<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/NCT01727414</url>
  </required_header>
  <id_info>
    <org_study_id>ADDMedStudy</org_study_id>
    <secondary_id>K23MH083881</secondary_id>
    <nct_id>NCT01727414</nct_id>
  </id_info>
  <brief_title>Attention Deficit Disorder Medication Response Study</brief_title>
  <official_title>Medication Response in Children With Predominately Inattentive Type ADHD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates how children with Attention Deficit Disorder without Hyperactivity (ADD)&#xD;
      respond to medication, and if their response is different from children who have problems&#xD;
      with both hyperactivity and inattention. In order to do this, children ages 7-11 whose&#xD;
      primary difficulty is with attention problems and who have never been on behavioral or&#xD;
      psychiatric medications are being recruited. Once enrolled, children will try one week each&#xD;
      of 3 different doses of methylphenidate, the most commonly prescribed Attention Deficit,&#xD;
      Hyperactivity Disorder (ADHD) medication, as well as placebo. Children will be randomly&#xD;
      assigned to one of six possible medication dose and placebo titration schedules, but the&#xD;
      study doctor, family, and teacher will not know which dose (if any) children are receiving&#xD;
      for a given week. Each week, behavioral and side effect ratings will be completed by both the&#xD;
      child's parent and teacher, and the family will meet with the study doctor for a physical&#xD;
      examination and to discuss how each week went. Some children will also have&#xD;
      neuropsychological testing to determine how methylphenidate influences their working memory,&#xD;
      sustained attention, and ability to inhibit (stop) inappropriate responses.&#xD;
&#xD;
      All data will be analyzed to decide which medication dose the child responded to best and&#xD;
      further recommendations for treatment will be given. Ultimately, this study aims to improve&#xD;
      understanding of how children with ADHD-Primarily Inattentive Type respond to stimulant&#xD;
      medications by&#xD;
&#xD;
        -  determining whether these children experience a diminished response to methylphenidate&#xD;
           compared to children with both hyperactivity and inattention&#xD;
&#xD;
        -  determining whether certain genetic and environmental factors play a role in this&#xD;
           response.&#xD;
&#xD;
      Findings from this study will be used to help streamline the identification of the most&#xD;
      effective doses of medication for children with ADHD-Primarily Inattentive Type.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Robust data indicate that stimulant medications reduce ADHD symptoms and impairment, but it&#xD;
      is unclear whether their efficacy generalizes across the ADHD subtypes. Although&#xD;
      predominately inattentive type (PIT) is the most prevalent ADHD subtype in U.S.&#xD;
      population-based studies, few studies have specifically examined response to stimulants in&#xD;
      this subtype. Instead, medication guidelines for PIT have largely been extrapolated from&#xD;
      studies enrolling all or mostly ADHD-combined type (CT). Thus, this application seeks to&#xD;
      improve understanding of stimulant medication response and its predictors in children with&#xD;
      PIT. We will evaluate participants' response to methylphenidate (MPH), the most widely&#xD;
      prescribed stimulant, via a prospective, double-blind, placebo-controlled crossover trial&#xD;
      with 3 dose conditions. Our first specific aim is to examine MPH medication and dose response&#xD;
      in children with PIT (n=120) and CT (n=45) to test the hypotheses that participants with PIT&#xD;
      have a diminished MPH response and derive less benefit from higher doses compared to those&#xD;
      with CT. Since only one prior study has examined genetic predictors of MPH response&#xD;
      variability within PIT-only samples, our second specific aim (exploratory) is to determine&#xD;
      the potential role of genetic polymorphisms (e.g., those in DAT1, DRD4, NET, ADRA2A, COMT,&#xD;
      SNAP25, CES1, GRM7, LPHN3) on MPH response in children with PIT (n=120), examining both&#xD;
      symptom change with MPH and MPH dose response curves. If we identify significant differences&#xD;
      in MPH response between the subtypes, our findings may guide clinical practice by suggesting&#xD;
      more effective medication strategies (such as different dosing schedules) for children with&#xD;
      PIT. In addition, this study may yield pharmacogenetic findings that, in the future, could&#xD;
      enable physicians to tailor individual treatment plans for children with PIT, ameliorating&#xD;
      the current prolonged and expensive practice of prescribing by trial and error.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2006</start_date>
  <completion_date type="Actual">July 2014</completion_date>
  <primary_completion_date type="Actual">July 2013</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Every participant receives placebo and three different dose of MPH for one week each in a triple blinded fashion</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Attention Deficit Hyperactivity Disorder Total Symptom Score</measure>
    <time_frame>End of placebo dose week, End of low dose week, End of medium dose week , End of high dose week</time_frame>
    <description>Assessed via parent and teacher Vanderbilt Attention Deficit Hyperactivity Disorder Rating Scales which were completed each the 4 weeks of the titration trial.&#xD;
Range: min=0, max=54 [sum of 18 symptom items, rated from 0 (none), 1 (occasionally), 2 (often), 3 (very often)], higher scores indicate worse outcomes.&#xD;
Note to address Review Comment: During the 4 week titration trial, the placebo condition and each of the three active dosages (low, medium, and high) were given for one week each. Because the placebo and active dosages were given in random order to preserve the triple blind, all participants did not receive the same order of dosages and it is not possible to connect the dosages (placebo, low dose MPH, medium dose MPH, high dose MPH) to a specific week number (week 1, week 2, week 3, week 4) which would hold for ALL participants. That is why Timeframe was revised from &quot;week 1, week 2, week 3, week 4&quot; to placebo, low dose, medium dose, and high dose week.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">171</enrollment>
  <condition>ADHD - Inattentive Type</condition>
  <condition>ADHD - Combined Type</condition>
  <arm_group>
    <arm_group_label>OROS-Methylphenidate and placebo for inattentive type pts</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Children with ADHD-inattentive type. Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>OROS-Methylphenidate and placebo for combined type pts</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Children with ADHD-combined type type. Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OROS-Methylphenidate and placebo for inattentive type pts</intervention_name>
    <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.</description>
    <arm_group_label>OROS-Methylphenidate and placebo for inattentive type pts</arm_group_label>
    <other_name>concerta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OROS-Methylphenidate and placebo for combined type pts</intervention_name>
    <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.</description>
    <arm_group_label>OROS-Methylphenidate and placebo for combined type pts</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Consent: The family must provide signature of informed consent by a parent or legal&#xD;
             guardian. Children must also assent to study participation.&#xD;
&#xD;
          -  Age at Screening:7.0 years to 11.9 years, inclusive.&#xD;
&#xD;
          -  Sex: Includes male and female children.&#xD;
&#xD;
          -  ADHD Diagnostic Status: Meets DSM-IV criteria for ADHD, Predominantly Inattentive or&#xD;
             Combined subtype with Clinical Global Impression-Severity rating corresponding to at&#xD;
             least &quot;moderately ill.&quot;&#xD;
&#xD;
          -  Cognitive Functioning-Intelligence Quotient (IQ) of greater than 80 as estimated by&#xD;
             Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for&#xD;
             Children--4th Edition, or an Intelligence Quotient (IQ) of 80 or greater when&#xD;
             administered the Full Scale Version of the Wechsler Intelligence Scale for&#xD;
             Children-4th Edition.&#xD;
&#xD;
          -  Absence of Learning Disability:On the abbreviated Wechsler Individual Achievement&#xD;
             Test-2nd edition Reading and Math subtests, participants must score above 80. However,&#xD;
             children may also be included if they receive a score of 75 or greater on the Word&#xD;
             Reading and/or Math subtests, as long as this score is not a significant discrepancy&#xD;
             from their full-scale IQ score (e.g., a difference of greater than one standard&#xD;
             deviation or 15 points).&#xD;
&#xD;
          -  School: Enrolled in a school setting rather than a home-school program.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Understanding Level: Participant and/or parent cannot understand or follow study&#xD;
             instructions.&#xD;
&#xD;
          -  Psychiatric Medications: Current or prior history of taking any medication for&#xD;
             psychological or psychiatric problems.&#xD;
&#xD;
          -  Behavioral Interventions: Current active participation in ADHD-related behavioral&#xD;
             interventions or counseling.&#xD;
&#xD;
          -  Exclusionary Psychiatric Conditions: Children with mania/hypomania and/or&#xD;
             schizophrenia will be excluded. The following comorbid diagnoses will not be excluded&#xD;
             unless they are determined to be the primary cause of ADHD symptomatology (see below&#xD;
             for description of this decision process): Post Traumatic Stress Disorder, Phobias and&#xD;
             Anxiety Disorders, Obsessive Compulsive Disorder, Major Depression / Dysthymia, Eating&#xD;
             Disorders, Elimination Disorders, Trichotillomania, Tic Disorder, Oppositional Defiant&#xD;
             Disorder, Conduct Disorder.&#xD;
&#xD;
          -  Organic Brain Injury: History of head trauma, neurological disorder, or other organic&#xD;
             disorder affecting brain function.&#xD;
&#xD;
          -  Cardiovascular Risk Factors: Children with a personal history or family history of&#xD;
             cardiovascular risk factors will be excluded, or given the option of participating in&#xD;
             the study after obtaining an EKG and a signed letter from a pediatric cardiologist&#xD;
             verifying the safety of their participation in a trial of methylphenidate. In this&#xD;
             case, families will be responsible for the costs of EKG and cardiologist evaluation.&#xD;
             If for any reason a family is unable to assume the cost of the EKG and cardiologist&#xD;
             evaluations but still wishes for their child to participate, study staff will&#xD;
             determine on a case-by-case basis whether the study budget allows the study to offer&#xD;
             financial assistance to the families for these evaluations.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>7 Years</minimum_age>
    <maximum_age>11 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tanya E. Froehlich, MS, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Medical Center, Cincinnati</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>August 1, 2012</study_first_submitted>
  <study_first_submitted_qc>November 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 16, 2012</study_first_posted>
  <results_first_submitted>April 4, 2017</results_first_submitted>
  <results_first_submitted_qc>June 19, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">July 18, 2017</results_first_posted>
  <last_update_submitted>April 28, 2021</last_update_submitted>
  <last_update_submitted_qc>April 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ADHD</keyword>
  <keyword>Inattention</keyword>
  <keyword>Methylphenidate</keyword>
  <keyword>Pharmacogenetics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Attention Deficit Disorder with Hyperactivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylphenidate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Inattentive Type</title>
          <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.&#xD;
Placebo: capsule, frequency - each AM, duration - 1 week</description>
        </group>
        <group group_id="P2">
          <title>Combined Type</title>
          <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.&#xD;
OROS-Methylphenidate: capsule; dosages - 18mg, 27mg, 36mg, 54 mg; frequency - each AM; duration - one week for each dose, with each child receiving 3 doses [children &lt; 25 kg receive 18mg, 27mg, 36mg; children &gt; or = to 25kg get 18mg, 36mg, 54mg]</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="126"/>
                <participants group_id="P2" count="45"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="123"/>
                <participants group_id="P2" count="45"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Children meeting DSM-IV criteria for ADHD-inattentive type are in the Inattentive Type Arm, while children meeting DSM-IV criteria for ADHD-combined type are in the Combined Type Arm.</population>
      <group_list>
        <group group_id="B1">
          <title>Inattentive Type</title>
        </group>
        <group group_id="B2">
          <title>Combined Type</title>
        </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="126"/>
            <count group_id="B2" value="45"/>
            <count group_id="B3" value="171"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.6" spread="1.3"/>
                    <measurement group_id="B2" value="7.9" spread="1.0"/>
                    <measurement group_id="B3" value="8.4" spread="1.3"/>
                  </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="40"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="49"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="86"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="122"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="109"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="139"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="8"/>
                  </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_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Attention Deficit Hyperactivity Disorder Total Symptom Score</title>
        <description>Assessed via parent and teacher Vanderbilt Attention Deficit Hyperactivity Disorder Rating Scales which were completed each the 4 weeks of the titration trial.&#xD;
Range: min=0, max=54 [sum of 18 symptom items, rated from 0 (none), 1 (occasionally), 2 (often), 3 (very often)], higher scores indicate worse outcomes.&#xD;
Note to address Review Comment: During the 4 week titration trial, the placebo condition and each of the three active dosages (low, medium, and high) were given for one week each. Because the placebo and active dosages were given in random order to preserve the triple blind, all participants did not receive the same order of dosages and it is not possible to connect the dosages (placebo, low dose MPH, medium dose MPH, high dose MPH) to a specific week number (week 1, week 2, week 3, week 4) which would hold for ALL participants. That is why Timeframe was revised from &quot;week 1, week 2, week 3, week 4&quot; to placebo, low dose, medium dose, and high dose week.</description>
        <time_frame>End of placebo dose week, End of low dose week, End of medium dose week , End of high dose week</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Inattentive Type</title>
            <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.&#xD;
OROS-Methylphenidate: capsule; dosages - 18mg, 27mg, 36mg, 54 mg; frequency - each AM; duration - one week for each dose, with each child receiving 3 doses [children &lt; 25 kg receive 18mg, 27mg, 36mg; children &gt; or = to 25kg get 18mg, 36mg, 54mg]</description>
          </group>
          <group group_id="O2">
            <title>Combined Type</title>
            <description>Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.&#xD;
OROS-Methylphenidate: capsule; dosages - 18mg, 27mg, 36mg, 54 mg; frequency - each AM; duration - one week for each dose, with each child receiving 3 doses [children &lt; 25 kg receive 18mg, 27mg, 36mg; children &gt; or = to 25kg get 18mg, 36mg, 54mg]</description>
          </group>
        </group_list>
        <measure>
          <title>Attention Deficit Hyperactivity Disorder Total Symptom Score</title>
          <description>Assessed via parent and teacher Vanderbilt Attention Deficit Hyperactivity Disorder Rating Scales which were completed each the 4 weeks of the titration trial.&#xD;
Range: min=0, max=54 [sum of 18 symptom items, rated from 0 (none), 1 (occasionally), 2 (often), 3 (very often)], higher scores indicate worse outcomes.&#xD;
Note to address Review Comment: During the 4 week titration trial, the placebo condition and each of the three active dosages (low, medium, and high) were given for one week each. Because the placebo and active dosages were given in random order to preserve the triple blind, all participants did not receive the same order of dosages and it is not possible to connect the dosages (placebo, low dose MPH, medium dose MPH, high dose MPH) to a specific week number (week 1, week 2, week 3, week 4) which would hold for ALL participants. That is why Timeframe was revised from &quot;week 1, week 2, week 3, week 4&quot; to placebo, low dose, medium dose, and high dose week.</description>
          <units>units 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="123"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>ADHD Total Symptom Score on Placebo</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.4" spread="8.9"/>
                    <measurement group_id="O2" value="30.0" spread="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ADHD Total Symptom Score on Low Dose MPH</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.2" spread="8.1"/>
                    <measurement group_id="O2" value="29.7" spread="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ADHD Total Symptom Score on Medium Dose MPH</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.0" spread="7.9"/>
                    <measurement group_id="O2" value="23.9" spread="10.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ADHD Total Symptom Score on High Dose MPH</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.5" spread="6.9"/>
                    <measurement group_id="O2" value="22.8" spread="10.8"/>
                  </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>Superiority</non_inferiority_type>
            <non_inferiority_desc>General linear mixed models were used to evaluate the subtype*dose interaction to determine if the subtypes have unique MPH dose-response curves, with the outcome being Attention Deficit Hyperactivity Disorder total symptom scores (minimum=0, maximum=54, higher=worse)</non_inferiority_desc>
            <p_value>&lt;0.05</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Slope</param_type>
            <param_value>0.29</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>4 week medication titration trial</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Inattentive Type</title>
          <description>Children meeting DSM-IV criteria for ADHD-inattentive type.</description>
        </group>
        <group group_id="E2">
          <title>Combined Type</title>
          <description>Children meeting DSM-IV criteria for ADHD-combined type.</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="123"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="123"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>Irritability</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="123"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Irritability</sub_title>
                <description>Parent rating of having moderate or severe irritability on the Pittsburgh side effect rating scale while taking the highest methylphenidate dose</description>
                <counts group_id="E1" events="17" subjects_affected="17" subjects_at_risk="123"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="45"/>
              </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>Tanya Froehlich</name_or_title>
      <organization>Cincinnati Children's Hospital</organization>
      <phone>5136361154</phone>
      <email>tanya.froehlich@cchmc.org</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/NCT01727414
org study id: ADDMedStudy
secondary id: K23MH083881
nct id: NCT01727414
lead sponsor: 
collaborator: 
has dmc: Yes
This study evaluates how children with Attention Deficit Disorder without Hyperactivity (ADD)
      respond to medication, and if their response is different from children who have problems
      with both hyperactivity and inattention. In order to do this, children ages 7-11 whose
      primary difficulty is with attention problems and who have never been on behavioral or
      psychiatric medications are being recruited. Once enrolled, children will try one week each
      of 3 different doses of methylphenidate, the most commonly prescribed Attention Deficit,
      Hyperactivity Disorder (ADHD) medication, as well as placebo. Children will be randomly
      assigned to one of six possible medication dose and placebo titration schedules, but the
      study doctor, family, and teacher will not know which dose (if any) children are receiving
      for a given week. Each week, behavioral and side effect ratings will be completed by both the
      child's parent and teacher, and the family will meet with the study doctor for a physical
      examination and to discuss how each week went. Some children will also have
      neuropsychological testing to determine how methylphenidate influences their working memory,
      sustained attention, and ability to inhibit (stop) inappropriate responses.

      All data will be analyzed to decide which medication dose the child responded to best and
      further recommendations for treatment will be given. Ultimately, this study aims to improve
      understanding of how children with ADHD-Primarily Inattentive Type respond to stimulant
      medications by

        -  determining whether these children experience a diminished response to methylphenidate
           compared to children with both hyperactivity and inattention

        -  determining whether certain genetic and environmental factors play a role in this
           response.

      Findings from this study will be used to help streamline the identification of the most
      effective doses of medication for children with ADHD-Primarily Inattentive Type.
Robust data indicate that stimulant medications reduce ADHD symptoms and impairment, but it
      is unclear whether their efficacy generalizes across the ADHD subtypes. Although
      predominately inattentive type (PIT) is the most prevalent ADHD subtype in U.S.
      population-based studies, few studies have specifically examined response to stimulants in
      this subtype. Instead, medication guidelines for PIT have largely been extrapolated from
      studies enrolling all or mostly ADHD-combined type (CT). Thus, this application seeks to
      improve understanding of stimulant medication response and its predictors in children with
      PIT. We will evaluate participants' response to methylphenidate (MPH), the most widely
      prescribed stimulant, via a prospective, double-blind, placebo-controlled crossover trial
      with 3 dose conditions. Our first specific aim is to examine MPH medication and dose response
      in children with PIT (n=120) and CT (n=45) to test the hypotheses that participants with PIT
      have a diminished MPH response and derive less benefit from higher doses compared to those
      with CT. Since only one prior study has examined genetic predictors of MPH response
      variability within PIT-only samples, our second specific aim (exploratory) is to determine
      the potential role of genetic polymorphisms (e.g., those in DAT1, DRD4, NET, ADRA2A, COMT,
      SNAP25, CES1, GRM7, LPHN3) on MPH response in children with PIT (n=120), examining both
      symptom change with MPH and MPH dose response curves. If we identify significant differences
      in MPH response between the subtypes, our findings may guide clinical practice by suggesting
      more effective medication strategies (such as different dosing schedules) for children with
      PIT. In addition, this study may yield pharmacogenetic findings that, in the future, could
      enable physicians to tailor individual treatment plans for children with PIT, ameliorating
      the current prolonged and expensive practice of prescribing by trial and error.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Every participant receives placebo and three different dose of MPH for one week each in a triple blinded fashion
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Attention Deficit Hyperactivity Disorder Total Symptom Score
time frame: End of placebo dose week, End of low dose week, End of medium dose week , End of high dose week
description: Assessed via parent and teacher Vanderbilt Attention Deficit Hyperactivity Disorder Rating Scales which were completed each the 4 weeks of the titration trial.
Range: min=0, max=54 [sum of 18 symptom items, rated from 0 (none), 1 (occasionally), 2 (often), 3 (very often)], higher scores indicate worse outcomes.
Note to address Review Comment: During the 4 week titration trial, the placebo condition and each of the three active dosages (low, medium, and high) were given for one week each. Because the placebo and active dosages were given in random order to preserve the triple blind, all participants did not receive the same order of dosages and it is not possible to connect the dosages (placebo, low dose MPH, medium dose MPH, high dose MPH) to a specific week number (week 1, week 2, week 3, week 4) which would hold for ALL participants. That is why Timeframe was revised from "week 1, week 2, week 3, week 4" to placebo, low dose, medium dose, and high dose week.
arm group label: OROS-Methylphenidate and placebo for inattentive type pts
arm group type: Other
description: Children with ADHD-inattentive type. Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.
arm group label: OROS-Methylphenidate and placebo for combined type pts
arm group type: Other
description: Children with ADHD-combined type type. Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.
intervention type: Drug
intervention name: OROS-Methylphenidate and placebo for inattentive type pts
description: Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.
arm group label: OROS-Methylphenidate and placebo for inattentive type pts
other name: concerta
intervention type: Drug
intervention name: OROS-Methylphenidate and placebo for combined type pts
description: Every participant receives low dose MPH, medium dose MPH, high dose MPH, and placebo for one week each in a triple-blinded fashion.
arm group label: OROS-Methylphenidate and placebo for combined type pts
criteria: 
gender: All
minimum age: 7 Years
maximum age: 11 Years
healthy volunteers: No
last name: Tanya E. Froehlich, MS, MD
role: Principal Investigator
affiliation: Children's Hospital Medical Center, Cincinnati
facility: 
country: United States
responsible party type: Sponsor
mesh term: Attention Deficit Disorder with Hyperactivity
mesh term: Methylphenidate
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 