Pneumonia Direct Pilot

Study Overview
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Brief Summary
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The Pneumonia Direct Pilot study is designed to assess whether combining molecular diagnostics for bacteria and AMR markers with host-response profiling improves agreement and predictive value for the diagnosis of VAP versus an adjudicated clinical reference standard. The feasibility design is intended to inform future interventional studies that will investigate the clinical impact of combined pathogen- and host-directed testing approaches.

Detailed Description
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This is a prospective, observational, diagnostic, feasibility study to determine the accuracy of pathogen- and host-directed testing for the diagnosis of VAP. Newly intubated adult patients admitted to the ICU will be assessed for eligibility around the time of intubation according to the inclusion/exclusion criteria. Screening and consent can occur any time within 48 hours of a patient being intubated. Between 48 and 60 hours after intubation, eligible participants will have blood drawn and dedicated research aliquots from SOC ETS samples retrieved. The dedicated research aliquots from SOC ETS samples will be obtained simultaneously with routine sampling for microbiologic testing or, when this is not possible, during routine suctioning as a part of standard airway care. Collection of other clinical data may occur 24 to 72 hours after intubation. Participants will be followed daily for a clinical change for up to 14 days from the time of intubation. Clinical change is defined as a clinical suspicion of new-onset VAP that prompts the collection of lower respiratory tract secretions for routine microbiologic testing and initiation, continuation, or modification of antibiotic therapy for a pneumonia indication. Participants who experience a clinical change will have additional blood samples drawn and dedicated aliquots of the sample retrieved from standard-of-care ETS procedures. Additionally, if available, leftover bronchoalveolar lavage (BAL) will be reclaimed, and respiratory and blood bacterial isolates will be obtained from SOC cultures. Participants will be followed through the diagnosis of clinical change and finalization of all local microbiological and radiological results obtained as a part of usual care. Clinical data will be recorded through medical record review. Participants who do not experience a clinical change will be followed through extubation, ICU discharge, death, or for up to 14 days after intubation - whichever comes first. Participants who do not have a clinical change will not undergo additional sample collection. Clinical change events will be used to assess whether the participant meets the clinical case definition (FDA criteria) for VAP: VAP-positive (VAP+) or VAP-negative (VAP-) categories will be obtained by an algorithm linked to the eCRF data. The VAP clinical case definition will be adjudicated against the participants' clinical data and microbiological evidence and the certainty of the VAP diagnosis will be classified as follows: Prove, Probable, Possible VAP, or No VAP. Every participant with a clinical change will be assessed for the presence of an extrapulmonary infection. Extrapulmonary infection will be classified as follows: Proven, Possible, or No Infection. Evaluable participant specimens will be sent to a central laboratory for distribution to the testing centers that will perform the index testing. This study will compare pathogen-directed tests and host biomarker tests. Pathogen-directed tests detect and identify the most common causes of bacterial pneumonia, while host biomarker tests assess the host's immune response to infection. Testing centers will be blinded to whether the samples were collected at baseline or clinical change. Neither the study sites, participants, nor adjudicators will receive the results from the index testing.

Official Title
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Pneumonia Direct Pilot

Conditions
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Pneumonia, Bacterial, Ventilator Associated Pneumonia

Intervention / Treatment
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* Diagnostic Test: Pathogen and Host Directed testing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are ≥18 years old Are newly intubated for less than 48 hours and for reasons other than suspected bacterial pneumonia or suspected acute bacterial infection Are expected to require intubation for at least 48 hours, per the discretion of the treating clinician Are able to provide protocol-accepted consent (legally authorized representative [LAR] is acceptable) Are expected to live long enough to receive a VAP diagnosis, at the discretion of the treating clinician Are able to provide study-required biological samples Exclusion Criteria: Have a witnessed or suspected aspiration event prompting the need for current, new intubation Have known active lung cancer or metastatic disease to a lung Received a lung transplant Have cystic fibrosis Are receiving comfort care Are receiving antibiotic treatment for suspected or proven active acute bacterial infection (eg, pneumonia, tracheobronchitis, sepsis) Have a current or within-the-last-30-days diagnosis of active bacterial pneumonia Were previously enrolled in this trial Require long-term ventilator support Have a tracheostomy tube in place Are currently participating in an interventional drug or device study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Standard of Care<br>There are no interventions in this study. Standard of care activities will be captured in the eCRF and samples will be collected and tested. Results will not be returned to the sites or participants. | Diagnostic Test: Pathogen and Host Directed testing<br>* This study will compare up to 6 pathogen-directed tests and 3 host biomarker tests. Pathogen-directed tests detect and identify the most common causes of bacterial pneumonia, while host biomarker tests assess the host's immune response to infection. Testing will occur at various testing centers. Evaluable participant specimens will be sent to a central laboratory for distribution to the testing centers that will perform the index testing. Testing centers will be blinded to whether the samples were collected at baseline or clinical change. Further, each testing center will prepare and test the specimens according to documented procedures, then transfer the testing results to the ARLG Statistics and Data Management Center for analysis. Neither the study sites, participants, nor adjudicators will receive the results from the index testing. After the study, untested aliquots of specimens will be stored in the ARLG Physical Biorepository.<br>* Other names: FilmArray Pneumonia Panel (BioFire);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants with positive results on the Respiratory Pathogen ID/AMR Enrichment Panel (Illumina) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the Metagenomic Next Generation Sequencing (Illumina) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the T2 Bacteria Panel (T2 Biosystems) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the T2 Resistance Panel (T2 Biosystems) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the Procalcitonin (Abbott) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the TriVerity host (Inflammatix) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the Host gene expression | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| The number of participants with positive results on the FilmArray Pneumonia Panel (BioFire) | This study will compare the results (positive, negative, or no result) of each index test. | Through study completion, or up to 18 months, whichever comes first | 
| Number of participants with a clinical diagnosis of VAP at the time of clinical change | Clinical diagnosis of VAP is defined as new findings in each category of signs and imaging o At least one of the following signs of inflammation: Fever >=38 °C or =35 °C Leukocytosis (white blood cell count ≥12K/mm3 or ≤4K/mm3) >15% immature neutrophils (bands) AND signs of respiratory worsening. AND New or progressive changes suggestive of bacterial pneumonia from imaging: infiltrate, consolidation, and/or cavitation Clinical change is defined as a clinical suspicion of new onset VAP that prompts collection of lower respiratory tract secretions for routine microbiologic testing and initiation or continuation of empiric antibiotic therapy for a pneumonia indication. | day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with an adjudicated diagnosis of of proven, probable, possible, or no VAP at the time of clinical change utilizing clinical and microbiological information | - clinical information collected from participants with a clinical change will be reviewed to discern the presence of signs and symptoms of VAP as well as evidence of extrapulmonary infection. Cases of suspected VAP and extra-pulmonary infection will then be classified as proven, probable/possible or no infection using expert adjudication and standardized definitions. | through extubation, ICU discharge, death, or for up to 14 days after intubation - whichever comes first |