<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/NCT04456478</url>
  </required_header>
  <id_info>
    <org_study_id>RC31/19/0503</org_study_id>
    <secondary_id>2020-A00221-38</secondary_id>
    <nct_id>NCT04456478</nct_id>
  </id_info>
  <brief_title>Impact of pH Values of the Embryo Culture Medium on Success of In Vitro Fertilization (IVF)</brief_title>
  <acronym>ACIDOFIV</acronym>
  <official_title>Randomized Trial in Assisted Reproductive Technology : Impact of pH Values of the Embryo Culture Medium on Live Birth Rate After In Vitro Fertilization (IVF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Toulouse</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Toulouse</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to compare, through a multicentric randomized trial, the&#xD;
      impact of two pH values in the embryo culture medium on the clinical results of In Vitro&#xD;
      Fertilization (IVF) process and especially the impact on live birth delivery rate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Despite progress in Assisted Reproductive Technology (ART), the livebirth rate per oocyte&#xD;
      retrieval during In Vitro Fertilization (IVF) remain relatively low (15 à 25%). This is in&#xD;
      part due to the sensitivity of the preimplantation embryo to its environment. Indeed, there&#xD;
      is growing evidence that culture conditions during IVF are critical not only for the&#xD;
      development of pre- and post-implantation embryo, but also for long-term health effects; and&#xD;
      numerous animal data suggest the importance of pH control in the IVF culture medium.&#xD;
      Maintaining the intercellular pH (pHi) is one of the vital roles of embryo homeostasis since&#xD;
      pHi regulates many cellular processes. Indeed, variations in pHi can affect embryonic&#xD;
      development. Although the embryo has biochemical systems to regulate its pHi, these systems&#xD;
      can be overtaken. Under the conditions of IVF embryo culture, the extracellular pH (pHe) in a&#xD;
      culture medium is the result of a balance between CO2 concentration in the incubator and&#xD;
      bicarbonate concentration in the culture medium (determined by the medium manufacturer). The&#xD;
      recommendations of the manufacturers of embryo culture media are to maintain a pHe slightly&#xD;
      higher (generally between 7.2 and 7.4) than the pHi (estimated between 7.1 to 7.2) to&#xD;
      compensate for the acidification due to cell metabolism. However, as the pH scale is&#xD;
      logarithmic, a pHe variation of 7.2 to 7.4 corresponds to a decrease in the concentration of&#xD;
      H+ ions by a factor of 1.6 in the medium. Actually, there is no clinical data to know what is&#xD;
      the ideal pH to apply to a culture medium during IVF.&#xD;
&#xD;
      This is a clinical study comparing two pH values in the culture medium of embryos obtained by&#xD;
      IVF, randomized, multicentric (3 centers), patient-blinded, in groups parallel to the ratio&#xD;
      1: 1. IVF-ICSI will be performed according to the usual procedure and the day of the oocyte&#xD;
      puncture, the embryologist will proceed to the 1: 1 randomization: culture of the oocytes and&#xD;
      embryos in the culture medium with a pH at 7.38 ± 0.02 or a pH at 7.22 ± 0.02.&#xD;
&#xD;
      In case of pregnancy after embryo transfer, patients will be followed until delivery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 14, 2020</start_date>
  <completion_date type="Anticipated">April 2025</completion_date>
  <primary_completion_date type="Anticipated">June 2024</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>
    <intervention_model_description>Multicentric randomized blinded trial</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Live birth delivery rate</measure>
    <time_frame>month 9</time_frame>
    <description>Number of deliveries that resulted in at least one live birth (gestational age ≥ 22 weeks) / Number of oocyte retrievals</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fertilization rate</measure>
    <time_frame>day 1</time_frame>
    <description>Number of 2PN zygotes at day 1 post-injection / Number of matures injected oocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cleavage rate</measure>
    <time_frame>day 2</time_frame>
    <description>Number of embryos with at least 2 blastomeres at day 2 / Number of diploid zygotes at day 1 post-injection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of top embryos</measure>
    <time_frame>day 3</time_frame>
    <description>Number of 7 to 10-blastomeres embryos at day 3 with less than 10% fragments / Total number of embryos at day 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Embryo freezing rate</measure>
    <time_frame>day 6</time_frame>
    <description>Number of frozen embryos / Total number of obtained embryos</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Implantation rate</measure>
    <time_frame>week 5</time_frame>
    <description>Number of gestational sacs observed with ultrasonography (5 weeks after embryo transfer) divided by the number of embryos transferred (expressed as a percentage)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical ongoing pregnancy rate by transfer</measure>
    <time_frame>week 5</time_frame>
    <description>Number of pregnancies diagnosed by ultrasonographic of at least one fetus with a discernible heartbeat at 5 weeks after embryo transfer / Number of embryo transfers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical ongoing pregnancy rate by oocyte retrieval</measure>
    <time_frame>week 5</time_frame>
    <description>Number of pregnancies diagnosed by ultrasonographic of at least one fetus with a discernible heartbeat at 5 weeks after embryo transfer / Number of oocyte retrieval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Miscarriage rate</measure>
    <time_frame>week 22</time_frame>
    <description>Number of spontaneous loss of an intrauterine pregnancy prior to 22 completed weeks of gestational age / Number of pregnancies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malformation rate diagnosed at birth</measure>
    <time_frame>month 9</time_frame>
    <description>Number of malformations according to Eurocat classification (in total and in Eurocat subgroups) / Total number of newborns</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">622</enrollment>
  <condition>Embryo Growth Disorder</condition>
  <condition>Humans</condition>
  <condition>Pregnancy</condition>
  <arm_group>
    <arm_group_label>pH 7.38 ± 0.02</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IVF-ICSI will be performed according to the usual procedure and the day of the oocyte puncture, the embryologist will proceed to the culture of the oocytes and embryos in the culture medium with a pH at 7.38 ± 0.02</description>
  </arm_group>
  <arm_group>
    <arm_group_label>pH 7.22 ± 0.02</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IVF-ICSI will be performed according to the usual procedure and the day of the oocyte puncture, the embryologist will proceed to the culture of the oocytes and embryos in the culture medium with a pH at 7.22 ± 0.02</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>pH at 7.38 ± 0.02</intervention_name>
    <description>In the 3 centers of the study, IVF-ICSI will be performed according to the usual procedure: ovarian stimulation, oocyte retrieval, sperm microinjection by ICSI, embryo culture in Global® Total HSA medium, embryo selection and transfer at day 3. The day of the oocyte puncture, the embryologist will proceed to the 1: 1 randomization: culture of the embryos in a medium with a pH at 7.38 ± 0.02. We have chosen to study specifically the early stages of fertilization and embryo development (until day 3), stages for which extracellular pH control is more critical because the intracellular pH regulatory mechanisms are somewhat limited and could be exceeded.</description>
    <arm_group_label>pH 7.38 ± 0.02</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>pH at 7.22 ± 0.02</intervention_name>
    <description>In the 3 centers of the study, IVF-ICSI will be performed according to the usual procedure: ovarian stimulation, oocyte retrieval, sperm microinjection by ICSI, embryo culture in Global® Total HSA medium, embryo selection and transfer at day 3. The day of the oocyte puncture, the embryologist will proceed to the 1: 1 randomization: culture of the embryos in a medium with a pH at 7.22 ± 0.02. We have chosen to study specifically the early stages of fertilization and embryo development (until day 3), stages for which extracellular pH control is more critical because the intracellular pH regulatory mechanisms are somewhat limited and could be exceeded.</description>
    <arm_group_label>pH 7.22 ± 0.02</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Couples whose woman is 18 to 40 years old and man is 18 to 60 at the time of&#xD;
             inclusion.&#xD;
&#xD;
          -  Infertile couple with a medical indication of IVF-ICSI according to criteria applied&#xD;
             in each center.&#xD;
&#xD;
          -  First or second ICSI attempt with fresh embryo transfer.&#xD;
&#xD;
          -  Signature of informed consent by both partners of the couple&#xD;
&#xD;
          -  Affiliation to a social security scheme or equivalent for both partners of the couple.&#xD;
&#xD;
          -  Fitting the inclusion criteria for IVF according the the French law.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of spermatozoa extracted by testicular biopsy.&#xD;
&#xD;
          -  Freeze-al strategy (without fresh embryo transfer) decided before embryo culture&#xD;
&#xD;
          -  Absence of mature oocyte (metaphase II) at the day of the puncture&#xD;
&#xD;
          -  Uterine pathology affecting implantation (uterine malformation, diffuse adenomyosis&#xD;
             ...)&#xD;
&#xD;
          -  One of the two partners (or both) is (are) infected with HIV, HCV or HBV in the year&#xD;
             before the inclusion&#xD;
&#xD;
          -  One of the two partners (or both) is (are) in safeguarding justice, under guardianship&#xD;
             or trusteeship.&#xD;
&#xD;
          -  Couple having already participated once in the study.&#xD;
&#xD;
          -  Couple enrolled in another interventional clinical study&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Couples whose woman is 18 to 40 years old and man is 18 to 60 at the time of inclusion because the study concerns in vitro fertilization</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicolas GATIMEL, ph</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Toulouse</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Nicolas GATIMEL, ph</last_name>
    <phone>05 67 77 10 08</phone>
    <phone_ext>33</phone_ext>
    <email>gatimel.n@chu-toulouse.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>CHU de BORDEAUX</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aline PAPAXANTHOS, PH</last_name>
      <phone>0556795681</phone>
      <phone_ext>33</phone_ext>
      <email>aline.papaxanthos@chu-bordeaux.fr</email>
    </contact>
    <investigator>
      <last_name>Aline PAPAXANTHOS, ph</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Centre AMP BIOPYRENEES</name>
      <address>
        <city>Pau</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Steven CENS, ph</last_name>
      <phone>0559275131</phone>
      <phone_ext>33</phone_ext>
      <email>steven.cens@biopyrenees.com</email>
    </contact>
    <investigator>
      <last_name>Steven CENS, ph</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU de TOULOUSE</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nicolas GATIMEL, PH</last_name>
      <phone>05 67 77 10 08</phone>
      <phone_ext>33</phone_ext>
      <email>gatimel.n@chu-toulouse.fr</email>
    </contact>
    <contact_backup>
      <last_name>Célia BETTIOL</last_name>
      <phone>05.67.77.13.87</phone>
      <phone_ext>33</phone_ext>
      <email>bettiol.c@chu-toulouse.fr</email>
    </contact_backup>
    <investigator>
      <last_name>Nicolas GATIMEL, PH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <last_update_submitted>August 25, 2023</last_update_submitted>
  <last_update_submitted_qc>August 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pH</keyword>
  <keyword>embryo culture</keyword>
  <keyword>In Vitro Fertilization</keyword>
  <keyword>live birth rate</keyword>
  <keyword>randomized trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Growth Disorders</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/NCT04456478
org study id: RC31/19/0503
secondary id: 2020-A00221-38
nct id: NCT04456478
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The objective of this study is to compare, through a multicentric randomized trial, the
      impact of two pH values in the embryo culture medium on the clinical results of In Vitro
      Fertilization (IVF) process and especially the impact on live birth delivery rate.
Despite progress in Assisted Reproductive Technology (ART), the livebirth rate per oocyte
      retrieval during In Vitro Fertilization (IVF) remain relatively low (15 à 25%). This is in
      part due to the sensitivity of the preimplantation embryo to its environment. Indeed, there
      is growing evidence that culture conditions during IVF are critical not only for the
      development of pre- and post-implantation embryo, but also for long-term health effects; and
      numerous animal data suggest the importance of pH control in the IVF culture medium.
      Maintaining the intercellular pH (pHi) is one of the vital roles of embryo homeostasis since
      pHi regulates many cellular processes. Indeed, variations in pHi can affect embryonic
      development. Although the embryo has biochemical systems to regulate its pHi, these systems
      can be overtaken. Under the conditions of IVF embryo culture, the extracellular pH (pHe) in a
      culture medium is the result of a balance between CO2 concentration in the incubator and
      bicarbonate concentration in the culture medium (determined by the medium manufacturer). The
      recommendations of the manufacturers of embryo culture media are to maintain a pHe slightly
      higher (generally between 7.2 and 7.4) than the pHi (estimated between 7.1 to 7.2) to
      compensate for the acidification due to cell metabolism. However, as the pH scale is
      logarithmic, a pHe variation of 7.2 to 7.4 corresponds to a decrease in the concentration of
      H+ ions by a factor of 1.6 in the medium. Actually, there is no clinical data to know what is
      the ideal pH to apply to a culture medium during IVF.

      This is a clinical study comparing two pH values in the culture medium of embryos obtained by
      IVF, randomized, multicentric (3 centers), patient-blinded, in groups parallel to the ratio
      1: 1. IVF-ICSI will be performed according to the usual procedure and the day of the oocyte
      puncture, the embryologist will proceed to the 1: 1 randomization: culture of the oocytes and
      embryos in the culture medium with a pH at 7.38 ± 0.02 or a pH at 7.22 ± 0.02.

      In case of pregnancy after embryo transfer, patients will be followed until delivery.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Multicentric randomized blinded trial
primary purpose: Other
masking: Double (Participant, Outcomes Assessor)
measure: Live birth delivery rate
time frame: month 9
description: Number of deliveries that resulted in at least one live birth (gestational age ≥ 22 weeks) / Number of oocyte retrievals
measure: Fertilization rate
time frame: day 1
description: Number of 2PN zygotes at day 1 post-injection / Number of matures injected oocytes
measure: Cleavage rate
time frame: day 2
description: Number of embryos with at least 2 blastomeres at day 2 / Number of diploid zygotes at day 1 post-injection
measure: Percentage of top embryos
time frame: day 3
description: Number of 7 to 10-blastomeres embryos at day 3 with less than 10% fragments / Total number of embryos at day 3
measure: Embryo freezing rate
time frame: day 6
description: Number of frozen embryos / Total number of obtained embryos
measure: Implantation rate
time frame: week 5
description: Number of gestational sacs observed with ultrasonography (5 weeks after embryo transfer) divided by the number of embryos transferred (expressed as a percentage)
measure: Clinical ongoing pregnancy rate by transfer
time frame: week 5
description: Number of pregnancies diagnosed by ultrasonographic of at least one fetus with a discernible heartbeat at 5 weeks after embryo transfer / Number of embryo transfers
measure: Clinical ongoing pregnancy rate by oocyte retrieval
time frame: week 5
description: Number of pregnancies diagnosed by ultrasonographic of at least one fetus with a discernible heartbeat at 5 weeks after embryo transfer / Number of oocyte retrieval
measure: Miscarriage rate
time frame: week 22
description: Number of spontaneous loss of an intrauterine pregnancy prior to 22 completed weeks of gestational age / Number of pregnancies
measure: Malformation rate diagnosed at birth
time frame: month 9
description: Number of malformations according to Eurocat classification (in total and in Eurocat subgroups) / Total number of newborns
arm group label: pH 7.38 ± 0.02
arm group type: Active Comparator
description: IVF-ICSI will be performed according to the usual procedure and the day of the oocyte puncture, the embryologist will proceed to the culture of the oocytes and embryos in the culture medium with a pH at 7.38 ± 0.02
arm group label: pH 7.22 ± 0.02
arm group type: Experimental
description: IVF-ICSI will be performed according to the usual procedure and the day of the oocyte puncture, the embryologist will proceed to the culture of the oocytes and embryos in the culture medium with a pH at 7.22 ± 0.02
intervention type: Procedure
intervention name: pH at 7.38 ± 0.02
description: In the 3 centers of the study, IVF-ICSI will be performed according to the usual procedure: ovarian stimulation, oocyte retrieval, sperm microinjection by ICSI, embryo culture in Global® Total HSA medium, embryo selection and transfer at day 3. The day of the oocyte puncture, the embryologist will proceed to the 1: 1 randomization: culture of the embryos in a medium with a pH at 7.38 ± 0.02. We have chosen to study specifically the early stages of fertilization and embryo development (until day 3), stages for which extracellular pH control is more critical because the intracellular pH regulatory mechanisms are somewhat limited and could be exceeded.
arm group label: pH 7.38 ± 0.02
intervention type: Procedure
intervention name: pH at 7.22 ± 0.02
description: In the 3 centers of the study, IVF-ICSI will be performed according to the usual procedure: ovarian stimulation, oocyte retrieval, sperm microinjection by ICSI, embryo culture in Global® Total HSA medium, embryo selection and transfer at day 3. The day of the oocyte puncture, the embryologist will proceed to the 1: 1 randomization: culture of the embryos in a medium with a pH at 7.22 ± 0.02. We have chosen to study specifically the early stages of fertilization and embryo development (until day 3), stages for which extracellular pH control is more critical because the intracellular pH regulatory mechanisms are somewhat limited and could be exceeded.
arm group label: pH 7.22 ± 0.02
criteria: 
gender: Female
gender based: Yes
gender description: Couples whose woman is 18 to 40 years old and man is 18 to 60 at the time of inclusion because the study concerns in vitro fertilization
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: No
last name: Nicolas GATIMEL, ph
role: Principal Investigator
affiliation: University Hospital, Toulouse
last name: Nicolas GATIMEL, ph
phone: 05 67 77 10 08
phone ext: 33
email: gatimel.n@chu-toulouse.fr
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Growth Disorders