A Clinical Trial to Determine the Effect of Lutropin Alfa on Embryo Quality and Implantation Rate in Advanced Reproductive Age

Study Overview
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Brief Summary
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This is a multicentric, open, randomized, comparative trial aimed to assess the influence of recombinant luteinizing hormone (r-LH) supplementation during controlled ovarian stimulation (COS) in advanced reproductive age in terms of improved embryo competence which allows to transfer less embryos to avoid high grade multiple pregnancy without reducing the pregnancy rate.

Detailed Description
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This study will be carried out by the Grupo de Interés de Salud Embrionaria (GISE) group (part of the Spanish Fertility Society) who uses strict criteria to select the embryos most suitable for successful transference. OBJECTIVES Primary objective: To determine the benefit of r-LH supplementation in COS prior to in-vitro fertilization (IVF)/intracytosolic sperm injection (ICSI) in advanced reproductive age, in terms of embryo competence to implant, as compared against no r-LH supplementation Secondary objectives: To evaluate the benefit of r-LH supplementation in COS, in terms of: follicular development length of the stimulation oocyte number and their maturity fertilization rate embryo number and quality gestational sacs abortion ongoing pregnancies local and systemic safety of r-LH administration The study will consist of 2 groups randomized in 1:1 ratio and each subject would be followed up until the confirmation of her pregnancy status. Each subject will be administered gonadotropin releasing hormone (GnRH) agonist subcutaneously daily from previous mid luteal phase to r-hCG administration as a standard practice to achieve down regulation. Each subject will also be administered recombinant follicle stimulating hormone (r-FSH) at a starting dose of 300 IU from S1 up to ovarian stimulation completion (r-hCG day) as a part of standard practice. In addition to the above concurrent therapies, one group will be administered experimental treatment (Luveris®) and the other group (control group) will not be administered any other drug (control treatment) during the stimulation period from stimulation start (S1) up to ovarian stimulation completion or stimulation cancellation respectively. Ovarian stimulation on an average takes 11 days and it is expected that stimulation period will not be extended beyond 15 days. A single injection of r-hCG will be administered intramuscularly or subcutaneously after the last injection of Luveris or r-FSH to achieve final follicular maturation. After, 34-36 hours of administration of r-hCG OPU will be done for oocyte retrieval and embryo transfer (ET) will be conducted within 5 days from OPU. Subjects will also be provided luteal support with natural progesterone and will be followed until delivery or miscarriage. Ultrasound and estradiol (E2) assessment of follicular growth will be conducted at various time points during the stimulation period with or without treatment adjustment.

Official Title
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Exploratory Study to Determine the Effect of Lutropin Alfa on Embryo Quality and Their Implantation in Women of Advanced Reproductive Age

Conditions
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Infertility, Ovulation Induction

Intervention / Treatment
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* Drug: Recombinant human luteinizing hormone (rhLH)
* Drug: Recombinant follicle-stimulating hormone (rFSH)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-menopausal female subject aged greater than (>) 35 years Subjects with baseline FSH serum level less than or equal to (<=) 10 IU/liter (l), LH and E2 levels within local normal range and plasma prolactin levels < 30 nanogram/milliliter (ng/ml) Subjects with regular spontaneous menstrual cycles of 25-35 days Subjects with infertility justifying IVF/ICSI-ET treatment Subjects programmed for COS with r-FSH under GnRH agonist protocol Sperm from current male partner suitable for IVF/ICSI according to local lab, unless sperm donor is foreseen Subjects with presence of both ovaries Subjects whose uterine cavity is able to sustain embryo implantation or pregnancy Subjects with normal papanicolaou test (PAP) smear within previous 3 years Subjects with body mass index (BMI) < 30 at stimulation start Subjects who receive confirmation of not being pregnant by a negative beta-hCG test (urine or blood) prior to starting r-FSH administration Subjects willing and able to comply with the protocol for the duration of the study Subjects who have given informed consent prior to any study-related procedure not part of normal medical care Exclusion Criteria: Subjects or her male partners who are known to be human immunodeficiency virus, hepatitis B virus or hepatitis C virus positive Subjects with any clinically significant systemic disease; tumors of the hypothalamus and pituitary gland; ovarian, uterine or mammary cancer; hormonal abnormality and/or medical, biochemical, hematological condition which in the judgment of the investigator may interfere with gonadotropin treatment Subjects with more than 2 previous assisted reproductive technologies (ART) cycles Subjects in which previous cycles were cancelled due to poor response (< 3 antral follicles after 15 day of stimulation) Subjects with cryopreserved embryos from previous ART cycles Subjects with unexplained gynecological bleeding Subjects with polycystic ovaries, ovarian enlargement or cyst of unknown etiology Subjects known to have any contraindication to being pregnant and/or carrying pregnancy to term Subjects with known allergy to gonadotrophin preparations or any of the excipients Subjects known to have any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years Subjects with previous entry into this study or simultaneous participation in another clinical drug trial Subjects who have refused to or inability to comply with the protocol

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rFSH + rhLH<br>Recombinant human luteinizing hormone (rhLH,Luveris®) injection 150 IU subcutaneously daily along with rFSH 300 IU subcutaneously daily from S1 to S4 and then rFSH dose can be adjusted depending on the ovarian response till r-hCG administration day. | Drug: Recombinant human luteinizing hormone (rhLH)<br> <br> * Other names: Lutropin alfa;Drug: Recombinant follicle-stimulating hormone (rFSH)<br> <br> |
| Active Comparator: rFSH<br>rFSH injection 300 IU subcutaneously daily from S1 to S4 and then dose can be adjusted depending on the ovarian response till r-hCG administration day. | Drug: Recombinant follicle-stimulating hormone (rFSH)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Implantation Rate | Implantation rate was measured as the number of gestational sacs observed, divided by the number of embryos transferred. | Day 35-42 post ovum pick-up (OPU) (34-38 hours post recombinant human choriogonadotropin day {end of stimulation cycle}[approximately 28 days]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean 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 28 days]) | 
| Mean Number of Oocytes Retrieved | Mean number of oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) 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. | 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 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 (end of stimulation cycle [approximately 28 days]) 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 was evaluated based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage. | 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| Number of Fertilized Oocytes (2 Pronuclei [PN]) | 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 two 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. | 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| Number and Quality of Embryos | Embryos were graded according to Spanish Association for the Study of Reproductive Biology (ASEBIR) criteria into different categories: (A) optimal quality with maximum capacity for implantation, (B) good quality with a high capacity for implantation, (C) regular with low possibility of implantation and (D) poor quality with very little possibility of implantation. | Day 2-3 post OPU (34-38 hours post r-hCG day {end of stimulation cycle}[approximately 28 days]) | 
| Number of Participants With Biochemical Pregnancies | Biochemical pregnancy was defined as a pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy. | 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Number of Participants With Clinical Pregnancies | 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. | 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Total Dose of Recombinant Follicle Stimulating Hormone (r-FSH) |  | 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Estradiol (E2) Levels on r-hCG Day |  | r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| Number of Ovarian Stimulation Days | Ovarian stimulation included from first rFSH injection (S1) until day on which r-hCG was administered (r-hCG day). This period was divided into 2 parts: the first period in which 300 International Unit (IU) rFSH dose was constant and which covered from S1 to Day 4 of stimulation period (S4); the second period in which the rFSH dose could be adjusted depending on the ovarian response and which began on S4 and finished on the day on which the criteria for administration of r-hCG to induce the final follicular maturation were met. | S1 up to r-hCG day (end of stimulation cycle [approximately 28 days]) | 
| Number of Recombinant Human Choriogonadotropin (r-hCG) Cycles Cancelled Due to Poor Response | 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. | Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Total Number of Births | Total number of births per reporting group was calculated. | Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Number of Participants With Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting. | Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 
| Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS) | OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting. | Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, Ovulation induction, Luveris, Controlled ovarian stimulation, Reproductive technologies, assisted