A Phase II Study to Assess the Efficacy and Safety of Luveris® (Lutropin Alfa) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age

Ovarian reserve is related to chronological age; 35 years of age is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. New therapeutic schemes are sought to improve follicular response in ovarian ageing because of the increasing number of infertile women aged older than 35 years who are trying to get pregnant. The advent of gonadotropin releasing hormone analogue antagonist (GnRHant) offers new perspectives to address the issues related to advanced reproductive age since it prevents premature luteinizing hormone (LH) surges while not causing suppression in the early follicular phase. Gonadotropin releasing hormone analogue antagonists are administered in the latter stage of the ovarian stimulation to prevent LH surge by competitive blockade of gonadotropin releasing hormone (GnRH) receptors, thus producing a marked decrease in LH levels just when the interplay between follicle stimulating hormone (FSH) and LH becomes important to complete follicular development and oocyte competence. Some studies in the past have shown the potential of recombinant human LH (r-hLH) supplementation in women of advanced reproductive age to improve oocyte quality, but these studies are of small size and did not provide data on the physiological mechanism behind the benefit obtained.

This randomized, comparative, parallel controlled Phase II study will be conducted in infertile female subjects aged 35-42 years undergoing in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), to investigate whether the addition of r-hLH (when the lead follicle is greater than \[\>\] 14 millimeter \[mm\] in size), to the standard protocol with recombinant human FSH (r-hFSH) under GnRHant, improves the number and quality of oocytes retrieved, implantation rate, and pregnancy rate, while assessing the hormonal milieu in the ovarian follicular fluid. Comparison will be performed against ovarian stimulation without addition of r-hLH, that is (i.e.) with r-hFSH under GnRHant alone.

Preclinical pharmacology studies have demonstrated that r-hLH has a LH/human chorionic gonadotropin (hCG) receptor affinity similar to pituitary human luteinizing hormone (p-hLH), and is biologically active in-vitro in stimulating steroidogenesis and in promoting oocyte germinal vesicle breakdown. Several clinical studies have investigated the usefulness of r-hLH supplementation in normal ovulatory women undergoing ART and in almost all of them sub-populations of subjects have been identified who will benefit, when r-hLH is added to FSH.

OBJECTIVES

Primary objectives:

* To determine the efficacy of adding r-hLH at mid-follicular phase compared to not adding r-hLH, in women of 35-42 years of age included in a COS with r-hFSH under treatment with a GnRHant for IVF/ICSI, assessed by the number and quality of the oocyte
* To determine the safety of using r-hLH combined with r-hFSH in a protocol with a GnRHant, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerability

Secondary objectives:

* To complete the verification of efficacy with additional assessments such as follicular growth, oocyte fertilization, embryo quality and pregnancy rates
* To investigate the underlying mechanism of possible improvement in oocyte quality by means of determining hormone levels (LH, FSH, T, E2, and hCG) levels in follicular fluid

Tertiary objectives:

* This is a phase-II study that did not aim to carry out assessment of pharmacoeconomics or quality of life

All subjects will undergo treatment with r-hFSH at a daily dose of 300-450 IU by subcutaneous route starting on the stimulation Day 1 (S1) until r-hCG administration. Upon detection of a lead follicle \> 14 mm in diameter, GnRHant 0.25 milligram (mg)/day subcutaneous administration will be initiated and continued up to r-hCG administration day. Subjects will be then randomly allocated (at any time between S1 and GnRHant initiation day) either to additional treatment with r-hLH at a daily fixed dose of 150 IU or continue treatment with r-hFSH alone. Gonadotropin releasing hormone antagonist and combined treatment with r-hLH plus (+) r-hFSH or r-hFSH alone will be administered until at least one follicle \> 18 mm in diameter and two additional follicles \> 16 mm in diameter are present and E2 levels are commensurate with the number and size of follicles present. A single injection of 250-500 microgram of r-hCG, will be given to induce final follicular maturation within 36 hours of the last r-hLH and/or r-hFSH injections and on the same day of the last GnRHant morning administration. Oocytes will be retrieved 34-38 hours after r-hCG administration, assessed, and fertilized in-vitro by ICSI. Not more than 3 embryos will be replaced on day 2 or 3 after OPU. The luteal phase will be supported by a daily vaginal administration of natural progesterone, starting after OPU and continuing either up to menstruation or the pregnancy test or, if the subject is pregnant, for at least 30 days after laboratory evidence of pregnancy. Each subject will be followed-up and the treatment outcome (pregnancy or menstruation) will be recorded.

For all subjects who received r-hCG and do not menstruate, a blood sample will be collected for local determination of serum beta-hCG level between post-hCG days 15-20. If positive (beta-hCG \> 10 International Unit/liter \[IU/L\]), it should be confirmed by performing a second test within one week later. An ultrasound scan (US) will be performed at post-hCG days 35-42 on all subjects who will become pregnant provided that no miscarriage has occurred. The number of fetal sacs and fetal heart activity will be recorded. Active follow-up of all pregnancies will be performed, including those subjects withdrawn from the study.

Eligibility Criteria:
Inclusion Criteria:

* Premenopausal woman, aged 35 to 42 years wanting to become pregnant
* Subjects with FSH baseline plasma levels less than or equal to 10 IU/L (Day 2-5 of the cycle) and with LH and E2 levels within the normal limits of the local laboratory
* Subjects having regular spontaneous menstrual cycle lasting 25-35 days
* Subjects with infertility that is susceptible to treatment with IVF/ICSI
* Subjects to be included in a COS protocol with r-hFSH and GnRHant
* Subjects with partner's sperm suitable for IVF/ICSI according to local laboratory, unless sperm donor is to be used
* Subjects with both ovaries
* Subjects with uterine cavity capable of sustaining the implantation of embryo or carrying a pregnancy
* Subjects with normal pap smear (papanicolaou) 6 months prior to be included in the study (signature of informed consent)
* Subjects with body mass index (BMI) less than (\<) 30 at the beginning of ovarian stimulation
* Subjects with confirmed absence of pregnancy with the beta-hCG test (urine or blood) before starting the administration of r-hFSH
* Subjects willing to adjust to the protocol for the entire duration of the study
* Subjects who have given informed consent prior to any study-related procedure that is not part of normal medical care

Exclusion Criteria:

* Subjects or her partner with known positivity for human immunodeficiency virus (HIV) or Hepatitis-B /Hepatitis-C virus (HBV/HCV)
* Subjects with any systemic illnesses of clinical significance, hypothalamus and pituitary tumors; cancer of ovaries, uterus or breast; hormonal anomalies and/or medical, biochemical, hematological illnesses that, according to the investigator, could interfere with the treatment with gonadotropins
* Subjects with more than 2 previous ART cycles
* Subjects who have cancelled two previous ART cycles
* Subjects with frozen embryos from previous ART cycles
* Subjects with non-specific gynecological bleeding
* Subjects with ovaries that are polycystic, increased in size or with cysts of unknown etiology
* Subjects with any contraindication for becoming pregnant and/or carrying pregnancy to term
* Subjects with known allergy to gonadotropin preparations or any of the excipients
* Subjects with drug dependence or history of drug or alcohol abuse in the previous 5 years
* Subjects who have previously entered into this study or simultaneous participation in another clinical drug trial with drugs
* Subjects who are unwilling to or not being able to adjust to the study protocol