xml: <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/NCT05975554</url>
    </required_header>
    <id_info>
      <org_study_id>A096090</org_study_id>
      <nct_id>NCT05975554</nct_id>
    </id_info>
    <brief_title>The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution.</brief_title>
    <acronym>ELLIPSE</acronym>
    <official_title>The Effect of Low-dose Interleukin-2 on the Immune Landscape of Human Atherosclerotic Plaques at Single Cell Resolution.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Cambridge University Hospitals NHS Foundation Trust</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</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>
        The goal of this clinical trail is to compare the differences in carotid plaque Treg cells'&#xD;
        gene signature for activation, proliferation, and suppressive function using scRNA-seq in&#xD;
        patients treated with IL-2 compared to control.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Up till now our Lab has looked at Tregs and immune cells in the blood. The question remains&#xD;
        whether low dose IL-2 can have the desired effect on Tregs in atherosclerotic plaques where&#xD;
        they could alter the pathophysiology and potentially clinical outcomes for patients.&#xD;
  &#xD;
        Up until recently, the cellular composition and cell-specific expression patterns of human&#xD;
        atherosclerotic plaques remained elusive. However, recent breakthroughs studies using&#xD;
        scRNA-seq, CITE-seq, and single-cell ATAC-seq on human carotid plaques have offered important&#xD;
        insight into plaque composition, cell heterogeneity, and cell-cell interactions giving new&#xD;
        perspectives on mechanisms of disease. The next logical stage is to use this new insight and&#xD;
        powerful biological tool to assist in drug development for patients.&#xD;
  &#xD;
        Therefore, the aims of the study are:&#xD;
  &#xD;
          1. To assess if low dose IL-2, given systemically to patients at our proposed dose, can&#xD;
             alter Tregs in atherosclerotic plaques (the disease tissue) to exhibit a proliferating,&#xD;
             activated, and immunosuppressive phenotype&#xD;
  &#xD;
          2. To assess if modulating plaque Tregs can cause a shift in the plaque immune landscape to&#xD;
             a less inflammatory phenotype&#xD;
  &#xD;
          3. To study the relationship between plaque and circulating immune cells after systemic&#xD;
             immune modulation&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 26, 2023</start_date>
    <completion_date type="Anticipated">September 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">August 1, 2025</primary_completion_date>
    <phase>N/A</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>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>None (Open Label)</masking>
      <masking_description>Analysis blinded</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Difference in gene expression in Tregs</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Comparing differential gene expression using scRNA-seq technologies, from isolated Tregs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Difference in gene expression in Teff cells.</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Comparing differential gene expression using scRNA-seq technologies, from isolated Teffs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Immune cell gene signature, in plaque and blood.</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Difference in immune cell gene signature will be compared using scRNA-seq in both plaque and blood samples, and further compared between IL-2 and control groups. Comparative analysis will be completed using gene set enrichment analysis (Enrichment Score).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Difference in gene expression patterns in Treg &amp; Teff cells.</measure>
      <time_frame>Baseline and at time of surgery</time_frame>
      <description>Comparison between Treg and Teff cells collected at baseline and day of surgery will be compared between IL-2 and control groups. Differential gene expression will be assessed using standard techniques (Z-Score)</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Other immune cell and vascular smooth muscle cell gene expression</measure>
      <time_frame>Time of surgery</time_frame>
      <description>As per primary outcome measure but in immune cells and vascular smooth muscle cells (excluding Treg &amp; Teff cells). Differential gene expression will be assessed using standard techniques (Z-Score)</description>
    </other_outcome>
    <other_outcome>
      <measure>Ligand-receptor interactions.</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Differential regulation of ligand-receptor interactions between control and IL-2 treated cells will be identified by comparing single-cell/single-cell ligand-receptor interaction scores for the two groups. This measure is descriptive in nature.</description>
    </other_outcome>
    <other_outcome>
      <measure>T-Cell receptor profile</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Difference in TCR clonality in plaques between the two groups will be assessed from clonotypes based on identical V-J gene usage and identical CDR3 junctions.</description>
    </other_outcome>
    <other_outcome>
      <measure>Inflammatory pathway activation.</measure>
      <time_frame>Time of surgery</time_frame>
      <description>Activation of inflammatory pathways both at plaque and systemic level. Assess for enrichment of genes involved in inflammatory pathways - enrichment score.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">30</enrollment>
    <condition>TIA</condition>
    <condition>Carotid Artery Plaque</condition>
    <condition>Carotid Atherosclerosis</condition>
    <arm_group>
      <arm_group_label>Low dose interleukin-2</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Standard of care treatment</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Interleukin-2 [IL-2]</intervention_name>
      <description>5 sequential days of treatment (1.5MIU/day subcutaneously)</description>
      <arm_group_label>Low dose interleukin-2</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Standard care - Carotid Endarterectomy</intervention_name>
      <description>Standard care for patients with carotid stenosis undergoing carotid endarterectomy</description>
      <arm_group_label>Control</arm_group_label>
      <arm_group_label>Low dose interleukin-2</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Presence of carotid stenosis on either ultrasound or CT scan.&#xD;
  &#xD;
            -  Planned to undergo carotid endarterectomy.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Autoimmune disease&#xD;
  &#xD;
            -  Any regular immunosuppressive treatment [Inhaled or topical steroids are permissible]&#xD;
  &#xD;
            -  Modified Rankin Scale score of ≥4 at screening&#xD;
  &#xD;
            -  Known active hepatic disease or alanine aminotransferase (ALT) &gt; 2xULN&#xD;
  &#xD;
            -  Severe chronic kidney disease (defined as eGFR &lt; 30 ml/min/1.73m2)&#xD;
  &#xD;
            -  Allergy or intolerance to aldesleukin&#xD;
  &#xD;
            -  Signs or symptoms of active infection&#xD;
  &#xD;
            -  History of human immunodeficiency virus (HIV), hepatitis B or C&#xD;
  &#xD;
            -  Current malignancy requiring active treatment&#xD;
  &#xD;
            -  Vaccine within 4 weeks prior to screening or plans for vaccination during study period&#xD;
  &#xD;
            -  Women of child-bearing potential and pregnancy&#xD;
  &#xD;
            -  Women who are breast-feeding&#xD;
  &#xD;
            -  Clinically relevant medical or surgical conditions that, in the opinion of the&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Addenbrookes Hospital</name>
        <address>
          <city>Cambridge</city>
          <state>Cambridgeshire</state>
          <zip>CB2 0QQ</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
      <contact>
        <last_name>Tian Zhao, MBBS, PhD</last_name>
        <phone>01223768678</phone>
        <email>Txz20@cam.ac.uk</email>
      </contact>
    </location>
    <location_countries>
      <country>United Kingdom</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>June 14, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>August 2, 2023</last_update_submitted>
    <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 4, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Cambridge University Hospitals NHS Foundation Trust</investigator_affiliation>
      <investigator_full_name>Tian Zhao</investigator_full_name>
      <investigator_title>BHF Clinical Lecturer in Cardiovascular Medicine.</investigator_title>
    </responsible_party>
    <keyword>Interleukin-2</keyword>
    <keyword>IL-2</keyword>
    <keyword>TIA</keyword>
    <keyword>Carotid Stenosis</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carotid Artery Diseases</mesh_term>
      <mesh_term>Carotid Stenosis</mesh_term>
      <mesh_term>Atherosclerosis</mesh_term>
      <mesh_term>Plaque, Atherosclerotic</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Interleukin-2</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05975554
  org study id: A096090
  nct id: NCT05975554
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The goal of this clinical trail is to compare the differences in carotid plaque Treg cells'
        gene signature for activation, proliferation, and suppressive function using scRNA-seq in
        patients treated with IL-2 compared to control.
  Up till now our Lab has looked at Tregs and immune cells in the blood. The question remains
        whether low dose IL-2 can have the desired effect on Tregs in atherosclerotic plaques where
        they could alter the pathophysiology and potentially clinical outcomes for patients.
  
        Up until recently, the cellular composition and cell-specific expression patterns of human
        atherosclerotic plaques remained elusive. However, recent breakthroughs studies using
        scRNA-seq, CITE-seq, and single-cell ATAC-seq on human carotid plaques have offered important
        insight into plaque composition, cell heterogeneity, and cell-cell interactions giving new
        perspectives on mechanisms of disease. The next logical stage is to use this new insight and
        powerful biological tool to assist in drug development for patients.
  
        Therefore, the aims of the study are:
  
          1. To assess if low dose IL-2, given systemically to patients at our proposed dose, can
             alter Tregs in atherosclerotic plaques (the disease tissue) to exhibit a proliferating,
             activated, and immunosuppressive phenotype
  
          2. To assess if modulating plaque Tregs can cause a shift in the plaque immune landscape to
             a less inflammatory phenotype
  
          3. To study the relationship between plaque and circulating immune cells after systemic
             immune modulation
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Basic Science
  masking: None (Open Label)
  masking description: Analysis blinded
  measure: Difference in gene expression in Tregs
  time frame: Time of surgery
  description: Comparing differential gene expression using scRNA-seq technologies, from isolated Tregs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)
  measure: Difference in gene expression in Teff cells.
  time frame: Time of surgery
  description: Comparing differential gene expression using scRNA-seq technologies, from isolated Teffs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score)
  measure: Immune cell gene signature, in plaque and blood.
  time frame: Time of surgery
  description: Difference in immune cell gene signature will be compared using scRNA-seq in both plaque and blood samples, and further compared between IL-2 and control groups. Comparative analysis will be completed using gene set enrichment analysis (Enrichment Score).
  measure: Difference in gene expression patterns in Treg & Teff cells.
  time frame: Baseline and at time of surgery
  description: Comparison between Treg and Teff cells collected at baseline and day of surgery will be compared between IL-2 and control groups. Differential gene expression will be assessed using standard techniques (Z-Score)
  measure: Other immune cell and vascular smooth muscle cell gene expression
  time frame: Time of surgery
  description: As per primary outcome measure but in immune cells and vascular smooth muscle cells (excluding Treg & Teff cells). Differential gene expression will be assessed using standard techniques (Z-Score)
  measure: Ligand-receptor interactions.
  time frame: Time of surgery
  description: Differential regulation of ligand-receptor interactions between control and IL-2 treated cells will be identified by comparing single-cell/single-cell ligand-receptor interaction scores for the two groups. This measure is descriptive in nature.
  measure: T-Cell receptor profile
  time frame: Time of surgery
  description: Difference in TCR clonality in plaques between the two groups will be assessed from clonotypes based on identical V-J gene usage and identical CDR3 junctions.
  measure: Inflammatory pathway activation.
  time frame: Time of surgery
  description: Activation of inflammatory pathways both at plaque and systemic level. Assess for enrichment of genes involved in inflammatory pathways - enrichment score.
  arm group label: Low dose interleukin-2
  arm group type: Experimental
  description: Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC.
  arm group label: Control
  arm group type: Active Comparator
  description: Standard of care treatment
  intervention type: Drug
  intervention name: Interleukin-2 [IL-2]
  description: 5 sequential days of treatment (1.5MIU/day subcutaneously)
  arm group label: Low dose interleukin-2
  intervention type: Procedure
  intervention name: Standard care - Carotid Endarterectomy
  description: Standard care for patients with carotid stenosis undergoing carotid endarterectomy
  arm group label: Control
  arm group label: Low dose interleukin-2
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  facility: 
  contact: 
  country: United Kingdom
  responsible party type: Principal Investigator
  investigator affiliation: Cambridge University Hospitals NHS Foundation Trust
  investigator full name: Tian Zhao
  investigator title: BHF Clinical Lecturer in Cardiovascular Medicine.
  mesh term: Carotid Artery Diseases
  mesh term: Carotid Stenosis
  mesh term: Atherosclerosis
  mesh term: Plaque, Atherosclerotic
  mesh term: Interleukin-2