<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/NCT03238833</url>
  </required_header>
  <id_info>
    <org_study_id>VGHKS15-CT11-12</org_study_id>
    <nct_id>NCT03238833</nct_id>
  </id_info>
  <brief_title>Poor Ovarian Responders Undergoing IVF Using Luteal Ovarian Stimulation Versus Follicular Ovarian Stimulation</brief_title>
  <official_title>Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kaohsiung Veterans General Hospital.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Kaohsiung Veterans General Hospital.</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The investigators attempted to compare the clinical outcomes and cumulus genes expression in&#xD;
      poor ovarian responders undergoing luteal ovarian stimulation or follicular ovarian&#xD;
      stimulation in in vitro fertilization cycles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple follicular wave theory proposed by Baerwald et al. implied that follicle recruitment&#xD;
      may occur in the luteal phase of menstrual cycle. Therefore, luteal phase ovarian stimulation&#xD;
      (LPOS) was considered as a potential feasible stimulation method during in vitro&#xD;
      fertilization (IVF) cycle. In the beginning, in order to avoid delaying cancer treatment,&#xD;
      LPOS was applied for fertility preservation of cancer patients, showing no difference in&#xD;
      numbers of oocyte retrieved, mature oocytes and fertilization rate between luteal or&#xD;
      follicular phase stimulation. In the recent, LPOS was used for infertility women, suggesting&#xD;
      that LPOS owned quite good IVF outcomes. In previous studies, premature luteinizing hormone&#xD;
      (LH) surge, a major reason worsening ovarian quality in poor ovarian responders (PORs), was&#xD;
      seldom found in LPOS. High progesterone in luteal phase may aid in suppressing premature LH&#xD;
      surge. An updated research claimed that numbers of oocyte retrieved, mature oocytes and&#xD;
      fertilized oocytes in LPOS significantly increased when compared to follicular ovarian&#xD;
      stimulation. Therefore, the investigators presumed that LPOS was a more effective method than&#xD;
      follicular stimulation in PORs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 3, 2017</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>oocytes and embryos</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>retrieved oocytes in number, matured oocytes in number, fertilized oocytes in number, day 3 embryos in number, top-quality day 3 embryos in number</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>pregnancy rate</measure>
    <time_frame>Pregnancy will be confirmed 4 weeks after embryo transfer.</time_frame>
    <description>Clinical pregnancy rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>genes expression</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>cumulus cells genes expression</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">96</enrollment>
  <condition>Fertilization in Vitro</condition>
  <arm_group>
    <arm_group_label>luteal ovarian stimulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The controlled ovarian stimulation in in vitro fertilization cycle was started since luteal phase.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>follicular ovarian stimulation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The controlled ovarian stimulation in in vitro fertilization cycle was started since early follicular phase phase.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>luteal ovarian stimulation</intervention_name>
    <description>In the in vitro fertilization cycle, controlled ovarian stimulation was started since the luteal phase.</description>
    <arm_group_label>luteal ovarian stimulation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>follicular ovarian stimulation</intervention_name>
    <description>In the in vitro fertilization cycle, controlled ovarian stimulation was started since the follicular phase.</description>
    <arm_group_label>follicular ovarian stimulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Poor ovarian responders (PORs) met the Bologna criteria, having at least two of the&#xD;
             three following features:&#xD;
&#xD;
               1. advanced maternal age (≥ 40 years) or any other risk factor for POR,&#xD;
&#xD;
               2. a previous POR (≤ 3 oocytes with a conventional stimulation protocol), and&#xD;
&#xD;
               3. an abnormal ovarian reserve test. An abnormal ovarian reserve test was defined as&#xD;
                  antral follicle count (AFC) &lt; 5 or anti-Müllerian hormone (AMH) &lt; 1 ng/mL in this&#xD;
                  study.&#xD;
&#xD;
        Moreover, two episodes of a previous POR after maximal stimulation alone would be&#xD;
        sufficient to define a patient as a POR.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  oophorectomy&#xD;
&#xD;
          -  exposure to cytotoxic or pelvic irradiation for malignancy&#xD;
&#xD;
          -  taking herbal drugs or other hormonal agents&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kuan-Hao Tsui, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Kaohsiung Veterans General Hospital.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Salvatore Giovanni Vitale, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Messina</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kaohsiung Veterans General Hospital</name>
      <address>
        <city>Kaohsiung</city>
        <zip>81362</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</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>Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8.</citation>
    <PMID>22068695</PMID>
  </reference>
  <results_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>
  </results_reference>
  <results_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>
  </results_reference>
  <results_reference>
    <citation>Maman E, Meirow D, Brengauz M, Raanani H, Dor J, Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil Steril. 2011 Jan;95(1):64-7. doi: 10.1016/j.fertnstert.2010.06.064. Epub 2010 Aug 5.</citation>
    <PMID>20688325</PMID>
  </results_reference>
  <results_reference>
    <citation>Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril. 2013 May;99(6):1476-84. doi: 10.1016/j.fertnstert.2013.03.029.</citation>
    <PMID>23635348</PMID>
  </results_reference>
  <results_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>
  </results_reference>
  <results_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>
  </results_reference>
  <results_reference>
    <citation>Martinez F, Clua E, Devesa M, Rodriguez I, Arroyo G, Gonzalez C, Sole M, Tur R, Coroleu B, Barri PN. Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes. Fertil Steril. 2014 Nov;102(5):1307-11. doi: 10.1016/j.fertnstert.2014.07.741. Epub 2014 Aug 22.</citation>
    <PMID>25154677</PMID>
  </results_reference>
  <results_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>
  </results_reference>
  <results_reference>
    <citation>Li Y, Yang W, Chen X, Li L, Zhang Q, Yang D. Comparison between follicular stimulation and luteal stimulation protocols with clomiphene and HMG in women with poor ovarian response. Gynecol Endocrinol. 2016;32(1):74-7. doi: 10.3109/09513590.2015.1081683. Epub 2015 Sep 15.</citation>
    <PMID>26370530</PMID>
  </results_reference>
  <results_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>
  </results_reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>February 17, 2021</last_update_submitted>
  <last_update_submitted_qc>February 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Kaohsiung Veterans General Hospital.</investigator_affiliation>
    <investigator_full_name>Li-Te Lin</investigator_full_name>
    <investigator_title>Department of Obstetrics and Gynecology</investigator_title>
  </responsible_party>
  <keyword>In vitro fertilization</keyword>
  <keyword>Poor ovarian responder</keyword>
  <keyword>Luteal ovarian stimulation</keyword>
  <keyword>Antagonist protocol</keyword>
  <keyword>Cumulus cells</keyword>
  <patient_data>
    <sharing_ipd>No</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/NCT03238833
org study id: VGHKS15-CT11-12
nct id: NCT03238833
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigators attempted to compare the clinical outcomes and cumulus genes expression in
      poor ovarian responders undergoing luteal ovarian stimulation or follicular ovarian
      stimulation in in vitro fertilization cycles.
Multiple follicular wave theory proposed by Baerwald et al. implied that follicle recruitment
      may occur in the luteal phase of menstrual cycle. Therefore, luteal phase ovarian stimulation
      (LPOS) was considered as a potential feasible stimulation method during in vitro
      fertilization (IVF) cycle. In the beginning, in order to avoid delaying cancer treatment,
      LPOS was applied for fertility preservation of cancer patients, showing no difference in
      numbers of oocyte retrieved, mature oocytes and fertilization rate between luteal or
      follicular phase stimulation. In the recent, LPOS was used for infertility women, suggesting
      that LPOS owned quite good IVF outcomes. In previous studies, premature luteinizing hormone
      (LH) surge, a major reason worsening ovarian quality in poor ovarian responders (PORs), was
      seldom found in LPOS. High progesterone in luteal phase may aid in suppressing premature LH
      surge. An updated research claimed that numbers of oocyte retrieved, mature oocytes and
      fertilized oocytes in LPOS significantly increased when compared to follicular ovarian
      stimulation. Therefore, the investigators presumed that LPOS was a more effective method than
      follicular stimulation in PORs.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: oocytes and embryos
time frame: through study completion, an average of 1 year
description: retrieved oocytes in number, matured oocytes in number, fertilized oocytes in number, day 3 embryos in number, top-quality day 3 embryos in number
measure: pregnancy rate
time frame: Pregnancy will be confirmed 4 weeks after embryo transfer.
description: Clinical pregnancy rate
measure: genes expression
time frame: through study completion, an average of 1 year
description: cumulus cells genes expression
arm group label: luteal ovarian stimulation
arm group type: Experimental
description: The controlled ovarian stimulation in in vitro fertilization cycle was started since luteal phase.
arm group label: follicular ovarian stimulation
arm group type: Active Comparator
description: The controlled ovarian stimulation in in vitro fertilization cycle was started since early follicular phase phase.
intervention type: Other
intervention name: luteal ovarian stimulation
description: In the in vitro fertilization cycle, controlled ovarian stimulation was started since the luteal phase.
arm group label: luteal ovarian stimulation
intervention type: Other
intervention name: follicular ovarian stimulation
description: In the in vitro fertilization cycle, controlled ovarian stimulation was started since the follicular phase.
arm group label: follicular ovarian stimulation
criteria: 
gender: Female
minimum age: 30 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kuan-Hao Tsui, PhD
role: Study Director
affiliation: Kaohsiung Veterans General Hospital.
last name: Salvatore Giovanni Vitale, M.D.
role: Principal Investigator
affiliation: University of Messina
facility: 
country: Taiwan
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: Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8.
PMID: 22068695
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: 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: Maman E, Meirow D, Brengauz M, Raanani H, Dor J, Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil Steril. 2011 Jan;95(1):64-7. doi: 10.1016/j.fertnstert.2010.06.064. Epub 2010 Aug 5.
PMID: 20688325
citation: Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril. 2013 May;99(6):1476-84. doi: 10.1016/j.fertnstert.2013.03.029.
PMID: 23635348
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: 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: Martinez F, Clua E, Devesa M, Rodriguez I, Arroyo G, Gonzalez C, Sole M, Tur R, Coroleu B, Barri PN. Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes. Fertil Steril. 2014 Nov;102(5):1307-11. doi: 10.1016/j.fertnstert.2014.07.741. Epub 2014 Aug 22.
PMID: 25154677
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: Li Y, Yang W, Chen X, Li L, Zhang Q, Yang D. Comparison between follicular stimulation and luteal stimulation protocols with clomiphene and HMG in women with poor ovarian response. Gynecol Endocrinol. 2016;32(1):74-7. doi: 10.3109/09513590.2015.1081683. Epub 2015 Sep 15.
PMID: 26370530
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
responsible party type: Principal Investigator
investigator affiliation: Kaohsiung Veterans General Hospital.
investigator full name: Li-Te Lin
investigator title: Department of Obstetrics and Gynecology
sharing ipd: No