<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/NCT03781765</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 17-0423</org_study_id>
    <secondary_id>1R21DA045218-01A1</secondary_id>
    <nct_id>NCT03781765</nct_id>
  </id_info>
  <brief_title>Stimulant vs. Non-stimulant Treatments and Reward Processing in Drug-naive Youth at SUD Risk</brief_title>
  <acronym>MPH-ATX</acronym>
  <official_title>Stimulant vs. Non-stimulant Treatments and Reward Processing in Drug-naive Youth at SUD Risk</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Icahn School of Medicine at Mount Sinai</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</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>
      The study team will examine the effects of FDA approved stimulant and non-stimulant&#xD;
      medications for ADHD, among youth with ADHD and with and without Oppositional Defiant&#xD;
      Disorder (ODD) or Conduct Disorder (CD), on reward systems of the brain using fMRI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Longitudinal studies have shown that childhood Attention Deficit/Hyperactivity Disorder&#xD;
      (ADHD) and child disruptive behavior disorders play an important role in the development of&#xD;
      later Substance Use Disorders (SUD). Although available evidence suggests that abnormal&#xD;
      reward processing is likely to mediate vulnerability for addiction, the functioning of the&#xD;
      brain reward systems in at-risk individuals preceding the exposure to drugs remains largely&#xD;
      unknown. Better understanding the baseline characteristics of reward processing in drug-naïve&#xD;
      individuals at risk for later SUD is an important initial step in refining our knowledge of&#xD;
      the neurobiological basis of addiction. Reward processing in at-risk individuals may be&#xD;
      further influenced by exposure to first-line treatments (e.g. methylphenidate (MPH)) for ADHD&#xD;
      that also happen to be controlled substances.&#xD;
&#xD;
      Findings from animal research have raised the possibility that stimulants such as&#xD;
      methylphenidate (MPH) may have &quot;sensitization&quot; effects - which prime the brain reward system&#xD;
      for enhanced responding to the rewarding effects of abusable substances, whereas&#xD;
      non-stimulants such as atomoxetine (ATX) may diminish drug self-administration. However, no&#xD;
      studies have examined the purported different effects of stimulants vs. non-stimulants on the&#xD;
      brain reward system utilizing a targeted biomarker approach linked to an a priori model,&#xD;
      which focuses on intermediate phenotypes. Such research could provide important knowledge&#xD;
      regarding the biological basis of addiction vulnerability and aid in the development of&#xD;
      preventive interventions.&#xD;
&#xD;
      This proposal will provide pilot data for the hypotheses that stimulant and non-stimulant&#xD;
      medications have differential effects on activation in the brain reward system in High Risk&#xD;
      (HR) youth, and that differences activation will be related to changes in measures of reward&#xD;
      sensitivity on psychometric tests. The study team believes that this protocol is uniquely&#xD;
      innovative in its approach to study drug-naïve children at the highest levels of risk for&#xD;
      SUD, thus providing an opportunity to delineate differential effects of medication treatment&#xD;
      in relation to SUD risk. This research is also significant since it will be the first&#xD;
      neuroimaging study to assess the biological correlates of the effects of stimulants on reward&#xD;
      sensitivity in HR children, and especially in relation to purported changes in reward&#xD;
      processing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 4, 2019</start_date>
  <completion_date type="Anticipated">November 2024</completion_date>
  <primary_completion_date type="Anticipated">November 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a pilot study with no control group. All youth will be treated with MPH or ATX and receive pre and post fMRI.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>fMRI Measure</measure>
    <time_frame>3 Weeks</time_frame>
    <description>Bold activation change within the reward system (e.g., ventral striatum, insula and orbitofrontal cortex)</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">44</enrollment>
  <condition>ADHD</condition>
  <condition>Attention Deficit Hyperactivity Disorder</condition>
  <arm_group>
    <arm_group_label>Methylphenidate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atomoxetine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylphenidate</intervention_name>
    <description>stimulant medication</description>
    <arm_group_label>Methylphenidate</arm_group_label>
    <other_name>MPH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atomoxetine</intervention_name>
    <description>non-stimulant medication</description>
    <arm_group_label>Atomoxetine</arm_group_label>
    <other_name>ATX</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pre-pubertal (e.g. Tanner stage 1 or 2)&#xD;
&#xD;
          -  Age 7-12 inclusive&#xD;
&#xD;
          -  Signed consent/assent&#xD;
&#xD;
          -  Parent communicates sufficiently in English to provide informed consent and complete&#xD;
             assessment instruments;&#xD;
&#xD;
          -  ADHD as determined by computerized DISC (C-DISC) parent interview&#xD;
&#xD;
          -  ADHD-Rating Scale-5 total score (interview with parent )&#xD;
&#xD;
          -  SNAP ADHD total score (teacher) of 1.5 SD &gt; age/sex norms&#xD;
&#xD;
          -  CD or severe ODD: CD or ODD + 2 symptoms of CD on C-DISC&#xD;
&#xD;
          -  SNAP ODD/CD subscale (parent and teacher) 1.5 SD &gt; age/sex norms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major neurological/medical illness&#xD;
&#xD;
          -  History of head injury&#xD;
&#xD;
          -  Fetal exposure to alcohol/drugs&#xD;
&#xD;
          -  Diagnosis of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, major&#xD;
             depression, generalized anxiety, social phobia, Tourette's Disorder, PTSD, autism&#xD;
             spectrum disorder)&#xD;
&#xD;
          -  Current suicidal ideation or past history of suicide attempt&#xD;
&#xD;
          -  Wechsler Abbreviated Scale of Intelligence (WASI)75 score &lt;75&#xD;
&#xD;
          -  Prior or current treatment with stimulants (prior or current treatment with&#xD;
             non-stimulants is permitted, but participants must be off medication for 2 weeks at&#xD;
             baseline)&#xD;
&#xD;
          -  Current or past alcohol/drug use (DISC interview; urine toxicology)&#xD;
&#xD;
          -  Psychological or medical condition which precludes being in the scanner (e.g.,&#xD;
             claustrophobia, morbid obesity)&#xD;
&#xD;
          -  Metal in the body that cannot be removed (e.g., braces, metal plate)&#xD;
&#xD;
          -  Visual disturbances that may impair task performance&#xD;
&#xD;
          -  Precocious puberty (e.g. Tanner stage &gt;2) or pregnancy&#xD;
&#xD;
        Notes:&#xD;
&#xD;
          -  History of SUD in a 1st degree relative is permitted, and is expected in ~1/2 of the&#xD;
             subjects&#xD;
&#xD;
          -  Ongoing psychosocial treatment is allowed but should not be initiated during the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>7 Years</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeffrey Newcorn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Iliyan Ivanov, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Beth Krone, PhD</last_name>
    <phone>212-241-8012</phone>
    <email>beth.krone@mssm.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jeffrey Newcorn, MD</last_name>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Beth Krone, PhD</last_name>
      <phone>212-241-8012</phone>
      <email>beth.krone@mssm.edu</email>
    </contact>
    <investigator>
      <last_name>Jeffrey Newcorn, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Iliyan Ivanov, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>April 14, 2023</last_update_submitted>
  <last_update_submitted_qc>April 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Jeffrey Newcorn</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>fMRI Study</keyword>
  <keyword>MPH</keyword>
  <keyword>Methylphenidate</keyword>
  <keyword>ATX</keyword>
  <keyword>Atomoxetine</keyword>
  <keyword>Reward System</keyword>
  <keyword>Substance Abuse Risk</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Attention Deficit Disorder with Hyperactivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylphenidate</mesh_term>
    <mesh_term>Atomoxetine Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03781765
org study id: GCO 17-0423
secondary id: 1R21DA045218-01A1
nct id: NCT03781765
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The study team will examine the effects of FDA approved stimulant and non-stimulant
      medications for ADHD, among youth with ADHD and with and without Oppositional Defiant
      Disorder (ODD) or Conduct Disorder (CD), on reward systems of the brain using fMRI.
Longitudinal studies have shown that childhood Attention Deficit/Hyperactivity Disorder
      (ADHD) and child disruptive behavior disorders play an important role in the development of
      later Substance Use Disorders (SUD). Although available evidence suggests that abnormal
      reward processing is likely to mediate vulnerability for addiction, the functioning of the
      brain reward systems in at-risk individuals preceding the exposure to drugs remains largely
      unknown. Better understanding the baseline characteristics of reward processing in drug-naïve
      individuals at risk for later SUD is an important initial step in refining our knowledge of
      the neurobiological basis of addiction. Reward processing in at-risk individuals may be
      further influenced by exposure to first-line treatments (e.g. methylphenidate (MPH)) for ADHD
      that also happen to be controlled substances.

      Findings from animal research have raised the possibility that stimulants such as
      methylphenidate (MPH) may have "sensitization" effects - which prime the brain reward system
      for enhanced responding to the rewarding effects of abusable substances, whereas
      non-stimulants such as atomoxetine (ATX) may diminish drug self-administration. However, no
      studies have examined the purported different effects of stimulants vs. non-stimulants on the
      brain reward system utilizing a targeted biomarker approach linked to an a priori model,
      which focuses on intermediate phenotypes. Such research could provide important knowledge
      regarding the biological basis of addiction vulnerability and aid in the development of
      preventive interventions.

      This proposal will provide pilot data for the hypotheses that stimulant and non-stimulant
      medications have differential effects on activation in the brain reward system in High Risk
      (HR) youth, and that differences activation will be related to changes in measures of reward
      sensitivity on psychometric tests. The study team believes that this protocol is uniquely
      innovative in its approach to study drug-naïve children at the highest levels of risk for
      SUD, thus providing an opportunity to delineate differential effects of medication treatment
      in relation to SUD risk. This research is also significant since it will be the first
      neuroimaging study to assess the biological correlates of the effects of stimulants on reward
      sensitivity in HR children, and especially in relation to purported changes in reward
      processing.
allocation: Randomized
intervention model: Single Group Assignment
intervention model description: This is a pilot study with no control group. All youth will be treated with MPH or ATX and receive pre and post fMRI.
primary purpose: Basic Science
masking: None (Open Label)
measure: fMRI Measure
time frame: 3 Weeks
description: Bold activation change within the reward system (e.g., ventral striatum, insula and orbitofrontal cortex)
arm group label: Methylphenidate
arm group type: Active Comparator
description: 0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks
arm group label: Atomoxetine
arm group type: Active Comparator
description: 0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks
intervention type: Drug
intervention name: Methylphenidate
description: stimulant medication
arm group label: Methylphenidate
other name: MPH
intervention type: Drug
intervention name: Atomoxetine
description: non-stimulant medication
arm group label: Atomoxetine
other name: ATX
criteria: 
gender: All
minimum age: 7 Years
maximum age: 12 Years
healthy volunteers: No
last name: Jeffrey Newcorn, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Iliyan Ivanov, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Beth Krone, PhD
phone: 212-241-8012
email: beth.krone@mssm.edu
last name: Jeffrey Newcorn, MD
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Jeffrey Newcorn
investigator title: Professor
mesh term: Attention Deficit Disorder with Hyperactivity
mesh term: Methylphenidate
mesh term: Atomoxetine Hydrochloride
sharing ipd: No