<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/NCT04450160</url>
  </required_header>
  <id_info>
    <org_study_id>Terra-001-201</org_study_id>
    <nct_id>NCT04450160</nct_id>
  </id_info>
  <brief_title>Trial of AEO in New Glioblastoma (GBM)</brief_title>
  <acronym>AEO</acronym>
  <official_title>A Phase 2, Randomized, Open-Label Study of Anhydrous Enol-Oxaloacetate in Subjects With Newly Diagnosed Glioblastoma Multiforme</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MetVital, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>MetVital, Inc.</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicenter, Phase 2, Proof-of-concept study in subjects with newly diagnosed&#xD;
      glioblastoma multiforme (GBM).&#xD;
&#xD;
      All subjects will receive standard of care therapy for the treatment of their GBM and any&#xD;
      Anti-Epileptic Drug (AED) deemed necessary for their surgical resection of the GBM. Patients&#xD;
      who are taking concomitant AEDs will be eligible for the study. Treatment with Anhydrous&#xD;
      Enol-Oxaloacetate will be added to the Standard of Care.&#xD;
&#xD;
      This study is testing adjuvant Anhydrous Enol-Oxaloacetate (AEO) in GBM, an orally active&#xD;
      drug candidate which in animal studies has demonstrated decreased tumor growth rate and&#xD;
      increased survival.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Currently, the multidisciplinary Standard of Care treatment for Glioblastoma multiforme&#xD;
      includes maximal surgical resection of the tumor followed by radiotherapy plus concomitant&#xD;
      and maintenance temozolomide chemotherapy.This study will treat newly diagnosed GBM patients&#xD;
      by adding Anhydrous Enol-Oxaloacetate treatment to their current Standard of Care.&#xD;
&#xD;
      In the body, Anhydrous Enol-Oxaloacetate (AEO) converts into &quot;Oxaloacetate&quot;, a metabolite&#xD;
      important for many biochemical reactions in the body. On a cellular level, oxaloacetate&#xD;
      treatment has been found to modify cancer metabolism in GBM cells, reversing the &quot;Warburg&#xD;
      Effect&quot;, reducing glycolysis and reducing lactate production. In animals, oxaloacetate&#xD;
      treatment has increased survival and reduced tumor growth of implanted GBM tumors.&#xD;
&#xD;
      In other animal studies, oxaloacetate has also shown to have neuo-protective effects&#xD;
      including positive effects on seizure development.&#xD;
&#xD;
      .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">December 2020</start_date>
  <completion_date type="Anticipated">September 2022</completion_date>
  <primary_completion_date type="Anticipated">July 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>6 months</time_frame>
    <description>Measurement of Overall Survival</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression Free Survival-6</measure>
    <time_frame>6 months</time_frame>
    <description>Survival at 6 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Seizures</measure>
    <time_frame>6 months</time_frame>
    <description>Time from randomization to first seizure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chalfont-National Hospital Seizure Severity</measure>
    <time_frame>6 months</time_frame>
    <description>Measure of Seizure Severity Ranging from a minimum of 1 to a maximum of 27 with higher score indicating worse outcome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PROMIS-Cancer - Fatigue</measure>
    <time_frame>6 months</time_frame>
    <description>Measure of Fatigue Ranging from a minimum of 0 to a maximum of 95 with the higher score indicating worse outcome.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Glioblastoma Multiforme</condition>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Current GBM Treatment of surgery, radiation and chemotherapy with temozolomide.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AEO with Standard of Care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anhydrous Enol-Oxaloacetate added to the Standard of Care (surgery, radiation and chemotherapy with temozolomide).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anhydrous Enol-Oxaloacetate (AEO)</intervention_name>
    <description>Oral supplementation with AEO along with the Standard of Care (Temozolomide)</description>
    <arm_group_label>AEO with Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care</intervention_name>
    <description>Standard of Care Temozolomide</description>
    <arm_group_label>AEO with Standard of Care</arm_group_label>
    <arm_group_label>Standard of Care</arm_group_label>
    <other_name>Chemotherapy with Temozolomide</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  • Histopathologic diagnosis of glioblastoma multiforme&#xD;
&#xD;
               -  Standard of care maximal feasible surgical resection of the glioma&#xD;
&#xD;
               -  Post-operative pre-enrollment MRI-Note: measurable disease is not required&#xD;
&#xD;
               -  Concomitant anti-epileptic drugs&#xD;
&#xD;
               -  Hemoglobin &gt;9 g/dL&#xD;
&#xD;
               -  Platelets &gt;100,000/microliter (mcL)&#xD;
&#xD;
               -  &lt;3.0 Upper Limit of Normal Range (ULN) for Alanine aminotransferase (ALT),&#xD;
                  Aspartate aminotransferase (AST) and/or Alkaline Phosphatase&#xD;
&#xD;
               -  &lt;2.0 Upper Limit of Normal Range (ULN) for serum creatinine&#xD;
&#xD;
               -  Karnofsky performance status &gt;70&#xD;
&#xD;
               -  Mentally competent to follow study procedures&#xD;
&#xD;
               -  Male and female patients of childbearing potential must agree to use a dual&#xD;
                  method of contraception (a highly effective method of contraception in&#xD;
                  conjunction with barrier contraception) consistently and correctly from the first&#xD;
                  dose of study drug until 90 days after the last dose of study drug&#xD;
&#xD;
               -  Able to answer questions on the Patient-Reported Outcomes Measurement Information&#xD;
                  System (PROMIS) questionnaire&#xD;
&#xD;
               -  Subject is willing and able to give informed consent and to follow instructions&#xD;
                  as per the protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  • Concomitant treatment with carmustine wafers or tumor-treating electric fields&#xD;
             (TTFields)&#xD;
&#xD;
               -  QT Interval corrected with the fridericia formula (QTcF) &gt;480ms&#xD;
&#xD;
               -  Significant concurrent illness / disease&#xD;
&#xD;
               -  Predicted life expectancy &lt; 6 months from date of randomization&#xD;
&#xD;
               -  Pregnancy&#xD;
&#xD;
               -  Enrollment in another clinical trial during the course of the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Alan B Cash, MS</last_name>
    <phone>858-947-5722</phone>
    <email>acash@MetVital.com</email>
  </overall_contact>
  <link>
    <url>http://doi.org/10.1093/neuonc/noz175.171</url>
    <description>Oxaloacetate alters glucose metabolism in Glioblastoma</description>
  </link>
  <link>
    <url>http://doi.org/10.1093/neuonc/nox168.238</url>
    <description>Oxaloacetate increases survival in GBM implanted mice</description>
  </link>
  <link>
    <url>http://doi.org/10.1093/neuonc/noy148.1154</url>
    <description>New Bioanalytical method and single-dose pharmacokinetics for oxaloacetate</description>
  </link>
  <reference>
    <citation>Augur ZM, Doyle CM, Li M, Mukherjee P, Seyfried TN. Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma. Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.</citation>
    <PMID>30349820</PMID>
  </reference>
  <reference>
    <citation>Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. 2012 Dec;30(6):2226-35. doi: 10.1007/s10637-012-9799-5.</citation>
    <PMID>22392507</PMID>
  </reference>
  <reference>
    <citation>Yamamoto HA, Mohanan PV. Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Toxicol Lett. 2003 Jul 20;143(2):115-22. doi: 10.1016/s0378-4274(03)00114-0.</citation>
    <PMID>12749815</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 29, 2020</study_first_posted>
  <last_update_submitted>June 25, 2020</last_update_submitted>
  <last_update_submitted_qc>June 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glioblastoma</keyword>
  <keyword>Oxaloacetate</keyword>
  <keyword>Seizures</keyword>
  <keyword>Warburg</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temozolomide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04450160
org study id: Terra-001-201
nct id: NCT04450160
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
This is a multicenter, Phase 2, Proof-of-concept study in subjects with newly diagnosed
      glioblastoma multiforme (GBM).

      All subjects will receive standard of care therapy for the treatment of their GBM and any
      Anti-Epileptic Drug (AED) deemed necessary for their surgical resection of the GBM. Patients
      who are taking concomitant AEDs will be eligible for the study. Treatment with Anhydrous
      Enol-Oxaloacetate will be added to the Standard of Care.

      This study is testing adjuvant Anhydrous Enol-Oxaloacetate (AEO) in GBM, an orally active
      drug candidate which in animal studies has demonstrated decreased tumor growth rate and
      increased survival.
Currently, the multidisciplinary Standard of Care treatment for Glioblastoma multiforme
      includes maximal surgical resection of the tumor followed by radiotherapy plus concomitant
      and maintenance temozolomide chemotherapy.This study will treat newly diagnosed GBM patients
      by adding Anhydrous Enol-Oxaloacetate treatment to their current Standard of Care.

      In the body, Anhydrous Enol-Oxaloacetate (AEO) converts into "Oxaloacetate", a metabolite
      important for many biochemical reactions in the body. On a cellular level, oxaloacetate
      treatment has been found to modify cancer metabolism in GBM cells, reversing the "Warburg
      Effect", reducing glycolysis and reducing lactate production. In animals, oxaloacetate
      treatment has increased survival and reduced tumor growth of implanted GBM tumors.

      In other animal studies, oxaloacetate has also shown to have neuo-protective effects
      including positive effects on seizure development.

      .
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival
time frame: 6 months
description: Measurement of Overall Survival
measure: Progression Free Survival-6
time frame: 6 months
description: Survival at 6 months
measure: Seizures
time frame: 6 months
description: Time from randomization to first seizure
measure: Chalfont-National Hospital Seizure Severity
time frame: 6 months
description: Measure of Seizure Severity Ranging from a minimum of 1 to a maximum of 27 with higher score indicating worse outcome
measure: PROMIS-Cancer - Fatigue
time frame: 6 months
description: Measure of Fatigue Ranging from a minimum of 0 to a maximum of 95 with the higher score indicating worse outcome.
arm group label: Standard of Care
arm group type: Placebo Comparator
description: Current GBM Treatment of surgery, radiation and chemotherapy with temozolomide.
arm group label: AEO with Standard of Care
arm group type: Experimental
description: Anhydrous Enol-Oxaloacetate added to the Standard of Care (surgery, radiation and chemotherapy with temozolomide).
intervention type: Drug
intervention name: Anhydrous Enol-Oxaloacetate (AEO)
description: Oral supplementation with AEO along with the Standard of Care (Temozolomide)
arm group label: AEO with Standard of Care
intervention type: Other
intervention name: Standard of Care
description: Standard of Care Temozolomide
arm group label: AEO with Standard of Care
arm group label: Standard of Care
other name: Chemotherapy with Temozolomide
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alan B Cash, MS
phone: 858-947-5722
email: acash@MetVital.com
url: http://doi.org/10.1093/neuonc/noz175.171
description: Oxaloacetate alters glucose metabolism in Glioblastoma
url: http://doi.org/10.1093/neuonc/nox168.238
description: Oxaloacetate increases survival in GBM implanted mice
url: http://doi.org/10.1093/neuonc/noy148.1154
description: New Bioanalytical method and single-dose pharmacokinetics for oxaloacetate
citation: Augur ZM, Doyle CM, Li M, Mukherjee P, Seyfried TN. Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma. Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.
PMID: 30349820
citation: Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. 2012 Dec;30(6):2226-35. doi: 10.1007/s10637-012-9799-5.
PMID: 22392507
citation: Yamamoto HA, Mohanan PV. Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Toxicol Lett. 2003 Jul 20;143(2):115-22. doi: 10.1016/s0378-4274(03)00114-0.
PMID: 12749815
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Temozolomide
sharing ipd: No