<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/NCT04447872</url>
  </required_header>
  <id_info>
    <org_study_id>20-0080</org_study_id>
    <nct_id>NCT04447872</nct_id>
  </id_info>
  <brief_title>The LUTEAL Trial: Luteal Stimulation vs. Estrogen Priming Protocol</brief_title>
  <official_title>Prospective, Randomized Trial Comparing Luteal Phase Ovarian Stimulation, and Luteal Estradiol Priming Protocol for Patients With Diminished Ovarian Reserve - The LUTEAL Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwell Health</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>
      Ovarian reserve defines the quantity and quality of the ovarian primordial follicular pool.&#xD;
      Diminished ovarian reserve (DOR) indicates a reduction in the quantity of ovarian follicular&#xD;
      pool to less than expected for age. It is an important cause of infertility in many couples.&#xD;
&#xD;
      To date, there is no clear consensus in the literature on the definition of diminished&#xD;
      ovarian reserve, and it is unclear whether low oocyte yield results from an abnormal atresia&#xD;
      rate of the follicle pool, or from a lower follicle pool at birth or whether it can just&#xD;
      occur as a normal variation in the population.&#xD;
&#xD;
      The ovarian response to controlled ovarian stimulation with gonadotropins (for example, for&#xD;
      in vitro fertilization) is largely determined by the ovarian reserve, and there are numerous&#xD;
      different ovarian stimulation protocols that are employed to try and increase the oocyte&#xD;
      yield of a particular cycle. There is no consensus on which, if any, of these protocols are&#xD;
      superior and preferred for patient with DOR.&#xD;
&#xD;
      Luteal gonadotropin stimulation is a protocol of controlled ovarian stimulation (COS) for use&#xD;
      in assisted reproductive technologies (ART) that has emerged over the past decade as an&#xD;
      acceptable alternative to the classic follicular gonadotropin stimulation.&#xD;
&#xD;
      The luteal estradiol patch protocol was introduced in 2005 in patients with poor response to&#xD;
      controlled ovarian stimulation (COS) and to address the phenomenon of early follicle&#xD;
      recruitment in patients with diminished ovarian reserve (DOR). Luteal gonadotropin&#xD;
      stimulation can potentially achieve the same effect by initiating follicular recruitment for&#xD;
      IVF prior to the body's own premature recruitment.&#xD;
&#xD;
      Our hypothesis is that the luteal stimulation protocol and estradiol priming protocol are&#xD;
      equivalent with regard to the outcome of number of mature oocytes retrieved. Patients who&#xD;
      will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished&#xD;
      ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and&#xD;
      no exclusion criteria.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of&#xD;
      diminished ovarian reserve will be considered for this trial, and enrolled if meeting all&#xD;
      inclusion and no exclusion criteria. Patients will be randomized to one of two possible&#xD;
      stimulation cycles as will be described.&#xD;
&#xD;
      Luteal Phase Ovarian Stimulation (LPOS)&#xD;
&#xD;
      Patients will present for an appointment on approximately day 15-18 of her menstrual cycle.&#xD;
      If serum progesterone &gt;3 ng/mL, and bHCG &lt; 5 mIU/mL, the patient will begin 450 IU of daily&#xD;
      injectable gonadotropins: 150 IU of hMG (Menopur®, Ferring Pharmaceuticals) and 300 IU of&#xD;
      recombinant FSH (rFSH) (Gonal F®,Serono; or Follitropin beta (Follistim®, Organo)). The&#xD;
      specific rFSH chosen will be based on the individual patient's insurance coverage. The&#xD;
      patient will perform daily injections during the course of her stimulation, and will also&#xD;
      take oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH dose&#xD;
      will be titrated during the stimulation (per physician discretion) based on serum estradiol&#xD;
      levels and ovarian response to a minimum of no gonadotropins and a maximum of 600 IU daily.&#xD;
      She will present for follicular monitoring ultrasound and serum blood tests on stimulation&#xD;
      day 3-4, 5-6, and 7-8-~15. Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix,&#xD;
      Organon; and cetrorelix, Serono) will be started daily once either (1) serum estradiol level&#xD;
      reaches &gt; 400 pg/mL, lead follicle size &gt; 13mm, or (2) on stimulation day 6. Once patient are&#xD;
      ready for ovulation trigger as determine by physician, 5-10,000 units of human chorionic&#xD;
      gonadotropin (Novarel®: Ferring Pharmaceuticals; or Pregnyl®: Schering-Plough) will be&#xD;
      administered. A patient's trigger shot could be changed to include a GnRH agonist (i.e&#xD;
      Luprolide acetate 40 IU) if deemed clinically necessary for ovarian hyperstimulation syndrome&#xD;
      prevention. On the morning after hCG administration, patients' blood will be drawn and serum&#xD;
      analyzed for hCG concentration to ensure adequate absorption (mean time 8-10 hours).&#xD;
      Transvaginal oocyte retrieval will be performed 35 to 37 hours after hCG trigger. All&#xD;
      metaphase II oocytes will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF&#xD;
      per patient request and laboratory protocol. Embryos will be cultured to the blastocyst stage&#xD;
      and vitrified on day 5-7. If patient requests preimplantation genetic testing for aneuploidy&#xD;
      (PGT-A), an embryo biopsy will be performed on day 5-7 of development prior to vitrification,&#xD;
      and biopsy specimen will be sent to an outside laboratory for chromosome analysis.&#xD;
&#xD;
      Luteal Estradiol priming protocol (E2 prime)&#xD;
&#xD;
      Patients will present for an appointment on approximately day 18-21 of her menstrual cycle.&#xD;
      If serum progesterone &gt;3 ng/mL, and bHCG &lt; 5 mIU/mL, the patient will begin Estradiol patches&#xD;
      (Vivelle Dot 0.1mg, Novartis Pharmaceuticals; or Climara, Bayer) and change them every other&#xD;
      day. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix,&#xD;
      Organon; and cetrorelix, Serono) for the following three days.&#xD;
&#xD;
      Patients will then present for a baseline appointment with onset of her menses. If serum&#xD;
      progesterone &lt; 1.0 ng/mL, and bHCG &lt; 5 mIU/mL, on cycle day 2-3 the patient will stop her&#xD;
      estrogen patches and start 450 IU of daily injectable gonadotropins: 150 IU of hMG (Menopur®,&#xD;
      Ferring Pharmaceuticals) and 300 IU of recombinant FSH (rFSH) (Gonal F®,Serono; or&#xD;
      Follitropin beta (Follistim®, Organo)). The specific rFSH chosen will be based on the&#xD;
      individual patient's insurance coverage. Estrogen patch will be removed the day of starting&#xD;
      gonadotropin injections. The patient will perform daily injections during the course of her&#xD;
      stimulation, and will also take oral Clomiphene citrate 100mg daily for the first five days&#xD;
      of the stimulation. FSH dose will be titrated during the stimulation (per physician&#xD;
      discretion) based on serum estradiol levels and ovarian response to a minimum of no&#xD;
      gonadotropins and a maximum of 600 IU daily. She will present for follicular monitoring&#xD;
      ultrasound and serum blood tests on stimulation day 3-4, 5-6, and 7-8-~15. Gonadotropin&#xD;
      releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be&#xD;
      started daily once either (1) serum estradiol level reaches &gt; 400 pg/mL, lead follicle size &gt;&#xD;
      13mm, or (2) on stimulation day 6. Once patient are ready for ovulation trigger as determine&#xD;
      by physician, 5-10,000 units of human chorionic gonadotropin (Novarel®: Ferring&#xD;
      Pharmaceuticals; or Pregnyl®: Schering-Plough) will be administered. A patient's trigger shot&#xD;
      could be changed to include a GnRH agonist (i.e Luprolide acetate 40 IU) if deemed clinically&#xD;
      necessary for ovarian hyperstimulation syndrome prevention. On the morning after hCG&#xD;
      administration, patients' blood will be drawn and serum analyzed for hCG concentration to&#xD;
      ensure adequate absorption (mean time 8-10 hours). Transvaginal oocyte retrieval will be&#xD;
      performed 35 to 37 hours after hCG trigger. All metaphase II oocytes will be fertilized with&#xD;
      intracytoplasmic sperm injection (ICSI) or IVF per patient request and laboratory protocol.&#xD;
      Embryos will be cultured to the blastocyst stage and vitrified on day 5-7. If patient&#xD;
      requests preimplantation genetic testing for aneuploidy (PGT-A), an embryo biopsy will be&#xD;
      performed on day 5-7 of development prior to vitrification, and biopsy specimen will be sent&#xD;
      to an outside laboratory for chromosomal analysis.&#xD;
&#xD;
      Outcomes between the two stimulation protocols will be compared.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 15, 2020</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">June 2024</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of mature (Metaphase II) oocytes retrieved</measure>
    <time_frame>First day after oocyte retrieval</time_frame>
    <description>Mature oocytes, capable of being fertilized in vitro</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of oocytes cumulus complexes retrieved</measure>
    <time_frame>First day after oocyte retrieval</time_frame>
    <description>Total oocytes from oocyte retrieval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oocyte fertilization rate</measure>
    <time_frame>First day after oocyte retrieval</time_frame>
    <description>Rate of oocytes that develop two pronuclei</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blastocyst development rate</measure>
    <time_frame>Day 5-7 following oocyte retrieval</time_frame>
    <description>Rate of embryos that develop to the blastocyst stage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cycle cancellation rate</measure>
    <time_frame>Within two weeks of cycle start</time_frame>
    <description>Rate of cycle cancellation prior to oocyte retrieval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total FSH dosage (IU) used</measure>
    <time_frame>From the first day of injections, through the day of oocyte retrieval</time_frame>
    <description>Total dosage of injected gonadotropins during ovarian stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of stimulation (days)</measure>
    <time_frame>From the first day of injections, through the day of oocyte retrieval</time_frame>
    <description>How many days from first injection until trigger shot injection</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Embryo ploidy status</measure>
    <time_frame>When biopsy results return, usually within four weeks after oocyte retrieval</time_frame>
    <description>If patient undergoes preimplantation for genetic testing of aneuploidy (PGT-A), we will compare the rate of euploid embryos between the groups</description>
  </other_outcome>
  <other_outcome>
    <measure>Implantation rate</measure>
    <time_frame>Two weeks post embryo transfer</time_frame>
    <description>Rate of successful embryo implantation if undergoes embryo transfer</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical pregnancy rate</measure>
    <time_frame>Five to seven weeks post embryo transfer</time_frame>
    <description>Rate of successful clinical intrauterine pregnancy if undergoes embryo transfer</description>
  </other_outcome>
  <other_outcome>
    <measure>Live birth rate</measure>
    <time_frame>40 weeks post embryo transfer</time_frame>
    <description>Rate of live birth if undergoes embryo transfer</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">142</enrollment>
  <condition>Infertility</condition>
  <condition>Diminished Ovarian Reserve</condition>
  <condition>IVF</condition>
  <arm_group>
    <arm_group_label>Luteal phase ovarian stimulation (LPOS)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will present in the luteal phase, and will begin 150 IU hMG and 300 IU recombinant FSH daily, as well as oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH can then be titrated per patient response. Gonadotropin releasing hormone antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be started per criteria. Once patients are ready for ovulation trigger, 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU), will be administered. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Luteal estradiol priming protocol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the luteal phase, the patient will begin Estradiol patches 0.1mg QOD. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) for three days. With menses, she will begin 150 IU hMG, 300 IU recombinant FSH daily, and oral Clomiphene citrate 100mg qd (for five days). FSH can be titrated per patient response. GnRH antagonist will be started per criteria. 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU) will be administered for ovulation trigger. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Timing of injectable gonadotropins</intervention_name>
    <description>Gonadotropins will with be started in the luteal phase or in follicular phase (preceded by Estradiol patches)</description>
    <arm_group_label>Luteal estradiol priming protocol</arm_group_label>
    <arm_group_label>Luteal phase ovarian stimulation (LPOS)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of signed and dated informed consent form&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study&#xD;
&#xD;
          3. Female aged 20 - 45&#xD;
&#xD;
          4. Regular menstrual cycles between 21 and 40 days&#xD;
&#xD;
          5. Presence of both ovaries&#xD;
&#xD;
          6. Meets criteria for DOR by the recent ASRM/ACOG Committee Opinion&#xD;
&#xD;
               1. antimüllerian hormone (AMH) value less than 1 ng/mL&#xD;
&#xD;
               2. antral follicle count less than 5-7 and&#xD;
&#xD;
               3. follicle-stimulating hormone (FSH) greater than 10 IU/L or&#xD;
&#xD;
               4. a history of poor response to in vitro fertilization stimulation (fewer than four&#xD;
                  oocytes at time of egg retrieval).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Oocyte donation cycle&#xD;
&#xD;
          2. Oocyte freezing cycle&#xD;
&#xD;
          3. Current ovarian cyst &gt; 3cm&#xD;
&#xD;
          4. Anovulatory or oligo-ovulatory (&lt;6 ovulation per year)&#xD;
&#xD;
          5. Previous oophorectomy&#xD;
&#xD;
          6. Exposure to cytotoxic or pelvic irradiation&#xD;
&#xD;
          7. Planned aromatase inhibitor usage during current ovarian stimulation&#xD;
&#xD;
          8. Sensitizing or ovarian stimulating therapy in the past one month&#xD;
&#xD;
             Additional contraindications to this study re, as follows (because such patients&#xD;
             cannot receive an estrogen patch):&#xD;
&#xD;
          9. Undiagnosed abnormal genital bleeding&#xD;
&#xD;
         10. Known, suspected, or history of breast cancer&#xD;
&#xD;
         11. Known or suspected estrogen-dependent neoplasia&#xD;
&#xD;
         12. Active DVT, PE, or a history of these conditions&#xD;
&#xD;
         13. Active arterial thromboembolic disease (for example, stroke and MI), or a history of&#xD;
             these conditions&#xD;
&#xD;
         14. Known anaphylactic reaction or angioedema with estradiol patches&#xD;
&#xD;
         15. Known liver impairment or disease&#xD;
&#xD;
         16. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic&#xD;
             disorders&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Baruch Abittan, MD</last_name>
    <phone>5165621735</phone>
    <email>babittan2@northwell.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Northwell Fertility</name>
      <address>
        <city>Manhasset</city>
        <state>New York</state>
        <zip>11030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Baruch Abittan, MD</last_name>
      <phone>516-562-1735</phone>
      <email>babittan2@northwell.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Lin LT, Vitale SG, Chen SN, Wen ZH, Tsai HW, Chern CU, Tsui KH. Luteal Phase Ovarian Stimulation May Improve Oocyte Retrieval and Oocyte Quality in Poor Ovarian Responders Undergoing In Vitro Fertilization: Preliminary Results from a Single-Center Prospective Pilot Study. Adv Ther. 2018 Jun;35(6):847-856. doi: 10.1007/s12325-018-0713-1. Epub 2018 Jun 4.</citation>
    <PMID>29869107</PMID>
  </reference>
  <reference>
    <citation>Zhang W, Wang M, Wang S, Bao H, Qu Q, Zhang N, Hao C. Luteal phase ovarian stimulation for poor ovarian responders. JBRA Assist Reprod. 2018 Sep 1;22(3):193-198. doi: 10.5935/1518-0557.20180045.</citation>
    <PMID>29931967</PMID>
  </reference>
  <reference>
    <citation>Wei LH, Ma WH, Tang N, Wei JH. Luteal-phase ovarian stimulation is a feasible method for poor ovarian responders undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer treatment compared to a GnRH antagonist protocol: A retrospective study. Taiwan J Obstet Gynecol. 2016 Feb;55(1):50-4. doi: 10.1016/j.tjog.2015.07.001.</citation>
    <PMID>26927248</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Zhao FC, Sun Y, Liu PS. Luteal-phase protocol in poor ovarian response: a comparative study with an antagonist protocol. J Int Med Res. 2017 Dec;45(6):1731-1738. doi: 10.1177/0300060516669898. Epub 2017 Jan 16.</citation>
    <PMID>28661216</PMID>
  </reference>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>September 29, 2022</last_update_submitted>
  <last_update_submitted_qc>September 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwell Health</investigator_affiliation>
    <investigator_full_name>Mary Rausch, MD</investigator_full_name>
    <investigator_title>Assistant Professor, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell</investigator_title>
  </responsible_party>
  <keyword>IVF</keyword>
  <keyword>In Vitro Fertilization</keyword>
  <keyword>DOR</keyword>
  <keyword>Diminished Ovarian Reserve</keyword>
  <keyword>Controlled ovarian stimulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <!-- 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/NCT04447872
org study id: 20-0080
nct id: NCT04447872
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Ovarian reserve defines the quantity and quality of the ovarian primordial follicular pool.
      Diminished ovarian reserve (DOR) indicates a reduction in the quantity of ovarian follicular
      pool to less than expected for age. It is an important cause of infertility in many couples.

      To date, there is no clear consensus in the literature on the definition of diminished
      ovarian reserve, and it is unclear whether low oocyte yield results from an abnormal atresia
      rate of the follicle pool, or from a lower follicle pool at birth or whether it can just
      occur as a normal variation in the population.

      The ovarian response to controlled ovarian stimulation with gonadotropins (for example, for
      in vitro fertilization) is largely determined by the ovarian reserve, and there are numerous
      different ovarian stimulation protocols that are employed to try and increase the oocyte
      yield of a particular cycle. There is no consensus on which, if any, of these protocols are
      superior and preferred for patient with DOR.

      Luteal gonadotropin stimulation is a protocol of controlled ovarian stimulation (COS) for use
      in assisted reproductive technologies (ART) that has emerged over the past decade as an
      acceptable alternative to the classic follicular gonadotropin stimulation.

      The luteal estradiol patch protocol was introduced in 2005 in patients with poor response to
      controlled ovarian stimulation (COS) and to address the phenomenon of early follicle
      recruitment in patients with diminished ovarian reserve (DOR). Luteal gonadotropin
      stimulation can potentially achieve the same effect by initiating follicular recruitment for
      IVF prior to the body's own premature recruitment.

      Our hypothesis is that the luteal stimulation protocol and estradiol priming protocol are
      equivalent with regard to the outcome of number of mature oocytes retrieved. Patients who
      will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished
      ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and
      no exclusion criteria.
Patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of
      diminished ovarian reserve will be considered for this trial, and enrolled if meeting all
      inclusion and no exclusion criteria. Patients will be randomized to one of two possible
      stimulation cycles as will be described.

      Luteal Phase Ovarian Stimulation (LPOS)

      Patients will present for an appointment on approximately day 15-18 of her menstrual cycle.
      If serum progesterone >3 ng/mL, and bHCG < 5 mIU/mL, the patient will begin 450 IU of daily
      injectable gonadotropins: 150 IU of hMG (Menopur®, Ferring Pharmaceuticals) and 300 IU of
      recombinant FSH (rFSH) (Gonal F®,Serono; or Follitropin beta (Follistim®, Organo)). The
      specific rFSH chosen will be based on the individual patient's insurance coverage. The
      patient will perform daily injections during the course of her stimulation, and will also
      take oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH dose
      will be titrated during the stimulation (per physician discretion) based on serum estradiol
      levels and ovarian response to a minimum of no gonadotropins and a maximum of 600 IU daily.
      She will present for follicular monitoring ultrasound and serum blood tests on stimulation
      day 3-4, 5-6, and 7-8-~15. Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix,
      Organon; and cetrorelix, Serono) will be started daily once either (1) serum estradiol level
      reaches > 400 pg/mL, lead follicle size > 13mm, or (2) on stimulation day 6. Once patient are
      ready for ovulation trigger as determine by physician, 5-10,000 units of human chorionic
      gonadotropin (Novarel®: Ferring Pharmaceuticals; or Pregnyl®: Schering-Plough) will be
      administered. A patient's trigger shot could be changed to include a GnRH agonist (i.e
      Luprolide acetate 40 IU) if deemed clinically necessary for ovarian hyperstimulation syndrome
      prevention. On the morning after hCG administration, patients' blood will be drawn and serum
      analyzed for hCG concentration to ensure adequate absorption (mean time 8-10 hours).
      Transvaginal oocyte retrieval will be performed 35 to 37 hours after hCG trigger. All
      metaphase II oocytes will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF
      per patient request and laboratory protocol. Embryos will be cultured to the blastocyst stage
      and vitrified on day 5-7. If patient requests preimplantation genetic testing for aneuploidy
      (PGT-A), an embryo biopsy will be performed on day 5-7 of development prior to vitrification,
      and biopsy specimen will be sent to an outside laboratory for chromosome analysis.

      Luteal Estradiol priming protocol (E2 prime)

      Patients will present for an appointment on approximately day 18-21 of her menstrual cycle.
      If serum progesterone >3 ng/mL, and bHCG < 5 mIU/mL, the patient will begin Estradiol patches
      (Vivelle Dot 0.1mg, Novartis Pharmaceuticals; or Climara, Bayer) and change them every other
      day. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix,
      Organon; and cetrorelix, Serono) for the following three days.

      Patients will then present for a baseline appointment with onset of her menses. If serum
      progesterone < 1.0 ng/mL, and bHCG < 5 mIU/mL, on cycle day 2-3 the patient will stop her
      estrogen patches and start 450 IU of daily injectable gonadotropins: 150 IU of hMG (Menopur®,
      Ferring Pharmaceuticals) and 300 IU of recombinant FSH (rFSH) (Gonal F®,Serono; or
      Follitropin beta (Follistim®, Organo)). The specific rFSH chosen will be based on the
      individual patient's insurance coverage. Estrogen patch will be removed the day of starting
      gonadotropin injections. The patient will perform daily injections during the course of her
      stimulation, and will also take oral Clomiphene citrate 100mg daily for the first five days
      of the stimulation. FSH dose will be titrated during the stimulation (per physician
      discretion) based on serum estradiol levels and ovarian response to a minimum of no
      gonadotropins and a maximum of 600 IU daily. She will present for follicular monitoring
      ultrasound and serum blood tests on stimulation day 3-4, 5-6, and 7-8-~15. Gonadotropin
      releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be
      started daily once either (1) serum estradiol level reaches > 400 pg/mL, lead follicle size >
      13mm, or (2) on stimulation day 6. Once patient are ready for ovulation trigger as determine
      by physician, 5-10,000 units of human chorionic gonadotropin (Novarel®: Ferring
      Pharmaceuticals; or Pregnyl®: Schering-Plough) will be administered. A patient's trigger shot
      could be changed to include a GnRH agonist (i.e Luprolide acetate 40 IU) if deemed clinically
      necessary for ovarian hyperstimulation syndrome prevention. On the morning after hCG
      administration, patients' blood will be drawn and serum analyzed for hCG concentration to
      ensure adequate absorption (mean time 8-10 hours). Transvaginal oocyte retrieval will be
      performed 35 to 37 hours after hCG trigger. All metaphase II oocytes will be fertilized with
      intracytoplasmic sperm injection (ICSI) or IVF per patient request and laboratory protocol.
      Embryos will be cultured to the blastocyst stage and vitrified on day 5-7. If patient
      requests preimplantation genetic testing for aneuploidy (PGT-A), an embryo biopsy will be
      performed on day 5-7 of development prior to vitrification, and biopsy specimen will be sent
      to an outside laboratory for chromosomal analysis.

      Outcomes between the two stimulation protocols will be compared.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of mature (Metaphase II) oocytes retrieved
time frame: First day after oocyte retrieval
description: Mature oocytes, capable of being fertilized in vitro
measure: Number of oocytes cumulus complexes retrieved
time frame: First day after oocyte retrieval
description: Total oocytes from oocyte retrieval
measure: Oocyte fertilization rate
time frame: First day after oocyte retrieval
description: Rate of oocytes that develop two pronuclei
measure: Blastocyst development rate
time frame: Day 5-7 following oocyte retrieval
description: Rate of embryos that develop to the blastocyst stage
measure: Cycle cancellation rate
time frame: Within two weeks of cycle start
description: Rate of cycle cancellation prior to oocyte retrieval
measure: Total FSH dosage (IU) used
time frame: From the first day of injections, through the day of oocyte retrieval
description: Total dosage of injected gonadotropins during ovarian stimulation
measure: Duration of stimulation (days)
time frame: From the first day of injections, through the day of oocyte retrieval
description: How many days from first injection until trigger shot injection
measure: Embryo ploidy status
time frame: When biopsy results return, usually within four weeks after oocyte retrieval
description: If patient undergoes preimplantation for genetic testing of aneuploidy (PGT-A), we will compare the rate of euploid embryos between the groups
measure: Implantation rate
time frame: Two weeks post embryo transfer
description: Rate of successful embryo implantation if undergoes embryo transfer
measure: Clinical pregnancy rate
time frame: Five to seven weeks post embryo transfer
description: Rate of successful clinical intrauterine pregnancy if undergoes embryo transfer
measure: Live birth rate
time frame: 40 weeks post embryo transfer
description: Rate of live birth if undergoes embryo transfer
arm group label: Luteal phase ovarian stimulation (LPOS)
arm group type: Active Comparator
description: Patients will present in the luteal phase, and will begin 150 IU hMG and 300 IU recombinant FSH daily, as well as oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH can then be titrated per patient response. Gonadotropin releasing hormone antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be started per criteria. Once patients are ready for ovulation trigger, 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU), will be administered. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.
arm group label: Luteal estradiol priming protocol
arm group type: Active Comparator
description: In the luteal phase, the patient will begin Estradiol patches 0.1mg QOD. She will also take daily Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) for three days. With menses, she will begin 150 IU hMG, 300 IU recombinant FSH daily, and oral Clomiphene citrate 100mg qd (for five days). FSH can be titrated per patient response. GnRH antagonist will be started per criteria. 5-10,000 units of human chorionic gonadotropin, +/- GnRH agonist (i.e Luprolide acetate 40 IU) will be administered for ovulation trigger. All metaphase II oocytes obtained by oocyte retrieval will be fertilized with intracytoplasmic sperm injection (ICSI) or IVF. Embryos will be cultured to the blastocyst stage and vitrified on day 5-7 with or without embryo biopsy for genetic analysis.
intervention type: Procedure
intervention name: Timing of injectable gonadotropins
description: Gonadotropins will with be started in the luteal phase or in follicular phase (preceded by Estradiol patches)
arm group label: Luteal estradiol priming protocol
arm group label: Luteal phase ovarian stimulation (LPOS)
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 45 Years
healthy volunteers: No
last name: Baruch Abittan, MD
phone: 5165621735
email: babittan2@northwell.edu
facility: 
status: Recruiting
contact: 
country: United States
citation: Lin LT, Vitale SG, Chen SN, Wen ZH, Tsai HW, Chern CU, Tsui KH. Luteal Phase Ovarian Stimulation May Improve Oocyte Retrieval and Oocyte Quality in Poor Ovarian Responders Undergoing In Vitro Fertilization: Preliminary Results from a Single-Center Prospective Pilot Study. Adv Ther. 2018 Jun;35(6):847-856. doi: 10.1007/s12325-018-0713-1. Epub 2018 Jun 4.
PMID: 29869107
citation: Zhang W, Wang M, Wang S, Bao H, Qu Q, Zhang N, Hao C. Luteal phase ovarian stimulation for poor ovarian responders. JBRA Assist Reprod. 2018 Sep 1;22(3):193-198. doi: 10.5935/1518-0557.20180045.
PMID: 29931967
citation: Wei LH, Ma WH, Tang N, Wei JH. Luteal-phase ovarian stimulation is a feasible method for poor ovarian responders undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer treatment compared to a GnRH antagonist protocol: A retrospective study. Taiwan J Obstet Gynecol. 2016 Feb;55(1):50-4. doi: 10.1016/j.tjog.2015.07.001.
PMID: 26927248
citation: Wu Y, Zhao FC, Sun Y, Liu PS. Luteal-phase protocol in poor ovarian response: a comparative study with an antagonist protocol. J Int Med Res. 2017 Dec;45(6):1731-1738. doi: 10.1177/0300060516669898. Epub 2017 Jan 16.
PMID: 28661216
responsible party type: Principal Investigator
investigator affiliation: Northwell Health
investigator full name: Mary Rausch, MD
investigator title: Assistant Professor, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
mesh term: Infertility