Double vs. Single Stimulation in Young Poor Prognosis Patients Followed by a Fresh Embryo Transfer. A Randomized Clinical Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Number of good-quality blastocysts
研究概览
简要总结
The major goal of controlled ovarian stimulation (COS) is to increase the number of oocytes harvested in order to result in the generation of a higher number of available embryos, extended embryo culture, embryo selection and finally providing higher cumulative live birth rates in infertile patients. Moreover, with the idea of the multiple waves of follicular production, we could start to take full advantage of the whole follicular cohort, and not only of the follicular wave.
In the context of low prognosis women such as women with poor ovarian response where, the success rates are very low due to the low number of oocytes retrieved and consequently of viable embryos), Dual stimulation may be of great value as a tool to improve outcomes.
The reported advantage of DuoStim is retrieved of more oocytes within a shorter time span, resulting in an increase in the probability of having transferable embryos increases, and theoretically reducing time to live birth as well as cycle cancellation.
详细描述
In assisted reproductive technologies (ART), despite the progress of the last decades, the achievement of a live birth still remains a challenge, especially for some categories of patients such as the one with poor ovarian reserve. One of the main tolls in reproductive medicine is controlled ovarian stimulation (COS) which is performed with the aim of obtaining multiple oocytes, so as to increase the chance of a live birth (LB) .
In order to induce multifollicular development in ovarian stimulation, recombinant FSH (or other products based on FSH) are given at the beginning of the follicular phase for an average of 10-12 days. The reason for this timing is mainly due to the fact that the follicular phase is clearly the moment when the ovaries are recruiting new follicles in order to establish the dominant for the cycle. However, as previously described follicular production by the ovaries follows a pattern of multicyclic waves. More specifically, a wave is a synchronous growth of follicles that have similar diameter and that can be documented with ultrasound . Beside the very well-known follicular wave (which is the one exploited in the COS), 64% of the women has two waves (follicular and luteal) and 32% of women has up to 3 waves in a normal cycle (early follicular, late follicular and luteal) .
The innovative concept of multiple waves of follicular development has been utilized in previous studies aiming to evaluate the effect of more than 1 stimulation cycles in a short period of time (less than 1 month). Specifically, two stimulation cycles have been performed in the same cycle by previous researcher (starting from the classical follicular COS and followed by a subsequent stimulation 5 days after the first oocyte retrieval) and it has been shown to be associated with improved cycle outcomes, alias higher number of oocytes retrieved and number of embryos obtained in total. Furthermore, in women with low ovarian response recent studies have suggested that the luteal phase stimulation appears to result in a higher number of oocytes retrieved as compared to the first follicular phase stimulation cycle .
Nevertheless, in spite of the accumulating evidence, a common characteristic of all of the published trials up to date is that in all of them dual stimulation cycle was initiated in the classical follicular phase followed by second stimulation cycle 5 days after oocytes retrieval. This approach had two major limitations:
- Owing to this extended protocol and the luteal phase start the lack of synchronization between embryos and endometrium, a freeze-only protocol was considered essential to be adopted .
- The fact that the 2nd stimulation cycle (luteal phase) always started 5 days after the first stimulation cycle does allow an unbiased evaluation of whether the improved outcomes on the second cycle are attributed to the luteal phase initiation of stimulation or to a carry-over effect of the first stimulation cycle.
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
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Poor prognosis patients according to the POSEIDON group 3 & 4 (based on AMH)
- •AMH <1.2
- •age <40 years old
- •BMI >18 and <35 kg/m2
- •Body weight >50kg (in women <36 years old body weight >60kg)
排除标准
- •Maternal age > 40 years
- •History of untreated autoimmune, endocrine or metabolic disorders
- •Previous ovarian cystectomy or oophorectomy
- •Body weight <50kg (and body weight <60kg in women <36 years old)
研究组 & 干预措施
Double Stimulation (Elonva+rFSH) in luteal /follicular phase
A first stimulation Stimulation will initiate in the luteal phase of the menstrual cycle On day 21 of the previous cycle150mcg of corifollitropin alfa (Elonva, Merck Sharp & Dohme (MSD), Spain) will be administrated and from day 8 of the stimulation when necessary, r-FSH of 250 IU per day will start until the day of ovulation trigger in a flexible gonadotropin-releasing hormone (GnRH) antagonist protocol. The first ovulation triggering will be induced with GnRH-agonist (triptorelin 0.2 ml). The embryos obtained from the first stimulation will be cryopreserved in a freeze-all approach.
A second stimulation will start on day 2 of bleeding after the first oocyte retrieval.
This time will correspond to a conventional COS where corifollitropin alfa will be administered on the beginning of the follicular phase, in a flexible antagonist protocol, and the second ovulation will be triggered with 250μg of Recombinant Human Chorionic Gonadotropin (rhCG)
干预措施: Double Stimulation (Elonva+rFSH) in luteal /follicular phase (Drug)
Conventional Stimulation (Elonva+rFSH) in follicular phase
A conventional COS where Corifollitropin alfa will be administered on the beginning of the follicular phase, in a flexible antagonist protocol, and the second ovulation will be triggered with 250μg of rhCG
干预措施: Conventional Stimulation (Elonva+rFSH) in follicular phase (Drug)
结局指标
主要结局
Number of good-quality blastocysts
时间窗: Day of embryo transfer (9 -20 days from initiation of the last ovarian stimulation)
Embryo quality will be assessed according to the Istanbul consensus workshop criteria (Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Human Reproduction 2011) and good quality embryo (GQE) at this developmental will be an expanded through to hatched blastocyst with an inner cell mass (ICM) that is prominent, easily discernible and consisting of many cells, with the cells compacted and tightly adhered together, and with a trophectoderm (TE) that comprises many cells forming a cohesive epithelium
次要结局
- Number oocytes retrieved(9 -20 days from initiation of the last ovarian stimulation)
- Number of cycles reaching the stage of embryo transfer(9 -20 days from initiation of the last ovarian stimulation)
- Clinical pregnancy(6-7 weeks of gestation)
- Ongoing pregnancy(8-10 weeks of gestation)
- Time to pregnancy(4-6 weeks of gestation)
- Number of oocytes between follicular phase or luteal phase initiation of ovarian stimulation(9 -20 days from initiation of the ovarian stimulation)
- Number of Metaphase II oocytes (MII) between follicular phase or luteal phase initiation of ovarian stimulation(9 -20 days from initiation of the ovarian stimulation)
- Total additional dose of recombinant follicle stimulating hormone (rFSH)(9 -20 days from initiation of the ovarian stimulation)
- Length of stimulation(9 -20 days from initiation of the ovarian stimulation)
- Endocrine profile(Day 1, Day 6 , Day 8 of stimulation and Day of trigger 9 -20 days from initiation of the ovarian stimulation in each ovarian stimulation cycle)