<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/NCT03283670</url>
  </required_header>
  <id_info>
    <org_study_id>201608024</org_study_id>
    <nct_id>NCT03283670</nct_id>
  </id_info>
  <brief_title>Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies</brief_title>
  <acronym>NARSAD</acronym>
  <official_title>Inhaled Nitrous Oxide for Treatment-Resistant Depression: Optimizing Dosing Strategies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Brain &amp; Behavior Research Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study aims to determine whether different concentrations of nitrous oxide&#xD;
      (N2O) have different antidepressant effects for adults with treatment-resistant major&#xD;
      depression.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Most clinical major depression responds to standard treatments (medication and&#xD;
      psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond&#xD;
      to these treatments and are referred to as treatment-resistant major depression (TRMD). New&#xD;
      treatments for TRMD are needed, and one promising line of research are drugs known as&#xD;
      N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our&#xD;
      group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD.&#xD;
&#xD;
      All patients will receive 3 randomized, one hour nitrous oxide inhalations to placebo (0%&#xD;
      N2O), low dose (25% N2O), and high dose (50% N2O). Inhalation sessions will be at least 4&#xD;
      weeks apart. Mood will be assessed at baseline, 2 and 24 hours, and 1, 2, and 4 weeks&#xD;
      post-inhalation for each dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 22, 2016</start_date>
  <completion_date type="Actual">February 18, 2020</completion_date>
  <primary_completion_date type="Actual">February 18, 2020</primary_completion_date>
  <phase>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>
    <intervention_model_description>Each participant receives the 3 inhalation types in randomized, one hour sessions separated by at least 4 weeks</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items</measure>
    <time_frame>2 and 24 hours after inhalation</time_frame>
    <description>Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items. The HAMD-21 is designed to rate the severity of depression in patients. Although it contains 21 areas, calculate the patient's score as the total score on the first 17 answers. Scale: 0=absent, 4=worst level possible) the scores on the individual items are summed. Changes will be based on measurements obtained at baseline, approximately 2 hours after inhalation, and approximately 24 hours after inhalation. Changes are based on subtracti on of baseline score.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Depressive Disorder, Major</condition>
  <condition>Depressive Disorder, Treatment-Resistant</condition>
  <arm_group>
    <arm_group_label>1. 25% nitrous oxide, 25% nitrogen, 25% oxygen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2. 50% nitrous oxide, 50% oxygen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3. Placebo gas: 50% nitrogen(inert), 50% oxygen</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitrous Oxide 25%</intervention_name>
    <description>Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 25% nitrous oxide/50% oxygen/25% nitrogen.</description>
    <arm_group_label>1. 25% nitrous oxide, 25% nitrogen, 25% oxygen</arm_group_label>
    <other_name>One hour inhalation of 25% nitrous oxide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitrous Oxide 50%</intervention_name>
    <description>Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 50% nitrous oxide/50% oxygen.</description>
    <arm_group_label>2. 50% nitrous oxide, 50% oxygen</arm_group_label>
    <other_name>One hour inhalation of 50% nitrous oxide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Gas</intervention_name>
    <description>Placebo gas given at 50% nitrogen [inert]/50% oxygen.</description>
    <arm_group_label>3. Placebo gas: 50% nitrogen(inert), 50% oxygen</arm_group_label>
    <other_name>One hour inhalation of placebo gas</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Adults 18-75 years of age;&#xD;
&#xD;
          2. Current diagnosis of unipolar major depressive disorder (MDD) without psychosis as&#xD;
             confirmed by structured clinical interview for DSM-IV disorders;&#xD;
&#xD;
          3. A score of &gt;= 9 on the Montgomery-Åsberg Depression Rating Scale (MADRS);&#xD;
&#xD;
          4. Documented (i.e., chart review) lifetime failure to respond to &gt;=3 adequate&#xD;
             dose/duration antidepressant treatment trials, ≥1 medication failure in the current&#xD;
             depressive episode;&#xD;
&#xD;
          5. Good command of the English language.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Meets criteria for any DSM-IV diagnosis for schizophrenia, bipolar, schizoaffective,&#xD;
             obsessive-compulsive, personality, or panic disorders;&#xD;
&#xD;
          2. Any recent (within past 12 months) history of substance dependence or abuse (except&#xD;
             tobacco), determined by reported history or urine drug screen;&#xD;
&#xD;
          3. Ability to become pregnant and not using effective contraception;&#xD;
&#xD;
          4. Contraindication against the use of nitrous oxide:&#xD;
&#xD;
               1. Pneumothorax&#xD;
&#xD;
               2. Bowel obstruction&#xD;
&#xD;
               3. Middle ear occlusion&#xD;
&#xD;
               4. Elevated intracranial pressure&#xD;
&#xD;
               5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12&#xD;
&#xD;
               6. Pregnant patients&#xD;
&#xD;
               7. Breastfeeding women&#xD;
&#xD;
          5. Inability to provide informed consent;&#xD;
&#xD;
          6. Any other factor that in the investigators' judgment may affect patient safety or&#xD;
             compliance&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ben Palanca, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>November 9, 2016</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <results_first_submitted>February 9, 2021</results_first_submitted>
  <results_first_submitted_qc>March 28, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">April 4, 2022</results_first_posted>
  <last_update_submitted>March 28, 2022</last_update_submitted>
  <last_update_submitted_qc>March 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Washington University School of Medicine</investigator_affiliation>
    <investigator_full_name>Ben Palanca</investigator_full_name>
    <investigator_title>Associate Professor of Anesthesiology and Psychiatry</investigator_title>
  </responsible_party>
  <keyword>Depression</keyword>
  <keyword>treatment-resistant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Treatment-Resistant</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitrous Oxide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to share IPD.</ipd_description>
  </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>May 24, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/70/NCT03283670/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Study Participants</title>
          <description>Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.&#xD;
25% nitrous oxide, 25% nitrogen, 25% oxygen&#xD;
50% nitrous oxide, 50% oxygen&#xD;
Placebo gas: 50% nitrogen(inert), 50% oxygen</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Placebo Gas</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </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>25% Nitrous Oxide</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
              </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="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>50% Nitrous Oxide</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
              </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>Study Participants</title>
          <description>Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.&#xD;
25% nitrous oxide, 25% nitrogen, 25% oxygen&#xD;
50% nitrous oxide, 50% oxygen&#xD;
Placebo gas: 50% nitrogen(inert), 50% oxygen</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>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="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44" lower_limit="26" upper_limit="68"/>
                  </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="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </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="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items</title>
        <description>Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items. The HAMD-21 is designed to rate the severity of depression in patients. Although it contains 21 areas, calculate the patient's score as the total score on the first 17 answers. Scale: 0=absent, 4=worst level possible) the scores on the individual items are summed. Changes will be based on measurements obtained at baseline, approximately 2 hours after inhalation, and approximately 24 hours after inhalation. Changes are based on subtracti on of baseline score.</description>
        <time_frame>2 and 24 hours after inhalation</time_frame>
        <group_list>
          <group group_id="O1">
            <title>25% Nitrous Oxide</title>
            <description>25% nitrous oxide, 25% nitrogen, 25% oxygen. Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
          </group>
          <group group_id="O2">
            <title>50% Nitrous Oxide</title>
            <description>50% nitrous oxide, 50% oxygen. Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
          </group>
          <group group_id="O3">
            <title>Placebo Gas</title>
            <description>50% nitrogen(inert), 50% oxygen. Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items</title>
          <description>Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items. The HAMD-21 is designed to rate the severity of depression in patients. Although it contains 21 areas, calculate the patient's score as the total score on the first 17 answers. Scale: 0=absent, 4=worst level possible) the scores on the individual items are summed. Changes will be based on measurements obtained at baseline, approximately 2 hours after inhalation, and approximately 24 hours after inhalation. Changes are based on subtracti on of baseline score.</description>
          <units>score on a scale</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="23"/>
                <count group_id="O3" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>2 Hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.0" spread="3.9"/>
                    <measurement group_id="O2" value="-3.8" spread="4.30"/>
                    <measurement group_id="O3" value="-3.9" spread="4.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>24 Hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.0" spread="6.6"/>
                    <measurement group_id="O2" value="-5.5" spread="5.8"/>
                    <measurement group_id="O3" value="-6.0" spread="6.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>HAMD-21 at 2 Hours, placebo vs 25% nitrous oxide</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.55</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.75</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Change in HAMD-21, 25% nitrous oxide vs placebo at 24 hours</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.47</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.4</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>HAMD-21 at 2 Hours, placebo vs 50% nitrous oxide</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.49</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Median Difference (Net)</param_type>
            <param_value>-0.87</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Change in HAMD-21 at 24 hours, placebo vs 50% nitrous oxide</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.34</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.9</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Change in HAMD-21 at 2 hours, 25% nitrous oxide vs 50% nitrous oxide</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.94</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.11</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Change in HAMD-21 at 24 hours, 25% nitrous oxide vs 50% nitrous oxide</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.80</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.5</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>18 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Placebo gas: 50% nitrogen(inert), 50% oxygen</description>
        </group>
        <group group_id="E2">
          <title>25% Nitrous Oxide</title>
          <description>25% nitrous oxide, 25% nitrogen, 25% oxygen</description>
        </group>
        <group group_id="E3">
          <title>50% Nitrous Oxide</title>
          <description>50% nitrous oxide, 50% oxygen</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="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="23"/>
              </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="5" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Intestinal gas</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Stomach virus</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Car crash (minor)</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Common cold/strep throat</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Cramps</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Haziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Lightheadedness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Feeling high</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Sleepiness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Weakness/heave</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Tingling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Fainting spell</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Laughing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Feeling disconnected</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Memory gaps</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Paranoia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Ben Palanca, MD PhD</name_or_title>
      <organization>Washington University</organization>
      <phone>314 273-9076</phone>
      <email>palancab@wustl.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/NCT03283670
org study id: 201608024
nct id: NCT03283670
lead sponsor: 
collaborator: 
has dmc: No
The purpose of the study aims to determine whether different concentrations of nitrous oxide
      (N2O) have different antidepressant effects for adults with treatment-resistant major
      depression.
Most clinical major depression responds to standard treatments (medication and
      psychotherapy); however, a significant subset of depressed patients (15-20%) do not respond
      to these treatments and are referred to as treatment-resistant major depression (TRMD). New
      treatments for TRMD are needed, and one promising line of research are drugs known as
      N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. In a recent pilot study, our
      group demonstrated that the NMDA antagonist nitrous oxide is effective in TRMD.

      All patients will receive 3 randomized, one hour nitrous oxide inhalations to placebo (0%
      N2O), low dose (25% N2O), and high dose (50% N2O). Inhalation sessions will be at least 4
      weeks apart. Mood will be assessed at baseline, 2 and 24 hours, and 1, 2, and 4 weeks
      post-inhalation for each dose.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Each participant receives the 3 inhalation types in randomized, one hour sessions separated by at least 4 weeks
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Change in Depression Symptoms Measured by the Hamilton Depression Rating Scale- 21 Items
time frame: 2 and 24 hours after inhalation
description: Change in depression symptoms measured by the Hamilton Depression Rating Scale- 21 items. The HAMD-21 is designed to rate the severity of depression in patients. Although it contains 21 areas, calculate the patient's score as the total score on the first 17 answers. Scale: 0=absent, 4=worst level possible) the scores on the individual items are summed. Changes will be based on measurements obtained at baseline, approximately 2 hours after inhalation, and approximately 24 hours after inhalation. Changes are based on subtracti on of baseline score.
arm group label: 1. 25% nitrous oxide, 25% nitrogen, 25% oxygen
arm group type: Experimental
description: Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
arm group label: 2. 50% nitrous oxide, 50% oxygen
arm group type: Experimental
description: Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
arm group label: 3. Placebo gas: 50% nitrogen(inert), 50% oxygen
arm group type: Placebo Comparator
description: Participants will be studied for 14 visits over approximately 18 weeks. The participants will receive 1 hour-long gas inhalation mixtures at 3 different times, which are randomly assigned.
intervention type: Drug
intervention name: Nitrous Oxide 25%
description: Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 25% nitrous oxide/50% oxygen/25% nitrogen.
arm group label: 1. 25% nitrous oxide, 25% nitrogen, 25% oxygen
other name: One hour inhalation of 25% nitrous oxide
intervention type: Drug
intervention name: Nitrous Oxide 50%
description: Nitrous oxide, an odorless, colorless gas typically used as an induction agent for general anesthesia or for dental sedation, is a known N-methyl-D-aspartate (NMDA) antagonist. It will be given at a concentration of 50% nitrous oxide/50% oxygen.
arm group label: 2. 50% nitrous oxide, 50% oxygen
other name: One hour inhalation of 50% nitrous oxide
intervention type: Drug
intervention name: Placebo Gas
description: Placebo gas given at 50% nitrogen [inert]/50% oxygen.
arm group label: 3. Placebo gas: 50% nitrogen(inert), 50% oxygen
other name: One hour inhalation of placebo gas
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Ben Palanca, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Washington University School of Medicine
investigator full name: Ben Palanca
investigator title: Associate Professor of Anesthesiology and Psychiatry
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Treatment-Resistant
mesh term: Depressive Disorder, Major
mesh term: Nitrous Oxide
sharing ipd: No
ipd description: There is no plan to share IPD.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 