<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/NCT01694641</url>
  </required_header>
  <id_info>
    <org_study_id>TL-SET</org_study_id>
    <nct_id>NCT01694641</nct_id>
  </id_info>
  <brief_title>Embryo Selection by Time Lapse Monitoring for Single Embryo Transfer (&quot;SET&quot;)</brief_title>
  <official_title>Time Lapse Embryo Monitoring Versus Standard Embryo Monitoring for Selection for Single Blastocyst Transfer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kaali Institute IVF Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Forgacs Intezet Kft.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kaali Institute IVF Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A multiple pregnancy is an undesired outcome of assisted reproduction. Current embryo&#xD;
      selection technologies are inefficient in identifying the embryo with the highest&#xD;
      implantation potential. Time lapse (TL) embryo monitoring provides additional information&#xD;
      about embryo development and therefore may aid embryo selection. The investigators aim is to&#xD;
      study whether TL monitoring is superior to traditional embryo observation when a single&#xD;
      blastocyst is selected for transfer (ET).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Prospective RCT comparing two embryo selection methods (TL algorithm vs standard morphology&#xD;
      based) for SET. Infertile couples scheduled to undergo IVF or intracytoplasmic sperm&#xD;
      injection (ICSI) and met the inclusion-exclusion criteria were enrolled. Randomization to&#xD;
      Groups 1 or 2 was performed prior to the start of stimulation. Randomization was carried out&#xD;
      in blocks of two, by selecting TL or control assignments from closed, opaque envelopes.&#xD;
      Patients were blinded to allocation. Standard luteal long (Suprefact, Sanofi Aventis) and&#xD;
      flexible gonadotropin-releasing hormone (GnRH) antagonist (Cetrotide, Merck Serono) protocols&#xD;
      and recombinant FSH(Gonal-f, Merck Serono) were used for stimulation. Embryos were placed&#xD;
      into individual wells of a 9-well Primo Vision culture dish (Vitrolife AB, Sweden) on day 1&#xD;
      of culture, after checking for fertilization. Out of incubator handling was same in the&#xD;
      groups;: day 1: fertilization check; day 3: culture medium change; day 5: transfer. On days 3&#xD;
      and 5, the embryos were morphologically assessed under an inverted microscope. Embryos in TL&#xD;
      group were imaged at 10-minute intervals. The Primo Vision software was used for the analysis&#xD;
      of TL images. The first appearance of the 2, 3, 4 and 5 cell stages (t2, t3, t4 and t5,&#xD;
      respectively) were annotated. Timing of the kinetic events was calculated from the time of&#xD;
      the fertilization (t0). (for TL parameter definitions see supplement) There were no&#xD;
      adjustments of the kinetic events depending on the method of fertilization. Blastocyst&#xD;
      morphology was assessed using the Gardner score. Fragmentation was assessed when it reached&#xD;
      the highest grade in the sequence of the TL images. Cytoplasmic abnormalities (vacuoles) were&#xD;
      also recorded. The TL reference ranges were defined and fixed before the start of the&#xD;
      recruitment, Embryos in the control group were selected based on actual morphology. The&#xD;
      primary end point was pregnancy rate (PR; rise in β human chorionic gonadotropin [hCG]) per&#xD;
      patient based on intention to treat. Further endpoints were ongoing pregnancy rate (OPR;&#xD;
      pregnancy that progresses beyond 12 weeks gestation), pregnancy loss (loss of pregnancy after&#xD;
      an initial rise in βhCG up to 12 weeks gestation), live birth rate (LBR), gestational age&#xD;
      (GA) at delivery and birth weight of the offspring.&#xD;
&#xD;
      When calculating sample size we assumed a 13% increase in pregnancy rate from an expected 42%&#xD;
      to 55%. We planned to run the study with 1:1 ratio between the groups and do one interim&#xD;
      monitoring with 0.1 information fraction. Using two-sided test and Pocock boundaries for&#xD;
      estimation, 282 patients in each group was calculated (power of 80%, p of 5%). Assuming a 10%&#xD;
      dropout rate we needed to enroll 620 patients.&#xD;
&#xD;
      Based on the results of the interim monitoring (61 cases in two arms) the pregnancy rate in&#xD;
      the TL group was 15% higher than in controls (58.3% vs. 44.0%). Assuming 58% pregnancy rate&#xD;
      in the TL group and 44% in controls, a sample size of 210 per group, was needed to achieve a&#xD;
      power of 80%, at a significance level of 5%. Assuming 10% dropout rate a total sample of size&#xD;
      of 462 patients were needed.&#xD;
&#xD;
      The groups were compared based on maximum likelihood estimation principles. We hypothesized&#xD;
      and then showed that the patients in the treatment arms were similar at baseline, on average,&#xD;
      with respect to variables that might influence outcome. Chi-square tests, likelihood-ratio&#xD;
      tests and exact tests were used for the analysis of categorical variables. Continuous&#xD;
      variables were compared using independent group t-test and. analysis of variance. Normality&#xD;
      and homogeneity of variances were examined.&#xD;
&#xD;
      At the interim analysis of the trial the primary endpoint (pregnancy rate) between TL and&#xD;
      control group was compared with Fisher's exact test. After closing the trial the primary&#xD;
      endpoint (pregnancy rate) among the groups was compared with Fisher's exact test. Bonferroni&#xD;
      correction was used for the p-value at the end of the trial. All other p-values were&#xD;
      considered exploratory in nature. During the analyses the extent and distribution of missing&#xD;
      data were also examined. No imputations were made for missing data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    A general TL algorithm with higher predicting power became available in 2015 (Petersen et al.)&#xD;
    and speed of recruitment was slower than expected.&#xD;
  </why_stopped>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">April 2015</completion_date>
  <primary_completion_date type="Actual">April 2015</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>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pregnancy Rate</measure>
    <time_frame>12-14 days after transfer</time_frame>
    <description>rise in beta HCG 12-14 days after transfer</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Live Birth</measure>
    <time_frame>delivery after 24 weeks</time_frame>
    <description>live birth after 24 weeks gestation</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Time Lapse Score</measure>
    <time_frame>the time lapse score is assessed on the day of embryo transfer (day 5 after the egg retrieval)</time_frame>
    <description>a score based on 8 observations by time lapse monitoring</description>
  </other_outcome>
  <other_outcome>
    <measure>Perinatal Outcome</measure>
    <time_frame>perinatal outcome assessed after delivery</time_frame>
    <description>gestational age at delivery, birth weight,</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">161</enrollment>
  <condition>Clinical Pregnancy After Single Embryo Transfer</condition>
  <arm_group>
    <arm_group_label>time-lapse morphokinetic evaluation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos in a petri dish that allows individual assessment (Primo Vision Dish) are placed onto an automated time-lapse equipment in an incubator. The time-lapse equipment performs imaging in 10 minutes intervals. The software is presenting the up-to-date images and allows the operator to assess the &quot;time-lapse&quot; movie of the developmental history of the embryos to perform annotations and apply evaluation/selection algorithm. This morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection, which actually describes the intervention.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>standard embryo monitoring</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>time-lapse morphokinetic evaluation</intervention_name>
    <description>embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
    <arm_group_label>time-lapse morphokinetic evaluation</arm_group_label>
    <other_name>time-lapse morphokintic score</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 36 yrs&#xD;
&#xD;
          -  baseline FSH &lt;10 IU/l&#xD;
&#xD;
          -  regular 25-35 day cycles&#xD;
&#xD;
          -  less than 2 previous failed IVF cycles&#xD;
&#xD;
          -  intact uterus&#xD;
&#xD;
          -  an indication for IVF&#xD;
&#xD;
          -  BMI &lt;18- &lt;30 kg/m2&#xD;
&#xD;
          -  acceptance of single embryo transfer&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  PCOS&#xD;
&#xD;
          -  Sperm obtained by surgical extraction&#xD;
&#xD;
          -  chromosome abnormality&#xD;
&#xD;
          -  Presence of hydrosalpinx&#xD;
&#xD;
          -  stage III/IV endometriosis&#xD;
&#xD;
          -  Less than 3 good quality day 3 embryos&#xD;
&#xD;
          -  only one good quality day 5 embryos&#xD;
&#xD;
          -  lack of consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>36 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Kovacs, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kaali Inst. IVF Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kaali Institute IVF Center</name>
      <address>
        <city>Budapest</city>
        <zip>1125</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Forgacs Intezet</name>
      <address>
        <city>Budapest</city>
        <zip>1205</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hungary</country>
  </location_countries>
  <reference>
    <citation>Pribenszky C, Matyas S, Kovacs P, Losonczi E, Zadori J, Vajta G. Pregnancy achieved by transfer of a single blastocyst selected by time-lapse monitoring. Reprod Biomed Online. 2010 Oct;21(4):533-6. doi: 10.1016/j.rbmo.2010.04.015. Epub 2010 Apr 24.</citation>
    <PMID>20638906</PMID>
  </reference>
  <reference>
    <citation>Pribenszky C, Losonczi E, Molnar M, Lang Z, Matyas S, Rajczy K, Molnar K, Kovacs P, Nagy P, Conceicao J, Vajta G. Prediction of in-vitro developmental competence of early cleavage-stage mouse embryos with compact time-lapse equipment. Reprod Biomed Online. 2010 Mar;20(3):371-9. doi: 10.1016/j.rbmo.2009.12.007. Epub 2010 Jan 25.</citation>
    <PMID>20089456</PMID>
  </reference>
  <reference>
    <citation>Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011 Oct;26(10):2658-71. doi: 10.1093/humrep/der256. Epub 2011 Aug 9.</citation>
    <PMID>21828117</PMID>
  </reference>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>September 21, 2012</study_first_submitted>
  <study_first_submitted_qc>September 25, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 27, 2012</study_first_posted>
  <results_first_submitted>November 2, 2016</results_first_submitted>
  <results_first_submitted_qc>November 2, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">December 29, 2016</results_first_posted>
  <last_update_submitted>January 16, 2018</last_update_submitted>
  <last_update_submitted_qc>January 16, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>time lapse monitoring</keyword>
  <keyword>blastocyst</keyword>
  <keyword>single embryo transfer</keyword>
  <keyword>clinical pregnancy</keyword>
  <keyword>implantation rate</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Time Lapse Embryo Observation</title>
          <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos are placed in an incubator that is hooked up to a monitor that allows continuous embryo observation. A morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection.&#xD;
time-lapse morphokinetic evaluation: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
        </group>
        <group group_id="P2">
          <title>Standard Embryo Monitoring</title>
          <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="80"/>
                <participants group_id="P2" count="81"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="68"/>
                <participants group_id="P2" count="71"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>161 patients were randomized. Each patient participated only once in the RCT.</population>
      <group_list>
        <group group_id="B1">
          <title>Time Lapse Embryo Observation</title>
          <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos are placed in an incubator that is hooked up to a monitor that allows continuous embryo observation. A morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection.&#xD;
time-lapse morphokinetic evaluation: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
        </group>
        <group group_id="B2">
          <title>Standard Embryo Monitoring</title>
          <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="80"/>
            <count group_id="B2" value="81"/>
            <count group_id="B3" value="161"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="80"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="161"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31.2" spread="2.7"/>
                    <measurement group_id="B2" value="32.1" spread="2.5"/>
                    <measurement group_id="B3" value="31.7" spread="2.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="80"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="161"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Hungary</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="80"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="161"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pregnancy Rate</title>
        <description>rise in beta HCG 12-14 days after transfer</description>
        <time_frame>12-14 days after transfer</time_frame>
        <population>All patients randomized are analyszs (intention to treat analysis).</population>
        <group_list>
          <group group_id="O1">
            <title>Time Lapse Embryo Observation</title>
            <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos are placed in an incubator that is hooked up to a monitor that allows continuous embryo observation. A morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection.&#xD;
time-lapse morphokinetic evaluation: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
          </group>
          <group group_id="O2">
            <title>Standard Embryo Monitoring</title>
            <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
          </group>
        </group_list>
        <measure>
          <title>Pregnancy Rate</title>
          <description>rise in beta HCG 12-14 days after transfer</description>
          <population>All patients randomized are analyszs (intention to treat analysis).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="80"/>
                <count group_id="O2" value="81"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                    <measurement group_id="O2" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Live Birth</title>
        <description>live birth after 24 weeks gestation</description>
        <time_frame>delivery after 24 weeks</time_frame>
        <population>All patients randomzed regardless whether completed the study or not according to their assignment (intention to treat population).</population>
        <group_list>
          <group group_id="O1">
            <title>Time-lapse Morphokinetic Evaluation</title>
            <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos in a petri dish that allows individual assessment (Primo Vision Dish) are placed onto an automated time-lapse equipment in an incubator. The time-lapse equipment performs imaging in 10 minutes intervals. The software is presenting the up-to-date images and allows the operator to assess the &quot;time-lapse&quot; movie of the developmental history of the embryos to perform annotations and apply evaluation/selection algorithm. This morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection, which actually describes the intervention.&#xD;
time-lapse morphokinetic evaluation: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
          </group>
          <group group_id="O2">
            <title>Standard Embryo Monitoring</title>
            <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
          </group>
        </group_list>
        <measure>
          <title>Live Birth</title>
          <description>live birth after 24 weeks gestation</description>
          <population>All patients randomzed regardless whether completed the study or not according to their assignment (intention to treat population).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="80"/>
                <count group_id="O2" value="81"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                    <measurement group_id="O2" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Time Lapse Score</title>
        <description>a score based on 8 observations by time lapse monitoring</description>
        <time_frame>the time lapse score is assessed on the day of embryo transfer (day 5 after the egg retrieval)</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Perinatal Outcome</title>
        <description>gestational age at delivery, birth weight,</description>
        <time_frame>perinatal outcome assessed after delivery</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Time Lapse Embryo Observation</title>
          <description>Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos are placed in an incubator that is hooked up to a monitor that allows continuous embryo observation. A morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection.&#xD;
time-lapse morphokinetic evaluation: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse</description>
        </group>
        <group group_id="E2">
          <title>Standard Embryo Monitoring</title>
          <description>Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="81"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="81"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The downside of the study demographics is that we limited the study population to good prognosis cases therefore the conclusions can only be applied to similar patients. Stopped the study before meeting calculated sample size.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Peter Kovacs</name_or_title>
      <organization>Kaali Inst. IVF Center</organization>
      <phone>36-1-202-2802</phone>
      <email>peterkovacs1970@hotmail.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01694641
org study id: TL-SET
nct id: NCT01694641
lead sponsor: 
collaborator: 
has dmc: Yes
A multiple pregnancy is an undesired outcome of assisted reproduction. Current embryo
      selection technologies are inefficient in identifying the embryo with the highest
      implantation potential. Time lapse (TL) embryo monitoring provides additional information
      about embryo development and therefore may aid embryo selection. The investigators aim is to
      study whether TL monitoring is superior to traditional embryo observation when a single
      blastocyst is selected for transfer (ET).
Prospective RCT comparing two embryo selection methods (TL algorithm vs standard morphology
      based) for SET. Infertile couples scheduled to undergo IVF or intracytoplasmic sperm
      injection (ICSI) and met the inclusion-exclusion criteria were enrolled. Randomization to
      Groups 1 or 2 was performed prior to the start of stimulation. Randomization was carried out
      in blocks of two, by selecting TL or control assignments from closed, opaque envelopes.
      Patients were blinded to allocation. Standard luteal long (Suprefact, Sanofi Aventis) and
      flexible gonadotropin-releasing hormone (GnRH) antagonist (Cetrotide, Merck Serono) protocols
      and recombinant FSH(Gonal-f, Merck Serono) were used for stimulation. Embryos were placed
      into individual wells of a 9-well Primo Vision culture dish (Vitrolife AB, Sweden) on day 1
      of culture, after checking for fertilization. Out of incubator handling was same in the
      groups;: day 1: fertilization check; day 3: culture medium change; day 5: transfer. On days 3
      and 5, the embryos were morphologically assessed under an inverted microscope. Embryos in TL
      group were imaged at 10-minute intervals. The Primo Vision software was used for the analysis
      of TL images. The first appearance of the 2, 3, 4 and 5 cell stages (t2, t3, t4 and t5,
      respectively) were annotated. Timing of the kinetic events was calculated from the time of
      the fertilization (t0). (for TL parameter definitions see supplement) There were no
      adjustments of the kinetic events depending on the method of fertilization. Blastocyst
      morphology was assessed using the Gardner score. Fragmentation was assessed when it reached
      the highest grade in the sequence of the TL images. Cytoplasmic abnormalities (vacuoles) were
      also recorded. The TL reference ranges were defined and fixed before the start of the
      recruitment, Embryos in the control group were selected based on actual morphology. The
      primary end point was pregnancy rate (PR; rise in β human chorionic gonadotropin [hCG]) per
      patient based on intention to treat. Further endpoints were ongoing pregnancy rate (OPR;
      pregnancy that progresses beyond 12 weeks gestation), pregnancy loss (loss of pregnancy after
      an initial rise in βhCG up to 12 weeks gestation), live birth rate (LBR), gestational age
      (GA) at delivery and birth weight of the offspring.

      When calculating sample size we assumed a 13% increase in pregnancy rate from an expected 42%
      to 55%. We planned to run the study with 1:1 ratio between the groups and do one interim
      monitoring with 0.1 information fraction. Using two-sided test and Pocock boundaries for
      estimation, 282 patients in each group was calculated (power of 80%, p of 5%). Assuming a 10%
      dropout rate we needed to enroll 620 patients.

      Based on the results of the interim monitoring (61 cases in two arms) the pregnancy rate in
      the TL group was 15% higher than in controls (58.3% vs. 44.0%). Assuming 58% pregnancy rate
      in the TL group and 44% in controls, a sample size of 210 per group, was needed to achieve a
      power of 80%, at a significance level of 5%. Assuming 10% dropout rate a total sample of size
      of 462 patients were needed.

      The groups were compared based on maximum likelihood estimation principles. We hypothesized
      and then showed that the patients in the treatment arms were similar at baseline, on average,
      with respect to variables that might influence outcome. Chi-square tests, likelihood-ratio
      tests and exact tests were used for the analysis of categorical variables. Continuous
      variables were compared using independent group t-test and. analysis of variance. Normality
      and homogeneity of variances were examined.

      At the interim analysis of the trial the primary endpoint (pregnancy rate) between TL and
      control group was compared with Fisher's exact test. After closing the trial the primary
      endpoint (pregnancy rate) among the groups was compared with Fisher's exact test. Bonferroni
      correction was used for the p-value at the end of the trial. All other p-values were
      considered exploratory in nature. During the analyses the extent and distribution of missing
      data were also examined. No imputations were made for missing data.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Single (Participant)
measure: Pregnancy Rate
time frame: 12-14 days after transfer
description: rise in beta HCG 12-14 days after transfer
measure: Live Birth
time frame: delivery after 24 weeks
description: live birth after 24 weeks gestation
measure: Time Lapse Score
time frame: the time lapse score is assessed on the day of embryo transfer (day 5 after the egg retrieval)
description: a score based on 8 observations by time lapse monitoring
measure: Perinatal Outcome
time frame: perinatal outcome assessed after delivery
description: gestational age at delivery, birth weight,
arm group label: time-lapse morphokinetic evaluation
arm group type: Experimental
description: Embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse: upon fertilization embryos in a petri dish that allows individual assessment (Primo Vision Dish) are placed onto an automated time-lapse equipment in an incubator. The time-lapse equipment performs imaging in 10 minutes intervals. The software is presenting the up-to-date images and allows the operator to assess the "time-lapse" movie of the developmental history of the embryos to perform annotations and apply evaluation/selection algorithm. This morpho-kinetic TL algorithm (made up of standard moprhology as seen on time lapse and kinetci scores) is used for embryo selection, which actually describes the intervention.
arm group label: standard embryo monitoring
arm group type: No Intervention
description: Upon fertilization embryos are observed once on days 1-3-5 by the embryologist to check for development. The single embryo for transfer is selected based on actual morphology as seen under light microscope.
intervention type: Other
intervention name: time-lapse morphokinetic evaluation
description: embryo selection for transfer based on a combind score made up of scores for kinetic parameters and standard morphology as seen on time-lapse
arm group label: time-lapse morphokinetic evaluation
other name: time-lapse morphokintic score
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 36 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Peter Kovacs, MD
role: Principal Investigator
affiliation: Kaali Inst. IVF Center
facility: 
facility: 
country: Hungary
citation: Pribenszky C, Matyas S, Kovacs P, Losonczi E, Zadori J, Vajta G. Pregnancy achieved by transfer of a single blastocyst selected by time-lapse monitoring. Reprod Biomed Online. 2010 Oct;21(4):533-6. doi: 10.1016/j.rbmo.2010.04.015. Epub 2010 Apr 24.
PMID: 20638906
citation: Pribenszky C, Losonczi E, Molnar M, Lang Z, Matyas S, Rajczy K, Molnar K, Kovacs P, Nagy P, Conceicao J, Vajta G. Prediction of in-vitro developmental competence of early cleavage-stage mouse embryos with compact time-lapse equipment. Reprod Biomed Online. 2010 Mar;20(3):371-9. doi: 10.1016/j.rbmo.2009.12.007. Epub 2010 Jan 25.
PMID: 20089456
citation: Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011 Oct;26(10):2658-71. doi: 10.1093/humrep/der256. Epub 2011 Aug 9.
PMID: 21828117
responsible party type: Sponsor
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The downside of the study demographics is that we limited the study population to good prognosis cases therefore the conclusions can only be applied to similar patients. Stopped the study before meeting calculated sample size.
point of contact: 