<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/NCT04490096</url>
  </required_header>
  <id_info>
    <org_study_id>834366</org_study_id>
    <nct_id>NCT04490096</nct_id>
  </id_info>
  <brief_title>Multimodal Imaging Outcome Measures for ALS (Image ALS)</brief_title>
  <official_title>Multimodal Imaging Outcome Measures for ALS (Image ALS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Biogen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Miami</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Kansas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</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>
      The primary aim of this study is to determine whether longitudinal neuroimaging acquired&#xD;
      across multiple research and clinical centers is a feasible biomarker to use as an outcome&#xD;
      measure for clinical trials in amyotrophic lateral sclerosis (ALS)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ALS is a progressive neurodegenerative disorder that manifests with extensive clinical&#xD;
      heterogeneity, including variable degrees of upper motor neuron (UMN) and lower motor neuron&#xD;
      (LMN) impairment. While ALS is classically defined as a neuromuscular disorder, approximately&#xD;
      15% of individuals also develop cognitive and/or behavioral dysfunction of the frontotemporal&#xD;
      variety, ranging in severity from ALS with cognitive or behavior impairment to a frank form&#xD;
      of dementia consistent with FTD2&#xD;
&#xD;
        -  Recent consensus criteria capture this heterogeneity by defining these conditions&#xD;
           together as amyotrophic lateral sclerosis frontotemporal spectrum disorder (ALS-FTSD)3&#xD;
&#xD;
        -  There are emerging and in-progress interventional clinical trials underway that aim to&#xD;
           arrest ALS and/or FTD disease progression; however, there are limited objective and&#xD;
           quantitative biomarkers to directly track disease progression during life. Multi-modal&#xD;
           neuroimaging provides an ideal candidate biomarker for clinical trials because ALS-FTSD&#xD;
           affects a distributed neuroanatomic network and we can reliably measure&#xD;
           neurodegeneration of grey matter (GM) and arterial spin labeling based perfusion MRI&#xD;
           (pMRI) measurements of cerebral blood flow (CBF). However, there are many unaddressed&#xD;
           technical challenges associated with measuring disease progression using neuroimaging&#xD;
           techniques in a multi-center setting. The overall aim of this protocol is to leverage a&#xD;
           team science approach to develop disease-specific candidate neuroimaging outcome&#xD;
           measures for ALS-FTSD clinical trials.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Funding issues.&#xD;
  </why_stopped>
  <start_date type="Actual">February 25, 2021</start_date>
  <completion_date type="Actual">March 17, 2022</completion_date>
  <primary_completion_date type="Actual">March 17, 2022</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Volume measurement (cubic mm) of brain regions using MRI</measure>
    <time_frame>Change from baseline volume measurement (cubic mm) at 6 months</time_frame>
    <description>Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Volume measurement (cubic mm) of brain regions using MRI</measure>
    <time_frame>Change from baseline volume measurement (cubic mm) at 12 months</time_frame>
    <description>Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Thickness measurement (mm) of brain regions using MRI</measure>
    <time_frame>Change from baseline thickness measurement (mm) at 6 months</time_frame>
    <description>Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Thickness measurement (mm) of brain regions using MRI</measure>
    <time_frame>Change from baseline thickness measurement (mm) at 12 months</time_frame>
    <description>Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI</measure>
    <time_frame>Change from baseline cerebral blood flow measurement (mL of blood/100g per minute) at 6 months</time_frame>
    <description>Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI</measure>
    <time_frame>Change from baseline cerebral blood flow measurement (mL of blood/100g per minute at 12 months</time_frame>
    <description>Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>[18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan</measure>
    <time_frame>Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 3 months</time_frame>
    <description>[18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>[18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan</measure>
    <time_frame>Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 6 months</time_frame>
    <description>[18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>[11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan</measure>
    <time_frame>Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 3 months</time_frame>
    <description>[11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>[11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan</measure>
    <time_frame>Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 6 months</time_frame>
    <description>[11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>ALS</condition>
  <arm_group>
    <arm_group_label>[11C]-PBR28 ALS</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Neuroinflammatory pathways have been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), but the vast majority of this evidence is from animal or ex vivo human studies. In vivo measurement of the 18 kDa translocator protein (TSPO) has become possible with [11C]-PBR28 PET imaging. Briefly, TSPO expression is increased when microglial are activated. Cross-sectional studies have demonstrated that [11C]-PBR28 uptake is elevated in ALS compared to controls, is correlated with upper motor neuron severity, and that microglial activation is associated with more severe upper motor neuron disease and faster disease progression. We are only aware of a single 6-month study of 10 patients evaluating longitudinal change of [11C]-PBR28 in ALS. We hypothesize that we will observe increased [11C]-PBR28 uptake over a 6-month period in motor cortex and prefrontal cortex in ALS. This portion of the study will be performed at UPenn only.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>[11C]-PBR28</intervention_name>
    <description>A dose of ≤ 20 mCi (approximate range for most studies is anticipated to be 5-20 mCi) of [11C]-PBR28 will be administered by IV injection to the patient under the direct supervision of a Nuclear Medicine Authorized User. A lesser activity may be injected if, in the opinion of a nuclear medicine authorized user complete imaging data could be generated.&#xD;
Subjects will undergo an approximately 90 minute dynamic PET/CT scan over the brain starting at approximately the same time as the [11C]-PBR-28 injection. Scans will be acquired using a Philips PET/CT time-of-flight Ingenuity scanner (Philips Healthcare, Cleveland, OH, USA). At the end of the dynamic imaging the participant will be allowed to get off the scanner.</description>
    <arm_group_label>[11C]-PBR28 ALS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria for participants in PET sub-study (Penn Only):&#xD;
&#xD;
          1. Enrolled in the MRI study at Penn.&#xD;
&#xD;
          2. Willing to participate in a 30 minute [18F]-FDG and 1.5 hour [11C]-PBR28 PET scan&#xD;
             within 15 days baseline and longitudinally at the 3-month and 6-month follow-up&#xD;
             visits, if able.&#xD;
&#xD;
        Exclusion criteria for PET sub-study participants:&#xD;
&#xD;
          1. Females who are pregnant at the time of study visits will not be eligible for the PET&#xD;
             sub-study; urine or serum pregnancy test will be performed in women of child-bearing&#xD;
             potential at each of the baseline, 3-month, and 6-month study visit.&#xD;
&#xD;
          2. Homozygous genotype for the threonine-associated substitution allele (A) in the rs6971&#xD;
             polymorphism.&#xD;
&#xD;
          3. Blood glucose less than or equal to 250 mg/dl, or at the discretion of the authorized&#xD;
             user&#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>Corey McMillan, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>April 4, 2022</last_update_submitted>
  <last_update_submitted_qc>April 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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/NCT04490096
org study id: 834366
nct id: NCT04490096
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary aim of this study is to determine whether longitudinal neuroimaging acquired
      across multiple research and clinical centers is a feasible biomarker to use as an outcome
      measure for clinical trials in amyotrophic lateral sclerosis (ALS)
ALS is a progressive neurodegenerative disorder that manifests with extensive clinical
      heterogeneity, including variable degrees of upper motor neuron (UMN) and lower motor neuron
      (LMN) impairment. While ALS is classically defined as a neuromuscular disorder, approximately
      15% of individuals also develop cognitive and/or behavioral dysfunction of the frontotemporal
      variety, ranging in severity from ALS with cognitive or behavior impairment to a frank form
      of dementia consistent with FTD2

        -  Recent consensus criteria capture this heterogeneity by defining these conditions
           together as amyotrophic lateral sclerosis frontotemporal spectrum disorder (ALS-FTSD)3

        -  There are emerging and in-progress interventional clinical trials underway that aim to
           arrest ALS and/or FTD disease progression; however, there are limited objective and
           quantitative biomarkers to directly track disease progression during life. Multi-modal
           neuroimaging provides an ideal candidate biomarker for clinical trials because ALS-FTSD
           affects a distributed neuroanatomic network and we can reliably measure
           neurodegeneration of grey matter (GM) and arterial spin labeling based perfusion MRI
           (pMRI) measurements of cerebral blood flow (CBF). However, there are many unaddressed
           technical challenges associated with measuring disease progression using neuroimaging
           techniques in a multi-center setting. The overall aim of this protocol is to leverage a
           team science approach to develop disease-specific candidate neuroimaging outcome
           measures for ALS-FTSD clinical trials.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Volume measurement (cubic mm) of brain regions using MRI
time frame: Change from baseline volume measurement (cubic mm) at 6 months
description: Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.
measure: Volume measurement (cubic mm) of brain regions using MRI
time frame: Change from baseline volume measurement (cubic mm) at 12 months
description: Volume measurement (cubic mm) of brain regions using MRI for ALS patients and healthy controls.
measure: Thickness measurement (mm) of brain regions using MRI
time frame: Change from baseline thickness measurement (mm) at 6 months
description: Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.
measure: Thickness measurement (mm) of brain regions using MRI
time frame: Change from baseline thickness measurement (mm) at 12 months
description: Thickness measurement (mm) of brain regions using MRI in ALS patients and healthy controls.
measure: Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI
time frame: Change from baseline cerebral blood flow measurement (mL of blood/100g per minute) at 6 months
description: Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.
measure: Cerebral blood flow measurement (mL of blood/100g per minute) of brain regions using MRI
time frame: Change from baseline cerebral blood flow measurement (mL of blood/100g per minute at 12 months
description: Determine whether MRI is a feasible for measuring longitudinal change comparing ALS patients relative to healthy controls. ALS will have increased rate of hyperperfusion, reflected by reduced cerebral blood flow (mL of blood/100g per minute), in the motor cortex and frontal cortex brain regions relative to healthy controls.
measure: [18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan
time frame: Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 3 months
description: [18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.
measure: [18F]-FDG signal measurement (standard uptake volume or SUV) in brain regions using PET scan
time frame: Change from baseline [18F]-FDG signal measurement (standard uptake volume or SUV) at 6 months
description: [18F]-FDG signal measurement (Standard Uptake Value or SUV) of [18F]-FDG PET for ALS patients at PENN only.
measure: [11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan
time frame: Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 3 months
description: [11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.
measure: [11C]-PBR28 signal measurement (standard uptake volume or SUV) in brain regions using PET scan
time frame: Change from baseline [11C]-PBR28 signal measurement (standard uptake volume or SUV) at 6 months
description: [11C]-PBR28 signal measurement (Standard Uptake Value or SUV) of [11C]-PBR28 PET for ALS patients at PENN only.
arm group label: [11C]-PBR28 ALS
arm group type: Other
description: Neuroinflammatory pathways have been implicated in a variety of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), but the vast majority of this evidence is from animal or ex vivo human studies. In vivo measurement of the 18 kDa translocator protein (TSPO) has become possible with [11C]-PBR28 PET imaging. Briefly, TSPO expression is increased when microglial are activated. Cross-sectional studies have demonstrated that [11C]-PBR28 uptake is elevated in ALS compared to controls, is correlated with upper motor neuron severity, and that microglial activation is associated with more severe upper motor neuron disease and faster disease progression. We are only aware of a single 6-month study of 10 patients evaluating longitudinal change of [11C]-PBR28 in ALS. We hypothesize that we will observe increased [11C]-PBR28 uptake over a 6-month period in motor cortex and prefrontal cortex in ALS. This portion of the study will be performed at UPenn only.
intervention type: Drug
intervention name: [11C]-PBR28
description: A dose of ≤ 20 mCi (approximate range for most studies is anticipated to be 5-20 mCi) of [11C]-PBR28 will be administered by IV injection to the patient under the direct supervision of a Nuclear Medicine Authorized User. A lesser activity may be injected if, in the opinion of a nuclear medicine authorized user complete imaging data could be generated.
Subjects will undergo an approximately 90 minute dynamic PET/CT scan over the brain starting at approximately the same time as the [11C]-PBR-28 injection. Scans will be acquired using a Philips PET/CT time-of-flight Ingenuity scanner (Philips Healthcare, Cleveland, OH, USA). At the end of the dynamic imaging the participant will be allowed to get off the scanner.
arm group label: [11C]-PBR28 ALS
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Corey McMillan, PhD
role: Principal Investigator
affiliation: University of Pennsylvania
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No