimulation]: The median and IQR of inhibin B levels on stimulation Day 6 are presented.
• Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: The median and IQR of inhibin B levels at end-of-stimulation are presented.
• Number of Stimulation Days [End-of-stimulation (up to 20 stimulation days)]
• Total Gonadotropin Dose of FE 999049 [End-of-stimulation (up to 20 stimulation days)]
• Total Gonadotropin Dose of FOLLISTIM [End-of-stimulation (up to 20 stimulation days)]
• Number of Participants With Adverse Events (AEs) Stratified by Intensity [From signed informed consent up to 5-6 weeks after transfer]: The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. 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).
• Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
• Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation [End-of-stimulation (up to 20 stimulation days)]: Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
• Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial [Up to 5-6 weeks after transfer]: Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
• Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial [Up to 5-6 weeks after transfer]: Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
• Frequency and Intensity of Injection Site Reactions [End-of-stimulation (up to 20 stimulation days)]: The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
• Technical Malfunctions of the Administration Pens [End-of-stimulation (up to 20 stimulation days)]

Sex: Female, ages: 20 Years to 40 Years

Inclusion Criteria:

* Informed Consent Documents signed prior to any trial-related procedures.
* In good physical and mental health.
* Japanese females between the ages of 20 and 40 years.
* Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine (ASRM) classification) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from male partner.
* Infertility for at least 1 year before randomization (not applicable in case of tubal or severe male factor infertility).
* The trial cycle will be the participant's first controlled ovarian stimulation cycle for IVF/ICSI.
* Hysterosalpingography, hysteroscopy, saline infusion sonography or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior to screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening.
* Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and fallopian tubes and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
* Early follicular phase (cycle day 2-4) serum levels of follicle stimulating hormone (FSH) between 1 and 15 IU/L (results obtained within 3 months prior to screening).
* Body mass index (BMI) between 17.5 and 32.0 kg/m\^2 (both inclusive) at screening.

Exclusion Criteria:

* Known endometriosis stage III-IV (defined by the revised ASRM classification).
* One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomization is allowed).
* Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy).
* Known abnormal karyotype of participant or of her partner. In case the sperm production is severely impaired (concentration <1 million/mL), normal karyotype, including no Y chromosome microdeletion, must be documented.
* Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
* Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
* Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease.
* Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.

Participant flow

Outcome results

• Number of Oocytes Retrieved (Primary), Mean, Oocytes retrieved: FE 999049 (Follitropin Delta) 9.3 +/- 5.4; FOLLISTIM (Follitropin Beta) 10.5 +/- 6.1
• Clinical Pregnancy Rate (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 25.3; FOLLISTIM (Follitropin Beta) 23.7
• Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 29.4; FOLLISTIM (Follitropin Beta) 29.4
• Vital Pregnancy Rate (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 23.5; FOLLISTIM (Follitropin Beta) 21.5
• Implantation Rate (Secondary), Number, % of sacs/blastocysts transferred: FE 999049 (Follitropin Delta) 31.9; FOLLISTIM (Follitropin Beta) 29.8
• Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 1.2; FOLLISTIM (Follitropin Beta) 0.6
• Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 7.6; FOLLISTIM (Follitropin Beta) 11.3 (p 0.244)
• Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 8.3; FOLLISTIM (Follitropin Beta) 5.2 (p 0.254)
• Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 11.6; FOLLISTIM (Follitropin Beta) 12.3 (p 0.893)
• Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 0; FOLLISTIM (Follitropin Beta) 1.1
• Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 10.0; FOLLISTIM (Follitropin Beta) 18.6 (p 0.017)
• Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) (Secondary), Number, percentage of participants: FE 999049 (Follitropin Delta) 1.2; FOLLISTIM (Follitropin Beta) 1.1 (p 0.968)
• Number of Follicles on Stimulation Day 6 (Secondary), Mean, Follicles: FE 999049 (Follitropin Delta) 12.8 +/- 7.2; FOLLISTIM (Follitropin Beta) 13.3 +/- 7.1 (p 0.198)
• Number of Follicles at End-of-stimulation (Secondary), Mean, Follicles: FE 999049 (Follitropin Delta) 14.9 +/- 8.0; FOLLISTIM (Follitropin Beta) 16.3 +/- 8.8 (p 0.036)
• Size of Follicles on Stimulation Day 6 (Secondary), Mean, mm: FE 999049 (Follitropin Delta) 12.7 +/- 2.1; FOLLISTIM (Follitropin Beta) 12.8 +/- 2.0 (p 0.592)
• Size of Follicles at End-of-Stimulation (Secondary), Mean, mm: FE 999049 (Follitropin Delta) 19.2 +/- 1.5; FOLLISTIM (Follitropin Beta) 19.4 +/- 1.6 (p 0.286)
• Fertilization Rate (Secondary), Mean, percentage of fertilized oocytes: FE 999049 (Follitropin Delta) 54.5 +/- 26.1; FOLLISTIM (Follitropin Beta) 57.1 +/- 23.4 (p 0.395)
• Number and Quality of Embryos (Secondary), Mean, Embryo: FE 999049 (Follitropin Delta) 5.8 +/- 4.2; FOLLISTIM (Follitropin Beta) 7.0 +/- 4.3 (p 0.001)
• Number and Quality of Blastocysts (Secondary), Mean, Blastocysts: FE 999049 (Follitropin Delta) 3.1 +/- 2.7; FOLLISTIM (Follitropin Beta) 4.2 +/- 3.4 (p <.001)
• Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 (Secondary), Median, IU/L: FE 999049 (Follitropin Delta) 15.4 (12.0 to 19.6); FOLLISTIM (Follitropin Beta) 14.7 (12.8 to 17.3) (p 0.228)
• 19 more outcome measures not shown.

Adverse events

Time frame: Adverse events were monitored from the time of obtaining informed consent until the last visit (end-of-trial) (up to approximately 2 years) .

Serious adverse events by term

Other adverse events by term

• Results publication: Ishihara O, Arce JC; Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial. Reprod Biomed Online. 2021 May;42(5):909-918. doi: 10.1016/j.rbmo.2021.01.023. Epub 2021 Feb 9. PMID 33722477
• Results publication: Ishihara O, Nelson SM, Arce JC. Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients. Reprod Biomed Online. 2022 Jan;44(1):177-184. doi: 10.1016/j.rbmo.2021.09.014. Epub 2021 Sep 23. PMID 34799275
• Results publication: Fernandez-Sanchez M, Fatemi H, Garcia-Velasco JA, Heiser PW, Daftary GS, Mannaerts B. Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in "freeze-all" approach. Gynecol Endocrinol. 2023 Dec;39(1):2205952. doi: 10.1080/09513590.2023.2205952. PMID 37156263

• Study Protocol (PDF, 2018-03-16)
• Statistical Analysis Plan (PDF, 2019-08-22)

• Global Clinical Compliance, Study director, Ferring Pharmaceuticals