EXpression PRofile Endometrium Samples Study

Open Label Pilot Study on Gene Expression Profiling of the Endometrial Tissue in Patients Undergoing Assisted Reproductive Technology [ART: In Vitro Fertilization (IVF)/ Intracytoplasmic Sperm Injection (ICSI)] With GONAL-f®

This is a Phase IV, pilot, open-label, national, multi-centric study planned to determine the gene expression profiles and histologic changes of the endometrial tissue before and after stimulation with Gonal-f®. Physicians are interested in identifying predictive genetic markers in assisted reproductive technologies (ART) in addition to the clinical predictive factors already known. Among those predictive factors, the state of the endometrium is considered as an important implantation determining factor for which pharmacogenomic research is of great interest.

The direct benefits of this study will be to know whether the endometrial gene expression profile is modified in response to stimulation treatment and have an impact or not on the endometrial tissue receptivity. The potential benefits of this study could be to assess the therapy optimization based on individual treatment response and gene expression profile compared to group treatment response in infertile women and prediction of response to therapy based on gene expression profiling before and after Gonal-f® stimulation in infertile women.

This is a pilot open-label, national, multi-centre, Phase IV trial. This trial will be conducted with outpatients. Once subject has met all eligibility criteria, she will be treated with Gonal-f® prefilled pen and will receive on a randomization basis the GnRH agonist or antagonist. The follicle stimulating hormone (FSH) stimulation will start on day 2 of the menstrual cycle with a pre-defined fixed dose of 150 IU per day until follicles are recruited and developed. Dose adjustment will be allowed strictly in case of risk of ovarian hyperstimulation syndrome (OHSS). Ovulation triggering will be performed using a single injection of 250 mcg Ovitrelle®.

Ultrasound scans (US) will be performed concomitantly with hormonal assessment at each visit. Ovulation will be triggered as soon as there are at least 3 follicles > 16 mm, and with E2 > 1 mcg/L if agonist used. Oocyte retrieval, in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) and blastocyst transfer will be performed as per centre's standard practice. Vaginal progesterone will be administered in the luteal phase for all subjects (600 milligram per day [mg/d]).

Hormonal assessment and endometrial biopsy will be performed on:

• Day Luteinizing Hormone+7 ("LH+7") of the previous spontaneous cycle
• Day of Oocyte Retrieval (OR) of the stimulated cycle
• Day "OR+5 or 6" (biopsy performed only in subjects that did not have blastocyst(s) transfer).

Gene expression profiling will be carried out on ribonucleic acid (RNA) from endometrial tissue. As the main objective of this trial is to determine the gene expression profiles of endometrial tissue before and after controlled ovarian stimulation with Gonal-f®, a minimum of 2 endometrial samples per subject will be collected, 1 at day LH+7 of spontaneous cycle and 1 after the stimulation, on the day of OR.

The subjects will be followed up until 15 days after the last injection of Investigational Medicinal Products (IMPs) for the safety assessment. For subjects who will have blastocyst implantation, the pregnancy outcomes will be recorded until 12 weeks of gestation if a pregnancy is ongoing up to that period.

OBJECTIVES

Primary objective:

• To determine the gene expression profile and histological changes of endometrial tissue before (at day LH + 7 of spontaneous cycle) and after stimulation with Gonal-f® (Day of OR: 36 +/- 2 hours post r-hCG administration) in Assisted Reproductive Technology (ART) [IVF/ICSI]

Secondary objectives:

• To correlate the gene expression profile of the endometrial tissue at Day LH + 7 of the spontaneous cycle with the blastocyst implantation rate in subjects undergoing ART with Gonal-f®

• To correlate the gene expression profile and histological changes in endometrial tissue before and after stimulation by Gonal-f® with the "down regulation" protocol used (agonist or antagonist) and fertilization mode, IVF/ICSI

• To correlate the gene expression profile and histological changes in endometrial tissue before and after stimulation by Gonal-f® according to the hormonal status of subjects

• To characterize the gene expression profile and histology of endometrial tissue after stimulation with Gonal-f in subjects without blastocyst during the theoretical window of implantation (OR + 5 or 6 days)

• To characterize the gene expression profile and histology of endometrial tissue of good and poor responders to stimulation with Gonal-f® on the Day of OR (response being based on the following criteria):

  1. Quantity of mature oocytes retrieved:

     • Poor responders: 5 mature oocytes or less
     • Good responders: more than 8 mature oocytes

  2. Quantity of Gonal-f® used

Inclusion Criteria:

• Infertile female or infertile male. Infertile female means diverse infertility etiologies including tubal disease (excepting hydrosalpinx) and so called "unexplained infertility"
• Suitable for ART: IVF undergoing first or second attempt, ICSI undergoing first attempt
• 18-35 years old, body mass index (BMI) less than or equal to 27 kilogram per square meter (kg/m^2), non smoking
• Normal ovarian status (FSH less than or equal to 9.45 International Units per Liter [IU/L], E2 less than or equal to 40 picogram per milliliter [pg/mL], Anti-Mullerian Hormone [AMH] greater than or equal to 18 picomole/liter [pmol/L]; within normal laboratory range values, normal ovaries sonography and uterine echo doppler)
• No history of active genito-urinary infection
• Normal thyroid function (or adequate substitution for at least 3 months)
• Negative cervical papanicolaou test within the last 12 months prior to study entry
• No hormonal therapy, including gonadotropins and progesterone, for at least 2 months prior to the study
• In couple with female infertility, male partner with normal sperm or moderate oligoasthenospermia in semen analysis and negative semen culture less than 6 months at the study entry
• Willingness and ability to comply with the protocol for the duration of the study
• Written informed consent prior to any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care

Exclusion Criteria:

• Subjects with ongoing pregnancy, any pregnancy within 3 months prior to study entry, or any contraindication to pregnancy or carrying pregnancy to term
• Subjects with uterine malformation, diethylstilbestrol syndrome, adenomyosis, synechia
• Subjects with history of previous OHSS
• Subjects with polycystic ovarian syndrome (PCOS) according to the revised Rotterdam Consensus 2003
• Subjects with extra-uterine pregnancy during the previous 3 months
• Subjects with recurrent miscarriages (early or late, more than 2)
• Subjects having known infection with human immunodeficiency virus (HIV), hepatitis B or C virus, for subject or partner
• Subjects with abnormal gynecological bleeding of undetermined origin
• Subjects with history of major thromboembolic disease
• Subjects with endometriosis
• Subjects with presence or history of malignant tumors and related treatment
• Subjects with clinically significant systemic disease or clinically significant abnormal hematology, chemistry, or urinalysis results at screening
• Subjects with known allergy or hypersensitivity to Gonal-f® or Ovitrelle®
• Subjects with any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years
• Subjects who have participated within 3 months prior to study entry in another clinical trial