<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/NCT04466384</url>
  </required_header>
  <id_info>
    <org_study_id>MDT19049SONORA</org_study_id>
    <nct_id>NCT04466384</nct_id>
  </id_info>
  <brief_title>Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA)</brief_title>
  <acronym>SONORA</acronym>
  <official_title>Bispectral Index and Levels of Sedation With Propofol With/Without Remifentanil in Healthy Volunteers (SONORA)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medtronic - MITG</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medtronic - MITG</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is investigate the relationship between BIS™ and propofol&#xD;
      with/without remifentanil across a wide range of hypnotic states.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-center, prospective, non-randomized, cross-over study to collect data to&#xD;
      evaluate the relationship between BIS™ and anesthetic regimens. The subjects will receive two&#xD;
      regimens of anesthesia with different drug combinations, with at least a 1-week washout&#xD;
      period between regimens. Subjects will be sequentially assigned to start with either Propofol&#xD;
      (P) or Propofol with 4 ng/ml of Remifentanil (R) regimens while BIS™ bilateral sensor placed&#xD;
      on the subject's forehead. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S)&#xD;
      scale, refer to Appendix A, will be used to measure the level of alertness in sedated&#xD;
      subjects with Tetanic Electrical Stimulation (TES) being used once subjects reach a MOAA/S&#xD;
      score &lt;2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 11, 2020</start_date>
  <completion_date type="Actual">March 3, 2021</completion_date>
  <primary_completion_date type="Actual">March 3, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>The subjects will receive two regimens of anesthesia with different drug combinations, with at least a 1-week washout period between regimens. Subjects will be sequentially assigned to start with either propofol or propofol with remifentanil regiments.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>BIS50</measure>
    <time_frame>4 hours</time_frame>
    <description>To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS50.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>BIS95</measure>
    <time_frame>4 hours</time_frame>
    <description>To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS95.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Anesthesia</condition>
  <arm_group>
    <arm_group_label>Propofol</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Propofol will be started at a concentration of 0.5 µg/ml followed by incremental increases in the target effect-site concentrations of 1.5, 2, 2.5, 3, 4, 6, and 8 µg/ml until a MOAA/S score less than 2 is reached.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Propofol with Remifentanil</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Approximately 2 minutes before starting propofol, to attain an effect-site targeted concentration of remifentanil of 4 ng/ml, remifentanil will be given by a continuous infusion. Within approximately 7 minutes, the infusion rate of Remifentanil may be adjusted to maintain the effect-site concentration of remifentanil of 4 ng/ml throughout the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>BIS</intervention_name>
    <description>Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.</description>
    <arm_group_label>Propofol</arm_group_label>
    <arm_group_label>Propofol with Remifentanil</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy (ASA physical status 1), male or female subjects between the ages of 18 to 60&#xD;
             years;&#xD;
&#xD;
          2. Completion of a health screening for a medical history by a licensed physician, nurse&#xD;
             practitioner or physician assistant;&#xD;
&#xD;
          3. Vital signs must be within the following ranges to be included: Vital signs measured&#xD;
             sitting after 3 minutes rest; heart rate: 45-90 bpm; systolic blood pressure: 110-140;&#xD;
             diastolic blood pressure: 50-90. Out-of-range vital signs may be repeated once.&#xD;
             [Pre-dose vital signs will be assessed by the Principal Investigator or designee&#xD;
             (e.g., a medically qualified sub-investigator) before study drug administration. The&#xD;
             Principal Investigator or designee will verify the eligibility of each subject before&#xD;
             dosing];&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Has severe contact allergies that may cause a reaction to standard adhesive materials&#xD;
             found in pulse oximetry sensors, ECG electrodes, respiration monitor electrodes, or&#xD;
             other medical sensors [self-reported];&#xD;
&#xD;
          2. Known neurological disorder (e.g., epilepsy, the presence of a brain tumor, a history&#xD;
             of brain surgery, hydrocephalic disorders, depression needing treatment with&#xD;
             anti-depressive drugs, a history of brain trauma) [self-reported and assessment by PI&#xD;
             or delegate];&#xD;
&#xD;
          3. Known cardiovascular disease (e.g., hypertension, coronary artery disease, prior acute&#xD;
             myocardial infarction, any valvular and/or myocardial disease involving a decrease in&#xD;
             ejection fraction, arrhythmias, which are either symptomatic or require continuous&#xD;
             medication/ pacemaker/ automatic internal cardioverter defibrillator), current&#xD;
             implanted pacemaker or automatic internal cardioverter defibrillator [self-reported&#xD;
             and assessment by PI or delegate];&#xD;
&#xD;
          4. Has a clinically significant abnormal finding on medical history, physical&#xD;
             examination, clinical laboratory tests, or ECG at the screening [self-reported and&#xD;
             assessment by PI or delegate];&#xD;
&#xD;
          5. Recent use of psychoactive medication (e.g., benzodiazepines, antiepileptic drugs,&#xD;
             ADHD medication, Parkinson's medication, anti-depressant drugs, opioids)&#xD;
             [self-reported and assessment by PI or delegate];&#xD;
&#xD;
          6. Subjects with known gastric diseases [self-reported and assessment by PI or delegate];&#xD;
&#xD;
          7. Has a positive urine cotinine test or urine drug screen or oral ethanol test [POC&#xD;
             testing];&#xD;
&#xD;
          8. Known history of allergic or adverse response to drugs to be administered&#xD;
             [self-reported];&#xD;
&#xD;
          9. Known history of complications relating to previous general anesthesia or conscious&#xD;
             sedation [self-reported and assessment by PI or delegate];&#xD;
&#xD;
         10. Known history of malignant hyperthermia [self-reported and assessment by PI or&#xD;
             delegate];&#xD;
&#xD;
         11. Has a room air saturation less than 95% by pulse oximetry [measurement by PI or&#xD;
             delegate];&#xD;
&#xD;
         12. Has a clinically significant abnormal ECG [assessment by PI or delegate];&#xD;
&#xD;
         13. Has a clinically significant abnormal pulmonary function test via spirometry&#xD;
             [assessment by PI or delegate];&#xD;
&#xD;
         14. Pregnant or lactating women [assessed by urine test and self-reported];&#xD;
&#xD;
         15. Subjects with tattooed skin specific to the sensor placement areas (forehead, fingers,&#xD;
             chest) [self-reported and assessment by PI or delegate];&#xD;
&#xD;
         16. The subject must not take any prescription medication, except female hormonal&#xD;
             contraceptives or hormone replacement therapy, from 146 days before the dosing until&#xD;
             the end-of-study visit without evaluation and approval by the Investigator. Subjects&#xD;
             who participated in a previous clinical trial who received a required FDA approved&#xD;
             concomitant medication, for example, naltrexone, but were not randomized may be&#xD;
             considered for participation in this study if they meet the washout requirement&#xD;
             [assessment by PI or delegate];&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 7, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <results_first_submitted>February 28, 2022</results_first_submitted>
  <results_first_submitted_qc>May 9, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">June 8, 2022</results_first_posted>
  <last_update_submitted>July 5, 2022</last_update_submitted>
  <last_update_submitted_qc>July 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 28, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/84/NCT04466384/Prot_002.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 5, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/84/NCT04466384/SAP_004.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study recruited healthy, non-smoking (or has refrained from smoking for 2 days) subjects, 18 to 60 years of age. The subjects were distributed across both sexes as equally as practical.</recruitment_details>
      <pre_assignment_details>During the study, 34 subjects were consented. 6 subjects were inclusion / exclusion criteria screen failures after consent leaving 28 enrolled subjects. Of these 28 enrolled subjects, 4 subjects were withdrawn due to safety events leaving 24 subjects to be assigned to randomization arms.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Propofol First</title>
          <description>Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).</description>
        </group>
        <group group_id="P2">
          <title>First Propofol With Remifentanil</title>
          <description>Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Missing data</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Cross Over Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>the subjects received two regimens of anesthesia with different drug combinations, with at least a 1-week washout period between regimens. Once the pre-procedure part was completed, the subject was sequentially assigned to start with either Propofol (P) or Propofol with 4 ng/ml of Remifentanil (R) regimens.&#xD;
The Safety Population includes all ITT subjects (results will be shown accordingly).</population>
      <group_list>
        <group group_id="B1">
          <title>Randomized Study Participants</title>
          <description>Baseline measures are reported for subjects who were enrolled and randomized to Propofol first or First Propofol with Remifentanil arms (n=24). Baseline measurements are not reported for subjects who were screen failures (n=6) or withdrawn due to safety events (n=4).</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="24"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="28.5" spread="7.8"/>
                  </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="15"/>
                  </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="23"/>
                  </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>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="4"/>
                  </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="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </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="1"/>
                  </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="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Skin Pigmentation</title>
          <description>The Fitzpatrick scale was used to evaluate skin pigmentation</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Very Light</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Olive Hue</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dark Olive</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extremely Dark</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>BIS50</title>
        <description>To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS50.</description>
        <time_frame>4 hours</time_frame>
        <population>Intention to Treat (ITT)</population>
        <group_list>
          <group group_id="O1">
            <title>Propofol</title>
            <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Propofol will be started at a concentration of 0.5 µg/ml followed by incremental increases in the target effect-site concentrations of 1.5, 2, 2.5, 3, 4, 6, and 8 µg/ml until a MOAA/S score less than 2 is reached.&#xD;
BIS: Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.</description>
          </group>
          <group group_id="O2">
            <title>Propofol With Remifentanil</title>
            <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Approximately 2 minutes before starting propofol, to attain an effect-site targeted concentration of remifentanil of 4 ng/ml, remifentanil will be given by a continuous infusion. Within approximately 7 minutes, the infusion rate of Remifentanil may be adjusted to maintain the effect-site concentration of remifentanil of 4 ng/ml throughout the study.&#xD;
BIS: Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.</description>
          </group>
        </group_list>
        <measure>
          <title>BIS50</title>
          <description>To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS50.</description>
          <population>Intention to Treat (ITT)</population>
          <units>BIS50 Index Score</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.4" lower_limit="57.7" upper_limit="63.0"/>
                    <measurement group_id="O2" value="71.6" lower_limit="69.0" upper_limit="74.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>BIS95</title>
        <description>To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS95.</description>
        <time_frame>4 hours</time_frame>
        <population>Intention to Treat (ITT)</population>
        <group_list>
          <group group_id="O1">
            <title>Propofol</title>
            <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Propofol will be started at a concentration of 0.5 µg/ml followed by incremental increases in the target effect-site concentrations of 1.5, 2, 2.5, 3, 4, 6, and 8 µg/ml until a MOAA/S score less than 2 is reached.&#xD;
BIS: Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.</description>
          </group>
          <group group_id="O2">
            <title>Propofol With Remifentanil</title>
            <description>Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Approximately 2 minutes before starting propofol, to attain an effect-site targeted concentration of remifentanil of 4 ng/ml, remifentanil will be given by a continuous infusion. Within approximately 7 minutes, the infusion rate of Remifentanil may be adjusted to maintain the effect-site concentration of remifentanil of 4 ng/ml throughout the study.&#xD;
BIS: Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.</description>
          </group>
        </group_list>
        <measure>
          <title>BIS95</title>
          <description>To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an &quot;awake&quot; clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS95.</description>
          <population>Intention to Treat (ITT)</population>
          <units>BIS95 index score</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.7" lower_limit="40.5" upper_limit="51.7"/>
                    <measurement group_id="O2" value="63.1" lower_limit="57.3" upper_limit="66.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>48 hours</time_frame>
      <desc>For the adverse event analysis, events were analyzed for the two treatment groups (Propofol + Opioid vs. Propofol).</desc>
      <group_list>
        <group group_id="E1">
          <title>Propofol First (First Phase)</title>
          <description>Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).</description>
        </group>
        <group group_id="E2">
          <title>First Propofol With Remifentanil (First Phase)</title>
          <description>Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).</description>
        </group>
        <group group_id="E3">
          <title>Propofol First (Cross Over Phase)</title>
          <description>Participants first received two regimens of Propofol (first phase). After a 1-week washout period, then received two regimens of Propofol with 4 ng/ml Remifentanil (cross over phase).</description>
        </group>
        <group group_id="E4">
          <title>First Propofol With Remifentanil (Cross Over Phase)</title>
          <description>Participants first received two regimens of Propofol with 4 ng/ml Remifentanil (first phase). After a 1-week washout period, then received two regimens of Propofol (cross over phase).</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="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="10"/>
              </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="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="10"/>
              </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="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Haematemesis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>COVID-19</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </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>
    <limitations_and_caveats>While there are known risks with providing general anesthesia to adults, this study was deemed to be a non-significant risk study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Ami Stuart PhD</name_or_title>
      <organization>Medtronic</organization>
      <phone>8017934800</phone>
      <email>ami.stuart@medtronic.com</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/NCT04466384
org study id: MDT19049SONORA
nct id: NCT04466384
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
The purpose of this study is investigate the relationship between BIS™ and propofol
      with/without remifentanil across a wide range of hypnotic states.
This is a single-center, prospective, non-randomized, cross-over study to collect data to
      evaluate the relationship between BIS™ and anesthetic regimens. The subjects will receive two
      regimens of anesthesia with different drug combinations, with at least a 1-week washout
      period between regimens. Subjects will be sequentially assigned to start with either Propofol
      (P) or Propofol with 4 ng/ml of Remifentanil (R) regimens while BIS™ bilateral sensor placed
      on the subject's forehead. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S)
      scale, refer to Appendix A, will be used to measure the level of alertness in sedated
      subjects with Tetanic Electrical Stimulation (TES) being used once subjects reach a MOAA/S
      score <2.
allocation: Non-Randomized
intervention model: Crossover Assignment
intervention model description: The subjects will receive two regimens of anesthesia with different drug combinations, with at least a 1-week washout period between regimens. Subjects will be sequentially assigned to start with either propofol or propofol with remifentanil regiments.
primary purpose: Other
masking: None (Open Label)
measure: BIS50
time frame: 4 hours
description: To determine BIS50 (BIS™ value at which 50% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an "awake" clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/ Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS50.
measure: BIS95
time frame: 4 hours
description: To determine BIS95 (BIS™ value at which 95% of patients will be unresponsive at given drug concentrations) and other dose-response parameters. BIS™ is a scale 0-100 with values near 100 represent an "awake" clinical state while 0 denotes the maximal EEG effect possible (i.e., an isoelectric EEG). Responsiveness is measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). Below a MOAA/S of 2, responsiveness is measured with Tetanic Electrical Stimulation (TES). The subject will receive one stimulation of 50mA, 50 Hz for 5 seconds. Their response, such as withdrawal of the extremity, a facial grimace, or a verbal groan will be recorded. Approximately 2 minutes after this assessment, the BIS™ value will be recorded. When the subject does not respond to the TES stimulation, they will be considered unresponsive and that BIS™ value will be used to determine the BIS95.
arm group label: Propofol
arm group type: Other
description: Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Propofol will be started at a concentration of 0.5 µg/ml followed by incremental increases in the target effect-site concentrations of 1.5, 2, 2.5, 3, 4, 6, and 8 µg/ml until a MOAA/S score less than 2 is reached.
arm group label: Propofol with Remifentanil
arm group type: Other
description: Subjects will be sequentially assigned to start with propofol or propofol with remifentanil. Approximately 2 minutes before starting propofol, to attain an effect-site targeted concentration of remifentanil of 4 ng/ml, remifentanil will be given by a continuous infusion. Within approximately 7 minutes, the infusion rate of Remifentanil may be adjusted to maintain the effect-site concentration of remifentanil of 4 ng/ml throughout the study.
intervention type: Device
intervention name: BIS
description: Subjects will be sequentially assigned to the propofol or propofol and remifentanil group. The purpose is to capture the BIS value in association with these anesthetics.
arm group label: Propofol
arm group label: Propofol with Remifentanil
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: While there are known risks with providing general anesthesia to adults, this study was deemed to be a non-significant risk study.
point of contact: 