Comparing Ovarian Stimulation for Assisted Reproduction With Two Different Forms of Pituitary Suppression
Condition: Female Infertility Due to Nonimplantation of Ovum; Complications Associated With Artificial Fertilization
MeSH terms: Infertility; Infertility, Female
Study type: Interventional

Summary: 
      The purpose of this study is to assess the non-inferiority of a multidose GnRH antagonist
      (cetrorelix) regimen to a GnRH agonist (triptorelin) long protocol in young infertile women
      undergoing ovarian stimulation with Pergoveris 150 I.U./75 I.U. (r-hFSH/ r-hLH) for ICSI
      treatment because of male infertility.

      To assess the efficacy of ovarian stimulation using either a GnRH antagonist (cetrorelix) or
      a GnRH agonist (triptorelin) long protocol in infertile women with good prognosis and to
      determine the safety of ovarian stimulation.

      Subsample analysis: in 10 patients of each of both arms, serum samples will be collected
      daily during the stimulation period and be stored frozen at -70 °C. The following hormone
      concentrations will be measured later in single assay batches: LH, FSH, oestradiol,
      progesterone, androstenedione, testosterone, inhibin A, inhibin B, AMH.

      Multinational, multicentre, open label, randomized, 2-arm parallel-group phase IV study.
      Eligible patients will be randomly allocated to one of the two groups: the agonist group will
      receive Decapeptyl® 0.1 mg (triptorelin) starting in the mid-luteal phase of the natural
      cycle until downregulation until the day of ovulation induction. The antagonist group will
      receive cetrorelix 0.25 mg from stimulation day 6 to ovulation induction. In both groups,
      Pergoveris® 150 I.U./75 I.U. (r-hFSH/r-hLH) will be used for ovarian stimulation from cycle
      day 2 to ovulation induction.
    

Detailed description: 
      In assisted reproductive technology (ART), follicular growth is stimulated with exogenous
      gonadotropins to obtain multiple mature oocytes for fertilization. In a natural cycle, oocyte
      maturation and ovulation is triggered by endogenous luteinizing hormone (LH). To prevent a
      premature surge of LH and subsequent premature ovulation and cancellation of the ART cycle, a
      gonadotropin releasing hormone (GnRH) agonist is commonly used to inhibit endogenous
      gonadotropin release leading to premature ovulation or luteinization. After a short-term
      initial stimulation of the pituitary gland, continuous administration of a GnRH agonist leads
      to the downregulation of GnRH receptors of the pituitary and thus prevents synthesis and
      release of follicle-stimulating hormone (FSH) and LH from that organ.

      Endogenous gonadotropin release may also be prevented by using GnRH antagonists instead of
      GnRH agonists. During the past decade, two GnRH antagonists (cetrorelix, ganirelix) have been
      licensed for prevention of premature LH surge and ovulation during ovarian hyperstimulation
      for assisted reproduction. The antagonist competes directly with the physiological GnRH for
      binding to the pituitary GnRH receptors and provides quicker suppression of gonadotropin
      release without the initial flare up. Compared with the GnRH agonist long protocol, GnRH
      antagonists require a considerably shorter treatment period, less exogenous gonadotropin for
      ovarian stimulation, and are associated with fewer side effects, and a lower risk of ovarian
      hyperstimulation syndrome (OHSS). An early meta-analysis from 2002, which included the first
      studies comparing GnRH agonist and antagonist treatment regimens, showed that clinical
      pregnancy was lower with GnRH antagonist treatment. However, there were no statistically
      significant differences in life-birth rate or in the probability of life birth between the
      protocols, as shown in a more recent review. However, GnRH agonists are still routinely used
      in most infertility centres, whereas GnRH antagonists are still preferentially prescribed to
      older women with unfavourable prognosis. The equivalence of both protocols has only been
      evaluated in ovarian hyperstimulation based on recombinant FSH only.

      Another difference among both protocols consists of the sudden blockage of endogenous LH
      secretion caused by the administration of the GnRH antagonist, which is usually given when
      the follicles reach the size of 12 mm (around day 6 of the menstrual cycle). At that
      developmental stage, the LH receptor is present in the follicles participating in follicular
      function. In women treated with the long protocol, low endogenous levels of LH have been
      associated with low pregnancy rates. At present, conflicting data have been reported with
      regard to the effect of either low or high levels of LH during the midfollicular phase on the
      pregnancy rates, regardless whether GnRH agonists or GnRH antagonists were used. However, all
      these studies were performed with recombinant FSH lacking all LH activity and one single day
      measurement of LH concentration in the serum may not reflect the endocrine activity of LH
      throughout follicular development. The need for the presence of LH during follicular
      development has been demonstrated unequivocally in women suffering of hypogonadotropic
      ovarian failure (WHO I), which lead to the development of Pergoveris® 150 I.U./75 I.U.

      Pergoveris® 150 I.U./75 I.U. is used to stimulate the development of follicles in the ovaries
      and was granted European marketing authorization in 2007. It consists of a fixed combination
      of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing
      hormone (r-hLH) and allows the administration of both substances in a single injection. So
      far, no study has been performed to demonstrate the equivalence of Pergoveris® in the GnRH
      antagonist protocol as compared to the long protocol based on a GnRH agonist.

      The current study aims to assess the non-inferiority of a multidose GnRH antagonist treatment
      regimen to a GnRH agonist long protocol in young infertile women (< 36 years) with good
      prognosis undergoing ovarian stimulation with Pergoveris® for intracytoplasmic sperm
      injection (ICSI) because of non-borderline male infertility. In addition, the safety of
      ovarian stimulation with Pergoveris will be evaluated for both treatment regimens, especially
      with regard to the incidence of OHSS.

      The primary objective of this study is to assess the non-inferiority of a multidose GnRH
      antagonist (cetrorelix) regimen to a GnRH agonist (triptorelin) long protocol in young
      infertile women undergoing ovarian hyperstimulation with Pergoveris® 150 I.U./75 I.U.
      (r-hFSH/ r-hLH) for ICSI treatment because of male infertility. Non-inferiority is defined by
      the number of mature metaphase II oocytes available for ICSI.

      Secondary objectives:

        -  To assess the efficacy of ovarian stimulation with Pergoveris using either a GnRH
           antagonist (cetrorelix) or a GnRH agonist (triptorelin) long protocol in infertile women
           with good prognosis with respect to the number of pregnancies achieved in each group.

        -  To determine the safety of ovarian stimulation with respect to the number of women
           suffering of the ovarian hyperstimulation syndrome (OHSS).

      This is a clinical phase IV, multinational, multicentre study using an open label,
      randomized, 2-arm parallel-group design. The study will be conducted at various treatment
      units in Europe, including Switzerland (1 centre) and Israel.

      Eligible patients will be randomly assigned to one of the two treatment arms:

        -  agonist group: r-hFSH/r-hLH 150 I.U./75 I.U. (Pergoveris®) daily from cycle day 2 to
           ovulation induction and triptorelin 0.1 mg daily from the mid-luteal phase (day 21 - 24)
           of the pre-ART cycle to ovulation induction.

        -  antagonist group: r-hFSH/r-hLH 150 I.U./75 I.U. (Pergoveris®) daily from cycle day 2 to
           ovulation induction and cetrorelix 0.25 mg daily from cycle day 7 (stimulation day 6) to
           ovulation induction.
    

Intervention name(s): Pergoveris in long protocol with GnRH agonist; Pergoveris in GnRH antagonist protocol
Intervention type(s): Drug; Drug
Intervention description(s): Ovarian hyperstimulation with recombinant FSH and recombinant FSH Ovulation induction with recombinant HCG Oocyte collection for ICSI; Ovarian hyperstimulation with recombinant FSH and recombinant FSH Ovulation induction with recombinant HCG Oocyte collection for ICSI
Other intervention name(s): Pergoveris; Cetrotide
Intervention MeSH terms: Cetrorelix; Prolactin Release-Inhibiting Factors; Follicle Stimulating Hormone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ovarian hyperstimulation; GnRH antagonist; GnRH agonist; assisted reproduction; FSH; LH