<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/NCT04445025</url>
  </required_header>
  <id_info>
    <org_study_id>elagolix</org_study_id>
    <nct_id>NCT04445025</nct_id>
  </id_info>
  <brief_title>Comparison Elagolix vs Depot Leuprolide Prior to Frozen Embryo Transfers in Patients With Endometriosis</brief_title>
  <official_title>The Effect of Elagolix in Comparison to Leuprolide Acetate on in Vitro Fertilization (IVF) Cycle Outcomes After a Transfer of Euploid Embryos to Patients With Surgically Diagnosed Endometriosis: A Pilot Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Colorado Center for Reproductive Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AbbVie</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Colorado Center for Reproductive Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients who have been previously surgically diagnosed with endometriosis and have embryos&#xD;
      predicted to be euploid after in vitro fertilization will be divided into 2 groups via&#xD;
      randomization. The test group will receive Elagolix for 60 days prior to starting frozen&#xD;
      embryo transfer preparation. The control group will be given leuprolide acetate every 28 days&#xD;
      x 2 prior to starting the frozen embryo transfer preparation.&#xD;
&#xD;
      Comparative implantation rates between two groups of patients will be evaluated&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Baseline visit prior to initiation of IVF cycle:&#xD;
&#xD;
           Review nature of study, confirm surgical diagnosis of endometriosis, obtain informed&#xD;
           consent, confirm absence of exclusion criteria&#xD;
&#xD;
        2. Standard IVF and preimplantation genetic screening (prior to study entry):&#xD;
&#xD;
           Subjects will undergo standard ovarian stimulation, monitoring (serum and ultrasound),&#xD;
           oocyte aspiration, in vitro fertilization (IVF), intracytoplasmic sperm injection&#xD;
           (ICSI), embryo culture to the blastocyst stage of development, trophectoderm biopsy,&#xD;
           comprehensive chromosomal screening of embryos (CCS) and embryo vitrification as per&#xD;
           protocols of CCRM and as determined by the primary CCRM physician.&#xD;
&#xD;
        3. Initial study entry visit performed within 4 weeks of initial medication administration&#xD;
           after confirmation of presence of euploid embryo(s): Complete blood count, chemistry,&#xD;
           renal and liver function panels. Computer generated randomization Obtain serum sample&#xD;
           for micro RNA evaluation (results will not impact treatment and will only be analyzed&#xD;
           retrospectively) Cycle Day2-4 serum FSH, estradiol, LH, progesterone, hCG level and&#xD;
           transvaginal ultrasound examination to evaluate endometrial lining and the&#xD;
           presence/absence of ovarian cysts All patients will be instructed to avoid pregnancy&#xD;
           through use of barrier contraception while on study drug&#xD;
&#xD;
        4. Initial dosing Once screening evaluation has been cleared by the investigator, subject&#xD;
           will be administered Lupron Depot 3.75 mg intramuscularly on cycle day 2-6 or will&#xD;
           self-administer elagolix 200 mg orally twice daily beginning 2-6&#xD;
&#xD;
        5. Week 4 (30 days after initial dosing) Subjects will have repeat FSH, estradiol, LH,&#xD;
           progesterone, and hCG levels drawn Subjects will be interviewed by study coordinator&#xD;
           regarding presence or absence adverse outcomes/side effects including incidence and&#xD;
           severity of hot flushes, vaginal bleeding, headache, nausea and vomiting Unless subject&#xD;
           wishes to discontinue trial or is experiencing significant adverse events necessitating&#xD;
           drop-out, patients in Lupron group will receive a second dose of Lupron Depot 3.75 mg&#xD;
           intramuscularly and those in the elagolix dose will continue 200 mg twice daily oral&#xD;
           dosing for an additional 30 days which will be dispensed at this visit&#xD;
&#xD;
        6. Week 8 (60 days after initial dosing) Subjects will have repeat FSH, estradiol, LH,&#xD;
           progesterone and hCG levels as well as CBC and chem panel including liver function tests&#xD;
           drawn Serum sample will be obtained for follow-up microarray analysis Transvaginal&#xD;
           ultrasound examination will be performed to evaluate endometrial thickness and&#xD;
           presence/absence of ovarian cysts Interview with study coordinator regarding&#xD;
           presence/absence of adverse events/ side effects as described above&#xD;
&#xD;
        7. First menses after completion of study drug/ Endometrial preparation for embryo transfer&#xD;
           Initiation of standard endometrial preparation with exogenous trans-dermal estradiol in&#xD;
           conjunction with oral and/or intramuscular preparations per standard CCRM protocols and&#xD;
           as determined by the primary physician to achieve an endometrial thickness of 7.0-15.0&#xD;
           mm with a trilaminar pattern. Standard monitoring with serial ultrasound examination and&#xD;
           assessment of serial estradiol, LH and progesterone levels will be performed per CCRM&#xD;
           protocols. Once appropriate endometrial development has been achieved after a minimum of&#xD;
           10 days of preparation, both intravaginal and intramuscular progesterone will be added&#xD;
           to the estradiol with planned embryo transfer on the sixth day of progesterone&#xD;
           administration&#xD;
&#xD;
        8. Embryo transfer Vitrified euploid embryo(s) selected for transfer will be warmed on the&#xD;
           day of transfer which will be performed under ultrasound guidance using standard CCRM&#xD;
           protocols. No more than 2 euploid embryos may be transferred and all patients will be&#xD;
           encouraged to undergo a single transfer. Indication for a two embryo transfer will be&#xD;
           documented. Best quality embryo(s) will be transferred preferentially choosing day 5&#xD;
           euploid blastocysts over day 6 or 7 euploid blastocysts. Embryos will be graded using&#xD;
           the classification system of Gardner et al. (see reference section)&#xD;
&#xD;
        9. Luteal support Subjects will receive standard luteal support with both injectable and&#xD;
           intravaginal progesterone with doses adjusted per CCRM guidelines.&#xD;
&#xD;
       10. Pregnancy diagnosis and monitoring Subjects will have an initial serum hCG level&#xD;
           obtained 9 days after embryo transfer in their local clinic. Estradiol and progesterone&#xD;
           levels will also be measured if hCG is positive. Repeat hCG level will obtained two days&#xD;
           after the first level if the first level was positive. First pregnancy ultrasound will&#xD;
           be obtained 2-2.5 weeks after initial positive hCG level unless there is a clinical&#xD;
           indication for an earlier evaluation. If all is normal with first pregnancy ultrasound&#xD;
           examination, a second ultrasound examination to evaluate pregnancy will be performed&#xD;
           2-2.5 weeks thereafter unless clinical circumstances require earlier evaluation.&#xD;
           Progesterone and estradiol supplementation will typically be tapered using CCRM&#xD;
           guidelines beginning at 10 weeks of pregnancy and be discontinued entirely no later than&#xD;
           the end of the 13th week of pregnancy. Subjects will be referred to their primary&#xD;
           obstetricians after the second pregnancy ultrasound examination at 8 weeks of pregnancy&#xD;
&#xD;
       11. Pregnancy outcome data collection The outcomes of all pregnancies shall be obtained from&#xD;
           the patient and recorded. If live birth, all data required by Center for Disease Control&#xD;
           will be collected including gestational age, birth weight, immediately diagnosed&#xD;
           anomalies and pregnancy complications. The gestational age, management, and pathology&#xD;
           reports (if available) from pregnancy loss, ectopic pregnancy and still birth shall also&#xD;
           be collected.&#xD;
&#xD;
      Any pregnancies that occur while on study drugs or which occur after completion of the drugs&#xD;
      but prior to embryo transfer will be recorded and monitored in the same fashion as described&#xD;
      above&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2023</primary_completion_date>
  <phase>Early Phase 1</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>Test group will receive Elagolix 60 days prior to initiating frozen embryo transfer preparation.&#xD;
Control group will receive depot leuprolide twice (once every 28 days) prior to initiation frozen embryo transfer preparation.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison of Implantation Rates</measure>
    <time_frame>2-3 weeks after initial positive pregnancy test (approx 14-15 weeks post initiation of treatment)</time_frame>
    <description>Implantation rates of both groups will be compared (defined as number of intrauterine gestational sacs with visible cardiac activity noted on ultrasound examination performed 2-3 weeks after initial positive pregnancy test)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comparison of Biochemical pregnancy rates</measure>
    <time_frame>2-3 weeks after initial positive pregnancy test (approx 14-15 weeks post initiation of treatment)</time_frame>
    <description>Comparative biochemical pregnancy rates (positive pregnancy tests with no evidence of intrauterine gestational sac noted at ultrasound performed 2-3 weeks after initial positive pregnancy test) per embryo transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of hormone levels between the two groups</measure>
    <time_frame>4 weeks and 8 weeks after initiation of treatment</time_frame>
    <description>FSH, LH, Estradiol, progesterone will compared after 4 weeks and 8 weeks of initiation of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of live birth rates and pregnancy loss rates</measure>
    <time_frame>10-11 months after initiation of treatment</time_frame>
    <description>At the end of the pregnancy. Live birth rates and pregnancy loss rates will be compared between the two groups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Infertility</condition>
  <condition>Endometriosis</condition>
  <arm_group>
    <arm_group_label>Test group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive the medication elagolix</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive leuprolide acetate</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Elagolix 200 MG</intervention_name>
    <description>Elagolix 200mg twice daily orally for 60 days prior to beginning frozen embryo transfer preparation</description>
    <arm_group_label>Test group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leuprolide Acetate 3.75 MG/ML</intervention_name>
    <description>Leuprolide Acetate intramuscularly every 28 days (twice) prior to beginning frozen embryo transfer preparation</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Lab work</intervention_name>
    <description>Serum follicle stimulating hormone (FSH), estradiol, luteinizing hormone (LH), progesterone, human chorionic gonadotropin (hCG), serum for microarray analysis, complete blood count, and chemistry panel with liver functions levels will be drawn via blood draw</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Test group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of infertility who are candidate for IVF&#xD;
&#xD;
          2. Surgical diagnosis of endometriosis within 10 years of study entry&#xD;
&#xD;
          3. Willing to sign/give informed consent and adhere to parameters of study&#xD;
&#xD;
          4. Normal endometrial cavity as diagnosed by 3D ultrasound and office hysteroscopy&#xD;
             examinations at baseline or after correction of underlying clinically relevant cavity&#xD;
             abnormalities&#xD;
&#xD;
          5. Day 2-4 serum FSH level ≤ 12 mIu/mL and/or random serum AMH level ≥ 0.9 ng/mL and/or&#xD;
             antral follicular phase follicle count obtained by trans-vaginal ultrasound&#xD;
             examination ≥ 5&#xD;
&#xD;
          6. No contraindication to GnRH agonist or GnRH antagonist use&#xD;
&#xD;
          7. No prolonged use of GnRH agonist or antagonist (&gt; 30 consecutive days) or other&#xD;
             treatment for endometriosis within 4 months of study entry&#xD;
&#xD;
          8. Have at least one euploid embryo available for transfer&#xD;
&#xD;
          9. Agrees to transfer best quality embryo as determined by CCRM physician and embryology&#xD;
             team&#xD;
&#xD;
         10. Regular menses ranging from 22-36 days&#xD;
&#xD;
         11. Agrees to use barrier contraception throughout GnRH agonist or antagonist&#xD;
             administration&#xD;
&#xD;
         12. No evidence of untreated hydrosalpinx&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt;21 or &gt; 42 years at time of initiation of IVF cycle&#xD;
&#xD;
          2. Day 2-4 FSH level &gt;12 mIu/mL or random serum AMH level &lt;1.0 ng/mL and antral follicle&#xD;
             count obtained by trans-vaginal ultrasound examination &lt; 5&#xD;
&#xD;
          3. Planned use of donor oocytes or embryos&#xD;
&#xD;
          4. Planned use of gestational carrier&#xD;
&#xD;
          5. Use of GnRH agonist, GnRH antagonist or other approved medical therapy for&#xD;
             endometriosis (with the exception of combination contraceptives) for &gt; 30 consecutive&#xD;
             days prior to study entry&#xD;
&#xD;
          6. Unwilling to abide by study parameters or sign informed consent&#xD;
&#xD;
          7. No documentation of surgical diagnosis of endometriosis with study timeline (10 years&#xD;
             of study entry)&#xD;
&#xD;
          8. Absence of embryos predicted to be euploid available for transfer (embryos with no&#xD;
             results may not be included in transfer)&#xD;
&#xD;
          9. Prior adverse reaction to any GnRH agonist or antagonist&#xD;
&#xD;
         10. Uncorrected or uncorrectable clinically relevant uterine cavity abnormalities or&#xD;
             hydrosalpinx&#xD;
&#xD;
         11. Acute or chronic renal, pulmonary, hepatic, or cardiac disease&#xD;
&#xD;
         12. Prior diagnosis of pituitary adenoma or any other intracranial lesion&#xD;
&#xD;
         13. Menstrual cycles outside the range of inclusion criteria&#xD;
&#xD;
         14. Diagnosis of polycystic ovary syndrome (PCOS)&#xD;
&#xD;
         15. Pregnancy prior to study initiation or initiation of endometrial preparation for&#xD;
             embryo transfer.&#xD;
&#xD;
         16. Undiagnosed vaginal bleeding&#xD;
&#xD;
         17. Clinically relevant adenomyosis as diagnosed by baseline 3D ultrasound exam (and/or&#xD;
             MRI if felt to be appropriate)&#xD;
&#xD;
         18. Bipolar disorder, history of suicidal ideation, any other psychiatric disorder&#xD;
             requiring lithium or anti-psychotic medications&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>42 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eric Surrey, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Colorado Center for Reproductive Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Rachel Makloski, RN</last_name>
    <phone>303-788-8300</phone>
    <phone_ext>1769</phone_ext>
    <email>rmakloski@colocrm.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Colorado Center for Reproductive Medicine</name>
      <address>
        <city>Lone Tree</city>
        <state>Colorado</state>
        <zip>80124</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Eric S Surrey, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis. Fertil Steril. 2016 Aug;106(2):402-9. doi: 10.1016/j.fertnstert.2016.04.013. Epub 2016 May 11.</citation>
    <PMID>27179784</PMID>
  </reference>
  <reference>
    <citation>Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-Jaffe M, Scott RT Jr. Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients. Fertil Steril. 2011 Sep;96(3):638-40. doi: 10.1016/j.fertnstert.2011.06.049. Epub 2011 Jul 23.</citation>
    <PMID>21782169</PMID>
  </reference>
  <reference>
    <citation>Surrey ES, Minjarez DA, Schoolcraft WB. The incidence of aberrant endometrial alphavbeta(3) vitronectin expression in a high risk infertility population: could prolonged GnRH agonist therapy play a role? J Assist Reprod Genet. 2007 Nov;24(11):553-6. doi: 10.1007/s10815-007-9164-3. Epub 2007 Nov 17.</citation>
    <PMID>18026832</PMID>
  </reference>
  <reference>
    <citation>Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Rowan JP, Duan WR, Ng J, Schwefel B, Thomas JW, Jain RI, Chwalisz K. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017 Jul 6;377(1):28-40. doi: 10.1056/NEJMoa1700089. Epub 2017 May 19.</citation>
    <PMID>28525302</PMID>
  </reference>
  <reference>
    <citation>Surrey ES, Katz-Jaffe M, Kondapalli LV, Gustofson RL, Schoolcraft WB. GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression. Reprod Biomed Online. 2017 Aug;35(2):145-151. doi: 10.1016/j.rbmo.2017.05.004. Epub 2017 May 17.</citation>
    <PMID>28601378</PMID>
  </reference>
  <reference>
    <citation>Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004 Mar;81(3):551-5. doi: 10.1016/j.fertnstert.2003.07.023.</citation>
    <PMID>15037401</PMID>
  </reference>
  <reference>
    <citation>Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;2006(1):CD004635. doi: 10.1002/14651858.CD004635.pub2.</citation>
    <PMID>16437491</PMID>
  </reference>
  <results_reference>
    <citation>Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002 Oct;78(4):699-704. doi: 10.1016/s0015-0282(02)03373-3.</citation>
    <PMID>12372443</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>February 22, 2023</last_update_submitted>
  <last_update_submitted_qc>February 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Colorado Center for Reproductive Medicine</investigator_affiliation>
    <investigator_full_name>Eric Surrey, M.D.</investigator_full_name>
    <investigator_title>Medical Director</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Endometriosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leuprolide</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/NCT04445025
org study id: elagolix
nct id: NCT04445025
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Patients who have been previously surgically diagnosed with endometriosis and have embryos
      predicted to be euploid after in vitro fertilization will be divided into 2 groups via
      randomization. The test group will receive Elagolix for 60 days prior to starting frozen
      embryo transfer preparation. The control group will be given leuprolide acetate every 28 days
      x 2 prior to starting the frozen embryo transfer preparation.

      Comparative implantation rates between two groups of patients will be evaluated
1. Baseline visit prior to initiation of IVF cycle:

           Review nature of study, confirm surgical diagnosis of endometriosis, obtain informed
           consent, confirm absence of exclusion criteria

        2. Standard IVF and preimplantation genetic screening (prior to study entry):

           Subjects will undergo standard ovarian stimulation, monitoring (serum and ultrasound),
           oocyte aspiration, in vitro fertilization (IVF), intracytoplasmic sperm injection
           (ICSI), embryo culture to the blastocyst stage of development, trophectoderm biopsy,
           comprehensive chromosomal screening of embryos (CCS) and embryo vitrification as per
           protocols of CCRM and as determined by the primary CCRM physician.

        3. Initial study entry visit performed within 4 weeks of initial medication administration
           after confirmation of presence of euploid embryo(s): Complete blood count, chemistry,
           renal and liver function panels. Computer generated randomization Obtain serum sample
           for micro RNA evaluation (results will not impact treatment and will only be analyzed
           retrospectively) Cycle Day2-4 serum FSH, estradiol, LH, progesterone, hCG level and
           transvaginal ultrasound examination to evaluate endometrial lining and the
           presence/absence of ovarian cysts All patients will be instructed to avoid pregnancy
           through use of barrier contraception while on study drug

        4. Initial dosing Once screening evaluation has been cleared by the investigator, subject
           will be administered Lupron Depot 3.75 mg intramuscularly on cycle day 2-6 or will
           self-administer elagolix 200 mg orally twice daily beginning 2-6

        5. Week 4 (30 days after initial dosing) Subjects will have repeat FSH, estradiol, LH,
           progesterone, and hCG levels drawn Subjects will be interviewed by study coordinator
           regarding presence or absence adverse outcomes/side effects including incidence and
           severity of hot flushes, vaginal bleeding, headache, nausea and vomiting Unless subject
           wishes to discontinue trial or is experiencing significant adverse events necessitating
           drop-out, patients in Lupron group will receive a second dose of Lupron Depot 3.75 mg
           intramuscularly and those in the elagolix dose will continue 200 mg twice daily oral
           dosing for an additional 30 days which will be dispensed at this visit

        6. Week 8 (60 days after initial dosing) Subjects will have repeat FSH, estradiol, LH,
           progesterone and hCG levels as well as CBC and chem panel including liver function tests
           drawn Serum sample will be obtained for follow-up microarray analysis Transvaginal
           ultrasound examination will be performed to evaluate endometrial thickness and
           presence/absence of ovarian cysts Interview with study coordinator regarding
           presence/absence of adverse events/ side effects as described above

        7. First menses after completion of study drug/ Endometrial preparation for embryo transfer
           Initiation of standard endometrial preparation with exogenous trans-dermal estradiol in
           conjunction with oral and/or intramuscular preparations per standard CCRM protocols and
           as determined by the primary physician to achieve an endometrial thickness of 7.0-15.0
           mm with a trilaminar pattern. Standard monitoring with serial ultrasound examination and
           assessment of serial estradiol, LH and progesterone levels will be performed per CCRM
           protocols. Once appropriate endometrial development has been achieved after a minimum of
           10 days of preparation, both intravaginal and intramuscular progesterone will be added
           to the estradiol with planned embryo transfer on the sixth day of progesterone
           administration

        8. Embryo transfer Vitrified euploid embryo(s) selected for transfer will be warmed on the
           day of transfer which will be performed under ultrasound guidance using standard CCRM
           protocols. No more than 2 euploid embryos may be transferred and all patients will be
           encouraged to undergo a single transfer. Indication for a two embryo transfer will be
           documented. Best quality embryo(s) will be transferred preferentially choosing day 5
           euploid blastocysts over day 6 or 7 euploid blastocysts. Embryos will be graded using
           the classification system of Gardner et al. (see reference section)

        9. Luteal support Subjects will receive standard luteal support with both injectable and
           intravaginal progesterone with doses adjusted per CCRM guidelines.

       10. Pregnancy diagnosis and monitoring Subjects will have an initial serum hCG level
           obtained 9 days after embryo transfer in their local clinic. Estradiol and progesterone
           levels will also be measured if hCG is positive. Repeat hCG level will obtained two days
           after the first level if the first level was positive. First pregnancy ultrasound will
           be obtained 2-2.5 weeks after initial positive hCG level unless there is a clinical
           indication for an earlier evaluation. If all is normal with first pregnancy ultrasound
           examination, a second ultrasound examination to evaluate pregnancy will be performed
           2-2.5 weeks thereafter unless clinical circumstances require earlier evaluation.
           Progesterone and estradiol supplementation will typically be tapered using CCRM
           guidelines beginning at 10 weeks of pregnancy and be discontinued entirely no later than
           the end of the 13th week of pregnancy. Subjects will be referred to their primary
           obstetricians after the second pregnancy ultrasound examination at 8 weeks of pregnancy

       11. Pregnancy outcome data collection The outcomes of all pregnancies shall be obtained from
           the patient and recorded. If live birth, all data required by Center for Disease Control
           will be collected including gestational age, birth weight, immediately diagnosed
           anomalies and pregnancy complications. The gestational age, management, and pathology
           reports (if available) from pregnancy loss, ectopic pregnancy and still birth shall also
           be collected.

      Any pregnancies that occur while on study drugs or which occur after completion of the drugs
      but prior to embryo transfer will be recorded and monitored in the same fashion as described
      above
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Test group will receive Elagolix 60 days prior to initiating frozen embryo transfer preparation.
Control group will receive depot leuprolide twice (once every 28 days) prior to initiation frozen embryo transfer preparation.
primary purpose: Treatment
masking: None (Open Label)
measure: Comparison of Implantation Rates
time frame: 2-3 weeks after initial positive pregnancy test (approx 14-15 weeks post initiation of treatment)
description: Implantation rates of both groups will be compared (defined as number of intrauterine gestational sacs with visible cardiac activity noted on ultrasound examination performed 2-3 weeks after initial positive pregnancy test)
measure: Comparison of Biochemical pregnancy rates
time frame: 2-3 weeks after initial positive pregnancy test (approx 14-15 weeks post initiation of treatment)
description: Comparative biochemical pregnancy rates (positive pregnancy tests with no evidence of intrauterine gestational sac noted at ultrasound performed 2-3 weeks after initial positive pregnancy test) per embryo transfer
measure: Comparison of hormone levels between the two groups
time frame: 4 weeks and 8 weeks after initiation of treatment
description: FSH, LH, Estradiol, progesterone will compared after 4 weeks and 8 weeks of initiation of treatment
measure: Comparison of live birth rates and pregnancy loss rates
time frame: 10-11 months after initiation of treatment
description: At the end of the pregnancy. Live birth rates and pregnancy loss rates will be compared between the two groups
arm group label: Test group
arm group type: Experimental
description: Subjects will receive the medication elagolix
arm group label: Control group
arm group type: Active Comparator
description: Subjects will receive leuprolide acetate
intervention type: Drug
intervention name: Elagolix 200 MG
description: Elagolix 200mg twice daily orally for 60 days prior to beginning frozen embryo transfer preparation
arm group label: Test group
intervention type: Drug
intervention name: Leuprolide Acetate 3.75 MG/ML
description: Leuprolide Acetate intramuscularly every 28 days (twice) prior to beginning frozen embryo transfer preparation
arm group label: Control group
intervention type: Diagnostic Test
intervention name: Lab work
description: Serum follicle stimulating hormone (FSH), estradiol, luteinizing hormone (LH), progesterone, human chorionic gonadotropin (hCG), serum for microarray analysis, complete blood count, and chemistry panel with liver functions levels will be drawn via blood draw
arm group label: Control group
arm group label: Test group
criteria: 
gender: Female
gender based: Yes
minimum age: 21 Years
maximum age: 42 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Eric Surrey, MD
role: Principal Investigator
affiliation: Colorado Center for Reproductive Medicine
last name: Rachel Makloski, RN
phone: 303-788-8300
phone ext: 1769
email: rmakloski@colocrm.com
facility: 
status: Recruiting
investigator: 
country: United States
citation: Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis. Fertil Steril. 2016 Aug;106(2):402-9. doi: 10.1016/j.fertnstert.2016.04.013. Epub 2016 May 11.
PMID: 27179784
citation: Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-Jaffe M, Scott RT Jr. Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients. Fertil Steril. 2011 Sep;96(3):638-40. doi: 10.1016/j.fertnstert.2011.06.049. Epub 2011 Jul 23.
PMID: 21782169
citation: Surrey ES, Minjarez DA, Schoolcraft WB. The incidence of aberrant endometrial alphavbeta(3) vitronectin expression in a high risk infertility population: could prolonged GnRH agonist therapy play a role? J Assist Reprod Genet. 2007 Nov;24(11):553-6. doi: 10.1007/s10815-007-9164-3. Epub 2007 Nov 17.
PMID: 18026832
citation: Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, Gallagher JC, Simon JA, Carr BR, Dmowski WP, Leyland N, Rowan JP, Duan WR, Ng J, Schwefel B, Thomas JW, Jain RI, Chwalisz K. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017 Jul 6;377(1):28-40. doi: 10.1056/NEJMoa1700089. Epub 2017 May 19.
PMID: 28525302
citation: Surrey ES, Katz-Jaffe M, Kondapalli LV, Gustofson RL, Schoolcraft WB. GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression. Reprod Biomed Online. 2017 Aug;35(2):145-151. doi: 10.1016/j.rbmo.2017.05.004. Epub 2017 May 17.
PMID: 28601378
citation: Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004 Mar;81(3):551-5. doi: 10.1016/j.fertnstert.2003.07.023.
PMID: 15037401
citation: Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;2006(1):CD004635. doi: 10.1002/14651858.CD004635.pub2.
PMID: 16437491
citation: Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002 Oct;78(4):699-704. doi: 10.1016/s0015-0282(02)03373-3.
PMID: 12372443
responsible party type: Principal Investigator
investigator affiliation: Colorado Center for Reproductive Medicine
investigator full name: Eric Surrey, M.D.
investigator title: Medical Director
mesh term: Infertility
mesh term: Endometriosis
mesh term: Leuprolide
sharing ipd: No