<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/NCT02212275</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00065239</org_study_id>
    <secondary_id>14-1141</secondary_id>
    <nct_id>NCT02212275</nct_id>
  </id_info>
  <brief_title>Cortical Metrics in Intervention Trials With Autism Spectrum Disorders</brief_title>
  <official_title>Initial Development of Cortical Metrics, an Objective, Physiologically-Based Outcome Measure, for Intervention Trials in Autism Spectrum Disorders (ASD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>North Carolina Translational and Clinical Sciences Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators overarching aim is to obtain preliminary data to support a larger grant to&#xD;
      validate a novel objective, physiologically-based outcome measure for clinical trials in&#xD;
      autism spectrum disorders (ASDs) called the cortical metric. Absence of such an outcome&#xD;
      measure has greatly hindered the development of treatments for core symptoms of ASD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The cortical metric is a single numeric measurement that is calculated using a&#xD;
      multi-parametric mathematical approach from a series of measurements of the speed, intensity,&#xD;
      diameter, and distance between two vibrations with which a person reacts to and can&#xD;
      distinguish vibrations from small brushes that touch the top side of fingers on the left hand&#xD;
      under multiple conditions designed to elicit cortical adaptation The cortical metric is based&#xD;
      on the neurobiological principle that the nerves in the fingertips project to adjacent groups&#xD;
      of neurons that work together to continuously optimize perceptions of touch under varying&#xD;
      conditions. Such perceptual optimization reflects the shifting excitatory and inhibitory&#xD;
      actions of individual neurons. We hypothesize that the brain's processing of vibration is&#xD;
      similar to its processing of other kinds of information. We also hypothesize that in people&#xD;
      with ASD adjacent groups of neurons work together less well to process information.&#xD;
&#xD;
      Specific Aim 1: Obtain evidence regarding the ability of the &quot;cortical metric&quot; to distinguish&#xD;
      between 8-12 year-olds with typical development and with high functioning autism spectrum&#xD;
      disorders (ASDs).&#xD;
&#xD;
      Hypothesis 1: The cortical metric of children with ASD will differ from that of age matched,&#xD;
      typically developing children. This difference will be consistent with lower than normal&#xD;
      local functional connectivity.&#xD;
&#xD;
      Specific Aim 2: Validate the test-retest reliability of the cortical metric by examining its&#xD;
      stability of over an average of 3 weeks with no intervening interventions in both groups of&#xD;
      children.&#xD;
&#xD;
      Hypothesis 2: Test-retest reliability will be highly correlated in both groups of children.&#xD;
&#xD;
      Specific Aim 3: Obtain preliminary proof of mechanism data that the cortical metric assesses&#xD;
      the excitatory: inhibitory balance of intra-cortical connections by examining the effect of&#xD;
      acute exposure to dextromethorphan (DXM), which transiently blocks one type of excitatory&#xD;
      neurotransmission&#xD;
&#xD;
      Hypothesis 3: DXM will alter the cortical metric consistent with reduced adaptation.&#xD;
&#xD;
      The completion of these aims will be essential to design a larger federally funded trial to&#xD;
      validate the cortical metric as an outcome measure in a more heterogeneous pediatric ASD&#xD;
      sample. Specifically, we will aim to demonstrate that 1) the cortical metric differs between&#xD;
      children with ASD and with normal development, 2) that the cortical metric has minimal&#xD;
      variability over time in the absence of fno major changes in brain function, and 3) that the&#xD;
      cortical metric changes in response to a specific, temporary reduction in excitatory&#xD;
      stimulation caused by a single DXM dose.&#xD;
&#xD;
      A larger grant could focus on determining how sensitive and clinically relevant changes in&#xD;
      the cortical metric are.&#xD;
&#xD;
      If we are not able to demonstrate the potential for the cortical metric to be changed by&#xD;
      agents that reduce excitatory stimulation acutely or if the variability of the cortical&#xD;
      metric over 3 weeks is too great, no further examination of the cortical metric as an outcome&#xD;
      measure in ASD trials would be pursued. If there are not differences in the cortical metric&#xD;
      of children with and without ASD, we would be less interested in further examining the&#xD;
      cortical metric.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    lack of funding&#xD;
  </why_stopped>
  <start_date>August 2015</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The difference in the Cortical Metric before and after acute exposure to dextromethorphan (DXM)</measure>
    <time_frame>2 hours after DXM exposure and 20 min before DXM</time_frame>
    <description>At visit 2 the cortical metric will be measured 20 min prior to a single dose of DXM and 2hrs after the dose of DXM. . This addresses Specific Aim 3 of the trial. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response. Visit 2 occurs 3 weeks after baseline = time 0</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the cortical metric</measure>
    <time_frame>3 weeks</time_frame>
    <description>The difference between the cortical metric measured 20 minutes before DXM treatment at visit 2, which occurs 3 weeks after the baseline = time 0 visit, and the cortical metric measured 3 weeks earlier at the baseline visit = time 0. We presume their will be no major changes in brain functioning over 3 weeks.&#xD;
This addresses Specific Aim 2 of the trial, regarding test retest stability. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The Cortical Metric</measure>
    <time_frame>Baseline = time 0</time_frame>
    <description>The cortical metric will be measured at the baseline of the study = time 0. We will compare the mean cortical metric and the range of the cortical metric between the ASD and typically developing groups.&#xD;
This addresses Specific Aim 1 of the trial. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response. The goal of this aim is to replicate the findings of the John Hopkins University group that found differences in the cortical metric between groups of children 8-12 years old with ASD and with typical development.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Aberrant Behavior Checklist (ABC) Total Score</measure>
    <time_frame>time 0 (baseline)</time_frame>
    <description>The ABC focuses on problem behaviors in five subdomains: irritability, attention, repetitive behaviors, unusual speech, and social withdrawal and will be completed by subject's parent/guardian or caregiver.&#xD;
We will examine the correlation between the ABC Total score and the cortical metric.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pervasive Developmental Disorders Behavior Inventory - Screening Version Score (PDDBI-SV) Social Deficit Score</measure>
    <time_frame>Baseline = time 0</time_frame>
    <description>The PDDBI-SV examines both adaptive and maladaptive behaviors related to autism. The adaptive items are reverse scored and then all items are summed to generate the social deficit score. It is not age specific. This questionnaire will be completed by subject's parent/guardian or caregiver. The correlation between the PDD-BI SV Social Deficit score and the cortical metric will be examined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Social Responsiveness Scale, Version 2 Total Score (SRS)</measure>
    <time_frame>Time 0 = Baseline</time_frame>
    <description>This 65-item rating scale measures the severity of autism spectrum symptoms as they occur in natural social settings (Constantino, Davis et al. 2003). Completed by a parent or teacher in just 15 to 20 minutes, the SRS provides a clear picture of a child's social impairments, assessing social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. It is appropriate for use with children from 4 to 18 years of age. The SRS measures impairment on a quantitative scale across a wide range of severity--which is consistent with recent research indicating that autism is best conceptualized as a spectrum condition rather than an all-or-nothing diagnosis. This will be completed by the subject's parent/guardian or caregiver.&#xD;
The correlation between the SRS Total score and the cortical metric will be examined.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Autism Spectrum Disorders</condition>
  <arm_group>
    <arm_group_label>Dextromethorphan in ASD</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>8-12 years old: &gt; 30 boys will be recruited who have a known or suspected diagnosis of ASD confirmed by DSM-5 checklist and the ADOS-2 at screening. They will have the cortical metric measured 20 min prior to receiving DXM and 2 hours after receiving a single age and weight appropriate dose of DXM. The outcome reported is the difference in the cortical metric after the DXM dose and before the DXM dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dextromethorphan in controls</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>30 typically developing boys 8-12 years old who have the cortical metric measured 20 min before receiving a single age and weight appropriate dose of DXM and 2 hours after the single dose of DXM. The reported value will be the difference between the cortical metric 2hrs after the single dose of DXM and the cortical metric 20 minutes prior to the single dose of DXM.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dextromethophan</intervention_name>
    <description>A single age and weight appropriate dose of over the counter Delsym Cough Syrup containing only DXM as an active ingredient.</description>
    <arm_group_label>Dextromethorphan in ASD</arm_group_label>
    <arm_group_label>Dextromethorphan in controls</arm_group_label>
    <other_name>Delsym Cough Syrup</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Group 1 Typically Developing Youth: We will recruit 30 typically developing boys 8-12 years&#xD;
        old to participate in a screening visit, and two tactile perception sessions (visit 1 and&#xD;
        2).&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy Male Boys ages 8-12&#xD;
&#xD;
          -  Normal developmental milestones and school performance&#xD;
&#xD;
          -  Primary caretaker is able to participate in study appointments as is indicated&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Significant lifetime medical history including non-febrile seizures, neurological&#xD;
             problems, psychiatric problems or learning disabilities&#xD;
&#xD;
          -  Any sensory impairment (i.e. deafness or blindness)&#xD;
&#xD;
          -  1st or 2nd degree family members with a history of ASD&#xD;
&#xD;
          -  1st or 2nd degree family members with ADHD or other developmental problems&#xD;
&#xD;
          -  Adverse reaction to dextromethorphan&#xD;
&#xD;
          -  Inability to successfully complete and fully understand the reaction time subtest&#xD;
             (cortical metrics)&#xD;
&#xD;
        Group 2 Youth with ASD: 8-12 years old: &gt; 30 boys will be recruited who have a known or&#xD;
        suspected diagnosis of ASD confirmed by DSM-5 checklist and the ADOS-2 at screening.&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Male Boys ages 8-12 with ASD (confirmed by DSM-5 checklist and the ADOS-2)&#xD;
&#xD;
          -  IQ's should be within the normal range (≥ 70) (by prior testing or Stanford Binet 5 at&#xD;
             screening)&#xD;
&#xD;
          -  Primary caretaker is able to participate in study appointments as is clinically&#xD;
             indicated&#xD;
&#xD;
          -  Ability of child to participate in all aspects of the protocol per investigator&#xD;
             clinical judgment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  New educational or behavioral intervention within 4 weeks of baseline&#xD;
&#xD;
          -  History of non-febrile seizures, other neurological disorders, psychosis, bipolar&#xD;
             disorder, or Tourette Syndrome.&#xD;
&#xD;
          -  Any sensory impairment (i.e. deafness or blindness)&#xD;
&#xD;
          -  Adverse reaction to dextromethorphan&#xD;
&#xD;
          -  Inability to successfully complete and understand the reaction time subtest (cortical&#xD;
             metrics)&#xD;
&#xD;
          -  Changes in psychiatric medications within 4 weeks of baseline visit&#xD;
&#xD;
          -  Taking epileptic medication (including but not limited to carbamazepine,&#xD;
             phenobarbital, Depakote, lamictal, oxycarbazepine, topiramate)&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Linmarie Sikich, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of North Carolina, Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27517</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Center for Autism and Brain Development</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>July 29, 2014</study_first_submitted>
  <study_first_submitted_qc>August 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 8, 2014</study_first_posted>
  <last_update_submitted>August 24, 2016</last_update_submitted>
  <last_update_submitted_qc>August 24, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 25, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ASD</keyword>
  <keyword>autism</keyword>
  <keyword>typical development</keyword>
  <keyword>sensory testing</keyword>
  <keyword>the cortical metric</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Autistic Disorder</mesh_term>
    <mesh_term>Autism Spectrum Disorder</mesh_term>
    <mesh_term>Child Development Disorders, Pervasive</mesh_term>
  </condition_browse>
  <!-- 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/NCT02212275
org study id: Pro00065239
secondary id: 14-1141
nct id: NCT02212275
lead sponsor: 
collaborator: 
has dmc: No
The investigators overarching aim is to obtain preliminary data to support a larger grant to
      validate a novel objective, physiologically-based outcome measure for clinical trials in
      autism spectrum disorders (ASDs) called the cortical metric. Absence of such an outcome
      measure has greatly hindered the development of treatments for core symptoms of ASD.
The cortical metric is a single numeric measurement that is calculated using a
      multi-parametric mathematical approach from a series of measurements of the speed, intensity,
      diameter, and distance between two vibrations with which a person reacts to and can
      distinguish vibrations from small brushes that touch the top side of fingers on the left hand
      under multiple conditions designed to elicit cortical adaptation The cortical metric is based
      on the neurobiological principle that the nerves in the fingertips project to adjacent groups
      of neurons that work together to continuously optimize perceptions of touch under varying
      conditions. Such perceptual optimization reflects the shifting excitatory and inhibitory
      actions of individual neurons. We hypothesize that the brain's processing of vibration is
      similar to its processing of other kinds of information. We also hypothesize that in people
      with ASD adjacent groups of neurons work together less well to process information.

      Specific Aim 1: Obtain evidence regarding the ability of the "cortical metric" to distinguish
      between 8-12 year-olds with typical development and with high functioning autism spectrum
      disorders (ASDs).

      Hypothesis 1: The cortical metric of children with ASD will differ from that of age matched,
      typically developing children. This difference will be consistent with lower than normal
      local functional connectivity.

      Specific Aim 2: Validate the test-retest reliability of the cortical metric by examining its
      stability of over an average of 3 weeks with no intervening interventions in both groups of
      children.

      Hypothesis 2: Test-retest reliability will be highly correlated in both groups of children.

      Specific Aim 3: Obtain preliminary proof of mechanism data that the cortical metric assesses
      the excitatory: inhibitory balance of intra-cortical connections by examining the effect of
      acute exposure to dextromethorphan (DXM), which transiently blocks one type of excitatory
      neurotransmission

      Hypothesis 3: DXM will alter the cortical metric consistent with reduced adaptation.

      The completion of these aims will be essential to design a larger federally funded trial to
      validate the cortical metric as an outcome measure in a more heterogeneous pediatric ASD
      sample. Specifically, we will aim to demonstrate that 1) the cortical metric differs between
      children with ASD and with normal development, 2) that the cortical metric has minimal
      variability over time in the absence of fno major changes in brain function, and 3) that the
      cortical metric changes in response to a specific, temporary reduction in excitatory
      stimulation caused by a single DXM dose.

      A larger grant could focus on determining how sensitive and clinically relevant changes in
      the cortical metric are.

      If we are not able to demonstrate the potential for the cortical metric to be changed by
      agents that reduce excitatory stimulation acutely or if the variability of the cortical
      metric over 3 weeks is too great, no further examination of the cortical metric as an outcome
      measure in ASD trials would be pursued. If there are not differences in the cortical metric
      of children with and without ASD, we would be less interested in further examining the
      cortical metric.
allocation: Non-Randomized
intervention model: Single Group Assignment
masking: None (Open Label)
measure: The difference in the Cortical Metric before and after acute exposure to dextromethorphan (DXM)
time frame: 2 hours after DXM exposure and 20 min before DXM
description: At visit 2 the cortical metric will be measured 20 min prior to a single dose of DXM and 2hrs after the dose of DXM. . This addresses Specific Aim 3 of the trial. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response. Visit 2 occurs 3 weeks after baseline = time 0
measure: Change in the cortical metric
time frame: 3 weeks
description: The difference between the cortical metric measured 20 minutes before DXM treatment at visit 2, which occurs 3 weeks after the baseline = time 0 visit, and the cortical metric measured 3 weeks earlier at the baseline visit = time 0. We presume their will be no major changes in brain functioning over 3 weeks.
This addresses Specific Aim 2 of the trial, regarding test retest stability. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response.
measure: The Cortical Metric
time frame: Baseline = time 0
description: The cortical metric will be measured at the baseline of the study = time 0. We will compare the mean cortical metric and the range of the cortical metric between the ASD and typically developing groups.
This addresses Specific Aim 1 of the trial. There are 3 primary outcomes all involving the cortical metric because the tool will not be useful to detect treatment changes unless all three outcomes demonstrate the desired response. The goal of this aim is to replicate the findings of the John Hopkins University group that found differences in the cortical metric between groups of children 8-12 years old with ASD and with typical development.
measure: Aberrant Behavior Checklist (ABC) Total Score
time frame: time 0 (baseline)
description: The ABC focuses on problem behaviors in five subdomains: irritability, attention, repetitive behaviors, unusual speech, and social withdrawal and will be completed by subject's parent/guardian or caregiver.
We will examine the correlation between the ABC Total score and the cortical metric.
measure: Pervasive Developmental Disorders Behavior Inventory - Screening Version Score (PDDBI-SV) Social Deficit Score
time frame: Baseline = time 0
description: The PDDBI-SV examines both adaptive and maladaptive behaviors related to autism. The adaptive items are reverse scored and then all items are summed to generate the social deficit score. It is not age specific. This questionnaire will be completed by subject's parent/guardian or caregiver. The correlation between the PDD-BI SV Social Deficit score and the cortical metric will be examined.
measure: Social Responsiveness Scale, Version 2 Total Score (SRS)
time frame: Time 0 = Baseline
description: This 65-item rating scale measures the severity of autism spectrum symptoms as they occur in natural social settings (Constantino, Davis et al. 2003). Completed by a parent or teacher in just 15 to 20 minutes, the SRS provides a clear picture of a child's social impairments, assessing social awareness, social information processing, capacity for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. It is appropriate for use with children from 4 to 18 years of age. The SRS measures impairment on a quantitative scale across a wide range of severity--which is consistent with recent research indicating that autism is best conceptualized as a spectrum condition rather than an all-or-nothing diagnosis. This will be completed by the subject's parent/guardian or caregiver.
The correlation between the SRS Total score and the cortical metric will be examined.
arm group label: Dextromethorphan in ASD
arm group type: Experimental
description: 8-12 years old: > 30 boys will be recruited who have a known or suspected diagnosis of ASD confirmed by DSM-5 checklist and the ADOS-2 at screening. They will have the cortical metric measured 20 min prior to receiving DXM and 2 hours after receiving a single age and weight appropriate dose of DXM. The outcome reported is the difference in the cortical metric after the DXM dose and before the DXM dose.
arm group label: Dextromethorphan in controls
arm group type: Active Comparator
description: 30 typically developing boys 8-12 years old who have the cortical metric measured 20 min before receiving a single age and weight appropriate dose of DXM and 2 hours after the single dose of DXM. The reported value will be the difference between the cortical metric 2hrs after the single dose of DXM and the cortical metric 20 minutes prior to the single dose of DXM.
intervention type: Drug
intervention name: Dextromethophan
description: A single age and weight appropriate dose of over the counter Delsym Cough Syrup containing only DXM as an active ingredient.
arm group label: Dextromethorphan in ASD
arm group label: Dextromethorphan in controls
other name: Delsym Cough Syrup
criteria: 
gender: Male
minimum age: 8 Years
maximum age: 12 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Linmarie Sikich, MD
role: Principal Investigator
affiliation: Duke University
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Autistic Disorder
mesh term: Autism Spectrum Disorder
mesh term: Child Development Disorders, Pervasive