<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/NCT04467957</url>
  </required_header>
  <id_info>
    <org_study_id>2019-1192</org_study_id>
    <nct_id>NCT04467957</nct_id>
  </id_info>
  <brief_title>Non-contrast Lung Perfusion Mapping Applied for New Insights in Cystic Fibrosis</brief_title>
  <official_title>Non-contrast Lung Perfusion Mapping Applied for New Insights in Cystic Fibrosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</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>
      Cystic fibrosis (CF) results in the thickening of mucus in the lungs and other organs due to&#xD;
      dysfunction of a transmembrane conductance protein. This allows buildup of bacteria that&#xD;
      results in inflammation, leading to tissue breakdown and loss of function. In the lungs, this&#xD;
      process causes loss of air exchange structures progressing to diminished lung function. The&#xD;
      exchange of oxygen in the lungs depends on both the integrity of air conduits and&#xD;
      vasculature. Most clinical assessments, however, focus on ventilatory function, with the&#xD;
      assumption that any vascular compromise is secondary. Nevertheless, there is evidence, some&#xD;
      from the investigator's lab, to suggest that perfusion anomalies in the lung occur before&#xD;
      signs of ventilatory dysfunction. Thus, the inflammatory processes of CF may impact pulmonary&#xD;
      microvasculature specifically and concurrently or prior to damage to ventilatory structures.&#xD;
      This study aims to apply a new MRI method to serially measure regional lung perfusion,&#xD;
      without the use of contrast agent, in children with CF and to associate it with regional&#xD;
      assessments of ventilation and to serum cytokines or proteomic markers of angiogenesis and&#xD;
      inflammatory processes.&#xD;
&#xD;
      The investigator's lab has recently developed a noninvasive, non-contrast, method of labeling&#xD;
      blood flowing into the lungs and generating a map of perfusion. The investigator aims to&#xD;
      couple this technique to existing methods using hyperpolarized Xenon to map ventilation. The&#xD;
      investigator will apply these methods over time in CF patients, monitoring the relationship&#xD;
      between regional perfusion and ventilation defects.&#xD;
&#xD;
      This pilot work will provide the foundation for larger studies to establish the essential&#xD;
      etiological role of perfusion deficits in CF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Lung Perfusion in CF trial is a case-control observational study conducted at Cincinnati&#xD;
      Children's Hospital.&#xD;
&#xD;
      Patients will be assessed before and approximately 6 months after the clinical initiation of&#xD;
      triple-combination modulator therapy with the following imaging to demonstrate aim 1, that&#xD;
      pulmonary perfusion is regionally altered in CF patients in association with the status and&#xD;
      progression of lung ventilatory function: Ultra-short echo time (UTE) protocol to obtain&#xD;
      structural lung imaging primarily for anatomic reference, Hyperpolarized Xenon gas inhalation&#xD;
      protocol to measure regional lung ventilation and arterial spin labeling protocol to measure&#xD;
      regional lung perfusion.&#xD;
&#xD;
      To demonstrate aim 2, that different profiles of serum proteomic markers related to&#xD;
      angiogenesis and vascular remodeling, characterize states of pulmonary hyperfusion and&#xD;
      hypoperfusion, blood sample data analysis from a separate study conducted at Cincinnati&#xD;
      Children's Hospital Medical Center will also be obtained before and 6 months after initiation&#xD;
      of triple-combination modulator therapy.&#xD;
&#xD;
      Safety will be assessed by recording adverse events. Vital signs (heart rate, SPO2) will be&#xD;
      recorded before, immediately following inhalation, and 2 minutes after each Xenon gas&#xD;
      inhalation; O2 saturation will be monitored continuously throughout the Xenon portion of the&#xD;
      MRI, and the time and duration of nadir will be recorded.&#xD;
&#xD;
      The overarching goal of this study is to demonstrate that arterial spin labeling MRI lung&#xD;
      perfusion can be used to measure regional manifestations of pulmonary vascular disease in CF&#xD;
      that precedes and contributes to global and local decline in ventilatory lung function.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 15, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 4</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>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ventilation Defect Percentage (VDP)</measure>
    <time_frame>Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.</time_frame>
    <description>Lung defect calculations (total and lobar defect percentages) will be performed by evaluating the percentage of voxels with signals below a threshold value of 60% of the total lung mean signal. This threshold (60%) represents our estimate of the visually accurate defect selection threshold for CF patients. To assign the pixels in the hyperpolarized Xenon gas (129Xe) MRI slices to a lobe, corresponding CT and/or UTE MRI images will be segmented and analyzed with custom MATLAB software.&#xD;
VDP for CF and Control groups will be compared by 2-sample T-test at baseline. VDP at baseline and 6 months for the CF group will be compared by paired T-test to determine if the change is significantly different from zero change.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Perfusion Defect Percentage (PDP)</measure>
    <time_frame>Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.</time_frame>
    <description>Similar to the VDP, total and lobar defect percentages will be calculated for lung perfusion.&#xD;
As for VDP, PDP will be compared between CF and Control groups at baseline via 2-sample T-test.&#xD;
PDP change from baseline to 6 months will be measured for the CF group via paired T-test to determine change significantly different from zero change.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Degree of concordance between ventilation and perfusion defects</measure>
    <time_frame>Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.</time_frame>
    <description>Degree of concordance between ventilation and perfusion defects will be calculated as percentage of overlap between ventilation and perfusion defect volumes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proteome assays as global indicators of inflammatory/angiogenic processes</measure>
    <time_frame>Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.</time_frame>
    <description>Proteome assays as global indicators of inflammatory/angiogenic processes, will be compared between groups by 2-sample T-test. Correlation analyses will be performed to examine associations between quantitative image scores for each modality (VDP and PDP) and lung function (FEV1%), as well as proteome concentrations.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">26</enrollment>
  <condition>Cystic Fibrosis</condition>
  <arm_group>
    <arm_group_label>CF Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>16 Cystic Fibrosis Patients will undergo MRI imaging before and 6 months after initiation of triple-combination modulator therapy. Initiation of triple -combination modulator therapy will be determined by clinician and family prior to study enrollment. Hyperpolarized Xenon 129 will be administered through inhalation at two MRI imaging study visits.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 Healthy control study participants matched for age and gender will undergo one MRI imaging study visit. Hyperpolarized Xenon 129 will be administered through inhalation at one MRI imaging study visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Initiation of CFTR Modulator</intervention_name>
    <description>Inhaled contrast for MRI occurring at each visit</description>
    <arm_group_label>CF Cohort</arm_group_label>
    <other_name>129Xe</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hyperpolarized Xenon 129</intervention_name>
    <description>Inhaled contrast for MRI occurring at each visit</description>
    <arm_group_label>CF Cohort</arm_group_label>
    <arm_group_label>Control Cohort</arm_group_label>
    <other_name>129Xe</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion CF Cohort&#xD;
&#xD;
          -  male or female between the ages of 6 through 21 years&#xD;
&#xD;
          -  diagnosis of CF by positive sweat test and genetic test&#xD;
&#xD;
          -  planning to start Trikafta based on clinical decision&#xD;
&#xD;
          -  baseline pulmonary function test (PFT) defined as FEV1% that is no less than 5% of the&#xD;
             best PFT in the previous 6 months&#xD;
&#xD;
          -  Absence of exacerbation defined as&#xD;
&#xD;
               -  No acute antibiotic usage for 14 days prior to MRI visit&#xD;
&#xD;
               -  Able to perform an acceptable and reproducible spirometry&#xD;
&#xD;
               -  O2 saturation level at 90% or greater when laying flat&#xD;
&#xD;
        Inclusion Healthy Control Cohort&#xD;
&#xD;
          -  male or female between the ages of 6 through 21 years&#xD;
&#xD;
          -  no known diagnoses that impact lung function in the opinion of the investigators&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion both cohorts&#xD;
&#xD;
          -  standard MRI exclusions (metal implants, claustrophobia)&#xD;
&#xD;
          -  pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark DiFrancesco, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CCHMC</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jason Woods, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>CCHMC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>August 29, 2022</last_update_submitted>
  <last_update_submitted_qc>August 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cystic Fibrosis</keyword>
  <keyword>Cystic fibrosis transmembrane conductance regulator modulator therapy</keyword>
  <keyword>hyperpolarized xenon</keyword>
  <keyword>Cystic fibrosis transmembrane conductance regulator (CFTR)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cystic Fibrosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Xenon</mesh_term>
  </intervention_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/NCT04467957
org study id: 2019-1192
nct id: NCT04467957
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Cystic fibrosis (CF) results in the thickening of mucus in the lungs and other organs due to
      dysfunction of a transmembrane conductance protein. This allows buildup of bacteria that
      results in inflammation, leading to tissue breakdown and loss of function. In the lungs, this
      process causes loss of air exchange structures progressing to diminished lung function. The
      exchange of oxygen in the lungs depends on both the integrity of air conduits and
      vasculature. Most clinical assessments, however, focus on ventilatory function, with the
      assumption that any vascular compromise is secondary. Nevertheless, there is evidence, some
      from the investigator's lab, to suggest that perfusion anomalies in the lung occur before
      signs of ventilatory dysfunction. Thus, the inflammatory processes of CF may impact pulmonary
      microvasculature specifically and concurrently or prior to damage to ventilatory structures.
      This study aims to apply a new MRI method to serially measure regional lung perfusion,
      without the use of contrast agent, in children with CF and to associate it with regional
      assessments of ventilation and to serum cytokines or proteomic markers of angiogenesis and
      inflammatory processes.

      The investigator's lab has recently developed a noninvasive, non-contrast, method of labeling
      blood flowing into the lungs and generating a map of perfusion. The investigator aims to
      couple this technique to existing methods using hyperpolarized Xenon to map ventilation. The
      investigator will apply these methods over time in CF patients, monitoring the relationship
      between regional perfusion and ventilation defects.

      This pilot work will provide the foundation for larger studies to establish the essential
      etiological role of perfusion deficits in CF.
The Lung Perfusion in CF trial is a case-control observational study conducted at Cincinnati
      Children's Hospital.

      Patients will be assessed before and approximately 6 months after the clinical initiation of
      triple-combination modulator therapy with the following imaging to demonstrate aim 1, that
      pulmonary perfusion is regionally altered in CF patients in association with the status and
      progression of lung ventilatory function: Ultra-short echo time (UTE) protocol to obtain
      structural lung imaging primarily for anatomic reference, Hyperpolarized Xenon gas inhalation
      protocol to measure regional lung ventilation and arterial spin labeling protocol to measure
      regional lung perfusion.

      To demonstrate aim 2, that different profiles of serum proteomic markers related to
      angiogenesis and vascular remodeling, characterize states of pulmonary hyperfusion and
      hypoperfusion, blood sample data analysis from a separate study conducted at Cincinnati
      Children's Hospital Medical Center will also be obtained before and 6 months after initiation
      of triple-combination modulator therapy.

      Safety will be assessed by recording adverse events. Vital signs (heart rate, SPO2) will be
      recorded before, immediately following inhalation, and 2 minutes after each Xenon gas
      inhalation; O2 saturation will be monitored continuously throughout the Xenon portion of the
      MRI, and the time and duration of nadir will be recorded.

      The overarching goal of this study is to demonstrate that arterial spin labeling MRI lung
      perfusion can be used to measure regional manifestations of pulmonary vascular disease in CF
      that precedes and contributes to global and local decline in ventilatory lung function.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Ventilation Defect Percentage (VDP)
time frame: Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.
description: Lung defect calculations (total and lobar defect percentages) will be performed by evaluating the percentage of voxels with signals below a threshold value of 60% of the total lung mean signal. This threshold (60%) represents our estimate of the visually accurate defect selection threshold for CF patients. To assign the pixels in the hyperpolarized Xenon gas (129Xe) MRI slices to a lobe, corresponding CT and/or UTE MRI images will be segmented and analyzed with custom MATLAB software.
VDP for CF and Control groups will be compared by 2-sample T-test at baseline. VDP at baseline and 6 months for the CF group will be compared by paired T-test to determine if the change is significantly different from zero change.
measure: Perfusion Defect Percentage (PDP)
time frame: Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.
description: Similar to the VDP, total and lobar defect percentages will be calculated for lung perfusion.
As for VDP, PDP will be compared between CF and Control groups at baseline via 2-sample T-test.
PDP change from baseline to 6 months will be measured for the CF group via paired T-test to determine change significantly different from zero change.
measure: Degree of concordance between ventilation and perfusion defects
time frame: Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.
description: Degree of concordance between ventilation and perfusion defects will be calculated as percentage of overlap between ventilation and perfusion defect volumes.
measure: Proteome assays as global indicators of inflammatory/angiogenic processes
time frame: Baseline and 6 months post Trikafta initiation for CF group. Baseline for CF and control groups.
description: Proteome assays as global indicators of inflammatory/angiogenic processes, will be compared between groups by 2-sample T-test. Correlation analyses will be performed to examine associations between quantitative image scores for each modality (VDP and PDP) and lung function (FEV1%), as well as proteome concentrations.
arm group label: CF Cohort
arm group type: Experimental
description: 16 Cystic Fibrosis Patients will undergo MRI imaging before and 6 months after initiation of triple-combination modulator therapy. Initiation of triple -combination modulator therapy will be determined by clinician and family prior to study enrollment. Hyperpolarized Xenon 129 will be administered through inhalation at two MRI imaging study visits.
arm group label: Control Cohort
arm group type: Experimental
description: 10 Healthy control study participants matched for age and gender will undergo one MRI imaging study visit. Hyperpolarized Xenon 129 will be administered through inhalation at one MRI imaging study visit.
intervention type: Drug
intervention name: Initiation of CFTR Modulator
description: Inhaled contrast for MRI occurring at each visit
arm group label: CF Cohort
other name: 129Xe
intervention type: Drug
intervention name: Hyperpolarized Xenon 129
description: Inhaled contrast for MRI occurring at each visit
arm group label: CF Cohort
arm group label: Control Cohort
other name: 129Xe
criteria: 
gender: All
minimum age: 6 Years
maximum age: 21 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mark DiFrancesco, PhD
role: Principal Investigator
affiliation: CCHMC
last name: Jason Woods, PhD
role: Study Chair
affiliation: CCHMC
facility: 
country: United States
responsible party type: Sponsor
mesh term: Cystic Fibrosis
mesh term: Fibrosis
mesh term: Xenon
sharing ipd: No