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Metagenomic NGS for Diagnosis of Pneumonia

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ClinicalTrials.gov Identifier: NCT05979350
Recruitment Status : Not yet recruiting
First Posted : August 7, 2023
Last Update Posted : August 14, 2023
Sponsor:
Collaborators:
National Taiwan University Hospital Hsin-Chu Branch
Far Eastern Memorial Hospital
Information provided by (Responsible Party):
National Taiwan University Hospital

Tracking Information
First Submitted Date  ICMJE July 30, 2023
First Posted Date  ICMJE August 7, 2023
Last Update Posted Date August 14, 2023
Estimated Study Start Date  ICMJE August 1, 2023
Estimated Primary Completion Date May 31, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 30, 2023)
Time to achieving definite diagnosis in modified intention-to-treat (mITT) analysis. [ Time Frame: 7 days ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2023)
  • Time to achieving definite diagnosis in intention-to-treat analysis. [ Time Frame: 7 days ]
    To test the robustness of mITT analysis for the primary study endpoint as compared with standard ITT analysis. (Sensitivity analysis)
  • Pathogen detection rate between two groups by the 72th hour. [ Time Frame: 72 hours ]
    Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the 72th hour after randomization in mITT analysis.
  • Pathogen detection rate between two groups by the end of study. [ Time Frame: 28 days ]
    Proportion of participants with accurate diagnosis for the causative pathogens of pneumonia by the day 28 after randomization in mITT analysis.
  • Impact of mNGS on appropriate antibiotic prescription. [ Time Frame: 72 hours ]
    Proportion of participants on effective antimicrobial therapy by the 72th hour after randomization in mITT analysis.
  • 28-day mortality in mITT analysis. [ Time Frame: 28 days ]
    Kaplan-Meier curves of 28-day survival using mITT cohort. Log-rank tests are used to test statistical significance.
  • 28-day mortality in ITT analysis (total cohort). [ Time Frame: 28 days ]
    Kaplan-Meier curves of 28-day survival using total cohort. Log-rank tests are used to test statistical significance.
  • Impact of mNGS on respiratory and mortality outcome. [ Time Frame: 28 days ]
    Kaplan-Meier curves of ventilator-free survival in 28 days after randomization using mITT cohort. Log-rank tests are used to test statistical significance.
  • Impact of mNGS on the length of ICU stay [ Time Frame: ICU discharge or 28 days ]
    Curves of alive ICU discharge in 28 days after randomization using the Fine-Gray model. Death will treated as a competing risk.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metagenomic NGS for Diagnosis of Pneumonia
Official Title  ICMJE Impact of Incorporating Metagenomic Next-generation Sequencing in the Management of Pneumonia on Diagnostic Efficiency and Outcomes: A Randomized Controlled Trial
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Paralleled 1:1 randomized trial
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Pneumonia
  • Diagnosis
Intervention  ICMJE
  • Diagnostic Test: Metagenomic next-generation sequencing
    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).
  • Diagnostic Test: Standard work-up for pneumonia
    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.
Study Arms  ICMJE
  • Active Comparator: Standard care group
    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.
    Intervention: Diagnostic Test: Standard work-up for pneumonia
  • Experimental: mNGS group
    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: Diagnostic Test: Metagenomic next-generation sequencing
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 30, 2023)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2025
Estimated Primary Completion Date May 31, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Presenting to the ICU with a diagnosis of pneumonia (fulfilled with both radiographic and clinical criteria)
  2. Adults aged ≥18 years
  3. Orotracheally intubated
  4. ICU admission for <24 hours
  5. APACHE II score <35 on ICU admission

Exclusion Criteria:

  1. Life expectancy below 4 weeks
  2. With an existing directive to withhold life-sustaining treatment
  3. Patients not willing or able to provide a lower respiratory tract sample at ICU admission
  4. Previous work-up has identified specific pathogens which can account for the index event of pneumonia
  5. Multiplex PCR or NGS testing has been done for pathogen detection before screening
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sheng-Yuan Ruan, MD 886-2-23123456 syruan@ntu.edu.tw
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05979350
Other Study ID Numbers  ICMJE 202305104RINB
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party National Taiwan University Hospital
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Taiwan University Hospital
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • National Taiwan University Hospital Hsin-Chu Branch
  • Far Eastern Memorial Hospital
Investigators  ICMJE
Principal Investigator: Sheng-Yuan Ruan, MD National Taiwan University Hospital
PRS Account National Taiwan University Hospital
Verification Date July 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP