<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/NCT02197208</url>
  </required_header>
  <id_info>
    <org_study_id>HKU-VL-NChCGFET</org_study_id>
    <nct_id>NCT02197208</nct_id>
  </id_info>
  <brief_title>A RCT Comparing Spontaneous Natural Cycles and Human Chorionic Gonadotrophin-induced Natural Cycles in FET</brief_title>
  <official_title>A Randomized Controlled Comparison of Spontaneous Natural Cycles and Human Chorionic Gonadotrophin-induced Natural Cycles in Frozen-thawed Embryos Transfer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized controlled trial on the comparison of the ongoing pregnancy rate in&#xD;
      frozen-thawed embryo transfer cycles with spontaneous ovulation and hCG-induced natural&#xD;
      cycles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Embryo cryopreservation is essential nowadays. It allows the usage of surplus good quality&#xD;
      embryos in frozen-thawed embryo transfer (FET) cycles which avoids embryo wastage and&#xD;
      facilitates the adoption of transferring a small number of embryos in the fresh stimulation&#xD;
      cycle so as to reduce the risk of multiple pregnancy during in vitro fertilization (IVF)&#xD;
      treatment. Elective cryopreservation of all fresh embryos is also required in special&#xD;
      circumstances where fresh transfer is undesirable, for example in cases where a high risk of&#xD;
      ovarian hyperstimulation syndrome is anticipated. Fresh transfer is not advisable when serum&#xD;
      progesterone level is elevated or hydrosalpinx is detected during ovarian stimulation.&#xD;
&#xD;
      The availability of FETs would increase the likelihood of successful pregnancy from a single&#xD;
      superovulation and oocyte retrieval cycle. It has been estimated that in modern IVF&#xD;
      programmes which incorporates embryo cryopreservation, up to 42% of all conceptions could be&#xD;
      derived from FET (Borini et al, 2008).&#xD;
&#xD;
      Although the pregnancy rate in FET is comparable with stimulated IVF cycles, the optimal&#xD;
      regimen to prepare the endometrium for implantation is not yet well proven. By a recent&#xD;
      Cochrane review, there is no evidence to prove the use of one regimen in preference to&#xD;
      another (Ghobara T 2008).&#xD;
&#xD;
      Natural cycles (NC) are considered the best regimen as it is physiological, where natural&#xD;
      conception occurs in. However, there are two most commonly employed methods to time the&#xD;
      ovulation in natural cycles. One is to use ultrasound (USG) to monitor the follicular growth&#xD;
      and endometrial thickness, with the use of human chorionic gonadotrophin (hCG) to trigger&#xD;
      ovulation in the presence of a dominant follicle around 17-18mm in diameter. Another is to&#xD;
      monitor the blood hormonal concentration to detect the luteinising hormone (LH) surge&#xD;
      associated with natural ovulation. There is scarce information in this area as only one&#xD;
      randomized controlled trial compared these two approaches. The authors aimed to recruit 240&#xD;
      subjects, but the study was prematurely terminated as significant results were resulted in&#xD;
      the first interim analysis when the sample size reached 124. The ongoing pregnancy rate was&#xD;
      31.1% in the group with spontaneous LH surge and 14.3% in the hCG-induced group (Fatemi et&#xD;
      al., 2010).&#xD;
&#xD;
      The use of natural LH surge and hCG trigger in intrauterine insemination was compared too. A&#xD;
      meta-analysis revealed a significantly higher clinical pregnancy rate in IUI cycles with&#xD;
      natural LH surge than that with hCG trigger. However, the data from randomized controlled&#xD;
      trial showed no significant difference. Also the data were contradictory when the analysis&#xD;
      confined to a specific indication of subfertility (Kosmas et al., 2007). A cochrane review in&#xD;
      2012 also suggested there was no evidence to advise that any regimen was better than another&#xD;
      (Cantineau et al., 2012).&#xD;
&#xD;
      This randomized controlled trial aims to compare the ongoing pregnancy rate of FET in&#xD;
      spontaneous NC and hCG-induced NC. The hypothesis of this trial is that the ongoing pregnancy&#xD;
      rate of FET is similar for spontaneous NC and hCG-induced NC. The advantage of hCG-induced NC&#xD;
      is likely a reduction in the duration of monitoring for timing FET when compared with&#xD;
      spontaneous NC.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ongoing pregnancy rate</measure>
    <time_frame>12 weeks after embryos transfer</time_frame>
    <description>the ongoing pregnancy rate which is defined as the number of viable pregnancies beyond 10-12 weeks gestation per transfer cycle</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Days of monitoring for timing FET</measure>
    <time_frame>4 weeks after last menstrual period</time_frame>
    <description>The number of days needed for the monitoring for the timing of FET</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endometrial thickness on day of hCG or the next day after LH surge</measure>
    <time_frame>2-3 weeks after LMP</time_frame>
    <description>The measurement of the endometrial thickness on the day of hCG or the next day after LH surge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Implantation rate</measure>
    <time_frame>4-6 weeks after embryo transfer</time_frame>
    <description>Implantation rate: number of gestational sacs per number of embryos transferred</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>pregnancy rate</measure>
    <time_frame>2-4 weeks after embryo transfer</time_frame>
    <description>number of positive pregnancy rate per transfer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical pregnancy rate</measure>
    <time_frame>6-8 weeks after embryo transfer</time_frame>
    <description>Number of pregnancy with positive fetal pulsation on scanning at 6 weeks of gestation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Miscarriage rate</measure>
    <time_frame>20 weeks after embryo transfer</time_frame>
    <description>rate of pregnancy loss &lt;20 weeks per transfer cycles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multiple pregnancy rate</measure>
    <time_frame>20 weeks after embryo transfer</time_frame>
    <description>The rate of multiple pregnancy after ET</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">300</enrollment>
  <condition>Subfertility</condition>
  <condition>Pregnancy</condition>
  <arm_group>
    <arm_group_label>Spontaneous NC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Timing by the onset of LH surge as shown daily blood monitoring of serum estradiol and LH levels</description>
  </arm_group>
  <arm_group>
    <arm_group_label>hCG induced NC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Timing by giving hCG when the dominant follicle reaches &gt;=17mm in diameter on ultrasound monitoring</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Daily monitoring of LH and E2</intervention_name>
    <description>ultrasound scanning would be carried out from 18 days before the expected period to confirm follicular growth, followed by daily blood monitoring of serum E2 and LH levels when the dominant follicle reaches 13-14mm in diameter. Ultrasound scanning can be arranged accordingly if the leading follicle remains less than 10mm in diameter. 5 ml of blood would be taken daily. LH surge is defined as the LH level being double of the average of the previous three days and higher than 20 IU/L. Ultrasound examination will be performed on the next day after the LH surge to measure the endometrial thickness. The transfer will be scheduled three or four days after the LH surge (for cleavage stage embryos) or six days after LH surge (for blastocyst transfer).</description>
    <arm_group_label>Spontaneous NC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>hCG induced natural cycle</intervention_name>
    <description>ultrasound monitoring would be started from 18 days before the expected period to monitor follicular growth, followed by USG every 2-3 days. hCG, 5,000-10,000 IU will be given when the leading follicle is &gt;/= 17 mm and the endometrium measures &gt;/=8 mm. Serum E2, LH and progesterone levels will be measured on the day of hCG. Embryo transfer would be scheduled on the fourth or fifth days after hCG injection (for cleavage stage embryos) or seventh days (for blastocyst transfer).</description>
    <arm_group_label>hCG induced NC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>ultrasound</intervention_name>
    <arm_group_label>Spontaneous NC</arm_group_label>
    <arm_group_label>hCG induced NC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age of women &lt;43 years&#xD;
&#xD;
          -  Regular menstrual cycles ranging from 21-35 days with not more than 4 days variation&#xD;
             between cycles&#xD;
&#xD;
          -  Undergoing FET in natural cycles&#xD;
&#xD;
          -  Normal uterine cavity as shown on saline sonogram performed before the IVF cycle or&#xD;
             normal uterine cavity shown on pelvic scanning during the stimulated IVF cycle&#xD;
&#xD;
          -  Endometrial thickness &gt;=8mm in both stimulated IVF and FET cycles&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  &gt;3 previous IVF cycles&#xD;
&#xD;
          -  &gt;6 embryos replaced without pregnancy&#xD;
&#xD;
          -  Irregular menstrual cycles&#xD;
&#xD;
          -  Subjects requiring clomid-induced cycles and hormonal replacement (HRT) cycles&#xD;
&#xD;
          -  History of previous FET cycles within the study period&#xD;
&#xD;
          -  Blastocyst transfer&#xD;
&#xD;
          -  Preimplantation genetic diagnosis treatment&#xD;
&#xD;
          -  Use of donor oocytes&#xD;
&#xD;
          -  Presence of hydrosalpinx not corrected surgically prior to FET&#xD;
&#xD;
          -  Recurrent miscarriage&#xD;
&#xD;
          -  Serum progesterone level on the day of LH surge or day of hCG &gt;5 nmol/L or 1.5 pg/L&#xD;
             (these patients will be retrospectively excluded)&#xD;
&#xD;
          -  Refusal to join the study&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>43 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vivian CY Lee, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen Mary Hospital / University of Hong Kong.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University</name>
      <address>
        <city>Guangzhou</city>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Mary Hospital</name>
      <address>
        <city>Hong Kong</city>
        <zip>852</zip>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>December 2015</verification_date>
  <study_first_submitted>July 20, 2014</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>December 10, 2015</last_update_submitted>
  <last_update_submitted_qc>December 10, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 11, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Frozen-thawed embryo transfer</keyword>
  <keyword>natural cycle</keyword>
  <keyword>spontaneous ovulation</keyword>
  <keyword>hCG induced natural cycles</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02197208
org study id: HKU-VL-NChCGFET
nct id: NCT02197208
lead sponsor: 
has dmc: No
This is a randomized controlled trial on the comparison of the ongoing pregnancy rate in
      frozen-thawed embryo transfer cycles with spontaneous ovulation and hCG-induced natural
      cycles.
Embryo cryopreservation is essential nowadays. It allows the usage of surplus good quality
      embryos in frozen-thawed embryo transfer (FET) cycles which avoids embryo wastage and
      facilitates the adoption of transferring a small number of embryos in the fresh stimulation
      cycle so as to reduce the risk of multiple pregnancy during in vitro fertilization (IVF)
      treatment. Elective cryopreservation of all fresh embryos is also required in special
      circumstances where fresh transfer is undesirable, for example in cases where a high risk of
      ovarian hyperstimulation syndrome is anticipated. Fresh transfer is not advisable when serum
      progesterone level is elevated or hydrosalpinx is detected during ovarian stimulation.

      The availability of FETs would increase the likelihood of successful pregnancy from a single
      superovulation and oocyte retrieval cycle. It has been estimated that in modern IVF
      programmes which incorporates embryo cryopreservation, up to 42% of all conceptions could be
      derived from FET (Borini et al, 2008).

      Although the pregnancy rate in FET is comparable with stimulated IVF cycles, the optimal
      regimen to prepare the endometrium for implantation is not yet well proven. By a recent
      Cochrane review, there is no evidence to prove the use of one regimen in preference to
      another (Ghobara T 2008).

      Natural cycles (NC) are considered the best regimen as it is physiological, where natural
      conception occurs in. However, there are two most commonly employed methods to time the
      ovulation in natural cycles. One is to use ultrasound (USG) to monitor the follicular growth
      and endometrial thickness, with the use of human chorionic gonadotrophin (hCG) to trigger
      ovulation in the presence of a dominant follicle around 17-18mm in diameter. Another is to
      monitor the blood hormonal concentration to detect the luteinising hormone (LH) surge
      associated with natural ovulation. There is scarce information in this area as only one
      randomized controlled trial compared these two approaches. The authors aimed to recruit 240
      subjects, but the study was prematurely terminated as significant results were resulted in
      the first interim analysis when the sample size reached 124. The ongoing pregnancy rate was
      31.1% in the group with spontaneous LH surge and 14.3% in the hCG-induced group (Fatemi et
      al., 2010).

      The use of natural LH surge and hCG trigger in intrauterine insemination was compared too. A
      meta-analysis revealed a significantly higher clinical pregnancy rate in IUI cycles with
      natural LH surge than that with hCG trigger. However, the data from randomized controlled
      trial showed no significant difference. Also the data were contradictory when the analysis
      confined to a specific indication of subfertility (Kosmas et al., 2007). A cochrane review in
      2012 also suggested there was no evidence to advise that any regimen was better than another
      (Cantineau et al., 2012).

      This randomized controlled trial aims to compare the ongoing pregnancy rate of FET in
      spontaneous NC and hCG-induced NC. The hypothesis of this trial is that the ongoing pregnancy
      rate of FET is similar for spontaneous NC and hCG-induced NC. The advantage of hCG-induced NC
      is likely a reduction in the duration of monitoring for timing FET when compared with
      spontaneous NC.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: ongoing pregnancy rate
time frame: 12 weeks after embryos transfer
description: the ongoing pregnancy rate which is defined as the number of viable pregnancies beyond 10-12 weeks gestation per transfer cycle
measure: Days of monitoring for timing FET
time frame: 4 weeks after last menstrual period
description: The number of days needed for the monitoring for the timing of FET
measure: Endometrial thickness on day of hCG or the next day after LH surge
time frame: 2-3 weeks after LMP
description: The measurement of the endometrial thickness on the day of hCG or the next day after LH surge
measure: Implantation rate
time frame: 4-6 weeks after embryo transfer
description: Implantation rate: number of gestational sacs per number of embryos transferred
measure: pregnancy rate
time frame: 2-4 weeks after embryo transfer
description: number of positive pregnancy rate per transfer
measure: Clinical pregnancy rate
time frame: 6-8 weeks after embryo transfer
description: Number of pregnancy with positive fetal pulsation on scanning at 6 weeks of gestation.
measure: Miscarriage rate
time frame: 20 weeks after embryo transfer
description: rate of pregnancy loss <20 weeks per transfer cycles
measure: Multiple pregnancy rate
time frame: 20 weeks after embryo transfer
description: The rate of multiple pregnancy after ET
arm group label: Spontaneous NC
arm group type: Active Comparator
description: Timing by the onset of LH surge as shown daily blood monitoring of serum estradiol and LH levels
arm group label: hCG induced NC
arm group type: Experimental
description: Timing by giving hCG when the dominant follicle reaches >=17mm in diameter on ultrasound monitoring
intervention type: Procedure
intervention name: Daily monitoring of LH and E2
description: ultrasound scanning would be carried out from 18 days before the expected period to confirm follicular growth, followed by daily blood monitoring of serum E2 and LH levels when the dominant follicle reaches 13-14mm in diameter. Ultrasound scanning can be arranged accordingly if the leading follicle remains less than 10mm in diameter. 5 ml of blood would be taken daily. LH surge is defined as the LH level being double of the average of the previous three days and higher than 20 IU/L. Ultrasound examination will be performed on the next day after the LH surge to measure the endometrial thickness. The transfer will be scheduled three or four days after the LH surge (for cleavage stage embryos) or six days after LH surge (for blastocyst transfer).
arm group label: Spontaneous NC
intervention type: Procedure
intervention name: hCG induced natural cycle
description: ultrasound monitoring would be started from 18 days before the expected period to monitor follicular growth, followed by USG every 2-3 days. hCG, 5,000-10,000 IU will be given when the leading follicle is >/= 17 mm and the endometrium measures >/=8 mm. Serum E2, LH and progesterone levels will be measured on the day of hCG. Embryo transfer would be scheduled on the fourth or fifth days after hCG injection (for cleavage stage embryos) or seventh days (for blastocyst transfer).
arm group label: hCG induced NC
intervention type: Device
intervention name: ultrasound
arm group label: Spontaneous NC
arm group label: hCG induced NC
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 43 Years
healthy volunteers: No
last name: Vivian CY Lee, MBBS
role: Principal Investigator
affiliation: Queen Mary Hospital / University of Hong Kong.
facility: 
facility: 
country: China
country: Hong Kong
responsible party type: Sponsor
mesh term: Infertility