<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/NCT03755973</url>
  </required_header>
  <id_info>
    <org_study_id>1806-LIS-044-SD</org_study_id>
    <nct_id>NCT03755973</nct_id>
  </id_info>
  <brief_title>Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity</brief_title>
  <official_title>How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Valenciano de Infertilidade de Lisboa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Instituto Valenciano de Infertilidade de Lisboa</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>
      This study will assess the change in endometrial gene expression signature on the day of&#xD;
      embryo transfer according to the type of exogenous gonadotropins administered.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Late-follicular elevated progesterone (LFEP) following ovarian stimulation for assisted&#xD;
      reproductive technologies (ART) has been linked to abnormal endometrial receptivity&#xD;
      expression profiles and lower pregnancy rates. For this reason, physicians frequently propose&#xD;
      that patients with LFEP avoid performing a fresh embryo transfer, postponing instead it to a&#xD;
      subsequent unstimulated cycle. Although this strategy may reduce the detrimental effect LFEP&#xD;
      may have on cumulative ART pregnancy rates, it may also frustrate couples who wish to become&#xD;
      pregnant as soon as possible.&#xD;
&#xD;
      With the intent of minimizing potentially-avoidable treatment delays, an increasing number of&#xD;
      researchers are proposing that physicians revisit their current ovarian stimulation regimens.&#xD;
      One strategy which may reduce the incidence of LFEP is to decrease the dose of gonadotropins&#xD;
      administered at the end of stimulation (i.e. a stepdown protocol). A similar approach, using&#xD;
      corifollitropin alpha (CFA), has also been recently advanced, taking advantage of the&#xD;
      stepdown-like pharmacodynamic profile of this compound.&#xD;
&#xD;
      In order to assess the clinical usefulness of these strategies, the investigators propose a&#xD;
      single-center, open-label, paired, randomized trial. The main objective of this study is to&#xD;
      assess the changes in the endometrial gene expression profile on the day of fresh embryo&#xD;
      transfer according to the type of gonadotropins administered for ovarian stimulation. In&#xD;
      summary, all consenting subjects will first undergo an endometrial biopsy seven days after&#xD;
      the luteinizing hormone peak in an unmedicated natural cycle. This biopsy will serve as the&#xD;
      baseline endometrial biopsy (natural cycle biopsy) for a gene expression analysis. Following&#xD;
      this baseline biopsy, subjects will be randomly allocated to a specific type of ovarian&#xD;
      stimulation regimen in order to later perform a second endometrial biopsy, this time five&#xD;
      days after oocyte retrieval (stimulated cycle biopsy). Subjects will be randomized to&#xD;
      administer, on the third day of their menstrual cycle, either a single dose of 150 IU of CFA&#xD;
      (study arms 1A and 1B) or a fixed daily dose of 200 or 300 IU of recombinant follicle&#xD;
      stimulating (rFSH, study arm 2). On the eighth day of stimulation, it is expected that 15% to&#xD;
      30% of all subjects who performed CFA will have reached the follicular development criteria&#xD;
      for final oocyte maturation and ovulation triggering.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 29, 2020</start_date>
  <completion_date type="Actual">May 22, 2023</completion_date>
  <primary_completion_date type="Actual">May 22, 2023</primary_completion_date>
  <phase>Phase 4</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>All consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone (LH) peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for the gene expression signature analysis. Following this baseline biopsy, the subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform some second endometrial biopsy, five days after oocyte retrieval (stimulated cycle biopsy).</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Endometrial gene expression signature on the day of embryo transfer</measure>
    <time_frame>7 days after the last day of ovarian stimulation</time_frame>
    <description>RNA sequencing of specimen of endometrium</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer</measure>
    <time_frame>3 weeks</time_frame>
    <description>Measurement of serum circulating progesterone levels (in ng/mL)</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Infertility, Female</condition>
  <condition>Endometrial Diseases</condition>
  <arm_group>
    <arm_group_label>CFA plus step-down rFSH (1A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single dose of 150 IU of CFA followed by daily rFSH will be administered. The initial rFSH administration will be dosed between 100 IU and 200 IU according to the following criteria:&#xD;
200 or 300 IU: &lt;3 follicles above 13 mm visible on transvaginal ultrasound;&#xD;
150 IU, &gt;2 follicles above 13 mm and circulating day-8 follicle-stimulating hormone (FSH) levels ≤20 IU/mL.&#xD;
100 IU, &gt;2 follicles above 13 mm and circulating day-8 FSH levels &gt;20 IU/mL;&#xD;
Subjects will perform a step-down daily rFSH dose (fixed decreases in the dosing of 25 IU/day) until the triggering criteria are met or a minimum of 50 IU/day is reached. Subjects with &lt;3 follicles above 13 mm visible will maintain 200 IU/day of rFSH until this criterion is met, initiating a fixed 25 IU/day stepdown protocol only from then onwards.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CFA plus fixed daily dose rFSH (1B)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fixed daily dose rFSH only</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CFA</intervention_name>
    <description>Long-acting exogenous ovarian stimulation</description>
    <arm_group_label>CFA plus fixed daily dose rFSH (1B)</arm_group_label>
    <arm_group_label>CFA plus step-down rFSH (1A)</arm_group_label>
    <other_name>Corifollitropin alpha</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>rFSH</intervention_name>
    <description>Daily rFSH</description>
    <arm_group_label>CFA plus fixed daily dose rFSH (1B)</arm_group_label>
    <arm_group_label>CFA plus step-down rFSH (1A)</arm_group_label>
    <arm_group_label>Fixed daily dose rFSH only</arm_group_label>
    <other_name>Puregon</other_name>
    <other_name>Follitropin beta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Fixed daily rFSH dosing protocol of 200-300 IU</intervention_name>
    <description>The dose of daily rFSH is fixed at 200 or 300 IU</description>
    <arm_group_label>CFA plus fixed daily dose rFSH (1B)</arm_group_label>
    <arm_group_label>Fixed daily dose rFSH only</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Step-down daily rFSH dose</intervention_name>
    <description>The dose of daily rFSH is progressively reduced</description>
    <arm_group_label>CFA plus step-down rFSH (1A)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Informed consent form (ICF) dated and signed.&#xD;
&#xD;
          2. Age: ≥18 and ≤42 years old.&#xD;
&#xD;
          3. AFC &lt;20.&#xD;
&#xD;
          4. AMH &lt;2.5 ng/mL, performed in the 12 months prior to inclusion.&#xD;
&#xD;
          5. Body Mass Index (BMI): ≥18.5 Kg/m2 and &lt;30 Kg/m2.&#xD;
&#xD;
          6. Weight: ≥50 kg and &lt;80 kg.&#xD;
&#xD;
          7. First or second ART cycle (with pregnancy wish and planned for single blastocyst&#xD;
             transfer) at the study site, or fertility preservation cycle.&#xD;
&#xD;
          8. Regular menstrual cycles (between 22 and 35 days).&#xD;
&#xD;
          9. Two ovaries present.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Simultaneous participation in another clinical study.&#xD;
&#xD;
          2. Previous history of poor ovarian response (&lt;4 oocytes retrieved) with a maximal dose&#xD;
             of OS (≥300 IU/day) or OHSS, regardless of gonadotropin dose.&#xD;
&#xD;
          3. Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the&#xD;
             endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis).&#xD;
&#xD;
          4. Repeated miscarriages (&gt;2 previous biochemical pregnancies or &gt;2 spontaneous&#xD;
             miscarriages).&#xD;
&#xD;
          5. Recurrent implantation failure (&gt;3 failed cycles with good quality embryos).&#xD;
&#xD;
          6. Polycystic ovary syndrome (PCOS).&#xD;
&#xD;
          7. Tumours of the ovary, breast, uterus, pituitary or hypothalamus.&#xD;
&#xD;
          8. Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.&#xD;
&#xD;
          9. Ovarian cysts or enlarged ovaries.&#xD;
&#xD;
         10. Fibroid tumours of the uterus incompatible with pregnancy.&#xD;
&#xD;
         11. Malformations of the reproductive organs incompatible with pregnancy.&#xD;
&#xD;
         12. Primary gonadal failure.&#xD;
&#xD;
         13. Renal impairment defined as estimated glomerular filtration rate of 90 ml/min/1.73 m2&#xD;
             determined by the Modified Diet and Renal Disease (MDRD) equation at screening.&#xD;
&#xD;
         14. Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin).&#xD;
&#xD;
         15. Risk factors for thromboembolic events, such as a personal or family history, severe&#xD;
             obesity or thrombophilia.&#xD;
&#xD;
         16. Moderate or severe hepatic impairment.&#xD;
&#xD;
         17. Untreated and uncontrolled thyroid dysfunction.&#xD;
&#xD;
         18. Current use of oral contraceptive, anti-depressants, anti-psychotics, steroids,&#xD;
             anti-epileptics or chemotherapy.&#xD;
&#xD;
         19. Administration of exogenous Estradiol (E2), Progesterone (P4) or gonadotropins in the&#xD;
             preceding menstrual cycle.&#xD;
&#xD;
         20. Active female smoking.&#xD;
&#xD;
         21. Acceptors of donated oocytes/embryos.&#xD;
&#xD;
         22. Ongoing pregnancy.&#xD;
&#xD;
         23. Women who have previously enrolled in the trial.&#xD;
&#xD;
         24. Those unable to comprehend the investigational nature of the proposed study.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>42 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Samuel Santos-Ribeiro, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instutito Valenciano de Infertilidade de Lisboa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto Valenciano de Infertilidade</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Portugal</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>May 31, 2023</last_update_submitted>
  <last_update_submitted_qc>May 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Endometrial receptivity</keyword>
  <keyword>Ovarian stimulation</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>
    <mesh_term>Uterine Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Follicle Stimulating Hormone</mesh_term>
  </intervention_browse>
  <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/NCT03755973
org study id: 1806-LIS-044-SD
nct id: NCT03755973
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study will assess the change in endometrial gene expression signature on the day of
      embryo transfer according to the type of exogenous gonadotropins administered.
Late-follicular elevated progesterone (LFEP) following ovarian stimulation for assisted
      reproductive technologies (ART) has been linked to abnormal endometrial receptivity
      expression profiles and lower pregnancy rates. For this reason, physicians frequently propose
      that patients with LFEP avoid performing a fresh embryo transfer, postponing instead it to a
      subsequent unstimulated cycle. Although this strategy may reduce the detrimental effect LFEP
      may have on cumulative ART pregnancy rates, it may also frustrate couples who wish to become
      pregnant as soon as possible.

      With the intent of minimizing potentially-avoidable treatment delays, an increasing number of
      researchers are proposing that physicians revisit their current ovarian stimulation regimens.
      One strategy which may reduce the incidence of LFEP is to decrease the dose of gonadotropins
      administered at the end of stimulation (i.e. a stepdown protocol). A similar approach, using
      corifollitropin alpha (CFA), has also been recently advanced, taking advantage of the
      stepdown-like pharmacodynamic profile of this compound.

      In order to assess the clinical usefulness of these strategies, the investigators propose a
      single-center, open-label, paired, randomized trial. The main objective of this study is to
      assess the changes in the endometrial gene expression profile on the day of fresh embryo
      transfer according to the type of gonadotropins administered for ovarian stimulation. In
      summary, all consenting subjects will first undergo an endometrial biopsy seven days after
      the luteinizing hormone peak in an unmedicated natural cycle. This biopsy will serve as the
      baseline endometrial biopsy (natural cycle biopsy) for a gene expression analysis. Following
      this baseline biopsy, subjects will be randomly allocated to a specific type of ovarian
      stimulation regimen in order to later perform a second endometrial biopsy, this time five
      days after oocyte retrieval (stimulated cycle biopsy). Subjects will be randomized to
      administer, on the third day of their menstrual cycle, either a single dose of 150 IU of CFA
      (study arms 1A and 1B) or a fixed daily dose of 200 or 300 IU of recombinant follicle
      stimulating (rFSH, study arm 2). On the eighth day of stimulation, it is expected that 15% to
      30% of all subjects who performed CFA will have reached the follicular development criteria
      for final oocyte maturation and ovulation triggering.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: All consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone (LH) peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for the gene expression signature analysis. Following this baseline biopsy, the subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform some second endometrial biopsy, five days after oocyte retrieval (stimulated cycle biopsy).
primary purpose: Diagnostic
masking: None (Open Label)
measure: Endometrial gene expression signature on the day of embryo transfer
time frame: 7 days after the last day of ovarian stimulation
description: RNA sequencing of specimen of endometrium
measure: Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
time frame: 3 weeks
description: Measurement of serum circulating progesterone levels (in ng/mL)
arm group label: CFA plus step-down rFSH (1A)
arm group type: Experimental
description: A single dose of 150 IU of CFA followed by daily rFSH will be administered. The initial rFSH administration will be dosed between 100 IU and 200 IU according to the following criteria:
200 or 300 IU: <3 follicles above 13 mm visible on transvaginal ultrasound;
150 IU, >2 follicles above 13 mm and circulating day-8 follicle-stimulating hormone (FSH) levels ≤20 IU/mL.
100 IU, >2 follicles above 13 mm and circulating day-8 FSH levels >20 IU/mL;
Subjects will perform a step-down daily rFSH dose (fixed decreases in the dosing of 25 IU/day) until the triggering criteria are met or a minimum of 50 IU/day is reached. Subjects with <3 follicles above 13 mm visible will maintain 200 IU/day of rFSH until this criterion is met, initiating a fixed 25 IU/day stepdown protocol only from then onwards.
arm group label: CFA plus fixed daily dose rFSH (1B)
arm group type: Experimental
description: A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
arm group label: Fixed daily dose rFSH only
arm group type: Active Comparator
description: A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
intervention type: Drug
intervention name: CFA
description: Long-acting exogenous ovarian stimulation
arm group label: CFA plus fixed daily dose rFSH (1B)
arm group label: CFA plus step-down rFSH (1A)
other name: Corifollitropin alpha
intervention type: Drug
intervention name: rFSH
description: Daily rFSH
arm group label: CFA plus fixed daily dose rFSH (1B)
arm group label: CFA plus step-down rFSH (1A)
arm group label: Fixed daily dose rFSH only
other name: Puregon
other name: Follitropin beta
intervention type: Procedure
intervention name: Fixed daily rFSH dosing protocol of 200-300 IU
description: The dose of daily rFSH is fixed at 200 or 300 IU
arm group label: CFA plus fixed daily dose rFSH (1B)
arm group label: Fixed daily dose rFSH only
intervention type: Procedure
intervention name: Step-down daily rFSH dose
description: The dose of daily rFSH is progressively reduced
arm group label: CFA plus step-down rFSH (1A)
criteria: 
gender: Female
gender based: Yes
minimum age: 18 Years
maximum age: 42 Years
healthy volunteers: No
last name: Samuel Santos-Ribeiro, MD PhD
role: Principal Investigator
affiliation: Instutito Valenciano de Infertilidade de Lisboa
facility: 
country: Portugal
responsible party type: Sponsor
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Uterine Diseases
mesh term: Follicle Stimulating Hormone
sharing ipd: No