DuoStim in Cases of PGT: Comparison of Embryo Quantity and Embryonic Quality Using MitoScore
Condition: Infertility, Female
MeSH terms: Infertility; Infertility, Female
Study type: Interventional

Summary: 
      Since preimplantation genetic testing (PGT) is being more frequently requested from patients
      as women pursue infertility treatments at an advanced age with a poorer prognosis, sometimes
      physicians are compelled to perform several stimulation cycles to obtain more eggs and,
      consequently, a greater number of biopsied embryos. Hence, the idea of carrying out this
      study arises as an attempt to optimize each menstrual cycle to the maximum.

      It is believed that the double stimulation (DuoStim) protocol could be an alternative for
      this group of patients, allowing to obtain a larger number of oocytes in a shorter period,
      thus, increasing the number of biopsied embryos and possibly decreasing the interval to
      achieve a successful pregnancy.

      The investigators aim to evaluate the potential usefulness of the DuoStim protocol for
      patients desiring to obtain oocytes as soon as possible. Using PGT, the investigators will
      compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol versus
      patients undergoing two conventional controlled ovarian hyperstimulation in consecutive
      cycles. Patients will include women with advanced age and poor response.

      This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV
      clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is
      similar in the DuoStim group compared to the group undergoing two conventional controlled
      ovarian hyperstimulation in consecutive cycles.

      Furthermore the investigators will evaluate if there are differences regarding the number of
      total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and
      the MitoScore index of the available euploid embryos.
    

Detailed description: 
      Classically, the follicular development was thought to occur only during the follicular phase
      of the menstrual cycle. However, new data demonstrated several waves of cyclic development of
      the antral follicles within the same menstrual cycle. Some authors insist that follicles
      formed during the luteal phase may have a similar ovulation potential of those formed in the
      follicular phase, thus offering new possibilities for ovarian stimulation.

      Due to the use of vitrification technique and the appearance of the gonadotropins, physicians
      have been allowed to innovate the protocols applied to controlled ovarian hyperstimulation
      and have been able to obtain more oocytes in a shorter period for patients requiring rapid
      intervention, such as oncologic patients. Because of the accumulated experience with these
      new approaches, some investigators have recently proposed a double stimulation (DuoStim)
      protocol. Evidence of the competence of oocytes obtained from the luteal phase have been
      recently defined and published. Also, it has not been related with an increased risk for
      congenital anomalies.

      The DuoStim is a protocol consisting of two stimulations within the same menstrual cycle, one
      in the follicular phase starting in day 2 of the cycle and the other in the luteal phase
      starting 5 days after the first ovarian puncture. Trigger is always performed with GnRH
      agonist.

      Additionally, patients demanding infertility treatments are increasingly older and the use of
      preimplantation genetic testing (PGT) allows for a finer embryo selection along with better
      reproductive outcomes. Currently, most of PGTs are carried out at the blastocysts stage,
      which improve the prognosis but, on the contrary, also oblige to frozen those embryos and
      perform a deferred transfer, lengthening the procedure.

      Another innovative tool for a more accurate embryo selection which has been recently
      described is the MitoScore. The MitoScore is a mitochondrial biomarker index developed by
      Igenomix aiming to indicate the energetic status of the embryo. It intends to select those
      embryos with best implantation potential and, therefore, more likely to result in an ongoing
      pregnancy after an IVF treatment. It is calculated dividing the number of mitochondrial DNA
      copies by the amount of nuclear DNA. Although still controversial, it has been proved by some
      authors to increase success rates of implantation and ongoing pregnancies in IVF cycles and
      to diminish the number of multiple gestations.

      Since PGT is being more frequently requested from patients as women pursue infertility
      treatments at an advanced age with a poorer prognosis, sometimes physicians are compelled to
      perform several stimulation cycles to obtain more eggs and, consequently, a greater number of
      biopsied embryos. Hence, the idea of carrying out this study arises as an attempt to optimize
      each menstrual cycle to the maximum.

      It is believed that the DuoStim protocol could be an alternative for this group of patients,
      allowing to obtain a larger number of oocytes in a shorter period, thus, increasing the
      number of biopsied embryos and possibly decreasing the interval to achieve a successful
      pregnancy.

      The investigators aim to evaluate the potential usefulness of the DuoStim protocol for
      patients desiring to obtain oocytes as soon as possible. Also, using PGT, the investigators
      will compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol
      versus patients undergoing two conventional controlled ovarian hyperstimulation in
      consecutive cycles. Patients will include women with advanced age and poor response.

      This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV
      clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is
      similar in the DuoStim group compared to the group undergoing two conventional controlled
      ovarian hyperstimulation in consecutive cycles.

      Furthermore the investigators will evaluate if there are differences regarding the number of
      total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and
      the MitoScore index of the available euploid embryos. These variables will be assessed and
      compared depending on whether the oocytes were obtained in the follicular phase or the luteal
      phase for the DuoStim group. Resulting data will be compared with those obtained from the
      conventional stimulation group. The period elapsed from the beginning of the ovarian
      stimulation until the embryo transfer will also be addressed.

      Patients will call the clinic at the Cycle Programing Department to arrange a treatment.
      After a short period taking contraceptive pills, patients will be referred to a medical
      appointment. At the time of the first consultation the attending physician will randomize
      patients desiring to participate and meeting inclusion criteria, using a random allocation
      software commissioned by the department of informatics. There will be no blinding since this
      study is an open trial.

      Participants have the right to withdraw from the study at any time and for any reason without
      any inconvenience for their future medical care. Withdrawal means that the subject does not
      want to receive any further treatment nor does the patient wish to continue participating in
      the study. Reasons for withdrawal from the study: patient desire, lack of collaboration,
      toxicity or adverse event affecting patient's safety, decision of the principal investigator
      whenever the interruption is in favor of the patient's interests, death, and violation or
      breach of the study protocol.

      The trial will be terminated when all participants have completed an adequate follow-up
      period. It might also be interrupted before completion date due to security reasons, failure
      to meet expected recruitment deadlines or even if there are any risks concerning patient's
      safety or health. All participants discontinued from the trial will remain in the follow-up
      phase, except for those who withdraw their informed consent or die.

      Entries made in the Clinical Research Data Capture Profile (CRD) must be in accordance with
      those contained in the source documents. Data will be exported from the institutional
      repository software platform which withholds patient´s medical records. Integrity and
      accuracy will be checked by at least one investigator assuring that both extracted
      information and all the required regulatory documents are appropriate. Study files and all
      source documents will be stored for the time needed.

      Considering an euploid embryo rate per cycle of 20% for conventional stimulation and a
      difference between means of 10% (Conventional X DuoStim group), a sample size of 136 patients
      (68 per arm) was estimated to obtain a power of 80% with an alfa error of 5%. A loss rate of
      5% was also considered to calculate the sample size.

      Categorical variables will be assessed by the number of subjects as well as absolute and
      relative frequencies. Continuous variables will be assessed by the means, medians, standard
      deviations, 25th and 75th percentiles, minimum and maximum. For both categorical and
      continuous variables, a confidence interval of 95% will be considered. The exploratory
      analysis of data will allow to determine quality of the data and to detect any abnormality.

      The means and proportions of the descriptive variables will be compared to verify if the
      randomization was correctly performed. Whenever the variables are normally distributed, it
      will be applied a parametric test such as chi-square test for categorical variables and a
      T-student test or ANOVA for continuous variables. If the distribution is not normal a
      non-parametric test such as a Mann-Whitney U or Wilcoxon test will be applied according to
      the characteristics of the variable.

      If the investigators find statically significant differences for descriptive variables
      between the two groups, those variables will be included in a regression model to control
      their interference.

      Additionally, linear or logistic regression models will be defined, depending on whether the
      outcome variable is quantitative or categorical, respectively. It will allow to adjust
      possible confounding factors that may potentially influence the results.
    

Intervention name(s): human menopausal gonadotropin; GnRH antagonist; GnRH analog; Trophectoderm biopsy; MitoScore; Intracytoplasmic sperm injection; Ovarian puncture; Preimplantation genetic test; Embryo transfer; Pregnancy test; Embryo freezing; Embryo thawing
Intervention type(s): Drug; Drug; Drug; Procedure; Diagnostic Test; Procedure; Procedure; Diagnostic Test; Procedure; Diagnostic Test; Procedure; Procedure
Intervention description(s): human menopausal gonadotropin subcutaneously; GnRH antagonist subcutaneously; GnRH analog subcutaneously; Trophectoderm biopsy is the process of removing few cells from an in vitro fertilization embryo.; The cells removed from an in vitro fertilization embryo during the trophectoderm biopsy will be used to assess the mitochondrial DNA content as a viability indicator in the euploid embryos.; ICSI is an in vitro fertilization procedure in which a single sperm is injected directly into an oocyte.; Egg retrieval is a simple procedure. It is performed in an operating room for safety reasons. It is performed vaginally and involves aspirating the follicular fluid through a thin needle. Embryologists then retrieve from this fluid the eggs that have matured during stimulation. It lasts for 5 to 15 minutes, and a mild sedative is administered to prevent any kind of pain during the procedure.; The cells removed from an in vitro fertilization embryo during the trophectoderm biopsy will be tested for chromosomal normalcy before transferring the embryo to the uterus.; Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus; A pregnancy test is used to determine whether a woman is pregnant.; Embryo freezing is a method for cryopreserving embryos.; Embryo thawing is the procedure to recover previously frozen embryos prior to an embryo transfer.
Other intervention name(s): menopur; meriofert; orgalutran; cetrotide; decapeptyl; embryo biopsy; blastocyst biopsy; ICSI; pick up; egg retrieval; embryo cryopreservation; embryo vitrification
Intervention MeSH terms: Triptorelin Pamoate; Cetrorelix; Menotropins; Prolactin Release-Inhibiting Factors; Ganirelix
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV clinical study.
Masking: None (Open Label)
Primary purpose: Other
Keywords: DuoStim; MitoScore; Preimplantation genetic diagnosis; MII oocyte