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

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ClinicalTrials.gov Identifier: NCT01565265
Recruitment Status : Completed
First Posted : March 28, 2012
Last Update Posted : May 1, 2017
Sponsor:
Collaborator:
Merck Serono International SA
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

Brief 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.


Condition or disease Intervention/treatment Phase
Female Infertility Due to Nonimplantation of Ovum Complications Associated With Artificial Fertilization Drug: Pergoveris in long protocol with GnRH agonist Drug: Pergoveris in GnRH antagonist protocol Not Applicable

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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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : April 2012
Actual Primary Completion Date : December 2012
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Infertility

Arm Intervention/treatment
Active Comparator: GnRH agonist long protocol
Pergoveris will be administered daily from cycle day 2 to ovulation induction together with decapeptyl, which will be administered from the midluteal phase of the preceding menstrual cycle up to ovulation induction.
Drug: Pergoveris in long protocol with GnRH agonist
Ovarian hyperstimulation with recombinant FSH and recombinant FSH Ovulation induction with recombinant HCG Oocyte collection for ICSI
Other Name: Pergoveris

Experimental: antagonist protocol
Pergoveris will be administered daily from cycle day 2 to ovulation induction together with Cetrotide, which will be administered from the day six up to ovulation induction.
Drug: Pergoveris in GnRH antagonist protocol
Ovarian hyperstimulation with recombinant FSH and recombinant FSH Ovulation induction with recombinant HCG Oocyte collection for ICSI
Other Name: Cetrotide




Primary Outcome Measures :
  1. number of mature oocytes [ Time Frame: up to two years ]
    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 for ICSI treatment because of male infertility. Non-inferiority is defined by the number of mature metaphase II oocytes available for ICSI.


Secondary Outcome Measures :
  1. incidence of ovarian hyperstimulation syndrome (OHSS) [ Time Frame: up to two years ]
    The safety of ovarian stimulation with respect to the number of women suffering of the ovarian hyperstimulation syndrome (OHSS). OHSS is defined by enlargement of both ovaries together with ascites and haematocrit rise above 45%.

  2. The number of early miscarriages. [ Time Frame: up to two years ]
    Miscarriage is defined a pregnancy loss within 12 weeks after the last menstruation.

  3. The number of participants with adverse events. [ Time Frame: up to two years ]
    Adverse event is defined as any untoward medical occurrence in a patient or a clinical investigation subject, who was administerd a pharmaceutical product and which does not necessarily must have a causal relationship with the treatment.



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Ages Eligible for Study:   20 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01565265


Locations
Switzerland
University Hospital of Basel
Basel, Switzerland, CH-4031
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Merck Serono International SA
Investigators
Principal Investigator: Christian De Geter, Prof. University of Basel

Publications:

Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT01565265     History of Changes
Other Study ID Numbers: UBCH001
UBCH001 ( Other Grant/Funding Number: University Hospital of Basel, Switzerland )
First Posted: March 28, 2012    Key Record Dates
Last Update Posted: May 1, 2017
Last Verified: April 2017

Keywords provided by University Hospital, Basel, Switzerland:
ovarian hyperstimulation
GnRH antagonist
GnRH agonist
assisted reproduction
FSH
LH

Additional relevant MeSH terms:
Infertility
Infertility, Female
Genital Diseases, Male
Genital Diseases, Female
Prolactin Release-Inhibiting Factors
Follicle Stimulating Hormone
Cetrorelix
Deslorelin
Triptorelin Pamoate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Luteolytic Agents
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Fertility Agents, Female
Fertility Agents
Hormone Antagonists