Double Stimulation Followed by a Fresh Embryo Transfer
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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:

        1. 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 .

        2. 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

        1. compare the double stimulation with a single stimulation strategy followed by fresh
           embryo transfer and

        2. perform comparison of a luteal phase (1st cycle of the double stimulation group) and a
           follicular phase stimulation (control group) in a randomized setting
    

Intervention name(s): Double Stimulation (Elonva+rFSH) in luteal /follicular phase; Conventional Stimulation (Elonva+rFSH) in follicular phase
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment