Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Pan-Asian Women

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

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

Conditions
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Controlled Ovarian Simulation

Intervention / Treatment
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* Drug: Follitropin alfa
* Drug: Follitropin delta


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent Documents signed prior to screening evaluations. In good physical and mental health in the judgement of the investigator. Asian pre-menopausal females between the ages of 20 and 40 years. The participants must be at least 20 years (including the 20th 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 fertilisation (IVF) and/or intracytoplasmic sperm injection (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 visualisation 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 2 years prior to randomization. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (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 (excl. 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; i.e. not based on the anti-FSH antibody analyses conducted in the trial). Known tumours 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 three years prior to randomization (unless the clinical significance has been resolved). Findings at the gynaecological 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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Follitropin delta<br>Recombinant follicle-stimulating hormone (rFSH). Follitropin delta for subcutaneous injection | Drug: Follitropin delta<br>* REKOVELLE (FE 999049) was fixed throughout the stimulation period.<br>* Other names: REKOVELLE;|
| Active Comparator: Gonal-F<br>rFSH. Follitropin alfa for subcutaneous injection | Drug: Follitropin alfa<br>* GONAL-F dose was fixed for the first 5 stimulation days.<br>* Other names: GONAL-F;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy Rate | Defined as at least one intrauterine viable fetus 10-11 weeks after transfer. | 10-11 weeks after transfer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive Beta Unit of Human Chorionic Gonadotropin (βhCG) Rate | Defined as positive βhCG test 13-15 days after transfer. | 13-15 days after transfer | 
| Clinical Pregnancy Rate | Defined as at least one gestational sac 5-6 weeks after transfer. | 5-6 weeks after transfer | 
| Vital Pregnancy Rate | Defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. | 5-6 weeks after transfer | 
| Implantation Rate | Defined as number of gestational sacs 5-6 weeks after transfer divided by number of embryos transferred. | 5-6 weeks after transfer | 
| Ongoing Implantation Rate | Defined as number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of embryos transferred. | 10-11 weeks after transfer | 
| Proportion of Subjects With Extreme Ovarian Responses | Extreme ovarian response defined as <4, ≥15 or ≥ 20 oocytes retrieved. Participants with cycle cancellation due to poor ovarian response are included as <4 oocytes retrieved. | Oocyte retrieval visit | 
| Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS | Early OHSS was defined as OHSS with onset ≤9 days after triggering of final follicular maturation. Classification of grade was according to Golan's classification system, and all OHSS cases were graded as mild, moderate or severe. | Up to 9 days after triggering of final follicular maturation | 
| Proportion of Subjects With Cycle Cancellation Due to Poor or Excessive Ovarian Response or Embryo Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk | For each participant the reason for each cycle cancellation was recorded. Embryo transfer cancellation due to adverse events, such as ovarian hyperfunction, OHSS and progesterone increased in participants with embryos available for transfer, were considered as transfer cancellations due to excessive response / OHSS risk. | End-of-stimulation visit (up to 20 days) or transfer visit | 
| Number of Follicles on Stimulation Day 6 | Counted by ultrasound for the right and left ovary for each participant. | On stimulation Day 6 | 
| Number of Follicles At End-of-stimulation (up to 20 Stimulation Days) | Counted by ultrasound for the right and left ovary for each participant. | At end-of-stimulation (up to 20 stimulation days) | 
| Size of Follicles on Stimulation Day 6 | Counted by ultrasound for the right and left ovary for each participant. | On stimulation Day 6 | 
| Size of Follicles At End-of-stimulation (up to 20 Stimulation Days) | Counted by ultrasound for the right and left ovary for each participant. | At end-of-stimulation (up to 20 stimulation days) | 
| Number of Oocytes Retrieved | The number of oocytes retrieved was recorded at the oocyte retrieval visit. | On the day of oocyte retrieval (36 h [±2h] after triggering of final follicular maturation) | 
| 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 the day of oocyte retrieval | 
| Percentage of Metaphase II (MII) Oocytes | The percentage of MII oocytes to oocytes retrieved for participants where all oocytes were inseminated using intracytoplasmic sperm injection (ICSI) are presented. | Prior to insemination | 
| Fertilization Rate | The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved. | On Day 1 after oocyte retrieval | 
| Number and Quality of Embryos | 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 ≤20% fragmentation, without signs of multinucleation. | On Day 3 after oocyte retrieval | 
| Circulating Concentrations of Luteinizing Hormone (LH) | Blood samples for analysis of circulating concentrations of LH were drawn. The median and inter-quartile range (IQR) of LH levels on stimulation Day 6 are presented. | On stimulation Day 6 | 
| Circulating Concentrations of LH | Blood samples for analysis of circulating concentrations of LH were drawn. The median and IQR of LH levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| 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 6 are presented. | On stimulation Day 6 | 
| Circulating Concentrations of Estradiol | Blood samples for analysis of circulating concentrations of estradiol were drawn. The median and IQR of estradiol levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| 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 6 are presented. | On stimulation Day 6 | 
| Circulating Concentrations of Progesterone | Blood samples for analysis of circulating concentrations of progesterone were drawn. The median and IQR of progesterone levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| Circulating Concentrations of Inhibin A | Blood samples for analysis of circulating concentrations of inhibin A. The median and IQR of inhibin A levels on stimulation Day 6 are presented. | On stimulation Day 6 | 
| 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 at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| 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 6 are presented. | On stimulation Day 6 | 
| 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 at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| 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 6 are presented. | On stimulation Day 6 | 
| Circulating Concentrations of FSH | Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels at end-of-stimulation are presented. | End-of-stimulation (up to 20 stimulation days) | 
| Circulating Concentrations of FSH | Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels at oocyte retrieval are presented. | At oocyte retrieval | 
| Total Gonadotropin Dose | Calculated by start dates, end dates and daily dose of IMP. | Up to 20 stimulation days | 
| Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments | Investigator-requested decreases and increases of the gonadotropin dose were captured during the stimulation period. | Up to 20 stimulation days | 
| Number of Stimulation Days | Calculated by start dates and end dates. | Up to 20 stimulation days | 
| Number of Participants With Adverse Events | Any adverse event occurring after start of IMP and before the end-of-trial visit, or a pre-treatment adverse event 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. | From screening up to end-of-trial (up to approximately 5.5 months) | 
| Intensity of Adverse Events | The intensity of adverse event 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). | From screening up to end-of-trial (up to approximately 5.5 months) | 
| Changes From Baseline in Clinical Chemistry Parameters: 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. | From screening up to end-of-trial (up to approximately 5.5 months) | 
| Change From Baseline in Clinical Chemistry Parameters: 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. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein | Blood samples were collected for the analysis of clinical chemistry parameters including: Albumin and Protein. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase | Blood samples were collected for the analysis of clinical chemistry parameter including: Lactate dehydrogenase. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Clinical Chemistry Parameter: Direct Bilirubin, Bilirubin, Creatinine, Urate | Blood samples were collected for the analysis of clinical chemistry parameter including: Direct bilirubin, Bilirubin, Creatinine, Urate. | From screening up to end-of-trial (approximately 5.5 months) | 
| Proportion of Subjects With Markedly Abnormal Changes of Clinical Chemistry: Alanine Aminotransferase, Aspartate Aminotransferase, Bicarbonate, Calcium, Phosphate | The table represents the percentage of participants in each group with normal baseline values and markedly abnormal end-of-stimulation or end-of-trial values for alanine aminotransferase, aspartate aminotransferase, bicarbonate, calcium, phosphate. | End-of-stimulation visit and end-of-trial visit | 
| Change From Baseline in Haematology Parameter: Erythrocytes | Blood samples were collected for the analysis of haematology parameter including: Erythrocytes. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameters: Leukocytes and Platelets | Blood samples were collected for the analysis of haematology parameters including: Leukocytes and Platelets. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameter: Haemoglobin | Blood samples were collected for the analysis of haematology parameter including: Haemoglobin. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameter: Haematocrit | Blood samples were collected for the analysis of haematology parameter including: Haematocrit. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Volume | Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular volume. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin | Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular haemoglobin. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin Concentration | Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular haemoglobin concentration. | From screening up to end-of-trial (approximately 5.5 months) | 
| Change From Baseline in Haematology Parameters: 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. | From screening up to end-of-trial (approximately 5.5 months) | 
| Proportion of Subjects With Markedly Abnormal Changes of Haematology Parameters: Leukocytes, Lymphocytes/Leukocytes | The table represents the percentage of participants in each group with normal baseline values and markedly abnormal end-of-stimulation and end-of-trial values for leukocytes and lymphocytes/leukocytes. | End-of-stimulation visit and end-of-trial visit | 
| Number of Immune-related Adverse Events | Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs). | From screening up to end-of-trial (approximately 5.5 months) | 
| Frequency of Injection Site Reactions | 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) | 
| Intensity of Injection Site Reactions | Assessed by the participant during the stimulation period as mild, moderate or severe. Participants are tabulated according to the highest severity of their reported injection site reactions. | End-of-stimulation (up to 20 stimulation days) | 
| Proportion of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralizing Capacity | Measured by presence of anti-FSH antibodies. | Up to 28 days after end of the stimulation period | 
| Intensity of Immune-related Adverse Events | The intensity of immune-related adverse event 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). | From screening up to end-of-trial (approximately 5.5 months) | 
| Proportion of Subjects With Cycle Cancellations Due to an Adverse Event, Including Immune-related Adverse Events, or Due to Technical Malfunctions of the Administration Pen | For each participant the reason for cycle cancellation will be recorded. | Up to 20 stimulation days | 
| Proportion of Subjects With Late OHSS | 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. | After 9 days post triggering of final follicular maturation | 
| Proportion of Participants With Multi-fetal Gestation | Defined as pregnancy with more than one fetus. Among participants with ongoing pregnancy, percentage of participants with twin pregnancies are presented. | End-of-trial | 
| Proportion of Participants With Early Pregnancy Losses | Grouped according to occurrence of biochemical pregnancy, spontaneous abortion, vanishing twin or ectopic pregnancy (with and without medical/surgical intervention). Frequency of early pregnancy losses are presented. | End-of-trial | 
| Proportion of Participants With Technical Malfunctions of the Administration Pen | Incidences of technical malfunctions of the administration pen were recorded. | End-of-stimulation (up to 20 stimulation days) |