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

NCT01079949 | Terminated Phase 2 Results

• 2 other identifiers: 272622006-005268-19
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Infertility; Ovulation Induction

Keywords

Infertility; Ovulation induction; Luveris; Lutropin alfa; Controlled ovarian stimulation; Reproductive technologies, Assisted

Outcome Measures

Primary Outcomes (5)

• Number of Oocytes Retrieved

  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.

  Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])

• Number of Mature Oocytes Retrieved

  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.

  OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])

• Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)

  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.

  S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])

• Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS)

  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.

  S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])

• Number of Participants With Adverse Events (AEs)

  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.

  S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])

Secondary Outcomes (14)

• Number of Follicles Greater Than or Equal to 14 Millimeter (mm) on Recombinant Human Choriogonadotropin (r-hCG) Day

  r-hCG day (end of stimulation cycle [approximately 9 days])

• Endometrial Thickness on Recombinant Human Choriogonadotropin (r-hCG) Day

  r-hCG day (end of stimulation cycle [approximately 9 days])

• Number of Fertilized Oocytes (2 Pronuclei [PN])

  OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])

• Number of Fertilized Oocytes at Stage 2 Pronuclei (2PN) or Higher Than 2PN

  Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days])

• Number and Quality of Embryos

  Day 2-3 post OPU (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])

Study Arms (2)

r-hLH + r-hFSH

EXPERIMENTAL

Drug: r-hLH + r-hFSH; Drug: Recombinant Human Choriogonadotropin (r-hCG); Drug: GnRH antagonist

r-hFSH

ACTIVE COMPARATOR

Drug: r-hFSH; Drug: Recombinant Human Choriogonadotropin (r-hCG); Drug: GnRH antagonist

Interventions

r-hLH + r-hFSH DRUG

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.

Also known as: Luveris®, Lutropin alfa

r-hLH + r-hFSH

r-hFSH DRUG

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.

r-hFSH

Recombinant Human Choriogonadotropin (r-hCG) DRUG

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.

Also known as: Ovitrelle®

r-hFSH; r-hLH + r-hFSH

GnRH antagonist DRUG

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.

Also known as: Cetrotide®

r-hFSH; r-hLH + r-hFSH

Eligibility Criteria

• Age: 35 Years - 42 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead
• Merck, S.L., Spain: collaborator

Study Sites (1)

Instituto Marqués

Barcelona, 08034, Spain

Location

MeSH Terms

Conditions

Infertility; Helping Behavior

Interventions

Luteinizing Hormone, beta Subunit; Chorionic Gonadotropin; LHRH, Ac-Nal(1)-Cpa(2)-Trp(3)-Arg(6)-Ala(10)-; cetrorelix

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases; Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Luteinizing Hormone; Gonadotropins, Pituitary; Gonadotropins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormones, Anterior; Pituitary Hormones; Peptides; Amino Acids, Peptides, and Proteins; Placental Hormones; Pregnancy Proteins; Proteins

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck, S.L., Spain

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2010
• First Posted: March 3, 2010
• Study Start: November 1, 2007
• Primary Completion: October 1, 2010
• Study Completion: October 1, 2010
• Last Updated: February 27, 2014
• Results First Posted: February 20, 2013

Record last verified: 2014-01

Locations

ES (1)