<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/NCT03797222</url>
  </required_header>
  <id_info>
    <org_study_id>17-014550</org_study_id>
    <secondary_id>T32DK063688</secondary_id>
    <nct_id>NCT03797222</nct_id>
  </id_info>
  <brief_title>Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome</brief_title>
  <official_title>Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Elizabeth A Rosenfeld</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lawson Wilkins Pediatric Endocrine Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital of Philadelphia</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with&#xD;
      congenital hyperinsulinism (HI) and hyperammonemia (HA) syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion&#xD;
      that causes persistent and severe hypoglycemia starting at birth.&#xD;
      Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital&#xD;
      HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with&#xD;
      HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia,&#xD;
      hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These&#xD;
      effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons,&#xD;
      and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on&#xD;
      the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on&#xD;
      other cell types. Thus, there remains a significant unmet need for improved therapies for&#xD;
      this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity&#xD;
      in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical&#xD;
      studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact&#xD;
      hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This&#xD;
      hypothesis will be tested in a future study. In this initial pilot study, investigators will&#xD;
      assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 15, 2019</start_date>
  <completion_date type="Actual">March 23, 2020</completion_date>
  <primary_completion_date type="Actual">March 23, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This open-label tolerability and feasibility pilot clinical study will use a before-and-after design, with blood tests and fasting oral protein tolerance test performed prior to and after 2 weeks of daily oral Vitamin E supplementation in individuals with HI/HA syndrome.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline</measure>
    <time_frame>2 weeks</time_frame>
    <description>The following symptoms will be scored as either &quot;none&quot; (did not occur)=0, &quot;mild&quot; (minimal symptoms, no treatment needed)=1, &quot;moderate&quot; (symptoms requiring treatment at home or as an outpatient=2, or &quot;severe&quot; (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4:&#xD;
Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other&#xD;
Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation).&#xD;
The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Alpha-tocopherol Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delta-plasma Glucose Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Plasma Glucose Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nadir Plasma Glucose Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Plasma Insulin Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Plasma Insulin Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delta-plasma Insulin Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Plasma Ammonia Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delta-plasma Ammonia Concentration</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hypoglycemia Frequency</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in frequency of hypoglycemia (plasma glucose &lt;70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Hyperinsulinism-Hyperammonemia Syndrome</condition>
  <arm_group>
    <arm_group_label>Vitamin E Supplementation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin E</intervention_name>
    <description>Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
    <arm_group_label>Vitamin E Supplementation</arm_group_label>
    <other_name>alpha-tocopherol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Individuals age ≥12 months and ≤40 years&#xD;
&#xD;
          -  Diagnosis of HI/HA syndrome&#xD;
&#xD;
          -  On diazoxide therapy for treatment of hypoglycemia&#xD;
&#xD;
          -  Females ≥11 years of age or menstruating must have a negative urine/serum pregnancy&#xD;
             test and must use an acceptable method of contraception, including abstinence, a&#xD;
             barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the&#xD;
             duration of the study.&#xD;
&#xD;
          -  Informed consent for participants ≥18 years. Parental/guardian permission (informed&#xD;
             consent) and, if appropriate, child assent for participants &lt;18 years.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Individuals age &lt;12 months or &gt;40 years&#xD;
&#xD;
          -  Individuals who have experienced an allergic reaction to Vitamin E&#xD;
&#xD;
          -  Individuals with a known allergy to dairy, whey, or soy&#xD;
&#xD;
          -  On concurrent therapy with a medication known to be metabolized by the CYP3A pathway&#xD;
&#xD;
          -  Individuals with a known increased risk of bleeding (bleeding disorder or on&#xD;
             antiplatelet or anticoagulation therapy)&#xD;
&#xD;
          -  Vitamin E supplementation within 30 days prior to enrollment, including multivitamins&#xD;
             containing Vitamin E&#xD;
&#xD;
          -  Severe hypoglycemia (plasma glucose &lt;50 mg/dL on repeat checks using home glucose&#xD;
             meter) more than once weekly within 30 days prior to enrollment.&#xD;
&#xD;
          -  Evidence of a medical condition that might alter results or compromise the&#xD;
             interpretation of results, including active infection, kidney failure, severe liver&#xD;
             dysfunction, severe respiratory or cardiac failure.&#xD;
&#xD;
          -  Evidence of severe hematologic abnormality including severe anemia and/or&#xD;
             thrombocytopenia.&#xD;
&#xD;
          -  Any investigational drug use within 30 days prior to enrollment.&#xD;
&#xD;
          -  Pregnant or lactating females.&#xD;
&#xD;
          -  Parents/guardians or subjects who, in the opinion of the Investigator, may be&#xD;
             non-compliant with study schedules or procedures.&#xD;
&#xD;
          -  Unable to provide informed consent (e.g. impaired cognition or judgment).&#xD;
&#xD;
          -  Parents/guardians or subjects with limited English proficiency.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth Rosenfeld, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital of Philadelphia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0.</citation>
    <PMID>20936362</PMID>
  </reference>
  <reference>
    <citation>Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.</citation>
    <PMID>23275527</PMID>
  </reference>
  <reference>
    <citation>Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818.</citation>
    <PMID>11241047</PMID>
  </reference>
  <reference>
    <citation>Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. 1976 May;57(5):702-11.</citation>
    <PMID>940710</PMID>
  </reference>
  <reference>
    <citation>Li M, Smith CJ, Walker MT, Smith TJ. Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. J Biol Chem. 2009 Aug 21;284(34):22988-3000. doi: 10.1074/jbc.M109.020222. Epub 2009 Jun 15.</citation>
    <PMID>19531491</PMID>
  </reference>
  <reference>
    <citation>McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal Serum alpha-Tocopherol Concentrations Observed among Younger Adults and Those Depending Exclusively upon Food Sources, NHANES 2003-20061-3. PLoS One. 2015 Aug 19;10(8):e0135510. doi: 10.1371/journal.pone.0135510. eCollection 2015.</citation>
    <PMID>26287975</PMID>
  </reference>
  <reference>
    <citation>Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013;33:87-103. doi: 10.1146/annurev-nutr-071812-161252. Epub 2013 Apr 29.</citation>
    <PMID>23642196</PMID>
  </reference>
  <reference>
    <citation>Pfeiffer CM, Sternberg MR, Schleicher RL, Haynes BM, Rybak ME, Pirkle JL. The CDC's Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers. J Nutr. 2013 Jun;143(6):938S-47S. doi: 10.3945/jn.112.172858. Epub 2013 Apr 17.</citation>
    <PMID>23596164</PMID>
  </reference>
  <reference>
    <citation>Ferslew KE, Acuff RV, Daigneault EA, Woolley TW, Stanton PE Jr. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol. 1993 Jan;33(1):84-8. doi: 10.1002/j.1552-4604.1993.tb03909.x.</citation>
    <PMID>8429120</PMID>
  </reference>
  <reference>
    <citation>Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1219-25. doi: 10.1152/ajpendo.00028.2010. Epub 2010 Mar 23.</citation>
    <PMID>20332361</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 6, 2019</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <results_first_submitted>June 24, 2022</results_first_submitted>
  <results_first_submitted_qc>November 2, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">November 25, 2022</results_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Children's Hospital of Philadelphia</investigator_affiliation>
    <investigator_full_name>Elizabeth A Rosenfeld</investigator_full_name>
    <investigator_title>Attending Physician</investigator_title>
  </responsible_party>
  <keyword>hyperinsulinism</keyword>
  <keyword>hyperammonemia</keyword>
  <keyword>hypoglycemia</keyword>
  <keyword>vitamin e</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperinsulinism</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Hyperammonemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin E</mesh_term>
    <mesh_term>Tocopherols</mesh_term>
    <mesh_term>alpha-Tocopherol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 11, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/22/NCT03797222/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Vitamin E Supplementation</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Vitamin E Supplementation</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="14"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8" lower_limit="2" upper_limit="28"/>
                  </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="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline</title>
        <description>The following symptoms will be scored as either &quot;none&quot; (did not occur)=0, &quot;mild&quot; (minimal symptoms, no treatment needed)=1, &quot;moderate&quot; (symptoms requiring treatment at home or as an outpatient=2, or &quot;severe&quot; (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4:&#xD;
Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other&#xD;
Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation).&#xD;
The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.</description>
        <time_frame>2 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline</title>
          <description>The following symptoms will be scored as either &quot;none&quot; (did not occur)=0, &quot;mild&quot; (minimal symptoms, no treatment needed)=1, &quot;moderate&quot; (symptoms requiring treatment at home or as an outpatient=2, or &quot;severe&quot; (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4:&#xD;
Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other&#xD;
Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation).&#xD;
The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Alpha-tocopherol Concentration</title>
        <description>change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Alpha-tocopherol Concentration</title>
          <description>change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
          <units>micromolar</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.6" spread="12.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Delta-plasma Glucose Concentration</title>
        <description>change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Delta-plasma Glucose Concentration</title>
          <description>change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.1" spread="8.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fasting Plasma Glucose Concentration</title>
        <description>change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Fasting Plasma Glucose Concentration</title>
          <description>change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.3" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Nadir Plasma Glucose Concentration</title>
        <description>change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Nadir Plasma Glucose Concentration</title>
          <description>change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.01" spread="9.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fasting Plasma Insulin Concentration</title>
        <description>change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Fasting Plasma Insulin Concentration</title>
          <description>change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
          <units>uIU/mL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.4" spread="4.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Plasma Insulin Concentration</title>
        <description>change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Plasma Insulin Concentration</title>
          <description>change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
          <units>uIU/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.3" spread="18.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Delta-plasma Insulin Concentration</title>
        <description>change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Delta-plasma Insulin Concentration</title>
          <description>change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>Per the study protocol, the oral protein tolerance test was not repeated at 2 weeks (visit 2) if the baseline (visit 1) oral protein tolerance test was not tolerated. Of the 13 participants who completed the study, 7 did not tolerate the baseline (visit 1) oral protein tolerance test. The 2 week (visit 2) oral protein tolerance test was performed in 6 participants. Oral protein tolerance test parameters were analyzed for these 6 participants.</population>
          <units>uIU/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.2" spread="16.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fasting Plasma Ammonia Concentration</title>
        <description>change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Fasting Plasma Ammonia Concentration</title>
          <description>change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>The 2 week (visit 2) laboratory draw was unable to be obtained for 1 participant, yielding n=12 analyzed for this outcome</population>
          <units>micromolar</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" spread="31.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Delta-plasma Ammonia Concentration</title>
        <description>change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>The 2 week (visit 2) plasma ammonia at 60 minutes was not obtained in 1 participant in whom the visit 2 oral protein tolerance test was performed, yielding n=5 for analysis of this outcome.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Delta-plasma Ammonia Concentration</title>
          <description>change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>The 2 week (visit 2) plasma ammonia at 60 minutes was not obtained in 1 participant in whom the visit 2 oral protein tolerance test was performed, yielding n=5 for analysis of this outcome.</population>
          <units>micromolar</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.4" spread="15.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Hypoglycemia Frequency</title>
        <description>change in frequency of hypoglycemia (plasma glucose &lt;70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
        <time_frame>2 weeks</time_frame>
        <population>Home glucose meter testing was not performed by 3 participants, yielding n=10 analyzed for this outcome.</population>
        <group_list>
          <group group_id="O1">
            <title>Vitamin E Supplementation</title>
            <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
          </group>
        </group_list>
        <measure>
          <title>Hypoglycemia Frequency</title>
          <description>change in frequency of hypoglycemia (plasma glucose &lt;70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])</description>
          <population>Home glucose meter testing was not performed by 3 participants, yielding n=10 analyzed for this outcome.</population>
          <units>Hypoglycemia events</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6" spread="2.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected over the 2 week study period.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Vitamin E Supplementation (All Doses)</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.&#xD;
Vitamin E: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if &gt;17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive &lt;600 IU daily, or for any subjects who prefer liquid medication to capsules.</description>
        </group>
        <group group_id="E2">
          <title>Vitamin E 150 IU</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) 150 IU for 2 weeks.</description>
        </group>
        <group group_id="E3">
          <title>Vitamin E 300 IU</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) 300 IU for 2 weeks.</description>
        </group>
        <group group_id="E4">
          <title>Vitamin E 450 IU</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) 450 IU for 2 weeks.</description>
        </group>
        <group group_id="E5">
          <title>Vitamin E 600 IU</title>
          <description>Daily oral supplementation with Vitamin E (alpha-tocopherol) 600 IU for 2 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="3" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Increased menstrual bleeding</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>
    <point_of_contact>
      <name_or_title>Lauren Mitteer</name_or_title>
      <organization>Children's Hospital of Philadelphia</organization>
      <phone>215-590-3174</phone>
      <email>mitteerl@chop.edu</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/NCT03797222
org study id: 17-014550
secondary id: T32DK063688
nct id: NCT03797222
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with
      congenital hyperinsulinism (HI) and hyperammonemia (HA) syndrome.
Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion
      that causes persistent and severe hypoglycemia starting at birth.
      Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital
      HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with
      HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia,
      hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These
      effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons,
      and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on
      the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on
      other cell types. Thus, there remains a significant unmet need for improved therapies for
      this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity
      in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical
      studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact
      hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This
      hypothesis will be tested in a future study. In this initial pilot study, investigators will
      assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This open-label tolerability and feasibility pilot clinical study will use a before-and-after design, with blood tests and fasting oral protein tolerance test performed prior to and after 2 weeks of daily oral Vitamin E supplementation in individuals with HI/HA syndrome.
primary purpose: Other
masking: None (Open Label)
measure: Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline
time frame: 2 weeks
description: The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4:
Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other
Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation).
The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.
measure: Plasma Alpha-tocopherol Concentration
time frame: 2 weeks
description: change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Delta-plasma Glucose Concentration
time frame: 2 weeks
description: change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Fasting Plasma Glucose Concentration
time frame: 2 weeks
description: change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Nadir Plasma Glucose Concentration
time frame: 2 weeks
description: change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Fasting Plasma Insulin Concentration
time frame: 2 weeks
description: change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Peak Plasma Insulin Concentration
time frame: 2 weeks
description: change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Delta-plasma Insulin Concentration
time frame: 2 weeks
description: change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Fasting Plasma Ammonia Concentration
time frame: 2 weeks
description: change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Delta-plasma Ammonia Concentration
time frame: 2 weeks
description: change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
measure: Hypoglycemia Frequency
time frame: 2 weeks
description: change in frequency of hypoglycemia (plasma glucose <70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks [visit 2] - baseline [visit 1])
arm group label: Vitamin E Supplementation
arm group type: Experimental
description: Daily oral supplementation with Vitamin E (alpha-tocopherol) for 2 weeks.
intervention type: Dietary Supplement
intervention name: Vitamin E
description: Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if >17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive <600 IU daily, or for any subjects who prefer liquid medication to capsules.
arm group label: Vitamin E Supplementation
other name: alpha-tocopherol
criteria: 
gender: All
minimum age: 1 Year
maximum age: 40 Years
healthy volunteers: No
last name: Elizabeth Rosenfeld, MD
role: Principal Investigator
affiliation: Children's Hospital of Philadelphia
facility: 
country: United States
citation: Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0.
PMID: 20936362
citation: Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.
PMID: 23275527
citation: Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001 Mar;138(3):383-9. doi: 10.1067/mpd.2001.111818.
PMID: 11241047
citation: Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. 1976 May;57(5):702-11.
PMID: 940710
citation: Li M, Smith CJ, Walker MT, Smith TJ. Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. J Biol Chem. 2009 Aug 21;284(34):22988-3000. doi: 10.1074/jbc.M109.020222. Epub 2009 Jun 15.
PMID: 19531491
citation: McBurney MI, Yu EA, Ciappio ED, Bird JK, Eggersdorfer M, Mehta S. Suboptimal Serum alpha-Tocopherol Concentrations Observed among Younger Adults and Those Depending Exclusively upon Food Sources, NHANES 2003-20061-3. PLoS One. 2015 Aug 19;10(8):e0135510. doi: 10.1371/journal.pone.0135510. eCollection 2015.
PMID: 26287975
citation: Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013;33:87-103. doi: 10.1146/annurev-nutr-071812-161252. Epub 2013 Apr 29.
PMID: 23642196
citation: Pfeiffer CM, Sternberg MR, Schleicher RL, Haynes BM, Rybak ME, Pirkle JL. The CDC's Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers. J Nutr. 2013 Jun;143(6):938S-47S. doi: 10.3945/jn.112.172858. Epub 2013 Apr 17.
PMID: 23596164
citation: Ferslew KE, Acuff RV, Daigneault EA, Woolley TW, Stanton PE Jr. Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration. J Clin Pharmacol. 1993 Jan;33(1):84-8. doi: 10.1002/j.1552-4604.1993.tb03909.x.
PMID: 8429120
citation: Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1219-25. doi: 10.1152/ajpendo.00028.2010. Epub 2010 Mar 23.
PMID: 20332361
responsible party type: Sponsor-Investigator
investigator affiliation: Children's Hospital of Philadelphia
investigator full name: Elizabeth A Rosenfeld
investigator title: Attending Physician
mesh term: Hyperinsulinism
mesh term: Syndrome
mesh term: Hyperammonemia
mesh term: Vitamin E
mesh term: Tocopherols
mesh term: alpha-Tocopherol
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 