Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in India Women (IRIS)

A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial in India Comparing the Efficacy and Safety of FE 999049 (Follitropin Delta) With Follitropin Alfa (GONAL-F) in Controlled Ovarian Stimulation in Women Undergoing an Assisted Reproductive Technology Programme

To demonstrate non-inferiority of FE 999049 compared with GONAL-F with respect to ongoing pregnancy rate in women undergoing controlled ovarian stimulation.

FE 999049 will be administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 will have their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. For participants with low AMH (<15 pmol/L) the daily FE 999049 dose will be 12 μg, irrespective of body weight. For participants with high AMH (≥15 pmol/L) the daily FE 999049 dose will be on a continuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent on actual AMH and body weight. The daily FE 999049 dose will be fixed throughout the stimulation period and maximum allowed daily dose will be 12 μg. Participants could be treated for a maximum of 20 days.

GONAL-F will be administered as single daily subcutaneous injections in the abdomen. The starting dose of GONAL-F will be 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose will be 450 IU. Participants could be treated for a maximum of 20 days.

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

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

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

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

Proportion of subjects with early ovarian hyperstimulation syndrome (OHSS) (including OHSS of moderate/severe grade) and/or preventive interventions for early OHSS

The proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS will be presented.

Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or embryo transfer cancellation due to excessive ovarian response / OHSS risk

The proportion of participants with cycle cancellation due to poor or excessive ovarian response or embryo transfer cancellation due to excessive ovarian response / OHSS risk will be presented.

Percentage of metaphase II oocytes (only applicable for those inseminated using intracytoplasmic sperm injection [ICSI])

The percentage of metaphase II oocytes to oocytes retrieved for participants where all oocytes were inseminated using ICSI will be presented.

The fertilisation rate is defined as the number of fertilized oocytes with 2 pronuclei divided by the number of oocytes retrieved.

The total number of embryos and the number of good-quality embryos will be counted on Day 3. A good-quality embryo is defined as an embryo with ≥6 blastomeres and ≤20% fragmentation, without signs of multinucleation.

Changes from baseline in circulating levels of clinical chemistry parameters: Albumin and Total protein

Blood samples will be collected for the analysis of clinical chemistry parameters including: Albumin and Total protein.

Changes from baseline in circulating levels of clinical chemistry parameters: Alanine transaminase, Alkaline phosphatase, Aspartate aminotransferase, Gamma-glutamyl transpeptidase

Blood samples will be collected for the analysis of clinical chemistry parameters including: Alanine transaminase, Alkaline phosphatase, Aspartate aminotransferase and Gamma-glutamyl transpeptidase.

Changes from baseline in circulating levels of clinical chemistry parameters: Bicarbonate, Blood urea nitrogen, Calcium, Chloride, Cholesterol total, Glucose, Phosphorus, Potassium, Sodium, Uric acid

Blood samples will be collected for the analysis of clinical chemistry parameters including: Bicarbonate, Blood urea nitrogen, Calcium, Chloride, Cholesterol total, Glucose, Phosphorus, Potassium, Sodium and Uric acid.

Changes from baseline in circulating levels of clinical chemistry parameters: Bilirubin direct, Bilirubin, Creatinine

Blood samples will be collected for the analysis of clinical chemistry parameters including: Bilirubin direct, Bilirubin and Creatinine.

Blood samples will be collected for the analysis of clinical chemistry parameter including: Lactate dehydrogenase.

Proportion of subjects with markedly abnormal changes from baseline in clinical chemistry at end-of-stimulation

Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) will be reported. The clinical chemistry parameters include: albumin, alanine transaminase, alkaline phosphatase, aspartate aminotransferase, 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 subjects with markedly abnormal changes from baseline in clinical chemistry at end-of-trial

Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) will be reported. The clinical chemistry parameters include: albumin, alanine transaminase, alkaline phosphatase, aspartate aminotransferase, 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.

Changes from baseline in circulating levels of clinical haematology parameters: Red blood cells, Red blood cells morphology

Blood samples will be collected for the analysis of clinical haematology including: Red blood cells and Red blood cell morphology.

Changes from baseline in circulating levels of clinical haematology parameters: White blood cells, White blood cell morphology, Platelets

Blood samples will be collected for the analysis of clinical haematology including: White blood cells, White blood cell morphology and Platelets.

Blood samples will be collected for the analysis of clinical haematology parameter including: Haemoglobin.

Blood samples will be collected for the analysis of clinical haematology parameter including: Haematocrit.

Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Volume

Blood samples will be collected for the analysis of clinical haematology parameter including: Mean Corpuscular Volume.

Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Haemoglobin

Blood samples will be collected for the analysis of clinical haematology parameter including: Mean Corpuscular Haemoglobin.

Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Hemoglobin Concentration

Blood samples will be collected for the analysis of clinical haematology parameter including: Mean Corpuscular Hemoglobin Concentration.

Proportion of subjects with markedly abnormal changes from baseline in haematology parameters at end-of-stimulation

Defined as number of participants with at least one markedly abnormal changes in haematology parameters (as assessed by investigator) will be reported. Haematology parameters include: red blood cells, red blood cell morphology, white blood cells, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.

Proportion of subjects with markedly abnormal changes from baseline in haematology parameters end-of-trial

Defined as number of participants with at least one markedly abnormal changes in haematology parameters (as assessed by investigator) will be reported. Haematology parameters include: red blood cells, red blood cell morphology, white blood cells, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.

Assessed by the participant during the stimulation period. Participants will self-assess injection site reactions (redness, pain, itching, swelling, and bruising) immediately, 30 minutes and 24 hours after each injection.

Assessed by the participant during the stimulation period as mild, moderate or severe. Participants will be tabulated according to the highest severity of their reported injection site reactions.

All adverse events reported in the trial will be analyzed to identify those that are potentially immune-related. They will be tabulated using the Standardised Medical Dictionary for Regulatory Activities [MedDRA] Queries (SMQs).

Proportion of subjects with cycle cancellations due to an adverse event, including immune-related adverse events, or due to technical malfunctions of the pre-filled injection pen

Late OHSS is 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 will be presented.

The proportion of participants with early and/or late OHSS and/or preventive interventions for early OHSS will be presented.

Percentage of subjects with multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic pregnancy (with and without medical/surgical intervention) and vanishing twins

Participants will report any technical malfunctions of the pre-filled injection pen. Percentage of participants with confirmed technical malfunctions will be presented.

Inclusion Criteria: Informed Consent Forms signed prior to screening evaluations. In good physical and mental health as judged by the investigator. Indian (i.e., possessing an Indian identification card and having native Indian parents) pre-menopausal females between the ages of 21 and 40 years. The participants must be at least 21 years (including the 21st birthday) when they sign the informed consent and no more than 40 years (up to the day before the 41st birthday) at the time of randomization. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine [ASRM] classification, 1996) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or ICSI using fresh or frozen ejaculated sperm from male partner or sperm donor. Infertility for at least one year before randomization for participants <35 years or for at least 6 months for participants ≥35 years (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. Regular menstrual cycles of 24-35 days (both inclusive), presumed to be ovulatory. 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 randomization. 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) within 1 year prior to randomization. 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 within 1 year prior to randomization. Body mass index (BMI) between 17.5 and 32.0 kg/m^2 (both inclusive) at screening. Willing to accept transfer of 1-2 embryos. Exclusion Criteria: Known endometriosis stage III-IV (defined by the revised ASRM classification, 1996). One or more follicles ≥10 mm (including cysts) observed on the transvaginal ultrasound prior to randomization on stimulation day 1 (puncture of cysts is allowed prior to randomization). 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. Any known clinically significant systemic disease (e.g., insulin-dependent diabetes). Known inherited or acquired thrombophilia disease. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. Known porphyria. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of controlled thyroid function disease. Known presence of anti-FSH antibodies (based on the information available in the participant's medical records). 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, haematology or vital signs at screening which is clinically significant as judged by the investigator. Currently breast-feeding. Undiagnosed vaginal bleeding. Known abnormal cervical cytology of clinical significance observed within 3 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. Use of hormonal preparations (except for thyroid medication) during the last menstrual cycle before randomization. Known history of chemotherapy (except for gestational conditions) or radiotherapy. Current or past (1 year prior to randomization) abuse of alcohol or drugs. Current (last month) intake of more than 14 units of alcohol per week. Current or past (3 months prior to randomization) smoking habit of more than 10 cigarettes per day. Hypersensitivity to any active ingredient or excipients in the medicinal products used in the trial. Previous participation in the trial. Use of any non-registered investigational drugs during the last 3 months prior to randomization.