<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03291821</url>
  </required_header>
  <id_info>
    <org_study_id>1702-MAD-014-MC</org_study_id>
    <nct_id>NCT03291821</nct_id>
  </id_info>
  <brief_title>DuoStim in Cases of PGT: Comparison of Embryo Quantity and Embryonic Quality Using MitoScore</brief_title>
  <official_title>Double Ovarian Stimulation in Cases of Preimplantation Genetic Testing: Comparison of Embryo Quantity and Embryonic Quality Using MitoScore</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IVI Madrid</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IVI Madrid</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Since preimplantation genetic testing (PGT) is being more frequently requested from patients&#xD;
      as women pursue infertility treatments at an advanced age with a poorer prognosis, sometimes&#xD;
      physicians are compelled to perform several stimulation cycles to obtain more eggs and,&#xD;
      consequently, a greater number of biopsied embryos. Hence, the idea of carrying out this&#xD;
      study arises as an attempt to optimize each menstrual cycle to the maximum.&#xD;
&#xD;
      It is believed that the double stimulation (DuoStim) protocol could be an alternative for&#xD;
      this group of patients, allowing to obtain a larger number of oocytes in a shorter period,&#xD;
      thus, increasing the number of biopsied embryos and possibly decreasing the interval to&#xD;
      achieve a successful pregnancy.&#xD;
&#xD;
      The investigators aim to evaluate the potential usefulness of the DuoStim protocol for&#xD;
      patients desiring to obtain oocytes as soon as possible. Using PGT, the investigators will&#xD;
      compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol versus&#xD;
      patients undergoing two conventional controlled ovarian hyperstimulation in consecutive&#xD;
      cycles. Patients will include women with advanced age and poor response.&#xD;
&#xD;
      This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV&#xD;
      clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is&#xD;
      similar in the DuoStim group compared to the group undergoing two conventional controlled&#xD;
      ovarian hyperstimulation in consecutive cycles.&#xD;
&#xD;
      Furthermore the investigators will evaluate if there are differences regarding the number of&#xD;
      total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and&#xD;
      the MitoScore index of the available euploid embryos.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Classically, the follicular development was thought to occur only during the follicular phase&#xD;
      of the menstrual cycle. However, new data demonstrated several waves of cyclic development of&#xD;
      the antral follicles within the same menstrual cycle. Some authors insist that follicles&#xD;
      formed during the luteal phase may have a similar ovulation potential of those formed in the&#xD;
      follicular phase, thus offering new possibilities for ovarian stimulation.&#xD;
&#xD;
      Due to the use of vitrification technique and the appearance of the gonadotropins, physicians&#xD;
      have been allowed to innovate the protocols applied to controlled ovarian hyperstimulation&#xD;
      and have been able to obtain more oocytes in a shorter period for patients requiring rapid&#xD;
      intervention, such as oncologic patients. Because of the accumulated experience with these&#xD;
      new approaches, some investigators have recently proposed a double stimulation (DuoStim)&#xD;
      protocol. Evidence of the competence of oocytes obtained from the luteal phase have been&#xD;
      recently defined and published. Also, it has not been related with an increased risk for&#xD;
      congenital anomalies.&#xD;
&#xD;
      The DuoStim is a protocol consisting of two stimulations within the same menstrual cycle, one&#xD;
      in the follicular phase starting in day 2 of the cycle and the other in the luteal phase&#xD;
      starting 5 days after the first ovarian puncture. Trigger is always performed with GnRH&#xD;
      agonist.&#xD;
&#xD;
      Additionally, patients demanding infertility treatments are increasingly older and the use of&#xD;
      preimplantation genetic testing (PGT) allows for a finer embryo selection along with better&#xD;
      reproductive outcomes. Currently, most of PGTs are carried out at the blastocysts stage,&#xD;
      which improve the prognosis but, on the contrary, also oblige to frozen those embryos and&#xD;
      perform a deferred transfer, lengthening the procedure.&#xD;
&#xD;
      Another innovative tool for a more accurate embryo selection which has been recently&#xD;
      described is the MitoScore. The MitoScore is a mitochondrial biomarker index developed by&#xD;
      Igenomix aiming to indicate the energetic status of the embryo. It intends to select those&#xD;
      embryos with best implantation potential and, therefore, more likely to result in an ongoing&#xD;
      pregnancy after an IVF treatment. It is calculated dividing the number of mitochondrial DNA&#xD;
      copies by the amount of nuclear DNA. Although still controversial, it has been proved by some&#xD;
      authors to increase success rates of implantation and ongoing pregnancies in IVF cycles and&#xD;
      to diminish the number of multiple gestations.&#xD;
&#xD;
      Since PGT is being more frequently requested from patients as women pursue infertility&#xD;
      treatments at an advanced age with a poorer prognosis, sometimes physicians are compelled to&#xD;
      perform several stimulation cycles to obtain more eggs and, consequently, a greater number of&#xD;
      biopsied embryos. Hence, the idea of carrying out this study arises as an attempt to optimize&#xD;
      each menstrual cycle to the maximum.&#xD;
&#xD;
      It is believed that the DuoStim protocol could be an alternative for this group of patients,&#xD;
      allowing to obtain a larger number of oocytes in a shorter period, thus, increasing the&#xD;
      number of biopsied embryos and possibly decreasing the interval to achieve a successful&#xD;
      pregnancy.&#xD;
&#xD;
      The investigators aim to evaluate the potential usefulness of the DuoStim protocol for&#xD;
      patients desiring to obtain oocytes as soon as possible. Also, using PGT, the investigators&#xD;
      will compare the rate of euploid embryos per cycle in patients undergoing DuoStim protocol&#xD;
      versus patients undergoing two conventional controlled ovarian hyperstimulation in&#xD;
      consecutive cycles. Patients will include women with advanced age and poor response.&#xD;
&#xD;
      This is a unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV&#xD;
      clinical study. The investigators hypothesize that the rate of euploid embryos per cycle is&#xD;
      similar in the DuoStim group compared to the group undergoing two conventional controlled&#xD;
      ovarian hyperstimulation in consecutive cycles.&#xD;
&#xD;
      Furthermore the investigators will evaluate if there are differences regarding the number of&#xD;
      total oocytes obtained, the number of mature oocytes, the number of biopsied blastocysts and&#xD;
      the MitoScore index of the available euploid embryos. These variables will be assessed and&#xD;
      compared depending on whether the oocytes were obtained in the follicular phase or the luteal&#xD;
      phase for the DuoStim group. Resulting data will be compared with those obtained from the&#xD;
      conventional stimulation group. The period elapsed from the beginning of the ovarian&#xD;
      stimulation until the embryo transfer will also be addressed.&#xD;
&#xD;
      Patients will call the clinic at the Cycle Programing Department to arrange a treatment.&#xD;
      After a short period taking contraceptive pills, patients will be referred to a medical&#xD;
      appointment. At the time of the first consultation the attending physician will randomize&#xD;
      patients desiring to participate and meeting inclusion criteria, using a random allocation&#xD;
      software commissioned by the department of informatics. There will be no blinding since this&#xD;
      study is an open trial.&#xD;
&#xD;
      Participants have the right to withdraw from the study at any time and for any reason without&#xD;
      any inconvenience for their future medical care. Withdrawal means that the subject does not&#xD;
      want to receive any further treatment nor does the patient wish to continue participating in&#xD;
      the study. Reasons for withdrawal from the study: patient desire, lack of collaboration,&#xD;
      toxicity or adverse event affecting patient's safety, decision of the principal investigator&#xD;
      whenever the interruption is in favor of the patient's interests, death, and violation or&#xD;
      breach of the study protocol.&#xD;
&#xD;
      The trial will be terminated when all participants have completed an adequate follow-up&#xD;
      period. It might also be interrupted before completion date due to security reasons, failure&#xD;
      to meet expected recruitment deadlines or even if there are any risks concerning patient's&#xD;
      safety or health. All participants discontinued from the trial will remain in the follow-up&#xD;
      phase, except for those who withdraw their informed consent or die.&#xD;
&#xD;
      Entries made in the Clinical Research Data Capture Profile (CRD) must be in accordance with&#xD;
      those contained in the source documents. Data will be exported from the institutional&#xD;
      repository software platform which withholds patient´s medical records. Integrity and&#xD;
      accuracy will be checked by at least one investigator assuring that both extracted&#xD;
      information and all the required regulatory documents are appropriate. Study files and all&#xD;
      source documents will be stored for the time needed.&#xD;
&#xD;
      Considering an euploid embryo rate per cycle of 20% for conventional stimulation and a&#xD;
      difference between means of 10% (Conventional X DuoStim group), a sample size of 136 patients&#xD;
      (68 per arm) was estimated to obtain a power of 80% with an alfa error of 5%. A loss rate of&#xD;
      5% was also considered to calculate the sample size.&#xD;
&#xD;
      Categorical variables will be assessed by the number of subjects as well as absolute and&#xD;
      relative frequencies. Continuous variables will be assessed by the means, medians, standard&#xD;
      deviations, 25th and 75th percentiles, minimum and maximum. For both categorical and&#xD;
      continuous variables, a confidence interval of 95% will be considered. The exploratory&#xD;
      analysis of data will allow to determine quality of the data and to detect any abnormality.&#xD;
&#xD;
      The means and proportions of the descriptive variables will be compared to verify if the&#xD;
      randomization was correctly performed. Whenever the variables are normally distributed, it&#xD;
      will be applied a parametric test such as chi-square test for categorical variables and a&#xD;
      T-student test or ANOVA for continuous variables. If the distribution is not normal a&#xD;
      non-parametric test such as a Mann-Whitney U or Wilcoxon test will be applied according to&#xD;
      the characteristics of the variable.&#xD;
&#xD;
      If the investigators find statically significant differences for descriptive variables&#xD;
      between the two groups, those variables will be included in a regression model to control&#xD;
      their interference.&#xD;
&#xD;
      Additionally, linear or logistic regression models will be defined, depending on whether the&#xD;
      outcome variable is quantitative or categorical, respectively. It will allow to adjust&#xD;
      possible confounding factors that may potentially influence the results.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Actual">June 1, 2020</completion_date>
  <primary_completion_date type="Actual">December 1, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV clinical study.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of euploid embryos per cycle</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Rate of chromosomally normal embryos per cycle in the DuoStim group compared to the group undergoing two controlled ovarian hyperstimulation in consecutives cycles.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of oocytes obtained</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Total number of oocytes obtained in both arms after ovarian puncture</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of fertilized oocytes</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Number of fertilized oocytes in both arms after FIV/ICSI procedure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of biopsied blastocysts</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Number of biopsied blastocysts in both arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MitoScore index of the euploid embryos</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Analysis of the MitoScore index of the euploid embryos obtained in both arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Implantation rate</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Implantation rate of euploid embryos in both arms after single or double embryo transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pregnancy rate</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Pregnancy rate of euploid embryos in both arms after single or double embryo transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abortion rate</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Abortion rate presented by each arm after single or double embryo transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time until embryo transfer</measure>
    <time_frame>up to 9 months</time_frame>
    <description>Period elapsed from the beginning of the ovarian stimulation until the embryo transfer</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">136</enrollment>
  <condition>Infertility, Female</condition>
  <arm_group>
    <arm_group_label>DuoStim</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two controlled ovarian stimulation within the same menstrual cycle using human menopausal gonadotropin 225 IU/day subcutaneously, GnRH antagonist in a dose of 0.25 mg/day subcutaneously and 0.2 mg of GnRH analog to induce oocyte maturation. It will be followed by ovarian puncture, oocyte isolation, intracytoplasmic sperm injection and trophectoderm biopsy at the blastocyst stage. Preimplantation genetic test and MitoScore will be performed in all the embryos prior to the embryo transfer. At this step embryos will be frozen to wait for the results. Chromossomally normal embryos will be thawed and transferred to the uterus in a deferred cycle. A pregnancy test will be performed when appropriate.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Two controlled ovarian stimulation in different menstrual cycles using human menopausal gonadotropin 225 IU/day subcutaneously, GnRH antagonist in a dose of 0.25 mg/day subcutaneously and 0.2 mg of GnRH analog to induce oocyte maturation. It will be followed by ovarian puncture, oocyte isolation, intracytoplasmic sperm injection and trophectoderm biopsy at the blastocyst stage. Preimplantation genetic test and MitoScore will be performed in all the embryos prior to the embryo transfer. At this step embryos will be frozen to wait for the results. Chromossomally normal embryos will be thawed and transferred to the uterus in a deferred cycle. A pregnancy test will be performed when appropriate.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>human menopausal gonadotropin</intervention_name>
    <description>human menopausal gonadotropin subcutaneously</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>menopur</other_name>
    <other_name>meriofert</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GnRH antagonist</intervention_name>
    <description>GnRH antagonist subcutaneously</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>orgalutran</other_name>
    <other_name>cetrotide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GnRH analog</intervention_name>
    <description>GnRH analog subcutaneously</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>decapeptyl</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Trophectoderm biopsy</intervention_name>
    <description>Trophectoderm biopsy is the process of removing few cells from an in vitro fertilization embryo.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>embryo biopsy</other_name>
    <other_name>blastocyst biopsy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>MitoScore</intervention_name>
    <description>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.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Intracytoplasmic sperm injection</intervention_name>
    <description>ICSI is an in vitro fertilization procedure in which a single sperm is injected directly into an oocyte.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>ICSI</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Ovarian puncture</intervention_name>
    <description>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.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>pick up</other_name>
    <other_name>egg retrieval</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Preimplantation genetic test</intervention_name>
    <description>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.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Embryo transfer</intervention_name>
    <description>Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Pregnancy test</intervention_name>
    <description>A pregnancy test is used to determine whether a woman is pregnant.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Embryo freezing</intervention_name>
    <description>Embryo freezing is a method for cryopreserving embryos.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
    <other_name>embryo cryopreservation</other_name>
    <other_name>embryo vitrification</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Embryo thawing</intervention_name>
    <description>Embryo thawing is the procedure to recover previously frozen embryos prior to an embryo transfer.</description>
    <arm_group_label>Conventional Stimulation</arm_group_label>
    <arm_group_label>DuoStim</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent;&#xD;
&#xD;
          -  35-42 years of age;&#xD;
&#xD;
          -  Patients from the IVI Madrid undergoing controlled ovarian hyperstimulation cycle&#xD;
             including PGT analysis for infertility treatment;&#xD;
&#xD;
          -  BMI 18-30 kg/m2;&#xD;
&#xD;
          -  Suspicion of suboptimal or poor response:&#xD;
&#xD;
        AMH &lt; 1.5 ng/mL; AFC &lt; 8; FSH &gt; 10; Poor response in a previous cycle (defined as &lt; 6&#xD;
        oocytes).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Simultaneous participation in another clinical trial or in any other study that could&#xD;
             result in a confounding factor.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>42 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Maria Cerrillo, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>IVI Madrid</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IVI Madrid</name>
      <address>
        <city>Madrid</city>
        <zip>28035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.</citation>
    <PMID>12849812</PMID>
  </reference>
  <reference>
    <citation>Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013 Dec;100(6):1673-80. doi: 10.1016/j.fertnstert.2013.07.1992. Epub 2013 Aug 26.</citation>
    <PMID>23987516</PMID>
  </reference>
  <reference>
    <citation>Cakmak H, Rosen MP. Random-start ovarian stimulation in patients with cancer. Curr Opin Obstet Gynecol. 2015 Jun;27(3):215-21. doi: 10.1097/GCO.0000000000000180.</citation>
    <PMID>25919235</PMID>
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  <reference>
    <citation>Sonmezer M, Turkcuoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril. 2011 May;95(6):2125.e9-11. doi: 10.1016/j.fertnstert.2011.01.030. Epub 2011 Feb 3.</citation>
    <PMID>21292255</PMID>
  </reference>
  <reference>
    <citation>von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, Strowitzki T. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril. 2009 Oct;92(4):1360-1365. doi: 10.1016/j.fertnstert.2008.08.011. Epub 2008 Oct 18.</citation>
    <PMID>18930226</PMID>
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  <reference>
    <citation>Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet. 2010 Aug;27(8):491-4. doi: 10.1007/s10815-010-9429-0. Epub 2010 May 9.</citation>
    <PMID>20455017</PMID>
  </reference>
  <reference>
    <citation>Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6.</citation>
    <PMID>25444501</PMID>
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  <reference>
    <citation>Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016 Jun;105(6):1488-1495.e1. doi: 10.1016/j.fertnstert.2016.03.002. Epub 2016 Mar 25.</citation>
    <PMID>27020168</PMID>
  </reference>
  <reference>
    <citation>Bentov Y, Esfandiari N, Gokturk A, Burstein E, Fainaru O, Casper RF. An ongoing pregnancy from two waves of follicles developing during a long follicular phase of the same cycle. Fertil Steril. 2010 Jun;94(1):350.e8-11. doi: 10.1016/j.fertnstert.2009.12.033.</citation>
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  <reference>
    <citation>Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23.</citation>
    <PMID>24161646</PMID>
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  <reference>
    <citation>Chen H, Wang Y, Lyu Q, Ai A, Fu Y, Tian H, Cai R, Hong Q, Chen Q, Shoham Z, Kuang Y. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. Fertil Steril. 2015 May;103(5):1194-1201.e2. doi: 10.1016/j.fertnstert.2015.02.020. Epub 2015 Mar 23.</citation>
    <PMID>25813280</PMID>
  </reference>
  <reference>
    <citation>Diez-Juan A, Rubio C, Marin C, Martinez S, Al-Asmar N, Riboldi M, Diaz-Gimeno P, Valbuena D, Simon C. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Fertil Steril. 2015 Sep;104(3):534-41.e1. doi: 10.1016/j.fertnstert.2015.05.022. Epub 2015 Jun 11.</citation>
    <PMID>26051102</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>December 28, 2020</last_update_submitted>
  <last_update_submitted_qc>December 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DuoStim</keyword>
  <keyword>MitoScore</keyword>
  <keyword>Preimplantation genetic diagnosis</keyword>
  <keyword>MII oocyte</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Infertility, Female</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Triptorelin Pamoate</mesh_term>
    <mesh_term>Cetrorelix</mesh_term>
    <mesh_term>Menotropins</mesh_term>
    <mesh_term>Prolactin Release-Inhibiting Factors</mesh_term>
    <mesh_term>Ganirelix</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03291821
org study id: 1702-MAD-014-MC
nct id: NCT03291821
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Unicentric, prospective, randomized, non-blind, parallel-group controlled phase IV clinical study.
primary purpose: Other
masking: None (Open Label)
measure: Rate of euploid embryos per cycle
time frame: up to 9 months
description: Rate of chromosomally normal embryos per cycle in the DuoStim group compared to the group undergoing two controlled ovarian hyperstimulation in consecutives cycles.
measure: Number of oocytes obtained
time frame: up to 9 months
description: Total number of oocytes obtained in both arms after ovarian puncture
measure: Number of fertilized oocytes
time frame: up to 9 months
description: Number of fertilized oocytes in both arms after FIV/ICSI procedure
measure: Number of biopsied blastocysts
time frame: up to 9 months
description: Number of biopsied blastocysts in both arms
measure: MitoScore index of the euploid embryos
time frame: up to 9 months
description: Analysis of the MitoScore index of the euploid embryos obtained in both arms
measure: Implantation rate
time frame: up to 9 months
description: Implantation rate of euploid embryos in both arms after single or double embryo transfer
measure: Pregnancy rate
time frame: up to 9 months
description: Pregnancy rate of euploid embryos in both arms after single or double embryo transfer
measure: Abortion rate
time frame: up to 9 months
description: Abortion rate presented by each arm after single or double embryo transfer
measure: Time until embryo transfer
time frame: up to 9 months
description: Period elapsed from the beginning of the ovarian stimulation until the embryo transfer
arm group label: DuoStim
arm group type: Experimental
description: Two controlled ovarian stimulation within the same menstrual cycle using human menopausal gonadotropin 225 IU/day subcutaneously, GnRH antagonist in a dose of 0.25 mg/day subcutaneously and 0.2 mg of GnRH analog to induce oocyte maturation. It will be followed by ovarian puncture, oocyte isolation, intracytoplasmic sperm injection and trophectoderm biopsy at the blastocyst stage. Preimplantation genetic test and MitoScore will be performed in all the embryos prior to the embryo transfer. At this step embryos will be frozen to wait for the results. Chromossomally normal embryos will be thawed and transferred to the uterus in a deferred cycle. A pregnancy test will be performed when appropriate.
arm group label: Conventional Stimulation
arm group type: Active Comparator
description: Two controlled ovarian stimulation in different menstrual cycles using human menopausal gonadotropin 225 IU/day subcutaneously, GnRH antagonist in a dose of 0.25 mg/day subcutaneously and 0.2 mg of GnRH analog to induce oocyte maturation. It will be followed by ovarian puncture, oocyte isolation, intracytoplasmic sperm injection and trophectoderm biopsy at the blastocyst stage. Preimplantation genetic test and MitoScore will be performed in all the embryos prior to the embryo transfer. At this step embryos will be frozen to wait for the results. Chromossomally normal embryos will be thawed and transferred to the uterus in a deferred cycle. A pregnancy test will be performed when appropriate.
intervention type: Drug
intervention name: human menopausal gonadotropin
description: human menopausal gonadotropin subcutaneously
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: menopur
other name: meriofert
intervention type: Drug
intervention name: GnRH antagonist
description: GnRH antagonist subcutaneously
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: orgalutran
other name: cetrotide
intervention type: Drug
intervention name: GnRH analog
description: GnRH analog subcutaneously
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: decapeptyl
intervention type: Procedure
intervention name: Trophectoderm biopsy
description: Trophectoderm biopsy is the process of removing few cells from an in vitro fertilization embryo.
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: embryo biopsy
other name: blastocyst biopsy
intervention type: Diagnostic Test
intervention name: MitoScore
description: 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.
arm group label: Conventional Stimulation
arm group label: DuoStim
intervention type: Procedure
intervention name: Intracytoplasmic sperm injection
description: ICSI is an in vitro fertilization procedure in which a single sperm is injected directly into an oocyte.
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: ICSI
intervention type: Procedure
intervention name: Ovarian puncture
description: 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.
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: pick up
other name: egg retrieval
intervention type: Diagnostic Test
intervention name: Preimplantation genetic test
description: 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.
arm group label: Conventional Stimulation
arm group label: DuoStim
intervention type: Procedure
intervention name: Embryo transfer
description: Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus
arm group label: Conventional Stimulation
arm group label: DuoStim
intervention type: Diagnostic Test
intervention name: Pregnancy test
description: A pregnancy test is used to determine whether a woman is pregnant.
arm group label: Conventional Stimulation
arm group label: DuoStim
intervention type: Procedure
intervention name: Embryo freezing
description: Embryo freezing is a method for cryopreserving embryos.
arm group label: Conventional Stimulation
arm group label: DuoStim
other name: embryo cryopreservation
other name: embryo vitrification
intervention type: Procedure
intervention name: Embryo thawing
description: Embryo thawing is the procedure to recover previously frozen embryos prior to an embryo transfer.
arm group label: Conventional Stimulation
arm group label: DuoStim
criteria: 
gender: Female
minimum age: 35 Years
maximum age: 42 Years
healthy volunteers: No
last name: Maria Cerrillo, M.D., Ph.D.
role: Principal Investigator
affiliation: IVI Madrid
facility: 
country: Spain
citation: Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.
PMID: 12849812
citation: Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013 Dec;100(6):1673-80. doi: 10.1016/j.fertnstert.2013.07.1992. Epub 2013 Aug 26.
PMID: 23987516
citation: Cakmak H, Rosen MP. Random-start ovarian stimulation in patients with cancer. Curr Opin Obstet Gynecol. 2015 Jun;27(3):215-21. doi: 10.1097/GCO.0000000000000180.
PMID: 25919235
citation: Sonmezer M, Turkcuoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril. 2011 May;95(6):2125.e9-11. doi: 10.1016/j.fertnstert.2011.01.030. Epub 2011 Feb 3.
PMID: 21292255
citation: von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, Strowitzki T. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril. 2009 Oct;92(4):1360-1365. doi: 10.1016/j.fertnstert.2008.08.011. Epub 2008 Oct 18.
PMID: 18930226
citation: Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet. 2010 Aug;27(8):491-4. doi: 10.1007/s10815-010-9429-0. Epub 2010 May 9.
PMID: 20455017
citation: Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6.
PMID: 25444501
citation: Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016 Jun;105(6):1488-1495.e1. doi: 10.1016/j.fertnstert.2016.03.002. Epub 2016 Mar 25.
PMID: 27020168
citation: Bentov Y, Esfandiari N, Gokturk A, Burstein E, Fainaru O, Casper RF. An ongoing pregnancy from two waves of follicles developing during a long follicular phase of the same cycle. Fertil Steril. 2010 Jun;94(1):350.e8-11. doi: 10.1016/j.fertnstert.2009.12.033.
PMID: 20138269
citation: Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23.
PMID: 24161646
citation: Chen H, Wang Y, Lyu Q, Ai A, Fu Y, Tian H, Cai R, Hong Q, Chen Q, Shoham Z, Kuang Y. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. Fertil Steril. 2015 May;103(5):1194-1201.e2. doi: 10.1016/j.fertnstert.2015.02.020. Epub 2015 Mar 23.
PMID: 25813280
citation: Diez-Juan A, Rubio C, Marin C, Martinez S, Al-Asmar N, Riboldi M, Diaz-Gimeno P, Valbuena D, Simon C. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Fertil Steril. 2015 Sep;104(3):534-41.e1. doi: 10.1016/j.fertnstert.2015.05.022. Epub 2015 Jun 11.
PMID: 26051102
responsible party type: Sponsor
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Triptorelin Pamoate
mesh term: Cetrorelix
mesh term: Menotropins
mesh term: Prolactin Release-Inhibiting Factors
mesh term: Ganirelix
sharing ipd: Undecided