<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/NCT03802396</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00088855</org_study_id>
    <nct_id>NCT03802396</nct_id>
  </id_info>
  <brief_title>Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction</brief_title>
  <acronym>MARBLE</acronym>
  <official_title>Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction (MARBLE): A Phase 2 Trial to Evaluate the Efficacy and Feasibility of CN-105 in Preventing Postoperative Cognitive Dysfunction and Delirium</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Miles Berger, MD PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Duke 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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study will evaluate the effectiveness and estimate the feasibility of&#xD;
      administering an investigational drug called 'CN-105' (the study drug), to prevent&#xD;
      postoperative cognitive decline, delirium (serious confusion) and underlying brain&#xD;
      inflammatory and brain activity changes in adults 60 years and older undergoing surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study will evaluate the effectiveness and estimate the feasibility of&#xD;
      administering an investigational drug called 'CN-105' (the study drug), to prevent&#xD;
      postoperative cognitive decline, delirium (serious confusion) and underlying brain&#xD;
      inflammatory and brain activity changes in adults 60 years and older undergoing surgery. The&#xD;
      word &quot;investigational&quot; means the study drug is still being tested in research studies and is&#xD;
      not approved by the U.S. Food and Drug Administration (FDA).&#xD;
&#xD;
      It is hoped that CN-105 will block signaling via a gene known as ApoE4, the most common gene&#xD;
      implicated in late life Alzheimer's disease.&#xD;
&#xD;
      Depending on when patients enroll in this study, participants will receive either a placebo&#xD;
      or a progressively higher dose of CN-105 until the safest and best tolerated dose is reached.&#xD;
      The study drug is given via IV (intravenous, meaning through a vein) infusion in the&#xD;
      hospital. Study drug infusions will be given up to 4 days after surgery.&#xD;
&#xD;
      Participants will also perform memory and thinking tests, as well as complete a survey and&#xD;
      functional assessments, both prior to surgery and again 6 weeks after surgery. Each of those&#xD;
      research visits will last about 1 hour.&#xD;
&#xD;
      Additionally, the investigators will collect a blood sample and a cerebrospinal fluid (CSF)&#xD;
      sample prior to the participant's surgery, 24 hours after surgery, and again 6 weeks after&#xD;
      surgery. To obtain the CSF (cerebrospinal fluid) sample, investigators will perform a lumbar&#xD;
      (the lower part of the spinal column) puncture. During surgery, investigators will also&#xD;
      record participant brain waves from the scalp using an EEG (electroencephalography) monitor.&#xD;
      An electroencephalography monitor reads the electrical activity of the brain in different&#xD;
      places using a cap with sensors that is worn on the head.&#xD;
&#xD;
      Although previous studies have not found any associations between the study drug and any&#xD;
      serious medical problems, investigators will monitor its effect on wound healing and&#xD;
      postoperative infections.&#xD;
&#xD;
      Benefits of this study include the possibility of fewer problems in thinking and memory after&#xD;
      surgery if this study drug works as hoped.&#xD;
&#xD;
      Risks of participation in this study include headache, infection/discomfort from the lumbar&#xD;
      puncture, discomfort from the blood draw, and minor skin irritation or redness from the EEG&#xD;
      and heart rate monitor procedures.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 15, 2018</start_date>
  <completion_date type="Actual">December 28, 2022</completion_date>
  <primary_completion_date type="Actual">December 28, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Investigators will enroll 201 patients total in this phase 2 escalating dose study, with escalating CN-105 doses occurring in three successive groups of 67 patients each. In each group of 67 patients, 50 will receive a given dose of CN-105 and 17 will receive placebo.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants will be randomized to receive either CN-105 or placebo after they consent to participate in the trial. Participants will be enrolled in 1 of 3 dose cohorts of 67 subjects each. An independent statistician will prepare dose stratified mixed block size randomization lists in a 3 to 1 ratio to achieve the desired distribution of drug and placebo. In each block of 67 trial participants, 50 will receive CN-105 and 17 will receive placebo, in a double-blind fashion.&#xD;
CN-105 and placebo will be prepared in identical bags labelled simply with the trial participant's number (1-201) to keep all trial staff and clinicians blinded to randomization. Only the investigational pharmacist will have the randomization list for each participant showing what dose of CN-105 or placebo will be administered. To minimize bias, investigators conducting the laboratory assays on the CSF and blood samples will be blinded to trial group assignment during the course of the trial.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of adverse events (AEs) of grade II or higher, per CTCAE criteria</measure>
    <time_frame>2 years for entire study; until 6 week follow-up for individual patients</time_frame>
    <description>safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in cerebrosprinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients</measure>
    <time_frame>Baseline, 24 hours, 6 weeks +/- 3 weeks</time_frame>
    <description>Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CSF IL-8 cytokine levels between drug vs placebo treated patients</measure>
    <time_frame>Baseline, 24 hours, 6 weeks +/- 3 weeks</time_frame>
    <description>Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients</measure>
    <time_frame>Baseline, 24 hours, 6 weeks +/- 3 weeks</time_frame>
    <description>Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CSF G-CSF cytokine levels between drug vs placebo treated patients</measure>
    <time_frame>Baseline, 24 hours, 6 weeks +/- 3 weeks</time_frame>
    <description>Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in cognitive change index (CCI) between drug vs placebo treated patients</measure>
    <time_frame>Baseline, 6 weeks +/- 3 weeks</time_frame>
    <description>Change in CCI before to after surgery between drug vs placebo treated patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of drug administration within correct time windows</measure>
    <time_frame>within 1 hour prior to the scheduled or actual start time of the surgery, and every 6 hours afterwards within a +/- 90 minute time window for subsequent drug doses</time_frame>
    <description>The feasibility of perioperative CN-105 administration is assessed by tracking the percentage of doses given within the correct time window (i.e. within 1 hour prior to the scheduled or actual start time of the surgery, and within a +/- 90 minute time window for subsequent doses, which are administered every 6 hours after the start of surgery).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of delirium between drug vs. placebo treated patients</measure>
    <time_frame>Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks</time_frame>
    <description>Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of delirium symptoms between drug vs. placebo treated patients</measure>
    <time_frame>Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks</time_frame>
    <description>Scores on the 3D CAM (in non-intubated patients) are used to determine delirium symptom severity based on a 0 - 20 point scale of the test.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">203</enrollment>
  <condition>Postoperative Delirium</condition>
  <condition>Postoperative Cognitive Dysfunction</condition>
  <arm_group>
    <arm_group_label>CN-105</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17&#xD;
Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17&#xD;
Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17&#xD;
Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17&#xD;
Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CN-105</intervention_name>
    <description>Three doses of CN-105 will be used in three successive cohorts of 67 patients each (50 receiving drug and 17 receiving placebo) 0.1 mg/kg (cohort 1) 0.5 mg/kg (cohort 2)&#xD;
1 mg/kg (cohort 3)&#xD;
The study drug will be administered by IV every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses.</description>
    <arm_group_label>CN-105</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients will receive placebo intravenously every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses, identical to those receiving the study drug.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 60&#xD;
&#xD;
          -  Ability to speak English&#xD;
&#xD;
          -  Undergoing non-cardiac, non-neurologic surgical procedures; surgery scheduled to last&#xD;
             &gt; 2 hours; due to be admitted to the hospital following surgery&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inmate of a correctional facility&#xD;
&#xD;
          -  Scheduled to receive systemic chemotherapy between the time of the two cognitive&#xD;
             testing sessions&#xD;
&#xD;
          -  Known inability to undergo LPs due to anticoagulant use, severe anxiety, or other&#xD;
             clinical contraindication known ahead of time.&#xD;
&#xD;
          -  Inappropriate for study inclusion based on the judgement of the principal&#xD;
             investigator.&#xD;
&#xD;
          -  If a patient undergoes major head trauma that occurs between the times of the two&#xD;
             cognitive testing sessions, then they will be withdrawn from the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Miles Berger, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke University Hospital</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>February 22, 2023</last_update_submitted>
  <last_update_submitted_qc>February 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>Miles Berger, MD PhD</investigator_full_name>
    <investigator_title>Assistant Professor, Neuroanesthesiology Division, Anesthesiology Department</investigator_title>
  </responsible_party>
  <keyword>Delirium</keyword>
  <keyword>Aging</keyword>
  <keyword>Elderly</keyword>
  <keyword>Postoperative</keyword>
  <keyword>Cognitive Dysfunction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infectious Encephalitis</mesh_term>
    <mesh_term>Delirium</mesh_term>
    <mesh_term>Emergence Delirium</mesh_term>
    <mesh_term>Encephalitis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Postoperative Cognitive Complications</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03802396
org study id: Pro00088855
nct id: NCT03802396
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This research study will evaluate the effectiveness and estimate the feasibility of
      administering an investigational drug called 'CN-105' (the study drug), to prevent
      postoperative cognitive decline, delirium (serious confusion) and underlying brain
      inflammatory and brain activity changes in adults 60 years and older undergoing surgery.
This research study will evaluate the effectiveness and estimate the feasibility of
      administering an investigational drug called 'CN-105' (the study drug), to prevent
      postoperative cognitive decline, delirium (serious confusion) and underlying brain
      inflammatory and brain activity changes in adults 60 years and older undergoing surgery. The
      word "investigational" means the study drug is still being tested in research studies and is
      not approved by the U.S. Food and Drug Administration (FDA).

      It is hoped that CN-105 will block signaling via a gene known as ApoE4, the most common gene
      implicated in late life Alzheimer's disease.

      Depending on when patients enroll in this study, participants will receive either a placebo
      or a progressively higher dose of CN-105 until the safest and best tolerated dose is reached.
      The study drug is given via IV (intravenous, meaning through a vein) infusion in the
      hospital. Study drug infusions will be given up to 4 days after surgery.

      Participants will also perform memory and thinking tests, as well as complete a survey and
      functional assessments, both prior to surgery and again 6 weeks after surgery. Each of those
      research visits will last about 1 hour.

      Additionally, the investigators will collect a blood sample and a cerebrospinal fluid (CSF)
      sample prior to the participant's surgery, 24 hours after surgery, and again 6 weeks after
      surgery. To obtain the CSF (cerebrospinal fluid) sample, investigators will perform a lumbar
      (the lower part of the spinal column) puncture. During surgery, investigators will also
      record participant brain waves from the scalp using an EEG (electroencephalography) monitor.
      An electroencephalography monitor reads the electrical activity of the brain in different
      places using a cap with sensors that is worn on the head.

      Although previous studies have not found any associations between the study drug and any
      serious medical problems, investigators will monitor its effect on wound healing and
      postoperative infections.

      Benefits of this study include the possibility of fewer problems in thinking and memory after
      surgery if this study drug works as hoped.

      Risks of participation in this study include headache, infection/discomfort from the lumbar
      puncture, discomfort from the blood draw, and minor skin irritation or redness from the EEG
      and heart rate monitor procedures.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Investigators will enroll 201 patients total in this phase 2 escalating dose study, with escalating CN-105 doses occurring in three successive groups of 67 patients each. In each group of 67 patients, 50 will receive a given dose of CN-105 and 17 will receive placebo.
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Participants will be randomized to receive either CN-105 or placebo after they consent to participate in the trial. Participants will be enrolled in 1 of 3 dose cohorts of 67 subjects each. An independent statistician will prepare dose stratified mixed block size randomization lists in a 3 to 1 ratio to achieve the desired distribution of drug and placebo. In each block of 67 trial participants, 50 will receive CN-105 and 17 will receive placebo, in a double-blind fashion.
CN-105 and placebo will be prepared in identical bags labelled simply with the trial participant's number (1-201) to keep all trial staff and clinicians blinded to randomization. Only the investigational pharmacist will have the randomization list for each participant showing what dose of CN-105 or placebo will be administered. To minimize bias, investigators conducting the laboratory assays on the CSF and blood samples will be blinded to trial group assignment during the course of the trial.
measure: Number of adverse events (AEs) of grade II or higher, per CTCAE criteria
time frame: 2 years for entire study; until 6 week follow-up for individual patients
description: safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.
measure: Change in cerebrosprinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients
time frame: Baseline, 24 hours, 6 weeks +/- 3 weeks
description: Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.
measure: Change in CSF IL-8 cytokine levels between drug vs placebo treated patients
time frame: Baseline, 24 hours, 6 weeks +/- 3 weeks
description: Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients
measure: Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients
time frame: Baseline, 24 hours, 6 weeks +/- 3 weeks
description: Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients
measure: Change in CSF G-CSF cytokine levels between drug vs placebo treated patients
time frame: Baseline, 24 hours, 6 weeks +/- 3 weeks
description: Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.
measure: Change in cognitive change index (CCI) between drug vs placebo treated patients
time frame: Baseline, 6 weeks +/- 3 weeks
description: Change in CCI before to after surgery between drug vs placebo treated patients.
measure: Feasibility of drug administration within correct time windows
time frame: within 1 hour prior to the scheduled or actual start time of the surgery, and every 6 hours afterwards within a +/- 90 minute time window for subsequent drug doses
description: The feasibility of perioperative CN-105 administration is assessed by tracking the percentage of doses given within the correct time window (i.e. within 1 hour prior to the scheduled or actual start time of the surgery, and within a +/- 90 minute time window for subsequent doses, which are administered every 6 hours after the start of surgery).
measure: Incidence of delirium between drug vs. placebo treated patients
time frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
description: Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).
measure: Severity of delirium symptoms between drug vs. placebo treated patients
time frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
description: Scores on the 3D CAM (in non-intubated patients) are used to determine delirium symptom severity based on a 0 - 20 point scale of the test.
arm group label: CN-105
arm group type: Experimental
description: Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
arm group label: Placebo
arm group type: Placebo Comparator
description: Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17
intervention type: Drug
intervention name: CN-105
description: Three doses of CN-105 will be used in three successive cohorts of 67 patients each (50 receiving drug and 17 receiving placebo) 0.1 mg/kg (cohort 1) 0.5 mg/kg (cohort 2)
1 mg/kg (cohort 3)
The study drug will be administered by IV every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses.
arm group label: CN-105
intervention type: Drug
intervention name: Placebo
description: Patients will receive placebo intravenously every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses, identical to those receiving the study drug.
arm group label: Placebo
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Miles Berger, MD, PhD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: Miles Berger, MD PhD
investigator title: Assistant Professor, Neuroanesthesiology Division, Anesthesiology Department
mesh term: Infectious Encephalitis
mesh term: Delirium
mesh term: Emergence Delirium
mesh term: Encephalitis
mesh term: Inflammation
mesh term: Postoperative Cognitive Complications
mesh term: Cognitive Dysfunction
sharing ipd: No