<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/NCT04444609</url>
  </required_header>
  <id_info>
    <org_study_id>20IC5943</org_study_id>
    <nct_id>NCT04444609</nct_id>
  </id_info>
  <brief_title>PROSAIC-19 - Prospective Longitudinal Assessment in a COVID-19 Infected Cohort</brief_title>
  <acronym>PROSAIC-19</acronym>
  <official_title>PROSAIC-19 - Prospective Longitudinal Assessment in a COVID-19 Infected Cohort</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Royal Brompton &amp; Harefield NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chelsea and Westminster NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Imperial College Healthcare NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Imperial College London</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      DESIGN Longitudinal prospective observational multicentre study.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      Understand the immune mechanisms driving COVID-19 disease in patients with a history of lung&#xD;
      disease&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION&#xD;
&#xD;
      1.1 BACKGROUND&#xD;
&#xD;
      Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is a new rapidly spreading&#xD;
      infectious disease with no proven treatment options. The virus causes a spectrum of disease&#xD;
      ranging from mild coryzal symptoms to severe respiratory compromise requiring ventilatory&#xD;
      support. Guidance from Public Health England identifies several groups that are at risk of&#xD;
      severe disease including the elderly and individuals with chronic lung disease. Additionally,&#xD;
      there is also debate over the role of corticosteroids with some hospital guidelines&#xD;
      recommending their use despite WHO guidance contradicting this due to concerns that they may&#xD;
      impair antiviral immunity and worsen disease. The mechanisms driving severity of disease in&#xD;
      certain individuals infected with COVID-19 are poorly understood. We urgently need to&#xD;
      understand these mechanisms to facilitate rapid development of novel effective therapies and&#xD;
      vaccines&#xD;
&#xD;
      1. Immunosusceptibility to severe COVID-19 disease&#xD;
&#xD;
      There are several putative mechanisms through which SARS-CoV-2 could drive greater disease&#xD;
      severity in pre-disposed individuals. These include:&#xD;
&#xD;
        1. Impaired innate anti-viral immune responses&#xD;
&#xD;
           Following viral entry, the innate immune response to respiratory viruses involves&#xD;
           induction of the type I and III interferons (IFN). This initiates a cascade that&#xD;
           triggers expression of a range of interferon-stimulated genes expressing proteins that&#xD;
           act in concert to limit viral replication. Chronic lung diseases, particularly asthma,&#xD;
           cystic Fibrosis (CF) and COPD are associated with impaired or dysregulated induction of&#xD;
           interferon to commonly encountered viruses such as rhinovirus and influenza and similar&#xD;
           dysregulation may occur with SARS-CoV-2. Inhaled interferon-β is currently in trials as&#xD;
           an anti-viral therapy for asthma and COPD.&#xD;
&#xD;
        2. Exaggerated inflammatory responses to viral infection&#xD;
&#xD;
           Common respiratory viral infections such as influenza and respiratory syncyitial virus&#xD;
           (RSV) can promote viral pathology mediated by antibodies and T cell responses. Early&#xD;
           evidence suggests that severe COVID-19 disease is associated with hyperinflammation, a&#xD;
           feature that could be directly driven by virus burden or occur due to independent&#xD;
           hyperactivation of the immune system. Human coronavirus infections including SARS-CoV&#xD;
           can induce immunopathology in the lungs through a number of different mechanisms&#xD;
           including antibody enhancement of SARS-CoV infection by human macrophages. Significant&#xD;
           increases in CD4 and CD8 expressing pro-inflammatory cytokines have been shown in severe&#xD;
           SARS-CoV disease compared to mild/moderate disease.&#xD;
&#xD;
           Accordingly, there has been considerable interest in a potential role of repurposing&#xD;
           existing immunosuppressive therapies for treatment of severe COVID-19. The key mediators&#xD;
           and pathways that drive hyperinflammation in COVID-19 are unclear and greater&#xD;
           elucidation of these processes will inform repurposing of existing therapies or&#xD;
           development of novel approaches to effective treatment. The implication of baseline&#xD;
           dysregulated T cell responses such as those seen in chronic lung disease (e.g. asthma,&#xD;
           COPD, Cystic Fibrosis) is again unclear and requires further mechanistic understanding.&#xD;
           As such it is, as yet, unclear whether immunosuppressive therapies currently in clinical&#xD;
           trials will be beneficial or harmful in these large cohorts of susceptible patients.&#xD;
&#xD;
        3. Dysregulated interferon-dependent endothelial function to COVID-19&#xD;
&#xD;
           Acute respiratory distress syndrome (ARDS) is characterised by hydrostatic pulmonary&#xD;
           oedema, elevated pulmonary vascular resistance and coagulopathy, there is disruption of&#xD;
           endothelial function with dysregulated release of the endothelially derived vasoactive&#xD;
           hormones. Circulating levels of endothelin-1 are raised in patients with ARDS[16],&#xD;
           likely due to increased production and decreased clearance in the lungs potentially&#xD;
           regulated by Angiopoietin-1.&#xD;
&#xD;
           Severe SARS-CoV-2 infection is associated with cytokine storm. Raised serum levels of a&#xD;
           number of key inflammatory cytokines including IFN-gamma, TNF-alpha, IP10, IL-8 and&#xD;
           IL-10 and elevated levels of IL-6 are strongly associated with mortality. IL-6 release&#xD;
           is synergistically induced by IFN-gamma and TNF-alpha and in a positive feedback&#xD;
           mechanism, a low dose of IL-6 strongly enhances the cellular responses to IFN-alpha and&#xD;
           modulates interferon-stimulated gene expression. In an experimental murine model, we&#xD;
           found that infection with rhinovirus with IFN co-stimulation leads to elevated&#xD;
           bronchoalveolar lavage levels of IL-6 (Singanayagam et al, unpublished observations).&#xD;
           These data suggest that in patients with severe COVID-19, a hyperinflammatory process&#xD;
           ensues and we hypothesise that through dysregulated and unchecked IFN production, key&#xD;
           vasculo-inflammatory interferon-stimulated genes including IP10 and ET-1 drive worse&#xD;
           outcomes with increased parenchymal and pulmonary vascular inflammation. This results in&#xD;
           a dichotomy whereby initial IFN induction is required to limit viral replication, but&#xD;
           late unchecked production can worsen pathophysiology. This is supported by emerging&#xD;
           clinical data suggesting a unique phenotype to SARS-CoV-2 critical care patients&#xD;
           characterised by severe hypoxia with near normal lung compliance.&#xD;
&#xD;
        4. Altered viral entry receptor expression: Recent data indicates SARS-CoV-2 utilises&#xD;
           angiotensin-converting enzyme (ACE)2 as a receptor for viral attachment and also the&#xD;
           protease TMPRSS2 which cleaves the spike(S) protein to allow fusion of the virus with&#xD;
           cellular membranes. ACE2 and TMPRSS2 are frequently co-expressed in the pulmonary&#xD;
           epithelium. A recent study also showed that ACE2 is an interferon stimulated gene&#xD;
           (ISG)(i.e. directly induced by the anti-viral response) and therefore, SARS-CoV-2 might&#xD;
           upregulate its own receptor to propagate infection. Recent data indicates that smokers&#xD;
           and subjects with chronic obstructive pulmonary disease (COPD) have increased pulmonary&#xD;
           ACE2 expression suggesting that chronic lung disease might facilitate greater infection&#xD;
           with SARS-CoV-2. Conversely, ACE2 expression protects against acute lung injury in the&#xD;
           context of acid aspiration or sepsis and therefore, if ACE2 induction by SARS-CoVs is&#xD;
           impaired in chronic lung disease, this could predispose to adverse outcome.&#xD;
&#xD;
        5. Increased secondary bacterial and/or fungal infections&#xD;
&#xD;
      In early case series, secondary infections have been observed more frequently in subjects&#xD;
      with severe COVID-19 disease. Secondary bacterial infection is a well-recognised phenomenon&#xD;
      following rhinovirus, influenza or respiratory syncytial virus and may be mechanistically&#xD;
      driven by a range of possible mechanisms including macrophage phagocytosis or neutrophil&#xD;
      elastase-mediated cleavage of anti-microbial peptides. These processes may be worsened by use&#xD;
      of corticosteroids28 and, notably, a greater proportion of patients with secondary infections&#xD;
      following COVID-19 had been prescribed steroids.&#xD;
&#xD;
      Invasive fungal disease consistent with aspergillosis has also been observed for both severe&#xD;
      acute respiratory syndrome coronavirus (SARS-CoV-2003) and Middle East Respiratory Syndrome&#xD;
      coronavirus (MERS-CoV), and anecdotal reports of post-mortems in patients with COVID-19 from&#xD;
      China suggest that Aspergillus pulmonary infections occur. These data are early warning signs&#xD;
      that secondary invasive fungal infections may present an increasingly serious complication in&#xD;
      patients affected with COVID-19 as the pandemic progresses. Understanding the mechanistic&#xD;
      basis for immune susceptibility to secondary bacterial/fungal infection and an ability to&#xD;
      prevent these secondary infections could be a key step towards improving outcomes from the&#xD;
      disease.&#xD;
&#xD;
      1.2 RATIONALE FOR CURRENT STUDY&#xD;
&#xD;
      In this study, the investigators will analyse blood and airway samples from individuals with&#xD;
      confirmed COVID-19 to understand the immune mechanisms that lead to severe disease. We will&#xD;
      elucidate specific mechanisms that drive more severe pathology in higher risk individuals&#xD;
      such as those with chronic lung disease. Through detailed immunoprofiling, we will identify&#xD;
      key pathways and druggable targets to exploit in future clinical intervention studies.&#xD;
&#xD;
      Hypotheses:&#xD;
&#xD;
        1. High risk individuals including individuals with chronic lung disease have impaired&#xD;
           anti-viral immune responses to SARS-CoV-2, increasing virus-induced inflammation.&#xD;
&#xD;
        2. Interferon-dependent endothelial dysfunction drives pathogenicity in SARS-CoV-2&#xD;
           infection.&#xD;
&#xD;
        3. Susceptibility to secondary bacterial and fungal infection in chronic lung disease is&#xD;
           related to selective pathway defects in innate immune function.&#xD;
&#xD;
      2. STUDY OBJECTIVES&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      1. Understand the immune mechanisms driving COVID-19 disease in patients with a history of&#xD;
      lung disease&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
        1. Identify immune correlates of protection and lung pathology in SARS-CoV-2 infection.&#xD;
&#xD;
        2. Analysis of endothelial function in mild and severe COVID-19 patients and ex vivo using&#xD;
           virus stimulated blood-derived endothelial cells from patients with COVID-19.&#xD;
&#xD;
        3. Evaluation of changes in upper/lower airway microbiota and mycobiota occurring during&#xD;
           COVID-19.&#xD;
&#xD;
        4. Evaluation of ex vivo peripheral blood immune responses to viral, bacterial and fungal&#xD;
           stimuli in patients with COVID-19 and chronic lung disease in comparison to patients&#xD;
           with COVID-19 and no chronic lung disease.&#xD;
&#xD;
        5. Analysis of quality of life impact of COVID-19 infection in chronic lung disease.&#xD;
&#xD;
      3. STUDY DESIGN&#xD;
&#xD;
      Through a 24 month prospective longitudinal multicentre (Royal Brompton &amp; Harefield NHS Trust&#xD;
      Chelsea and Westminster NHS Foundation Trust, and Imperial College Healthcare NHS Trusts)&#xD;
      observational study, the study team will analyse blood, sputum and nasal sampling alongside&#xD;
      non-invasive EndoPAT device testing in a total pf 230 subjects. The study team will obtain&#xD;
      peripheral blood, sputum, nasal lavage, brushings and nasal synthetic absorptive matrix (SAM)&#xD;
      samples and perform non-invasive EndoPAT testing on the day of hospital presentation and at&#xD;
      weekly intervals during inpatient setting and then during outpatient visits post-discharge&#xD;
      over a 12 month follow-up period. The study team will collect clinical information including&#xD;
      demographics, routine laboratory investigations, clinical symptom scores and outcomes. Linked&#xD;
      pseudoanonymised radiology imaging will also be transferred for analysis.&#xD;
&#xD;
      Spontaneously expectorated sputum, nasal lavage, brushings and nasal synthetic absorptive&#xD;
      matrix (SAM) samples will be taken and processed as previously described and stored at -800C&#xD;
      for downstream analyses including ELISA/MSD, viral load measurement and microbiome analysis.&#xD;
      Venous blood (60mls) will be taken into Lithium Heparin tubes and PAXgene RNA tubes and&#xD;
      transferred to Imperial College (RBH) for processing and storage. PBMCs will be extracted for&#xD;
      in vitro stimulation assays and whole blood (1ml) and serum (2mls) isolated and stored at&#xD;
      -80oC for further analysis. PAXgene tubes will be stored at -80C for further host genetic&#xD;
      sequencing analysis. Further immunological analysis using yeast surface display for serum&#xD;
      antibody profiling, single B cell sorting to generate monoclonal antibodies and ELISPOT to&#xD;
      analyse CD4 and CD8 T cell ELISPOT to SARS CoV-2 peptide pools. Further deep immunological&#xD;
      profiling using cytokine analysis, PBMC cytokine response to viral (or viral PRR agonist),&#xD;
      fungal stimuli, yeast surface display for serum antibody profiling, single memory B cell&#xD;
      expression cloning will be carried. CD4 and CD8 T cell ELISPOT will be performed as&#xD;
      previously described. Non-invasive EndoPAT testing will also be performed as previously&#xD;
      described.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 18, 2020</start_date>
  <completion_date type="Anticipated">June 2023</completion_date>
  <primary_completion_date type="Anticipated">June 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Anti-viral cytokine levels in blood samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Anti-viral cytokine protein concentration in blood samples by ELISA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anti-viral cytokines profiles within sputum samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Inflammatory cytokine protein concentration in sputum samples by ELISA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anti-viral cytokine profiles within nasal lavage samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Inflammatory cytokine protein concentration in nasal lavage samples by ELISA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Expression of inflammatory gene expression in upper respiratory epithelial airway cells using nasal brush specimens in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Inflammatory gene expression in upper airway respiratory epithelial cells by RNA sequencing.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Identify the T cell antigens and B cell epitopes in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Analysis of viral components recognized by the adaptive immune system</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood mononuclear cell (PBMC) interferon mediated immune responses to pathogen recognition receptor agonists in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Cytokine protein concentration following PBMC stimulation to pathogen recognition receptor agonists by Elispot</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify endothelial function in chronic respiratory disease associated with susceptibility to severe COVID-19 infection using EndoPAT testing</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Analysis of endothelial function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelial cell inflammation biomarkers in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Serum and plasma protein concentration of endothelial cell inflammation biomarkers by ELISA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify sputum 16S rRNA and ITS sequences in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Analysis of sputum microbiome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify nasal lavage 16S rRNA and ITS sequences in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Analysis of nasal microbiome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify quality of life markers in chronic respiratory disease associated with susceptibility to severe COVID-19 infection</measure>
    <time_frame>Through study completion an average of 1 year</time_frame>
    <description>Study participant survey</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">230</enrollment>
  <condition>COVID-19</condition>
  <condition>SARS-CoV 2</condition>
  <condition>ARDS, Human</condition>
  <condition>Immune System Disorder</condition>
  <arm_group>
    <arm_group_label>COVID -19 with chronic lung disease</arm_group_label>
    <description>Subjects with swab confirmed COVID-19 and underlying chronic lung disease (n=60)&#xD;
Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)&#xD;
Mild/Moderate ( n =30) (absence of severe criteria)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>COVID-19 without chronic lung disease</arm_group_label>
    <description>Subjects with swab confirmed COVID-19 and no chronic lung disease (n=60)&#xD;
Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)&#xD;
Mild/Moderate ( n =30) (absence of severe criteria)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chronic Lung disease</arm_group_label>
    <description>Subjects with chronic lung disease (identified as requiring shielding based on severity) but no COVID-19 (n=80)&#xD;
Asthma (defined as severe) - (n=20)&#xD;
CF (FEV1% predicted baseline &lt;50%) - (n=20)&#xD;
COPD (FEV1% predicted baseline &lt;50%) - (n=20)&#xD;
Idiopathic Pulmonary Fibrosis (n=20)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <description>Healthy subjects with no COVID-19 (n=30)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood tests sputum, nasal lavage and brushing</intervention_name>
    <description>Venesection, sputum nasal lavage and brushing if appropriate</description>
    <arm_group_label>COVID -19 with chronic lung disease</arm_group_label>
    <arm_group_label>COVID-19 without chronic lung disease</arm_group_label>
    <arm_group_label>Chronic Lung disease</arm_group_label>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <other_name>Blood tests</other_name>
    <other_name>Sputum</other_name>
    <other_name>Nasal lavage</other_name>
    <other_name>Nasal brushings</other_name>
    <other_name>EndoPAT</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Spontaneously expectorated sputum, nasal lavage, brushings and nasal synthetic absorptive&#xD;
      matrix (SAM) samples&#xD;
&#xD;
      Venous blood (60mls) will be taken into Lithium Heparin tubes and PAXgene RNA tubes&#xD;
&#xD;
      PAXgene tubes will be stored at -80C for further host genetic sequencing analysis. Further&#xD;
      immunological analysis using yeast surface display for serum antibody profiling, single B&#xD;
      cell sorting to generate monoclonal antibodies and ELISPOT to analyse CD4 and CD8 T cell&#xD;
      ELISPOT to SARS CoV-2 peptide pools.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Subjects with swab confirmed COVID-19 and underlying chronic lung disease (n=60)&#xD;
&#xD;
          -  Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)&#xD;
&#xD;
          -  Mild/Moderate ( n =30) Absence of features of severe disease&#xD;
&#xD;
        Subjects with swab confirmed COVID-19 and no chronic lung disease (n=60)&#xD;
&#xD;
          -  Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)&#xD;
&#xD;
          -  Mild/Moderate ( n =30) Absence of features of severe disease&#xD;
&#xD;
        Subjects with chronic lung disease (identified as requiring shielding based on severity)&#xD;
        but no COVID-19 (n=80)&#xD;
&#xD;
          -  Asthma (defined as severe) - (n=20)&#xD;
&#xD;
          -  CF (FEV1% predicted baseline &lt;50%) - (n=20)&#xD;
&#xD;
          -  COPD (FEV1% predicted baseline &lt;50%) - (n=20)&#xD;
&#xD;
          -  Idiopathic Pulmonary Fibrosis (n=20)&#xD;
&#xD;
             3.Healthy subjects with no COVID-19 (n=30)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. All patients ≥16 years old with confirmation of COVID-19&#xD;
&#xD;
          2. All patients ≥ 16 years old with chronic lung disease (CF, non-CF bronchiectasis,&#xD;
             asthma, COPD or Idiopathic Pulmonary Fibrosis) or with no evidence of prior chronic&#xD;
             lung disease&#xD;
&#xD;
          3. Healthy volunteers&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Kelleher, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Peter Kelleher, MD PhD</last_name>
    <phone>00 44 (0) 331 58228</phone>
    <email>p.kelleher@imperial.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anand Shah, MD PhD</last_name>
    <phone>00 44 (0) 352 8121</phone>
    <phone_ext>8674</phone_ext>
    <email>s.anand@imperial.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Royal Brompton &amp; Harefileld NHS Trusts</name>
      <address>
        <city>London</city>
        <zip>SW3 6PP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anand Shah, MD PhD</last_name>
      <phone>0044 352 8121</phone>
      <phone_ext>8674</phone_ext>
      <email>s.anand@imperial.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Peter Kelleher, MD PhD</last_name>
      <phone>0044 746 8000</phone>
      <phone_ext>58228</phone_ext>
      <email>p.kelleher@imperial.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>June 16, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>May 24, 2022</last_update_submitted>
  <last_update_submitted_qc>May 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Immune System Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Under consideration</ipd_description>
  </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/NCT04444609
org study id: 20IC5943
nct id: NCT04444609
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
DESIGN Longitudinal prospective observational multicentre study.

      Primary objective:

      Understand the immune mechanisms driving COVID-19 disease in patients with a history of lung
      disease
INTRODUCTION

      1.1 BACKGROUND

      Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is a new rapidly spreading
      infectious disease with no proven treatment options. The virus causes a spectrum of disease
      ranging from mild coryzal symptoms to severe respiratory compromise requiring ventilatory
      support. Guidance from Public Health England identifies several groups that are at risk of
      severe disease including the elderly and individuals with chronic lung disease. Additionally,
      there is also debate over the role of corticosteroids with some hospital guidelines
      recommending their use despite WHO guidance contradicting this due to concerns that they may
      impair antiviral immunity and worsen disease. The mechanisms driving severity of disease in
      certain individuals infected with COVID-19 are poorly understood. We urgently need to
      understand these mechanisms to facilitate rapid development of novel effective therapies and
      vaccines

      1. Immunosusceptibility to severe COVID-19 disease

      There are several putative mechanisms through which SARS-CoV-2 could drive greater disease
      severity in pre-disposed individuals. These include:

        1. Impaired innate anti-viral immune responses

           Following viral entry, the innate immune response to respiratory viruses involves
           induction of the type I and III interferons (IFN). This initiates a cascade that
           triggers expression of a range of interferon-stimulated genes expressing proteins that
           act in concert to limit viral replication. Chronic lung diseases, particularly asthma,
           cystic Fibrosis (CF) and COPD are associated with impaired or dysregulated induction of
           interferon to commonly encountered viruses such as rhinovirus and influenza and similar
           dysregulation may occur with SARS-CoV-2. Inhaled interferon-β is currently in trials as
           an anti-viral therapy for asthma and COPD.

        2. Exaggerated inflammatory responses to viral infection

           Common respiratory viral infections such as influenza and respiratory syncyitial virus
           (RSV) can promote viral pathology mediated by antibodies and T cell responses. Early
           evidence suggests that severe COVID-19 disease is associated with hyperinflammation, a
           feature that could be directly driven by virus burden or occur due to independent
           hyperactivation of the immune system. Human coronavirus infections including SARS-CoV
           can induce immunopathology in the lungs through a number of different mechanisms
           including antibody enhancement of SARS-CoV infection by human macrophages. Significant
           increases in CD4 and CD8 expressing pro-inflammatory cytokines have been shown in severe
           SARS-CoV disease compared to mild/moderate disease.

           Accordingly, there has been considerable interest in a potential role of repurposing
           existing immunosuppressive therapies for treatment of severe COVID-19. The key mediators
           and pathways that drive hyperinflammation in COVID-19 are unclear and greater
           elucidation of these processes will inform repurposing of existing therapies or
           development of novel approaches to effective treatment. The implication of baseline
           dysregulated T cell responses such as those seen in chronic lung disease (e.g. asthma,
           COPD, Cystic Fibrosis) is again unclear and requires further mechanistic understanding.
           As such it is, as yet, unclear whether immunosuppressive therapies currently in clinical
           trials will be beneficial or harmful in these large cohorts of susceptible patients.

        3. Dysregulated interferon-dependent endothelial function to COVID-19

           Acute respiratory distress syndrome (ARDS) is characterised by hydrostatic pulmonary
           oedema, elevated pulmonary vascular resistance and coagulopathy, there is disruption of
           endothelial function with dysregulated release of the endothelially derived vasoactive
           hormones. Circulating levels of endothelin-1 are raised in patients with ARDS[16],
           likely due to increased production and decreased clearance in the lungs potentially
           regulated by Angiopoietin-1.

           Severe SARS-CoV-2 infection is associated with cytokine storm. Raised serum levels of a
           number of key inflammatory cytokines including IFN-gamma, TNF-alpha, IP10, IL-8 and
           IL-10 and elevated levels of IL-6 are strongly associated with mortality. IL-6 release
           is synergistically induced by IFN-gamma and TNF-alpha and in a positive feedback
           mechanism, a low dose of IL-6 strongly enhances the cellular responses to IFN-alpha and
           modulates interferon-stimulated gene expression. In an experimental murine model, we
           found that infection with rhinovirus with IFN co-stimulation leads to elevated
           bronchoalveolar lavage levels of IL-6 (Singanayagam et al, unpublished observations).
           These data suggest that in patients with severe COVID-19, a hyperinflammatory process
           ensues and we hypothesise that through dysregulated and unchecked IFN production, key
           vasculo-inflammatory interferon-stimulated genes including IP10 and ET-1 drive worse
           outcomes with increased parenchymal and pulmonary vascular inflammation. This results in
           a dichotomy whereby initial IFN induction is required to limit viral replication, but
           late unchecked production can worsen pathophysiology. This is supported by emerging
           clinical data suggesting a unique phenotype to SARS-CoV-2 critical care patients
           characterised by severe hypoxia with near normal lung compliance.

        4. Altered viral entry receptor expression: Recent data indicates SARS-CoV-2 utilises
           angiotensin-converting enzyme (ACE)2 as a receptor for viral attachment and also the
           protease TMPRSS2 which cleaves the spike(S) protein to allow fusion of the virus with
           cellular membranes. ACE2 and TMPRSS2 are frequently co-expressed in the pulmonary
           epithelium. A recent study also showed that ACE2 is an interferon stimulated gene
           (ISG)(i.e. directly induced by the anti-viral response) and therefore, SARS-CoV-2 might
           upregulate its own receptor to propagate infection. Recent data indicates that smokers
           and subjects with chronic obstructive pulmonary disease (COPD) have increased pulmonary
           ACE2 expression suggesting that chronic lung disease might facilitate greater infection
           with SARS-CoV-2. Conversely, ACE2 expression protects against acute lung injury in the
           context of acid aspiration or sepsis and therefore, if ACE2 induction by SARS-CoVs is
           impaired in chronic lung disease, this could predispose to adverse outcome.

        5. Increased secondary bacterial and/or fungal infections

      In early case series, secondary infections have been observed more frequently in subjects
      with severe COVID-19 disease. Secondary bacterial infection is a well-recognised phenomenon
      following rhinovirus, influenza or respiratory syncytial virus and may be mechanistically
      driven by a range of possible mechanisms including macrophage phagocytosis or neutrophil
      elastase-mediated cleavage of anti-microbial peptides. These processes may be worsened by use
      of corticosteroids28 and, notably, a greater proportion of patients with secondary infections
      following COVID-19 had been prescribed steroids.

      Invasive fungal disease consistent with aspergillosis has also been observed for both severe
      acute respiratory syndrome coronavirus (SARS-CoV-2003) and Middle East Respiratory Syndrome
      coronavirus (MERS-CoV), and anecdotal reports of post-mortems in patients with COVID-19 from
      China suggest that Aspergillus pulmonary infections occur. These data are early warning signs
      that secondary invasive fungal infections may present an increasingly serious complication in
      patients affected with COVID-19 as the pandemic progresses. Understanding the mechanistic
      basis for immune susceptibility to secondary bacterial/fungal infection and an ability to
      prevent these secondary infections could be a key step towards improving outcomes from the
      disease.

      1.2 RATIONALE FOR CURRENT STUDY

      In this study, the investigators will analyse blood and airway samples from individuals with
      confirmed COVID-19 to understand the immune mechanisms that lead to severe disease. We will
      elucidate specific mechanisms that drive more severe pathology in higher risk individuals
      such as those with chronic lung disease. Through detailed immunoprofiling, we will identify
      key pathways and druggable targets to exploit in future clinical intervention studies.

      Hypotheses:

        1. High risk individuals including individuals with chronic lung disease have impaired
           anti-viral immune responses to SARS-CoV-2, increasing virus-induced inflammation.

        2. Interferon-dependent endothelial dysfunction drives pathogenicity in SARS-CoV-2
           infection.

        3. Susceptibility to secondary bacterial and fungal infection in chronic lung disease is
           related to selective pathway defects in innate immune function.

      2. STUDY OBJECTIVES

      Primary objective:

      1. Understand the immune mechanisms driving COVID-19 disease in patients with a history of
      lung disease

      Secondary objectives

        1. Identify immune correlates of protection and lung pathology in SARS-CoV-2 infection.

        2. Analysis of endothelial function in mild and severe COVID-19 patients and ex vivo using
           virus stimulated blood-derived endothelial cells from patients with COVID-19.

        3. Evaluation of changes in upper/lower airway microbiota and mycobiota occurring during
           COVID-19.

        4. Evaluation of ex vivo peripheral blood immune responses to viral, bacterial and fungal
           stimuli in patients with COVID-19 and chronic lung disease in comparison to patients
           with COVID-19 and no chronic lung disease.

        5. Analysis of quality of life impact of COVID-19 infection in chronic lung disease.

      3. STUDY DESIGN

      Through a 24 month prospective longitudinal multicentre (Royal Brompton & Harefield NHS Trust
      Chelsea and Westminster NHS Foundation Trust, and Imperial College Healthcare NHS Trusts)
      observational study, the study team will analyse blood, sputum and nasal sampling alongside
      non-invasive EndoPAT device testing in a total pf 230 subjects. The study team will obtain
      peripheral blood, sputum, nasal lavage, brushings and nasal synthetic absorptive matrix (SAM)
      samples and perform non-invasive EndoPAT testing on the day of hospital presentation and at
      weekly intervals during inpatient setting and then during outpatient visits post-discharge
      over a 12 month follow-up period. The study team will collect clinical information including
      demographics, routine laboratory investigations, clinical symptom scores and outcomes. Linked
      pseudoanonymised radiology imaging will also be transferred for analysis.

      Spontaneously expectorated sputum, nasal lavage, brushings and nasal synthetic absorptive
      matrix (SAM) samples will be taken and processed as previously described and stored at -800C
      for downstream analyses including ELISA/MSD, viral load measurement and microbiome analysis.
      Venous blood (60mls) will be taken into Lithium Heparin tubes and PAXgene RNA tubes and
      transferred to Imperial College (RBH) for processing and storage. PBMCs will be extracted for
      in vitro stimulation assays and whole blood (1ml) and serum (2mls) isolated and stored at
      -80oC for further analysis. PAXgene tubes will be stored at -80C for further host genetic
      sequencing analysis. Further immunological analysis using yeast surface display for serum
      antibody profiling, single B cell sorting to generate monoclonal antibodies and ELISPOT to
      analyse CD4 and CD8 T cell ELISPOT to SARS CoV-2 peptide pools. Further deep immunological
      profiling using cytokine analysis, PBMC cytokine response to viral (or viral PRR agonist),
      fungal stimuli, yeast surface display for serum antibody profiling, single memory B cell
      expression cloning will be carried. CD4 and CD8 T cell ELISPOT will be performed as
      previously described. Non-invasive EndoPAT testing will also be performed as previously
      described.
observational model: Cohort
time perspective: Prospective
measure: Anti-viral cytokine levels in blood samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Anti-viral cytokine protein concentration in blood samples by ELISA
measure: Anti-viral cytokines profiles within sputum samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Inflammatory cytokine protein concentration in sputum samples by ELISA
measure: Anti-viral cytokine profiles within nasal lavage samples in chronic respiratory disease associated with susceptibility to severe COVID-19 infection associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Inflammatory cytokine protein concentration in nasal lavage samples by ELISA
measure: Expression of inflammatory gene expression in upper respiratory epithelial airway cells using nasal brush specimens in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Inflammatory gene expression in upper airway respiratory epithelial cells by RNA sequencing.
measure: Identify the T cell antigens and B cell epitopes in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Analysis of viral components recognized by the adaptive immune system
measure: Peripheral blood mononuclear cell (PBMC) interferon mediated immune responses to pathogen recognition receptor agonists in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Cytokine protein concentration following PBMC stimulation to pathogen recognition receptor agonists by Elispot
measure: Identify endothelial function in chronic respiratory disease associated with susceptibility to severe COVID-19 infection using EndoPAT testing
time frame: Through study completion an average of 1 year
description: Analysis of endothelial function
measure: Endothelial cell inflammation biomarkers in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Serum and plasma protein concentration of endothelial cell inflammation biomarkers by ELISA
measure: Identify sputum 16S rRNA and ITS sequences in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Analysis of sputum microbiome
measure: Identify nasal lavage 16S rRNA and ITS sequences in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Analysis of nasal microbiome
measure: Identify quality of life markers in chronic respiratory disease associated with susceptibility to severe COVID-19 infection
time frame: Through study completion an average of 1 year
description: Study participant survey
arm group label: COVID -19 with chronic lung disease
description: Subjects with swab confirmed COVID-19 and underlying chronic lung disease (n=60)
Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)
Mild/Moderate ( n =30) (absence of severe criteria)
arm group label: COVID-19 without chronic lung disease
description: Subjects with swab confirmed COVID-19 and no chronic lung disease (n=60)
Severe (n=30) (defined by presence of ARDS, sepsis or severe pneumonia)
Mild/Moderate ( n =30) (absence of severe criteria)
arm group label: Chronic Lung disease
description: Subjects with chronic lung disease (identified as requiring shielding based on severity) but no COVID-19 (n=80)
Asthma (defined as severe) - (n=20)
CF (FEV1% predicted baseline <50%) - (n=20)
COPD (FEV1% predicted baseline <50%) - (n=20)
Idiopathic Pulmonary Fibrosis (n=20)
arm group label: Healthy volunteers
description: Healthy subjects with no COVID-19 (n=30)
intervention type: Other
intervention name: Blood tests sputum, nasal lavage and brushing
description: Venesection, sputum nasal lavage and brushing if appropriate
arm group label: COVID -19 with chronic lung disease
arm group label: COVID-19 without chronic lung disease
arm group label: Chronic Lung disease
arm group label: Healthy volunteers
other name: Blood tests
other name: Sputum
other name: Nasal lavage
other name: Nasal brushings
other name: EndoPAT
Spontaneously expectorated sputum, nasal lavage, brushings and nasal synthetic absorptive
      matrix (SAM) samples

      Venous blood (60mls) will be taken into Lithium Heparin tubes and PAXgene RNA tubes

      PAXgene tubes will be stored at -80C for further host genetic sequencing analysis. Further
      immunological analysis using yeast surface display for serum antibody profiling, single B
      cell sorting to generate monoclonal antibodies and ELISPOT to analyse CD4 and CD8 T cell
      ELISPOT to SARS CoV-2 peptide pools.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Peter Kelleher, MD PhD
role: Study Chair
affiliation: Imperial College London
last name: Peter Kelleher, MD PhD
phone: 00 44 (0) 331 58228
email: p.kelleher@imperial.ac.uk
last name: Anand Shah, MD PhD
phone: 00 44 (0) 352 8121
phone ext: 8674
email: s.anand@imperial.ac.uk
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Immune System Diseases
sharing ipd: Undecided
ipd description: Under consideration