Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2)

Phase 3CompletedNCT03738618

Ferring Pharmaceuticals588 enrolled

Overview

This trial investigates the effects of FE 999049 compared to placebo.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

588

Conditions

Infertility, Female

Interventions

Follitropin deltaDRUG

FE 999049 was administered as single daily subcutaneous injections in the abdomen at a starting dose of 15 μg daily that was fixed for the first four stimulation days. Based on ovarian response, the dose could be adjusted by 3 μg, with dose increases implemented not more frequently than once every 2 days and dose decreases implemented per investigator's judgement. The minimum daily dose was 6 μg, and the maximum daily dose was 24 μg. Participants could be treated for a maximum of 20 days. Coasting, use of dopamine agonist or any other drug to prevent early ovarian hyperstimulation syndrome (OHSS) with the exception of gonadotropin-releasing hormone (GnRH) agonist for triggering of final follicular maturation, was not allowed

PlaceboDRUG

Placebo was administered as single daily subcutaneous injection dialed to the same value (dose) as FE 999049. Participants could be treated for a maximum of 20 days. Coasting, use of dopamine agonist or any other drug to prevent early OHSS with the exception of GnRH agonist for triggering of final follicular maturation, was not allowed.

Eligibility

Sex: FEMALEMin age: 35 YearsMax age: 42 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Informed Consent Documents signed prior to any trial-related procedure. * In good physical and mental health in the judgement of the investigator. * Pre-menopausal women between the ages of 35 and 42 years. The participants must be at least 35 years (including the 35th birthday) when they sign the informed consent and no more than 42 years (up to the day before the 42nd birthday) at the time of randomization. * Body mass index (BMI) between 17.5 and 38.0 kg/m\^2 (both inclusive) at screening. * Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor. * Documented history of infertility for at least 6 months before randomization (not applicable in case of tubal or severe male factor infertility, or when the use of donor sperm is indicated). * Regular menstrual cycles of 24-35 days (both inclusive). * Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous fibroids of any size 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) at screening or within 1 year prior to screening. * 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) at screening. 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 at screening or within 6 months prior to screening. * Willing to accept the blastocyst transfer policy for the fresh cycle and the cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation using blastocysts obtained in this trial, i.e. transfer of one blastocyst (if a good-quality blastocyst is available) or transfer of one or two blastocysts (if no good-quality blastocyst is available). Exclusion Criteria: * More than one previous controlled ovarian stimulation cycle for IVF/ICSI. * Known endometriosis stage III-IV (defined by the revised ASRM classification, 2012). * Known history of anovulation. * One or more follicles greater than or equal to 10 mm (including cysts) observed on the transvaginal ultrasound prior to randomization on stimulation day 1. * 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. In case partner sperm will be used and the sperm production is severely impaired (concentration less than 1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented. * Any known clinically significant systemic disease (e.g. insulin-dependent diabetes). * Known inherited or acquired thrombophilia. * Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. * Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of pharmacologically controlled sub-clinical hypothyroidism. * 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, hematology, thyroid-stimulating hormone (TSH) or prolactin, or vital signs at screening, which is judged clinically significant by the investigator. * Known abnormal cervical cytology of clinical significance observed within three 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.

Locations (24)

Fertility Treatment Center

Tempe, Arizona, United States

Outcomes

Primary Outcomes

Cumulative Ongoing Pregnancy Rate After the Fresh Cycle and Cryopreserved Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation (COS)

Defined as at least one intrauterine viable fetus 8-9 weeks after transfer. Data in this endpoint are presented for the fresh cycle and the cryopreserved cycles.

Time frame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)

Secondary Outcomes

Ongoing Pregnancy Rate in the Fresh Cycle and in the Cryopreserved Cycles

Defined as at least one intrauterine viable fetus 8-9 weeks after transfer. Data in this endpoint are presented for the fresh cycle and the cryopreserved cycles.

Time frame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)

Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Including Duration

Time from start of COS to ongoing pregnancy, including both the fresh and cryopreserved cycles. In the placebo group, no participants achieved an ongoing pregnancy either after 12 calendar months or after 12 study months.

Time frame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)

Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Measured in Number of Cycles Before Achieving Ongoing Pregnancy

Time from start of COS to ongoing pregnancy, including both the fresh and cryopreserved cycles, measured in number of cycles before achieving ongoing pregnancy. In the placebo group, no participants achieved an ongoing pregnancy either after 12 calendar months or after 12 study months.

Time frame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)

Ongoing Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

Data from ClinicalTrials.gov

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HRC Fertility

Encino, California, United States

Center for Advanced Reproductive Services PC

Farmington, Connecticut, United States

Reproductive Associates of Delaware

Newark, Delaware, United States

Women's Medical Research Group, LLC

Clearwater, Florida, United States

Center for Reproductive Medicine

Winter Park, Florida, United States

Fertility Institute of Hawaii, INC

Honolulu, Hawaii, United States

Fertility Centers of Illinois (RH)

Chicago, Illinois, United States

InVia Fertility

Hoffman Estates, Illinois, United States

Boston IVF

Waltham, Massachusetts, United States

...and 14 more locations

Defined as the number of intrauterine viable fetuses 8-9 weeks after transfer divided by number of blastocysts transferred. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles. One participant can contribute with a range from zero to multiple blastocysts. Data is not shown for placebo arm because no subjects underwent blastocyst transfer in the fresh cycle or cryopreserved cycles. '%' in the unit of measure refers to 'percentage'.

Time frame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)

Clinical Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

Defined at least one gestational sac 5-6 weeks after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.

Time frame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)

Vital Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

Defined at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.

Time frame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)

Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

Defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred. The endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles. One participant can contribute with a range from zero to multiple blastocysts. Data is not shown for placebo arm because no subjects underwent blastocyst transfer in the fresh cycle or cryopreserved cycles. '%' in the unit of measure refers to 'percentage'.

Time frame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)

Positive Beta Human Chorionic Gonadotropin (βhCG) Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively

Defined as positive serum βhCG test 10-14 days after transfer. Data in this endpoint are presented for the fresh cycle, the cryopreserved cycles, and all cycles.

Time frame: 10-14 days after transfer (up to approximately 14 months after start of stimulation)

Proportion of Subjects in the Fresh Cycle With Triggering of Final Follicular Maturation (With hCG, With GnRH Agonist, and in Total), Cycle Cancellation and Transfer Cancellation

Data in this endpoint are presented for the fresh cycle.

Time frame: Up to 5 days after oocyte retrieval (up to 27 days after start of stimulation)

Number of Follicles on Stimulation Day 5

The total number of follicles and the number of follicles per size category are reported.

Time frame: On stimulation day 5

Number of Follicles at End-of-stimulation

The total number of follicles and the number of follicles per size category are reported.

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

Size of Follicles on Stimulation Day 5

Counted by ultrasound for the right and left ovary for each participant.

Time frame: On stimulation day 5

Size of Follicles at End-of-stimulation

Counted by ultrasound for the right and left ovary for each participant.

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

Number of Oocytes Retrieved

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

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

Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved

Grouped according to the number of oocytes retrieved. Participants with cycle cancellation due to poor ovarian response are included in the \<4 oocytes group.

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

Number of Metaphase II Oocytes

The number of MII oocytes to oocytes retrieved for participants where all oocytes were inseminated using ICSI are presented.

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

Number of Fertilized Oocytes

An oocyte was defined as fertilized if it had 2 pronuclei (2PN) at 19h (±2h).

Time frame: On day 1 after oocyte retrieval (up to 23 days after start of stimulation)

Fertilization Rate

The fertilization rate was defined as the number of 2PN oocytes divided by the number of oocytes retrieved. Fertilization rate relative to oocytes retrieved has been reported.

Time frame: On day 1 after oocyte retrieval (up to 23 days after start of stimulation)

Number and Quality of Blastocysts on Day 5 After Oocyte Retrieval

Number of blastocysts (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: On day 5 after oocyte retrieval

Endometrial Thickness on Stimulation Day 5

Mean endometrial thickness is reported.

Time frame: On stimulation day 5

Endometrial Thickness at End-of-stimulation

Mean endometrial thickness is reported.

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

Echogenicity Pattern on Stimulation Day 5

The distribution of participants with hypoechogenic, isoechogenic, or hyperechogenic endometrium is reported

Time frame: On stimulation day 5

Echogenicity Pattern at End-of-stimulation

The distribution of participants with hypoechogenic, isoechogenic, or hyperechogenic endometrium is reported.

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

Oocyte Utilization Rate

Defined as the number of blastocysts transferred or cryopreserved divided by the number of oocytes retrieved. Data in this endpoint are presented for the cryopreserved cycles.

Time frame: On day of oocyte retrieval up to 12 months after start of COS

Oocyte Efficiency Index

Defined as the cumulative number of ongoing pregnancies per oocyte retrieved. Data in this endpoint are presented for the cryopreserved cycles. The unit of measure for this endpoint is 'cumulative ongoing pregnancies/oocyte retrieved'.

Time frame: 8-9 weeks after transfer

Percentage of Blastocysts Surviving Cryopreservation

Data in this endpoint are presented for the cryopreserved cycles. The unit is number of blastocysts with observations. One participant can contribute with a range from zero to multiple blastocysts.

Time frame: 0 hour (+0.5 hour) after thawing

Percentage of Blastocysts With Re-expansion After Cryopreservation

Data in this endpoint are presented for the cryopreserved cycles. The unit is number of blastocysts with observations. One participant can contribute with a range from zero to multiple blastocysts.

Time frame: 2.5 hour (±0.5 hour) after thawing

Number of Cryopreserved Cycles Initiated Within 12 Months From the Start of COS

The total number of cryopreserved cycles initiated are reported. Data in this endpoint are presented for the cryopreserved cycles. One participant can contribute with a range from zero to multiple blastocysts.

Time frame: Up to 12 months after start of stimulation

Number of Cryopreserved Cycles With Blastocyst Transfer

The total number of cryopreserved cycles with blastocyst transfer are reported. Data in this endpoint are presented for the cryopreserved cycles. One participant can contribute with a range from zero to multiple blastocysts.

Time frame: Up to 12 months after start of stimulation

Circulating Concentrations of Anti-mullerian Hormone (AMH)

Blood samples for analysis of circulating concentrations of AMH were drawn. The median and inter-quartile range (IQR) of AMH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Follicle-stimulating Hormone (FSH)

Blood samples for analysis of circulating concentrations of FSH were drawn. The median and IQR of FSH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Luteinizing Hormone (LH)

Blood samples for analysis of circulating concentrations of LH were drawn. The median and IQR of LH levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Estradiol

Blood samples for analysis of circulating concentrations of estradiol were drawn. The median and IQR of estradiol levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Progesterone

Blood samples for analysis of circulating concentrations of progesterone were drawn. The median and IQR of progesterone levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Inhibin A

Blood samples for analysis of circulating concentrations of inhibin A were drawn. The median and IQR of inhibin A levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Circulating Concentrations of Inhibin B

Blood samples for analysis of circulating concentrations of inhibin B were drawn. The median and IQR of inhibin B levels on stimulation day 1, stimulation day 5, end-of-stimulation visit and oocyte retrieval visit are presented.

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

Total Gonadotropin Dose

Calculated by start dates, end dates and daily dose of IMP.

Time frame: Up to 20 stimulation days

Number of Stimulation Days

Calculated by start dates and end dates.

Time frame: Up to 20 stimulation days

Proportion of Participants With Investigator-requested Gonadotropin Dose Adjustments

Investigator-requested decreases and increases of the gonadotropin dose.

Time frame: Stimulation Day 5

Percentage of Participants With Adverse Events (AEs)

Any AE occurring after start of IMP and before the end-of-trial visit, or a pre-treatment AE or pre-existing medical condition that worsens in intensity after start of IMP and before the end-of-trial visit was considered treatment-emergent, and is presented for this endpoint. Data in this endpoint are presented for the fresh cycle.

Time frame: From time of signing informed consent until the end-of-cycle visit in the fresh cycle (approximately 6 months)

Intensity of AEs

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). Data in this endpoint are presented for the fresh cycle.

Time frame: From time of signing informed consent until the end-of-cycle visit in the fresh cycle (up to approximately 6 months)

Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Albumin, Protein

Blood samples were collected for the analysis of clinical chemistry parameters including: Albumin and protein. Data in this endpoint are presented for the fresh cycle.