Phase III Study Comparing Efficacy and Safety of AFOLIA vs Gonal-f® RFF in Women (35 to 42) Undergoing IVF

Phase III Investigator and Assessor Blinded 1:1 Randomized, Parallel-group Multicenter Study to Compare Efficacy and Safety of Two r-hFSH Formulations (AFOLIA vs Gonal-f® RFF) in Normal Ovulatory Women 35 to 42 Years Old Undergoing in Vitro Fertilization

The purpose of this study is to show that AFOLIA, a recombinant manufactured human follicle stimulating hormone (r-hFSH) has a similar efficacy and safety profile compared to Gonal-f® RFF.

Comparison of the clinical pregnancy rate in the AFOLIA group compared to the US approved Gonal-f® RFF Redi-ject group as the primary endpoint. Comparison of the number and size of follicles, the number of cycle cancellation, the hormone parameters and adverse events in the AFOLIA group compared to the Gonal-f® RFF group as secondary endpoints.

Inclusion Criteria:

• 35 to 42 years of age
• Indication for controlled ovarian stimulation and IVF or intracytoplasmic sperm injection (ICSI)
• Regular menstrual cycles (25-35 days)
• History of a maximum of two fresh cycle treatments in the present series of assisted reproductive technologies (ART) at the day of first screening (thawed cycles are not subject to that criteria)
• Body mass index (BMI) ≥18 and ≤38 kg/m2
• Basal FSH <12 IU/L (cycle day 2-5)
• Antral follicle count (AFC) ≥ 10 to ≤20 follicles with a diameter of <11mm (sum of both ovaries) as measured on ultrasound (US) in the early follicular phase (menstrual cycle day 2-5)
• Documented history of infertility due to any of the following factors: tubal factor, mild endometriosis (American Society for Reproductive Medicine [ASRM] stage 1-2), male factor, unexplained infertility
• Presence of both ovaries by ultrasonography and normal uterine cavity (confirmed by hysterosalpingography, saline infusion sonography or hysteroscopy within 6 months before randomization)
• Male partner with semen analysis that is at least adequate for ICSI within 6 months prior to patient beginning down-regulation (invasive or surgical sperm retrieval, donor and/or cryopreserved sperm may be used)
• Willingness to participate in the study and to comply with the study protocol
• Signed informed consent prior to screening

Exclusion Criteria:

• Presence of pregnancy
• History of or active polycystic ovary syndrome (PCOS)
• AFC >20 follicles with a diameter of <11 mm (both ovaries combined) as measured on US in the early follicular phase (menstrual cycle day 2-5)
• History of >2 unsuccessful fresh ART retrieval cycles
• Presence of uncontrolled endocrine disorder
• Previous history or presence of severe OHSS
• Intrauterine fibroids ≥5 cm or otherwise clinically relevant pathology that could impair embryo implantation or pregnancy continuation
• History of recurrent spontaneous abortion (3 or more, even when unexplained)
• Presence of severe endometriosis (ASRM stage 3 or stage 4) or hydrosalpinx
• Neoplasia, including tumors of the hypothalamus and pituitary gland
• Abnormal bleeding of undetermined origin
• History of extrauterine pregnancy in the previous 3 months
• Known allergy or hypersensitivity to progesterone or to any of the excipients (including peanut oil) of the additional study medications (GnRH agonist, Ovidrel®, and Crinone 8%®)
• History of poor response to gonadotropin treatment (defined as fewer than 5 oocytes retrieved in a previous attempt)
• Any hormonal treatment within 1 month before the start of the FSH treatment, with the exception of levothyroxine)
• Egg donor
• Administration of other investigational products within the previous month
• Clinically abnormal findings at Visit 1
• Concomitant participation in another study protocol