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/NCT05979350</url>
    </required_header>
    <id_info>
      <org_study_id>202305104RINB</org_study_id>
      <nct_id>NCT05979350</nct_id>
    </id_info>
    <brief_title>Metagenomic NGS for Diagnosis of Pneumonia</brief_title>
    <official_title>Impact of Incorporating Metagenomic Next-generation Sequencing in the Management of Pneumonia on Diagnostic Efficiency and Outcomes: A Randomized Controlled Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>National Taiwan University Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Taiwan University Hospital Hsin-Chu Branch</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Far Eastern Memorial Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>National Taiwan University Hospital</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>
        In this randomized controlled trial, we aim to evaluate the efficacy of incorporating mNGS in&#xD;
        the management of pneumonia on efficiency and accuracy of causative pathogen identification,&#xD;
        proportion of participants with effective antimicrobial therapy, length of hospitalization,&#xD;
        and mortality.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is an open-label, randomized, multi-center, phase 2 study that will evaluate the&#xD;
        efficacy of incorporating mNGS in the management of severe pneumonia on accuracy and&#xD;
        efficiency of achieving definite diagnosis of identifying causative pathogens of pneumonia,&#xD;
        appropriate antimicrobial therapy and patient outcomes. The diagnosis of pneumonia requires&#xD;
        radiological evidence of pneumonia and at least two of the following clinical criteria: new,&#xD;
        or worsening cough, new or worsening expectoration of sputum, new or worsening dyspnea,&#xD;
        hemoptysis, pleuritic chest pain, and fever (≥38.0°C). Severe pneumonia is defined as&#xD;
        pneumonia with hypoxemia requiring orotracheal intubation and mechanical ventilation support.&#xD;
  &#xD;
        Written informed consent is needed from the eligible subjects or from their legal guardian at&#xD;
        the time of recruitment. After completing informed consent, subjects will be randomized with&#xD;
        a 1:1 allocation ratio via a web-based randomization system to receive standard of care (SOC)&#xD;
        using culture and serology based work-up for pathogen detection or SOC with additional mNGS&#xD;
        method using APGseq ® (Asia Pathogenomics, New Taipei City, Taiwan) for pathogen detection.&#xD;
        The treatment for pneumonia is suggested following the Taiwan Guidelines for the Management&#xD;
        of Pneumonia published in 2018. After randomization, the subjects will be followed until&#xD;
        death, discharged from the hospital or 28 days after randomization whichever comes first. The&#xD;
        total study duration is expected to be two years from the first subject enrolled to the final&#xD;
        analysis.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 1, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2025</completion_date>
    <primary_completion_date type="Anticipated">May 31, 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>
      <intervention_model_description>Paralleled 1:1 randomized trial</intervention_model_description>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Time to achieving definite diagnosis in modified intention-to-treat (mITT) analysis.</measure>
      <time_frame>7 days</time_frame>
      <description>Cumulative probability of achieving definite diagnosis in terms of accurately identifying causative pathogens of pneumonia, estimated by the Kaplan-Meier method in a time frame of 7 days in modified intention-to-treat (mITT) analysis.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Time to achieving definite diagnosis in intention-to-treat analysis.</measure>
      <time_frame>7 days</time_frame>
      <description>To test the robustness of mITT analysis for the primary study endpoint as compared with standard ITT analysis. (Sensitivity analysis)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pathogen detection rate between two groups by the 72th hour.</measure>
      <time_frame>72 hours</time_frame>
      <description>Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the 72th hour after randomization in mITT analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pathogen detection rate between two groups by the end of study.</measure>
      <time_frame>28 days</time_frame>
      <description>Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the day 28 after randomization in mITT analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Impact of mNGS on appropriate antibiotic prescription.</measure>
      <time_frame>72 hours</time_frame>
      <description>Proportion of participants on effective antimicrobial therapy by the 72th hour after randomization in mITT analysis.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>28-day mortality in mITT analysis.</measure>
      <time_frame>28 days</time_frame>
      <description>Kaplan-Meier curves of 28-day survival using mITT cohort. Log-rank tests are used to test statistical significance.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>28-day mortality in ITT analysis (total cohort).</measure>
      <time_frame>28 days</time_frame>
      <description>Kaplan-Meier curves of 28-day survival using total cohort. Log-rank tests are used to test statistical significance.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Impact of mNGS on respiratory and mortality outcome.</measure>
      <time_frame>28 days</time_frame>
      <description>Kaplan-Meier curves of ventilator-free survival in 28 days after randomization using mITT cohort. Log-rank tests are used to test statistical significance.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Impact of mNGS on the length of ICU stay</measure>
      <time_frame>ICU discharge or 28 days</time_frame>
      <description>Curves of alive ICU discharge in 28 days after randomization using the Fine-Gray model. Death will treated as a competing risk.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Pneumonia</condition>
    <condition>Diagnosis</condition>
    <arm_group>
      <arm_group_label>Standard care group</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Endotracheal aspirates, blood samples, urine samples, and nasopharyngeal swabs were obtained from the patients as soon as possible after ICU admission. Bacterial culture was performed, with the use of standard techniques, on blood samples and endotracheal aspirates. Urine antigen detection was performed for detection of L. pneumophila and S. pneumoniae. A PCR assay was performed on nasopharyngeal swabs for the detection of influenza A and B viruses and SARS-CoV-2 viruses. Fungal or mycobacterial detections, and whether to use multiplex PCR for pathogen detection, such as the FilmArray system, were determined at the discretion of the physicians.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>mNGS group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Subjects assigned to the mNGS group will receive etiology work-up followed the protocol used in the standard care group and additional mNGS testing for two specimen of mini-bronchoalveolar lavage and one specimen of blood samples retrieved at the same time of standard work-up.</description>
    </arm_group>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Metagenomic next-generation sequencing</intervention_name>
      <description>Metagenomic NGS testing for pathogen identification will be done for airway and blood specimens using APGseq ® (Asia Pathogenomics, New Taipei City, Taiwan). The sample preparation for mNGS testing was as follows: 5-10 mL of whole blood were centrifuged at 1,600g for 10 min at 4°C to separate the plasma. Plasma samples were transferred to 2 mL sterile tubes for the following DNA or RNA extraction. In general, 300ul of plasma sample was used for DNA extraction. Total genomic DNA from samples were extracted using the column-based method (e.g. QIAamp DNA Microbiome Kit, Qiagen for DNA extraction; or QIAamp Viral RNA Mini Kit, Qiagen for RNA extraction, respectively), following the manufacturer's operational manual. The RNA was reverse transcribed and synthesized to double-stranded complementary DNA (ds cDNA) with SuperScript II Reverse Transcription Kit (Invitrogen).</description>
      <arm_group_label>mNGS group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Standard work-up for pneumonia</intervention_name>
      <description>Endotracheal aspirates, blood samples, urine samples, and nasopharyngeal swabs were obtained from the patients as soon as possible after ICU admission. Bacterial culture was performed, with the use of standard techniques, on blood samples and endotracheal aspirates. Urine antigen detection was performed for detection of L. pneumophila and S. pneumoniae. A PCR assay was performed on nasopharyngeal swabs for the detection of influenza A and B viruses and SARS-CoV-2 viruses. Fungal or mycobacterial detections, and whether to use multiplex PCR for pathogen detection, such as the FilmArray system, were determined at the discretion of the physicians.</description>
      <arm_group_label>Standard care group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Presenting to the ICU with a diagnosis of pneumonia (fulfilled with both radiographic&#xD;
               and clinical criteria)&#xD;
  &#xD;
            2. Adults aged ≥18 years&#xD;
  &#xD;
            3. Orotracheally intubated&#xD;
  &#xD;
            4. ICU admission for &lt;24 hours&#xD;
  &#xD;
            5. APACHE II score &lt;35 on ICU admission&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Life expectancy below 4 weeks&#xD;
  &#xD;
            2. With an existing directive to withhold life-sustaining treatment&#xD;
  &#xD;
            3. Patients not willing or able to provide a lower respiratory tract sample at ICU&#xD;
               admission&#xD;
  &#xD;
            4. Previous work-up has identified specific pathogens which can account for the index&#xD;
               event of pneumonia&#xD;
  &#xD;
            5. Multiplex PCR or NGS testing has been done for pathogen detection before screening&#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>Sheng-Yuan Ruan, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>National Taiwan University Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Sheng-Yuan Ruan, MD</last_name>
      <phone>886-2-23123456</phone>
      <email>syruan@ntu.edu.tw</email>
    </overall_contact>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 30, 2023</study_first_submitted>
    <study_first_submitted_qc>July 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 7, 2023</study_first_posted>
    <last_update_submitted>August 8, 2023</last_update_submitted>
    <last_update_submitted_qc>August 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>diagnosis</keyword>
    <keyword>next-generation sequencing</keyword>
    <keyword>outcome</keyword>
    <keyword>pneumonia</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Pneumonia</mesh_term>
      <mesh_term>Disease</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
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/NCT05979350
  org study id: 202305104RINB
  nct id: NCT05979350
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  In this randomized controlled trial, we aim to evaluate the efficacy of incorporating mNGS in
        the management of pneumonia on efficiency and accuracy of causative pathogen identification,
        proportion of participants with effective antimicrobial therapy, length of hospitalization,
        and mortality.
  This is an open-label, randomized, multi-center, phase 2 study that will evaluate the
        efficacy of incorporating mNGS in the management of severe pneumonia on accuracy and
        efficiency of achieving definite diagnosis of identifying causative pathogens of pneumonia,
        appropriate antimicrobial therapy and patient outcomes. The diagnosis of pneumonia requires
        radiological evidence of pneumonia and at least two of the following clinical criteria: new,
        or worsening cough, new or worsening expectoration of sputum, new or worsening dyspnea,
        hemoptysis, pleuritic chest pain, and fever (≥38.0°C). Severe pneumonia is defined as
        pneumonia with hypoxemia requiring orotracheal intubation and mechanical ventilation support.
  
        Written informed consent is needed from the eligible subjects or from their legal guardian at
        the time of recruitment. After completing informed consent, subjects will be randomized with
        a 1:1 allocation ratio via a web-based randomization system to receive standard of care (SOC)
        using culture and serology based work-up for pathogen detection or SOC with additional mNGS
        method using APGseq ® (Asia Pathogenomics, New Taipei City, Taiwan) for pathogen detection.
        The treatment for pneumonia is suggested following the Taiwan Guidelines for the Management
        of Pneumonia published in 2018. After randomization, the subjects will be followed until
        death, discharged from the hospital or 28 days after randomization whichever comes first. The
        total study duration is expected to be two years from the first subject enrolled to the final
        analysis.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Paralleled 1:1 randomized trial
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: Time to achieving definite diagnosis in modified intention-to-treat (mITT) analysis.
  time frame: 7 days
  description: Cumulative probability of achieving definite diagnosis in terms of accurately identifying causative pathogens of pneumonia, estimated by the Kaplan-Meier method in a time frame of 7 days in modified intention-to-treat (mITT) analysis.
  measure: Time to achieving definite diagnosis in intention-to-treat analysis.
  time frame: 7 days
  description: To test the robustness of mITT analysis for the primary study endpoint as compared with standard ITT analysis. (Sensitivity analysis)
  measure: Pathogen detection rate between two groups by the 72th hour.
  time frame: 72 hours
  description: Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the 72th hour after randomization in mITT analysis.
  measure: Pathogen detection rate between two groups by the end of study.
  time frame: 28 days
  description: Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the day 28 after randomization in mITT analysis.
  measure: Impact of mNGS on appropriate antibiotic prescription.
  time frame: 72 hours
  description: Proportion of participants on effective antimicrobial therapy by the 72th hour after randomization in mITT analysis.
  measure: 28-day mortality in mITT analysis.
  time frame: 28 days
  description: Kaplan-Meier curves of 28-day survival using mITT cohort. Log-rank tests are used to test statistical significance.
  measure: 28-day mortality in ITT analysis (total cohort).
  time frame: 28 days
  description: Kaplan-Meier curves of 28-day survival using total cohort. Log-rank tests are used to test statistical significance.
  measure: Impact of mNGS on respiratory and mortality outcome.
  time frame: 28 days
  description: Kaplan-Meier curves of ventilator-free survival in 28 days after randomization using mITT cohort. Log-rank tests are used to test statistical significance.
  measure: Impact of mNGS on the length of ICU stay
  time frame: ICU discharge or 28 days
  description: Curves of alive ICU discharge in 28 days after randomization using the Fine-Gray model. Death will treated as a competing risk.
  arm group label: Standard care group
  arm group type: Active Comparator
  description: Endotracheal aspirates, blood samples, urine samples, and nasopharyngeal swabs were obtained from the patients as soon as possible after ICU admission. Bacterial culture was performed, with the use of standard techniques, on blood samples and endotracheal aspirates. Urine antigen detection was performed for detection of L. pneumophila and S. pneumoniae. A PCR assay was performed on nasopharyngeal swabs for the detection of influenza A and B viruses and SARS-CoV-2 viruses. Fungal or mycobacterial detections, and whether to use multiplex PCR for pathogen detection, such as the FilmArray system, were determined at the discretion of the physicians.
  arm group label: mNGS group
  arm group type: Experimental
  description: Subjects assigned to the mNGS group will receive etiology work-up followed the protocol used in the standard care group and additional mNGS testing for two specimen of mini-bronchoalveolar lavage and one specimen of blood samples retrieved at the same time of standard work-up.
  intervention type: Diagnostic Test
  intervention name: Metagenomic next-generation sequencing
  description: Metagenomic NGS testing for pathogen identification will be done for airway and blood specimens using APGseq ® (Asia Pathogenomics, New Taipei City, Taiwan). The sample preparation for mNGS testing was as follows: 5-10 mL of whole blood were centrifuged at 1,600g for 10 min at 4°C to separate the plasma. Plasma samples were transferred to 2 mL sterile tubes for the following DNA or RNA extraction. In general, 300ul of plasma sample was used for DNA extraction. Total genomic DNA from samples were extracted using the column-based method (e.g. QIAamp DNA Microbiome Kit, Qiagen for DNA extraction; or QIAamp Viral RNA Mini Kit, Qiagen for RNA extraction, respectively), following the manufacturer's operational manual. The RNA was reverse transcribed and synthesized to double-stranded complementary DNA (ds cDNA) with SuperScript II Reverse Transcription Kit (Invitrogen).
  arm group label: mNGS group
  intervention type: Diagnostic Test
  intervention name: Standard work-up for pneumonia
  description: Endotracheal aspirates, blood samples, urine samples, and nasopharyngeal swabs were obtained from the patients as soon as possible after ICU admission. Bacterial culture was performed, with the use of standard techniques, on blood samples and endotracheal aspirates. Urine antigen detection was performed for detection of L. pneumophila and S. pneumoniae. A PCR assay was performed on nasopharyngeal swabs for the detection of influenza A and B viruses and SARS-CoV-2 viruses. Fungal or mycobacterial detections, and whether to use multiplex PCR for pathogen detection, such as the FilmArray system, were determined at the discretion of the physicians.
  arm group label: Standard care group
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Sheng-Yuan Ruan, MD
  role: Principal Investigator
  affiliation: National Taiwan University Hospital
  last name: Sheng-Yuan Ruan, MD
  phone: 886-2-23123456
  email: syruan@ntu.edu.tw
  responsible party type: Sponsor
  mesh term: Pneumonia
  mesh term: Disease
  sharing ipd: No