<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/NCT03243552</url>
  </required_header>
  <id_info>
    <org_study_id>ACEPIV</org_study_id>
    <nct_id>NCT03243552</nct_id>
  </id_info>
  <brief_title>Proof of Mechanism Study for the Treatment of Social Anhedonia in ASD</brief_title>
  <acronym>ACEP4</acronym>
  <official_title>Proof of Mecahism Study for the Treatment of Social Anhedonia in ASD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Los Angeles</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>University of California, Los Angeles</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This project will use the experimental medicine approach of a Phase IIa Proof of Mechanism&#xD;
      16-week, randomized, double-blind, controlled trial of L-DOPA versus placebo administration&#xD;
      in combination with a 16 week social skills training group in order to: 1) identify&#xD;
      differences in social reward processes in adolescent and young adult ASD participants versus&#xD;
      healthy controls as measured by fMRI activation in reward circuitry; 2) provide evidence of&#xD;
      dopaminergic moderating effects on social reward components in ASD with greater pre- to&#xD;
      post-treatment changes expected in the subjects randomized to L-DOPA versus placebo; 3)&#xD;
      examine the hypothesis that baseline readouts of putative dopamine signaling (wanting&#xD;
      activation responses) will predict the extent of fMRI reward-related activation changes pre-&#xD;
      to post-treatment; and, 4) examine the proposed relationship between pre- to post- L-DOPA&#xD;
      fMRI reward changes and changes in individual self-report ratings of social wanting and&#xD;
      ratings of videotaped positive affect in a structured interaction with an examiner. The study&#xD;
      will enroll 56 participants with DSM-5 ASD between the ages of 13-30 years of age and 18&#xD;
      healthy control participants without histories of psychopathology for baseline comparisons.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants will comprise two groups: 1) 56 (male and female) adolescents and young adults&#xD;
      likely to meet inclusion/exclusion confirmed by study assessment who will be outpatients,&#xD;
      ages 13 to 30 years, inclusive; and 2) 18 (male and female) healthy adolescents and young&#xD;
      adults without any history of significant psychiatric disorders or treatment, who will be&#xD;
      ambulatory, and will reflect the racial, ethnic, and socio-economic composition of Los&#xD;
      Angeles, and will be recruited without regard to gender, race, or ethnic background.&#xD;
&#xD;
      Healthy control adolescents (and parents) and young adults who meet all inclusion and&#xD;
      exclusion criteria, will undergo a one-day 4-5 hour research evaluation of current&#xD;
      functioning and behavior, cognitive function, including intellectual testing, urine drug&#xD;
      screen, completion of questionnaires about possible psychological symptoms, perform brief&#xD;
      tests to measure reward response, and complete a research Magnetic Resonance Imaging scan.&#xD;
      Healthy control will not receive any interventions or medication.&#xD;
&#xD;
      All eligible ASD participants will be enrolled concurrently in a 16-week, structured,&#xD;
      group-based, social skills training program (PEERS®). After screening evaluations, eligible&#xD;
      subjects will undergo baseline MRI scanning and behavioral assessments (self- and&#xD;
      parent-report measures, videotaped interaction) and then randomized in a blocked schedule to&#xD;
      yield 1:1 L-DOPA: placebo assignment, before beginning weekly social skills training.&#xD;
      Medication administration will begin simultaneously with social skills training, and subjects&#xD;
      will be seen weekly for the 1st 8 weeks, then biweekly for the final 4 weeks for safety&#xD;
      assessments, dose titration, and compliance checks. During the 16-week study period, primary&#xD;
      behavioral assessments will be repeated at Week 8 and at end of study on Week 16. A second&#xD;
      MRI scan will be obtained within + 4 days of last social skills session. A follow-up safety&#xD;
      phone call to assess post-study condition will be performed 30 days after completion of&#xD;
      double-blind. The rich set of behavioral observations obtained across the 16 weeks will allow&#xD;
      the possible identification of early clinical efficacy changes associated with L-DOPA&#xD;
      administration, which could add further support for investigating this mechanism in future&#xD;
      studies. Results from the project should inform reseacher's understanding of determinants of&#xD;
      social dysfunction in ASD and may support further investigation of treatments modulating&#xD;
      central nervous system dopamine function as a therapeutic strategy to enhance social&#xD;
      functioning in ASD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 1, 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>
    <intervention_model_description>Phase IIa Proof of Mechanism 16-week, randomized, double-blind, controlled trial of L-DOPA versus placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in fMRI: Social Reward Task from Baseline to week 16 (4 months)</measure>
    <time_frame>Baseline, week 16</time_frame>
    <description>BOLD Activation: VS, ACC, OFC, Amygdala, Hippocampus (same units of measure)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change on Anticipatory and Consummatory Interpersonal Pleasure Scale Adolescent (ACIPS-A)</measure>
    <time_frame>Baseline, week 8 (midpoint), week 16 (4 month/end of study)</time_frame>
    <description>Total Score (change in score by timepoint; before treatment, midpoint, end)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)</measure>
    <time_frame>Baseline, week 8 (midpoint), week 16 (4 month/end of study)</time_frame>
    <description>Total Score (change in score by timepoint; before treatment, midpoint, end)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on Child Behavior Checklist (CBCL)</measure>
    <time_frame>Baseline, week 16 (4 month/end of study)</time_frame>
    <description>T Scores of Syndrome Scales for ages 18 or under</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on Youth Self Report (YSR)</measure>
    <time_frame>Baseline, week 16 (4 month/end of study)</time_frame>
    <description>T Scores of Syndrome Scales for ages 18 or under</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on Adult Behavior Checklist (ABCL)</measure>
    <time_frame>Baseline, week 16 (4 month/end of study)</time_frame>
    <description>T Scores of Syndrome Scales for ages 18 or over</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on SRS Self Report</measure>
    <time_frame>Baseline, week 8 (midpoint), week 16 (4 month/end of study)</time_frame>
    <description>Social Anhedonia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on SRS Parent Report</measure>
    <time_frame>Baseline, week 8 (midpoint), week 16 (4 month/end of study)</time_frame>
    <description>Social Anhedonia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change on Social Communication Interaction Test (SCIT)</measure>
    <time_frame>Baseline, week 8 (midpoint), week 16 (4 month/end of study)</time_frame>
    <description>6 subscales and total score (0-30)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">56</enrollment>
  <condition>ASD</condition>
  <arm_group>
    <arm_group_label>L-DOPA versus Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>L-DOPA or placebo (1:1 randomization). Dosing will begin at 25mg carbidopa/100mg L-DOPA in 3 divided doses, with a fixed-flexible titration schedule, allowing dose increases once per week of 100mg L-DOPA. Maximum dose is 600mg/d.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Social Skills</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will receive 16-week manualized social skills training.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L-DOPA versus Placebo</intervention_name>
    <description>Participants will be randomized in a blocked schedule to yield 1:1 L-DOPA: placebo assignment.</description>
    <arm_group_label>L-DOPA versus Placebo</arm_group_label>
    <arm_group_label>Social Skills</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Social Skills Training</intervention_name>
    <description>ASD participants will be enrolled concurrently in a 16-week manualized, structured, group-based, social skills training program (PEERS).</description>
    <arm_group_label>L-DOPA versus Placebo</arm_group_label>
    <arm_group_label>Social Skills</arm_group_label>
    <other_name>PEERS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ages 13 - 30 years inclusive;&#xD;
&#xD;
          -  meets diagnostic criteria for ASD by clinical evaluation and ADOS;&#xD;
&#xD;
          -  estimated FS IQ &gt;70; 4) English reading ability of 6th grade;&#xD;
&#xD;
          -  ability to participate and complete protocol expectations (fMRI scan, testing) in the&#xD;
             examining clinician's judgment; and&#xD;
&#xD;
          -  planned enrollment and acceptance for the UCLA PEERS® adolescent or young adult social&#xD;
             skills training program.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  significant perceptual deficits;&#xD;
&#xD;
          -  need for continuation or anticipated of use of prohibited dopamine-modifying&#xD;
             medications (stimulants, antipsychotics);&#xD;
&#xD;
          -  presence of serious behavioral comorbidity such as aggression, major depressive&#xD;
             disorder requiring additional intervention, or self-injurious behavior, or current of&#xD;
             past history of suspected psychotic disorder;&#xD;
&#xD;
          -  history of tic disorder;&#xD;
&#xD;
          -  presence of significant medical illness which may impact CNS function.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James T McCracken, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, Los Angeles</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, Los Angeles</investigator_affiliation>
    <investigator_full_name>James McCracken</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anhedonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levodopa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03243552
org study id: ACEPIV
nct id: NCT03243552
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This project will use the experimental medicine approach of a Phase IIa Proof of Mechanism
      16-week, randomized, double-blind, controlled trial of L-DOPA versus placebo administration
      in combination with a 16 week social skills training group in order to: 1) identify
      differences in social reward processes in adolescent and young adult ASD participants versus
      healthy controls as measured by fMRI activation in reward circuitry; 2) provide evidence of
      dopaminergic moderating effects on social reward components in ASD with greater pre- to
      post-treatment changes expected in the subjects randomized to L-DOPA versus placebo; 3)
      examine the hypothesis that baseline readouts of putative dopamine signaling (wanting
      activation responses) will predict the extent of fMRI reward-related activation changes pre-
      to post-treatment; and, 4) examine the proposed relationship between pre- to post- L-DOPA
      fMRI reward changes and changes in individual self-report ratings of social wanting and
      ratings of videotaped positive affect in a structured interaction with an examiner. The study
      will enroll 56 participants with DSM-5 ASD between the ages of 13-30 years of age and 18
      healthy control participants without histories of psychopathology for baseline comparisons.
Participants will comprise two groups: 1) 56 (male and female) adolescents and young adults
      likely to meet inclusion/exclusion confirmed by study assessment who will be outpatients,
      ages 13 to 30 years, inclusive; and 2) 18 (male and female) healthy adolescents and young
      adults without any history of significant psychiatric disorders or treatment, who will be
      ambulatory, and will reflect the racial, ethnic, and socio-economic composition of Los
      Angeles, and will be recruited without regard to gender, race, or ethnic background.

      Healthy control adolescents (and parents) and young adults who meet all inclusion and
      exclusion criteria, will undergo a one-day 4-5 hour research evaluation of current
      functioning and behavior, cognitive function, including intellectual testing, urine drug
      screen, completion of questionnaires about possible psychological symptoms, perform brief
      tests to measure reward response, and complete a research Magnetic Resonance Imaging scan.
      Healthy control will not receive any interventions or medication.

      All eligible ASD participants will be enrolled concurrently in a 16-week, structured,
      group-based, social skills training program (PEERS®). After screening evaluations, eligible
      subjects will undergo baseline MRI scanning and behavioral assessments (self- and
      parent-report measures, videotaped interaction) and then randomized in a blocked schedule to
      yield 1:1 L-DOPA: placebo assignment, before beginning weekly social skills training.
      Medication administration will begin simultaneously with social skills training, and subjects
      will be seen weekly for the 1st 8 weeks, then biweekly for the final 4 weeks for safety
      assessments, dose titration, and compliance checks. During the 16-week study period, primary
      behavioral assessments will be repeated at Week 8 and at end of study on Week 16. A second
      MRI scan will be obtained within + 4 days of last social skills session. A follow-up safety
      phone call to assess post-study condition will be performed 30 days after completion of
      double-blind. The rich set of behavioral observations obtained across the 16 weeks will allow
      the possible identification of early clinical efficacy changes associated with L-DOPA
      administration, which could add further support for investigating this mechanism in future
      studies. Results from the project should inform reseacher's understanding of determinants of
      social dysfunction in ASD and may support further investigation of treatments modulating
      central nervous system dopamine function as a therapeutic strategy to enhance social
      functioning in ASD.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Phase IIa Proof of Mechanism 16-week, randomized, double-blind, controlled trial of L-DOPA versus placebo.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double-blind
measure: Change in fMRI: Social Reward Task from Baseline to week 16 (4 months)
time frame: Baseline, week 16
description: BOLD Activation: VS, ACC, OFC, Amygdala, Hippocampus (same units of measure)
measure: Change on Anticipatory and Consummatory Interpersonal Pleasure Scale Adolescent (ACIPS-A)
time frame: Baseline, week 8 (midpoint), week 16 (4 month/end of study)
description: Total Score (change in score by timepoint; before treatment, midpoint, end)
measure: Change on Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)
time frame: Baseline, week 8 (midpoint), week 16 (4 month/end of study)
description: Total Score (change in score by timepoint; before treatment, midpoint, end)
measure: Change on Child Behavior Checklist (CBCL)
time frame: Baseline, week 16 (4 month/end of study)
description: T Scores of Syndrome Scales for ages 18 or under
measure: Change on Youth Self Report (YSR)
time frame: Baseline, week 16 (4 month/end of study)
description: T Scores of Syndrome Scales for ages 18 or under
measure: Change on Adult Behavior Checklist (ABCL)
time frame: Baseline, week 16 (4 month/end of study)
description: T Scores of Syndrome Scales for ages 18 or over
measure: Change on SRS Self Report
time frame: Baseline, week 8 (midpoint), week 16 (4 month/end of study)
description: Social Anhedonia
measure: Change on SRS Parent Report
time frame: Baseline, week 8 (midpoint), week 16 (4 month/end of study)
description: Social Anhedonia
measure: change on Social Communication Interaction Test (SCIT)
time frame: Baseline, week 8 (midpoint), week 16 (4 month/end of study)
description: 6 subscales and total score (0-30)
arm group label: L-DOPA versus Placebo
arm group type: Active Comparator
description: L-DOPA or placebo (1:1 randomization). Dosing will begin at 25mg carbidopa/100mg L-DOPA in 3 divided doses, with a fixed-flexible titration schedule, allowing dose increases once per week of 100mg L-DOPA. Maximum dose is 600mg/d.
arm group label: Social Skills
arm group type: Experimental
description: All participants will receive 16-week manualized social skills training.
intervention type: Drug
intervention name: L-DOPA versus Placebo
description: Participants will be randomized in a blocked schedule to yield 1:1 L-DOPA: placebo assignment.
arm group label: L-DOPA versus Placebo
arm group label: Social Skills
intervention type: Behavioral
intervention name: Social Skills Training
description: ASD participants will be enrolled concurrently in a 16-week manualized, structured, group-based, social skills training program (PEERS).
arm group label: L-DOPA versus Placebo
arm group label: Social Skills
other name: PEERS
criteria: 
gender: All
minimum age: 13 Years
maximum age: 30 Years
healthy volunteers: Accepts Healthy Volunteers
last name: James T McCracken, MD
role: Principal Investigator
affiliation: University of California, Los Angeles
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, Los Angeles
investigator full name: James McCracken
investigator title: Principal Investigator
mesh term: Anhedonia
mesh term: Levodopa
sharing ipd: No