<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/NCT02206152</url>
  </required_header>
  <id_info>
    <org_study_id>Protocol 22498</org_study_id>
    <nct_id>NCT02206152</nct_id>
  </id_info>
  <brief_title>A Randomized Double Blinded Study to Examine the Use of N-acetyl Cysteine for the Prevention and Treatment of HAAF in Patients With Type 1 Diabetes</brief_title>
  <acronym>NAC for HAAF</acronym>
  <official_title>A Randomized Double Blinded Study to Examine the Use of N-Acetyl Cysteine for the Prevention and Treatment of HAAF in Patients With Type 1 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Minnesota</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <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 single center, double blind randomized cross over design trial that will compare&#xD;
      the impact of N-acetyl cysteine (200 mg) vs. saline infusion during experimental hypoglycemia&#xD;
      on day one on the responses to experimental hypoglycemia on day two. 18 participants will be&#xD;
      studied twice, 8 weeks apart. On each occasion they will undergo a 2 hour hypoglycemic clamp&#xD;
      (target 50 mg/dl) in the morning and in the afternoon on day one and then again on the&#xD;
      morning of day 2 and day 3. During the morning clamps, samples will be collected for later&#xD;
      measurement of serum epinephrine levels, plasma and red blood cell NAC, cysteine, and&#xD;
      glutathione concentrations and GSH/GSSG ratios (redox status), and participants will be asked&#xD;
      to complete a hypoglycemia symptom questionnaire&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will consist of a screening visit and two 2-day intervention visits separated by&#xD;
      approximately 8 weeks.&#xD;
&#xD;
      At the screening visit, informed consent will be obtained, a standardized form will be used&#xD;
      to ensure subjects meet inclusion/exclusion criteria, and baseline hemoglobin A1c will be&#xD;
      obtained. On arrival, two IVs will be placed and they will be randomized to receive NAC or&#xD;
      saline infusion. Baseline blood samples will be drawn for glucose, epinephrine,&#xD;
      norepinephrine, cortisol, cysteine and glutathione measurements. Subjects will then be given&#xD;
      25 mg IV diphenhydramine (Benadryl) followed by a 60 minute infusion of NAC (150 mg) or a&#xD;
      similar volume of saline between 8 am and 9 am, followed by a four hour infusion of 50 mg of&#xD;
      NAC. Thirty minutes after the start of the NAC infusion, a hyperinsulinemic (2.0 mu/kg/min)&#xD;
      hypoglycemic (target = 50 mg/dl) clamp protocol will be started. During the morning study,&#xD;
      blood samples will be collected every 5 minutes for monitoring of blood glucose levels and&#xD;
      every 15 minutes for later measurement of serum epinephrine, norepinephrine, cortisol. Plasma&#xD;
      and red blood cells samples will also be collected every 15 minutes for later measurement of&#xD;
      NAC, cysteine, glutathione, and GSH/GSSG ratios (redox status). During the final 15 minutes&#xD;
      of the morning clamp, subjects will be asked to quantitate their symptoms using a&#xD;
      standardized method (13). At the completion of the morning clamp, glucose will be given to&#xD;
      return the participant to euglycemia. 2 hours after the end of the morning clamp, a second&#xD;
      hyperinsulinemic (2.0 mu/kg/min) hypoglycemic (target = 50 mg/dl) clamp protocol will be&#xD;
      followed over two hours. . The afternoon clamp study will proceed as in the morning except&#xD;
      that no serum or plasma will be collected except for the monitoring of glucose and collection&#xD;
      of samples for subsequent measurement of NAC, cysteine, glutathione, and GSH/GSSG ratios.&#xD;
      After the completion of the afternoon clamps, subjects will be returned to euglycemia and fed&#xD;
      a meal. They will be discharged home.&#xD;
&#xD;
      At 7 AM the following morning they will under a single 2 hour hyperinsulinemic hypoglycemic&#xD;
      stepped clamp (75, 65, 55,45 mg/dl targets) during which blood samples will be collected as&#xD;
      on the morning of day 1. Symptom scores will be collected in the final 15 minutes of each&#xD;
      step in the clamp.&#xD;
&#xD;
      At the completion of the study on day 2 of Part 1, they will be scheduled to return for Part&#xD;
      2 in 8 weeks. This timing is selected to ensure that female participants are studied at the&#xD;
      same phase of the menstrual cycle. During Part 2 they will receive the treatment not provided&#xD;
      during Part 1 in a blinded fashion. The rest of the study protocol will be the same as in&#xD;
      Part 1.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 2015</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions</measure>
    <time_frame>8-10 weeks</time_frame>
    <description>Epinephrine secretion during hypoglycemia is assessed by collecting blood samples for measurement of epinephrine concentrations at baseline and every 15 minutes during the period of hypoglycemia (starting at point where blood glucose is first &lt; 55 mg/dl) in the clamp studies done in the mornings of days 1 and 2 of both parts 1 and 2. .</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Type 1 Diabetes</condition>
  <condition>Hypoglycemia Unawareness</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment with N-Acetyl Cysteine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N-acetyl cysteine IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-acetyl cysteine</intervention_name>
    <description>N-acetyl cysteine (or saline) IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp</description>
    <arm_group_label>Treatment with N-Acetyl Cysteine</arm_group_label>
    <other_name>NAC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy controls&#xD;
&#xD;
          -  Age 18 - 65 years&#xD;
&#xD;
          -  Baseline hemoglobin A1C &lt;6.0%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of stroke, seizures (other than those related to hypoglycemia), arrhythmias,&#xD;
             active cardiac disease (all of which could be associated with adverse cardiac or&#xD;
             neurological events during hypoglycemia)&#xD;
&#xD;
          -  Pregnancy or plan to become pregnant during the study period&#xD;
&#xD;
          -  Diagnosis of asthma (increases risk of hypersensitivity reactions to NAC)&#xD;
&#xD;
          -  Use of anti-oxidants or drugs that can alter glucose metabolism&#xD;
&#xD;
          -  Concomitant medical problems that may prevent the subject from successfully completing&#xD;
             the protocol&#xD;
&#xD;
          -  Unwillingness to avoid exercise during the 7 days before each part of the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth Seaquist, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Minnesota Department of Medicine, Division of Diabetes, Endocrinology and Metabolism</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>May 23, 2014</study_first_submitted>
  <study_first_submitted_qc>July 31, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 1, 2014</study_first_posted>
  <results_first_submitted>November 5, 2019</results_first_submitted>
  <results_first_submitted_qc>January 21, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">January 31, 2020</results_first_posted>
  <last_update_submitted>January 21, 2020</last_update_submitted>
  <last_update_submitted_qc>January 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Hypoglycemia</keyword>
  <keyword>Unawareness</keyword>
  <keyword>HAAF</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Unconsciousness</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
    <mesh_term>Hypoglycemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <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>October 12, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/52/NCT02206152/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/52/NCT02206152/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Crossover design</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>All Participants</title>
          <description>Crossover design: All participants included in baseline data.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Pre-Randomization</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Placebo, Then NAC</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>NAC, Then Placebo</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>This is a cross-over trial. All participants for whom baseline data was collected (20 out of 22) are pooled and reported here.</population>
      <group_list>
        <group group_id="B1">
          <title>All Subjects</title>
          <description>All participants at baseline</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37.7" spread="13.6"/>
                  </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="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </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="0"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </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="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions</title>
        <description>Epinephrine secretion during hypoglycemia is assessed by collecting blood samples for measurement of epinephrine concentrations at baseline and every 15 minutes during the period of hypoglycemia (starting at point where blood glucose is first &lt; 55 mg/dl) in the clamp studies done in the mornings of days 1 and 2 of both parts 1 and 2. .</description>
        <time_frame>8-10 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp&#xD;
Placebo</description>
          </group>
          <group group_id="O2">
            <title>Treatment With N-Acetyl Cysteine</title>
            <description>N-acetyl cysteine IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp&#xD;
N-acetyl cysteine: N-acetyl cysteine (or saline) IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp</description>
          </group>
        </group_list>
        <measure>
          <title>Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions</title>
          <description>Epinephrine secretion during hypoglycemia is assessed by collecting blood samples for measurement of epinephrine concentrations at baseline and every 15 minutes during the period of hypoglycemia (starting at point where blood glucose is first &lt; 55 mg/dl) in the clamp studies done in the mornings of days 1 and 2 of both parts 1 and 2. .</description>
          <units>ug/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="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="622.8" spread="334.1"/>
                    <measurement group_id="O2" value="867" spread="675.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp&#xD;
Placebo</description>
        </group>
        <group group_id="E2">
          <title>Treatment With N-Acetyl Cysteine</title>
          <description>N-acetyl cysteine IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp&#xD;
N-acetyl cysteine: N-acetyl cysteine (or saline) IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp</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="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="20"/>
              </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>Elizabeth Seaquist, MD</name_or_title>
      <organization>University of Minenesota</organization>
      <phone>612-624-9176</phone>
      <email>chape044@umn.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/NCT02206152
org study id: Protocol 22498
nct id: NCT02206152
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a single center, double blind randomized cross over design trial that will compare
      the impact of N-acetyl cysteine (200 mg) vs. saline infusion during experimental hypoglycemia
      on day one on the responses to experimental hypoglycemia on day two. 18 participants will be
      studied twice, 8 weeks apart. On each occasion they will undergo a 2 hour hypoglycemic clamp
      (target 50 mg/dl) in the morning and in the afternoon on day one and then again on the
      morning of day 2 and day 3. During the morning clamps, samples will be collected for later
      measurement of serum epinephrine levels, plasma and red blood cell NAC, cysteine, and
      glutathione concentrations and GSH/GSSG ratios (redox status), and participants will be asked
      to complete a hypoglycemia symptom questionnaire
This study will consist of a screening visit and two 2-day intervention visits separated by
      approximately 8 weeks.

      At the screening visit, informed consent will be obtained, a standardized form will be used
      to ensure subjects meet inclusion/exclusion criteria, and baseline hemoglobin A1c will be
      obtained. On arrival, two IVs will be placed and they will be randomized to receive NAC or
      saline infusion. Baseline blood samples will be drawn for glucose, epinephrine,
      norepinephrine, cortisol, cysteine and glutathione measurements. Subjects will then be given
      25 mg IV diphenhydramine (Benadryl) followed by a 60 minute infusion of NAC (150 mg) or a
      similar volume of saline between 8 am and 9 am, followed by a four hour infusion of 50 mg of
      NAC. Thirty minutes after the start of the NAC infusion, a hyperinsulinemic (2.0 mu/kg/min)
      hypoglycemic (target = 50 mg/dl) clamp protocol will be started. During the morning study,
      blood samples will be collected every 5 minutes for monitoring of blood glucose levels and
      every 15 minutes for later measurement of serum epinephrine, norepinephrine, cortisol. Plasma
      and red blood cells samples will also be collected every 15 minutes for later measurement of
      NAC, cysteine, glutathione, and GSH/GSSG ratios (redox status). During the final 15 minutes
      of the morning clamp, subjects will be asked to quantitate their symptoms using a
      standardized method (13). At the completion of the morning clamp, glucose will be given to
      return the participant to euglycemia. 2 hours after the end of the morning clamp, a second
      hyperinsulinemic (2.0 mu/kg/min) hypoglycemic (target = 50 mg/dl) clamp protocol will be
      followed over two hours. . The afternoon clamp study will proceed as in the morning except
      that no serum or plasma will be collected except for the monitoring of glucose and collection
      of samples for subsequent measurement of NAC, cysteine, glutathione, and GSH/GSSG ratios.
      After the completion of the afternoon clamps, subjects will be returned to euglycemia and fed
      a meal. They will be discharged home.

      At 7 AM the following morning they will under a single 2 hour hyperinsulinemic hypoglycemic
      stepped clamp (75, 65, 55,45 mg/dl targets) during which blood samples will be collected as
      on the morning of day 1. Symptom scores will be collected in the final 15 minutes of each
      step in the clamp.

      At the completion of the study on day 2 of Part 1, they will be scheduled to return for Part
      2 in 8 weeks. This timing is selected to ensure that female participants are studied at the
      same phase of the menstrual cycle. During Part 2 they will receive the treatment not provided
      during Part 1 in a blinded fashion. The rest of the study protocol will be the same as in
      Part 1.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions
time frame: 8-10 weeks
description: Epinephrine secretion during hypoglycemia is assessed by collecting blood samples for measurement of epinephrine concentrations at baseline and every 15 minutes during the period of hypoglycemia (starting at point where blood glucose is first < 55 mg/dl) in the clamp studies done in the mornings of days 1 and 2 of both parts 1 and 2. .
arm group label: Placebo
arm group type: Placebo Comparator
description: Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp
arm group label: Treatment with N-Acetyl Cysteine
arm group type: Experimental
description: N-acetyl cysteine IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp
intervention type: Drug
intervention name: N-acetyl cysteine
description: N-acetyl cysteine (or saline) IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp
arm group label: Treatment with N-Acetyl Cysteine
other name: NAC
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Elizabeth Seaquist, MD
role: Principal Investigator
affiliation: University of Minnesota
facility: 
country: United States
responsible party type: Sponsor
mesh term: Unconsciousness
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Hypoglycemia
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 