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

April 27, 2017 updated by: University Hospital, Basel, Switzerland

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

5

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Basel, Switzerland, CH-4031
        • University Hospital of Basel

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 33 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • Cetrotide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
up to two years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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%.
up to two years
The number of early miscarriages.
Time Frame: up to two years
Miscarriage is defined a pregnancy loss within 12 weeks after the last menstruation.
up to two years
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.
up to two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Basel, Switzerland

Collaborators

Merck Serono International SA

Investigators

  • Principal Investigator: Christian De Geter, Prof., University of Basel

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2012

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2013

Study Registration Dates

First Submitted

February 28, 2012

First Submitted That Met QC Criteria

March 25, 2012

First Posted (Estimate)

March 28, 2012

Study Record Updates

Last Update Posted (Actual)

May 1, 2017

Last Update Submitted That Met QC Criteria

April 27, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UBCH001 (Other Grant/Funding Number: University Hospital of Basel, Switzerland)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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