Double Stimulation Followed by a Fresh Embryo Transfer

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Based on the above evidence we decided to design the current randomized trial which is, to our knowledge, the first to evaluate the benefit from the dual stimulation approach, not followed by a freeze-only strategy, but by fresh embryo transfer. In order to achieve this, we aim to compare the COS with the double stimulation (first luteal stimulation and then follicular ovarian stimulation) followed by fresh embryo transfer (ET) in poor prognosis patients undergoing in vitro fertilization/intra-cytoplasmatic sperm injections (IVF/ICSI) treatment. The current randomized trial will allow us to compare the double stimulation with a single stimulation strategy followed by fresh embryo transfer and perform comparison of a luteal phase (1st cycle of the double stimulation group) and a follicular phase stimulation (control group) in a randomized setting

Official Title
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Double vs. Single Stimulation in Young Poor Prognosis Patients Followed by a Fresh Embryo Transfer. A Randomized Clinical Trial

Conditions
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Infertility

Intervention / Treatment
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* Drug: Double Stimulation (Elonva+rFSH) in luteal /follicular phase
* Drug: Conventional Stimulation (Elonva+rFSH) in follicular phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Double Stimulation (Elonva+rFSH) in luteal /follicular phase<br>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) | Drug: Double Stimulation (Elonva+rFSH) in luteal /follicular phase<br>* Following the 2nd oocyte retrieval, the patient will start luteal phase support (LPS) with vaginal micronized progesterone 200mg x 3 times a day until the day of the pregnancy test. All embryos will be cultured until day 5 in time-lapse incubators. In case of no blastocyst in the second cycle, or in case of poor embryo quality and in case of availability of frozen embryos from the first stimulation cycle, 1 frozen blastocyst from the first cycle will be thawed and will be transferred 5 days following the 2nd oocyte retrieval. Embryo transfer will be performed in all patients with available blastocysts, except in cases of high risk of ovarian hyperstimulation syndrome (OHSS) or progesterone elevation which is considered clinically relevant on the day of human chorionic gonadotropin (hCG) trigger, in which freeze-all strategy and deferred frozen embryo transferred will be considered.<br>|
| Active Comparator: Conventional Stimulation (Elonva+rFSH) in follicular phase<br>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 | Drug: Conventional Stimulation (Elonva+rFSH) in follicular phase<br>* From the day of oocyte retrieval, the patients will be asked to start the LPS with vaginal micronized progesterone 3 times a day until the day of the pregnancy test. Embryo transfer will be performed in all patients with available blastocysts, except in cases of high risk of OHSS or progesterone elevation which is considered clinically relevant on the day of hCG trigger, in which freeze-all strategy and deferred frozen embryo transferred will be considered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of good-quality blastocysts | 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 | Day of embryo transfer (9 -20 days from initiation of the last ovarian stimulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number oocytes retrieved | The outcome will be evaluated on the day of oocyte retrieval | 9 -20 days from initiation of the last ovarian stimulation | 
| Number of cycles reaching the stage of embryo transfer | The outcome will be evaluated 5 days after last oocyte retrieval | 9 -20 days from initiation of the last ovarian stimulation | 
| Clinical pregnancy | The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 6-7 weeks of gestation | 6-7 weeks of gestation | 
| Ongoing pregnancy | The presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 11-12 weeks of gestation | 8-10 weeks of gestation | 
| Time to pregnancy | Days between beginning of first stimulation and clinical pregnancy | 4-6 weeks of gestation | 
| Number of oocytes between follicular phase or luteal phase initiation of ovarian stimulation | The outcome will be evaluated on the day of oocyte retrieval | 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 | The outcome will be evaluated on the day of oocyte retrieval | 9 -20 days from initiation of the ovarian stimulation | 
| Total additional dose of recombinant follicle stimulating hormone (rFSH) | The outcome will be evaluated on the day of trigger | 9 -20 days from initiation of the ovarian stimulation | 
| Length of stimulation | The outcome will be evaluated on the day of trigger | 9 -20 days from initiation of the ovarian stimulation | 
| Endocrine profile | Estradiol, Progesterone, luteinizing hormone (LH) and FSH | 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 |