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

• Implantation Rate [ Time Frame: Day 35-42 post ovum pick-up (OPU) (34-38 hours post recombinant human choriogonadotropin day {end of stimulation cycle}[approximately 28 days]) ] [ Designated as safety issue: No ]
  Implantation rate was measured as the number of gestational sacs observed, divided by the number of embryos transferred.
  
  

• Mean Number of Follicles Greater Than or Equal to 14 Millimeter (mm) on Recombinant Human Choriogonadotropin (r-hCG) Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  
• Mean Number of Oocytes Retrieved [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  Mean number of oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body.
  
  
• Number of Mature Oocytes Retrieved [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  Number of mature oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. The nuclear maturity was evaluated based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage.
  
  
• Number of Fertilized Oocytes (2 Pronuclei [PN]) [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of two 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN.
  
  
• Number and Quality of Embryos [ Time Frame: Day 2-3 post OPU (34-38 hours post r-hCG day {end of stimulation cycle}[approximately 28 days]) ] [ Designated as safety issue: No ]
  Embryos were graded according to Spanish Association for the Study of Reproductive Biology (ASEBIR) criteria into different categories: (A) optimal quality with maximum capacity for implantation, (B) good quality with a high capacity for implantation, (C) regular with low possibility of implantation and (D) poor quality with very little possibility of implantation.
  
  
• Number of Participants With Biochemical Pregnancies [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: No ]
  Biochemical pregnancy was defined as a pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy.
  
  
• Number of Participants With Clinical Pregnancies [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: No ]
  Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.
  
  
• Total Dose of Recombinant Follicle Stimulating Hormone (r-FSH) [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: No ]
  
• Estradiol (E2) Levels on r-hCG Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  
• Number of Ovarian Stimulation Days [ Time Frame: S1 up to r-hCG day (end of stimulation cycle [approximately 28 days]) ] [ Designated as safety issue: No ]
  Ovarian stimulation included from first rFSH injection (S1) until day on which r-hCG was administered (r-hCG day). This period was divided into 2 parts: the first period in which 300 International Unit (IU) rFSH dose was constant and which covered from S1 to Day 4 of stimulation period (S4); the second period in which the rFSH dose could be adjusted depending on the ovarian response and which began on S4 and finished on the day on which the criteria for administration of r-hCG to induce the final follicular maturation were met.
  
  
• Number of Recombinant Human Choriogonadotropin (r-hCG) Cycles Cancelled Due to Poor Response [ Time Frame: Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: No ]
  Poor response was defined as 3 or less follicles of greater than or equal to 12 mm developing following at least 7 days of study treatment.
  
  
• Total Number of Births [ Time Frame: Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: No ]
  Total number of births per reporting group was calculated.
  
  
• Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: Yes ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
  
  
• Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: Yes ]
  OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
  
  
• Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ] [ Designated as safety issue: Yes ]
  OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
  
  

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.