<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/NCT02999958</url>
  </required_header>
  <id_info>
    <org_study_id>AOX-G_Series-2016</org_study_id>
    <nct_id>NCT02999958</nct_id>
  </id_info>
  <brief_title>Adding Antioxidants Into Human Sequential Culture Media System</brief_title>
  <acronym>Antioxidants</acronym>
  <official_title>Comparison of G-Series Media System With Antioxidants Versus Standard G-Series Media System</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vitrolife</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vitrolife</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Upon collection, human oocytes are fertilized and culture up to the blastocyst stage,&#xD;
      followed by transfer and / or cryopreservation. Culture media systems have been developed&#xD;
      that support each step of this process. Although these culture media systems try to mimic the&#xD;
      natural environment, several components of the in-vivo situation are not present in today´s&#xD;
      media. One such component is anti-oxidants that may protect embryos against damage by&#xD;
      reactive oxygen species.&#xD;
&#xD;
      This investigation aims to compare blastocyst development using 2 different types of culture&#xD;
      media systems, one of which contains antioxidants. Patients having at least eight oocytes and&#xD;
      meeting other inclusion criteria can be included in this investigation.&#xD;
&#xD;
      It is a prospective randomized multicenter study randomly dividing oocytes into two groups&#xD;
      and assessing parameters of embryo development from fertilization up to blastocyst formation&#xD;
      until day six. Embryos with acceptable developmental characteristics can be transferred into&#xD;
      the uterus or cryopreserved for later use.&#xD;
&#xD;
      The investigation is designed as a superiority study comparing utilization rate of&#xD;
      blastocysts per normally fertilized oocyte using both media systems. In patients receiving&#xD;
      embryo transfer in the fresh treatment cycle, detection of clinical pregnancy by ultrasound&#xD;
      after 12 weeks gestation is the final endpoint of the investigation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study objective:&#xD;
&#xD;
      Study comparing blastocyst development on the same cohort of oocytes using two different&#xD;
      media systems, sequential G-Series media versus sequential G-Series media supplemented with&#xD;
      antioxidants.&#xD;
&#xD;
      Primary endpoint:&#xD;
&#xD;
      Percentage of good quality blastocysts (GQB) per fertilized oocyte on day 5.&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
      Embryo development day 3, 5 and 6 Embryo quality day 3, 5 and 6 Total blastocyst formation&#xD;
      (day 5 and day 6) Utilization rate (embryos available for transfer and cryopreservation)&#xD;
      Biochemical pregnancy rate Implantation rate Clinical pregnancy rate&#xD;
&#xD;
      Setup:&#xD;
&#xD;
      Prospective oocyte sibling, superiority study&#xD;
&#xD;
      MATERIALS AND METHODS&#xD;
&#xD;
      Intervention:&#xD;
&#xD;
      New type of embryo culture media used for in vitro culture of human IVF embryos.&#xD;
&#xD;
      Power analysis:&#xD;
&#xD;
      The planning and the power analysis was made together with a statistician, Nils-Gunnar&#xD;
      Pehrsson.&#xD;
&#xD;
      From retrospective data using simulation, the intra individual SD for the difference in % GQB&#xD;
      between the two media strategies was estimated to 32%. In order to find a difference in 8% in&#xD;
      GQB between the two media with power 80% with paired T-test 128 couples will be needed.&#xD;
&#xD;
      Randomization:&#xD;
&#xD;
      Couples will be enrolled in the study at oocyte pick up (day 0). A minimum of 8&#xD;
      cumulus-oocyte-complexes is required for participation.&#xD;
&#xD;
      Stratified randomization of the oocytes by couple will be performed. For each couple the&#xD;
      oocytes will be numbered.&#xD;
&#xD;
      These oocytes for each couple will then be block (by two) randomized to the two media types;&#xD;
      A (Traditional G-Series media system = Control) and B (G-Series media system with antioxidant&#xD;
      = intervention). In both groups traditional culture will be performed. Allocation will be&#xD;
      performed in a 1:1 ratio according to a unique randomization list for each couple.&#xD;
&#xD;
      Blinding:&#xD;
&#xD;
      To minimize possible bias for the primary outcome (GQB D5) the embryologist performing the&#xD;
      morphological evaluation on day 5/6 will not know which group the embryos belong to.&#xD;
&#xD;
      Both the physician and the couple will be blinded in respect to from which group an embryo&#xD;
      was selected for transfer.&#xD;
&#xD;
      IVF treatment procedure:&#xD;
&#xD;
      A traditional IVF treatment will be performed including ovarian stimulation and oocyte&#xD;
      pick-up using the standard methods at the clinics.&#xD;
&#xD;
      Embryo assessment on day 3 according to Alpha/ESHRE consensus criteria and on day 5 according&#xD;
      to Gardner score.&#xD;
&#xD;
      Morphological scoring Embryo development and morphology on day 3 will be scored based on the&#xD;
      Alpha/ESHRE Consensus criteria. Blastocyst development and morphology will be scored&#xD;
      according to a published scoring system for blastocysts and will be documented with&#xD;
      individual photos of each blastocyst. Embryo &amp; Blastocyst scoring will be performed under an&#xD;
      inverted microscope on day 3 and days 5 &amp; 6, respectively. Blastocysts that have a score&#xD;
      equal or higher than 3BB are considered as GQB.&#xD;
&#xD;
      DOCUMENTATION All patients participating in the study will be documented on a computerized&#xD;
      CRF. This document will contain study-specific relevant clinical and laboratory data from the&#xD;
      specific IVF cycle.&#xD;
&#xD;
      STATISTICAL ANALYSIS Both an Intention-to-Treat (ITT) population and a Per Protocol (PP)&#xD;
      population will be defined. Primary efficacy variable in this superiority study will be&#xD;
      difference in % GQB between the two media types for each couple. Primary statistical analysis&#xD;
      will be two-sided paired T-test regarding the mean of difference in % GQB between Standard&#xD;
      sequential culture media and Antioxidant media on the ITT population. A two sided 95%&#xD;
      confidence interval for the mean difference in % GOB between the two media will be&#xD;
      calculated. All significance tests will be two-sided and conducted at the 5% significance&#xD;
      level.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Actual">May 2018</completion_date>
  <primary_completion_date type="Actual">May 2018</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>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of good quality blastocyst (GQB) per fertilized oocyte on day 5</measure>
    <time_frame>7 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Embryo development on day 3, 5 &amp; 6</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Embryo quality on day 3, 5 &amp; 6</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total blastocyst rate</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blastocyst utilization rate per fertilized oocyte</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical pregnancy rate</measure>
    <time_frame>8 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical pregnancy rate</measure>
    <time_frame>9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Implantation rate</measure>
    <time_frame>8 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">128</enrollment>
  <condition>Culture Media</condition>
  <condition>Blastocyst</condition>
  <condition>Antioxidants</condition>
  <condition>Embryo</condition>
  <condition>Human</condition>
  <condition>Oxygen</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Sequential culture media without addition of antioxidants</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Sequential culture media with the addition of antioxidants</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Antioxidants</intervention_name>
    <description>In the Treatment Arm, the G-Series culture media system will be used with antioxidants</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Acetyl-L-carnitine (ALC)</other_name>
    <other_name>N-acetyl-L-cysteine (NAC)</other_name>
    <other_name>alpha-Lipoic acid (ALA)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Minimum eight cumulus-oocyte-complexes.&#xD;
&#xD;
          -  Couples with female, male or unexplained infertility intending to undergo IVF&#xD;
&#xD;
          -  The couple should have received verbal and written information/consent about the&#xD;
             study.&#xD;
&#xD;
          -  Blastocyst culture and embryo transfer is decided.&#xD;
&#xD;
          -  If the couple fulfills the criteria above their consent to participate must be given&#xD;
             and documented in the couple's medical journal.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous participation in the study&#xD;
&#xD;
          -  PGD/PGS&#xD;
&#xD;
          -  Surgically retrieved sperm cells (TESA / TESE)&#xD;
&#xD;
          -  If split IVF is needed&#xD;
&#xD;
          -  Less than eight cumulus-oocyte-complexes&#xD;
&#xD;
          -  More than thirty cumulus-oocyte-complexes&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>A Yoshida, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kiba Park Clinic, Tokyo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kuramoto Women´s Clinic</name>
      <address>
        <city>Fukuoka</city>
        <zip>8120013</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kiba Park Clinic</name>
      <address>
        <city>Tokyo</city>
        <zip>135-0042</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <results_reference>
    <citation>Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000 Jun;73(6):1155-8. doi: 10.1016/s0015-0282(00)00518-5.</citation>
    <PMID>10856474</PMID>
  </results_reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>December 16, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 21, 2016</study_first_posted>
  <last_update_submitted>November 30, 2018</last_update_submitted>
  <last_update_submitted_qc>November 30, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thioctic Acid</mesh_term>
    <mesh_term>Acetylcarnitine</mesh_term>
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>Antioxidants</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>January 8, 2021</submitted>
    <returned>January 29, 2021</returned>
    <submitted>February 24, 2021</submitted>
    <returned>March 19, 2021</returned>
  </pending_results>
  <!-- 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/NCT02999958
org study id: AOX-G_Series-2016
nct id: NCT02999958
lead sponsor: 
has dmc: Yes
Upon collection, human oocytes are fertilized and culture up to the blastocyst stage,
      followed by transfer and / or cryopreservation. Culture media systems have been developed
      that support each step of this process. Although these culture media systems try to mimic the
      natural environment, several components of the in-vivo situation are not present in today´s
      media. One such component is anti-oxidants that may protect embryos against damage by
      reactive oxygen species.

      This investigation aims to compare blastocyst development using 2 different types of culture
      media systems, one of which contains antioxidants. Patients having at least eight oocytes and
      meeting other inclusion criteria can be included in this investigation.

      It is a prospective randomized multicenter study randomly dividing oocytes into two groups
      and assessing parameters of embryo development from fertilization up to blastocyst formation
      until day six. Embryos with acceptable developmental characteristics can be transferred into
      the uterus or cryopreserved for later use.

      The investigation is designed as a superiority study comparing utilization rate of
      blastocysts per normally fertilized oocyte using both media systems. In patients receiving
      embryo transfer in the fresh treatment cycle, detection of clinical pregnancy by ultrasound
      after 12 weeks gestation is the final endpoint of the investigation.
Study objective:

      Study comparing blastocyst development on the same cohort of oocytes using two different
      media systems, sequential G-Series media versus sequential G-Series media supplemented with
      antioxidants.

      Primary endpoint:

      Percentage of good quality blastocysts (GQB) per fertilized oocyte on day 5.

      Secondary endpoints:

      Embryo development day 3, 5 and 6 Embryo quality day 3, 5 and 6 Total blastocyst formation
      (day 5 and day 6) Utilization rate (embryos available for transfer and cryopreservation)
      Biochemical pregnancy rate Implantation rate Clinical pregnancy rate

      Setup:

      Prospective oocyte sibling, superiority study

      MATERIALS AND METHODS

      Intervention:

      New type of embryo culture media used for in vitro culture of human IVF embryos.

      Power analysis:

      The planning and the power analysis was made together with a statistician, Nils-Gunnar
      Pehrsson.

      From retrospective data using simulation, the intra individual SD for the difference in % GQB
      between the two media strategies was estimated to 32%. In order to find a difference in 8% in
      GQB between the two media with power 80% with paired T-test 128 couples will be needed.

      Randomization:

      Couples will be enrolled in the study at oocyte pick up (day 0). A minimum of 8
      cumulus-oocyte-complexes is required for participation.

      Stratified randomization of the oocytes by couple will be performed. For each couple the
      oocytes will be numbered.

      These oocytes for each couple will then be block (by two) randomized to the two media types;
      A (Traditional G-Series media system = Control) and B (G-Series media system with antioxidant
      = intervention). In both groups traditional culture will be performed. Allocation will be
      performed in a 1:1 ratio according to a unique randomization list for each couple.

      Blinding:

      To minimize possible bias for the primary outcome (GQB D5) the embryologist performing the
      morphological evaluation on day 5/6 will not know which group the embryos belong to.

      Both the physician and the couple will be blinded in respect to from which group an embryo
      was selected for transfer.

      IVF treatment procedure:

      A traditional IVF treatment will be performed including ovarian stimulation and oocyte
      pick-up using the standard methods at the clinics.

      Embryo assessment on day 3 according to Alpha/ESHRE consensus criteria and on day 5 according
      to Gardner score.

      Morphological scoring Embryo development and morphology on day 3 will be scored based on the
      Alpha/ESHRE Consensus criteria. Blastocyst development and morphology will be scored
      according to a published scoring system for blastocysts and will be documented with
      individual photos of each blastocyst. Embryo & Blastocyst scoring will be performed under an
      inverted microscope on day 3 and days 5 & 6, respectively. Blastocysts that have a score
      equal or higher than 3BB are considered as GQB.

      DOCUMENTATION All patients participating in the study will be documented on a computerized
      CRF. This document will contain study-specific relevant clinical and laboratory data from the
      specific IVF cycle.

      STATISTICAL ANALYSIS Both an Intention-to-Treat (ITT) population and a Per Protocol (PP)
      population will be defined. Primary efficacy variable in this superiority study will be
      difference in % GQB between the two media types for each couple. Primary statistical analysis
      will be two-sided paired T-test regarding the mean of difference in % GQB between Standard
      sequential culture media and Antioxidant media on the ITT population. A two sided 95%
      confidence interval for the mean difference in % GOB between the two media will be
      calculated. All significance tests will be two-sided and conducted at the 5% significance
      level.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: Percentage of good quality blastocyst (GQB) per fertilized oocyte on day 5
time frame: 7 months
measure: Embryo development on day 3, 5 & 6
time frame: 7 months
measure: Embryo quality on day 3, 5 & 6
time frame: 7 months
measure: Total blastocyst rate
time frame: 7 months
measure: Blastocyst utilization rate per fertilized oocyte
time frame: 7 months
measure: Biochemical pregnancy rate
time frame: 8 months
measure: Clinical pregnancy rate
time frame: 9 months
measure: Implantation rate
time frame: 8 months
arm group label: Control
arm group type: No Intervention
description: Sequential culture media without addition of antioxidants
arm group label: Treatment
arm group type: Active Comparator
description: Sequential culture media with the addition of antioxidants
intervention type: Biological
intervention name: Antioxidants
description: In the Treatment Arm, the G-Series culture media system will be used with antioxidants
arm group label: Treatment
other name: Acetyl-L-carnitine (ALC)
other name: N-acetyl-L-cysteine (NAC)
other name: alpha-Lipoic acid (ALA)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: A Yoshida, MD, PhD
role: Principal Investigator
affiliation: Kiba Park Clinic, Tokyo
facility: 
facility: 
country: Japan
citation: Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000 Jun;73(6):1155-8. doi: 10.1016/s0015-0282(00)00518-5.
PMID: 10856474
responsible party type: Sponsor
mesh term: Thioctic Acid
mesh term: Acetylcarnitine
mesh term: Acetylcysteine
mesh term: Antioxidants
mesh term: N-monoacetylcystine
sharing ipd: No
submitted: January 8, 2021
returned: January 29, 2021
submitted: February 24, 2021
returned: March 19, 2021