<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/NCT03814356</url>
  </required_header>
  <id_info>
    <org_study_id>140675</org_study_id>
    <nct_id>NCT03814356</nct_id>
  </id_info>
  <brief_title>Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness</brief_title>
  <acronym>STIMPACT</acronym>
  <official_title>Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</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>
      Phase 1 of the STIMPACT trial is an open label,dose-escalation,safety study of intravenous&#xD;
      (IV) methylphenidate (MPH) therapy in patients with disorders of consciousness (DoC) caused&#xD;
      by severe brain injuries. To be classified as having a DoC, a patient must be in a coma,&#xD;
      vegetative state (VS), or minimally conscious state (MCS), as determined by behavioral&#xD;
      assessment using the Coma Recovery Scale-Revised (CRS-R). Patients with DoC admitted to the&#xD;
      intensive care unit (ICU) will be eligible for the study. A total of 10 patients with DoC&#xD;
      will be enrolled in the Phase 1 study. Patients will receive escalating daily doses of IV MPH&#xD;
      starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event&#xD;
      (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the&#xD;
      patient stop participation in the study. Pharmacokinetics will be evaluated in selected&#xD;
      patients with indwelling venous catheters or arterial catheters via serial serum measurements&#xD;
      of MPH at each dose. The pharmacodynamic properties of IV MPH at each dose will be assessed&#xD;
      by comparison of pre-versus post-dose EEG-based measures. The pharmacodynamic properties of&#xD;
      the maximum tolerated dose will also be assessed by comparison of pre-versus post-dose&#xD;
      resting state functional MRI (rs-fMRI) connectivity measures. Finally, we will test the&#xD;
      association between structural connectivity of the ventral tegmental area (VTA), a&#xD;
      dopaminergic brainstem nucleus that is believed to mediate MPH activation of the cerebral&#xD;
      cortex, and EEG and rs-fMRI pharmacodynamic measures.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 24, 2020</start_date>
  <completion_date type="Anticipated">February 23, 2025</completion_date>
  <primary_completion_date type="Anticipated">February 23, 2024</primary_completion_date>
  <phase>Phase 1</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>Adverse Events</measure>
    <time_frame>4 Days</time_frame>
    <description>The number of drug-related adverse events at each dose of IV MPH</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximal Serum Concentration</measure>
    <time_frame>4 Days</time_frame>
    <description>The time to maximal serum concentration at each dose of IV MPH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Half-life</measure>
    <time_frame>4 Days</time_frame>
    <description>Serum half-life of IV MPH at each dose of IV MPH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebral Cortical Connectivity as Measured by fMRI</measure>
    <time_frame>4 Days</time_frame>
    <description>The effect of the maximum tolerated of IV MPH dose on brain connectivity, as measured by resting state fMRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebral Cortical Connectivity as Measured by EEG</measure>
    <time_frame>4 Days</time_frame>
    <description>The effect of each of IV MPH dose on cerebral cortical connectivity, as measured by EEG</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">22</enrollment>
  <condition>Brain Injury Traumatic Severe (Diagnosis)</condition>
  <condition>Coma</condition>
  <condition>Consciousness, Level Altered</condition>
  <condition>Anoxic Brain Injury</condition>
  <arm_group>
    <arm_group_label>IV MPH</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive IV Methylphenidate (MPH). Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylphenidate</intervention_name>
    <description>IV MPH</description>
    <arm_group_label>IV MPH</arm_group_label>
    <other_name>MPH</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years&#xD;
&#xD;
          2. Severe, acute traumatic brain injury&#xD;
&#xD;
          3. Diagnosis of Coma, Vegetative State, or Minimally Conscious State&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Penetrating brain injury caused by a metallic missile/object (e.g. bullet)&#xD;
&#xD;
          2. Body metal contraindicating MRI&#xD;
&#xD;
          3. Prisoner or ward of the state&#xD;
&#xD;
          4. Neurological&#xD;
&#xD;
               1. Bilateral dilated unresponsive pupils&#xD;
&#xD;
               2. Intracranial hypertension (Intracranial Pressure [ICP] &gt; 25 mmHg for &gt; 5 min&#xD;
                  within past 24 hours with head-of-bed at standard clinical angle of 30-45&#xD;
                  degrees)&#xD;
&#xD;
               3. Intracranial bolt&#xD;
&#xD;
               4. Status epilepticus or concern for post-ictal state&#xD;
&#xD;
          5. Cardiovascular&#xD;
&#xD;
               1. Poorly controlled hypertension (SBP &gt; 200 mmHg of DBP &gt; 120mmHg for 30 minutes,&#xD;
                  despite anti-hypertensive therapy, within the past 24 hours)&#xD;
&#xD;
               2. Coronary artery disease&#xD;
&#xD;
               3. ST elevation myocardial infarction&#xD;
&#xD;
               4. Acute coronary syndrome&#xD;
&#xD;
               5. Hemodynamically significant dysrhythmia&#xD;
&#xD;
               6. Congestive heart failure&#xD;
&#xD;
               7. Cardiomyopathy (including Takotsubo cardiomyopathy)&#xD;
&#xD;
               8. Other severe structural cardiac abnormalities&#xD;
&#xD;
          6. Renal&#xD;
&#xD;
             a. Renal failure requiring renal replacement therapy (e.g. CVVH or HD)&#xD;
&#xD;
          7. Endocrine&#xD;
&#xD;
             a. History of or clinical suspicion for thyrotoxicosis&#xD;
&#xD;
          8. Reproductive&#xD;
&#xD;
             a. Pregnancy&#xD;
&#xD;
          9. Ophthalmologic&#xD;
&#xD;
             a. History of glaucoma&#xD;
&#xD;
         10. Pharmacologic&#xD;
&#xD;
             a. Monoamine oxidase inhibitor therapy within past 14 days&#xD;
&#xD;
         11. Other&#xD;
&#xD;
               1. Any condition or finding that in the judgment of the PI or treating clinical team&#xD;
                  significantly increases the risk or significantly decreases the likelihood of a&#xD;
                  response to IV MPH&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brian L Edlow, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maryam Masood</last_name>
    <phone>6176433956</phone>
    <email>mmasood@mgh.harvard.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Yelena G Bodien, PhD</last_name>
    <phone>6176433956</phone>
    <email>ybodien@mgh.harvard.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Brian L Edlow, MD</last_name>
      <phone>617-724-6352</phone>
      <email>bedlow@mgh.harvard.edu</email>
    </contact>
    <contact_backup>
      <last_name>Yelena G Bodien, PhD</last_name>
      <phone>6176433956</phone>
      <email>ybodien@partners.org</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.comarecoverylab.org/</url>
    <description>Homepage of the Laboratory for NeuroImaging of Coma and Consciousness</description>
  </link>
  <reference>
    <citation>Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG. Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocrit Care. 2020 Oct;33(2):364-375. doi: 10.1007/s12028-020-01062-7. Epub 2020 Aug 13.</citation>
    <PMID>32794142</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>April 3, 2023</last_update_submitted>
  <last_update_submitted_qc>April 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Brian L. Edlow, M.D.</investigator_full_name>
    <investigator_title>Director, Laboratory for NeuroImaging of Coma and Consciousness (NICC)</investigator_title>
  </responsible_party>
  <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>Consciousness Disorders</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylphenidate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03814356
org study id: 140675
nct id: NCT03814356
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Phase 1 of the STIMPACT trial is an open label,dose-escalation,safety study of intravenous
      (IV) methylphenidate (MPH) therapy in patients with disorders of consciousness (DoC) caused
      by severe brain injuries. To be classified as having a DoC, a patient must be in a coma,
      vegetative state (VS), or minimally conscious state (MCS), as determined by behavioral
      assessment using the Coma Recovery Scale-Revised (CRS-R). Patients with DoC admitted to the
      intensive care unit (ICU) will be eligible for the study. A total of 10 patients with DoC
      will be enrolled in the Phase 1 study. Patients will receive escalating daily doses of IV MPH
      starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event
      (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the
      patient stop participation in the study. Pharmacokinetics will be evaluated in selected
      patients with indwelling venous catheters or arterial catheters via serial serum measurements
      of MPH at each dose. The pharmacodynamic properties of IV MPH at each dose will be assessed
      by comparison of pre-versus post-dose EEG-based measures. The pharmacodynamic properties of
      the maximum tolerated dose will also be assessed by comparison of pre-versus post-dose
      resting state functional MRI (rs-fMRI) connectivity measures. Finally, we will test the
      association between structural connectivity of the ventral tegmental area (VTA), a
      dopaminergic brainstem nucleus that is believed to mediate MPH activation of the cerebral
      cortex, and EEG and rs-fMRI pharmacodynamic measures.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Adverse Events
time frame: 4 Days
description: The number of drug-related adverse events at each dose of IV MPH
measure: Maximal Serum Concentration
time frame: 4 Days
description: The time to maximal serum concentration at each dose of IV MPH
measure: Serum Half-life
time frame: 4 Days
description: Serum half-life of IV MPH at each dose of IV MPH
measure: Cerebral Cortical Connectivity as Measured by fMRI
time frame: 4 Days
description: The effect of the maximum tolerated of IV MPH dose on brain connectivity, as measured by resting state fMRI
measure: Cerebral Cortical Connectivity as Measured by EEG
time frame: 4 Days
description: The effect of each of IV MPH dose on cerebral cortical connectivity, as measured by EEG
arm group label: IV MPH
arm group type: Experimental
description: All patients will receive IV Methylphenidate (MPH). Patients will receive escalating daily doses of IV MPH starting at 0.5 mg/kg, increasing stepwise to 1.0mg/kg and 2.0 mg/kg unless an adverse event (AE) necessitates dose de-escalation or a serious adverse event (SAE) necessitates that the patient stop participation in the study.
intervention type: Drug
intervention name: Methylphenidate
description: IV MPH
arm group label: IV MPH
other name: MPH
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Brian L Edlow, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Maryam Masood
phone: 6176433956
email: mmasood@mgh.harvard.edu
last name: Yelena G Bodien, PhD
phone: 6176433956
email: ybodien@mgh.harvard.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
url: https://www.comarecoverylab.org/
description: Homepage of the Laboratory for NeuroImaging of Coma and Consciousness
citation: Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG. Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocrit Care. 2020 Oct;33(2):364-375. doi: 10.1007/s12028-020-01062-7. Epub 2020 Aug 13.
PMID: 32794142
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Brian L. Edlow, M.D.
investigator title: Director, Laboratory for NeuroImaging of Coma and Consciousness (NICC)
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Consciousness Disorders
mesh term: Wounds and Injuries
mesh term: Methylphenidate