<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/NCT02262416</url>
  </required_header>
  <id_info>
    <org_study_id>01102014</org_study_id>
    <nct_id>NCT02262416</nct_id>
  </id_info>
  <brief_title>GnRH Agonist and Progesterone Versus Progesterone Only for Luteal Phase Support in Antagonist Cycles</brief_title>
  <acronym>GALA</acronym>
  <official_title>A Prospective Randomised Controlled Trial of GnRH Agonist and Progesterone Versus Progesterone Only for Luteal Phase Support in Antagonist Cycles</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queensland Fertility Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Queensland Fertility Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In-Vitro Fertilisation (IVF) is the term commonly applied to a form of treatment for&#xD;
      infertility that involves controlled ovarian hyperstimulation, egg maturation, egg&#xD;
      collection, fertilisation, embryo culture and finally embryo transfer. The period after egg&#xD;
      collection is called luteal phase. In Australia, vaginal progesterone is routinely used to&#xD;
      support the lining of the uterus so that it is susceptible to implantation of the embryos.&#xD;
&#xD;
      More recently, there has been some suggestion that additional supplementation of luteal phase&#xD;
      with GnRH agonist increases clinical pregnancy and live birth rate. These studies are however&#xD;
      heterogeneous and results were inconsistent.&#xD;
&#xD;
      This study is a prospective randomised controlled trial of additional GnRH agonist in luteal&#xD;
      phase of antagonist cycle. The primary hypothesis is that GnRH agonist increases the number&#xD;
      of live birth . The secondary hypothesis is that this increases the clinical pregnancy rate,&#xD;
      on-going pregnancy rate, without affecting the miscarriage rate, ovarian hyperstimulation&#xD;
      rate and multiple pregnancy rate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In-vitro fertilization has been used since 1978 to treat women with infertility. It involves&#xD;
      controlled ovarian stimulation, egg maturation, egg collection, fertilization and embryo&#xD;
      culture and finally embryo culture. The luteal phase is the latter phase of the menstrual&#xD;
      cycle which begins with the formation of the corpora lutea and ends in either pregnancy or&#xD;
      luteolysis. The main hormone associated with this stage is progesterone, which is&#xD;
      significantly higher during the luteal phase than other phases of the cycle. In the IVF&#xD;
      setting, however, luteal phase deficiency is present and over the last 40 years various&#xD;
      regimens have been used to support luteal phase of the cycle. Progesterone is currently&#xD;
      widely used for this purpose and has shown to be effective in improving pregnancy and live&#xD;
      birth rate (Van der Linden 2011).&#xD;
&#xD;
      There have been various other regimen used for luteal support in an attempt to further&#xD;
      enhance luteal phase support such as oestrogen, HCG and GnRH agonist. The recent Cochrane&#xD;
      study showed a significant benefit from addition of GnRH agonist to progesterone versus&#xD;
      progesterone alone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy.&#xD;
      (Van Der Linden 2011) However, the conclusion derived from the metaanalysis were derived from&#xD;
      limited number of studies that used various types additional luteal phase support, which also&#xD;
      included a myriad of agonist and antagonist IVF cycles. Only ICSI cycles were included in the&#xD;
      antagonist cycles.&#xD;
&#xD;
      A gonadotropin-releasing hormone (GnRH) agonist is a synthetic peptide that interacts with&#xD;
      the GnRH hormone receptor to elicit its biologic response, the release of the pituitary&#xD;
      hormones, FHS and LH. The exact mechanism of how GnRH could potentially increase pregnancy&#xD;
      rate is unknown. Tesarik et al performed a randomised study in which addition of GnRH agonist&#xD;
      increases implantation rate in donor recipient discounted the theory that GnRH acted on&#xD;
      corpora lutea. It is suggested that GnRH acts directly on embryo to secrete BHCG hence&#xD;
      enhances implantation. A prospective randomised study that was performed by Isik et al showed&#xD;
      a promising result of use of GnRH agonist administration in the luteal phase of GnRH&#xD;
      antagonist cycle (n=164). In this study, cases received 0.5mg leuprolide acetate in addition&#xD;
      to 600mg micronised progesterone day 6 after ICSI compared to control group who received&#xD;
      micronisd progesterone only. The study showed clinical pregnancy rate of 40% in cases vs 20%&#xD;
      in control group. The increased number of multiple pregnancies in these studies could be&#xD;
      partly explained by multiple embryos transferred. Answer is needed to determine if multiple&#xD;
      pregnancy rate is higher if single embryo transfer is executed.&#xD;
&#xD;
      The studies performed by Tesarik et al and Isik et al showed promising increase in live birth&#xD;
      rate and clinical pregnancy rates in antagonist cycles. Both studies were performed in&#xD;
      clinical settings that were vastly different from Australia: multiple embryos were&#xD;
      transferred, multiple luteal phase support were used in addition to progesterone and multiple&#xD;
      pregnancy rates were high. Given the significant increase in pregnancy rate (&gt;10%) were&#xD;
      observed in these studies, if the increase is real, a RCT in Australia setting is needed&#xD;
      prior to implementation of this intervention.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>January 2015</start_date>
  <completion_date type="Anticipated">January 2016</completion_date>
  <primary_completion_date type="Anticipated">January 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>live birth</measure>
    <time_frame>1 year</time_frame>
    <description>live birth</description>
  </primary_outcome>
  <primary_outcome>
    <measure>on-going pregnancy</measure>
    <time_frame>3 months</time_frame>
    <description>+ve fetal heart rate at nuchal scan</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>pregnancy</measure>
    <time_frame>2 weeks</time_frame>
    <description>positive serum pregnancy test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ovarian hyperstimulation syndrome</measure>
    <time_frame>3 months</time_frame>
    <description>hospitalisation due to the condition</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Infertility</condition>
  <arm_group>
    <arm_group_label>controls</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Normal saline of equivalent volume</description>
  </arm_group>
  <arm_group>
    <arm_group_label>case</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>0.5mg Leuprolide acetate injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>leuprolide</intervention_name>
    <description>normal saline</description>
    <arm_group_label>case</arm_group_label>
    <other_name>lucrin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Single embryo transfer&#xD;
&#xD;
          2. Antagonist cycle with HCG trigger&#xD;
&#xD;
          3. Use of progesterone as luteal phase support (crinone or progesterone pessary )&#xD;
&#xD;
          4. Women undergoing their first IVF cycle with TFC&#xD;
&#xD;
          5. Age 18-42 inclusive&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        No or frozen embryo transfer planned b. Use of other luteal support c. Known&#xD;
        contraindication to the use of GnRH analogue&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>42 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Queensland Fertility Group</name>
      <address>
        <city>Brisbane</city>
        <state>Queensland</state>
        <zip>4000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <reference>
    <citation>Isik AZ, Caglar GS, Sozen E, Akarsu C, Tuncay G, Ozbicer T, Vicdan K. Reprod Biomed Online. 2009 Oct;19(4):472-7. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Medsafe New Zealand. www.medsafe.govt.nz/profs/datasheet/l/Lucrininj.pdf Tarlatzis BC, Bili H.Expert Opin Drug Saf. 2004 Jan;3(1):39-46. Safety of GnRH agonists and antagonists Tesarik J, Hazout A, Mendoza C.Hum Reprod. 2004 May;19(5):1176-80. Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Hum Reprod. 2006 Oct;21(10):2572-9. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M.Cochrane Database Syst Rev. 2011 Oct 5;(10). Luteal phase support for assisted reproduction cycles</citation>
  </reference>
  <verification_date>October 2014</verification_date>
  <study_first_submitted>October 7, 2014</study_first_submitted>
  <study_first_submitted_qc>October 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>October 10, 2014</last_update_submitted>
  <last_update_submitted_qc>October 10, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 13, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>GnRH agonist</keyword>
  <keyword>IVF</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leuprolide</mesh_term>
  </intervention_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/NCT02262416
org study id: 01102014
nct id: NCT02262416
lead sponsor: 
has dmc: Yes
In-Vitro Fertilisation (IVF) is the term commonly applied to a form of treatment for
      infertility that involves controlled ovarian hyperstimulation, egg maturation, egg
      collection, fertilisation, embryo culture and finally embryo transfer. The period after egg
      collection is called luteal phase. In Australia, vaginal progesterone is routinely used to
      support the lining of the uterus so that it is susceptible to implantation of the embryos.

      More recently, there has been some suggestion that additional supplementation of luteal phase
      with GnRH agonist increases clinical pregnancy and live birth rate. These studies are however
      heterogeneous and results were inconsistent.

      This study is a prospective randomised controlled trial of additional GnRH agonist in luteal
      phase of antagonist cycle. The primary hypothesis is that GnRH agonist increases the number
      of live birth . The secondary hypothesis is that this increases the clinical pregnancy rate,
      on-going pregnancy rate, without affecting the miscarriage rate, ovarian hyperstimulation
      rate and multiple pregnancy rate.
In-vitro fertilization has been used since 1978 to treat women with infertility. It involves
      controlled ovarian stimulation, egg maturation, egg collection, fertilization and embryo
      culture and finally embryo culture. The luteal phase is the latter phase of the menstrual
      cycle which begins with the formation of the corpora lutea and ends in either pregnancy or
      luteolysis. The main hormone associated with this stage is progesterone, which is
      significantly higher during the luteal phase than other phases of the cycle. In the IVF
      setting, however, luteal phase deficiency is present and over the last 40 years various
      regimens have been used to support luteal phase of the cycle. Progesterone is currently
      widely used for this purpose and has shown to be effective in improving pregnancy and live
      birth rate (Van der Linden 2011).

      There have been various other regimen used for luteal support in an attempt to further
      enhance luteal phase support such as oestrogen, HCG and GnRH agonist. The recent Cochrane
      study showed a significant benefit from addition of GnRH agonist to progesterone versus
      progesterone alone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy.
      (Van Der Linden 2011) However, the conclusion derived from the metaanalysis were derived from
      limited number of studies that used various types additional luteal phase support, which also
      included a myriad of agonist and antagonist IVF cycles. Only ICSI cycles were included in the
      antagonist cycles.

      A gonadotropin-releasing hormone (GnRH) agonist is a synthetic peptide that interacts with
      the GnRH hormone receptor to elicit its biologic response, the release of the pituitary
      hormones, FHS and LH. The exact mechanism of how GnRH could potentially increase pregnancy
      rate is unknown. Tesarik et al performed a randomised study in which addition of GnRH agonist
      increases implantation rate in donor recipient discounted the theory that GnRH acted on
      corpora lutea. It is suggested that GnRH acts directly on embryo to secrete BHCG hence
      enhances implantation. A prospective randomised study that was performed by Isik et al showed
      a promising result of use of GnRH agonist administration in the luteal phase of GnRH
      antagonist cycle (n=164). In this study, cases received 0.5mg leuprolide acetate in addition
      to 600mg micronised progesterone day 6 after ICSI compared to control group who received
      micronisd progesterone only. The study showed clinical pregnancy rate of 40% in cases vs 20%
      in control group. The increased number of multiple pregnancies in these studies could be
      partly explained by multiple embryos transferred. Answer is needed to determine if multiple
      pregnancy rate is higher if single embryo transfer is executed.

      The studies performed by Tesarik et al and Isik et al showed promising increase in live birth
      rate and clinical pregnancy rates in antagonist cycles. Both studies were performed in
      clinical settings that were vastly different from Australia: multiple embryos were
      transferred, multiple luteal phase support were used in addition to progesterone and multiple
      pregnancy rates were high. Given the significant increase in pregnancy rate (>10%) were
      observed in these studies, if the increase is real, a RCT in Australia setting is needed
      prior to implementation of this intervention.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: live birth
time frame: 1 year
description: live birth
measure: on-going pregnancy
time frame: 3 months
description: +ve fetal heart rate at nuchal scan
measure: pregnancy
time frame: 2 weeks
description: positive serum pregnancy test
measure: Ovarian hyperstimulation syndrome
time frame: 3 months
description: hospitalisation due to the condition
arm group label: controls
arm group type: Placebo Comparator
description: Normal saline of equivalent volume
arm group label: case
arm group type: Active Comparator
description: 0.5mg Leuprolide acetate injection
intervention type: Drug
intervention name: leuprolide
description: normal saline
arm group label: case
other name: lucrin
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 42 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Australia
citation: Isik AZ, Caglar GS, Sozen E, Akarsu C, Tuncay G, Ozbicer T, Vicdan K. Reprod Biomed Online. 2009 Oct;19(4):472-7. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Medsafe New Zealand. www.medsafe.govt.nz/profs/datasheet/l/Lucrininj.pdf Tarlatzis BC, Bili H.Expert Opin Drug Saf. 2004 Jan;3(1):39-46. Safety of GnRH agonists and antagonists Tesarik J, Hazout A, Mendoza C.Hum Reprod. 2004 May;19(5):1176-80. Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Hum Reprod. 2006 Oct;21(10):2572-9. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M.Cochrane Database Syst Rev. 2011 Oct 5;(10). Luteal phase support for assisted reproduction cycles
responsible party type: Sponsor
mesh term: Infertility
mesh term: Leuprolide