<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/NCT02971878</url>
  </required_header>
  <id_info>
    <org_study_id>GTL-X</org_study_id>
    <nct_id>NCT02971878</nct_id>
  </id_info>
  <brief_title>Comparisons of Human Embryonic Development Using Single Medium With and Without the Addition of Antioxidants</brief_title>
  <official_title>Adding Antioxidants Into Human Embryo Culture Media</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fertilitetscentrum AB</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Vitrolife</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Fertilitetscentrum AB</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aim: To investigate the impact of antioxidants (acetyl-L-carnitine, N-acetyl-L-cysteine and&#xD;
      a-lipoic acid) on embryo development and subsequently the clinical outcome. Including clinics&#xD;
      using low oxygen and ambient air during embryo culture. Analysed with time-lapse system.&#xD;
&#xD;
      Study media: G-TL with antioxidants. Control media: Same media without antioxidants. Type of&#xD;
      study: Study comparing blastocyst development on the same cohort of oocytes using two&#xD;
      different media, G-TL versus G-TL supplemented with antioxidants. Statistics based on an&#xD;
      absolute increase in Good Quality Blastocysts on day 5 of 7%.&#xD;
&#xD;
      Design: Multicentre prospective randomized sibling trial. Single blastocyst transfer.&#xD;
      Superiority study Primary Endpoint: Good Quality Blastocysts on day 5 per allocated normally&#xD;
      fertilized oocyte.&#xD;
&#xD;
      Patients: Comparative embryo sibling study with 128 patients included.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study objective: Study comparing blastocyst development on the same cohort of oocytes using&#xD;
      two different media, G-TL versus G-TL supplemented with antioxidants.&#xD;
&#xD;
      Primary endpoint: Percentage of good quality blastocysts (GQB) per fertilized oocyte on day&#xD;
      5.&#xD;
&#xD;
      Secondary endpoints&#xD;
&#xD;
        -  Embryo development day 3, 5 and 6&#xD;
&#xD;
        -  Embryo quality day 3, 5 and 6&#xD;
&#xD;
        -  Total blastocyst formation (day 5 and day 6)&#xD;
&#xD;
        -  Utilization rate (embryos available for transfer and cryopreservation)&#xD;
&#xD;
        -  Implantation rate&#xD;
&#xD;
        -  Clinical pregnancy rate&#xD;
&#xD;
      Setup: Prospective embryo sibling, superiority study&#xD;
&#xD;
      MATERIALS AND METHODS Intervention New type of embryo culture media used for in vitro culture&#xD;
      of human IVF embryos.&#xD;
&#xD;
      Power analysis The planning and the power analysis was made together with a statistician,&#xD;
      Nils-Gunnar 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 Couples will be enrolled in the study after fertilization check (day 1). A&#xD;
      minimum of 6 zygotes is required for participation.&#xD;
&#xD;
      Stratified randomization of the zygotes by couple will be performed. For each couple the&#xD;
      zygotes will be numbered.&#xD;
&#xD;
      These zygotes for each couple will then be block (by two) randomized to the two media types;&#xD;
      A (Traditional culture media = Control) and B (Antioxidant media = intervention). In both&#xD;
      groups traditional culture will be performed. Allocation will be performed in a 1:1 ratio&#xD;
      according to a unique randomization list for each couple.&#xD;
&#xD;
      Blinding To minimize possible bias for the primary outcome (GQE D5) the embryologist&#xD;
      performing the morphological evaluation on day 5/6 will not know which group the embryos&#xD;
      belong to.&#xD;
&#xD;
      Both the physician and the couple will be blinded to which group they have been allocated.&#xD;
&#xD;
      IVF treatment procedure A traditional IVF treatment will be performed including ovarian&#xD;
      stimulation and oocyte pick-up using the standard methods at the clinics.&#xD;
&#xD;
      Embryo assessment and timing of assessment according to Alpha/ESHRE consensus criteria.&#xD;
&#xD;
      Morphological scoring Blastocyst morphology will be scored according to Consensus Scoring&#xD;
      system for blastocysts (Istanbul Consensus workshop on embryo assessment) and the morphology&#xD;
      will be documented with individual photos of each blastocyst. Blastocyst scoring will be&#xD;
      performed under an inverted microscope on day 5 and day 6. A good quality blastocyst is&#xD;
      defined as at least Grade 2:2:2 according to Istanbul Consensus grading system. (Balaban et&#xD;
      al., 2011).&#xD;
&#xD;
      DOCUMENTATION All patients participating in the study will be documented on a computerized&#xD;
      CRF. This document will be related to patients' records with all relevant clinical and&#xD;
      laboratory data from the specific IVF cycle. Through the journal system (WinIVF) used at&#xD;
      Fertilitetscentrum, it will be possible to generate a complete list of all the variables&#xD;
      included in the study.&#xD;
&#xD;
      Patients who have been asked to participate in the study but did not fulfill the criteria for&#xD;
      randomization will also be registered.&#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;
      culture media and Antioxidant media on the ITT population. A two sided 95% confidence&#xD;
      interval for the mean difference in %GOB between the two media will be calculated. All&#xD;
      significance tests will be two-sided and conducted at the 5% significance level.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">February 1, 2018</completion_date>
  <primary_completion_date type="Actual">February 1, 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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of good quality blastocysts (GQB) per randomized embryo</measure>
    <time_frame>7 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pregnancy rate</measure>
    <time_frame>10 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Utilization rate</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Embryo development (Kinetics) day 3,5 &amp; 6</measure>
    <time_frame>7 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Implantation rate</measure>
    <time_frame>8 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Embryo quality dag 3,5 and 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>
  <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>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>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>Culture media with the addition of antioxidants</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Acetyl-L-carnitine (ALC), N-acetyl-L-cysteine (NAC) and α-lipoic acid (ALA)</intervention_name>
    <description>Human embryos will be cultured in media that contains 3 antioxidants (Acetyl-L-carnitine (ALC), N-acetyl-L-cysteine (NAC) and α-lipoic acid (ALA)) that can be found in the in vivo Environment.</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#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;
          -  6 or more fertilized oocytes on day 1&#xD;
&#xD;
          -  Blastocyst culture and transfer on day 5&#xD;
&#xD;
          -  Signed written consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous participation in the study.&#xD;
&#xD;
          -  Testicular biopsy patients (TESA/TESE)&#xD;
&#xD;
          -  Fewer than 6 fertilized oocytes.&#xD;
&#xD;
          -  If split IVF is needed.&#xD;
&#xD;
          -  Total freeze on day 3&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>41 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thorir Hardarson, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Fertilitetscentrum AB</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fertilitetscentrum</name>
      <address>
        <city>Gothenburg</city>
        <state>Box 5418</state>
        <zip>40229</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>November 17, 2016</study_first_submitted>
  <study_first_submitted_qc>November 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 23, 2016</study_first_posted>
  <last_update_submitted>February 20, 2018</last_update_submitted>
  <last_update_submitted_qc>February 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 22, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fertilitetscentrum AB</investigator_affiliation>
    <investigator_full_name>Thorir Hardarson</investigator_full_name>
    <investigator_title>Laboratory Director</investigator_title>
  </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>N-monoacetylcystine</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/NCT02971878
org study id: GTL-X
nct id: NCT02971878
lead sponsor: 
collaborator: 
has dmc: Yes
Aim: To investigate the impact of antioxidants (acetyl-L-carnitine, N-acetyl-L-cysteine and
      a-lipoic acid) on embryo development and subsequently the clinical outcome. Including clinics
      using low oxygen and ambient air during embryo culture. Analysed with time-lapse system.

      Study media: G-TL with antioxidants. Control media: Same media without antioxidants. Type of
      study: Study comparing blastocyst development on the same cohort of oocytes using two
      different media, G-TL versus G-TL supplemented with antioxidants. Statistics based on an
      absolute increase in Good Quality Blastocysts on day 5 of 7%.

      Design: Multicentre prospective randomized sibling trial. Single blastocyst transfer.
      Superiority study Primary Endpoint: Good Quality Blastocysts on day 5 per allocated normally
      fertilized oocyte.

      Patients: Comparative embryo sibling study with 128 patients included.
Study objective: Study comparing blastocyst development on the same cohort of oocytes using
      two different media, G-TL versus G-TL 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)

        -  Implantation rate

        -  Clinical pregnancy rate

      Setup: Prospective embryo 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 after fertilization check (day 1). A
      minimum of 6 zygotes is required for participation.

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

      These zygotes for each couple will then be block (by two) randomized to the two media types;
      A (Traditional culture media = Control) and B (Antioxidant media = 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 (GQE 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 to which group they have been allocated.

      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 and timing of assessment according to Alpha/ESHRE consensus criteria.

      Morphological scoring Blastocyst morphology will be scored according to Consensus Scoring
      system for blastocysts (Istanbul Consensus workshop on embryo assessment) and the morphology
      will be documented with individual photos of each blastocyst. Blastocyst scoring will be
      performed under an inverted microscope on day 5 and day 6. A good quality blastocyst is
      defined as at least Grade 2:2:2 according to Istanbul Consensus grading system. (Balaban et
      al., 2011).

      DOCUMENTATION All patients participating in the study will be documented on a computerized
      CRF. This document will be related to patients' records with all relevant clinical and
      laboratory data from the specific IVF cycle. Through the journal system (WinIVF) used at
      Fertilitetscentrum, it will be possible to generate a complete list of all the variables
      included in the study.

      Patients who have been asked to participate in the study but did not fulfill the criteria for
      randomization will also be registered.

      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
      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: Triple (Participant, Care Provider, Investigator)
measure: Percentage of good quality blastocysts (GQB) per randomized embryo
time frame: 7 months
measure: Pregnancy rate
time frame: 10 months
measure: Utilization rate
time frame: 7 months
measure: Embryo development (Kinetics) day 3,5 & 6
time frame: 7 months
measure: Implantation rate
time frame: 8 months
measure: Embryo quality dag 3,5 and 6
time frame: 7 months
measure: Total blastocyst rate
time frame: 7 months
arm group label: Control
arm group type: No Intervention
description: Culture media without addition of antioxidants
arm group label: Treatment
arm group type: Active Comparator
description: Culture media with the addition of antioxidants
intervention type: Biological
intervention name: Acetyl-L-carnitine (ALC), N-acetyl-L-cysteine (NAC) and α-lipoic acid (ALA)
description: Human embryos will be cultured in media that contains 3 antioxidants (Acetyl-L-carnitine (ALC), N-acetyl-L-cysteine (NAC) and α-lipoic acid (ALA)) that can be found in the in vivo Environment.
arm group label: Treatment
criteria: 
gender: All
minimum age: 20 Years
maximum age: 41 Years
healthy volunteers: No
last name: Thorir Hardarson, PhD
role: Study Chair
affiliation: Fertilitetscentrum AB
facility: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Fertilitetscentrum AB
investigator full name: Thorir Hardarson
investigator title: Laboratory Director
mesh term: Thioctic Acid
mesh term: Acetylcarnitine
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine