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.
