Clinical trial NCT01121991: A Prospective Study to Evaluate the Addition of Subcutaneous Recombinant Human-Luteinizing Hormone With Recombinant Human-Follicle Stimulating Hormone on Follicular Development in Women Undergoing Ovarian Stimulation for Assisted Reproductive Technologies
Official title: A Phase III, Multicentre, Open-label Prospective Study to Evaluate the Addition of Subcutaneous Recombinant Human-Luteinizing Hormone (Luveris) With r-hFSH on Follicular Development in Women Undergoing Ovarian Stimulation for ART
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Ovarian Stimulation
Keywords: Infertility
Ovarian Stimulation
Luveris
Lutropin alpha
Controlled ovarian stimulation
Reproductive techniques, assisted
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2010-05-12
Enrollment: 55
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: In-vitro fertilization (IVF) of human oocytes followed by the replacement of embryo in the uterine cavity has become a well established treatment for female infertility attributable to damaged fallopian tubes, endometriosis or unexplained causes where alternative forms of therapy have failed. The most commonly used protocols of follicular stimulation now employs follicle stimulating hormone (FSH) and long-acting agonists of gonadotropin releasing hormone (GnRH) to prevent the occurrence of a mid-cycle luteinizing hormone (LH) surge and to ensure the induction of well-synchronized larger cohort of ovarian follicles.

The results of a number of studies have demonstrated that in the majority of clinical situations, FSH administration alone is sufficient to achieve successful follicular development. A study had shown that in subjects receiving recombinant human-follicle stimulating hormone (r-hFSH) and recombinant human-luteinizing hormone (r-hLH), pregnancy rates were similar in the younger and older age groups, however, in women receiving r-hFSH alone, there was a significant decline in pregnancy rates for women 35 and older. This particular study also went on to show that the subgroup of women 35 and older, may benefit from supplementary r-hLH. A number of studies have been conducted to assess the safety and efficacy of r-hLH administered concomitantly with r-hFSH in the presence of developing follicles to reduce the rate of growth of intermediate and small follicles while allowing the dominant follicle to continue to progress.

This was a Phase III, open-label, multicentre study to evaluate safety and efficacy of addition of Recombinant Human-Luteinizing Hormone (Luveris) to a standard assisted reproductive technologies (ART) protocol.

Detailed description: Luteinizing hormone is a heterodimeric glycoprotein composed of a non-covalent association of an α and a β subunit. Prior to the generation of human-LH (hLH) through recombinant technology, hLH had only been available for therapeutic use as human menopausal gonadotropins (hMG), a co-extracted, purified preparation of hLH and hFSH from urine of post menopausal women. Recombinant Human-Luteinizing Hormone (Luveris) has been found to be well tolerated in human pharmacokinetic and pharmacodynamic studies at doses of up to 40,000 IU in healthy female volunteers without any Serious Adverse Event (SAE) experience being reported.

OBJECTIVES

* To evaluate safety and efficacy of addition of Recombinant Human-Luteinizing Hormone (Luveris) to a standard ART procedure.

In this study, subjects were first treated with a GnRH agonist to induce pituitary desensitization according to centre's standard practice followed by administration of r-hFSH. All subjects were then treated with Recombinant Human -Luteinizing Hormone (Luveris)150 IU per day subcutaneous (s.c.) from Day 6 of stimulation of their ART treatment cycle, continuing at the same dose until injection of hCG upto and including day of last FSH dose.

Eligibility criteria: Inclusion Criteria:

* Female subjects who underwent ovarian stimulation for ART (IVF/ICSI) using r-hFSH.
* Subjects who in the opinion of the treating investigator met any of the following criteria to require r-LH supplementation during the ovarian stimulation:

  * were selected for a GnRH agonist protocol to induce pituitary desensitization
  * previous poor ovarian response to r-hFSH alone
  * aged 35 to 40 years
  * elevated baseline hormone parameters that were predictive of poor ovarian response
* Female subjects aged between 18-40 years
* Subjects with uterine cavity able to sustain embryo implantation or pregnancy
* Subject who had no known infection with human immunodeficiency virus, hepatitis B or C virus
* Subjects who were willing to participate and comply with the protocol for the duration of the study
* Subjects who had given informed consent, prior to any study-related procedure not part of normal medical care

Exclusion Criteria:

* Subjects with clinically significant systemic disease (e.g. insulin-dependent diabetes, epilepsy, severe migraine, intermittent porphyria, hepatic, renal or cardiovascular disease, severe corticosteroid-dependent asthma)
* Any contraindication to being pregnant and/or carrying a pregnancy to term
* Subjects with abnormal gynecological bleeding of undetermined origin
* Subjects with known allergy to gonadotrophin preparations
* Subjects with any medical condition for which the use of gonadotrophin preparations was contraindicated
* Subjects who had previously entered into this study or simultaneously participated in another clinical drug trial
* Subjects with any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years
* Subjects who had refused or were unable to comply with protocol

Primary outcomes:
measure: Mean Number of Metaphase II Oocytes Per Participant Who Underwent Ovum Pick up for Intra-cytoplasmic Sperm Injection (ICSI)
timeFrame: On the day of ovum pick up (Day 1 or 2 after human chorionic gonadotropin [hCG] administration).
measure: Mean Number of Mature Oocytes Per Participant Who Underwent Ovum Pick up for In Vitro Fertilization (IVF)
timeFrame: On the day of ovum pick up (Day 1 or 2 after hCG administration).
Secondary outcomes:
measure: Mean Number of Oocytes Retrieved Per Number of Follicles Aspirated on the Day of Ovum Pick up
timeFrame: On day of ovum pick up (Day 1 or 2 after hCG administration)
measure: Number of Participants With Confirmed Pregnancies: Biochemical Pregnancies and Clinical Pregnancies
timeFrame: Post-hCG days 15-20 and post-hCG days 35-42.
measure: Number of Participants With Multiple Pregnancies
timeFrame: Post-hCG Day 35-42.
measure: Number of Live Births
timeFrame: Post-hCG days 15-20 to pregnancy follow up.
measure: Pregnancy Loss Per Clinical Pregnancy
timeFrame: Post-hCG days 35-42.
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Study Drug Discontinuation.
timeFrame: From stimulation Day 1 (S1) to post-hCG days 35-42 (safety visit).
Other outcomes:
Locations:
Study officials:
affiliation: EMD Serono Canada Inc.
name: Medical Responsible
role: STUDY_DIRECTOR
References: