Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women

Infertility Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03228680
• Other study ID #: 000273
• Status: Completed
• Phase: Phase 3
• Start date: July 29, 2017
• Est. completion date: July 8, 2019

Study information

• Verified date: April 2021
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 373
• Est. completion date: July 8, 2019
• Est. primary completion date: June 10, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• Follitropin delta
Single daily subcutaneous administration through pre-filled injection pen
• Follitropin beta
Single daily subcutaneous injection in the abdomen

Locations

Country	Name	City	State
Japan	Akita University Hospital	Akita
Japan	Yachiyo Hospital	Anjo	Aichi
Japan	Investigational Site 8121	Chiba-shi	Chiba
Japan	Investigational Site 8123	Higashiosaka-shi	Osaka
Japan	Yamashita Ladies' Clinic	Hyogo
Japan	Yokota Maternity Hospital	Maebashi	Gunma
Japan	Investigational Site 8120	Osaka-Shi	Osaka
Japan	Ladies Clinic Kitahama	Osaka-shi	Osaka
Japan	Sophia Ladies Clinic	Sagamihara	Kanagawa
Japan	Investigational Site 8126	Saitama
Japan	Omiya Ladies Clinic	Saitama
Japan	Saint Women's Clinic	Saitama
Japan	Women's Clinic Fujimino	Saitama
Japan	Investigational Site 8125	Saitama-shi	Saitama
Japan	Investigational Site 8122	Sendai-shi	Miyagi
Japan	Investigational Site 8124	Shinjuku-Ku	Tokyo
Japan	Tokushima University Hospital	Tokushima

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Country where clinical trial is conducted

Japan, 

References & Publications (3)

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" approac — View 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 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Oocytes Retrieved	The number of oocytes retrieved was recorded at the oocyte retrieval visit.	36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)
Secondary	Clinical Pregnancy Rate	Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Secondary	Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate	Defined as positive serum beta-hCG test 13-15 days after transfer.	13-15 days after transfer (up to approximately 1.5 months after start of stimulation)
Secondary	Vital Pregnancy Rate	Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Secondary	Implantation Rate	Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.	5-6 weeks after transfer (up to approximately 3 months after start of stimulation)
Secondary	Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response		End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk		End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Participants With <4, 4-7, 8-14, 15-19 and =20 Oocytes Retrieved	Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and =20 oocytes (severe hyperresponse) are presented.	On the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Proportion of Participants With Extreme Ovarian Responses (Defined as <4, =15 or =20 Oocytes Retrieved) in Risk Population		On the day of oocyte retrieval (up to 22 days after start of stimulation)
Secondary	Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)		=9 days after triggering of final follicular maturation
Secondary	Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS	Defined as proportion of participants with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.	Up to 9 days after triggering of final follicular maturation
Secondary	Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade)	Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade).; 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.	>9 days after triggering of final follicular maturation
Secondary	Number of Follicles on Stimulation Day 6	Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).	At Day 6 of stimulation
Secondary	Number of Follicles at End-of-stimulation	Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).	End-of-stimulation (up to 20 stimulation days)
Secondary	Size of Follicles on Stimulation Day 6	Defined as size characteristics of follicles on stimulation Day 6.; Average size of 3 largest follicles has been presented in this endpoint.	At Day 6 of stimulation
Secondary	Size of Follicles at End-of-Stimulation	Defined as size characteristics of follicles at end-of-stimulation.; Average size of 3 largest follicles has been presented in this endpoint.	End-of-stimulation (up to 20 stimulation days)
Secondary	Fertilization Rate	The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.	Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)
Secondary	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 fragmentation =20% on Day 3.	Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)
Secondary	Number and Quality of Blastocysts	Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.	Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)
Secondary	Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6	The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.	At Day 6 of stimulation
Secondary	Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation	The median and IQR of FSH and LH levels at end-of-stimulation are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6	The median and IQR of estradiol levels on stimulation Day 6 are presented.	At Day 6 of stimulation
Secondary	Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation	The median and IQR of estradiol levels at end-of-stimulation are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6	The median and IQR of progesterone levels on stimulation Day 6 are presented.	At Day 6 of stimulation
Secondary	Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation	The median and IQR of progesterone levels at end-of-stimulation are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6	The median and IQR of Inhibin A levels on stimulation Day 6 are presented.	At Day 6 of stimulation
Secondary	Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation	The median and IQR of Inhibin A levels at end-of-stimulation are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6	The median and IQR of inhibin B levels on stimulation Day 6 are presented.	At Day 6 of stimulation
Secondary	Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation	The median and IQR of inhibin B levels at end-of-stimulation are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Number of Stimulation Days		End-of-stimulation (up to 20 stimulation days)
Secondary	Total Gonadotropin Dose of FE 999049		End-of-stimulation (up to 20 stimulation days)
Secondary	Total Gonadotropin Dose of FOLLISTIM		End-of-stimulation (up to 20 stimulation days)
Secondary	Number of Participants With Adverse Events (AEs) Stratified by Intensity	The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE 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 signed informed consent up to 5-6 weeks after transfer
Secondary	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation	Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.	End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation	Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.	End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial	Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.	Up to 5-6 weeks after transfer
Secondary	Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial	Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.	Up to 5-6 weeks after transfer
Secondary	Frequency and Intensity of Injection Site Reactions	The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Technical Malfunctions of the Administration Pens		End-of-stimulation (up to 20 stimulation days)