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
Condition: Infertility; Ovulation Induction
MeSH terms: Infertility
Intervention: r-hLH + r-hFSH; r-hFSH; Recombinant Human Choriogonadotropin (r-hCG); GnRH antagonist
Intervention description: Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from stimulation Day 1(S1) at a starting dose of 300-450 International Unit (IU) and then dose adjusted depending on the ovarian response till recombinant human choriogonadotropin (r-hCG) administration day. Recombinant human luteinizing hormone (r-hLH, Luveris®, Lutropin alfa) injection will be administered subcutaneously once daily at a constant dose of 150 IU with flexible start, depending on the follicular growth (when the lead follicle is greater than 14 mm in size), along with r-hFSH treatment as a separate injection till r-hCG administration day.; Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from S1 at a starting dose of 300-450 IU and then dose adjusted depending on the ovarian response till r-hCG administration day.; The r-hCG will be administered as a single dose of 250-500 microgram (mcg) subcutaneously in the same day after the last dose of the GnRH antagonist.; The GnRH antagonist will be administered at a starting at a dose of 0.25 milligram (mg) subcutaneously daily in the morning when the ultrasound discovers a follicle of greater than or equal to (>=) 14 mm, and maintained until at least one follicle of >=18 mm and two additional follicles of >=16 mm with appropriate plasma estradiol levels for the number and size of the existing follicles.
Intervention MeSH terms: Cetrorelix; Chorionic Gonadotropin; Follicle Stimulating Hormone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 93.0
Sex: Female
Minimum age: 35 Years
Maximum age: 42 Years
Healthy volunteers: No
Keywords: Infertility; Ovulation induction; Luveris; Lutropin alfa; Controlled ovarian stimulation; Reproductive technologies, Assisted

Summary:

      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.
    

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