An Exploratory Trial to Assess the Efficacy and Safety of Luveris in Women at Risk of Poor Response Undergoing Controlled Ovarian Stimulation (COS) Prior to Intracytoplasmic Sperm Injection (ICSI) With Gonal-f and Cetrotide

This study has been completed.
Sponsor:
Information provided by:
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01112358
First received: April 26, 2010
Last updated: July 15, 2014
Last verified: April 2010
  Purpose

This was a prospective, randomised, comparative with parallel control, Phase 2 exploratory trial to assess the efficacy and safety of mid follicular Luveris in 60 women at risk of poor response undergoing COS prior to ICSI with Gonal-f and Cetrotide.


Condition Intervention Phase
Controlled Ovarian Stimulation
Drug: Follitropin alpha (r-FSH) and Lutropin alfa (r-hLH)
Drug: Follitropin alpha (r-FSH)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Lutropin Alfa (Luveris®) in Women at Risk of Poor Response Suppressed With Cetrorelix: an Exploratory Trial

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Efficacy assessments [ Time Frame: 34-38 hours post r-hCG administration ] [ Designated as safety issue: No ]
    Efficacy endpoints are the number of metaphase II oocytes and the retrieved oocytes; and rate of metaphase II over the total number of oocytes retrieved


Secondary Outcome Measures:
  • Secondary efficacy assessments [ Time Frame: Baseline (first stimulation day [S1]) to clinical pregnancy assessment (post-hCG days 35-45) ] [ Designated as safety issue: No ]
    Number of follicles on r-hCG day or cancellation; number of follicles ≥ 14 mm Ø on r-hCG day or cancellation; endometrial thickness on the day of hCG administration; number of oocytes retrieved on the day of ovum pick up (OPU); number of fertilized (2PN) oocytes; fertilization rate; number of embryos and their quality; implantation rate per embryo transferred; number of clinical pregnancies; number of cycles cancelled; stimulation days; serum LH levels during the stimulation; total dose of r-hFSH used; serum E2 levels on r-hCG day

  • Safety assessments [ Time Frame: First stimulation day (S1) to days 13-45 post-hCG ] [ Designated as safety issue: Yes ]
    Safety endpoints are the incidence of OHSS; number of cycles cancelled (hCG not administered) due to risk of OHSS; adverse events, including local tolerance; local laboratory parameters.


Enrollment: 60
Study Start Date: November 2005
Study Completion Date: January 2007
Primary Completion Date: January 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: r-FSH + LH Drug: Follitropin alpha (r-FSH) and Lutropin alfa (r-hLH)
Recombinant-human luteinising hormone (r-hLH) was administered by subcutaneous (s.c.) route at a daily dose of 150 IU after administration of r-hFSH an GnRH antagonist. Administration of r-hFSH, GnRH antagonist, and r-hLH was stopped within 24 hours prior to r-hCG administration
Other Name: Luveris® (r-hLH); Gonal-f® (r-hFSH)
Experimental: r-FSH Drug: Follitropin alpha (r-FSH)
Recombinant-human follicle stimulating hormone (r-hFSH) was administered by s.c. route at a daily dose of 225-450 IU/day and then adjusted according to ovarian response as determined by ovarian ultrasound (US) and/or serum E2 levels. This was then followed by administration of GnRH antagonist. Administration of r-hFSH, GnRH antagonist, and r-hLH was stopped within 24 hours prior to r-hCG administration.
Other Name: Gonal-f®

Detailed Description:

Large protocols have been dedicated to overcome the problem of poor ovarian response and encouraging results have obtained. This proposal was to complement COS with follitropin alfa by adding lutropin alfa at the time of gonadotropin releasing hormone (GnRH) antagonist administration to prevent endogenous luteinising hormone (LH) surge. The reasons were:

  • Recombinant-follicle stimulating hormone (r-FSH) will promote follicular growth and by aromatase activation will stimulate estradiol (E2)synthesis.
  • Recombinant-human LH (r-hLH) besides acting on theca cells to provide androgens to be converted to E2, will finalize the maturation of granulosa cells from developed follicles and, at the same time, will produce atresia of less developed follicles lacking of mature granulosa cells.
  • The use of GnRH antagonist strongly suppresses serum LH levels thus the exogenous administration of lutropin alfa.

OBJECTIVES

  • To assess the efficacy of the simultaneous addition GnRH antagonist and r-hLH versus no addition of r-hLH, in subjects at risk of poor response aged < 38 years undergoing COS with r-hFSH prior to ICSI, in terms of oocyte number and quality as well as follicular development, oocyte fertilisation, embryo quality and pregnancy rates
  • To assess the safety of using r-hLH in combination with r-hFSH in a protocol of COS with GnRH antagonist, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerance.

The study was organised on an outpatient basis. All subjects underwent COS according to centre´s standard protocol (but Luveris) when a GnRH antagonist was going to be used. The COS was started on day 2-3 of the cycle with an initial dose of follitropin alfa ranging from 225 to 450 IU/day depending on subjects' baseline profile. Then the daily dose was adjusted according to ovarian response. When detected a follicle ≥ 14 mm or serum E2 levels > 200 pg/ml, then both 0.25 mg/day of Cetrotide and 150 IU/day of Luveris were initiated. Randomisation to Luveris supplementation or not took place at any time between the fourth day of COS (S4) and the first dose of Cetrotide, which were administered in the morning. Once COS completed, follitropin alfa, lutropin alfa, and Cetrorelix were stopped and recombinant-human choriogonadotropin (r-hCG) administered within the following 24 hours. Standard criteria for r-hCG administration were the presence of at least of one follicle ≥18 mm and two addition follicles > 16 mm together with appropriate E2 levels for the follicular number and size.

  Eligibility

Ages Eligible for Study:   up to 38 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pre-menopausal female subjects, aged < 38 years, wishing to conceive and included in an ICSI-embryo transfer (ET) protocol with GnRH antagonist
  • Subjects who were at risk of poor response by at least one of the following criteria:

    • Previous poor response by ≤3 fol ≥14 mm, ≤2 M-II, or E2 ≤600 pg/l at hCG
    • Cancellation of previous cycle
    • Early follicular phase serum FSH ≥ 8.5 IU/l
  • Subjects with normal baseline LH and E2 levels with normal gynaecological imaging
  • Subjects who were infertile justifying IVF/ET or ICSI treatment
  • Subjects who were able and willing to adhere to protocol and informed consent signature

Exclusion Criteria:

  • Subjects who had any clinically significant disease including known human immunodeficiency virus (HIV), hepatitis-B virus (HBV)/hepatitis-C virus (HCV) positivity
  • Subjects with more than 3 previous assisted reproductive techniques (ART) cycles
  • Subjects with polycystic ovaries, ovarian enlargement or cyst of unknown aetiology, unexplained gynaecological bleeding
  • Subjects who had any contraindication to being pregnant, active substance abuse
  • Subjects who had simultaneously participated in another clinical drug trial.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01112358

Locations
Spain
Hospital Universitario de La Fe
Valencia, Spain
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Dr. Enrique Granados Merck Serono Spain
  More Information

No publications provided

Responsible Party: Dr. Sebastián Burgués/Medical Manager, Merck Serono Spain, an affiliate of MerckKGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01112358     History of Changes
Other Study ID Numbers: IMP26170 (INI25954)
Study First Received: April 26, 2010
Last Updated: July 15, 2014
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Merck KGaA:
Lutropin alfa
Fertilization in vitro
Intracytoplasmic sperm injection
Reproductive techniques, assisted

Additional relevant MeSH terms:
Follicle Stimulating Hormone
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014