Complications Associated With Artificial Fertilization Clinical Trial
Official title:
Prospective Randomized Study Comparing Ovarian Stimulation With Pergoveris Supported by a GnRH Agonist in a Long Protocol Versus Multidose GnRH Antagonist Regimen in Young Infertile Women Treated With ICS
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.
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