<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/NCT03242772</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00085179</org_study_id>
    <secondary_id>1P50HD093074-01</secondary_id>
    <nct_id>NCT03242772</nct_id>
  </id_info>
  <brief_title>Impact of Combined Medication and Behavioral Treatment for ASD &amp; ADHD</brief_title>
  <official_title>Impact of Combined Medication and Behavioral Treatment in Young Children With Comorbid ASD and ADHD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Children with comorbid autism spectrum disorder (ASD) and attention deficit hyperactivity&#xD;
      disorder (ADHD) have significantly worse outcomes than those with either ASD alone or ADHD&#xD;
      alone. Effective early treatments that account for ADHD symptoms have not been developed for&#xD;
      young children with ASD+ADHD. The overarching goals of this randomized, placebo-controlled,&#xD;
      phase 2, pilot study are to (1) evaluate a novel early intervention that pharmacologically&#xD;
      addresses ADHD symptoms while providing an ASD-targeted behavioral intervention, and (2)&#xD;
      identify changes in behavioral and neurophysiological activity that may underlie improved&#xD;
      outcomes in children with comorbid ASD and ADHD ages 3-10 years. The primary aim of this&#xD;
      study is to evaluate whether a stimulant treatment augments efficacy of an ASD specific form&#xD;
      of parent child therapy based on the Early Start Denver Model called ESDM influenced Parent&#xD;
      Coaching. Secondary aims are to determine the efficacy of combined intervention in improving&#xD;
      ADHD symptoms and the efficacy, safety, and tolerability of Adzenys-XR-ODT in young children&#xD;
      with ASD+ADHD. The study will also examine correlations between behavioral changes and&#xD;
      state-of-the-art eye-gaze tracking (EGT) and electroencephalographic (EEG) biomarkers to&#xD;
      elucidate key ways in which ADHD impacts attentional and neural functioning in ASD+ADHD, and&#xD;
      to potentially identify new targets for intervention in children with ASD+ADHD. The study is&#xD;
      about 8 months long and will involve screening, baseline assessment followed by 10- 11 weeks&#xD;
      of study drug treatment (active or placebo) and 8 sessions of ESDM informed parent coaching&#xD;
      beginning after 2 weeks of study drug treatment, primary endpoint assessments at ~11 weeks,&#xD;
      AE follow-up by phone at ~week 13 and remote FU 24 weeks after baseline. Eligible&#xD;
      participants will be randomly assigned to the active medication or placebo, Between weeks 11&#xD;
      to 24, it is expected that the parent will use the behavioral strategies they were coached in&#xD;
      even though they will not receive parent coaching. Participants will be given the option to&#xD;
      pursue ADHD medication outside of the research study after week 11 assessments.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This randomized, placebo-controlled, Phase 2, single site, pilot study will evaluate the&#xD;
      developmental impact of combined medication and behavioral treatment (COMB) versus placebo&#xD;
      and behavioral treatment (BEH) in children with comorbid ASD +ADHD, who are between 36 and &lt;&#xD;
      132 months of age. The active medication treatment will be an orally dissolvable, extended&#xD;
      release amphetamine preparation (Adzenys-XR-ODT) administered from weeks 0-~11 and carefully&#xD;
      titrated to the optimal dose using an algorithm that considers adverse events and improvement&#xD;
      in attention symptoms with a flexible dose range of 1.55mg - 18.6mg/day. The target dose is&#xD;
      12.4mg/day. A placebo, matched to the active medication, will be titrated and adjusted using&#xD;
      the same algorithm in the BEH arm. The provided behavioral treatment will be eight ~ hour&#xD;
      long parent child therapy sessions of ESDM influenced parent coaching.&#xD;
&#xD;
      Approximately 48 participants will be randomly assigned to either the COMB or BEH treatment&#xD;
      arms. To account for possible differences in attrition due to potential poor tolerability of&#xD;
      Adzenys-XR-ODT, participants will be randomized in a 7 COMB to 6 BEH ratio. Treatment&#xD;
      assignment will be provided by the Data Management and Analysis Core (DMAC)using computer&#xD;
      generated algorithms.&#xD;
&#xD;
      The primary analyses will compare changes in outcomes between weeks 0 and 11 weeks.&#xD;
      Exploratory analyses will explore changes between weeks 0 and 24.&#xD;
&#xD;
      The primary outcome measure is change in amount and quality of joint engagement between the&#xD;
      child and the parent during a semi-structured, 6 minute parent child interaction task (PCIT),&#xD;
      which reflects the core symptom domain targeted by P-ESDM: social communication.&#xD;
&#xD;
      Our key secondary outcomes will be changes in 1) the mean of the interview version of the&#xD;
      VABS-3 socialization subscale and communication subscale standard scores and 2) clinician&#xD;
      ratings of ADHD symptoms using the preschool ADHD-RS.&#xD;
&#xD;
      We will also assess the safety and tolerability of Adzenys-XR-ODT compared to placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study stopped recruitment of new participants due to COVID. A substudy was developed with&#xD;
    adaptations to the main design.&#xD;
  </why_stopped>
  <start_date type="Actual">December 14, 2018</start_date>
  <completion_date type="Actual">April 19, 2021</completion_date>
  <primary_completion_date type="Actual">December 28, 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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task</measure>
    <time_frame>Baseline (Week -1), Endpoint (Week 10)</time_frame>
    <description>Child engagement states measured by the Joint Engagement Rating Inventory (JERI); our outcome contains four items (rated on a 7-point Likert scale) that characterize various aspects of engagement. Higher scores mean greater/higher quality engagement and lower scores represent less/poorer engagement. Total range of score is 4-28.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3)</measure>
    <time_frame>Baseline (Week -1), Endpoint (Week 10)</time_frame>
    <description>Mean of standard scores for VABS-3 (socialization subscale and communication subscales) assess how the participant actually has been functioning over the preceding month with regard to communication and social behaviors. The VABS-3 comprehensive form will be administered as a semi-structured interview by a trained and research reliable staff member. The standard score is based on the participant's age and is normed from a large sample of typically developing children. The standard score has a mean of 100 and a standard deviation of 15. The composite score range is 20-140; higher scores represent more adaptive functioning and lower scores represent less adaptive functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score</measure>
    <time_frame>Baseline (Week 0), Week 10</time_frame>
    <description>ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS. The ADHD-RS includes 18 items, each rated on a 4 point scale (0-3);Total Score is the sum of all responses (0-54). An Inattention subscale and Hyperactivity/Impulsivity subscale (each range 0-27) are calculated based on individual items assessing those symptoms. Higher values represent worse outcomes for the subscales and the total scale. Clinically significant scores in boys are 14 for inattention and 17 for hyperactivity/impulsivity items; thresholds in girls are 12 and 14 respectively. If subscales are used, they would be summed to compute the total score. *Baseline measures occur on visits weeks -1 and week 0 in the study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking</measure>
    <time_frame>Baseline (Week -1), Week 10</time_frame>
    <description>Eye Gaze Tracking (EGT) during presentation of social and nonsocial stimuli. Key measure used is Proportion Looking Time, which is a number between 0 and 1, with a higher number indicating improved attention.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Autism Spectrum Disorder</condition>
  <condition>Attention Deficit Hyperactivity Disorder</condition>
  <arm_group>
    <arm_group_label>ESDM informed parent coaching + Amphetamine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ESDM informed parent coaching + Placebo Oral Tablet</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amphetamine</intervention_name>
    <description>Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.</description>
    <arm_group_label>ESDM informed parent coaching + Amphetamine</arm_group_label>
    <other_name>Adzenys XR-ODT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>ESDM informed parent coaching</intervention_name>
    <description>All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
    <arm_group_label>ESDM informed parent coaching + Amphetamine</arm_group_label>
    <arm_group_label>ESDM informed parent coaching + Placebo Oral Tablet</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
    <arm_group_label>ESDM informed parent coaching + Placebo Oral Tablet</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of a parent signed and dated informed consent form.&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study.&#xD;
&#xD;
          3. Aged 36 months to less than 132 months.&#xD;
&#xD;
          4. Diagnosed with both ASD and ADHD based consensus diagnosis informed by results of the&#xD;
             Autism Diagnostic Observation Schedule 2nd edition (ADOS-2), Autism Diagnostic&#xD;
             Interview - Revised (ADI-R), and a Standardized ADHD Diagnostic Interview and the MINI&#xD;
             psychiatric diagnostic interview.&#xD;
&#xD;
          5. In good general health as evidenced by medical history and physical exam and review of&#xD;
             safety labs and electrocardiogram.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Recent use of prohibited psychoactive medication in close proximity of baseline&#xD;
             assessments. See MOP for specific medications that are prohibited and washout&#xD;
             procedures. Use of a monoamine oxidase inhibitor is prohibited within 14 days of&#xD;
             baseline.&#xD;
&#xD;
          2. Known allergic reactions to amphetamines or components of Adzenys-XR-ODT.&#xD;
&#xD;
          3. Known history of sudden non-ischemic cardiac death in a first or second degree family&#xD;
             member (sibling, parent, aunt, uncle, cousin or grandparent).&#xD;
&#xD;
          4. Personal history of significant cardiac abnormalities or disease, particularly rhythm&#xD;
             abnormalities.&#xD;
&#xD;
          5. Significant visual, auditory or motor impairments that would preclude participation in&#xD;
             ESDM-informed parent coaching or completion of key assessments.&#xD;
&#xD;
          6. Inability of the caregiver participating in P-ESDM and responding to questionnaires to&#xD;
             fluently speak English.&#xD;
&#xD;
          7. Parent's participation in another parent coaching intervention on more than a monthly&#xD;
             basis that may affect study provided therapy as determined by the PI or clinician.&#xD;
&#xD;
          8. Presence of any psychiatric conditions or psychiatric symptoms in addition to ASD and&#xD;
             ADHD that would confound assessments and/or affect participation in the study as&#xD;
             deemed by the PI or clinician.&#xD;
&#xD;
          9. Known genetic (e.g. Fragile X) or neurological syndrome or condition with established&#xD;
             link to autism, but not events in which the link to ASD is less well known/established&#xD;
             (e.g., 16p11.2 CNVs, CHD8 mutations, Trisomy 21, 22q deletion syndrome)&#xD;
&#xD;
         10. History of epilepsy or seizure disorder (except for history of simple febrile seizures&#xD;
             or if the child is seizure free (regardless of seizure type) for the past year).&#xD;
&#xD;
         11. History of neonatal brain damage. (eg., with diagnoses hypoxic or ischemic event)&#xD;
&#xD;
         12. Any known environmental circumstances that is likely to account for the picture of&#xD;
             autism in the proband (severe nutritional or psychological deprivation etc.)&#xD;
&#xD;
         13. Study clinician judgment that it is not in the best interests of the participant&#xD;
             and/or the study for the child to participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>36 Months</minimum_age>
    <maximum_age>131 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Geraldine Dawson, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Linmarie Sikich, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Scott Kollins, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke Center for Autism and Brain Development</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27705</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>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 8, 2017</study_first_posted>
  <results_first_submitted>December 20, 2021</results_first_submitted>
  <results_first_submitted_qc>February 11, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 9, 2022</results_first_posted>
  <last_update_submitted>March 11, 2022</last_update_submitted>
  <last_update_submitted_qc>March 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Attention Deficit Disorder with Hyperactivity</mesh_term>
    <mesh_term>Autism Spectrum Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amphetamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Through NDAR, core assessment and diagnostic data that is de-identified, including measures such as ADOS and Vineland.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>1 year after publication of the results for each of the specific aims or 3 years after the statistical analyses are completed</ipd_time_frame>
    <ipd_access_criteria>determined by committee of researchers/administrator at NDAR</ipd_access_criteria>
    <ipd_url>https://nda.nih.gov</ipd_url>
  </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>December 16, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03242772/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 24, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03242772/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment occurred through our autism research registry, community events and Duke clinics</recruitment_details>
      <pre_assignment_details>Confirmation of dual diagnosis was required prior to randomization</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>ESDM Informed Parent Coaching + Amphetamine</title>
          <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
        </group>
        <group group_id="P2">
          <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
          <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
              </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="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <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>
              <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>ESDM Informed Parent Coaching + Amphetamine</title>
          <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
        </group>
        <group group_id="B2">
          <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
          <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</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="9"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="18"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>months</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="86.83" spread="20.80"/>
                    <measurement group_id="B2" value="103.00" spread="18.88"/>
                    <measurement group_id="B3" value="94.92" spread="19.84"/>
                  </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="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="16"/>
                  </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>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="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </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>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task</title>
        <description>Child engagement states measured by the Joint Engagement Rating Inventory (JERI); our outcome contains four items (rated on a 7-point Likert scale) that characterize various aspects of engagement. Higher scores mean greater/higher quality engagement and lower scores represent less/poorer engagement. Total range of score is 4-28.</description>
        <time_frame>Baseline (Week -1), Endpoint (Week 10)</time_frame>
        <population>This variable required behavioral coding of videotaped caregiver-child interactions collected at two time points. This coding were not conducted due to the fact that the study was terminated and time 2 data were not collected for participants due to safety concerns related to Covid-19.</population>
        <group_list>
          <group group_id="O1">
            <title>ESDM Informed Parent Coaching + Amphetamine</title>
            <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
          </group>
          <group group_id="O2">
            <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
            <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task</title>
          <description>Child engagement states measured by the Joint Engagement Rating Inventory (JERI); our outcome contains four items (rated on a 7-point Likert scale) that characterize various aspects of engagement. Higher scores mean greater/higher quality engagement and lower scores represent less/poorer engagement. Total range of score is 4-28.</description>
          <population>This variable required behavioral coding of videotaped caregiver-child interactions collected at two time points. This coding were not conducted due to the fact that the study was terminated and time 2 data were not collected for participants due to safety concerns related to Covid-19.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3)</title>
        <description>Mean of standard scores for VABS-3 (socialization subscale and communication subscales) assess how the participant actually has been functioning over the preceding month with regard to communication and social behaviors. The VABS-3 comprehensive form will be administered as a semi-structured interview by a trained and research reliable staff member. The standard score is based on the participant's age and is normed from a large sample of typically developing children. The standard score has a mean of 100 and a standard deviation of 15. The composite score range is 20-140; higher scores represent more adaptive functioning and lower scores represent less adaptive functioning.</description>
        <time_frame>Baseline (Week -1), Endpoint (Week 10)</time_frame>
        <population>Not all participants completed all surveys.</population>
        <group_list>
          <group group_id="O1">
            <title>ESDM Informed Parent Coaching + Amphetamine</title>
            <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
          </group>
          <group group_id="O2">
            <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
            <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3)</title>
          <description>Mean of standard scores for VABS-3 (socialization subscale and communication subscales) assess how the participant actually has been functioning over the preceding month with regard to communication and social behaviors. The VABS-3 comprehensive form will be administered as a semi-structured interview by a trained and research reliable staff member. The standard score is based on the participant's age and is normed from a large sample of typically developing children. The standard score has a mean of 100 and a standard deviation of 15. The composite score range is 20-140; higher scores represent more adaptive functioning and lower scores represent less adaptive functioning.</description>
          <population>Not all participants completed all surveys.</population>
          <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="6"/>
                <count group_id="O2" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.92" spread="5.34"/>
                    <measurement group_id="O2" value="1.86" spread="6.89"/>
                  </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>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2664</p_value>
            <p_value_desc>Significance at &lt;0.05</p_value_desc>
            <method>95% confidence interval</method>
            <method_desc>confidence interval (CI) = -3.5729 - 11.6929</method_desc>
            <other_analysis_desc>Presentation of results will include p-values and 95% confidence intervals for the least mean square values at weeks 0, 10, 24 (week 24 is exploratory).</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score</title>
        <description>ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS. The ADHD-RS includes 18 items, each rated on a 4 point scale (0-3);Total Score is the sum of all responses (0-54). An Inattention subscale and Hyperactivity/Impulsivity subscale (each range 0-27) are calculated based on individual items assessing those symptoms. Higher values represent worse outcomes for the subscales and the total scale. Clinically significant scores in boys are 14 for inattention and 17 for hyperactivity/impulsivity items; thresholds in girls are 12 and 14 respectively. If subscales are used, they would be summed to compute the total score. *Baseline measures occur on visits weeks -1 and week 0 in the study.</description>
        <time_frame>Baseline (Week 0), Week 10</time_frame>
        <population>Not all participants completed all surveys.</population>
        <group_list>
          <group group_id="O1">
            <title>ESDM Informed Parent Coaching + Amphetamine</title>
            <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
          </group>
          <group group_id="O2">
            <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
            <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score</title>
          <description>ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS. The ADHD-RS includes 18 items, each rated on a 4 point scale (0-3);Total Score is the sum of all responses (0-54). An Inattention subscale and Hyperactivity/Impulsivity subscale (each range 0-27) are calculated based on individual items assessing those symptoms. Higher values represent worse outcomes for the subscales and the total scale. Clinically significant scores in boys are 14 for inattention and 17 for hyperactivity/impulsivity items; thresholds in girls are 12 and 14 respectively. If subscales are used, they would be summed to compute the total score. *Baseline measures occur on visits weeks -1 and week 0 in the study.</description>
          <population>Not all participants completed all surveys.</population>
          <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="4"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.00" spread="6.81"/>
                    <measurement group_id="O2" value="-4.75" spread="10.02"/>
                  </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>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.3721</p_value>
            <p_value_desc>Significance at &lt;0.05</p_value_desc>
            <method>95% confidence interval</method>
            <method_desc>confidence interval (CI) = -17.7698 - 7.2698</method_desc>
            <other_analysis_desc>Presentation of results will include p-values and 95% confidence intervals for the least mean square values at weeks 0, 10, 24 (week 24 is exploratory).</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking</title>
        <description>Eye Gaze Tracking (EGT) during presentation of social and nonsocial stimuli. Key measure used is Proportion Looking Time, which is a number between 0 and 1, with a higher number indicating improved attention.</description>
        <time_frame>Baseline (Week -1), Week 10</time_frame>
        <population>This variable required processing of eye tracking data collected at two time points. We chose not to process the eye tracking data due to the fact that the study was terminated and time 2 data were not collected for participants because of safety concerns related to Covid-19.</population>
        <group_list>
          <group group_id="O1">
            <title>ESDM Informed Parent Coaching + Amphetamine</title>
            <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
          </group>
          <group group_id="O2">
            <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
            <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking</title>
          <description>Eye Gaze Tracking (EGT) during presentation of social and nonsocial stimuli. Key measure used is Proportion Looking Time, which is a number between 0 and 1, with a higher number indicating improved attention.</description>
          <population>This variable required processing of eye tracking data collected at two time points. We chose not to process the eye tracking data due to the fact that the study was terminated and time 2 data were not collected for participants because of safety concerns related to Covid-19.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>First three participants had a time frame of 52-64 weeks, and the remaining 15 had a timeframe 24 weeks, per protocol.</time_frame>
      <desc>First three participants were systematic using the SLAES, next 15 subjects were spontaneous (non-systematic).</desc>
      <group_list>
        <group group_id="E1">
          <title>ESDM Informed Parent Coaching + Amphetamine</title>
          <description>Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.&#xD;
Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).</description>
        </group>
        <group group_id="E2">
          <title>ESDM Informed Parent Coaching + Placebo Oral Tablet</title>
          <description>Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).&#xD;
ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).&#xD;
Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.</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="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 19.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Motion Sickness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation, increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased Appetite</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Environmental Allergies, worsened</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Viral Infections</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Accidental Injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Inflamed Toe</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Subjective Temperature Dysregulation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mood Dysregulation</sub_title>
                <description>Mood Dysregulation includes verbatim reports of mood changes, poor coping, and low frustration tolerance.</description>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Aggression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Compulsions</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperfocused</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Stereotypies, worsened</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperactivity, worsened</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Flat affect, worsened</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oppositionality, worsened</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Geraldine Dawson, PhD, PI of Duke Autism Center of Excellence</name_or_title>
      <organization>Duke Center for Autism and Brain Development</organization>
      <phone>919-668-0070</phone>
      <email>geraldine.dawson@duke.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/NCT03242772
org study id: Pro00085179
secondary id: 1P50HD093074-01
nct id: NCT03242772
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Children with comorbid autism spectrum disorder (ASD) and attention deficit hyperactivity
      disorder (ADHD) have significantly worse outcomes than those with either ASD alone or ADHD
      alone. Effective early treatments that account for ADHD symptoms have not been developed for
      young children with ASD+ADHD. The overarching goals of this randomized, placebo-controlled,
      phase 2, pilot study are to (1) evaluate a novel early intervention that pharmacologically
      addresses ADHD symptoms while providing an ASD-targeted behavioral intervention, and (2)
      identify changes in behavioral and neurophysiological activity that may underlie improved
      outcomes in children with comorbid ASD and ADHD ages 3-10 years. The primary aim of this
      study is to evaluate whether a stimulant treatment augments efficacy of an ASD specific form
      of parent child therapy based on the Early Start Denver Model called ESDM influenced Parent
      Coaching. Secondary aims are to determine the efficacy of combined intervention in improving
      ADHD symptoms and the efficacy, safety, and tolerability of Adzenys-XR-ODT in young children
      with ASD+ADHD. The study will also examine correlations between behavioral changes and
      state-of-the-art eye-gaze tracking (EGT) and electroencephalographic (EEG) biomarkers to
      elucidate key ways in which ADHD impacts attentional and neural functioning in ASD+ADHD, and
      to potentially identify new targets for intervention in children with ASD+ADHD. The study is
      about 8 months long and will involve screening, baseline assessment followed by 10- 11 weeks
      of study drug treatment (active or placebo) and 8 sessions of ESDM informed parent coaching
      beginning after 2 weeks of study drug treatment, primary endpoint assessments at ~11 weeks,
      AE follow-up by phone at ~week 13 and remote FU 24 weeks after baseline. Eligible
      participants will be randomly assigned to the active medication or placebo, Between weeks 11
      to 24, it is expected that the parent will use the behavioral strategies they were coached in
      even though they will not receive parent coaching. Participants will be given the option to
      pursue ADHD medication outside of the research study after week 11 assessments.
This randomized, placebo-controlled, Phase 2, single site, pilot study will evaluate the
      developmental impact of combined medication and behavioral treatment (COMB) versus placebo
      and behavioral treatment (BEH) in children with comorbid ASD +ADHD, who are between 36 and <
      132 months of age. The active medication treatment will be an orally dissolvable, extended
      release amphetamine preparation (Adzenys-XR-ODT) administered from weeks 0-~11 and carefully
      titrated to the optimal dose using an algorithm that considers adverse events and improvement
      in attention symptoms with a flexible dose range of 1.55mg - 18.6mg/day. The target dose is
      12.4mg/day. A placebo, matched to the active medication, will be titrated and adjusted using
      the same algorithm in the BEH arm. The provided behavioral treatment will be eight ~ hour
      long parent child therapy sessions of ESDM influenced parent coaching.

      Approximately 48 participants will be randomly assigned to either the COMB or BEH treatment
      arms. To account for possible differences in attrition due to potential poor tolerability of
      Adzenys-XR-ODT, participants will be randomized in a 7 COMB to 6 BEH ratio. Treatment
      assignment will be provided by the Data Management and Analysis Core (DMAC)using computer
      generated algorithms.

      The primary analyses will compare changes in outcomes between weeks 0 and 11 weeks.
      Exploratory analyses will explore changes between weeks 0 and 24.

      The primary outcome measure is change in amount and quality of joint engagement between the
      child and the parent during a semi-structured, 6 minute parent child interaction task (PCIT),
      which reflects the core symptom domain targeted by P-ESDM: social communication.

      Our key secondary outcomes will be changes in 1) the mean of the interview version of the
      VABS-3 socialization subscale and communication subscale standard scores and 2) clinician
      ratings of ADHD symptoms using the preschool ADHD-RS.

      We will also assess the safety and tolerability of Adzenys-XR-ODT compared to placebo.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task
time frame: Baseline (Week -1), Endpoint (Week 10)
description: Child engagement states measured by the Joint Engagement Rating Inventory (JERI); our outcome contains four items (rated on a 7-point Likert scale) that characterize various aspects of engagement. Higher scores mean greater/higher quality engagement and lower scores represent less/poorer engagement. Total range of score is 4-28.
measure: Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3)
time frame: Baseline (Week -1), Endpoint (Week 10)
description: Mean of standard scores for VABS-3 (socialization subscale and communication subscales) assess how the participant actually has been functioning over the preceding month with regard to communication and social behaviors. The VABS-3 comprehensive form will be administered as a semi-structured interview by a trained and research reliable staff member. The standard score is based on the participant's age and is normed from a large sample of typically developing children. The standard score has a mean of 100 and a standard deviation of 15. The composite score range is 20-140; higher scores represent more adaptive functioning and lower scores represent less adaptive functioning.
measure: Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score
time frame: Baseline (Week 0), Week 10
description: ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS. The ADHD-RS includes 18 items, each rated on a 4 point scale (0-3);Total Score is the sum of all responses (0-54). An Inattention subscale and Hyperactivity/Impulsivity subscale (each range 0-27) are calculated based on individual items assessing those symptoms. Higher values represent worse outcomes for the subscales and the total scale. Clinically significant scores in boys are 14 for inattention and 17 for hyperactivity/impulsivity items; thresholds in girls are 12 and 14 respectively. If subscales are used, they would be summed to compute the total score. *Baseline measures occur on visits weeks -1 and week 0 in the study.
measure: Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking
time frame: Baseline (Week -1), Week 10
description: Eye Gaze Tracking (EGT) during presentation of social and nonsocial stimuli. Key measure used is Proportion Looking Time, which is a number between 0 and 1, with a higher number indicating improved attention.
arm group label: ESDM informed parent coaching + Amphetamine
arm group type: Active Comparator
description: Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.
arm group label: ESDM informed parent coaching + Placebo Oral Tablet
arm group type: Placebo Comparator
description: Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug).
intervention type: Drug
intervention name: Amphetamine
description: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time.
arm group label: ESDM informed parent coaching + Amphetamine
other name: Adzenys XR-ODT
intervention type: Behavioral
intervention name: ESDM informed parent coaching
description: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).
arm group label: ESDM informed parent coaching + Amphetamine
arm group label: ESDM informed parent coaching + Placebo Oral Tablet
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
arm group label: ESDM informed parent coaching + Placebo Oral Tablet
criteria: 
gender: All
minimum age: 36 Months
maximum age: 131 Months
healthy volunteers: No
last name: Geraldine Dawson, PhD
role: Principal Investigator
affiliation: Duke
last name: Linmarie Sikich, MD
role: Principal Investigator
affiliation: Duke
last name: Scott Kollins, PhD
role: Principal Investigator
affiliation: Duke
facility: 
country: United States
responsible party type: Sponsor
mesh term: Attention Deficit Disorder with Hyperactivity
mesh term: Autism Spectrum Disorder
mesh term: Amphetamine
sharing ipd: Yes
ipd description: Through NDAR, core assessment and diagnostic data that is de-identified, including measures such as ADOS and Vineland.
ipd info type: Study Protocol
ipd time frame: 1 year after publication of the results for each of the specific aims or 3 years after the statistical analyses are completed
ipd access criteria: determined by committee of researchers/administrator at NDAR
ipd url: https://nda.nih.gov
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 