Lutropin Alfa (Luveris®) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age: Phase II Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 93
- 试验地点
- 1
- 主要终点
- Number of Oocytes Retrieved
研究概览
简要总结
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.
详细描述
Preclinical pharmacology studies have demonstrated that r-hLH has a LH/human chorionic gonadotropin (hCG) receptor affinity similar to pituitary human luteinizing hormone (p-hLH), and is biologically active in-vitro in stimulating steroidogenesis and in promoting oocyte germinal vesicle breakdown. Several clinical studies have investigated the usefulness of r-hLH supplementation in normal ovulatory women undergoing ART and in almost all of them sub-populations of subjects have been identified who will benefit, when r-hLH is added to FSH.
OBJECTIVES
Primary objectives:
- To determine the efficacy of adding r-hLH at mid-follicular phase compared to not adding r-hLH, in women of 35-42 years of age included in a COS with r-hFSH under treatment with a GnRHant for IVF/ICSI, assessed by the number and quality of the oocyte
- To determine the safety of using r-hLH combined with r-hFSH in a protocol with a GnRHant, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerability
Secondary objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 35 Years 至 42 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
r-hLH + r-hFSH
干预措施: r-hLH + r-hFSH (Drug)
r-hLH + r-hFSH
干预措施: Recombinant Human Choriogonadotropin (r-hCG) (Drug)
r-hLH + r-hFSH
干预措施: GnRH antagonist (Drug)
r-hFSH
干预措施: r-hFSH (Drug)
r-hFSH
干预措施: Recombinant Human Choriogonadotropin (r-hCG) (Drug)
r-hFSH
干预措施: GnRH antagonist (Drug)
结局指标
主要结局
Number of Oocytes Retrieved
时间窗: Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
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
时间窗: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
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)
时间窗: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
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)
时间窗: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
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)
时间窗: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
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.
次要结局
- 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}]))
- Implantation Rate(Day 35-42 post OPU (34-38 hours post r-hCG day {end of stimulation cycle [approximately 9 days]}))
- Number of Participants With Clinical Pregnancies(Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days]))
- Number of Participants in Whom Recombinant Human Chorionic Gonadotropin (r-hCG) Was Not Administered Due to Poor Response(r-hCG day (end of stimulation cycle [approximately 9 days]))
- Number of Ovarian Stimulation Days(Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days]))
- Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)(Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days]))
- Estradiol (E2) Levels on r-hCG Day(r-hCG day (end of stimulation cycle [approximately 9 days]))
- Follicular Levels of Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and Human Chorionic Gonadotropin (hCG) at Ovum Pick up (OPU)(OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]))
- 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]))
- Follicular Levels of Estradiol (E2) at Ovum Pick up (OPU)(OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]))
- Follicular Levels of Testosterone (T) at Ovum Pick up (OPU)(OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}]))