<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/NCT02225106</url>
  </required_header>
  <id_info>
    <org_study_id>140169</org_study_id>
    <secondary_id>14-N-0169</secondary_id>
    <nct_id>NCT02225106</nct_id>
  </id_info>
  <brief_title>Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI</brief_title>
  <acronym>DAPET-TBI</acronym>
  <official_title>Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Deficits in memory, attention, cognitive, and executive functions are the most common&#xD;
      disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is&#xD;
      implicated in these neural functions and dopaminergic pathways are recognized to be&#xD;
      frequently disrupted after TBI. Methylphenidate increases synaptic DA levels by binding to&#xD;
      presynaptic dopamine transporters (DAT) and blocking re-uptake.&#xD;
&#xD;
      The objectives of this study are to use PET imaging with [11C]-raclopride, a D2/D3 receptor&#xD;
      ligand, before and after administering methylphenidate, to measure endogenous DA release in&#xD;
      patients who are experiencing problems with cognition, attention and executive function in&#xD;
      the chronic stage after TBI. In addition, we will use TMS to test short intracortical&#xD;
      inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is&#xD;
      under partial DA control, as a measure of dopaminergic activity on and off&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Deficits in memory, attention, cognitive, and executive functions are the most common&#xD;
      disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is&#xD;
      implicated in these neural functions and dopaminergic pathways are recognized to be&#xD;
      frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate&#xD;
      (Ritalin ). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine&#xD;
      transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure&#xD;
      tonic DA release provides valuable insight into the molecular basis of attention-deficit&#xD;
      hyperactivity disorder (ADHD) and addiction, as well as practical information regarding&#xD;
      likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with&#xD;
      [11C]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to&#xD;
      measure endogenous DA release in patients who are experiencing problems with cognition,&#xD;
      attention and executive function in the chronic stage after TBI. In addition, we will use TMS&#xD;
      to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) -&#xD;
      mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity&#xD;
      on and off&#xD;
&#xD;
      methylphenidate.&#xD;
&#xD;
      STUDY POPULATION:&#xD;
&#xD;
      Males and females (n=30), between the ages of 18 and 55 years in the chronic stage after TBI&#xD;
      who experience deficits in neuropsychological function from TBIs incurred 6 months after the&#xD;
      injury, will be recruited from military treatment facilities or civilian clinics when&#xD;
      presenting for clinical management of TBI or postconcussive symptoms.&#xD;
&#xD;
      DESIGN:&#xD;
&#xD;
        1. Study participants will be evaluated using brain MRI, psychometric measures adapted from&#xD;
           the TBI Common Data Elements, attention tests and information about details of the&#xD;
           injury and experience of post-concussive symptoms will be recorded. Transcranial&#xD;
           magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth)&#xD;
           challenge will be performed to predict a stimulant response.&#xD;
&#xD;
        2. Subjects will be studied with [11C]-raclopride PET in two imaging sessions. One session&#xD;
           will be after administration of placebo and the other after methylphenidate, 60 mg by&#xD;
           mouth. Both placebo and methylphenidate will be given 60 minutes prior to injection of&#xD;
           [11C]-raclopride to allow for peak uptake of methylphenidate in the brain. The binding&#xD;
           potential of [11C]-raclopride relative to a non-displaceable reference region&#xD;
           (cerebellum), BPND, will be used as a measure of D2/D3 receptor availability. The&#xD;
           difference in BPND between methylphenidate and placebo ( BPND) is used to measure of&#xD;
           tonic DA release.&#xD;
&#xD;
        3. Subjects will then be treated with oral methylphenidate, using a forced titration up to&#xD;
           a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests&#xD;
           are repeated.&#xD;
&#xD;
      OUTCOME MEASURES:&#xD;
&#xD;
      The primary outcome is change in information processing speed&#xD;
&#xD;
      during neuropsychologic testing&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 6, 2014</start_date>
  <completion_date type="Actual">June 21, 2017</completion_date>
  <primary_completion_date type="Actual">June 21, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Perceptual Organization and Processing Speed Index</measure>
    <time_frame>4 weeks</time_frame>
    <description>Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate.&#xD;
The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Cognition Disorder</condition>
  <condition>Attention Deficit Disorder</condition>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Open label methylphenidate treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylphenidate</intervention_name>
    <description>Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.</description>
    <arm_group_label>Open label methylphenidate treatment</arm_group_label>
    <other_name>Open label methylphenidate administration</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION:&#xD;
&#xD;
        To be included in the protocol, study participants must meet the following criteria:&#xD;
&#xD;
          1. Age 18 - 55 years, inclusive&#xD;
&#xD;
          2. A history of having sustained a moderate or severe TBI &gt;= 6 months prior to&#xD;
             enrollment. Evidence will be any one of the following 3 criteria:&#xD;
&#xD;
               1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)&#xD;
&#xD;
               2. Post-traumatic amnesia &gt; 24 hours&#xD;
&#xD;
               3. TBI-related abnormality on neuroimaging (either CT or MRI). (Some missing&#xD;
                  information about the initial injury (i.e., documentation of initial GCS) is not&#xD;
                  necessarily exclusionary if the bulk of the available history indicates that the&#xD;
                  patient suffered a TBI and meets the inclusion criteria)&#xD;
&#xD;
          3. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for&#xD;
&#xD;
             Post-Concussional Disorder, including:&#xD;
&#xD;
             a) Difficulty in attention or memory. b) One or more of the following symptoms, which&#xD;
             started shortly after the trauma and persist for at least three months: i)&#xD;
             Fatigability ii) Disordered sleep iii) Changes in personality iv) Apathy or lack of&#xD;
             spontaneity c) Symptoms in criteria (a) and (b) must have their onset after trauma, or&#xD;
             there was a significant worsening of pre-existing symptoms after trauma.&#xD;
&#xD;
             d) Disturbance from these symptoms causes significant impairment of social or&#xD;
             occupational functioning and represents a significant decline from previous level of&#xD;
             functioning.&#xD;
&#xD;
          4. Ability to read, write, and speak English&#xD;
&#xD;
          5. Ability to give informed consent.&#xD;
&#xD;
        EXCLUSION:&#xD;
&#xD;
          1. Evidence of penetrating brain injury.&#xD;
&#xD;
          2. Contraindication to methylphenidate therapy:&#xD;
&#xD;
               1. Known glaucoma (consistently raised intraocular pressure with or without&#xD;
                  associated optic nerve damage)&#xD;
&#xD;
               2. Motor tics or a family history of Tourette's syndrome (diagnosed by presence of&#xD;
                  both multiple motor and one or more vocal tics over the period of a year, with no&#xD;
                  more than three consecutive tic-free months)&#xD;
&#xD;
               3. Known hypersensitivity to methylphenidate (hives, difficulty breathing, and&#xD;
                  swelling of face, lips, tongue, or throat).&#xD;
&#xD;
               4. Known severe anxiety or restlessness which prevents from doing day to day&#xD;
                  activities.&#xD;
&#xD;
               5. Known preexisting hypertension, heart failure, myocardial infarction, or&#xD;
                  ventricular arrhythmia.&#xD;
&#xD;
               6. Known preexisting psychosis, bipolar illness.&#xD;
&#xD;
               7. History of seizures, or interictal epileptiform discharges (IEDs) on EEG in&#xD;
                  absence of seizures.&#xD;
&#xD;
               8. Known peripheral vasculopathy, including Raynaud s phenomenon.&#xD;
&#xD;
               9. History of drug dependence or alcoholism.&#xD;
&#xD;
              10. Concomitant treatment with coumadin anticoagulants, anticonvulsants (e.g.,&#xD;
                  phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g.,&#xD;
                  imipramine,clomipramine, desipramine).&#xD;
&#xD;
              11. Concomitant therapy with monoamine oxidase inhibitors (such as Marplan&#xD;
                  (isocarboxazid), Nardil (phenelzine), Emsam (selegiline), and Parnate&#xD;
                  (tranylcypromine)&#xD;
&#xD;
              12. Concomitant treatment with blood pressure medication (both for high and low blood&#xD;
                  pressure).&#xD;
&#xD;
              13. Pregnancy&#xD;
&#xD;
              14. Breastfeeding&#xD;
&#xD;
          3. History or evidence of disabling pre-existing or co-existing disabling neurologic or&#xD;
             psychiatric disorders not related to TBI, such as:&#xD;
&#xD;
               1. Multiple sclerosis, pre- or co-existing&#xD;
&#xD;
               2. Stroke (other than stroke at the time of TBI)&#xD;
&#xD;
               3. Pre-existing disabling developmental disorder&#xD;
&#xD;
               4. Pre-existing epilepsy&#xD;
&#xD;
               5. Pre-existing major depressive disorder, aggressive behavior, hostility&#xD;
&#xD;
               6. Pre-existing schizophrenia&#xD;
&#xD;
          4. Contraindication to MRI scanning&#xD;
&#xD;
               1. Ferromagnetic metal in the cranial cavity or eye, e.g., aneurysm clip, implanted&#xD;
                  neural stimulator, cochlear implant, or ocular foreign body&#xD;
&#xD;
               2. Implanted cardiac pacemaker or auto-defibrillator or pump&#xD;
&#xD;
               3. Non-removable body piercing&#xD;
&#xD;
               4. Claustrophobia&#xD;
&#xD;
               5. Inability to lie supine for two hours&#xD;
&#xD;
          5. Contraindication to TMS, such as metal in the cranial cavity or implanted electronic&#xD;
             hardware.&#xD;
&#xD;
          6. Current participation in other interventional clinical trial&#xD;
&#xD;
          7. Non-adherence to use of effective method of contraception for females of able to&#xD;
             become pregnant for time from enrollment to the study until 2 weeks after completion&#xD;
             of the study drug.&#xD;
&#xD;
          8. Present history of alcohol and substance abuse disorder determined (by DSM-IV).&#xD;
&#xD;
          9. Body mass index (BMI) &gt; 40&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eric M Wassermann, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Neurological Disorders and Stroke (NINDS)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-N-0169.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>August 23, 2014</study_first_submitted>
  <study_first_submitted_qc>August 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 26, 2014</study_first_posted>
  <results_first_submitted>January 16, 2019</results_first_submitted>
  <results_first_submitted_qc>November 13, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 15, 2019</results_first_posted>
  <last_update_submitted>November 13, 2019</last_update_submitted>
  <last_update_submitted_qc>November 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Dopamine Receptors</keyword>
  <keyword>Methylphenidate</keyword>
  <keyword>Traumatic Brain Injury</keyword>
  <keyword>C-11 Raclopride</keyword>
  <keyword>Dopamine Release</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Attention Deficit Disorder with Hyperactivity</mesh_term>
    <mesh_term>Cognition Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylphenidate</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 20, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/06/NCT02225106/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Open Label Methylphenidate Treatment</title>
          <description>Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.&#xD;
Methylphenidate: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Open Label Methylphenidate Treatment</title>
          <description>Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.&#xD;
Methylphenidate: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33" lower_limit="24" upper_limit="55"/>
                  </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>Maryland, United States</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Perceptual Organization and Processing Speed Index</title>
        <description>Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate.&#xD;
The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.</description>
        <time_frame>4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Open Label Methylphenidate Treatment</title>
            <description>Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.&#xD;
Methylphenidate: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.</description>
          </group>
        </group_list>
        <measure>
          <title>Perceptual Organization and Processing Speed Index</title>
          <description>Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate.&#xD;
The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.</description>
          <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="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89" spread="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>4 weeks</time_frame>
      <desc>Adverse events and serious adverse events were collected through structured questionnaires administered at the last study visit.</desc>
      <group_list>
        <group group_id="E1">
          <title>Open Label Methylphenidate Treatment</title>
          <description>Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.&#xD;
Methylphenidate: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.</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="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="11"/>
              </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>Ramon Diaz-Arrastia</name_or_title>
      <organization>University of Pennsylvania</organization>
      <phone>215-662-9732-</phone>
      <email>Ramon.Diaz-Arrastia@uphs.upenn.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/NCT02225106
org study id: 140169
secondary id: 14-N-0169
nct id: NCT02225106
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
Deficits in memory, attention, cognitive, and executive functions are the most common
      disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is
      implicated in these neural functions and dopaminergic pathways are recognized to be
      frequently disrupted after TBI. Methylphenidate increases synaptic DA levels by binding to
      presynaptic dopamine transporters (DAT) and blocking re-uptake.

      The objectives of this study are to use PET imaging with [11C]-raclopride, a D2/D3 receptor
      ligand, before and after administering methylphenidate, to measure endogenous DA release in
      patients who are experiencing problems with cognition, attention and executive function in
      the chronic stage after TBI. In addition, we will use TMS to test short intracortical
      inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is
      under partial DA control, as a measure of dopaminergic activity on and off
Deficits in memory, attention, cognitive, and executive functions are the most common
      disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is
      implicated in these neural functions and dopaminergic pathways are recognized to be
      frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate
      (Ritalin ). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine
      transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure
      tonic DA release provides valuable insight into the molecular basis of attention-deficit
      hyperactivity disorder (ADHD) and addiction, as well as practical information regarding
      likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with
      [11C]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to
      measure endogenous DA release in patients who are experiencing problems with cognition,
      attention and executive function in the chronic stage after TBI. In addition, we will use TMS
      to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) -
      mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity
      on and off

      methylphenidate.

      STUDY POPULATION:

      Males and females (n=30), between the ages of 18 and 55 years in the chronic stage after TBI
      who experience deficits in neuropsychological function from TBIs incurred 6 months after the
      injury, will be recruited from military treatment facilities or civilian clinics when
      presenting for clinical management of TBI or postconcussive symptoms.

      DESIGN:

        1. Study participants will be evaluated using brain MRI, psychometric measures adapted from
           the TBI Common Data Elements, attention tests and information about details of the
           injury and experience of post-concussive symptoms will be recorded. Transcranial
           magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth)
           challenge will be performed to predict a stimulant response.

        2. Subjects will be studied with [11C]-raclopride PET in two imaging sessions. One session
           will be after administration of placebo and the other after methylphenidate, 60 mg by
           mouth. Both placebo and methylphenidate will be given 60 minutes prior to injection of
           [11C]-raclopride to allow for peak uptake of methylphenidate in the brain. The binding
           potential of [11C]-raclopride relative to a non-displaceable reference region
           (cerebellum), BPND, will be used as a measure of D2/D3 receptor availability. The
           difference in BPND between methylphenidate and placebo ( BPND) is used to measure of
           tonic DA release.

        3. Subjects will then be treated with oral methylphenidate, using a forced titration up to
           a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests
           are repeated.

      OUTCOME MEASURES:

      The primary outcome is change in information processing speed

      during neuropsychologic testing
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Perceptual Organization and Processing Speed Index
time frame: 4 weeks
description: Relationship between tonic DA release (assessed by displacement of [11C] raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks of treatment with oral methylphenidate.
The Perceptual organization and processing speed index is measured from the Digit Symbol and Symbol Searches from the Weschler Adult Intelligence Scale (WAIS-IV). The tasks that comprise the PSI, (Coding, Symbol Search), are timed and require attending to visual material, visual perception and organization, visual scanning, and hand-eye coordination. It is a standardized scale were 100 is the mean of a normal population, and each 10 points represents 1 standard deviation above or below the mean. Thus, an index of 110 is 1 SD above the mean, 90 is 1 SD below the mean.
arm group label: Open label methylphenidate treatment
arm group type: Experimental
description: Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.
intervention type: Drug
intervention name: Methylphenidate
description: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.
arm group label: Open label methylphenidate treatment
other name: Open label methylphenidate administration
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Eric M Wassermann, M.D.
role: Principal Investigator
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-N-0169.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Attention Deficit Disorder with Hyperactivity
mesh term: Cognition Disorders
mesh term: Methylphenidate
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 