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

A Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Trial Investigating the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Women Aged 35-42 Years Undergoing Assisted Reproductive Technology

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

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.