A Phase II Study to Assess the Efficacy and Safety of Luveris® (Lutropin Alfa) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age

This study has been terminated.
(Trial was terminated due to low recruitment rate)
Sponsor:
Collaborator:
Merck, S.L., Spain
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01079949
First received: March 2, 2010
Last updated: January 26, 2014
Last verified: January 2014
  Purpose

Ovarian reserve is related to chronological age; 35 years of age is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. New therapeutic schemes are sought to improve follicular response in ovarian ageing because of the increasing number of infertile women aged older than 35 years who are trying to get pregnant. The advent of gonadotropin releasing hormone analogue antagonist (GnRHant) offers new perspectives to address the issues related to advanced reproductive age since it prevents premature luteinizing hormone (LH) surges while not causing suppression in the early follicular phase. Gonadotropin releasing hormone analogue antagonists are administered in the latter stage of the ovarian stimulation to prevent LH surge by competitive blockade of gonadotropin releasing hormone (GnRH) receptors, thus producing a marked decrease in LH levels just when the interplay between follicle stimulating hormone (FSH) and LH becomes important to complete follicular development and oocyte competence. Some studies in the past have shown the potential of recombinant human LH (r-hLH) supplementation in women of advanced reproductive age to improve oocyte quality, but these studies are of small size and did not provide data on the physiological mechanism behind the benefit obtained.

This randomized, comparative, parallel controlled Phase II study will be conducted in infertile female subjects aged 35-42 years undergoing in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), to investigate whether the addition of r-hLH (when the lead follicle is greater than [>] 14 millimeter [mm] in size), to the standard protocol with recombinant human FSH (r-hFSH) under GnRHant, improves the number and quality of oocytes retrieved, implantation rate, and pregnancy rate, while assessing the hormonal milieu in the ovarian follicular fluid. Comparison will be performed against ovarian stimulation without addition of r-hLH, that is (i.e.) with r-hFSH under GnRHant alone.


Condition Intervention Phase
Infertility
Ovulation Induction
Drug: r-hLH + r-hFSH
Drug: r-hFSH
Drug: Recombinant Human Choriogonadotropin (r-hCG)
Drug: GnRH antagonist
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 Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age: Phase II Clinical Trial

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Number of Oocytes Retrieved [ Time Frame: Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
    Number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body.

  • Number of Mature Oocytes Retrieved [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
    Number of mature oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. The nuclear maturity is assessed based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage or atretic.

  • Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: Yes ]
    Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.

  • Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: Yes ]
    Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.

  • Number of Participants With Adverse Events (AEs) [ Time Frame: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: Yes ]
    An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.


Secondary Outcome Measures:
  • Number of Follicles Greater Than or Equal to 14 Millimeter (mm) on Recombinant Human Choriogonadotropin (r-hCG) Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
  • Endometrial Thickness on Recombinant Human Choriogonadotropin (r-hCG) Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
    Endometrial thickness measurement was performed on the day of r-hCG administration.

  • Number of Fertilized Oocytes (2 Pronuclei [PN]) [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
    Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN.

  • Number of Fertilized Oocytes at Stage 2 Pronuclei (2PN) or Higher Than 2PN [ Time Frame: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
    Oocytes were fertilized using ICSI technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN. Fertilized oocytes at stage higher then 2PN are those oocytes which consist more than 2 pronuclei like oocyte having 3 pronuclei termed as 3PN, oocyte having 4 pronuclei termed as 4PN.

  • Number and Quality of Embryos [ Time Frame: Day 2-3 post OPU (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
    Embryos were classified into 5 different grades (1 to 5) based on their capacity of implantation. Grade 1 embryos were those with best capacity of implantation and Grade 5 embryos were those with worst capacity of implantation.

  • Implantation Rate [ Time Frame: Day 35-42 post OPU (34-38 hours post r-hCG day {end of stimulation cycle [approximately 9 days]}) ] [ Designated as safety issue: No ]
    Implantation rate was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100.

  • Number of Participants With Clinical Pregnancies [ Time Frame: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
    Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.

  • Number of Participants in Whom Recombinant Human Chorionic Gonadotropin (r-hCG) Was Not Administered Due to Poor Response [ Time Frame: r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
    Poor response was defined as 3 or less follicles of greater than or equal to 12 mm developing following at least 7 days of study treatment.

  • Number of Ovarian Stimulation Days [ Time Frame: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
    Ovarian stimulation included from first r-hFSH injection (S1) until day on which r-hCG was administered (r-hCG day).

  • Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) [ Time Frame: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
  • Estradiol (E2) Levels on r-hCG Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 9 days]) ] [ Designated as safety issue: No ]
  • Follicular Levels of Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and Human Chorionic Gonadotropin (hCG) at Ovum Pick up (OPU) [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
  • Follicular Levels of Estradiol (E2) at Ovum Pick up (OPU) [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]
  • Follicular Levels of Testosterone (T) at Ovum Pick up (OPU) [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]) ] [ Designated as safety issue: No ]

Enrollment: 93
Study Start Date: November 2007
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: r-hLH + r-hFSH Drug: r-hLH + r-hFSH
Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from stimulation Day 1(S1) at a starting dose of 300-450 International Unit (IU) and then dose adjusted depending on the ovarian response till recombinant human choriogonadotropin (r-hCG) administration day. Recombinant human luteinizing hormone (r-hLH, Luveris®, Lutropin alfa) injection will be administered subcutaneously once daily at a constant dose of 150 IU with flexible start, depending on the follicular growth (when the lead follicle is greater than 14 mm in size), along with r-hFSH treatment as a separate injection till r-hCG administration day.
Other Names:
  • Luveris®
  • Lutropin alfa
Drug: Recombinant Human Choriogonadotropin (r-hCG)
The r-hCG will be administered as a single dose of 250-500 microgram (mcg) subcutaneously in the same day after the last dose of the GnRH antagonist.
Other Name: Ovitrelle®
Drug: GnRH antagonist
The GnRH antagonist will be administered at a starting at a dose of 0.25 milligram (mg) subcutaneously daily in the morning when the ultrasound discovers a follicle of greater than or equal to (>=) 14 mm, and maintained until at least one follicle of >=18 mm and two additional follicles of >=16 mm with appropriate plasma estradiol levels for the number and size of the existing follicles.
Other Name: Cetrotide®
Active Comparator: r-hFSH Drug: r-hFSH
Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from S1 at a starting dose of 300-450 IU and then dose adjusted depending on the ovarian response till r-hCG administration day.
Drug: Recombinant Human Choriogonadotropin (r-hCG)
The r-hCG will be administered as a single dose of 250-500 microgram (mcg) subcutaneously in the same day after the last dose of the GnRH antagonist.
Other Name: Ovitrelle®
Drug: GnRH antagonist
The GnRH antagonist will be administered at a starting at a dose of 0.25 milligram (mg) subcutaneously daily in the morning when the ultrasound discovers a follicle of greater than or equal to (>=) 14 mm, and maintained until at least one follicle of >=18 mm and two additional follicles of >=16 mm with appropriate plasma estradiol levels for the number and size of the existing follicles.
Other Name: Cetrotide®

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   35 Years to 42 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Premenopausal woman, aged 35 to 42 years wanting to become pregnant
  • Subjects with FSH baseline plasma levels less than or equal to 10 IU/L (Day 2-5 of the cycle) and with LH and E2 levels within the normal limits of the local laboratory
  • Subjects having regular spontaneous menstrual cycle lasting 25-35 days
  • Subjects with infertility that is susceptible to treatment with IVF/ICSI
  • Subjects to be included in a COS protocol with r-hFSH and GnRHant
  • Subjects with partner's sperm suitable for IVF/ICSI according to local laboratory, unless sperm donor is to be used
  • Subjects with both ovaries
  • Subjects with uterine cavity capable of sustaining the implantation of embryo or carrying a pregnancy
  • Subjects with normal pap smear (papanicolaou) 6 months prior to be included in the study (signature of informed consent)
  • Subjects with body mass index (BMI) less than (<) 30 at the beginning of ovarian stimulation
  • Subjects with confirmed absence of pregnancy with the beta-hCG test (urine or blood) before starting the administration of r-hFSH
  • Subjects willing to adjust to the protocol for the entire duration of the study
  • Subjects who have given informed consent prior to any study-related procedure that is not part of normal medical care

Exclusion Criteria:

  • Subjects or her partner with known positivity for human immunodeficiency virus (HIV) or Hepatitis-B /Hepatitis-C virus (HBV/HCV)
  • Subjects with any systemic illnesses of clinical significance, hypothalamus and pituitary tumors; cancer of ovaries, uterus or breast; hormonal anomalies and/or medical, biochemical, hematological illnesses that, according to the investigator, could interfere with the treatment with gonadotropins
  • Subjects with more than 2 previous ART cycles
  • Subjects who have cancelled two previous ART cycles
  • Subjects with frozen embryos from previous ART cycles
  • Subjects with non-specific gynecological bleeding
  • Subjects with ovaries that are polycystic, increased in size or with cysts of unknown etiology
  • Subjects with any contraindication for becoming pregnant and/or carrying pregnancy to term
  • Subjects with known allergy to gonadotropin preparations or any of the excipients
  • Subjects with drug dependence or history of drug or alcohol abuse in the previous 5 years
  • Subjects who have previously entered into this study or simultaneous participation in another clinical drug trial with drugs
  • Subjects who are unwilling to or not being able to adjust to the study protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01079949

Locations
Spain
Instituto Marqués
Barcelona, Spain, 08034
Sponsors and Collaborators
Merck KGaA
Merck, S.L., Spain
Investigators
Study Director: Medical Responsible Merck, S.L., Spain
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01079949     History of Changes
Other Study ID Numbers: 27262, 2006-005268-19
Study First Received: March 2, 2010
Results First Received: November 12, 2012
Last Updated: January 26, 2014
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Merck KGaA:
Infertility
Ovulation induction
Luveris
Lutropin alfa
Controlled ovarian stimulation
Reproductive technologies, Assisted

Additional relevant MeSH terms:
Infertility
Genital Diseases, Male
Genital Diseases, Female
Chorionic Gonadotropin
Follicle Stimulating Hormone
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 15, 2014