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

Study Overview
=================
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.

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

Conditions
-----------------
Infertility, Ovarian Stimulation

Intervention / Treatment
-----------------
* Drug: Recombinant Human-Luteinizing Hormone (Luveris)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Recombinant Human-Luteinizing Hormone (Luveris)|Recombinant Human-Luteinizing Hormone (Luveris) was administered once daily subcutaneously at a starting dose of 150 IU per day beginning on stimulation Day 6.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of Metaphase II Oocytes Per Participant Who Underwent Ovum Pick up for Intra-cytoplasmic Sperm Injection (ICSI) | Mean number of metaphase II oocytes was calculated for each participant undergoing ovum pick up for ICSI. ICSI is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. Metaphase II stage of the oocyte was classified as the time at which the first polar body was observed microscopically. Metaphase II oocytes are a sub-group of the total number of oocytes. | On the day of ovum pick up (Day 1 or 2 after human chorionic gonadotropin [hCG] administration). | 
| Mean Number of Mature Oocytes Per Participant Who Underwent Ovum Pick up for In Vitro Fertilization (IVF) | Mean number of oocytes undergoing ovum pick up for IVF were calculated for each participant. IVF is a process by which egg cells are fertilized by sperm outside the body, in-vitro. | On the day of ovum pick up (Day 1 or 2 after hCG administration). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Number of Oocytes Retrieved Per Number of Follicles Aspirated on the Day of Ovum Pick up | Mean number of oocytes retrieved per number of follicles aspirated on the day of ovum pick up 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. | On day of ovum pick up (Day 1 or 2 after hCG administration) | 
| Number of Participants With Confirmed Pregnancies: Biochemical Pregnancies and Clinical Pregnancies | Biochemical pregnancy: A positive pregnancy test defined as hCG level >10 IU/L in a sample taken at least 14 days after Day 3 embryo transfer or 12 days after Day 5/6 embryo transfer with no further ultrasound confirmation of the existence of a gestational sac in the uterus. Clinical pregnancy: Existence of at least one ultrasonography confirmed gestational sac in the uterus, with or without heartbeat. | Post-hCG days 15-20 and post-hCG days 35-42. | 
| Number of Participants With Multiple Pregnancies | Multiple pregnancy is a pregnancy where more than one fetus develops simultaneously in the womb. There are two types of twinning-identical and fraternal. Identical twins represent the splitting of a single fertilized zygote (union of two gametes or male/female sex cells that produce a developing fetus) into two separate individuals. | Post-hCG Day 35-42. | 
| Number of Live Births | A live birth occurs when a fetus, whatever its gestational age, exits the maternal body and subsequently shows any sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, for however brief a time and regardless of whether the umbilical cord or placenta are intact. | Post-hCG days 15-20 to pregnancy follow up. | 
| Pregnancy Loss Per Clinical Pregnancy | Preclinical miscarriage: Spontaneous cessation of a biochemical pregnancy. Early spontaneous abortion: Any spontaneous abortion occurring after confirmation of clinical pregnancy and before completion of 12 weeks of gestation. Late spontaneous abortion: any spontaneous abortion occurring between completion of 12 weeks of gestation and prior to a viable stage. Pregnancy loss per clinical pregnancy was measured as a percentage. | Post-hCG days 35-42. | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Study Drug Discontinuation. | AEs: Any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. TEAEs: AEs that occur during treatment with the study drug. It also included incidences of mild, moderate and severe ovarian hyperstimulation syndrome (OHSS). SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued from the study due to AE were also recorded. | From stimulation Day 1 (S1) to post-hCG days 35-42 (safety visit). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infertility, Ovarian Stimulation, Luveris, Lutropin alpha, Controlled ovarian stimulation, Reproductive techniques, assisted