Clinical trial NCT04773353: Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Indian Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-02-26
Enrollment: 220
Sex: FEMALE
Minimum age (years): 21
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 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.

Primary outcomes:
measure: Ongoing pregnancy rate
timeFrame: 10-11 weeks after embryo transfer
Secondary outcomes:
measure: Positive beta human chorionic gonadotropin (βhCG) rate
timeFrame: 13-15 days after embryo transfer
measure: Clinical pregnancy rate
timeFrame: 5-6 weeks after embryo transfer
measure: Vital pregnancy rate
timeFrame: 5-6 weeks after embryo transfer
measure: Implantation rate
timeFrame: 5-6 weeks after embryo transfer
measure: Ongoing implantation rate
timeFrame: 10-11 weeks after embryo transfer
measure: Proportion of subjects with extreme ovarian responses
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Proportion of subjects with early ovarian hyperstimulation syndrome (OHSS) (including OHSS of moderate/severe grade) and/or preventive interventions for early OHSS
timeFrame: ≤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: At end-of-stimulation (up to 20 stimulation 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
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
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Number of oocytes retrieved
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Percentage of metaphase II oocytes (only applicable for those inseminated using intracytoplasmic sperm injection [ICSI])
timeFrame: On day of oocyte retrieval (up to 22 days after stimulation)
measure: Fertilisation rate
timeFrame: On Day 1 after oocyte retrieval (up to 23 days after start of stimulation)
measure: Number and quality of embryos on day 3 after oocyte retrieval
timeFrame: On Day 3 after oocyte retrieval (up to 25 days after start of stimulation)
measure: Circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
timeFrame: On stimulation day 6
measure: Circulating concentrations of estradiol
timeFrame: On stimulation day 6
measure: Circulating concentrations of progesterone
timeFrame: On stimulation day 6
measure: Circulating concentrations of inhibin A and inhibin B
timeFrame: On stimulation day 6
measure: Circulating concentrations of FSH and LH
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Circulating concentrations of estradiol
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Circulating concentrations of progesterone
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Circulating concentrations of inhibin A and inhibin B
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Total gonadotropin dose
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Number of stimulation days
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Proportion of subjects with investigator-requested gonadotropin dose adjustments
timeFrame: From stimulation Day 6 to end-of-stimulation (up to 20 stimulation days)
measure: Number of events and intensity of adverse events
timeFrame: From signing of the informed consent up to end-of-trial (approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical chemistry parameters: Albumin and Total protein
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical chemistry parameters: Alanine transaminase, Alkaline phosphatase, Aspartate aminotransferase, Gamma-glutamyl transpeptidase
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical chemistry parameters: Bicarbonate, Blood urea nitrogen, Calcium, Chloride, Cholesterol total, Glucose, Phosphorus, Potassium, Sodium, Uric acid
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical chemistry parameters: Bilirubin direct, Bilirubin, Creatinine
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical chemistry parameters: Lactate dehydrogenase
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Proportion of subjects with markedly abnormal changes from baseline in clinical chemistry at end-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Proportion of subjects with markedly abnormal changes from baseline in clinical chemistry at end-of-trial
timeFrame: At end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Red blood cells, Red blood cells morphology
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: White blood cells, White blood cell morphology, Platelets
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Haemoglobin
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Haematocrit
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Volume
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Haemoglobin
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Changes from baseline in circulating levels of clinical haematology parameters: Mean Corpuscular Hemoglobin Concentration
timeFrame: From screening up to end-of-trial (up to approximately 5.5 months)
measure: Proportion of subjects with markedly abnormal changes from baseline in haematology parameters at end-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Proportion of subjects with markedly abnormal changes from baseline in haematology parameters end-of-trial
timeFrame: At end-of-trial (up to approximately 5.5 months)
measure: Frequency of injection site reactions (redness, pain, itching, swelling and bruising)
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Intensity of injection site reactions
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Frequency of immune-related adverse events
timeFrame: From signing of the informed consent up to end-of-trial (approximately 5.5 months)
measure: Intensity of immune-related adverse events
timeFrame: From signing of the informed consent 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 pre-filled injection pen
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Proportion of subjects with late OHSS (including OHSS of moderate/severe grade)
timeFrame: >9 days after triggering of final follicular maturation
measure: Proportion of subjects with OHSS (early and/or late) and/or preventive interventions for early OHSS
timeFrame: >9 days after triggering of final follicular maturation
measure: Percentage of subjects with multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic pregnancy (with and without medical/surgical intervention) and vanishing twins
timeFrame: 10-11 weeks after transfer
measure: Technical malfunctions of the pre-filled injection pen
timeFrame: At end-of-stimulation (up to 20 stimulation days)
Other outcomes:
Locations:
city: Ahmedabad
country: India
facility: Ferring Investigational Site
state: Gujarat
city: Anand
country: India
facility: Ferring Investigational Site
state: Gujarat
city: Nashik
country: India
facility: Ferring Investigational Site
state: Maharashtra
city: Pune
country: India
facility: Ferring Investigational Site
state: Mumbai
city: Varanasi
country: India
facility: Ferring Investigational Site
state: New Delhi
city: Chennai
country: India
facility: Ferring Investigational Site
state: Tamil Nadu
city: Coimbatore
country: India
facility: Ferring Investigational Site
state: Tamil Nadu
city: Secunderabad
country: India
facility: Ferring Investigational Site
state: Telangana
city: Lucknow
country: India
facility: Ferring Investigational Site
state: Uttar Pradesh
city: Bangalore
country: India
facility: Ferring Investigational Site
city: Kolhapur
country: India
facility: Ferring Investigational Site
city: New Delhi
country: India
facility: Ferring Investigational Site
Study officials:
affiliation: Ferring Pharmaceuticals
name: Global Clinical Compliance
role: STUDY_DIRECTOR
References: