<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/NCT03801629</url>
  </required_header>
  <id_info>
    <org_study_id>2000024785</org_study_id>
    <nct_id>NCT03801629</nct_id>
  </id_info>
  <brief_title>Neuroimmune Effects of Opioid Administration</brief_title>
  <acronym>NOA</acronym>
  <official_title>Imaging the Neuroimmune Effects of Acute Opioid Administration</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Yale University</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>
      Preclinical research indicates acute opioid administration evokes an immune response in the&#xD;
      periphery and brain. Here, we will translate those preclinical findings to healthy human&#xD;
      volunteers and quantify the neuroimmune response to a morphine challenge using positron&#xD;
      emission tomography (PET) imaging with [11C]PBR28.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects will be recruited from the local community via media advertisements, flyers, and&#xD;
      word-of-mouth. Interested individuals will undergo a phone screen and in-person medical and&#xD;
      psychiatric examination. Up to 20 eligible individuals (see Inclusion/Exclusion criteria)&#xD;
      will be invited to participate in this study.&#xD;
&#xD;
      In a single day, subjects will complete behavioral and physiological testing, a [11C]PBR28&#xD;
      PET scan, and report subjective drug effects before and after a morphine challenge. Subjects&#xD;
      will complete either a 'High' or 'Low' morphine dose condition (single-blind): 0.07mg/kg i.m.&#xD;
      vs. 0.04mg/kg i.m., respectively. To measure the neuroimmune response to morphine, we will&#xD;
      use [11C]PBR28 PET imaging (120-minute scans on a High Resolution Research Tomograph with&#xD;
      Vicra motion correction). [11C]PBR28 binds with high affinity and specificity to the 18kDa&#xD;
      translocator protein (TSPO), which is highly expressed in microglia and has been shown to&#xD;
      respond to inflammatory challenges. TSPO volumes of distribution (VT), i.e., TSPO&#xD;
      availability, will be quantified in brain regions of interest using multilinear analysis-1&#xD;
      (MA-1) with the metabolite-corrected arterial input function. The post-morphine [11C]PBR28&#xD;
      PET scan will occur 2-hours after the morphine challenge.&#xD;
&#xD;
      Specific Aim 1: To determine whether an acute morphine administration increases brain TSPO&#xD;
      availability in healthy volunteers.&#xD;
&#xD;
      Hypothesis 1: Relative to pre-morphine levels, morphine will significantly increase TSPO&#xD;
      availability across brain regions of interest, consistent with a neuroimmune response.&#xD;
&#xD;
      Specific Aim 2: To determine whether morphine evokes a dose-dependent increase in brain TSPO&#xD;
      availability in healthy volunteers.&#xD;
&#xD;
      Hypothesis 2: Relative to pre-morphine levels, morphine will dose-dependently increase TSPO&#xD;
      availability across brain regions of interest.&#xD;
&#xD;
      Specific Aim 3: To determine whether morphine administration increases peripheral markers of&#xD;
      inflammation, e.g., cytokine/chemokine concentration in plasma.&#xD;
&#xD;
      Hypothesis 3: Relative to pre-morphine levels, morphine will increase cytokine/chemokine&#xD;
      concentrations in plasma, including IL-1B, IL-2, IL-6, IL-10, TNF-a, IFNy, MCP-1, and GM-CSF,&#xD;
      consistent with a peripheral immune response. Exploratory Hypotheses: 1) IL-1B, IL-6, TNF-a,&#xD;
      IFNy, MCP-1, and GM-CSF will exhibit morphine dose-dependent increases in plasma. 2) The&#xD;
      change in IL-6, TNF-a, IFN-y, and GM-CSF levels will be positively correlated with the change&#xD;
      in brain TSPO VT levels.&#xD;
&#xD;
      Specific Aim 4: To determine whether morphine administration alters pain sensitivity, pain&#xD;
      tolerance, cognitive function, and reward responsiveness.&#xD;
&#xD;
      Hypothesis 4: Relative to pre-morphine levels, morphine will enhance pain tolerance and&#xD;
      impair verbal learning/memory proficiency and impair reward responsiveness. Morphine will not&#xD;
      alter pain sensitivity, visual attention, psychomotor processing speed, or working memory&#xD;
      proficiency. Exploratory hypotheses: 1) The change in TSPO availability in thalamus will be&#xD;
      positively correlated with the change in pain tolerance. 2) The change in TSPO availability&#xD;
      in hippocampus will be inversely correlated with the change in verbal learning/memory&#xD;
      proficiency. 3) The change in TSPO availability in caudate, ACC, and OFC will be inversely&#xD;
      correlated with the change in reward responsiveness.&#xD;
&#xD;
      Specific Aim 5: To determine whether morphine administration alters vital signs.&#xD;
&#xD;
      Hypothesis 5: Relative to pre-morphine levels, morphine will dose-dependently reduce systolic&#xD;
      and diastolic blood pressure. Relative to pre-morphine levels, morphine will lower heart&#xD;
      rate.&#xD;
&#xD;
      Specific Aim 6: To measure the subjective response to morphine administration.&#xD;
&#xD;
      Hypothesis 6: Relative to pre-morphine levels, morphine will dose-dependently increase&#xD;
      subjective ratings of 'high', 'good drug effect', 'nausea', and 'bad drug effect'.&#xD;
      Exploratory hypotheses: 1) The change in TSPO availability in caudate, ACC, and OFC will be&#xD;
      positively correlated with the change in 'high' and 'good drug effect'. 2) The change in TSPO&#xD;
      availability in the insula and thalamus will be positively correlated with the change in&#xD;
      'nausea' and 'bad drug effect'.&#xD;
&#xD;
      Specific Aim 7: To determine whether morphine administration alters peripheral stress markers&#xD;
      of the autonomic nervous system and HPA-axis.&#xD;
&#xD;
      Hypothesis 7: Relative to pre-morphine levels, morphine will dose-dependently increase plasma&#xD;
      levels of epinephrine, norepinephrine, and cortisol.&#xD;
&#xD;
      Specific Aim 8: To determine whether morphine administration alters peripheral markers of&#xD;
      neurosteroids.&#xD;
&#xD;
      Hypothesis 8: Relative to pre-morphine levels, morphine will dose-dependently increase plasma&#xD;
      levels of allopregnanolone and pregnenolone.&#xD;
&#xD;
      Specific Aim 9: To determine whether morphine administration alters peripheral markers of the&#xD;
      metabolic hormone ghrelin.&#xD;
&#xD;
      Hypothesis 9: Relative to pre-morphine levels, morphine will dose-dependently increase plasma&#xD;
      levels of ghrelin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 12, 2019</start_date>
  <completion_date type="Actual">March 10, 2021</completion_date>
  <primary_completion_date type="Actual">March 10, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Subjects will receive a single intramuscular morphine dose: 'High' (0.07mg/kg i.m.) vs. 'Low' (0.04mg/kg i.m.)</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Subjects are informed that they will receive a single morphine injection. Subjects are blinded to the morphine dose condition. Investigators and assessors are not blinded to morphine dose condition.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Brain TSPO availability</measure>
    <time_frame>One 120-minute PET [11C]PBR28 scan before and one PET [11C]PBR28 scan 2hr after morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in brain regional TSPO availability (VT) after morphine. VT will be calculated for brain regions of interest using multi-linear analysis 1 (t*=30) using the metabolite-corrected arterial input function.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Verbal Learning Performance</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~40 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in verbal learning performance after morphine via the Cogstate computerized task: International Shopping List. In this task, subjects are asked to memorize and recite (without prompt) 12 common grocery shopping items across 3 trials. Number of correct items recalled across the 3 trials is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Verbal Memory Performance</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~70 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in verbal memory performance after morphine via the Cogstate computerized task: International Shopping List - Delayed Recall. In this task, subjects are asked to recall (after a time delay) the 12 common grocery shopping items from the International Shopping List task. Number of correct items recalled in this one trial is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Psychomotor Speed</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~45 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in psychomotor speed via the Cogstate computerized task: Detection. In this task, subjects are asked to respond via button press as soon as the playing card on screen flips over. The log10 of the mean latency to respond (ms) is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Visual Attention</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~50 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in visual attention via the Cogstate computerized task: Identification. In this task, subjects are asked to respond via button press as soon as he/she identifies that the playing card on screen matches the target card color (red). The log10 of the mean latency to respond (ms) is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Visual Learning</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~55 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in visual learning via the Cogstate computerized task: One Card Learning. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card has been shown previously. The arc sine of the percent correctly identified is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Working Memory (easy)</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~60 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: One Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown just prior to the current card. The log10 of the mean latency to respond (ms) is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Working Memory (hard)</measure>
    <time_frame>This Cogstate task will be administered twice: once before and once ~65 minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: Two Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown two prior to the current card. The arc sine of the percent correctly identified is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Cytokine/Chemokine Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous cytokine and chemokine concentrations (e.g., IL-6, IL-10, TNF-alpha, GM-CSF, and IFN-gamma) periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Cortisol Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous cortisol levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Epinephrine Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous epinephrine levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Norepinephrine Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous norepinephrine levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Allopregnanolone Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous allopregnanolone levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Pregnenolone Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous pregnenolone levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Venous Ghrelin Concentration</measure>
    <time_frame>Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in venous ghrelin levels periodically after morphine via ELISA assay kit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Thermal Pain Sensitivity</measure>
    <time_frame>The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in thermal pain sensitivity after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Subjects will be asked to indicate when he/she first experiences pain related to the cold water bath. Time to detection of pain (s) is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Thermal Pain Tolerance</measure>
    <time_frame>The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in thermal pain tolerance after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Time to withdrawal his/her hand from the cold water bath (s; max: 90s) is analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Reward Responsiveness</measure>
    <time_frame>The Probabilistic Reward Task will be administered once before and once ~260 minutes after morphine.</time_frame>
    <description>Relative to pre-morphine levels, we will measure the change in reward responsiveness after morphine via the computerized Probabilistic Reward Task. Reward responsiveness is calculated as the subject's propensity to modulate his/her response latency to discriminate two stimuli (short and long mouths on a face) based on prior reinforcement (monetary reward for 'correct' responses). This task allows objective measurement of an individuals' responsiveness to monetary reward.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in systolic blood pressure</measure>
    <time_frame>Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.</time_frame>
    <description>Systolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in diastolic blood pressure</measure>
    <time_frame>Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.</time_frame>
    <description>Diastolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in heart rate</measure>
    <time_frame>Heart rate will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.</time_frame>
    <description>Heart rate (beats per minute; while seated and resting) will be measured periodically before and after morphine.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in subjective drug effects</measure>
    <time_frame>Subjective drug effects measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.</time_frame>
    <description>Morphine drug effects are measured via visual analogue scale (VAS 0-100mm) for the following adjectives: 'high', 'nauseous', 'good effect', 'bad effect' and 'any effect'.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Drug Effect</condition>
  <arm_group>
    <arm_group_label>High Morphine Dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.07 mg/kg).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Low Morphine Dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.04 mg/kg).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High Morphine Dose</intervention_name>
    <description>Subjects will receive an intramuscular morphine injection (0.07mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.</description>
    <arm_group_label>High Morphine Dose</arm_group_label>
    <other_name>High Dose</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low Morphine Dose</intervention_name>
    <description>Subjects will receive an intramuscular morphine injection (0.04mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.</description>
    <arm_group_label>Low Morphine Dose</arm_group_label>
    <other_name>Low Dose</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        PBR_Morphine Study&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women aged between 21 and 50 years (driver's license or valid state ID).&#xD;
&#xD;
          2. Physically healthy by medical history, physical, neurological, EKG and laboratory&#xD;
             examinations (reviewed by the Study Physician).&#xD;
&#xD;
          3. Normal weight, as indicated by a body mass index (BMI) and body weight ≤ 250lbs.&#xD;
&#xD;
          4. Read, comprehend, and write English at a sufficient level to complete study-related&#xD;
             materials.&#xD;
&#xD;
          5. Able to provide voluntary and written informed consent.&#xD;
&#xD;
          6. Eligibility and willingness to participate in study procedures, including MRI and PET&#xD;
             scanning.&#xD;
&#xD;
          7. Previous medical use of opioids without adverse reactions (≥2 lifetime uses).&#xD;
&#xD;
          8. Medically eligible to receive up to 0.1 mg/kg deltoid intramuscular morphine (based on&#xD;
             medical history, medical exams, and not meeting any exclusion criteria below).&#xD;
&#xD;
          9. Medically eligible to receive 10mg of oral metoclopramide based on medical history,&#xD;
             medical exams, and current medications.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Any DSM-5 Axis I disorder diagnosis based on Structured Clinical Interview for DSM-5&#xD;
             (SCID-5), including meeting criteria for substance dependence.&#xD;
&#xD;
          2. Any current psychotropic medication use, including MAOI use within the past 14 days&#xD;
&#xD;
          3. Recent (past 6 months) medical or non-medical opioid-use.&#xD;
&#xD;
          4. Prior medical use prescription opioids for &gt;14 consecutive days (self-report)&#xD;
&#xD;
          5. Prior non-medical use of any opioid (i.e., recreational opioid use will be excluded).&#xD;
&#xD;
          6. Positive result on a urine drug screen (excluding marijuana).&#xD;
&#xD;
          7. Current or previous chronic pain disorder (&gt;6 months of continuous pain).&#xD;
&#xD;
          8. 'Low affinity binding' individuals based on rs6971 polymorphism (&lt;10% of the&#xD;
             population).&#xD;
&#xD;
          9. For females, pregnancy (positive urine test).&#xD;
&#xD;
         10. Current use of non-steroidal anti-inflammatory medications or statins.&#xD;
&#xD;
         11. Medical contraindication to receive up to 0.1 mg/kg intramuscular morphine&#xD;
             administration as determined by Study Physician. This includes:&#xD;
&#xD;
               1. known hypersensitivity/allergy to morphine;&#xD;
&#xD;
               2. acute or severe bronchial asthma;&#xD;
&#xD;
               3. known or suspected gastrointestinal obstruction, including paralytic ileus;&#xD;
&#xD;
               4. seizure disorder;&#xD;
&#xD;
               5. concomitant use of a benzodiazepine or any other CNS depressant;&#xD;
&#xD;
               6. any other significant medical condition, that in the opinion of the Study&#xD;
                  Physician and Investigators, could: put the patient at risk because of&#xD;
                  participation in the study, or influence the results of the study, or cause&#xD;
                  concern about the patient's ability to successfully complete in the study.&#xD;
&#xD;
         12. Known family history (first-degree relative) of opioid-use disorder or alcohol-use&#xD;
             disorder.&#xD;
&#xD;
         13. MRI contraindications, including metal in body (or work in metal/machine shop),&#xD;
             pacemaker, claustrophobia, or inability to tolerate MRI scanning.&#xD;
&#xD;
         14. Medical contraindications to metoclopramide, as determined by the Study Physician,&#xD;
             including:&#xD;
&#xD;
               1. known hypersensitivity/allergy to metoclopramide;&#xD;
&#xD;
               2. mechanical gastrointestinal obstruction, perforation, or hemorrhage;&#xD;
&#xD;
               3. seizure disorder;&#xD;
&#xD;
               4. history of tardive dyskinesia;&#xD;
&#xD;
               5. or concomitant use of medications/agents likely to increase extrapyramidal&#xD;
                  reactions.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eric Woodcock, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kelly Cosgrove, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cosgrove Lab</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06519</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>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>April 23, 2021</last_update_submitted>
  <last_update_submitted_qc>April 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Yale University</investigator_affiliation>
    <investigator_full_name>Eric Woodcock</investigator_full_name>
    <investigator_title>Associate Research Scientist</investigator_title>
  </responsible_party>
  <keyword>Neuroimmune System</keyword>
  <keyword>Morphine</keyword>
  <keyword>PET Imaging</keyword>
  <keyword>TSPO</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Morphine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified participant data will be shared upon reasonable request.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Study supporting information will be available upon reasonable request after publication of the primary manuscript.</ipd_time_frame>
    <ipd_access_criteria>Available to research scientists and clinicians for academic uses only.</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03801629
org study id: 2000024785
nct id: NCT03801629
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Preclinical research indicates acute opioid administration evokes an immune response in the
      periphery and brain. Here, we will translate those preclinical findings to healthy human
      volunteers and quantify the neuroimmune response to a morphine challenge using positron
      emission tomography (PET) imaging with [11C]PBR28.
Subjects will be recruited from the local community via media advertisements, flyers, and
      word-of-mouth. Interested individuals will undergo a phone screen and in-person medical and
      psychiatric examination. Up to 20 eligible individuals (see Inclusion/Exclusion criteria)
      will be invited to participate in this study.

      In a single day, subjects will complete behavioral and physiological testing, a [11C]PBR28
      PET scan, and report subjective drug effects before and after a morphine challenge. Subjects
      will complete either a 'High' or 'Low' morphine dose condition (single-blind): 0.07mg/kg i.m.
      vs. 0.04mg/kg i.m., respectively. To measure the neuroimmune response to morphine, we will
      use [11C]PBR28 PET imaging (120-minute scans on a High Resolution Research Tomograph with
      Vicra motion correction). [11C]PBR28 binds with high affinity and specificity to the 18kDa
      translocator protein (TSPO), which is highly expressed in microglia and has been shown to
      respond to inflammatory challenges. TSPO volumes of distribution (VT), i.e., TSPO
      availability, will be quantified in brain regions of interest using multilinear analysis-1
      (MA-1) with the metabolite-corrected arterial input function. The post-morphine [11C]PBR28
      PET scan will occur 2-hours after the morphine challenge.

      Specific Aim 1: To determine whether an acute morphine administration increases brain TSPO
      availability in healthy volunteers.

      Hypothesis 1: Relative to pre-morphine levels, morphine will significantly increase TSPO
      availability across brain regions of interest, consistent with a neuroimmune response.

      Specific Aim 2: To determine whether morphine evokes a dose-dependent increase in brain TSPO
      availability in healthy volunteers.

      Hypothesis 2: Relative to pre-morphine levels, morphine will dose-dependently increase TSPO
      availability across brain regions of interest.

      Specific Aim 3: To determine whether morphine administration increases peripheral markers of
      inflammation, e.g., cytokine/chemokine concentration in plasma.

      Hypothesis 3: Relative to pre-morphine levels, morphine will increase cytokine/chemokine
      concentrations in plasma, including IL-1B, IL-2, IL-6, IL-10, TNF-a, IFNy, MCP-1, and GM-CSF,
      consistent with a peripheral immune response. Exploratory Hypotheses: 1) IL-1B, IL-6, TNF-a,
      IFNy, MCP-1, and GM-CSF will exhibit morphine dose-dependent increases in plasma. 2) The
      change in IL-6, TNF-a, IFN-y, and GM-CSF levels will be positively correlated with the change
      in brain TSPO VT levels.

      Specific Aim 4: To determine whether morphine administration alters pain sensitivity, pain
      tolerance, cognitive function, and reward responsiveness.

      Hypothesis 4: Relative to pre-morphine levels, morphine will enhance pain tolerance and
      impair verbal learning/memory proficiency and impair reward responsiveness. Morphine will not
      alter pain sensitivity, visual attention, psychomotor processing speed, or working memory
      proficiency. Exploratory hypotheses: 1) The change in TSPO availability in thalamus will be
      positively correlated with the change in pain tolerance. 2) The change in TSPO availability
      in hippocampus will be inversely correlated with the change in verbal learning/memory
      proficiency. 3) The change in TSPO availability in caudate, ACC, and OFC will be inversely
      correlated with the change in reward responsiveness.

      Specific Aim 5: To determine whether morphine administration alters vital signs.

      Hypothesis 5: Relative to pre-morphine levels, morphine will dose-dependently reduce systolic
      and diastolic blood pressure. Relative to pre-morphine levels, morphine will lower heart
      rate.

      Specific Aim 6: To measure the subjective response to morphine administration.

      Hypothesis 6: Relative to pre-morphine levels, morphine will dose-dependently increase
      subjective ratings of 'high', 'good drug effect', 'nausea', and 'bad drug effect'.
      Exploratory hypotheses: 1) The change in TSPO availability in caudate, ACC, and OFC will be
      positively correlated with the change in 'high' and 'good drug effect'. 2) The change in TSPO
      availability in the insula and thalamus will be positively correlated with the change in
      'nausea' and 'bad drug effect'.

      Specific Aim 7: To determine whether morphine administration alters peripheral stress markers
      of the autonomic nervous system and HPA-axis.

      Hypothesis 7: Relative to pre-morphine levels, morphine will dose-dependently increase plasma
      levels of epinephrine, norepinephrine, and cortisol.

      Specific Aim 8: To determine whether morphine administration alters peripheral markers of
      neurosteroids.

      Hypothesis 8: Relative to pre-morphine levels, morphine will dose-dependently increase plasma
      levels of allopregnanolone and pregnenolone.

      Specific Aim 9: To determine whether morphine administration alters peripheral markers of the
      metabolic hormone ghrelin.

      Hypothesis 9: Relative to pre-morphine levels, morphine will dose-dependently increase plasma
      levels of ghrelin.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Subjects will receive a single intramuscular morphine dose: 'High' (0.07mg/kg i.m.) vs. 'Low' (0.04mg/kg i.m.)
primary purpose: Basic Science
masking: Single (Participant)
masking description: Subjects are informed that they will receive a single morphine injection. Subjects are blinded to the morphine dose condition. Investigators and assessors are not blinded to morphine dose condition.
measure: Change in Brain TSPO availability
time frame: One 120-minute PET [11C]PBR28 scan before and one PET [11C]PBR28 scan 2hr after morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in brain regional TSPO availability (VT) after morphine. VT will be calculated for brain regions of interest using multi-linear analysis 1 (t*=30) using the metabolite-corrected arterial input function.
measure: Change in Verbal Learning Performance
time frame: This Cogstate task will be administered twice: once before and once ~40 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in verbal learning performance after morphine via the Cogstate computerized task: International Shopping List. In this task, subjects are asked to memorize and recite (without prompt) 12 common grocery shopping items across 3 trials. Number of correct items recalled across the 3 trials is analyzed.
measure: Change in Verbal Memory Performance
time frame: This Cogstate task will be administered twice: once before and once ~70 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in verbal memory performance after morphine via the Cogstate computerized task: International Shopping List - Delayed Recall. In this task, subjects are asked to recall (after a time delay) the 12 common grocery shopping items from the International Shopping List task. Number of correct items recalled in this one trial is analyzed.
measure: Change in Psychomotor Speed
time frame: This Cogstate task will be administered twice: once before and once ~45 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in psychomotor speed via the Cogstate computerized task: Detection. In this task, subjects are asked to respond via button press as soon as the playing card on screen flips over. The log10 of the mean latency to respond (ms) is analyzed.
measure: Change in Visual Attention
time frame: This Cogstate task will be administered twice: once before and once ~50 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in visual attention via the Cogstate computerized task: Identification. In this task, subjects are asked to respond via button press as soon as he/she identifies that the playing card on screen matches the target card color (red). The log10 of the mean latency to respond (ms) is analyzed.
measure: Change in Visual Learning
time frame: This Cogstate task will be administered twice: once before and once ~55 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in visual learning via the Cogstate computerized task: One Card Learning. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card has been shown previously. The arc sine of the percent correctly identified is analyzed.
measure: Change in Working Memory (easy)
time frame: This Cogstate task will be administered twice: once before and once ~60 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: One Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown just prior to the current card. The log10 of the mean latency to respond (ms) is analyzed.
measure: Change in Working Memory (hard)
time frame: This Cogstate task will be administered twice: once before and once ~65 minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in working memory performance via the Cogstate computerized task: Two Back. In this task, subjects are asked to respond via button press if he/she identifies that the on-screen playing card matches the card shown two prior to the current card. The arc sine of the percent correctly identified is analyzed.
measure: Change in Venous Cytokine/Chemokine Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous cytokine and chemokine concentrations (e.g., IL-6, IL-10, TNF-alpha, GM-CSF, and IFN-gamma) periodically after morphine via ELISA assay kit.
measure: Change in Venous Cortisol Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous cortisol levels periodically after morphine via ELISA assay kit.
measure: Change in Venous Epinephrine Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous epinephrine levels periodically after morphine via ELISA assay kit.
measure: Change in Venous Norepinephrine Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous norepinephrine levels periodically after morphine via ELISA assay kit.
measure: Change in Venous Allopregnanolone Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous allopregnanolone levels periodically after morphine via ELISA assay kit.
measure: Change in Venous Pregnenolone Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous pregnenolone levels periodically after morphine via ELISA assay kit.
measure: Change in Venous Ghrelin Concentration
time frame: Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in venous ghrelin levels periodically after morphine via ELISA assay kit.
measure: Change in Thermal Pain Sensitivity
time frame: The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in thermal pain sensitivity after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Subjects will be asked to indicate when he/she first experiences pain related to the cold water bath. Time to detection of pain (s) is analyzed.
measure: Change in Thermal Pain Tolerance
time frame: The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.
description: Relative to pre-morphine levels, we will measure the change in thermal pain tolerance after morphine via the Cold Pressor Task. Subjects will place their hand in a warm water bath and then a cold water bath. Time to withdrawal his/her hand from the cold water bath (s; max: 90s) is analyzed.
measure: Change in Reward Responsiveness
time frame: The Probabilistic Reward Task will be administered once before and once ~260 minutes after morphine.
description: Relative to pre-morphine levels, we will measure the change in reward responsiveness after morphine via the computerized Probabilistic Reward Task. Reward responsiveness is calculated as the subject's propensity to modulate his/her response latency to discriminate two stimuli (short and long mouths on a face) based on prior reinforcement (monetary reward for 'correct' responses). This task allows objective measurement of an individuals' responsiveness to monetary reward.
measure: Change in systolic blood pressure
time frame: Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
description: Systolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.
measure: Change in diastolic blood pressure
time frame: Blood pressure will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
description: Diastolic blood pressure (mmHg; while seated and resting) will be measured periodically before and after morphine.
measure: Change in heart rate
time frame: Heart rate will be measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
description: Heart rate (beats per minute; while seated and resting) will be measured periodically before and after morphine.
measure: Change in subjective drug effects
time frame: Subjective drug effects measured 10-minutes before, and 30-minutes, 60-minutes, and 90-minutes after morphine.
description: Morphine drug effects are measured via visual analogue scale (VAS 0-100mm) for the following adjectives: 'high', 'nauseous', 'good effect', 'bad effect' and 'any effect'.
arm group label: High Morphine Dose
arm group type: Experimental
description: Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.07 mg/kg).
arm group label: Low Morphine Dose
arm group type: Experimental
description: Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.04 mg/kg).
intervention type: Drug
intervention name: High Morphine Dose
description: Subjects will receive an intramuscular morphine injection (0.07mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.
arm group label: High Morphine Dose
other name: High Dose
intervention type: Drug
intervention name: Low Morphine Dose
description: Subjects will receive an intramuscular morphine injection (0.04mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.
arm group label: Low Morphine Dose
other name: Low Dose
criteria: 
gender: All
minimum age: 21 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Eric Woodcock, PhD
role: Principal Investigator
affiliation: Yale University
last name: Kelly Cosgrove, PhD
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Yale University
investigator full name: Eric Woodcock
investigator title: Associate Research Scientist
mesh term: Morphine
sharing ipd: Yes
ipd description: De-identified participant data will be shared upon reasonable request.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: Study supporting information will be available upon reasonable request after publication of the primary manuscript.
ipd access criteria: Available to research scientists and clinicians for academic uses only.