A Clinical Trial to Determine the Effect of Lutropin Alfa on Embryo Quality and Implantation Rate in Advanced Reproductive Age

Exploratory Study to Determine the Effect of Lutropin Alfa on Embryo Quality and Their Implantation in Women of Advanced Reproductive Age

This is a multicentric, open, randomized, comparative trial aimed to assess the influence of recombinant luteinizing hormone (r-LH) supplementation during controlled ovarian stimulation (COS) in advanced reproductive age in terms of improved embryo competence which allows to transfer less embryos to avoid high grade multiple pregnancy without reducing the pregnancy rate.

This study will be carried out by the Grupo de Interés de Salud Embrionaria (GISE) group (part of the Spanish Fertility Society) who uses strict criteria to select the embryos most suitable for successful transference.

OBJECTIVES

Primary objective:

• To determine the benefit of r-LH supplementation in COS prior to in-vitro fertilization (IVF)/intracytosolic sperm injection (ICSI) in advanced reproductive age, in terms of embryo competence to implant, as compared against no r-LH supplementation

Secondary objectives:

To evaluate the benefit of r-LH supplementation in COS, in terms of:

• follicular development
• length of the stimulation
• oocyte number and their maturity
• fertilization rate
• embryo number and quality
• gestational sacs
• abortion
• ongoing pregnancies
• local and systemic safety of r-LH administration

The study will consist of 2 groups randomized in 1:1 ratio and each subject would be followed up until the confirmation of her pregnancy status. Each subject will be administered gonadotropin releasing hormone (GnRH) agonist subcutaneously daily from previous mid luteal phase to r-hCG administration as a standard practice to achieve down regulation. Each subject will also be administered recombinant follicle stimulating hormone (r-FSH) at a starting dose of 300 IU from S1 up to ovarian stimulation completion (r-hCG day) as a part of standard practice. In addition to the above concurrent therapies, one group will be administered experimental treatment (Luveris®) and the other group (control group) will not be administered any other drug (control treatment) during the stimulation period from stimulation start (S1) up to ovarian stimulation completion or stimulation cancellation respectively. Ovarian stimulation on an average takes 11 days and it is expected that stimulation period will not be extended beyond 15 days. A single injection of r-hCG will be administered intramuscularly or subcutaneously after the last injection of Luveris or r-FSH to achieve final follicular maturation. After, 34-36 hours of administration of r-hCG OPU will be done for oocyte retrieval and embryo transfer (ET) will be conducted within 5 days from OPU. Subjects will also be provided luteal support with natural progesterone and will be followed until delivery or miscarriage. Ultrasound and estradiol (E2) assessment of follicular growth will be conducted at various time points during the stimulation period with or without treatment adjustment.

Inclusion Criteria:

• Pre-menopausal female subject aged greater than (>) 35 years
• Subjects with baseline FSH serum level less than or equal to (<=) 10 IU/liter (l), LH and E2 levels within local normal range and plasma prolactin levels < 30 nanogram/milliliter (ng/ml)
• Subjects with regular spontaneous menstrual cycles of 25-35 days
• Subjects with infertility justifying IVF/ICSI-ET treatment
• Subjects programmed for COS with r-FSH under GnRH agonist protocol
• Sperm from current male partner suitable for IVF/ICSI according to local lab, unless sperm donor is foreseen
• Subjects with presence of both ovaries
• Subjects whose uterine cavity is able to sustain embryo implantation or pregnancy
• Subjects with normal papanicolaou test (PAP) smear within previous 3 years
• Subjects with body mass index (BMI) < 30 at stimulation start
• Subjects who receive confirmation of not being pregnant by a negative beta-hCG test (urine or blood) prior to starting r-FSH administration
• Subjects willing and able to comply with the protocol for the duration of the study
• Subjects who have given informed consent prior to any study-related procedure not part of normal medical care

Exclusion Criteria:

• Subjects or her male partners who are known to be human immunodeficiency virus, hepatitis B virus or hepatitis C virus positive
• Subjects with any clinically significant systemic disease; tumors of the hypothalamus and pituitary gland; ovarian, uterine or mammary cancer; hormonal abnormality and/or medical, biochemical, hematological condition which in the judgment of the investigator may interfere with gonadotropin treatment
• Subjects with more than 2 previous assisted reproductive technologies (ART) cycles
• Subjects in which previous cycles were cancelled due to poor response (< 3 antral follicles after 15 day of stimulation)
• Subjects with cryopreserved embryos from previous ART cycles
• Subjects with unexplained gynecological bleeding
• Subjects with polycystic ovaries, ovarian enlargement or cyst of unknown etiology
• Subjects known to have any contraindication to being pregnant and/or carrying pregnancy to term
• Subjects with known allergy to gonadotrophin preparations or any of the excipients
• Subjects known to have any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years
• Subjects with previous entry into this study or simultaneous participation in another clinical drug trial
• Subjects who have refused to or inability to comply with the protocol