Clinical trial NCT03296527: Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Pan-Asian Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Controlled Ovarian Simulation
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2017-09-28
Enrollment: 1011
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Ongoing Pregnancy Rate
timeFrame: 10-11 weeks after transfer
Secondary outcomes:
measure: Positive Beta Unit of Human Chorionic Gonadotropin (βhCG) Rate
timeFrame: 13-15 days after transfer
measure: Clinical Pregnancy Rate
timeFrame: 5-6 weeks after transfer
measure: Vital Pregnancy Rate
timeFrame: 5-6 weeks after transfer
measure: Implantation Rate
timeFrame: 5-6 weeks after transfer
measure: Ongoing Implantation Rate
timeFrame: 10-11 weeks after transfer
measure: Proportion of Subjects With Extreme Ovarian Responses
timeFrame: Oocyte retrieval visit
measure: Proportion of Subjects With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS
timeFrame: Up to 9 days after triggering of final follicular maturation
measure: Proportion of Subjects With Cycle Cancellation Due to Poor or Excessive Ovarian Response or Embryo Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk
timeFrame: End-of-stimulation visit (up to 20 days) or transfer visit
measure: Number of Follicles on Stimulation Day 6
timeFrame: On stimulation Day 6
measure: Number of Follicles At End-of-stimulation (up to 20 Stimulation Days)
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Size of Follicles on Stimulation Day 6
timeFrame: On stimulation Day 6
measure: Size of Follicles At End-of-stimulation (up to 20 Stimulation Days)
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Number of Oocytes Retrieved
timeFrame: On the day of oocyte retrieval (36 h [±2h] after triggering of final follicular maturation)
measure: Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
timeFrame: On the day of oocyte retrieval
measure: Percentage of Metaphase II (MII) Oocytes
timeFrame: Prior to insemination
measure: Fertilization Rate
timeFrame: On Day 1 after oocyte retrieval
measure: Number and Quality of Embryos
timeFrame: On Day 3 after oocyte retrieval
measure: Circulating Concentrations of Luteinizing Hormone (LH)
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of LH
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of Estradiol
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of Estradiol
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of Progesterone
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of Progesterone
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of Inhibin A
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of Inhibin A
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of Inhibin B
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of Inhibin B
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of Follicle-stimulating Hormone (FSH)
timeFrame: On stimulation Day 6
measure: Circulating Concentrations of FSH
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Concentrations of FSH
timeFrame: At oocyte retrieval
measure: Total Gonadotropin Dose
timeFrame: Up to 20 stimulation days
measure: Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
timeFrame: Up to 20 stimulation days
measure: Number of Stimulation Days
timeFrame: Up to 20 stimulation days
measure: Number of Participants With Adverse Events
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Intensity of Adverse Events
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase and Gamma Glutamyl Transferase
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Change From Baseline in Clinical Chemistry Parameters: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Cholesterol, Glucose, Phosphate, Potassium and Sodium
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Clinical Chemistry Parameter: Direct Bilirubin, Bilirubin, Creatinine, Urate
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Proportion of Subjects With Markedly Abnormal Changes of Clinical Chemistry: Alanine Aminotransferase, Aspartate Aminotransferase, Bicarbonate, Calcium, Phosphate
timeFrame: End-of-stimulation visit and end-of-trial visit
measure: Change From Baseline in Haematology Parameter: Erythrocytes
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameters: Leukocytes and Platelets
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameter: Haemoglobin
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameter: Haematocrit
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Volume
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameter: Erythrocyte Mean Corpuscular Haemoglobin Concentration
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Change From Baseline in Haematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Proportion of Subjects With Markedly Abnormal Changes of Haematology Parameters: Leukocytes, Lymphocytes/Leukocytes
timeFrame: End-of-stimulation visit and end-of-trial visit
measure: Number of Immune-related Adverse Events
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: Frequency of Injection Site Reactions
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Intensity of Injection Site Reactions
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralizing Capacity
timeFrame: Up to 28 days after end of the stimulation period
measure: Intensity of Immune-related Adverse Events
timeFrame: From screening up to end-of-trial (approximately 5.5 months)
measure: 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
timeFrame: Up to 20 stimulation days
measure: Proportion of Subjects With Late OHSS
timeFrame: After 9 days post triggering of final follicular maturation
measure: Proportion of Participants With Multi-fetal Gestation
timeFrame: End-of-trial
measure: Proportion of Participants With Early Pregnancy Losses
timeFrame: End-of-trial
measure: Proportion of Participants With Technical Malfunctions of the Administration Pen
timeFrame: End-of-stimulation (up to 20 stimulation days)
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Obstetrics and Gynecology Hospital,Capital Medical University
city: Beijing
country: China
facility: Medical Center for Human Reproduction, Peking University Third Hospital
city: Beijing
country: China
facility: Peking University First Hospital
city: Chengdu
country: China
facility: West China Second University Hospital of Sichuan University
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital, Sun Yat-sen University
city: Guangzhou
country: China
facility: The Sixth Affiliated Hospital of Sun Yat-sen University
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Guangzhou Medical University
city: Hefei
country: China
facility: The First Affiliated Hospital of An'hui Medical University
city: Nanjing
country: China
facility: Jiangsu Province Hospital
city: Shenyang
country: China
facility: ShengJing Hospital of China Medical University
city: Shenzhen
country: China
facility: Peking University Shenzhen Hospital
city: Tianjin
country: China
facility: Tianjin Central Hospital of Gynaecology and Obstetrics
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
city: Wuhan
country: China
facility: Tongji Hospital,Tongji Medical College, Huazhong University of Science & Technology
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Hanoi
country: Vietnam
facility: National Center for Assisted Reproductive Technology
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
Study officials:
affiliation: Ferring Pharmaceuticals
name: Global Clinical Compliance
role: STUDY_DIRECTOR
References:
citation: Qiao J, Zhang Y, Liang X, Ho T, Huang HY, Kim SH, Goethberg M, Mannaerts B, Arce JC. A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients. Hum Reprod. 2021 Aug 18;36(9):2452-2462. doi: 10.1093/humrep/deab155.
citation: Yang R, Zhang Y, Liang X, Song X, Wei Z, Liu J, Yang Y, Tan J, Zhang Q, Sun Y, Wang W, Qian W, Jin L, Wang S, Xu Y, Yang J, Goethberg M, Mannaerts B, Wu W, Zheng Z, Qiao J. Comparative clinical outcome following individualized follitropin delta dosing in Chinese women undergoing ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection. Reprod Biol Endocrinol. 2022 Oct 4;20(1):147. doi: 10.1186/s12958-022-01016-y.
citation: 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.