<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/NCT02986932</url>
  </required_header>
  <id_info>
    <org_study_id>AL001</org_study_id>
    <nct_id>NCT02986932</nct_id>
  </id_info>
  <brief_title>Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease</brief_title>
  <acronym>BBB-Alzheimers</acronym>
  <official_title>A Study to Evaluate the Safety and Feasibility of Blood-Brain Barrier (BBB) Opening Using Transcranial MR-Guided Focused Ultrasound With Intravenous Ultrasound Contrast Agents in Patients With Early Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>InSightec</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>InSightec</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, non-randomized, single-arm, feasibility study to evaluate the safety&#xD;
      and initial effectiveness of opening of the Blood-Brain Barrier with intravenous contrast&#xD;
      agents using the ExAblate Neuro System in patients with early stage Alzheimer's Disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a prospective, single-arm, non-randomized, feasibility, phase I trial to&#xD;
      evaluate the safety of focal BBB opening using the ExAblate® Transcranial (220 kHz) system&#xD;
      and Definity® ultrasound contrast in 6 patients with mild Alzheimer's Disease. This phase I&#xD;
      trial will be divided into two stages. In the first stage, patients will undergo small volume&#xD;
      BBB opening, establishing the minimum required sonication parameters to open the BBB, as&#xD;
      evidenced by gadolinium enhancement on T1-weighted MRI. Stage I is defined as a discrete&#xD;
      region of approximately 9 mm x 9 mm area in the right frontal lobe. Multiple sonications will&#xD;
      be performed starting at low energy and ramping up until the BBB is observed to open. The&#xD;
      subjects will then be removed from the ExAblate® Neuro device and followed for safety for 30&#xD;
      days. If the subject experienced BBB opening without any serious adverse effects (such as&#xD;
      brain edema), then the subject may proceed to Stage two where a larger volume (2.5-3.0 cm)&#xD;
      will be targeted. Subjects will be followed for an additional 60 days for safety and&#xD;
      preliminary effectiveness.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>Transcranial ExAblate</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in contrast enhancement (intensity) following BBB disruption</measure>
    <time_frame>Immediately post treatment</time_frame>
    <description>Change in contrast enhancement (intensity) following BBB disruption to pre-sonication images as a comparative ratio measured in percent as read from MR images and normalized to the contralateral hemisphere</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in amyloid uptake</measure>
    <time_frame>30 days after treatments</time_frame>
    <description>Change in amyloid uptake as compared to pre treatment scans in the targeted region</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>90 days</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MMSE - Mini Mental State Examination</measure>
    <time_frame>30 days</time_frame>
    <description>Treatment effect on patients' dementia state</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales</measure>
    <time_frame>30 days</time_frame>
    <description>Treatment effect on patients' Alzheimer's disease symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NPI - Neuropsychiatry Inventory</measure>
    <time_frame>30 days</time_frame>
    <description>Treatment effect on patients' dementia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GDS - Geriatric Depression Scale</measure>
    <time_frame>30 days</time_frame>
    <description>Treatment effect on patients' depression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory</measure>
    <time_frame>30 days</time_frame>
    <description>Treatment effect on patients' activities of daily living</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>BBB opening</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ExAblate focused ultrasound under MRI-guidance delivered through the intact human skull in conjunction with timed intravenous ultrasound contrast agents (Definity®) to temporarily and focally open the BBB.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>BBB opening</intervention_name>
    <description>Open BBB using ExAblate focused ultrasound and (Definity®) contrast agent</description>
    <arm_group_label>BBB opening</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Probable AD consistent with NIA/AA criteria (McKhann, Alzheimer &amp; Dementia 2011)&#xD;
&#xD;
          2. Modified Hachinski Ischemia Scale (MHIS) score of &lt;= 4.&#xD;
&#xD;
          3. Mini Mental State Exam (MMSE) scores 18-28&#xD;
&#xD;
          4. Short form Geriatric Depression Scale (GDS) score of &lt;= 6&#xD;
&#xD;
          5. Has a Florbetaben PET scan consistent with the presence of amyloid pathology in the&#xD;
             proposed target region (right frontal lobe)&#xD;
&#xD;
          6. Able to communicate sensations during the ExAblate® MRgFUS procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. MRI findings:&#xD;
&#xD;
               -  Active infection/inflammation&#xD;
&#xD;
               -  Acute or chronic hemorrhages, specifically &gt; 4 lobar microbleeds, and no&#xD;
                  siderosis or macrohemorrhages&#xD;
&#xD;
               -  Tumor/space occupying lesion&#xD;
&#xD;
               -  Meningeal enhancement&#xD;
&#xD;
          2. More than 30% of the skull area traversed by the sonication pathway is covered by&#xD;
             scars, scalp disorders (e.g., eczema), or atrophy of the scalp&#xD;
&#xD;
          3. Clips or other metallic implanted objects in the skull or the brain, except shunts;&#xD;
             other metallic objects implanted in body&#xD;
&#xD;
          4. Significant cardiac disease or unstable hemodynamic status including:&#xD;
&#xD;
          5. Uncontrolled hypertension on medication or abnormal ECG&#xD;
&#xD;
          6. Medications known to increase risk of hemorrhage, (e.g.: patients should be off of&#xD;
             aspirin or another anticoagulants for at least 7 days prior to treatment) or&#xD;
             anticoagulants (class I and III) or off Avastin for 30 days&#xD;
&#xD;
          7. History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or&#xD;
             use of anticoagulants&#xD;
&#xD;
          8. Abnormal coagulation profile (PLT &lt; 100,00/μl), PT (&gt;14 sec) or PTT (&gt;36 sec), and INR&#xD;
             &gt; 1.3&#xD;
&#xD;
          9. No more than 1 non-strategic lacune &lt;1.5 cm&#xD;
&#xD;
         10. Known cerebral or systemic vasculopathy&#xD;
&#xD;
         11. Significant depression and at potential risk of suicide&#xD;
&#xD;
         12. Known sensitivity/allergy to gadolinium (an alternative product may be used), Definity&#xD;
             or any of its components.&#xD;
&#xD;
         13. Any contraindications to MRI scanning such as metallic implants, claustrophibia or too&#xD;
             large for MRI scanner&#xD;
&#xD;
         14. Untreated, uncontrolled sleep apnea&#xD;
&#xD;
         15. Impaired renal function with estimated glomerular filtration rate &lt;30 mL/min/1.73m2&#xD;
&#xD;
         16. Does not have a reliable caregiver in frequent contact with the patient and can&#xD;
             accompany the patient to the clinic and treatment or be available by telephone at&#xD;
             designated times. Participants living in retirement homes may be included. Caregiver&#xD;
             not willing to sign the Informed Consent Form&#xD;
&#xD;
         17. Respiratory: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis,&#xD;
             or other causes of reduced pulmonary vascular cross-sectional area, patients with a&#xD;
             history of drug allergies, asthma or hay fever, and multiple allergies where the&#xD;
             benefit/risk of administering Definity® is considered unfavorable by the study&#xD;
             physicians in relation to the product monograph for Definity.&#xD;
&#xD;
         18. Currently in a clinical teial involving investigational product.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nir Lipsman, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sunnybrook Health Sciences Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <last_update_submitted>June 13, 2018</last_update_submitted>
  <last_update_submitted_qc>June 13, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Blood-Brain Barrier</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</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/NCT02986932
org study id: AL001
nct id: NCT02986932
lead sponsor: 
has dmc: Yes
This is a prospective, non-randomized, single-arm, feasibility study to evaluate the safety
      and initial effectiveness of opening of the Blood-Brain Barrier with intravenous contrast
      agents using the ExAblate Neuro System in patients with early stage Alzheimer's Disease.
This study is a prospective, single-arm, non-randomized, feasibility, phase I trial to
      evaluate the safety of focal BBB opening using the ExAblate® Transcranial (220 kHz) system
      and Definity® ultrasound contrast in 6 patients with mild Alzheimer's Disease. This phase I
      trial will be divided into two stages. In the first stage, patients will undergo small volume
      BBB opening, establishing the minimum required sonication parameters to open the BBB, as
      evidenced by gadolinium enhancement on T1-weighted MRI. Stage I is defined as a discrete
      region of approximately 9 mm x 9 mm area in the right frontal lobe. Multiple sonications will
      be performed starting at low energy and ramping up until the BBB is observed to open. The
      subjects will then be removed from the ExAblate® Neuro device and followed for safety for 30
      days. If the subject experienced BBB opening without any serious adverse effects (such as
      brain edema), then the subject may proceed to Stage two where a larger volume (2.5-3.0 cm)
      will be targeted. Subjects will be followed for an additional 60 days for safety and
      preliminary effectiveness.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Transcranial ExAblate
primary purpose: Treatment
masking: None (Open Label)
measure: Change in contrast enhancement (intensity) following BBB disruption
time frame: Immediately post treatment
description: Change in contrast enhancement (intensity) following BBB disruption to pre-sonication images as a comparative ratio measured in percent as read from MR images and normalized to the contralateral hemisphere
measure: Change in amyloid uptake
time frame: 30 days after treatments
description: Change in amyloid uptake as compared to pre treatment scans in the targeted region
measure: Adverse events
time frame: 90 days
description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
measure: MMSE - Mini Mental State Examination
time frame: 30 days
description: Treatment effect on patients' dementia state
measure: ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales
time frame: 30 days
description: Treatment effect on patients' Alzheimer's disease symptoms
measure: NPI - Neuropsychiatry Inventory
time frame: 30 days
description: Treatment effect on patients' dementia
measure: GDS - Geriatric Depression Scale
time frame: 30 days
description: Treatment effect on patients' depression
measure: ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory
time frame: 30 days
description: Treatment effect on patients' activities of daily living
arm group label: BBB opening
arm group type: Experimental
description: ExAblate focused ultrasound under MRI-guidance delivered through the intact human skull in conjunction with timed intravenous ultrasound contrast agents (Definity®) to temporarily and focally open the BBB.
intervention type: Device
intervention name: BBB opening
description: Open BBB using ExAblate focused ultrasound and (Definity®) contrast agent
arm group label: BBB opening
criteria: 
gender: All
minimum age: 55 Years
maximum age: 85 Years
healthy volunteers: No
last name: Nir Lipsman, MD, PhD
role: Principal Investigator
affiliation: Sunnybrook Health Sciences Centre
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Alzheimer Disease
sharing ipd: No