Predictive Factors for Ovarian Stimulation Using a Fixed Daily Dose of 200 IU Recombinant FSH (Study 142003)(P05696)

A Randomized, Open-Label Clinical Trial to Identify Predictive Factors for Controlled Ovarian Stimulation Using a Fixed Daily Dose of 200 IU Recombinant FSH in GnRH Antagonist Regimen With or Without Oral Contraceptive Scheduling

The success of assisted reproductive technologies (ART) is critically dependent on optimizing protocols for controlled ovarian stimulation to provide adequate numbers of good quality oocytes and embryos. This optimization is mainly valuable to a group of infertility patients (9%-24%) who respond poorly to Controlled Ovarian Stimulation(COS). It is also important for an additional 2.6% of the infertility patients who manifest a high response to gonadotropin and are at risk for hyperstimulation syndrome, a life-threatening situation. Extensive research was carried out and led to the introduction of GnRH antagonist, as an alternative to Gonadotropin Releasing Hormone (GnRH) agonist, for the prevention of premature Luteinizing Hormone (LH) surges. Further research to optimize the GnRH antagonist regimen concluded that a daily treatment with 200 IU of recombinant Follicle Stimulating Hormone (recFSH) in a GnRH antagonist regimen is safe, well tolerated and results in a good clinical outcome. This protocol is now frequently applied in the US and Europe.

Predicting a woman's response (based on the assessment of ovarian reserve) to COS is useful in determining individualized clinical management strategies for low and high responders and thus avoiding cancellation. Such prediction when based on reliable scientific evidence is valuable in consulting patients about their chances of success. A large number of studies have been performed, which used certain clinical, ultrasonographic and hormonal markers (called predictive factors), to try to optimize a COS protocol for patients who were down-regulated with a long GnRH agonist protocol. Prospective trials of predictive models have also been used to adjust the starting dose of FSH to prevent a too low or too high ovarian response. To date, however, none have been performed for women undergoing ovarian stimulation with a GnRH antagonist protocol.

The primary objective of this randomized, open-label, multicenter clinical trial was to identify one or more factors capable of predicting ovarian response in women treated with a daily dose of 200 IU recFSH in a GnRH antagonist protocol. Since many ART centers now use oral contraceptives as a means to schedule patients stimulated with recFSH and a GnRH antagonist for assisted reproduction, the trial evaluated also whether intervention with oral contraceptives affects the accuracy of predictive models for ovarian response.

Inclusion Criteria:

• Females of couples with an indication for In Vitro Fertilization (IVF) and/or Intracytoplasmic Sperm Injection (ICSI) scheduled for their first COS treatment cycle
• Females >18 and <=39 years of age at the time of signing informed consent
• Body Mass Index (BMI) <= 32 kg/m^2
• Normal menstrual cycle length; 24-35 days
• Availability of ejaculatory sperm (use of donated and/or cryopreserved sperm is allowed)
• Willing and able to sign informed consent

Exclusion Criteria:

• History of/or any current endocrine abnormality
• Less than 2 ovaries or any other ovarian abnormality (inc.>10mm endometrioma)
• Presence of unilateral or bilateral hydrosalpinx
• Presence of any clinically relevant pathology affecting the uterine cavity or fibroids >= 5cm
• History of recurrent miscarriage (3 or more, even when unexplained)
• FSH or LH > 12 IU/L as measured by a local laboratory (sample taken during the early follicular phase: menstrual day 2-5)
• Any clinically relevant abnormal laboratory value (FSH, LH, estradiol (E2), Progesterone (P), total Testosterone (T), prolactin, Thyroid Stimulating Hormone (TSH), blood biochemistry, hematology and urinalysis) based on a sample during the screening phase.
• Contraindications for the use of gonadotropins (tumors, pregnancy, lactation, undiagnosed vaginal bleeding, hypersensitivity, ovarian cysts)
• Contraindications for the use of oral contraceptive pills (history of (h/o) thromboembolism, breast cancer, undiagnosed vaginal bleeding)
• Recent history of/or current epilepsy, Human Immunodeficiency Virus (HIV) infection, diabetes, cardiovascular, gastrointestinal, hepatic, renal or pulmonary disease
• Abnormal karyotyping of the patient or her partner (if karyotyping is performed)
• History or presence of alcohol or drug abuse within 12 months of signing the consent
• Use of hormonal preparations within one month prior to randomization
• Hypersensitivity to any of the concomitant medication prescribed as part of the treatment regimen in this protocol
• Administration of investigational drugs within three months prior to signing the informed consent