<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/NCT03238300</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00058771</org_study_id>
    <secondary_id>K23AA025399</secondary_id>
    <nct_id>NCT03238300</nct_id>
  </id_info>
  <brief_title>Neuroscience-Informed Treatment Development for Adolescent Alcohol Use</brief_title>
  <official_title>Neuroscience-Informed Treatment Development for Adolescent Alcohol Use</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of South Carolina</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Alcohol Abuse and Alcoholism (NIAAA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical University of South Carolina</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will examine the effect of N-Acetylcysteine (NAC), an over-the-counter antioxidant&#xD;
      supplement, on brains of youth (ages 15-19) using magnetic resonance imaging (MRI).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      55 adolescents will receive, in a counterbalanced order, a 10-day course of NAC 1200 mg twice&#xD;
      daily and a subsequent 10-day course of matched placebo twice daily, separated by 11 days.&#xD;
      Urine and blood samples will be collected at baseline and urine samples again before and&#xD;
      after each course of medication treatment. Participants will receive a 1- hour MRI scan at&#xD;
      baseline and after each treatment trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 16, 2017</start_date>
  <completion_date type="Actual">March 1, 2022</completion_date>
  <primary_completion_date type="Actual">March 1, 2022</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>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region.</measure>
    <time_frame>31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)</time_frame>
    <description>Using magnetic resonance spectroscopy and a within-subjects design, we will determine the effect of N-Acetylcysteine versus placebo on modulating anterior cingulate glutamate levels in adolescents. Values provided are absolute values (mmol/kg) at the end of each intervention period. Due to complexities of this method, &quot;normal&quot; levels of glutamate are not known; thus, we cannot make conclusions about the meaning of &quot;higher&quot; or &quot;lower&quot; glutamate levels when comparing N-acetylcysteine to placebo.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task.</measure>
    <time_frame>31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)</time_frame>
    <description>Assessing the change in neural reactivity to alcohol cues after each round of medication: Placebo vs. N-Acetylcysteine.&#xD;
Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen.&#xD;
Change in BOLD signal are reported in Z-scores. A Z-score of 0 would indicate there is no statistical difference in BOLD signal between alcohol images and non-alcohol beverage images. A higher Z-score would indicated a higher BOLD signal during alcohol images compared to non-alcohol beverage images. A lower Z-score would indicate a lower BOLD signal during alcohol images compared to non-alcohol beverage images.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Alcohol Drinking</condition>
  <condition>Control</condition>
  <arm_group>
    <arm_group_label>N-Acetylcysteine, then Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants first received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, they then received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo, then N-Acetylcysteine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants first received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, they then received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-Acetylcysteine</intervention_name>
    <description>N-Acetylcysteine; 600mg capsules by mouth, two pills twice daily (total 2400 mg/day). Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.</description>
    <arm_group_label>N-Acetylcysteine, then Placebo</arm_group_label>
    <arm_group_label>Placebo, then N-Acetylcysteine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>N-acetylcysteine-matched placebo tablet two pills twice daily. Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.</description>
    <arm_group_label>N-Acetylcysteine, then Placebo</arm_group_label>
    <arm_group_label>Placebo, then N-Acetylcysteine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria: Participants were between the ages of 15-19 and may or may not have&#xD;
        used alcohol. All participants in the alcohol-using group met criteria for heavy drinking,&#xD;
        based on quantity and frequency of drinking (Squeglia et al. 2011; Squeglia et al. 2012)&#xD;
        (see Figure 2).&#xD;
&#xD;
        Exclusionary criteria: Not having a parent to consent (for those under age 18); history of&#xD;
        alcohol treatment or treatment-seeking; current DSM-5 diagnosis of moderate or severe&#xD;
        substance use disorder other than alcohol or cannabis (American Psychiatric Association&#xD;
        2013); positive urine toxicology screen for narcotics, amphetamines, sedatives, hypnotics,&#xD;
        or opiates (not prescribed by a doctor); alcohol withdrawal (&gt; 10 on the Clinical Institute&#xD;
        Withdrawal Assessment for Alcohol (Sullivan et al. 1989); medical conditions or medications&#xD;
        that contraindicate taking NAC; current use of N-acetylcysteine or any supplement&#xD;
        containing N-acetylcysteine (must agree not to take any such supplement throughout study&#xD;
        participation); medical history of severe asthma (uncontrolled with medication); history of&#xD;
        a serious medical, psychiatric, or neurological problem that could affect neural response,&#xD;
        brain development, or study participation, including diabetes, seizure disorder, and severe&#xD;
        head injury with loss of consciousness; history of learning disability, pervasive&#xD;
        developmental disorder, or other condition requiring special education; current use of&#xD;
        psychoactive medications that affect cerebral blood flow; non-correctable visual or hearing&#xD;
        problems; non-fluent in English; MRI contraindications (e.g., braces, claustrophobia,&#xD;
        irremovable metal implants or piercings); (for females) pregnancy or refusal to use&#xD;
        reliable methods of birth control; refusal of blood draw, abstinence from alcohol for &gt;14&#xD;
        days before participation, and use of alcohol &lt;12 hours before scanning (confirmed with&#xD;
        breathalyzer). While cigarette and marijuana use will not be exclusionary, we will exclude&#xD;
        any participants who are daily users of cannabis or tobacco.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>19 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lindsay M Squeglia, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University of South Carolina</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 31, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <results_first_submitted>April 17, 2023</results_first_submitted>
  <results_first_submitted_qc>June 20, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 22, 2023</results_first_posted>
  <last_update_submitted>June 20, 2023</last_update_submitted>
  <last_update_submitted_qc>June 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of South Carolina</investigator_affiliation>
    <investigator_full_name>Lindsay Squeglia</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>adolescent</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcohol Drinking</mesh_term>
    <mesh_term>Underage Drinking</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan: Detailed Protocol &amp; General Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/00/NCT03238300/Prot_SAP_003.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan: Detailed SAP</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>November 30, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/00/NCT03238300/SAP_004.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/00/NCT03238300/ICF_005.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>57 participants were screened for eligibility between October 16, 2017 and February 18, 2022 at the Medical University of South Carolina.</recruitment_details>
      <pre_assignment_details>35 of 57 were randomized. Of those not randomized, 12 were ineligible, 6 declined to participate, and 4 withdrew or were withdrawn during the baseline visit.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>N-Acetylcysteine, Then Placebo</title>
          <description>N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days.</description>
        </group>
        <group group_id="P2">
          <title>Placebo, Then N-Acetylcysteine</title>
          <description>Placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Baseline (Before Intervention)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <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="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>First Intervention (10-Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period (11-Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </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 group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Second Intervention (10-Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="16"/>
              </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>Lost to Follow-up</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="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>N-Acetylcysteine, Then Placebo</title>
          <description>N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days.</description>
        </group>
        <group group_id="B2">
          <title>Placebo, Then N-Acetylcysteine</title>
          <description>Placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="18"/>
            <count group_id="B2" value="17"/>
            <count group_id="B3" value="35"/>
          </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="18.90" spread="0.75"/>
                    <measurement group_id="B2" value="18.79" spread="0.60"/>
                    <measurement group_id="B3" value="18.85" spread="0.67"/>
                  </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 group_id="B2" value="11"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="15"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region.</title>
        <description>Using magnetic resonance spectroscopy and a within-subjects design, we will determine the effect of N-Acetylcysteine versus placebo on modulating anterior cingulate glutamate levels in adolescents. Values provided are absolute values (mmol/kg) at the end of each intervention period. Due to complexities of this method, &quot;normal&quot; levels of glutamate are not known; thus, we cannot make conclusions about the meaning of &quot;higher&quot; or &quot;lower&quot; glutamate levels when comparing N-acetylcysteine to placebo.</description>
        <time_frame>31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>N-Acetylcysteine</title>
            <description>N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days</description>
          </group>
        </group_list>
        <measure>
          <title>Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region.</title>
          <description>Using magnetic resonance spectroscopy and a within-subjects design, we will determine the effect of N-Acetylcysteine versus placebo on modulating anterior cingulate glutamate levels in adolescents. Values provided are absolute values (mmol/kg) at the end of each intervention period. Due to complexities of this method, &quot;normal&quot; levels of glutamate are not known; thus, we cannot make conclusions about the meaning of &quot;higher&quot; or &quot;lower&quot; glutamate levels when comparing N-acetylcysteine to placebo.</description>
          <units>mmol/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.7527667" spread="0.748460934"/>
                    <measurement group_id="O2" value="15.6265229" spread="0.778392692"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>With 31 participants, the study has 99% power to detect such effects on glutamate levels (calculated based on d =1.13 [reported in Schmaal et al., 2012], α = 0.05, two-tailed).&#xD;
We used linear mixed effects models with random intercepts with medication, visit, and sequence. Baseline metabolite levels and brain tissue composition [GM:BM = GM/(GM+WM)], cannabis use (days), and alcohol use disorder status (Yes/No) were included as covariates.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&gt;0.05</p_value>
            <p_value_desc>P-value &gt;0.05 for main effect of medication (N-acetylcysteine vs. placebo)</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Random intercepts were used</method_desc>
            <param_type>partial eta squared</param_type>
            <param_value>0.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.00</ci_lower_limit>
            <ci_upper_limit>0.22</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task.</title>
        <description>Assessing the change in neural reactivity to alcohol cues after each round of medication: Placebo vs. N-Acetylcysteine.&#xD;
Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen.&#xD;
Change in BOLD signal are reported in Z-scores. A Z-score of 0 would indicate there is no statistical difference in BOLD signal between alcohol images and non-alcohol beverage images. A higher Z-score would indicated a higher BOLD signal during alcohol images compared to non-alcohol beverage images. A lower Z-score would indicate a lower BOLD signal during alcohol images compared to non-alcohol beverage images.</description>
        <time_frame>31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>N-Acetylcysteine</title>
            <description>N-Acetylcysteine 600mg capsules by mouth, two pills twice daily for 10 days.&#xD;
N-Acetylcysteine: N-Acetylcysteine pill.</description>
          </group>
          <group group_id="O2">
            <title>Placebo Oral Capsule</title>
            <description>Placebo capsules by mouth, two pills twice daily for 10 days.&#xD;
Placebo Oral Capsule: Sugar pill to mimic.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task.</title>
          <description>Assessing the change in neural reactivity to alcohol cues after each round of medication: Placebo vs. N-Acetylcysteine.&#xD;
Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen.&#xD;
Change in BOLD signal are reported in Z-scores. A Z-score of 0 would indicate there is no statistical difference in BOLD signal between alcohol images and non-alcohol beverage images. A higher Z-score would indicated a higher BOLD signal during alcohol images compared to non-alcohol beverage images. A lower Z-score would indicate a lower BOLD signal during alcohol images compared to non-alcohol beverage images.</description>
          <units>Z-score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Left Amygdala</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.649576194" spread="0.968974541"/>
                    <measurement group_id="O2" value="0.3018234193548" spread="0.841575583"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Amygdala</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.56294871" spread="0.999382512"/>
                    <measurement group_id="O2" value="0.210653871" spread="0.946731462"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left Caudate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.137316806" spread="0.970053483"/>
                    <measurement group_id="O2" value="0.110683871" spread="0.826040069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Caudate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.065642839" spread="1.100274051"/>
                    <measurement group_id="O2" value="0.031422161" spread="0.79443319"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left Insula</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.258198161" spread="1.142477966"/>
                    <measurement group_id="O2" value="0.058738871" spread="0.846769387"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Insula</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.429143032" spread="1.2071406050607"/>
                    <measurement group_id="O2" value="-0.169528194" spread="1.075103119"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left Nucleus Accumbens</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.347468645" spread="1.0725798"/>
                    <measurement group_id="O2" value="0.2095879354838" spread="0.697815244"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Nucleus Accumbens</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.240204258" spread="1.151021574"/>
                    <measurement group_id="O2" value="0.072915871" spread="0.9231385308441"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left Putamen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.138118065" spread="0.894080737"/>
                    <measurement group_id="O2" value="0.225092871" spread="0.989678164"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Putamen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.165481516" spread="0.818905961"/>
                    <measurement group_id="O2" value="0.058414516" spread="0.9453397543003"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Contrast of interest was alcohol beverages vs. non-alcohol beverages. We used linear mixed effects models with random intercepts with medication, visit, and sequence. Baseline reactivity levels for each ROI, cannabis use (days), and an alcohol use covariate (quantity, frequency, AUD status, or AUD severity - depending on which best fit the model) were included as covariates. ROIs included were (left and right hemisphere): amygdala, caudate, insula, putamen, and nucleus accumbens.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&gt;0.05</p_value>
            <p_value_desc>P-value &gt;0.05 for main effect of medication (N-acetylcysteine vs. placebo) for all ROIs.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Random intercepts were used for all models.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>31 days (10 days of first intervention, 11-day wash out, 10 days of second intervention) Intervention = N-acetylcysteine, then Placebo OR Placebo, then N-acetylcysteine</time_frame>
      <desc>Participants were asked about adverse events at every visit, either from a research assistant, principal investigator, medical clinician, or other study staff.</desc>
      <group_list>
        <group group_id="E1">
          <title>N-Acetylcysteine</title>
          <description>N-Acetylcysteine 600mg capsules by mouth, two pills twice daily for 10 days.&#xD;
N-Acetylcysteine: N-Acetylcysteine pill.</description>
        </group>
        <group group_id="E2">
          <title>Placebo Oral Capsule</title>
          <description>Placebo capsules by mouth, two pills twice daily for 10 days.&#xD;
Placebo Oral Capsule: Sugar pill to mimic.</description>
        </group>
        <group group_id="E3">
          <title>Washout Period</title>
          <description>11-days with no medication, but check in with study staff and assessment of AEs</description>
        </group>
        <group group_id="E4">
          <title>Baseline</title>
          <description>Prior to first intervention</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="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA</default_vocab>
        <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="10" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="34"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <description>Milld, Definitely not related, Referred to/seen by PCP</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <description>Mild, remotely related, no action taken</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <description>Mild or moderate, possibly related, no action taken</description>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Stomachache</sub_title>
                <description>Mild, Possibly related, No action taken</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorder</sub_title>
                <description>Mild, probably related, no action taken</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <description>Mild, causality: remote, no action taken</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <description>Mild, Definitely Not Related, No Action Taken</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <description>Mild, Definitely not related, no action taken</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Sore Throat</sub_title>
                <description>Moderate, definitely not related, Referred to/seen by PCP</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Viral Upper Respiratory Tract Infection</sub_title>
                <description>Mild, definitely not related, no action taken</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin and subcutaneous tissue disorder</sub_title>
                <description>Mild, remotely related, no action taken</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </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>Lindsay M. Squeglia, PhD</name_or_title>
      <organization>Medical University of South Carolina</organization>
      <phone>843-792-5451</phone>
      <email>squegli@musc.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/NCT03238300
org study id: Pro00058771
secondary id: K23AA025399
nct id: NCT03238300
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study will examine the effect of N-Acetylcysteine (NAC), an over-the-counter antioxidant
      supplement, on brains of youth (ages 15-19) using magnetic resonance imaging (MRI).
55 adolescents will receive, in a counterbalanced order, a 10-day course of NAC 1200 mg twice
      daily and a subsequent 10-day course of matched placebo twice daily, separated by 11 days.
      Urine and blood samples will be collected at baseline and urine samples again before and
      after each course of medication treatment. Participants will receive a 1- hour MRI scan at
      baseline and after each treatment trial.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region.
time frame: 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)
description: Using magnetic resonance spectroscopy and a within-subjects design, we will determine the effect of N-Acetylcysteine versus placebo on modulating anterior cingulate glutamate levels in adolescents. Values provided are absolute values (mmol/kg) at the end of each intervention period. Due to complexities of this method, "normal" levels of glutamate are not known; thus, we cannot make conclusions about the meaning of "higher" or "lower" glutamate levels when comparing N-acetylcysteine to placebo.
measure: Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task.
time frame: 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)
description: Assessing the change in neural reactivity to alcohol cues after each round of medication: Placebo vs. N-Acetylcysteine.
Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen.
Change in BOLD signal are reported in Z-scores. A Z-score of 0 would indicate there is no statistical difference in BOLD signal between alcohol images and non-alcohol beverage images. A higher Z-score would indicated a higher BOLD signal during alcohol images compared to non-alcohol beverage images. A lower Z-score would indicate a lower BOLD signal during alcohol images compared to non-alcohol beverage images.
arm group label: N-Acetylcysteine, then Placebo
arm group type: Experimental
description: Participants first received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, they then received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days.
arm group label: Placebo, then N-Acetylcysteine
arm group type: Experimental
description: Participants first received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, they then received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days.
intervention type: Drug
intervention name: N-Acetylcysteine
description: N-Acetylcysteine; 600mg capsules by mouth, two pills twice daily (total 2400 mg/day). Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.
arm group label: N-Acetylcysteine, then Placebo
arm group label: Placebo, then N-Acetylcysteine
intervention type: Drug
intervention name: Placebo Oral Capsule
description: N-acetylcysteine-matched placebo tablet two pills twice daily. Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.
arm group label: N-Acetylcysteine, then Placebo
arm group label: Placebo, then N-Acetylcysteine
criteria: 
gender: All
minimum age: 15 Years
maximum age: 19 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Lindsay M Squeglia, PhD
role: Principal Investigator
affiliation: Medical University of South Carolina
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical University of South Carolina
investigator full name: Lindsay Squeglia
investigator title: Assistant Professor
mesh term: Alcohol Drinking
mesh term: Underage Drinking
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
provided document: 
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 