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

Phase 3

Completed

Conditions: Controlled Ovarian Simulation

Interventions: Drug: Follitropin delta
Drug: Follitropin alfa

Registration Number: NCT03296527

Lead Sponsor: Ferring Pharmaceuticals

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 1011

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Follitropin delta	Follitropin delta	Recombinant follicle-stimulating hormone (rFSH). Follitropin delta for subcutaneous injection
Gonal-F	Follitropin alfa	rFSH. Follitropin alfa for subcutaneous injection

Primary Outcome Measures

Name	Time	Method
Ongoing Pregnancy Rate	10-11 weeks after transfer	Defined as at least one intrauterine viable fetus 10-11 weeks after transfer.

Secondary Outcome Measures

Name	Time	Method
Ongoing Implantation Rate	10-11 weeks after transfer	Defined as number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of embryos transferred.
Number of Participants With Adverse Events	From screening up to end-of-trial (up to approximately 5.5 months)	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.
Clinical Pregnancy Rate	5-6 weeks after transfer	Defined as at least one gestational sac 5-6 weeks after transfer.
Vital Pregnancy Rate	5-6 weeks after transfer	Defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
Implantation Rate	5-6 weeks after transfer	Defined as number of gestational sacs 5-6 weeks after transfer divided by number of embryos transferred.
Positive Beta Unit of Human Chorionic Gonadotropin (βhCG) Rate	13-15 days after transfer	Defined as positive βhCG test 13-15 days after transfer.
Proportion of Subjects With Extreme Ovarian Responses	Oocyte retrieval visit	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.
Number of Follicles on Stimulation Day 6	On stimulation Day 6	Counted by ultrasound for the right and left ovary for each participant.
Number of Follicles At End-of-stimulation (up to 20 Stimulation Days)	At end-of-stimulation (up to 20 stimulation days)	Counted by ultrasound for the right and left ovary for each participant.
Size of Follicles on Stimulation Day 6	On stimulation Day 6	Counted by ultrasound for the right and left ovary for each participant.
Percentage of Metaphase II (MII) Oocytes	Prior to insemination	The percentage of MII oocytes to oocytes retrieved for participants where all oocytes were inseminated using intracytoplasmic sperm injection (ICSI) are presented.
Fertilization Rate	On Day 1 after oocyte retrieval	The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Circulating Concentrations of Follicle-stimulating Hormone (FSH)	On stimulation Day 6	Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels on stimulation Day 6 are presented.
Total Gonadotropin Dose	Up to 20 stimulation days	Calculated by start dates, end dates and daily dose of IMP.
Proportion of Subjects 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	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.
Number of Oocytes Retrieved	On the day of oocyte retrieval (36 h [±2h] after triggering of final follicular maturation)	The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved	On the day of oocyte retrieval	Grouped according to the number of oocytes retrieved. Participants with cycle cancellation due to poor ovarian response are included in the \<4 oocytes group.
Proportion of Subjects With Cycle Cancellation Due to Poor or Excessive Ovarian Response or Embryo Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk	End-of-stimulation visit (up to 20 days) or transfer visit	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.
Size of Follicles At End-of-stimulation (up to 20 Stimulation Days)	At end-of-stimulation (up to 20 stimulation days)	Counted by ultrasound for the right and left ovary for each participant.
Circulating Concentrations of Estradiol	End-of-stimulation (up to 20 stimulation days)	Blood samples for analysis of circulating concentrations of estradiol were drawn. The median and IQR of estradiol levels at end-of-stimulation are presented.
Circulating Concentrations of Inhibin B	End-of-stimulation (up to 20 stimulation days)	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.
Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments	Up to 20 stimulation days	Investigator-requested decreases and increases of the gonadotropin dose were captured during the stimulation period.
Change From Baseline in Haematology Parameter: Haemoglobin	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Haemoglobin.
Number and Quality of Embryos	On Day 3 after oocyte retrieval	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.
Circulating Concentrations of Luteinizing Hormone (LH)	On stimulation Day 6	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.
Circulating Concentrations of Inhibin A	End-of-stimulation (up to 20 stimulation days)	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.
Circulating Concentrations of FSH	At oocyte retrieval	Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels at oocyte retrieval are presented.
Number of Stimulation Days	Up to 20 stimulation days	Calculated by start dates and end dates.
Changes From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase and Gamma Glutamyl Transferase	From screening up to end-of-trial (up to approximately 5.5 months)	Blood samples were collected for the analysis of clinical chemistry parameters including: Alanine aminotransferase, Alkaline phosphatase, Aspartate aminotransferase and Gamma glutamyl transferase.
Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of clinical chemistry parameters including: Albumin and Protein.
Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of clinical chemistry parameter including: Lactate dehydrogenase.
Proportion of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralizing Capacity	Up to 28 days after end of the stimulation period	Measured by presence of anti-FSH antibodies.
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	Up to 20 stimulation days	For each participant the reason for cycle cancellation will be recorded.
Proportion of Participants With Early Pregnancy Losses	End-of-trial	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.
Proportion of Participants With Technical Malfunctions of the Administration Pen	End-of-stimulation (up to 20 stimulation days)	Incidences of technical malfunctions of the administration pen were recorded.
Circulating Concentrations of LH	End-of-stimulation (up to 20 stimulation days)	Blood samples for analysis of circulating concentrations of LH were drawn. The median and IQR of LH levels at end-of-stimulation are presented.
Intensity of Adverse Events	From screening up to end-of-trial (up to approximately 5.5 months)	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).
Change From Baseline in Clinical Chemistry Parameters: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Cholesterol, Glucose, Phosphate, Potassium and Sodium	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of clinical chemistry parameters including: Bicarbonate, Blood urea nitrogen, Calcium, Chloride, Cholesterol, Glucose, Phosphate, Potassium and Sodium.
Proportion of Subjects With Markedly Abnormal Changes of Clinical Chemistry: Alanine Aminotransferase, Aspartate Aminotransferase, Bicarbonate, Calcium, Phosphate	End-of-stimulation visit and end-of-trial visit	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.
Change From Baseline in Haematology Parameter: Erythrocytes	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Erythrocytes.
Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin Concentration	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular haemoglobin concentration.
Change From Baseline in Haematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameters including: Basophils/leukocytes, Eosinophils/leukocytes, Lymphocytes/leukocytes, Monocytes/leukocytes and Neutrophils/leukocytes.
Number of Immune-related Adverse Events	From screening up to end-of-trial (approximately 5.5 months)	Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs).
Intensity of Injection Site Reactions	End-of-stimulation (up to 20 stimulation days)	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.
Intensity of Immune-related Adverse Events	From screening up to end-of-trial (approximately 5.5 months)	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).
Proportion of Participants With Multi-fetal Gestation	End-of-trial	Defined as pregnancy with more than one fetus. Among participants with ongoing pregnancy, percentage of participants with twin pregnancies are presented.
Circulating Concentrations of Progesterone	End-of-stimulation (up to 20 stimulation days)	Blood samples for analysis of circulating concentrations of progesterone were drawn. The median and IQR of progesterone levels at end-of-stimulation are presented.
Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Volume	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular volume.
Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Erythrocyte mean corpuscular haemoglobin.
Proportion of Subjects With Markedly Abnormal Changes of Haematology Parameters: Leukocytes, Lymphocytes/Leukocytes	End-of-stimulation visit and end-of-trial visit	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.
Change From Baseline in Clinical Chemistry Parameter: Direct Bilirubin, Bilirubin, Creatinine, Urate	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of clinical chemistry parameter including: Direct bilirubin, Bilirubin, Creatinine, Urate.
Change From Baseline in Haematology Parameters: Leukocytes and Platelets	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameters including: Leukocytes and Platelets.
Change From Baseline in Haematology Parameter: Haematocrit	From screening up to end-of-trial (approximately 5.5 months)	Blood samples were collected for the analysis of haematology parameter including: Haematocrit.
Frequency of Injection Site Reactions	End-of-stimulation (up to 20 stimulation days)	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.
Proportion of Subjects With Late OHSS	After 9 days post triggering of final follicular maturation	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.

Trial Locations

Locations (26): Beijing Obstetrics and Gynecology Hospital,Capital Medical University
🇨🇳
Beijing, China
ShengJing Hospital of China Medical University
🇨🇳
Shenyang, China
The Third Affiliated Hospital of Guangzhou Medical University
🇨🇳
Guangzhou, China
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Chang Gung Memorial Hospital
🇨🇳
Taoyuan, Taiwan
Medical Center for Human Reproduction, Peking University Third Hospital
🇨🇳
Beijing, China
West China Second University Hospital of Sichuan University
🇨🇳
Chengdu, China
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
🇨🇳
Guangzhou, China
The First Affiliated Hospital of An'hui Medical University
🇨🇳
Hefei, China
Peking University Shenzhen Hospital
🇨🇳
Shenzhen, China
Tianjin Central Hospital of Gynaecology and Obstetrics
🇨🇳
Tianjin, China
Renmin Hospital of Wuhan University
🇨🇳
Wuhan, China
The First Affiliated Hospital of Zhengzhou University
🇨🇳
Zhengzhou, China
The Sixth Affiliated Hospital of Sun Yat-sen University
🇨🇳
Guangzhou, China
Tongji Hospital,Tongji Medical College, Huazhong University of Science & Technology
🇨🇳
Wuhan, China
Tianjin Medical University General Hospital
🇨🇳
Tianjin, China
National Center for Assisted Reproductive Technology
🇻🇳
Hanoi, Vietnam
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷
Seongnam-si, Korea, Republic of
Taichung Veterans General Hospital
🇨🇳
Taichung, Taiwan
My Duc Hospital
🇻🇳
Ho Chi Minh City, Vietnam
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Taipei Medical University Hospital
🇨🇳
Taipei, Taiwan
Jiangsu Province Hospital
🇨🇳
Nanjing, China
Peking University First Hospital
🇨🇳
Beijing, China