Clinical trial NCT03228680: Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women
Official title: A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial Assessing the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese 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: 2017-07-25
Enrollment: 373
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 to FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian stimulation.


Eligibility criteria: Inclusion Criteria:

* Informed Consent Documents signed prior to any trial-related procedures.
* In good physical and mental health.
* Japanese females between the ages of 20 and 40 years.
* Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine (ASRM) classification) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from male partner.
* Infertility for at least 1 year before randomization (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.
* 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 screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening.
* Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and fallopian tubes and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
* Early follicular phase (cycle day 2-4) serum levels of follicle stimulating hormone (FSH) between 1 and 15 IU/L (results obtained within 3 months prior to screening).
* Body mass index (BMI) between 17.5 and 32.0 kg/m\^2 (both inclusive) at screening.

Exclusion Criteria:

* Known endometriosis stage III-IV (defined by the revised ASRM classification).
* One or more follicles \>10 mm (including cysts) observed on the transvaginal ultrasound prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomization is allowed).
* 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. In case the sperm production is severely impaired (concentration \<1 million/mL), normal karyotype, including no Y chromosome microdeletion, must be documented.
* Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
* Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
* Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease.
* Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.

Primary outcomes:
measure: Number of Oocytes Retrieved
timeFrame: 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)
Secondary outcomes:
measure: Clinical Pregnancy Rate
timeFrame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
measure: Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate
timeFrame: 13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
measure: Vital Pregnancy Rate
timeFrame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
measure: Implantation Rate
timeFrame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
measure: Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
timeFrame: On the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population
timeFrame: On the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)
timeFrame: ≤9 days after triggering of final follicular maturation
measure: Proportions of Participants 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: Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade)
timeFrame: >9 days after triggering of final follicular maturation
measure: Number of Follicles on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Number of Follicles at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Size of Follicles on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Size of Follicles at End-of-Stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Fertilization Rate
timeFrame: Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)
measure: Number and Quality of Embryos
timeFrame: Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)
measure: Number and Quality of Blastocysts
timeFrame: Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)
measure: Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6
timeFrame: At Day 6 of stimulation
measure: Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Number of Stimulation Days
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Total Gonadotropin Dose of FE 999049
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Total Gonadotropin Dose of FOLLISTIM
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Number of Participants With Adverse Events (AEs) Stratified by Intensity
timeFrame: From signed informed consent up to 5-6 weeks after transfer
measure: Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial
timeFrame: Up to 5-6 weeks after transfer
measure: Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial
timeFrame: Up to 5-6 weeks after transfer
measure: Frequency and Intensity of Injection Site Reactions
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Technical Malfunctions of the Administration Pens
timeFrame: End-of-stimulation (up to 20 stimulation days)
Other outcomes:
Locations:
city: Anjo
country: Japan
facility: Yachiyo Hospital
state: Aichi
city: Chiba-shi
country: Japan
facility: Investigational Site 8121
state: Chiba
city: Maebashi
country: Japan
facility: Yokota Maternity Hospital
state: Gunma
city: Sagamihara
country: Japan
facility: Sophia Ladies Clinic
state: Kanagawa
city: Sendai-shi
country: Japan
facility: Investigational Site 8122
state: Miyagi
city: Higashiōsaka-shi
country: Japan
facility: Investigational Site 8123
state: Osaka
city: Osaka-Shi
country: Japan
facility: Investigational Site 8120
state: Osaka
city: Osaka-shi
country: Japan
facility: Ladies Clinic Kitahama
state: Osaka
city: Saitama-shi
country: Japan
facility: Investigational Site 8125
state: Saitama
city: Shinjuku-Ku
country: Japan
facility: Investigational Site 8124
state: Tokyo
city: Akita
country: Japan
facility: Akita University Hospital
city: Hyogo
country: Japan
facility: Yamashita Ladies' Clinic
city: Saitama
country: Japan
facility: Investigational Site 8126
city: Saitama
country: Japan
facility: Omiya Ladies Clinic
city: Saitama
country: Japan
facility: Saint Women's Clinic
city: Saitama
country: Japan
facility: Women's Clinic Fujimino
city: Tokushima
country: Japan
facility: Tokushima University Hospital
Study officials:
affiliation: Ferring Pharmaceuticals
name: Global Clinical Compliance
role: STUDY_DIRECTOR
References:
citation: Ishihara O, Arce JC; Japanese Follitropin Delta Phase 3 Trial (STORK) Group. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial. Reprod Biomed Online. 2021 May;42(5):909-918. doi: 10.1016/j.rbmo.2021.01.023. Epub 2021 Feb 9.
citation: Ishihara O, Nelson SM, Arce JC. Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients. Reprod Biomed Online. 2022 Jan;44(1):177-184. doi: 10.1016/j.rbmo.2021.09.014. Epub 2021 Sep 23.
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.