Comparing Ovarian Stimulation for Assisted Reproduction With Two Different Forms of Pituitary Suppression

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.

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.

Eligibility Criteria:
Inclusion Criteria:

Female patients younger than 36 years of age with an indication for ICSI:

* 20 to 35 years inclusive
* body mass index between 19 and 30 kg/m2
* indication for ICSI due to male infertility
* cycle length 27 to 32 days
* presence of both ovaries
* rubella immunity
* written informed consent

Exclusion Criteria:

* age \> 35 years
* pregnancy and breast feeding
* ovarian endometriosis
* uterine fibroids interfering with endometrial proliferation
* sperm retrieval from the epididymis or the testis
* more than one previous ART treatment with pregnancy
* known or suspected hypersensitivity to active substances
* clinically relevant systemic disease
* previous enrollment to this study
* know or suspected non-compliance, drug or alcohol abuse