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

Ferring Pharmaceuticals373 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

373

Conditions

Infertility

Interventions

Follitropin deltaDRUG

Single daily subcutaneous administration through pre-filled injection pen

Follitropin betaDRUG

Single daily subcutaneous injection in the abdomen

Eligibility

Sex: FEMALEMin age: 20 YearsMax age: 40 Years

Medical Language ↔ Plain English

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.

Locations (17)

Yachiyo Hospital

Anjo, Aichi-ken, Japan

Investigational Site 8121

Chiba, Chiba, Japan

Yokota Maternity Hospital

Maebashi, Gunma, Japan

Outcomes

Primary Outcomes

Number of Oocytes Retrieved

The number of oocytes retrieved was recorded at the oocyte retrieval visit.

Time frame: 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval)

Secondary Outcomes

Clinical Pregnancy Rate

Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.

Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate

Defined as positive serum beta-hCG test 13-15 days after transfer.

Time frame: 13-15 days after transfer (up to approximately 1.5 months after start of stimulation)

Vital Pregnancy Rate

Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.

Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Implantation Rate

Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.

Time frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation)

Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response

Time frame: End-of-stimulation (up to 20 stimulation days)

Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk

Time frame: End-of-stimulation (up to 20 stimulation days)

Data from ClinicalTrials.gov

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Sophia Ladies Clinic

Sagamihara, Kanagawa, Japan

Investigational Site 8122

Sendai, Miyagi, Japan

Investigational Site 8123

Higashiōsaka-shi, Osaka, Japan

Investigational Site 8120

Osaka, Osaka, Japan

Ladies Clinic Kitahama

Osaka, Osaka, Japan

Investigational Site 8125

Saitama-shi, Saitama, Japan

Investigational Site 8124

Shinjuku-Ku, Tokyo, Japan

...and 7 more locations

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.

Time frame: On the day of oocyte retrieval (up to 22 days after start of stimulation)

Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population

Time frame: On the day of oocyte retrieval (up to 22 days after start of stimulation)

Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS)

Time frame: ≤9 days after triggering of final follicular maturation

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.

Time frame: Up to 9 days after triggering of final follicular maturation

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.

Time frame: >9 days after triggering of final follicular maturation

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).

Time frame: At Day 6 of stimulation

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).

Time frame: End-of-stimulation (up to 20 stimulation days)

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.

Time frame: At Day 6 of stimulation

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

Fertilization Rate

The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.

Time frame: Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation)

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.

Time frame: Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation)

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.

Time frame: Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation)

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.

Time frame: At Day 6 of stimulation

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6

The median and IQR of estradiol levels on stimulation Day 6 are presented.

Time frame: At Day 6 of stimulation

Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation

The median and IQR of estradiol levels at end-of-stimulation are presented.

Time frame: End-of-stimulation (up to 20 stimulation days)

Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6

The median and IQR of progesterone levels on stimulation Day 6 are presented.

Time frame: At Day 6 of stimulation

Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation

The median and IQR of progesterone levels at end-of-stimulation are presented.

Time frame: End-of-stimulation (up to 20 stimulation days)

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.

Time frame: At Day 6 of stimulation

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

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.

Time frame: At Day 6 of stimulation

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

Number of Stimulation Days

Time frame: End-of-stimulation (up to 20 stimulation days)

Total Gonadotropin Dose of FE 999049

Time frame: End-of-stimulation (up to 20 stimulation days)

Total Gonadotropin Dose of FOLLISTIM

Time frame: End-of-stimulation (up to 20 stimulation days)

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).

Time frame: From signed informed consent up to 5-6 weeks after transfer

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial

Time frame: Up to 5-6 weeks after transfer

Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial

Time frame: Up to 5-6 weeks after transfer

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.

Time frame: End-of-stimulation (up to 20 stimulation days)

Technical Malfunctions of the Administration Pens

Time frame: End-of-stimulation (up to 20 stimulation days)